Category Archives: neoplasm

art, cultural, malignant, neoplasm, primary cancer

Art of Cancer

The Common Vein

Section Name

Section Text

Aberrant Time

Rebel in the Community

A Mean Monster is Born

87160pb06b02b02.81k.8s Different mean space occupation push shove multiplication cancer malignant division bizarre mean loose bonds lack cohesion small hyperchromatic dance movement units to unity individual uniqueness group Davidoff art Davidoff photography copyright 2009 all rights reserved

Dividing and The Battle for Space Begins

87160pb06b02b02.8k.8s Different mean space occupation push shove multiplication cancer malignant division bizarre mean loose bonds lack cohesion small hyperchromatic dance movement units to unity individual uniqueness group Davidoff art Davidoff photography copyright 2009 all rights reserved

85198gc25.08

85198gc25.08 cells epithelium columnar epithelium nucleus cytoplasm cell time adenocarcinoma aberrant growth malignant cancer neoplasm death cycle normal life span age growth mucus dysplasia histopathology hyperchromatic nucleus increased nuclear to cytoplasmic ratio Davidoff art Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

85198j03s.81s

85198j03s.81s The image represents the life of a single set of columnar cells showing a progressioon of generations as the cell lives dies and is regenerated. The orange secretions of the cell are seen in the background of the pink cytoplasm and the purple nucleus. The nucleus of the newesest generation and cell is seen as a clock that has become distorted and time has become disordered. This process is abnormal and is a forerunner of a malignant process. histology time malignancy cancer columnar cell histopathology Davidoff art copyright 2009 all rights reserved

32354c01.800

32354c01.800 tube colon trachea bronchus small bowel bile duct epithelium neoplasm benign malignant malignancy epithelial cell multiply multiplication growth mucosa submucosa muscularis serosa adventitia vein lymph node circumferential metastasixe metastasis metastases narrowing stenosis obstruction complication cancer uncontrolled growth Davidoff drawing Davidoff art Davidoff tube Davidoff MD

11528b.8

11528b.8 gallbladder food in the body green pepper cancer carcinoma gall stones cholelithiasis Davidoff art Davidoff photography copyright

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69595b09 star stellate corona radiata spiculated aggressive cancer carcinoma Davidoff art

85198fc02.8s

85198fc02.8s The image represents the evolution of a single cancer cell (a) that fails to conform to the usual time cycles, grows, multiplies, (b,c,d) and then invades the space of other parts of the tissue like the muscular layer in e and the serosal layer in f. histology time malignancy cancer columnar cell histopathology Davidoff art copyright 2009 all rights reserved

84049p.801

84049p.801 American militia Concord Massachusetts The beginning of the American Revolution resistance along the Battle Road Trail extending from Lexington to Concord Minute man National Historical Park Reenactment July 3rd 2007 in the fields of Hartwell tavern Davidoff photography

87090pb05.8k.8s

carcinoma, malignant, pancreas, primary cancer

Pancreas Carcinoma

Introduction

Pancreatic carcinoma is an aggressive malignant disease with a very poor prognosis. It is one of the more common malignancies that affect the American population, and accounts for about 30,000 deaths in America per year. It has an increased incidence in industrialized and Western cultures and is more common in men, usually occurring over the age of 60 (80%) It appears that chronic pancreatitis, diabetes and smoking are predisposing factors. 90% of the carcinomas arise from the epithelial cells of the exocrine pancreas. The disease is characterized by desmoplastic behavior so that it invades and encases neighboring vital structures early.

In most instances by the time the patient becomes symptomatic the disease is inoperable, and the patients usually succumb to the disease within a year of diagnosis.

Approach in the asymptomatic patient

If we are going to play any role in making a difference in this disease, early diagnosis, before involvement of other organs, is a key challenge. Unfortunately finding a small curable carcinoma is a rare occurrence and most the time we are left with a disease that has advanced too far for effective cure. Nevertheless our focus when reviewing the pancreas in any abdominal CT should be on the head and uncinate process because about 70% of pancreatic carcinomas arise from this part of the pancreas. Since the carcinoma is characteristically hypovascular, we should therefore be looking for a small hypodense rascal in the head of the pancreas. This is not to say of course suggesting that you should not look elsewhere but a focus using probability of finding disease is recommended. You will only find what you look for and so an active mind with a preconceived notion will sometimes yield remarkable results. Our search unfortunately is made more difficult and confounding by a few normal structures that reside in the region, including prominent ducts of the uncinate, and the bile duct itself.

In the following case the subtle nature of pancreatic cancer is noted.

This is a 61 year old male who presented with painless obstructive jaundice and required a stent to relieve the obstruction. On review of the CT scan a subtle hypodense hypovascular mass was noted. Can you see the mass? It is lateral to stent and is just over 1 cms. in diameter. At this stage we are probably too late in our diagnosis for cure. 29970 Courtesy Ashley Davidoff MD

This is a 61 year old male who presented with painless obstructive jaundice and required a stent to relieve the obstruction. On review of the CT scan a subtle hypodense hypovascular mass was noted. In this image the mass is overlaid in maroon. 29970b Courtesy Ashley Davidoff MD

The following case deserves showing to expand on the importance of the analyzing the component parts of the head of the pancreas and the importance of following the pancreatic duct and the bile duct individually to their confluence. Any extra hypodensities must be explained, and heightened sensitivity must be maintained even for the most subtle of changes.

In this CTscan of the abdomen we identify a rounding out of the head and uncinate process with two hypodense components. Associated finding include a dilated gallbladder and a suggestion of intrahepatic bile duct dilatation. Our suspicion on this single image is of pancreatic carcinoma, but how do we interpret the findings in the head? We know that we should have at least two normal hypodensities in this region (bile duct and pancreatic duct), and we also know there is a hypodense mass lurking. The need to review all the images is wanting. 40839 Courtesy Ashley Davidoff MD

The

References

The

MCQ

The

Introduction

In most instances by the time the patient becomes symptomatic the disease is inoperable, and the patients usually succumb to the disease within a year of diagnosis.

Approach in the asymptomatic patient

If we are going to play any role in making a difference in this disease, early diagnosis, before involvement of other organs, is a key challenge. Unfortunately finding a small curable carcinoma is a rare occurrence and most the time we are left with a disease that has advanced too far for effective cure. Nevertheless our focus when reviewing the pancreas in anyabdominal CT should be on the head and uncinate process because about 70% of pancreatic carcinomas arise from this part of the pancreas. Since the carcinoma is characteristically hypovascular, we should therefore be looking for a small hypodense rascal in the head of the pancreas. This is not to say of course suggesting that you should not look elsewhere but a focus using probability of finding disease is recommended. You will only find what you look for and so an active mind with a preconceived notion will sometimes yield remarkable results. Our search unfortunately is made more difficult and confounding by a few normal structures that reside in the region, including prominent ducts of the uncinate, and the bile duct itself.

In the following case the subtle nature of pancreatic cancer is noted.

This is a 61 year old male who presented with painless obstructive jaundice and required a stent to relieve the obstruction. On review of the CT scan a subtle hypodense hypovascular mass was noted. In this image the mass is overlaid in maroon. 29970b Courtesy Ashley Davidoff MD

This CT scan series is of a patient with obstructive jaundice and shows a double duct sign suspicious for carcinoma off the head of the pancreas. A dilated pancreatic duct and a dilated CBD (“double duct” sign) is shown (a,b) and then 3 hypodensities and a rotund appearance of the head suggests an extra and unwanted component in the head of the pancreas. Can you identify the unwanted component from these images?. The findings nevertheless are consistent with a primary adenocarcinoma of the pancreas. 40840c01 Courtesy Ashley Davidoff MD

As we review the case with overlays the component parts in the head become clearer. This type of analysis is required in the head with suspicious findings. It is very important to identify pancreatic duct position, bile duct position. Any extra hypodense structures, no matter how small, warrants explanation and or suspicion.

This CT scan series through the pancreas shows the findings of carcinoma of the head of the pancreas in overlay. In a and e the bile duct (green) and pancreatic duct (pink) are both dilated. In “b” and “f” the dilated ducts are approaching each other, and the first hint of a hypodensity (maroon in f) is suggested. In c and g, the bile duct is smaller and the pancreatic duct seems to be pushed to the side by the enlarging mass. The mass, which appears with a matrix of hypodensity and a rim of isodensity starts to enlarge and continues to push and encircle the ducts. (d,h). 40840c02 Courtesy Ashley Davidoff MD

The plea is for careful analysis particularly of the head of the pancreas even on routine abdominal CTscans.

Approach in the symptomatic patient

Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15-20% arises from the body of the pancreas, and 5-10% arises from the tail.

The pancreas has a very central location in the body and has significant and intimate contact or is closely apposed to many organs. The organs are tightly packed in the region of head where the stomach, duodenum, colon, liver, gallbladder, bile duct, right kidney, IVC, SMV, portal vein and SMA lie. The body of the pancreas is related to the stomach which lies anteriorly and the retroperitoneum with nerves aorta and IVC lie posteriorly. The splenic vein lies posteriorly and the splenic artery lies superiorly. The tail nestles in the hilum of the spleen but lies in close contact to the stomach, splenic artery and splenic vein as well.

A reasonable approach to imaging pancreatic carcinoma is to divide the disease into the three parts of the pancreas that it affects, head body and tail, and review the manifestations of the disease in each of these parts.

Nature of the disease.

Pancreatic carcinoma has a scirrhous and scurrilous nature.

This histopathologic specimen of pancreatic carcinoma shows a heterogeneous pattern to the cells, prominent nuclear to cytoplasmic ratio, and hyperchromatic nuclii. The cells do not obey the rules of the body and are rebels in the community without regard to the body at large. They invade the territory of neighboring structures. 15311 Courtesy Barbara Banner MD

The cells of adenocarcinoma of the pancreas are well appreciated in this cytological specimen from a biopsy. Noted is the heterogeneous pattern to the cells, prominent nuclear to cytoplasmic ratio, and hyperchromatic nuclii. 15310 Courtesy Barbara Banner MD

Thus the aggressive nature of malignant cells of the pancreas is characteristic of all malignant tissue. In addition to their aggressive nature they are characterized by desmoplastic behavior. As a result they encircle, constrict and strangle their neighbors.

The grosspathology specimen shows a white mass in the middle of the image. It was extremely hard to the touch because of the fibrosis shown at histopathology. The desmoplastic or fibrous nature of the tumor leads to encasement and narrowing of contiguous structures. This fibroblastic nature of the disease is characteristic of adenocarcinoma of the pancreas. 15307 Courtesy Barbara Banner MD

Aggression and desmoplasia are thus the pathological hallmarks of adenocarcinoma of the pancreas. Hypovacsularity is the radiologic hallmark

Head.

Ducts

The desmoplastic nature of the disease affects in characteristic location being near or within a few centimeters of the ampulla.

The following images come from a percutaneous transhepatic cholangiogram 9PTCA) and show a concentric stricture around the distal common bile duct with rat tailing of the stricture and secondary upstream dilatation. The location is characteristic, but not necessarily pathognomonic for carcinoma of the head of the pancreas. 04835c03 Courtesy Ashley Davidoff MD

The head of the pancreas houses the common bile duct which delivers 600-700ccs of bile to the duodenum per day. The pancreatic duct and bile duct fuse in the ampulla just prior to their common entrance into the duodenum. The bile duct is one of the closest allies if not the closest buddy of the pancreatic duct. In fact they are bosom buddies even from the time of organogenesis. On the other hand although they were born together and function together in health, in the presence of pancreatic carcinoma in the head they will commonly get sick together as well (“ ‘til death do us part”). The double duct sign implies the enlargement of both the bile duct and pancreatic duct and is almost pathgnomonic of carcinoma of the head of the pancreas. The association is taken one step further when as a result of the obstruction the gallbladder gets affected. This is part of the Courvoisier’s law that states ‘if in the presence of jaundice the gallbladder is palpable, then the jaundice is unlikely to be due to a stone.’ As an extension of this law, if in addition the jaundice is painless then carcinoma of the head of the pancreas is likely.

The case below demonstrates a classical double duct sign.

A 57 year old female presents with jaundice. Her ERCP shows dilatation of the bile duct and pancreatic duct – the “double duct” sign characteristic of adenocarcinoma of the head of the pancreas. In this case the stricture appears quite distal. Chronic pancreatitis can also rarely cause the “double duct” sign. In this case an ampullary carcinoma was the cause explaining the distal position of the strictures. 04655c03 Courtesy Ashley Davidoff MD

The combination of images below reflects the changes of the above case using a multimodality approach with pathological proof.

This is a series of images from the case history of a 57 year old female who presented with jaundice. The US image (a) shows a dilated bile duct and dilated pancreatic duct with no large mass between them. The CT shows a les impressive, but prominent pancreatic duct. The ERCP suggests a “double duct” sign. The pathology confirmed an ampullary carcinoma. 04655c05 Courtesy Ashley Davidoff MD

This ERCP shows a double duct sign with a dilated CBD and pancreatic duct. These findings are consistent with a primary adenocarcinoma of the pancreas. Chronic pancreatitis is a remote possibility. 31062c01 Courtesy Ashley Davidoff MD

Double duct sign is also used in other modalities and has the same implications.

This CT scan through the pancreas shows a dilated pancreatic duct and a dilated CBD (“double duct” sign). These findings are consistent with a primary adenocarcinoma of the pancreas. Chronic pancreatitis is a remote possibility. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas. 40837 Courtesy Ashley Davidoff MD

The image from an MRCP shows the MRI version of the double duct. The separation of the two ducts suggests a large size of the mass. This patient had pancreatic carcinoma. 41371 Courtesy of Ashley Davidoff MD

The combination of images below reflects the changes of the above case at different levels. Cranially the liver is seen and caudally the pancreas is seen.

The image from an MRCP shows the MRI version of the “double duct” sign. The separation of the two ducts suggests a large size of the mass (a). Image b shows intrahepatic biliary dilatation, while image c shows CBD dilatation. Image d shows a mass in the head of the pancreas on the contrast enhanced sequence. This patient had pancreatic carcinoma. 41371c Courtesy of Ashley Davidoff MD

There are instances where the double duct sign represents other diseases.

This is an ERCP showing a “double duct” sign. With the heavy intraductal calcification chronic alcoholic pancreatitis is definite. It is conceivable that the patient has a superimposed malignancy. In this case the double duct was caused by the strictures of the ducts caused by chronic pancreatitis. 41245c06 Courtesy Ashley Davidoff MD

At first glance this image from an ERCP looks like a double duct sign. In fact it does show that both ducts are dilated, but for different reasons other than cancer. The main pancreatic duct drains into the accessory duct of Santorini, while the CBD drains in usual fashion into the ampulla. This is a case of pancreas divisum. No pancreatic cancer was found on further workup. The etiology of the mild dilation is probably due to benign narrowing of both ducts at their insertion sites. 40615 Courtesy Ashley Davidoff MD

Arteries and Veins in the head

The gastroduodenal artery is closely linked to the head of the pancreas, and the branches of the pancreaticoduodenal arcade lie within the head of the pancreas. In years prior to the exquisite detail provided by CT and MRI, an angiogram was part of the workup of patients with suspected carcinoma of the pancreas for both confirmation of the diagnosis but also for operability. The presence of encasement of the vessel supported the diagnosis, and the presence of portal vein encasement specifically suggested inoperability. The following cases exemplify the discussion.

This series of percutaneous transhepatic cholangiography, PTCA (a), and arteriography (b) magnified in c, reveal an obstructed and dilated intrahepatic biliary system and encasement of some of the branches of the pancreaticoduodenal arcade.40328c Courtesy Ashley Davidoff MD

The following images are from the same case and the portal venous phase is demonstrated.

This series of arteriography of the common hepatic artery (a,c), with portal venous phase from an SMA injection(b,d) reveals the encasement of the pancreaticoduodenal arteries (c, yellow) magnified and portal vein (d yellow) The location and characteristic encasement point to pancreatic adenocarcinoma of the head of the pancreas. The portal vein involvement suggests inoperability. Courtesy Ashley Davidoff MD

The advent of MDCT has brought better resolution of soft tissue changes. The finding of a necklace of tumor around the SMA, and the degree to which it surrounds the SMA is being used as a predictor of operability.

This CT scan through the pancreas shows a small mass in the uncinate process of the pancreas associated with total encasement of the celiac axis. The CBD is dilated. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas. Based on the desmoplastic nature of the process the tumor is most likely an adenocarcinoma. 20599 Courtesy Ashley Davidoff MD

This CT scan through the pancreas is a series with overlay from the above case, and shows a small mass in the uncinate process of the pancreas associated with encasement of the celiac axis and SMA, with a dilated CBD. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas. Based on the desmoplastic nature of the process, the tumor is most likely an adenocarcinoma. The artery is in red the tumor orange and the normal pancreas is pink. 20607c06 Courtesy Ashley Davidoff MD

Stomach

40851c Courtesy Ashley Davidoff MD code abdomen stomach distended code stomach fx bezoar code pancreas pancreatic lateral uncinate process fx mass code dx carcinoma of the uncinate pancreas complicated by gastric outlet obstruction imaging radiology plain film KUB CT scan code neoplasm malignant primary tumor cancer mechanical code medical students 5 star

Duodenum

The head of the pancreas is housed in the c sweep of the duodenum and encasement at any point in the “c “ can be affected.

This CT scan through the pancreas shows a small mass in the uncinate process of the pancreas associated with a dilated and obstructed duodenum. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas. Based on the desmoplastic nature of the process the tumor is most likely an adenocarcinoma. 20601 Courtesy Ashley Davidoff MD

This CT scan through the pancreas shows a hypodense mass in the pancreatic head, associated with a central dystrophic calcification and a dilated pancreatic duct. These findings are consistent with a cystadenoma, and a malignant transformation of a mucinous neoplasm has to be considered in view of the dilated duct. The calcifications in the spleen are granulomatous in origin. 19394c01 Courtesy Ashley Davidoff MD

The CT scan, MRI, US and ERCP of the pancreas shows a dilated pancreatic duct and a dilated CBD (“double duct” sign). These findings are consistent with a primary adenocarcinoma of the pancreas. 41293a16c Courtesy Ashley Davidoff MD

Body

The central part of the pancreas is closest to the vessels nerves lymphatics of the abdomen. Pancreatic adenocarcinoma shows an affinity for nerves and the involvement of the nerve results in significant back pain in patients with pancreatic carcinoma. This is more common with body and tail carcinomas.

The body and tail of the pancreas are close to the lymphatics and nerves. In this histological section the rounded nerve seen to the right in the image is surrounded by advancing malignant pancreatic carcinoma seen as cluster of blue nuclii.

Courtesy Barbara Banner MD

The CT scan of the abdomen of a 71 year old male shows a hypovascular mass in the body of the pancreas with widespread metastatic disease in the liver. Some of the lesions in the liver are larger than the primary tumor. 40343c Courtesy Ashley Davidoff MD

Duct in the body

In patients with obstructed ducts there is usually secondary

This CT scan through the pancreas shows a mass in the neck and body of the pancreas associated with pancreatic duct dilatation and secondary atrophy in the pancreatic tail. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas. Based on the desmoplastic nature of the process the tumor is most likely an adenocarcinoma. 30101a05 Courtesy Ashley Davidoff MD

Arteries and Veins

This CT scan through the pancreas shows a mass in the body of the pancreas associated with encasement of the portal vein and splenic artery (subtotal occlusion) with an almost complete encirclement of the celiac axis by a necklace of aggressive tissue. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas. Based on the desmoplastic nature of the process the tumor is most likely an adenocarcinoma. Courtesy Ashley Davidoff MD18103

The CT scan of the abdomen of a 85 year old female shows a hypovascular mass in the body and tail of the pancreas (a) which has resulted in splenic vein compromise and the development a large venous collateral seen coursing over the greater curvature of the stomach. The mass is hypoechoic (c) and hypovascular d) on the US. 24942c Courtesy Ashley Davidoff MD

Unusual masses

This CT scan through the pancreas shows a mass in the body of the pancreas associated with metastatic liver disease. The patient presented with Cushingoid features which was associated with ectopic ACTH biochemistry. An adrenal nodule is noted reflective of hyperplasia from the effect of ACTH. The mass at autopsy was consistent with a malignant gastrinoma associated with ectopic ACTH production. Courtesy Ashley Davidoff MD 19859

This is a series of images from a middle aged female with a hypervascular mass in the body of the pancreas. Since adenocarcinoma of the pancreas tends to be hypovascular it is unlikely that the histological type is the common form. In this case the diagnosis was a micronodular carcinoma 40640c02 Courtesy Ashley Davidoff MD ..

This CT scan through the pancreas shows a complex cystic mass with central calcification in the tail of the pancreas associated with complex masses in the left kidney and surgically absent right kidney. These findings are consistent with a diagnosis of von Hippel-Lindau syndrome with a variety of cystic and solid, benign and malignant tumors of the pancreas and kidney. 40463c Courtesy Ashley Davidoff MD

Tail

Spleen

This CT scan through the pancreas shows a mass in the tail of the pancreas associated with splenic invasion ascites, a probably liver metastasis, and thickened omentum. These findings are consistent with a diagnosis of a primary carcinoma of the pancreas, with metastatic disease. 20796 Courtesy Ashley Davidoff MD

Peritoneum

Sometimes more than 2/3 of the circumference of the tail of the pancreas is covered by peritoneum making it a peritoneal structure. Thus more than any of the other parts of the pancreas malignancy in the tail may spread directly into the peritoneal cavity.

This CT scan through the pancreas shows a cystic mass in the pancreatic tail associated with thickened gastrolienal ligament and ascites. This case represents transperitoneal spread of a known pancreatic carcinoma. Metastatic nodules are also noted in the liver. 20114 Courtesy Ashley Davidoff MD

Cystadenocarcinoma

The cystic lesions of the pancreas are discussed as a separate entity in detail. However they are a variant of carcinoma but have a different biology and nature. Specifically they do not demonstrate the desmoplastic behavior of the more commonly occurring scirrhous adenocarcinoma.

This CTscan of an 83 year old female is through the body and tail of the pancreas shows a complex cystic mass in the tail with a more solid appearing tail that is in the body. (a,b). In c and d, the cystic component with a thickened wall is shown in yellow, and the solid component medially with a focal calcification is shown in brown. The pancreatic duct which is minimally prominent is shown in pink. These findings are consistent with a mucinous cystadenocarcinoma which was pathologically proven. 19911c01b03 Courtesy Ashley Davidoff MD

References

Courvoisier LJ. Casuistisch-statistische beitrage zur pathologie und chirurgie der gallenweger. Leipzig: Vogel; 1890.

Pancreatic Carcinoma from Radiologyassistant.nl web pressentation

carcinoma, gallbladder, malignant, neoplasm, primary cancer

Gallbladder Carcinoma

Carcinoma

Definition

Gallbladder carcinoma is a malignant disease usually originating in the epithelium lining. Its cause is unknown, but the high incidence of associated cholesterol gallstones (>75%) creates an etiological link between the two diseases.

Tumors of the biliary system are found mostly in the elderly in the seventh decade of life and are 3-4 times as common in women as in men. It is strongly associated with gallstones, but while nearly 80% of those with carcinoma have concomitant gallstones, less than 0.5% of all patients with gallstones will develop carcinoma. Porcelain gallbladder predisposes to the development of carcinoma.(25% incidence)

Structurally it can present with focal thickening of the wall, polypoid lesion, or a mass, and is most common in the fundus (60%) , followed by the body 30%, and then the neck (10%).

Functional impairment is limited and it is for this reason that presentation is late and prognosis is poor.

Complications include early spread to the regional nodes and direct invasion into the liver through the gallbladder fossa.

Clinically the patient usually presents late in the disease with symptoms similar to that of cholelithiasis. RUQ pain, jaundice, and nausea with vomiting. Occasionally this results in a palpable gallbladder before invasion into the adjacent structures. Still, it is rarely found at a time when surgical resection is possible, and thus has a 5-year survival rate of ~1%.

The diagnosis is rarely suspected given the above symptoms, and is often only found incidentally on resection of a gallbladader for symptomatic cholelithiasis.

From an imaging standpoint, ultrasonography will often reveal a thickened wall or polypoid masses, though these features may not specific for carcinoma. A polyp that is larger than 1cms is suspicious for carcinoma. CT may also identify a mass or thickening within the gallbladder, but the diagnosis is usually suggested when spread to the liver adjacent to the gallbladder fossa is identified or when regional adenopathy is present. Magnetic resonance cholangiopancreatogrphy may also help visualize the liver, biliary treee and neighboring lymph nodes but offers no clinical advantages over CT scan.

Surgical treatment is provides the only opportunity for cure but only a minority of patients are candidates. Patients who have a porcelain gall;bladdder should have elective cholecystectomy because of the high incidence of gallbladder cancer. The role of adjuvant chemotherapy following surgery is to control microscopic disease. Role of radiation therapy is unclear.

Carcinoma Thickening and Granular Appearance

This is a resected gallbladder cut longitudinally and opened like a book. You are looking into the lumen in the two halves created by the cut. The cystic duct is over the left side of the label, and the fundus of the gallbladder is over the right side. The tumor is in the fundus as tan-white tissue thickening the wall, and causing a granular appearance in the mucosa. There is a separate, 0.8 cm mucosal nodule nearby. The rest of the mucosal surface is normal appearing with small ridges, and a green-brown color. The wall is only about 1 – 2 mm thick. This carcinoma was found incidentally in this gallbladder, which was removed for gallstone. Unfortunately many gallbladder carcinomas are not diagnosed early. They are either found incidentally, like this one, or they are detected after they spread, when it is too late for effective therapy.

11951c01.8s gallbadder carcinoma grosspathology Courtesy Barbara Banner MD

Carcinoma – Mass

This gallbladder has been opened longitudinally and you are looking at the mucosal surface. Gallstones are present. Notice that the surface is pale tan, and irregular. The tumor produces only subtle changes in the mucosa; it is rare to have a large noticeable mass. Usually irregularity and granularity of the surface and thickening of the wall are the clues to the diagnosis.

11941.8s gallbladder carcinoma grosspathology Courtesy Barbara Banner MD

Carcinoma – Papillary Form

This photograph shows a gallbladder opened so that you are looking onto the lumenal surface. The gallbladder was enlarged to the size of a grapefruit, and only about half of it is visible in this picture. The warty excresences which cover the whole lumenal surface are papillary projections of a papillary carcinoma. This carcinoma grew over the mucosal surface and into the lumen, causing the gallbladder to be greatly distended. There was no invasion of the wall itself. A small part of the wall can be seen at one side of the picture. This is an uncommon form of adenocarcinoma of the gallbladder. It is by far more common for the carcinoma to invade through the gallbladder wall.

11947.81s gallbadder carcinoma grosspathology Courtesy Barbara Banner MD

Most exophytic carcinoma occurs in the fundus and the neck of the gallbladder.

Xanthogranulomatous Cholecystitis – Acute on Chronic

This gallbladder was opended longitudinally to show the lumenal surface. Four gallstones are present. The mucosal surface looks hemorrhagic, indicative of active inflammation. The most striking aspect of this gallbladder is the marked thickening and yellow color of its walls. This is due to extrusion of bile into the wall during inflammation when the integrity of the mucosa is interrupted. Once in the tissues of the wall, the bile triggers an intense inflammatory reaction, and a response by histiocytes, which phagocytose the bile and attempt to break it down. The marked accumulation of lipids and their break-down products imparts the yellow color. The significance of this variant of chronic cholecystitis is that it mimicks carcinoma by the way it thickens the wall. The radiologist, the surgeon, and even the pathologist may think this is carcinoma until the microscopic sections are examined.

11937b01.8s gallbladder dx cholelithiasis grosspathology Courtesy Barbara Banner MD

Morphology of gallbladder carcinoma may be infitrating or exophytic. The infiltrating pattern is more common, and is characterized by deep ulcerations of the wall. These may occasionally lead to fistulous tracts forming with adjacent visceral structures, most often the liver.

82755c01.8s

Porcelain Gallbladder – Variant of Chronic Inflammation

This is a specimen xray of a resected gallbladder. The walls were thin, fibrotic and heavily calcified, accounting for the radiodense (white) areas on the radiograph. This variant of chronic cholecystitis is a risk factor for development of carcinoma.

11939.8s gallbladder porcelain gallbladder X-ray Courtesy Barbara Banner MD

Porcelain Gallbladder

The plain film of the right upper quadrant shows faint calcification (white lines in b)) of the wall of the body and of the entire neck. This finding is subtle since it is intermingled with calcification of the costal cartilage, but it is important and poentially life saving since the patient has to undergo elective cholecystectomy because of the high association with carcinoma. (up to 25% incidence)

Porcelain Gallbladder

The gallbladder in this instance is contracted, and has porcelain like calcification. This suggests chronic cholecytitis though no stones are identified. The patient requires to undergo elective cholecystectomy.

47683c01 gallbladder fx calcification in wall calcified wall dx porcelain gallbladder CTscan Davidoff MD

Porcelain Gallbladder with Calcified Stone

In this CTscan calcification of the wall of the gallbladder (green) is associated with a large calcified stone (yellow) that appears to be impacted in the neck. Cholesterol stones are usually isodense with the bile but in this case it has calcified. The large size of the stone suggests its cholesterol nature in this case.

76225c01 gallbladder wall calcification calcified porcelain gallbladder premalignant CTscan Courtesy Ashley Davidoff MD

Carcinoma in Situ

This high power photomicrograph shows the mucosal epithelium and lamina propria, and part of the muscle layer of a gallbladder containing a carcinoma. In this picture, the epithelium is a normal simple, columnar epithelium at one side, (right) and it undergoes a change to a dense, disorganized, malignant epithelium (carcinoma-in-situ) as you follow it across to the other side of the picture. (left)

11946.8s gallbladder carcinoma histopathology Courtesy Barbara Banner MD

Carcinoma Pleomorphic Nuclii

This medium power photomicrograph shows the epithelium in a case of gallbladder carcinoma. The cells retain a columnar structure, but their nuclei are pleomorphic, and there is variable staining quality of their cytoplasm from cell to cell. Some of the cells look like Paneth cells, with their large, eosinophilic cytoplasmic granules. Variability in size, shape, and staining quality of cells is one of the hallmarks of malignancy.

11943.8s gallbladder carcinoma histopathology Courtesy Barbara Banner MD

Carcinoma – Back to Back Gland Arrangement

11944.8s gallbladder carcinoma histopathology Courtesy Barbara Banner MD

Carcinoma – Back to Back Gland Arrangement and Irregular Nuclii

This medium power photomicrograph shows an infiltrating adenocarcinoma of the gallbladder. Note the “back-to-back” gland arrangement, and the irregular distribution of cell nuclei within the glands. The histologic features of this adenocarcinoma are common to adenocarcinomas from many sites, such as the GI tract, pancreas, lung, endometrium etc. but they are also quite typical of gallbladder carcinomas. In this picture the nest of malignant glands is growing across bundles of muscle in the gallbladder wall. The muscle bundles are the deeply eosinophilic structures on either side of the tumor.

gallbladder carcinoma histopathology Courtesy Barbara Banner MD 11948s

Carcinoma – Papillary Form

This is a whole-mount section through the wall of a gallbladder with a non-invasive papillary carcinoma. Note how the tumor grows as complex papillary projections, which in the complete specimen projected into and filled up the lumen of the gallbladder. Although this carcinoma is also capable of invading into the wall, this one grew over the interior surface of the gallbladder without invading into the wall. In this picture, the wall is the dense eosinophilic part beneath the papillary projections of the tumor.

11945.8s gallbladder carcinoma histopathology Courtesy Barbara Banner MD

In the exophytic patterin illustrated above, the neoplasm remains within the wall, taking on a characteristic cauliflower like appearance. The luminal portion can be necrotic, hemmorrhagic and ulcerated.

Carcinoma – Lymph Nodes

This picture illustrates the major routes of spread of carcinoma (T) of the gallbladder, (GB) which are direct invasion into the liver, (L) and metastasis to regional lymph nodes. (LN) This is a slice taken through the gallbladder and porta hepatis, including small portions of the liver, stomach, and pancreas, from the autopsy of a patient who died of metastatic carcinoma of the gallbladder. The gallbladder wall is thickened by pale tan-white tumor. (T) The same tan-white tumor is present in lymph nodes (LN – black) of the porta hepatis (cystic node) situated along the common bile duct. These lymph nodes can cause extrahepatic biliary obstruction by compressing the common bile duct as they enlarge. The portions of Ampulla of Vater, (amp) stomach (ST) and pancreas seen in this picture are negative for tumor. Not shown is the fact that this tumor invaded directly through the gallbladder wall and directly into the liver.

11949bs gallbadder carcinoma grosspathology Courtesy Barbara Banner MD

Carcinoma – Restricted to the Gallbladder

Carcinoma of the Fundus CT and MRI

Mucosal and Submucosal Infiltration

In this patient the CTscan (a,b)shows a thick walled and contracted fundus of the gallbladder. The mucosa (pink) and the lamina propria muscular and serosal layer orange are thickened. The fundal lumen is small while the lumen of the body (green) of the gallbladder is normal. This non specific thickening was carcinoma of the gallbladder. The T1 weighted MRI reveals multiple small filling defects in the body of the gallbladder, that were obviously not calcified by CT. By these imaging techniques the carcinoma is confined to the gallbladder (at least macroscopically) and a chance of surgical cure is possible.

Carcinoma – Extending into the Liver via the Gallbladder Fossa

Direct Invasion into the Liver and Bile Duct Obstruction

The CTscan of this patient shows a normal sized gallbladder (green) associated with a 4-5cms mass (orange) adjacent to the gallbladder, and extending from the gallbladder fossa. There is asssociated biliary obstruction (dark green tubes) This case represents invasive gallbladder carcinoma with bile duct obstruction. Images c and d show the almost universal association of gallstones in patients with carcinoma. In this case the stones (white) are in the centre of the gallbladder. (green)

16254c03.8s gallbladder anterior wall liver invasion space occupatopn obstruction bile ducts aggressive gallbladder carcinoma complicated by direct invasion metastasis liver windows narroe windws tumor settings gallbladder fossa GBF CTscan Courtesy Ashley Davidoff copyright 2008

Dystrophic Calcification – Carcinoma of the Gallbladder Extending into the Gallbladder Fossa

The non-contrast CT of the 75year old female patient, shows dystrophic calcification in a mass that seems to be part of the wall of the gallbladder. The mass extends into the liver. These findings are consistent with an inoperable gallbladder mucinous adenocarcinoma, metastatic to the liver by direct extension. Calcification of adenocarcinomas is usually found in the mucinous variant of the disease.

24404c.8s 75 female gallbladder calcification adjacent mass in the liver local invasion into the gallbladder fossa dystrophic calcification probably mucinous adenocarcinoma of the gallbladder carcinoma stones cholelithiasis hydronephrosis

Carcinoma – Extending into the Liver via the Gallbladder Fossa and Additional Metastases

Local Invasion and Separate Liver Mestastasis

The CTscan in this patient shows two calcified gallstones in the gallbladder (green), with a mass like malignant abnormality extending into the liver on either side (yellow) and a remote metastasis (orange) which is deforming the liver edge.

Disease Extension Beyond the Liver

Cholangiocarcinoma with Involvement of the Gallbladder and Bile Duct

The multiple imaging modalities of this patient who is elderly female who presents with obstructive jaundice. Deformity of the gallbladder by CT is noted, with extension of a mass into the surrounding liver (a,b,c) In addition to a mass in the gallbladder (d), the ultrasound shows a shadowing stone (e). An ERCP (f), shows a circumferential stricture of the bile duct. The stricture is in the region of the cystic duct – bile duct junction, with non visualization of the cystic duct suggesting extension of the gallbladder cancer into the cystic duct and bile duct. Lymph node involvement with bile duct obstruction is a less likely possibility due to the circumferential nature of the stricture.

40018c02b.8s elderly female cholelithiasis obstructive jaundice common bile duct stricture dilated intrahepatic ducts irregular enhancing thickening of the gallbladder wall stent gallbladder carcinoma with extension into the CBD or CBD carcinoma with extension into the wall of the gallbladder CTscan USscan ultrasound ERCP Courtesy Ashley DAvidoff MD copyright 2008

Luminal Invasion

The CT scan through the gallbladder shows a central low density mass (gray) with a surrounding irregular wall (yellow). The ultrasound (c,d), shows complex echoes in the lumen (orange in d) probaly representing a combination of solid mass and tumefactive bile. A single shadowing stone can be seen in c (arrow) with shadowing confirming its presence. (arrow in d)

16254c05 gallbladder space occupation gallbladder carcinoma by CT it appears as a low density centrally and enhancing soft tissue peripherally by USscan looks like the whole lumen is filled with soft tissue tumor question of delayed tumor enhancement vs necrosis CTscan USscan ultrasound Courtesy Ashley Davidoff copyright 2008

Gallbladder Carcinoma with Perforation and Abscess Formation

This is the same case noted above, but it exemplifies extension of the tumor into the surrounding organs, and in this case probably colon with secondary abscess formation (small black airbubbles in c and d ) fluid collection (yellow) in c, and edematous changes in the surrounding fat and peritoneum (pink in c and d). The tumor has central non enhancing matrix (gray) surrounded by more solid enhancing tumor (orange)

16254c01b02.8s gallbladder thickened irregular wall air anterior wall small fluid collection gallbladder carcinoma complicated by perforation and abscess formation CTscan Courtesy Ashley Davidoff copyright 2008

Conclusion

From the anatomical point of view it is interesting to note that gallbladder cancer occurs most commonly in the fundus, and from the pathophysiological point of view it is so frequently associated with gallstones. It is attractive to consider the fact that in the “day” position of the gallbladder, the most dependant, concentrated bile is in contact with the mucosa, and similalrly stones will be in contact with the fundal mucosa for the longest time. In the prone position (if the person sleeps in prone position) stones will be in contact with the anteriorly positioned fundus as well. hence chronoic contact, chronic irritation of the fundus and aberrant chemical environments such as excessive bile salts, or cholesterol make a fertile environment for the evolution of the mucosa to dysplasia and carcinoma.

Gallbladder Cancer and Stones

The greenpepper sectioned in long axis has a mass like base, and remnant seeds reminiscent of the combination of fundal carcinoma in the presence of cholelithiasis.

11528b.8 gallbladder food in the body green pepper cancer carcinoma gall stones cholelithiasis Davidoff art Davidoff photography copyright

References

Denshaw-Burke Mary Denshaw-Burke, MD, Gallbladder Cancer eMedicine 2008

Szarnecki Gregory M Szarnecki, MD, Gallbladder, Carcinoma e Medicine 2007

References provided by e Medicine

National Cancer Institute. Treatment statement for health professionals: gallbladder cancer. Updated 2/15/07. Med News. Available at http://www.meb.uni-bonn.de/cancer.gov/CDR0000062904.html. Accessed August 23, 2007.

Fong Y, Wagman L, Gonen M, et al. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg. Jun 2006;243(6):767-71; discussion 771-4. [Medline]. [Full Text].

Levy AD, Murakata LA, Rohrmann CA Jr. Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics. Mar-Apr 2001;21(2):295-314; questionnaire, 549-55. [Medline]. [Full Text].

Douglass HO Jr, Kim SY, Merpol NJ. Neoplasms of the gallbladder. In: Holland JF, Frei E III, Best RC Jr, eds. Cancer Medicine. Vol 2. 4th ed. Baltimore, Md: Williams & Wilkins; 1997:1955-63.

Dudiak CM, Lawson TL. Carcinoma of the gallbladder. Diagnostic Ultrasound (Second Series) Test and Syllabus. St Louis, Mo: Mosby-Year Book; 1994:324-62.

Elsayes KM, Oliveira EP, Narra VR, El-Merhi FM, Brown JJ. Magnetic resonance imaging of the gallbladder: spectrum of abnormalities. Acta Radiol. Jun 2007;48(5):476-82. [Medline].

Grainger RG, Allison E. Grainger and Allison’s Diagnostic Radiology: a Textbook of Medical Imaging. Vol 2. 3rd ed. New York, NY: Churchill Livingstone; 1996:1224.

Greene FL, Page DL, Fleming ID, eds. Gallbladder. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002:139-44.

Haubrich WS, Schaffner F, Berk JE, eds. Bockus Gastroenterology. Vol 3. 5th ed. Philadelphia, Pa: WB Saunders; 1995:2739-44.

Kai M, Chijiiwa K, Ohuchida J, et al. A curative resection improves the postoperative survival rate even in patients with advanced gallbladder carcinoma. J Gastrointest Surg. Aug 2007;11(8):1025-32. [Medline].

Kim MJ, Kim KW, Kim HC, et al. Unusual malignant tumors of the gallbladder. AJR Am J Roentgenol. Aug 2006;187(2):473-80. [Medline]. [Full Text].

Mekeel KL, Hemming AW. Surgical management of gallbladder carcinoma: a review. J Gastrointest Surg. Sep 2007;11(9):1188-93. [Medline].

Memel DS, Balfe DM, Semelka RC. The biliary tract. In: Lee JKT, Sagel SS, Stanley RJ, eds. Computed Body Tomography With MRI Correlation. Vol 2. 3rd ed. Philadelphia, Pa: Lippincott-Raven; 1997:810-3.

Miller G, Schwartz LH, D’Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am. Apr 2007;16(2):343-68. [Medline].

Numata K, Oka H, Morimoto M, et al. Differential diagnosis of gallbladder diseases with contrast-enhanced harmonic gray scale ultrasonography. J Ultrasound Med. Jun 2007;26(6):763-74. [Medline].

Oe A, Kawabe J, Torii K, et al. Distinguishing benign from malignant gallbladder wall thickening using FDG-PET. Ann Nucl Med. Dec 2006;20(10):699-703. [Medline].

Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg. Jun 2007;245(6):893-901. [Medline].

Srivastava AK, Singh B, Gupta SL. Prevalence of Toxoplasma antibodies in sheep and goats in India. Trop Anim Health Prod. Nov 1983;15(4):207-8. [Medline].

Vitetta L, Sali A, Little P, Mrazek L. Gallstones and gall bladder carcinoma. Aust N Z J Surg. Sep 2000;70(9):667-73. [Medline].

Yamada T, Alpers DH, Owyang C, Powell DW, Silverstein FE, eds. Textbook of Gastroenterology. Vol 2. 2nd ed. Baltimore, Md: Lippincott Williams & Wilkins; 1999:2335-40.

carcinoma, esophagus, malignant, primary cancer

Esophagus Carcinoma

Carcinoma

Definition

Esophageal cancer is a malignant growth disorder of esophageal mucosa. Historically squamous cell cancer was the predominant type; however, more recently, a surge in adenocarcinoma as the more common entity has evolved. Sqaumous cell carcinoma characteristically occurs in the thoracic esophagus while adenocarcinoma occurs at the GE junction.

Many different causative factors have been associated with this condition including GERD, Barrett’s esophagus, dietary factors, smoking and geographic location.

The disease results in an aggressive space occupying mass that progressively impinges on the lumen of the esophagus to cause dysphagia

It is most commonly diagnosed by endoscopy and biopsy, staged with CT and PET scan, and best treated with a combination of surgical and medical therapies.

The overall prognosis is quite poor, with 5 year survival estimated to be between 10-13% for advanced disease. With the increased diagnosis of Barrett’s esophagus, and the routine surveillance that follows, earlier detection of cancer allows for treatment and better survival rates. Survival rates are much improved with more superficial cancers that are found with increasing frequency during endoscopic surveillance.

Ulcerating Squamous Cell Carcinoma of the Esophagus

02425 02420 code esophagus + mass narrowing stricture ulceration heaped edges squamous cell carcinoma + grosspathology

Ulcerating Esophageal Carcinoma with Heaped Edges

01270c code esophagus + fx mass + dx carcinoma + barium swallow upper GI UGI imaging radiology contrast X-Ray mass neoplasm malignant primary carcinoma cancer tumor Courtesy Ashley Davidoff MD

Causes and Predisposing Factors

ie etiology and pathogenesis

Squamous cell carcinoma and adenocarcinoma each have their own predisposing conditions, and as such, will be described separately.

Causes Related to Squamous Cell Carcinoma:

Geographic location has been shown to be a risk factor for the development of squamous cell carcinoma of the esophagus. Asian countries have a higher incidence than that of the western part of the world.

Dietary risk factors also exist. Much like that of other gastrointestinal cancers, foods with n-nitroso compounds are thought to increase the risk. Within the Asian countries, the common practice of chewing of the Betel nut, has been associated with squamous cell carcinoma.

Other dietary risk factors include the consumption of alcohol. A correlation between the amount consumed and the risk of cancer exists.

Tobacco use has also been closely associated with squamous cell esophageal cancer.

Patients with underlying conditions that affect the esophagus are also at increased risk. A previous history of caustic ingestion, classically with lye, increases the risk.

Causes Related to Adenocarcinoma:

The most important risk factor for the development of adenocarcinoma of the esophagus is a history of Barrett’s esophagus. The progression of Barrett’s to carcinoma is well documented and reviewed at length in the section on Barrett’s.

Other risk factors for the development of adenocarcinoma of the esophagus include tobacco use, obesity, GERD, and other conditions that will increase acid exposure in the esophagus

Statistics

In the USA it is relatively uncommon with about 10,000 new cases per year or between 2 – 8 people per 100,000

There are certain areas in China with 100 new cases per 100,000

Race

Higher in the black population – could this show a genetic predisposition?

Sex

M:F range from
2:1 to 20:1.

Age

adult disease
usually over age 50

Other Statistics

1% of all cancers
10% of gastrointestinal malignancies

Result

Since the lymphatic network in the submucosa is so allows both circumferential and longitudinal spread and the disease is usually more extensive than the macrsosopic appearance and early lymphatic spread to areas remote from main mass is characteristic. As mentioned above, the 5 year survival rates for esophageal cancer are quite low. Early detection is important as if found prior to metastasis, the treatment options are more plentiful.

Gross Pathology

polypoid or fungating (common)
ulcerating form
infiltrating form
varicoid form

Ill Defined GE Junction Tumor – Adenocarcinoma

00567c03 distal esophagus GE junction gastroesophageal junction stomach GE junction tumor fx nodular appearance to the GE junction dx adenocarcinoma of the GE junction grosspathology malignant cancer Courtesy Ashley Davidoff MD

Histopath

squamous cell carcinoma (95%) Squamous cell carcinomas are moderately to well differentiatedsquamous cell carcinoma (common)
adenocarcinoma (4%)
Barrett 70%
GE junction 30%

other
adenoid cystic carcinoma
carcinosarcoma

Squamous cell carcinomas are moderately to well differentiatedsquamous cell carcinoma (common)

They pesent as;

well differentiated (common)
mderately differentiated (common)
poorly differentiated

Complications

The mass may cause local obstruction. Local extension into mediastinal structures is early and common. Tracheoesophageal fistula can occur in 5 -10%. Other complications include ulceration, bleeding airway compression, and invasion into the aorta. Systemic complications are characterized by metatastasis to nodes, lung, liver, adrenal gland.

Classification based on Staging

TNM system:

T, tumor <5 cm in length without circumferential involvement

T2 tumor >5 cm in length / circumferential or obstructive lesion

T3 extraesophageal spread

classification based on radiologic appearance

Diagnosis

Clinical

Clinically, patients present with a myriad of complaints, the most common of which is dysphagia. As the lumen narrows for the growth of the lesion, food is unable to pass smoothly thru the esophagus. Patients can present with upper gastrointestinal bleeding, weight loss, halitosis, in addition to many non-specific complaints.

The onset of the dysphagia is insidious. The esophagus is a pliable and mobile organ and is therefore forgiving and can accomodate the advancing mass. Thus clinical presentation and the onset of dysphagia is late.The delay in time to clinical presentation implies advanced disease at presentation and this affects outcome.

Imaging

With clinical suspicion, most patients undergo an upper endoscopy to evaluate the symptoms. This modality allows for direct visualization of the lesion and for biopsy for tissue diagnosis.

Carcinoma of the Esophagus

73940.400 73941.400 esophagus distal mass ulcerating bleeding carcinoma of the esophagus endoscopy endoscopic view Courtesy Joshua Namias MD

Carcinoma of the Esophagus

73941.400 73941.400 esophagus distal mass ulcerating bleeding carcinoma of the esophagus endoscopy endoscopic view Courtesy Joshua Namias MD

Irregular Distal Esophagus with Stricture – Adenocarcinoma of the GE junction

75711c01 dysphagia esophagus distal irregular stricture dx adenocarcinoma of the esophagus barium swallow Courtesy Ashley Davidoff MD

Long Relatively Smooth Malignant Stricture

Courtesy Ashley Davidoff MD 01240 esophagus + fx irregular stricture + dx carcinoma + barium swallow upper GI UGI imaging radiology contrast X-Ray mass neoplasm malignant primary carcinoma cancer tumor

Long Mid Esophagus Malignant Stricture

Courtesy Ashley Davidoff MD 01246 code esophagus + fx irregular + fx long fx narrowed + dx squamous cell carcinoma + barium swallow upper GI UGI imaging radiology contrast X-Ray mass neoplasm malignant primary carcinoma cancer tumor

Depending on the initial complaint, a barium study may also be performed.

Findigs may include a polypoid or fungating form, ulcerating form, or infiltrating form. If ulcerated a filling defect would be apparent, anf if it involves the esophagus ircumferentially an apple core lesion or a focal narrowing will be present. Once the diameter of the lumen becomes less than 13mm partial obstruction occrs, the lumen becomes functionally compromised the proximal esophagus dilates and dysphagia ensues.Any mucosal irregularity that raises uspicion should be evaluated an biopsied as dwcided by the endoscopist at the tine.

CT shows wall thickening anf the relationship to
mediastinal structures. Ominous signs iclude 1oss of fat planes invasion into trachea, aorta, pericardium, and distant metastases

Once a lesion is found, further diagnostic studies are often performed. Endoscopic ultrasound allows for great definition of the extent of the disease. This modality allows for visualization of the layers of the esophagus, such that the level of invasion can be identified. Biopsies of involved tissue and nodes can be performed.

CT scan allows for evaluation for metastatic disease as well.

Staging by Non Invasive Method

29885c03 esophagus lymph nodes primary esophageal carcinoma probably squamous carcinoma metastases to lymph nodes mediastinal lymphadenopathy mediastinum irregular lumen long segment single contrast bariu swallow CTscan PET scan NM Courtesy Ashley Davidoff MD

Treatment

Treatment of esophageal cancer greatly depends on the staging of the disease.

If the tumor is localized to the esophagus, without evidence of direct or metastatic spread, surgery provides a cure. Typically an esophagectomy with gastric pull up is the treatment of choice. Mucosal resections, photodynamic therapies, and ablative techniques can be entertained.

If the disease is not resectable at the time of diagnosis, chemotherapy, often in combination with radiation therapy is undertaken.

Stent in the Distal Esophagus

18203c esophagus carcinoma stricture tube stent dilatation treatment Courtesy Ashley Davidoff MD

Gastric Pull Through

76384 esophagus carcinoma cancer gastric pull through surgery treatment differential diagnosis dd dilated esophagus barium swallow Courtesy Ashley Davidoff MD 76386c01

Prognosis

3 – 75% 5-year survival rate

For superficial superficial esophageal carcinoma 5-year survival rate is 75% and for advanced lesions 5-25% 5-year survival rate. The presence of involved Iymph node metastases at the time of resection reduces the 5 year survival.

esophagus, premalignant

Esophagus Barrett’s

Definition

Barrett’s esophagus is an abnormal growth disorder of the gastroesophageal junction characterized by metaplastic change of the squamous epithelium into a glandular columnar epithelium caused by longstanding gastroesophageal reflux. With this change there may be resulting alteration in the DNA rendering the entity a premalignant condition.

The clinical presentation is non specific and include the dyspeptic symptoms of GERD . The diagnosis is made by endoscopy, where the extension of the gastric mucosa into the squamous territory is seen as cracks of salmon colored areas in the white esophageal mucosa. Biopsies need to be taken to evaluate for dysplasia. In the absence of dysplasia treatment includes ongoing surveillance, with aggressive medical treatment of the GERD. In the presence of dysplasia removal of the dysplastic abnormalities is indicated. A variety of endoscopic ablative therapies and surgical options are available.

Normal Regular “Z” line (left) and and Barrett’s Esophagus (right)

73474 squamocolumnar junction gastroesophageal junction squamous epithelium gastric epithelium columnar epithelium normal Z line anatomy histology endoscopy endoscope Courtesy Joshua Namias MD

73475 squamocolumnar junction gastroesophageal junction squamous epithelium gastric epithelium columnar epithelium Extension of columnar epithelium toward the squamous epithelium space occupation Barrett’s esophagus endoscopy endoscope Courtesy Joshua Namias MD

Barretts Esophagus

12254 Gross specimen showing Barrett’s mucosa. The lighter white portion is normal esophageal squamous epithelium, and the tan-brown area is abnormal. This is where the normal squamous epithelium has been replaced by metaplastic columnar epithelium, comprising Barrett’s esophagus. Courtesy Barbara Banner MD

Barretts Esophagus

12255 Microscopic section at low power showing Barrett’s mucosa. Note that a glandular type of mucosa is present overlying the cluster of esophageal glands. This tells us that where there ought to be squamous epithelium, there is now columnar metaplasia, and this is the definition of Barrett’s esophagus. histopathology Courtesy Barbara Banner MD

Causes and Predisposing Factors

Barrett’s is a sequela of longstanding reflux. The mean age of diagnosis is 55, although can be seen earlier with rare cases reported in the pediatric population. The male to female ratio is 2 to 1 with a higher incidence in the white and Hispanic population. It is less frequently seen in the black and asian population.

With the continuous injury from acid, the esophagus attempts to protect itself by changing to the more acid resistant intestinal type mucosa. However, with this transformation, there is DNA alteration and malignant changes can occur.

Result

The specialized intestinal metaplasia is glandular mucosa with mucin-type cells and abundant goblet cells.

The risk of Barrett’s Esophagus is the conversion to carcinoma. This conversion can be thought of as a stepwise process.

GERD-à Erosive Esophagitisà Specialized Intestinal Metaplasiaà Low Grade Dysplasiaà High Grade Dysplasiaà Carcinoma

Esophageal carcinoma has increased 300% since the 1970s. There are many reasons for this but clearly detection by endoscopic procedure and routine surveillance for Barrett’s plays a large role.

Diagnosis

Barrett’s Esophagus is a endoscopic and histopathologic diagnosis. Upon endoscopic visualization of the GE junction, one can appreciate a regular appearing “Z” line. Again, this is the area of change from squamous esophageal mucosa to gastric type mucosa.

With Barrett’s, however, there is an irregularity of this line with finger like projections starting at the transition point and traversing more proximally. This salmon colored tissue is the specialized intestinal metaplasia.

Barrett’s Esophagus

01235c03 01235 by endoscopy Barret’s Courtesy Ashley Davidoff MD code esophagus epiphrenic ampulla hiatus hernia esophagitis barium swallow upper GI UGI imaging radiology contrast X-Ray

This finding is not uncommonly seen and it has been estimated that 1/100 “routine” EGDs will demonstrate Barrett’s, while those done for “reflux” will show a incidence of approximately 1/10.

Barrett’s itself does not have associated symptoms. Instead, patients are often symptomatic from the underlying reflux. There are cases where the first presenting symptom is dysphagia or odynophagia and endoscopy reveals Barrett’s and esophageal carcinoma. Autopsy studies have shown Barrett’s to be present in 1/57-1/105 cases.

Biopsies should be taken at the initial finding of Barrett’s. The biopsies are taken from 4 quadrants and in 1cm intervals. It is extremely important to have patients with no evidence of dysplasia to undergo surveillance endoscopies. After Barrett’s is found endoscopy should be performed annually for 2 years and the every three if no dysplasia is found.

Those patients who have progressed to dysplasia must consider further therapies. Regardless of the modality chosen (described below) annual endoscopies are required.

Barret’s Esophagus by Endoscopy No Specific Findings

Suspect in the Setting of Peptic Esohagitis and its Sequelae

This series of images of the esophagus from a double contrast barium swallow shows a focal irregular stricture at the GE junction (a) associated with a hiatus hernia. (d,e,f). The irregularity suggest ongoing esophagitis but Barrett’s esophagus has to be considered. The patient complained of cervical dysphagia. A 13mm barium pill was held up at the junction implying a significant narrowing. The stricture seen in d,e,f has a concentric ring like appearance reminiscent of a Schatki’s ring.

Courtesy Ashley Davidoff MD 38421c02 code esophagus stricture narrowing irregular HH Schatzki’s ring barium pill

Treatment

Strict acid suppression is key, but it should be noted that regression of Barrett’s is not thought to be possible. Instead, the acid suppression is thought to reduce the ongoing acid exposure and damage to the wall.

There are four main therapeutic options in patients with Barrett’s.

Endscopic Ablative Therapies include Multipolar Electrocoagulation (MPEC) which is heat induced damage to the Barrett’s mucosa. It is reserved for non-dysplastic cases. It carries a risk of perforation, stricture formation, and residual Barrett’s can be found in upto 28% of cases.

Argon Plasma Coagulation is another endoscopic modality that uses ionized electronically charged gas, again to burn the mucosa. Strictures can form in upto 10%.

Photodynamic therapy involves giving systemic administration of a photo-sensitizing agent and the endoscopic to laser light that causes and oxidative damage to the mucosa.

Endoscopic Mucosal Resection consists of an upper endoscopy with the removal of the esophageal mucosa.

Surgical esophagectomy is a invasive approach but one that completely removes the Barrett’s and the possible conversion to cancer. However, clearly, complications and post-surgical morbidity is higher. Patients can develop dysphagia, weight loss, dumping syndrome, in addition to the surgical complications.

colon, malignant, neoplasm, primary cancer

Colon Cancer

Colon Carcinoma

Definition

Colon carcinoma is a malignant disease and is characterized by insidious but progressive nature and late clinical presentation.

It is the second most common cancer and cause of cancer deaths in the United States.

The disease has multifactorial causes with the most common cause having no single known specific etiological factor. The strongest causative link relates to patients with familial adenomatous polyposis. 100% of patients with this entity will develop carcinoma of the colon and a large percentage of patients with longstanding ulcerative colitis will develop carcinoma as well. It is therefore imperative that these patients undergo colectomies before the risk of carcinoma becomes a reality.

As a malignant epithelial tumor in a capacious organ the clues to its presence are few in the early stages of the disease. The earliest clinical clue in the unsuspected patient is the presence of blood in the stool (hemoccult test) or the presence of anemia.

The neoplastic proliferation usually starts out as an adenomatous polyp and progresses over many years resulting in a clinical or pathological feature

Complications include systemic and local metastatic disease, obstruction and perforation.

The diagnosis is suspected clinically in middle aged or elderly patients who are anemic or who have guiaic positive stools and it is confirmed by colonoscopy with biopsy.

If detected early, colorectal cancer is curable by surgery.

Imaging includes the use of endoscopy, barium enema and CTcolonography.

Treatment options depend on the staging of the disease but include surgery, systemic and locoregional chemotherapy Adjuvant chemotherapy can prolong survival in disease that has reached the lymph nodes. Radiotherapy is used in cases of rectal cancer to reduce local recurrence.

Ulcerating Colon Carcinoma

This specimen has obvious malignant characteristics macroscopically, characterized by heaped edges and central ulceration.

Note 02499 colon large bowel fx mass fx ulcerating mass fx raised edges fx central necrosis dx carcinoma malignant primary tumor cancer grosspathology Courtesy Dr Gutkin MD

Mucosal disease -a benign polyp in its early stages

Over time this neoplasm will continue to grow. If it grows slowly with monotony and uniformity in the morphology of cells, minding its own business and not disturbing its neighbors it is considered a benign neoplasm. It would be called a benign polyp and since it arises from the mucosa, it would be called an adenomatous polyp.

Courtesy Ashley Davidoff MD

32355

Principles

The mucosa is a metabolically active structure with rapid turnover. Intermittantly new cells with either spontaneous mutation or mutations as a result of an environmental pathogen or carcinogen, proliferate. Malignant growth is characterized by unrelenting expansion of the malignant cell population without regard for the organism. When the malignant growth arises from an epithelium it develops into a carcinoma, and when it arises from stromal tissue it becomes a sarcoma. Since the mucosa of the colon has glandular elements the carcinoma arising from the colon is called an adenocarcinoma. The colonic mucosa also secretes mucin and so histopathologically entity may present as a mucinous adenocarcinoma.

The colon is a capacious tube and the tumor is usually far advanced before the transport function becomes impeded. Thus obstruction is a late manifestation. because of the occult nature of the disease diagnostic endeavours are focused on screening for early detection to enable the chance for prevention and cure.

Principles of Disease

Most colorectal cancers are adenocarcinomas, which arise from preexisting adenomatous polyps that develop in the normal colonic mucosa. There is a well recognized adenoma-carcinoma sequence. The most common site for tumor development is the mucosa. The mucosa is a highly active structure and cell turnover is rapid, with the reproduction of new cells and death of old cells occurring about every four days.

Mucosal disease –beginning of a neoplasm

The diagram shows a single columnar cell on the top side of the lumen that for whatever reason has been programmed to become “different” and instead of growing with characteristic columnar shape with pink nucleus and “peaches and cream” cytoplasm in this case has become round with white cytoplasm and black nucleus. It is a neoplasm – ie a new growth.

Courtesy Ashley Davidoff MD

32354

The single aberrant cell that develops at the initiation odf the diesease process, multiplies and forms its own community of cells that enlarges with time – and in its infancy is seen as a benign adenomatous polyp.

5mm benign polyp

This 5mm polyp is a common finding on colonic evaluation and at this size is a benign abnormality. Left intact it can grow into a monster. Hence it is usually removed by the endoscopist.

Courtesy Ashley Davidoff MD

12087

Most colonic polyps however (90%), are not adenomatous but are hyperplastic (size < 5 mm) meaning that they are still under the control of normal regulatory mechanisms of the body. Hyperplastic polyps are benign and, in most instances, are not considered premalignant. On the other 10% are adenomatous and are premalignant.

The endoscopist cannot distinguish between a hyperplastic polyp and a adenomatous polyp and therefore the endoscopist removes all polyps.

When polyps are less than a 1cms the possibility that they are malignant is less than 5%. As they grow into the 1-2cms range the chances of malignancy are in the 10% range. Once they grow beyond 2cms the chances of malignancy increase to 50%. There are three types of adenomatouis polyps; tubular, tubulovillous, and villous. Tubular adenomas are the most common while villous adenoma has the greatest potential to become malignant.

Benign polyp – Virtual Colonoscopy
This series of images from a virtual colonoscopy shows an 8 mms polyp seen on the surface rendering images (salmon colored images) referenced to the sigmoid colon (bottom left) and with conventional CTimaging (bottom middle) At this size the polyp is almost certainly benign and can be removed through the colonoscope safely.
Courtesy Scott Tsai MD
45119

An adenomatous polyp if it is destined to become malignant usually takes 10-15 years to evolve. It will slowly invade the space of the lumen. but more importantly the space of the wall of the bowel, first into the submucosa and subsequently into the muscularis, serosa, adventitia lymphatics and finally into the systemic circulation.

Malignant and aggressive growth

The diagram illustrates the transformation from benign to malignant as the neoplasm starts to reveal an aggressive nature and invades and destroys surrounding tissue. In this instance it has advanced into the submucosa and muscularis as well as expanded into the lumen.

Courtesy Ashley Davidoff MD

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Pathology whole mount showing malignant transformation of a polyp

In this pathology specimen the tree like morphology of the polyp is characterized by benign features to the left and superior with malignant features to the right and toward the base and below the green bars. The malignant disease extends into the deeper layers at the base.

Courtesy Barbara Banner MD

12160

Ugly ulcerating malignant tumor

The grosspathology specimen shows an inflamed, angry looking mass in the colon that has central necrotic area surrounded by heaped tissue.

Courtesy Barbara Banner MD

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Virtual colonoscopy showing an ulcerating cecal carcinoma
This series of images from a virtual colonoscopy shows a 5cms ulcerated mass seen on the surface rendering images (salmon colored images) referenced to the cecum (bottom left) and with conventional CT imaging (bottom middle) At this size and shape the mass is almost certainly malignant and cannot be removed through the colonoscope safely. Note how similar the morphology of this tumor is to the pathology of the specimen above (different patient)
Courtesy Scott Tsai MD
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As the disease progresses there is expansion of the tumor in the submucosa so that a circumferential lesion evolves. There may be extension into the deep layers of the wall, into lymphatics and portal venous system and eventually into the liver.

As the tumor grows locally it spreads circumferentially and eventually totally surrounds the bowel in a “napkin ring” like manner as depicted in the image below.

Malignant growth through the all into veins and nodes

Left undiagnosed and untreated the malignant cells continue to grow without regard to the neighboring structures. It encircles the colon in “napkin-ring” fashion (as shown above) eventually blocking off the lumen and causing a bowel obstruction. It may grow through the wall and cause a bowel perforation and or grow into regional lymph nodes and portal venous radicles after which it will metastasize to the liver and other organs.

Courtesy Ashley Davidoff MD

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Radiologically the “napkin ring” translates into an apple core lesion when viewed radiologically and is best appreciated with a double contrast barium enema.

Apple core lesion of the sigmoid colon

The double contrast barium enema shows an apple core lesion caused by circumferential growth of a malignant tumor of the colon in “napkin-ring” fashion. The second image shows the apple core-shape of the lumen. The third image shows the yellow mass of tumor that has surrounded the lumen in napkin ring fashion essentially strangling the lumen. Note how the distal colon which is receiving air and barium via the enema tip is relatively dilated when compared to the descending colon which is relatively decompressed suggesting an obstructive process. Note also the presence of contrast filled diverticuli at the rectosigmoid junction. The two entities of carcinoma and diverticulosis often coexist since diverticulosis is very common in Westernized nations.

Courtesy Ashley Davidoff MD

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Napkin Ring Circunferential Tumor -aka Apple Core

Portion of left colon with a constricting carcinoma. The carcinoma has infiltrated the full thickness of the wall. This can be seen on the cut portion of the wall, where the wall is much paler than the surrounding mucosa.

colon large bowel fx apple core fx constriction fx narrowing fx wall thickening fx mass dx carcinoma malignant stricture grosspathology

Courtesy Barbara Banner MD aka applecore12313

Cause and Predisposing Factors

Colon cancer is a disease that has its highest in developed countries such as the United States and Japan, and lowest in developing countries in Africa and Asia. It is interesting to note that in the US it has its highest incidence in African American men.

It is thought or appears to be closely linked to Western diet where high fat content and relatively low fiber content are considered major factors in the cause of the disease. In patients who develop colon cancer, it is thought that diet and other factors alter the genetics of a cell or a group of cells and an adenomatous polyp results. Most polyps will not evolve into cancer. A entity called multiple aberrant mutations seems to be the responsible process that will cause about 10% of adenomatous polyps to evolve into cancer. This process disinhibits normal regenerative processes, and enables the mucosa to advance from an adenomatous polyp into a carcinoma over 10-15years. Evolving work on the genetic aberrancies is allowing advances in both the diagnosis and treatment of the disease. Identifying the genetic mutation of a cell in the stool may prove to be an important screening technique. Another example is the DCC gene, which causes the neoplastic cells to adhere to each other. The absence of this gene in the mutated gene would decrease cell adherence and theoretically enable malignant cells to metastasise easily. Thus testing for the DCC gene may shed light on the virulence and natural history of colon carcinoma in a particular patient and thus aid in prognostication.

Other known associated diseases include a prior history of colon carcinoma (metachronous = multiple separate occurrences – 4-5% of colon cancers), synchronous lesions (two or more at the same time = 1%) and inflammatory bowel diseases (IBD). Ulcerative colitis is a well esatablished associated disease, while the association with Crohn’s colitis is less common.

Synchronous Tumors Lying Side By Side in the Cecum

Two tumors lie side by side in the cecum. The polyp on the left was a large villous adenoma with malignant potential and the lesion on the right was a carcinoma.

12070 colon large bowel cecum ileocecal valve fx mass masses dx villous adenoma dx carcinoma malignant primary tumor cancer grosspathology Courtesy Barbara Banner MD

Hereditary factors that predispose to colon cancer are seen in conditions such as familial polyposis and Gardener’s syndrome, where there is a very strong association. (see below) Other conditions such as prior history of breast or endometrial carcinoma and retinitis pigmentosa also raise the awareness of associated colonic carcinoma.

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome, and it is characterized by the presence of innumerable neoplastic tubular adenomatous polyps of the colon. The cause of the disease relates to an autosomal dominant inherited disorder. In early life (about 16 years) the genetic defect evolves into and resultsin a colonic mucosa that is carpeted with hundreds to thousands of adenomatous polyps. In 100% of patients the syndrome is complicated by the development of cancer at the age of 30 – 40years, and hence all patients should be treated with colectomy in early years of the disease. (teenage to early 20’s)

Associated diseases include desmoid tumors (4-30%) and other rarer associations including medulloblastoma, thyroid cancer, adrenal cancer, gastric cancer and pancreatic cancer.

The diagnosis is established in patients who have a positive family history and by colonoscopy demonstrate more than 100 polyps.

Familial Polyposis Syndrome with Carcinoma

The normal mucosa in this patient has been replaced by inumerable carpet of polyps extending throughout the colon. A malignancy has evolved (“ca” = carcinoma) at the distal end of the colon.

Clinically it is usually asymptomatic and only presents presents once the patient has developed cancer. Symptoms include abdominal pain, diarrhea, mucus diarrhea, and bloody diarrhea.

Colonoscopy is the imaging and diagnostic study of choice since the diagnosis can be established and biopsy of suspicious lesions can be accomplished.

Colectomy with mucosal proctectomy and ileoanal pouch pull-through is the therapeutic procedure of choice

References

eMedicine Familial Adenomatous Polyposis

Gardner’s Syndrome

Gardners syndrome is an autosomal dominant inherited disease of the soft tissues, and is a variant of familial adenomatous polyposis syndrome. It is characterized by multiple osteomas, gastrointestinal polyps, and skin and soft tissue tumors. Cutaneous findings include epidermoid cysts, and desmoid tumors. The resulting osteomas are characteristic of the disease and their presence is a prerequisite to the diagnosis. They most commonly occur in the mandible but also in the skull. The colonic polyps appear in puberty and have a 100% risk of progressing to malignant disease between 30 and 40 years. The diagnosis is suspected clinically if there is a family history of the disease, or a young patient presents with multiple cutaneous lesions that may include epidermoid cysts, or other unusual skin lesions such as lipomas fibromas or neurofibromas at a young age. Imaging includes a skull X-ray to evaluate for osteomas and colonoscopy is indicated as well particularly if osteomas are present. Polyps usually are seen only once the osteomas are present.

Treatment options depend on the findings at colonoscopy. If more than 30 polyps are found, colectomy and stripping of the rectal mucosa is recommended because of the high risk of rectal carcinoma.

Thereafter there should be a continued surveillance for other associated tumors including hepatoblastoma, skeletal tumors, brain tumors and thyroid carcinoma.

Gardner’s Syndrome – Polyps and Carcinoma

12182 colon large bowel rectum fx mass fx multiple polyps dx Gardner’s syndrome complicated by rectal carcinoma Gardners syndrome grosspathology Courtesy Barbara Banner MD 5star

References

Gardner, EJ: A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 3: 167-176, 1951.

EMedicine

Ulcerative Colitis

Ulcerative colitis is an idiopathic inflammatory process of the mucosa of the colon and rectum, and is characterized by its involvement of the the rectum, and retrograde progressive involvement of sigmoid then descending, transverse and ascending colon. It is in essence a mucosal disease. The cause of the disease is unknown but the result is mucosal inflammation and ulceration. The risk of cancer increases with the chronicity and extent of the disease. About 5% of patients with UC develop colon cancer. As chronicity increases and extent of involvement increases the incidence of colon cancer also increases. Carcinoma is usually preceded by a dysplastic phase. Patients who have had a pancolitis for 8 years should receive a screening colonoscopy and biopsy, while those whose disease is restricted to the left colon should have screening colonoscopy and biopsy after about 12 years from the onset of disease. The biopsy is taken every 10cms at a random location. All patients with IBD should have repeat colonoscopy and biopsy every 2-3 years. These recommendations have been endorsed by the American Cancer Society, the American College of Gastroenterology, the American Society of Colon and Rectal Surgeons, and the Crohn’s & Colitis Foundation of America.

Colon Carcinoma in a Background of Chronic Ulcerative Colitis

This is a resected right colon open longitudinally in a patient with chronic ulcerative colitis. This patient had two simultaneous carcinomas. In this picture the terminal ileum and the ileocecal valve and a protruding appendix are present to the right of the label. Just beyond this, in the ascending colon, there is a thickened, strictured area which represents one of the carcinomas. Notice how ill defined and poorly seen this tumor is. The carcinomas in ulcerative colitis tend to be very difficult to see grossly. Beyond this first carcinoma the bowel mucosa is irregularly flattened indicating an old area of regenerated ulcer. At the opposite end of the specimen is another thickened strictured area which represents the second carcinoma.

colon large bowel fx masses fx ulcerating dx UC ulcerative colitis dx carcinoma malignant 12864 Ulcerative Colitis: carcinoma. transformation cancer grosspathology Courtesy Barbara Banner MD

Statistics

Adenocarcinomas of the colon are the most common cancers seen in the GI tract in western society. 1 in 20 Americans will develop colon cancer and 150,000 new diagnoses will be made each year and about 50,000 patients will die of the disease per year. While it ranks third among both men and women in mortality in western society, it is really second to lung cancer in women and second to lung cancer in men because men do not get breast cancer and women do not get prostate cancer.

Both men and women face a lifetime risk of nearly 6% for the development of invasive colorectal cancer. The disease is most common after the age of 70, but in the patient at high risk such as those with familial syndromes, colonic carcinoma could present in the late twenties or 30’s , while in the general population it could occur as early as the 40’s.

Pathology

Most tumors are adenocarcinomas. The most common site is the sigmoid colon (20%) followed by rectum (15%), transverse colon (12%), descending colon (10%), ascending colon (8%) and cecum (8%). As the population ages there is a tendency for the right sided colonic carcinomas to become more common. In ulcerative colitis, since the longest standing inflammation is left sided it is not surprising that left sided colon carcinoma is more common.

This polyp is greater than 2cms and was malignant on histopathologyical examination

The distinction between a malignant polyp and a benign polyp is sometimes difficult to discern based on gross pathology, but as the lesion becomes greater than 2cms., concern for malignant change should be considered. In the above specimen, there were no signs of overt malignancy other than its size, and the histopathology showed malignant change.

00317 colon cecum fx mass dx carcinoma dx cancer grosspathology Courtesy Ashley Davidoff MD

Ulcerating Colon Carcinoma

This specimen has obvious malignant characteristics macroscopically, characterized by heaped edges and central ulceration.

Note 02499 colon large bowel fx mass fx ulcerating mass fx raised edges fx central necrosis dx carcinoma malignant primary tumor cancer grosspathology Courtesy Dr Gutkin MD

Normal Colonic Mucosa (left) and Mucin Secreting Colon Carcinoma (right)

The image on the left shows the normal crypts while the image on the right shows a mucin secreting adenocarcinoma. The most obvious difference between the two images is the nuclear cytoplasmic ratio. Note in the case on the right, the cancer nuclii are large and heterogeneous while there is a relative paucity cytoplasm.

12860 12208 colon large bowel fx mucin secreting fx mucinous accumulation dx carcinoma mucin secreting adenocarcinoma histopathology Courtesy Barbara Banner MD ask

Colon Carcinoma – Cytopathology

These cells represent a group of malignant cells characterized by large heterogeneous nuclii and a paucity of cytoplasm. The nuclear to cytoplasmic ratio is high and this feature is characteristic of malignant cells.

44834 colon large bowel dx carcinoma mucin mucinous histopathology cytopathology Courtesy Barbara Banner MD ask

Potential Complications

The most common site for metastases is the liver (25%), mesenteric and retroperitoneal nodes (15%), kidney obstruction (10%). Large bowel obstruction, perforation and intussusception are potential complications of the disease.

Hematogenous Spread – Liver Metatsases

Carcinoma of the Colon with Metatstasis to the Liver

The MRI of the liver shows a space occupying abnormality at the dome of the liver with central hyperintensity on T1 weighted image, (a) as well as diffuse hyperintensity on T2 weighting (b) representing a hemorrhagic mucin secreting adenocarcinoma seen on the gross specimen (c) and on the histological; section (d).

03028c02 liver hepatic mass a = T1 weighted central intensity rim and matrix of low intensity periphery b = T2 weighting = T2 bright c = gross pathology hemorrhagic lesion d = mucin secreting metastasis with hemorrhagic ring fx metastattic colon carcinoma mucin secreting adenocarcinoma with central hemorrhage peripheral hemorrhage MRIscan histopathology grosspathology Davidoff MD

Colon Carcinoma with Multiple Metastases to the Liver and Involvement of the Capsule

The abdominal CT is from a middle aged female with right sided discomfort. The image reveals multiple space occupying lesions (light green) in the liver. The patient was found to have a primary colonic carcinoma. The capsule of the liver is involved by tumor extending to the surface of the liver and deforming the surface (dark green). The disease is also close to the diaphragm (maroon). The involvement of the liver capsule and possibly the right hemidiaphragm is likely the cause of the patients pain. There is also a small amount of ascites present (yellow) either as a response to involvement of the liver capsule or the early development of malignant ascites.

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middle aged female with right sided discomfort liver diaphragm fx enlarged hepatic enlargement hepatomegaly fx hepatic masses shrunken left lobe fx abdominal ascites dx colonic carcinoma with hepatic metastasis (metastatic liver disease) metastases with diaphragmatic and renal displacement from the large liver ascites probably malignant note hepatic capsule is involved abdominal CTscan of the abdomen Courtesy Ashley Davidoff MD 45049 45050 45051 45052 45053 45054

Sigmoid Carcinoma with Metastases to the Liver and Lung (green)

The PET scan in this elderly female with known carcinoma of the sigmoid colon shows metastatic disease to the liver, (dark green), lungs (light green) and mediastinum (light green with arrows) There is normal increased acivity in the heart (red) and excretion of the FDG into minimally dilated collecting systems (yellow).

45132c03 elderly female with known sigmoid colon carcinoma liver lungs mediastinum fx FDG positive uptake fx high intensity uptake in a single focus in the dome of the right lobe of the hepatic parenchyma meadiastinal lymph nodes and within the pulmonary parenchyma dx colonic mucinous adenocarcinoma complicated by metastatic lung disease and hepatic metastasis PETscan Courtesy Ashley Davidoff MD 45132 45133 45134 45135 45136 45139 45141

Lymph Node Metastases

Regional Lymph Node Enlarged

The pathology speimens are from a patient with long standing ulcerative colitis complicated by carcinoma. The nodule (overlaid in orange represents an enlarged regional lymph node that was positive for malignancy.

12196c01 colon large bowel lymph node dx enlarged fx invaded dx colonic carcinoma with metastasis lymphadenopathy grosspathologyu Courtesy Barbara Banner MD

Rectal Carcinoma with a Perirectal Node

The CT scan of the rectosigmoid region shows diffuse thickening of the rectum (light green) with an abnormal lymph node in the perirectal fat (dark green) in this patient with carcinoma.

colon large bowel rectum fx rectal wall thickening fx nodule lymph node dx rectal carcinoma primary malignant tumor cancer CTscan Courtesy Ashley Davidoff MD 12092 12092b01

Local Extension

Obsructing Rectal Carcinoma with Extension into Levator Ani and Pelvic Wall

CT scan through the rectum shows a large mass (1) extending through the perirectal fat (2) and into the levator ani (3) and progressing into the lateral pelvic wall (4)

00885c03 colon large bowel rectum mass carcinoma extension to levator ani pelvic sidewall CTscan Courtesy Ashley Davidoff MD

Bowel Obstruction

Colonic Distension No Rectal Air

The Diagnosis was Large Bowel Obstruction Secondary to a Rectal Tumor

00879 hx 55M with distension abdomen colon large bowel rectum fx enlarged dilated dx rectal carcinoma malignant tumor dx large bowel obstruction LBO KUB abdominal plain film Courtesy Ashley Davidoff MD

Obstructing Colon Carcinoma with Upstream Dilatation

28683c01 colon obstruction LBO large bowel obstruction colon carcinoma dilated obstructed CTscan Courtesy Ashley Davidoff MD

Cecal Carcinoma with Peritoneal Involvement presents with RLQ Pain

83037c03.8s 70 F presents with right lower quadrant pain RLQ colon cecum mass colon carcinoma napkin ring peritoneum peritonism somatic pain induration CTscan Courtesy Ashley Davidoff MD copyright 2008

Diagnosis

In general colon carcinoma is symptomatically occult and patients in general are asymptomatic in the early stages but may present with anemia and hemoccult positivity. As the anemia progresses the patients may present with weakness and weight loss and occasionally with abdominal pain

The diagnosis of colon carcinoma as the 2nd most common cause of death from malignancy in the US should be on the mind of caregivers in all patients starting at about the age of forty where unexplained hemoccult positive test or occult anemia should be viewed with high suspicion. Such a patient should undergo colonoscopy as the diagnostic study of choice. All patients should be screened with colonoscopy after the age of 50 years and thereafter every 10 years.

In addition to the colonoscopy annual fecal occult blood testing (FOBT) and periodic flexible sigmoidoscopy. Alternatively barium enema should be used every 3-5 years. (Helm)

Despite the guidelines a large prportion of the US population are not being screened because of insufficient numbers of trained colonoscopists to meet the need, fear of the procedure, or ignorance of the guidelines. CT colonography is an excellent alternative for screening when colonoscopy is not possible. Sensisitivity for small polyps is high and is similar to that of optical colonoscopy.

Lab Tests

In the patient with suspected colon carcinoma, blood tests should include cell count and hematocrit for the evaluation of anemia. The serum carcinoembryonic antigen (CEA ) is a tumor marker most often used for the evaluation of gastrointestinal tract malignancies. In about 60% of patients with colon carcinoma it is elevated and it is therefore a worthwhile test to obtain. It is also reasonable to evaluate liver function tests in the patient with suspected colon carcinoma to evaluate for the presence of liver metastases, though a negative result does not exclude the diagnosis.

Imaging

Optical colonoscopy is the study of choice for the patient with suspected carcinoma since it offers the opportunity to biopsy suspicious lesions, and to remove small polyps. When this method fails or is not possible, then CT colonography has now become the second line diagnostic study of choice. Fly through cecal carcinoma

Once the diagnosis is established a CTscan of the abdomen is used for staging the disease preoperatively. The local disease and extension into pericolic fat and lymph nodes can sometimes be established. Liver involvement is also best evaluated at this time with and if necessary suspicious lesions can be biopsied or further chharacterized with MRI.

It is also reasonable to perform a chest X-ray preoperatively to aid in staging though sensitivity for small lesions is low.

Treatment and Management

Surgery

A right, transverse or left hemicolectomy encompassing the lymphdrainage area is standard surgical care. At the time additional staging procedures are critical in the management. regiomnal lymph nnodes should be removed for pathological evaluation, nodular lesions in the peritoneal cavity should also be evaluated, and the liver should be exanmined with ultrasound and suspicious lesions biopsied as well.

Thereafter it is important to stage the disease when all the data is gathered to assess the post operative management

Staging

Two classifications have been of use: the TNM ([primary] tumor, [regional lymph] node, [remote] metastasis) staging and the Dukes classification.

TNM Staging System for Colon Cancer

Stage	Primary Tumor (T)	Regional Lymph Node (N)	Remote Metastasis (M)
Stage 0	Carcinoma in situ	N0	M0
Stage I	Tumor may invade submucosa (T1) or muscularis (T2).	N0	M0
Stage II	Tumor invades muscularis (T3) or perirectal tissues (T4).	N0	M0
Stage IIIA	T1-4	N1	M0
Stage IIIB	T1-4	N2	M0
Stage IV	T1-4	N2	M1

*N0: No regional lymph node metastasis.
N1: Metastasis in 1 to 3 regional lymph nodes.
N2: Metastasis in 4 or more regional lymph nodes.

Dukes Classification

Stage	Characteristics
Dukes stage A	Carcinoma in situ limited to mucosa or submucosa (T1, N0, M0)
Dukes stage B	Cancer that extends into the muscularis (B1), into or through the serosa (B2)
Dukes stage C	Cancer that extends to regional lymph nodes (T1-4, N1, M0)
Dukes stage D	Modified classification; cancer that has metastasized to distant sites (T1-4, N1-3, M1)

Endoscopic Ultrasound Showing a 1.5cms Rectal Tumor That Has Extended into the Submucosa and Muscularis In the TNM classification sytem it would be a T3 lesion

00896 colon rectal rectum fx mass dx colon carcinoma endoscopic USscan Courtesy Ashley Davidoff MD

Treatment

Stage 1 and 2 cancers are treated with surgery alone and have a very high cure rate. Stage 1 disease has a 90 to 95 percent five-year survival and early stage 2 disease (B-1) has an 85 percent five-year survival. Once the tumor invades the muscularis layer (advanced stage 2 or B-2, T3N0M0) treatment protocols are more controversial as to whether post operative chemotherapy offers advantage. The overall five-year survival with surgery alone in this group is 70 percent.

Stage 3 disease (node positive)benefits from postoperative chemotherapy. The overall five-year survival in this stageranges from 25 percent to 60 percent.

Stage 4 metastatic colon cancer occurs in approximately 30% of all patients diagnosed with the disease. If metatstatic disease is not identified within 5 years of diagnosis it would be quite unusual for it to develop at all. Patients with isolated liver metastases may benefit from resection, and if surgery is contraindicated then alternative techniques such as cryoablation radiofrequency ablation or stereotactic radiation. Systemic chemotherapy is an option for patients who cannot undergo the above options and a combination chemotherapy may cause regression in 20-25% of patients. The average survival for patients with metastatic colon cancer is between 12 and 18 months, and 5 year survival is approximately 5%.

Conclusion

Colon carcinoma is a common disease, and its pathogenesis from an adenomatous polyp to a malignancy is between 10-15 years. The colon offers a unique window for the endoscopist or radiologist by exposing its entire mucosa to the examining scope, and thus small early lesions can be visualized, biopsied and treated. Hence if all patients and their caregivers would adhere to screening protocols for both the common and uncommon forms, early detection and hence treatment and cure can be accomplished. The challenge is to create a system where screening techniques are made available to all.

References

American Cancer Society. Cancer facts & figures–2001. Atlanta, Ga.: American Cancer Society, 2001. Retrieved September 2001 from: www.cancer.org.

Helm JF, Sandler RS. Colorectal cancer screening. Med Clin North Am 1999;83(6):1403-1422, vi.

Ries LA, Miller BA, Hankey BF, eds. U.S. Dept of Health and Human Services, Public Health Service. SEER cancer statistics review, 1973-1991: tables and graphs. Bethesda, Md.: National Institutes of Health, 1994; NIH publication no. 94-2789:151.

Morson BC. The evolution of colorectal carcinoma. Clin Radiol 1984;35:425-31.

Rozen P. The OMED Colorectal Cancer Screening Committee: a report of its aims and activities. Organisation Mondiale d’Endoscopie Digestive. Gastrointest Endosc 1999;50:453-4.

Byers T, Levin B, Rothenberger D, Dodd GD, Smith RA. American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997. American Cancer Society Detection and Treatment Advisory Group on Colorectal Cancer. CA Cancer J Clin 1997;47:154-60.

Web References

eMedicine

MCQ

The

Colon carcinoma is a malignant condition of the colon with the causes being multifactorial but resulting in a mass or a narrowing in the large bowel.

UNDER CONSTRUCTION

UHRad Case report

liver, malignant, neoplasm, primary cancer

Liver Epithelioid Hemangioendothelioma

Section Name

Section Text

Malignant Hemangioendothelioma is epithelioid hemangioendothelioma is a primary malignant growth in the liver of unknown cause originating in connective tissue elements of the liver resulting in a mass with abundant sclerosis and myxoid elements characterised by a slow growing yet malignant nature

CT scan

The CT is from a 57 year old female with severe athereosclerotic disease and multiple liver lesions.The liver lesions are characteristic for malignant hemangioendothelioma and are characterized by the target like appearance (green overlay in image b) with a hypervascular inner rim and umbilicated appearance on the surface with a cocave in border. (overlay in green in d).

MRI

16700c001 liver hepatic nodules masses ring enhancement flattened lesion dimple on liver capsule multiple adult malignant hemangioendothelioma T1 weighted with and without gadolinium contrast MRI T1 weighted pre and post contrast Davidoff MD

References

Frank Earnest MD and C. Daniel Johnson, MD Case 96: Hepatic Epithelioid Hemangioendothelioma¹

liver, malignant, metastatic

Liver Metastases

Metastatic Disease to the Liver

Definition

Metastatic liver disease :

The liver is a common site for metastatic disease (Metastatic liver disease is 20 times more common than primary liver malignancy )because of it is rich, dual blood supply (the liver receives blood via the hepatic artery and portal vein) and hormonal mileu . The liver is the second most commonly involved organ by metastatic disease, after the lymph nodes.

The most common site of primary tumor is the gastro intestinal tract (colon, stomach and pancreas). The other common primary sites are the eye, breast, and lung. Neuroblastoma , Wilms tumor, or leukemias are common primary sites in children.

Metastatic liver disease is usually asymptomatic . Other patients present with right upper quadrant tenderness, abdominal swelling, jaundice , anorexia , weight loss and fever . Liver is hardened with irregular edges on palpation. Splenomegaly may be appreciated secondary to metastasis .

Imaging : Clues to metastatic liver lesions are (1) multiple lesions and (2) predominant involvement of the right lobe . Ultrasound is the imaging of choice for initial evaluation. Contrast CT and MRI provide more detailed information of the size, number and extent of metastatic lesions. Liver biopsy is indicated in situations of unknown primary tumor .

Chemotherapy is the treatment of choice for metastatic disease . Surgical options are limited in metastatic liver lesions . Cure rates are dependent on the growth characteristics of the primary tumor .

metastatic carcinoma is a metatstatic malignant neoplasm of the liver caused by a primary carcinoma elsewhere resulting in a mass or multiple masses characterised by space occupying lesions divided into types by cell origin pathogenesis new cell growth continues aggressively with no regard to the body at large and relatively unabated structural disorder space occupying lesion or lesions functional disorder usually of no functional significance until liver extensively involved clinical presentation local pain weight loss jaundice mild hepatomegaly systemic anorexia diagnostic studies include LFT’S US, CT, MRI treatment is commonly by chemotherapy

The Battleground – Tumor vs Healthy Tissue
The histopathology of a surgically resected hepatic metastasis from a primary colon carcinoma shows a mucinous secreting tumor at the bottom of the image labeled “advancing tumor”. The cellular detail is not well seen in the low power view but the columnar epithelial nature, hyperchromicity, and bizarre appearance of squatter tissue in the liver are recognized as malignant characteristics. The white spaces in between the cellular structure, represents mucin in the tumor. The edge of the tumor shows a rounded and aggressive push into the liver where the injured liver in the battlefield is recognized as compressed normal liver with linear areas of hemorrhage· evidenced by a curvilinear line at 11 and 12 oclock of· increased area of redness representing ·extravascular red cells (“layer of “injured liver”). The uppermost layer represents the normal liver which at this time looks healthy but is in jeopardy.
The radial red spokes seen at the edge of the tumor are artifacts of preparation but are indicators of the direction of the battle.
·liver cancer metastasis malignant tumor battlefield mucinous secreting adenocarcinoma colon primary histopathology destruction hemorrhageCourtesy Ashley Davidoff MD copyright 2009 all rights reserved 5star 03028b01.81s

46587.800

Liver Metastases
liver bone vertebra fx mass space occupying disease dx liver metastases metastasis dx primary lung carcinoma malignancy cancer CTscan Davidoff MD 46587.800

The post mortem specimen (a) shows a 2cms primary duodenal carcinoma (white arrow) with extensive nodular hepatic metastases occupying 80% of the liver. (b) In image c, the metastasis reflects an overall a blue hue caused by the increased nuclear presence. The image reveals an irregular and advancing threat on the normal liver. The higher power in d, shows a rind of compressed liver that is in the process of destruction and hemorrhage (red patches) in the tumor, in the border, as well as in the normal liver. This image is reminiscent of an advancing enemy in a battlefield with victory apparent for the aggressor. code liver duodenum adenocarcinoma metastases metastasis cancer malignant space occupation pressure atrophy death grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved
02643c03.8s

PANCREATIC METSASTASES TO THE LIVER
primary adenocarcinoma of the pancreas complicated by metastasis metastatic disease to the liver imaging radiology CTscan neoplasm malignant tumor cancer
Courtesy Ashley Davidoff MD code pancreas pancreatic body fx mass code liver fx multiple nodules and masses code dx primary adenoca
40343c

The liver on the left is normal except for gallstones in the gallbladder.· Gallstones are squatters but they usually do not have aggressive tendencies unless they block the outflow of bile.· The liver shown in the right image is from a patient who succumbed to metastatic pancreatic carcinoma.· The normal liver cells have been displaced and have been overridden by metastatic squatters.· The metastases have contributed to the demise of the patient by their relentless displacement of normal tissue, causing progressive impairment of function.·

The liver shown in the right image is from a patient who succumbed to metastatic pancreatic carcinoma.· The normal liver cells have been displaced and have been overridden by metastatic squatters.· The metastases have contributed to the demise of the patient by their relentless displacement of normal tissue, causing progressive impairment of function.·

13448b01

Normal Liver –·(left) ·and Cancer in the Liver (right)

This unfortunate patient presented in pregnancy with metastatic disease to the liver showing rounded discrete metastases in the liver on CTscan (a) confirmed at autopsy to be metastatic pancreatic carcinoma. The lesions in the liver (b) show a bile tinged green halo caused by local cholestasis caused by space occupation and obstruction. In c and d, the metastatic tumor (m) is seen to the left of the images, the middle layer of bile stained injured liver cells caused by cholestsais (ch) is seen as a subtle orange tinged section (c). The bile tinged layer (ch) is digitally enhanced in orange in d. Therelatively normal liver tissue (l) is seen to the right and is enhanced in with pink (d). code liver malignant cancer pancreatic primary pancreas bile tinge cholestasis space occupation bile stain CTscan grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved
02891c03.8s

45220 liver fx large hepatic mass dx colonic rectosigmoid carcinoma with hepatic metatsasis s/p stent placement CTscan Courtesy Ashley Davidoff MD 45220 45221 45222

Normal Liver and Single Group of Cancer Cells
Microscopic events described in the macroscopic examples above.· The left image shows normal liver cords at high power,
·
normal liver cords
13445 liver hepatocytes normal nodule Davidoff MD

The lower image shows slightly lower power of the liver cords in pink, and a blue, rounded, space occupying metastasis. ·· · 11440 liver hepatocytes normal metastasis adenocarcinoma histopathology nodule Davidoff MD

This specimen is from a biopsy of the liver. The medium power view of malignant adenocarcinoma shows groups of columnar cells arranged in rosettes in a bed of malignant stromal tissue and surrounded by normal liver. Although the nuclii in this case are not particulalrly enlarged the cytoplasm is basophilic, and the appearance is of a “squatter” in the liver, ie tissue that does not belong, is consistent with metastatic adenocarcinoma malignant cancer liver hepatic adenocarcinoma histopathology Courtesy Barbara Banner MD copyright 2009 all rights reserved GW question 5star

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liver colon large bowel liver fx hepatic mass fx fine stippled calcifications calcified mass dx metastattic mucin secreting adenocarcinoma of colon carcinoma metastasis CTscan Courtesy Ashley Davidoff MD 18370

liver CTscan imaging radiology mass dystrophic calcification calcified neoplasm mass metastasis malignant carcinoma adenocarcinoma cancer tumor 39484

51 year old male with history of rectal carcinoma with extensive hepatic metastases. (orange) The metastases surround gallbladder and by space occupation result in venous and lymphatic congestion causing a thickened edematous gallbladder wall (orange) with a small lumen (green) Tthe portal triad shows surrounding edema (white arrow). This is called periportal tracking which is another sign of venous and lymphatic engorgement. The metastases are calcified confirming the mucinous nature of the tumor. calcified metastasis in gallbladder fossa edema of the wall lymphatics contracted gallbladder CTscan copyright 2008 Courtesy Ashley Davidoff MD gallbladder liver portal triad 82313c01.8s

The gross and histopathological specimens are from the autopsy of a patient who died of breast carcinoma that was metastatic to the liver. The right lobe of the liver shows two patterns of metastases. In the posterior aspect of the liver there is diffuse disease, and in the anterior aspect there are innumerable nodules of varying sizes. The left lobe is relatively spared, and the pattern is of a nodular nature. The low power histopathological section shows a diffuse infiltrate of hyperchromatic malignant nuclii in the bottom of the image and relatively normal liver in the upper portion. code liver metastases metastasis breast primary cancer malignant space occupation infiltration infiltrative pattern right lobe left lobe grosspathology histopathology Courtesy Ashley DAvidoff MD copyright 2009 all rights reserved GW question 03034c.8s

The series is from a patient who died of metastatic adenocarcinoma. In image a, the ultrasound shows diffuse increased echogenicity in the dome of the right lobe of the liver that suggests diffuse infiltration of metastatic disease. the liver at autopsy showed a combination of diffuse infiltration and discrete nodules. It seems that the discrete nodules in this case become confluent to become infiltrative disease. The histolopathology in d shows discrete metastatic deposits of glandular type metastases separated by spaces within the lesion of mucus consistent with metastatic mucinous adenocarcinoma in a bed of malignant stroma. The distinct blueness and “badness of the malignant tissue is reflective of the hyperchromicity of the nuclii and their dominance in the cell. code liver metastases metastasis discrete diffuse ultrasound grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question The series is from a patient who died of metastatic adenocarcinoma. In image a, the ultrasound shows diffuse increased echogenicity in the dome of the right lobe of the liver that suggests diffuse infiltration of metastatic disease. the liver at autopsy showed a combination of diffuse infiltration and discrete nodules. It seems that the discrete nodules in this case become confluent to become infiltrative disease. The histolopathology in d shows discrete metastatic deposits of glandular type metastases separated by spaces within the lesion of mucus consistent with metastatic mucinous adenocarcinoma in a bed of malignant stroma. The distinct blueness and “badness of the malignant tissue is reflective of the hyperchromicity of the nuclii and their dominance in the cell. code liver metastases metastasis discrete diffuse ultrasound grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question

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39473 Courtesy Philips Medical Systems liver imaging radiology USscan

The ultrasound of the liver is from a 72 year old patient with metastatic breast carcinoma. There is a region overlaid in green ) that is hyperechoic and diffuse without clear nor rounded borders. No obvious mass or nodule can be defined. This finding represents the less common infiltrating metastatic pattern characteristically, but not exclusively observed in patients with breast carcinoma. code liver cancer malignancy malignant carcinoma metastasis infiltrating infiltrative US USscan ultrasound Courtsy Ashley DAvidoff MD copyright 2009 all rights reserved 24012c01.8s

CYSTIC METASTASES from CARCINOID + fx mass + complex cystic solid metastasis dx carcinoid tumor + imaging radiology CTscan C- mass neoplasm malignant metastasis carcinoma cancer tumor Courtesy Ashley Davidoff MD 20912

20912 liver + fx mass + complex cystic solid metastasis dx carcinoid tumor + imaging radiology CTscan C- mass neoplasm malignant metastasis carcinoma cancer tumor Courtesy Ashley Davidoff MD

The autopsy series is from an elderly female who died with metastatic ovarian carcinoma. The CTscan (a) shows a focal hypodensity at the edge of the right lobe of the liver that was shown to be a metastasis. There is ascites around the spleen. Image b shows a white patch on the liver capsule in the region of the CT finding. Image c shows metastatic disease on the diaphragm characterized by a white rind of malignant tissue. (orange arrow). The histipathology shows three layers of tissue with normal liver at the bottom, the capsule in the middle and the matastatic deposit on the edge of the capsule. liver capsule ovary metastasis malignant primary cancer metastases transpertoneal spread of disease diaphragm Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question 02996c02.8s

liver + lymph nodes lymphatics+ lymphatic drainage portal triad + fx normal + anatomy + imaging radiology CTscan 24776 R W c

Courtesy Ashley Davidoff MD code pancreas + dx carcinoma code abdomen fx abdominal ascites spleen stomach liver gastrolienal ligament lesser omentum gastrohepatic ligament masses metastasis abdomen + imaging radiology CTscan primary pancreas neoplasm malignant carcinoma cancer tumor

20115c

liver + capsule + spleen fx mass nodule + fx calcification + calcified dx pseudomyxoma peritonei + imaging radiology CTscan 22993

56 year old male with gastric carcinoma and T2 weighted MRI that shows diffuse infiltration of metastic disease (areas of increased water (white) are abnormal and the darker areas are normal liver. The liver is almost totally replaced by diffuse metastases. The histopathology shows an infiltrative patternof dark tissue caused by hyperchromatic nuclii and diminished basophilic cytoplasm. The pink cells in between represent the normal liver. code liver metastases metastasis stomach primary gastric metastases to liver hepatic infiltrative malignant malignancy cancer MRI T 2 weighted image histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved 03146c.8s

51 M hepatic bare area liver abdomen ascites fx mass fx stippled calcification calcified fx psammomatous psamomatous calcifications dx metastattic mucinous adenocarcinoma of the rectum CTscan soft tissue windows Davidoff MD 22359 22357.800

diaphragm liver porta hepatis gastrohepatic ligament Glissons capsule + fx calcification + primary ovary + metastasis + imaging radiology CTscan neoplasm malignant carcinoma tumor cancer 16868

spleen + capsule + fx calcification + metastatic primary ovary + carcinoma + imaging radiology CTscan C- liver Glisson’s capsule ligamentum venosum + fx calcification falciform ligament ligamentum teres fx calcium calcified dx metastatic primary ovary neoplasm malignant metastasis metastases cancer tumor abdomen peritoneum peritoneal cavity calcium deposit calcification calcified punctate ascites neoplasm malignant metastasis metastases cancer tumor 20893

liver metatstasis primary ovarian cancer adenocarcinoma psammomatous calcifications psammoma bodies glandular malignancy histopathology Davidoff MD 03779.800

03779.800

03779.800 liver metatstasis primary ovarian cancer adenocarcinoma psammomatous calcifications psammoma bodies glandular malignancy histopathology Davidoff MD

code spleen + capsule + fx calcification + metastatic primary ovary + carcinoma + imaging radiology CTscan C- liver Glisson’s capsule + fx calcification + metastatic primary ovary gastrohepatic gastrolienal falciform ligament ligamentum teres fx calcium calcification dx metastatic primary ovary neoplasm malignant metastasis metastases cancer tumor 20886

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20886 code spleen + capsule + fx calcification + metastatic primary ovary + carcinoma + imaging radiology CTscan C- liver Glisson’s capsule + fx calcification + metastatic primary ovary gastrohepatic gastrolienal falciform ligament ligamentum teres fx calcium calcification dx metastatic primary ovary neoplasm malignant metastasis metastases cancer tumor

liver + fx psammomatous calcification + dystrophic calcification calcium metastatic primary ovary ovarian carcinoma + cytopathology 03780

The images show a series of 4 images that reveal a metastaic lesion in the liver from a primary colon carcinoma. The lesion is about 2.5cms in size, has rounded pseudopod like advancing edges (best seen in image b – CT and image C MRI), is situated in the superior aspect of the right lobe of the liver and appears to have a complex nature. The through transmission seen in the ultrasound (a), the low density seen in the CT(b) and brightness on T2 (d) suggest complex fluid. The bright central region and bright lobulated rim on T1 (c) suggest mucin and or hemorrhage. liver hepatic mass a= US through transmission b= CT hypodense lesion c = T1 weighted cental intensity rim and matrix of low intensity periphery hyperintense d = T2 weighting = T2 bright fx metastattic colon carcinoma mucin secreting adenocarcinoma with central hemorrhage peripheral hemorrhage USscan CTscan MRIscan Davidoff MD copyright 2009 all rights reserved 03028c01

Liver metastases Impinging on the IVC resulting in Budd Chiari Syndrome
Courtesy Ashley Davidoff MD code pancreas + fx mass endocrine tumor + code liver capsule fx mass dx metastasis code IVC fx stent dx obstruction Budd Chiari imaging radiology CTscan neoplasm tumor carcinoma cancer
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Tumor Thrombus in the Hepatic Vein
liver hepatic vein fx tumor thrombus lung fx consolidation dx infiltrative adenocarcinoma of the lung with metastases to the liver and adrenal and invasion of the hepatic veins malignancy cancer Davidoff MD 46581 46588 46587

The collage consists of a CT scan (a) showing a focal well circumscribed low density liver lesion. Biopsy of this lesion yielded the histopathological specimen (b) that shows hyperchromatic nuclii and spindle shaped cells consistent with metastatic leiomyosarcoma. The cytological aspirate (c) shows spindle shaped nuclii with pleomorphism and hyperchromicity. code malignant cancer sarcoma histopathology CTscan Courtesy Ashley Davidoff MD copyright 2009 all rights reserved 03057c01.8s

liver focal filling defect lymph nodes retrocrural enlarged dx lymphoma CTscan imaging radiology periportal tracking 22068

This series is from a patient who died with diffuse histiocytic lymphoma and DIC. The CT scan (a) shows hepatosplenomegaly with a low density liver suggestive of steatosis. The grosspathology specimen shows an enlarged liver with punctate hemorrhages. The low power histopathology shows a diffuse inflitration of dark nuclii reminiscent of a malignant infiltration, and the high power shows fatty vacuoles within the cytoplasm of the hepatocytes and an infiltrate of histiocytic appearing cells with increased nuclear cytoplasmic ratio (d). liver fatty change steatosis malignant cancer histiocytic lymphoma DIC metastases metastasis CTscan grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question 03172c01.8s

Liver Metastases Before and After Therapy
liver metastatic small lung carcinoma with diffuse metatstattic disease to the liver )hepatic metastases metastasis before and after treatment 6weeks post chemotherapy successful result size change character change CTscan Davidoff MD 5star 70248c01

Carcinoma – Extending into the Liver via the Gallbladder Fossa

Direct Invasion into the Liver and Bile Duct Obstruction
The CTscan of this patient shows a normal sized gallbladder (green) associated with a 4-5cms mass (orange) adjacent to the gallbladder, and extending from the gallbladder fossa. There is asssociated biliary obstruction (dark green tubes)· This case represents invasive gallbladder carcinoma with bile duct obstruction. Images c and d show the almost universal association of gallstones in patients with carcinoma.···In this case the stones (white) are in the centre of the gallbladder. (green)
·16254c03.8s gallbladder anterior wall liver invasion space occupatopn obstruction bile ducts aggressive gallbladder carcinoma complicated by direct invasion metastasis liver windows narroe windws tumor settings gallbladder fossa GBF CTscan Courtesy Ashley Davidoff copyright 2008

Dystrophic Calcification – Carcinoma of the Gallbladder Extending into the Gallbladder Fossa
The non-contrast CT of the 75year old female patient, shows dystrophic calcification·in a mass that seems to be part of the wall of the gallbladder.· The·mass extends into the liver.· These findings are consistent with an inoperable gallbladder mucinous adenocarcinoma, metastatic to the liver by direct extension.· Calcification of adenocarcinomas is usually found in the mucinous variant of the disease.
24404c.8s 75 female gallbladder calcification adjacent mass in the liver local invasion into the gallbladder fossa dystrophic calcification probably mucinous adenocarcinoma of the gallbladder carcinoma stones cholelithiasis hydronephrosis

Carcinoma – Extending into the Liver via the Gallbladder Fossa and Additional Metastases

Local Invasion and Separate Liver Mestastasis
The CTscan in this patient shows two calcified gallstones in the gallbladder (green), with a mass like malignant abnormality extending into the liver on either side (yellow) and a remote metastasis (orange) which is deforming the liver edge.
17280c02b01.8s gallbladder liver mass local invasion cholelithiasis metastasis carcinoma primary gallbladder gallbladder fossa Courtesy Ashley Davidoff MD copyright 2008

Disease Extension Beyond the Liver·

introduction, liver, malignant, neoplasm, primary cancer

Liver Hepatocellular Carcinoma Introduction

Liver Cancer

Ganesh Athappan MD Ashley Davidoff MD

Definition

Liver cancer is an aggressive growth disorder initiated by a cell or a group of renegade cells, either as a primary event in the liver, but commonly as a metastatic diesease. As a primary event, the usual causes include spontaneous genetic aberration, a carcinogen in the environment, or less commonly by an inherited genetic abnormality.

The structuralchanges are characterized by proliferation and space occupation of non functioning tissue, with a variety of macroscopic morphologies, but often characterized at a cellular level by large hyperchromatic nuclii with diminished cytoplasm.

Functionally the rebel cells and cell group parasitize nutrition and oxygen, but do not contribute to the overall function of the mother organ, in this case the liver, or to the community at large.

The disease is complicatedby local spread within the organ and surrounding tissues, displacing well meaning and well functioning tissue. Continued uncontrolled growth results in the invasion of blood vessels and lymphatics and spread to distant organs where metastatic disease repeats the pattern of continued advance of rebellious parasitization on normal tissue. Other local complications include bleeding, necrosis, and obstruction. Systemic and non specific complications include fatigue, weight loss, night sweats and pain

The diagnosis is suspected clinicallywhen a patient presents with unexplained weight loss, or a new mass is felt on clinical examination.

Imagingcharacteristics include finding a mass, often multicentric, characteristically round or infltrating, that shows evidence of local invasion and or metastatic disease. When cancer is suspected, pathological confirmation is almost universally indicated to confirm the diagnosis, and to evaluate and classify the type and virulence of the cancer. Types of biopsy include aspiration technique where individual cells are sucked up into a needle, core biopsy where a cutting needle provides a small sample of tissue, and incisional biopsy where a part of a lump or a sample is removed using a scalpel.

Staging the disease is essential in the diagnostic workup since treatment plans depend on the extent and location of the disease.

Treatmentoptions depend on staging of the cancer. In the early stages the goal of treatment is cure and may include surgical resection. In advanced stages the role of treatment is control of disease and prolongation of life. This may include surgery, chemotherapy and radiation. Recent advances include localized chemical ablation with alcohol for example, or thermal or electrical ablation.

Liver Cancer Occupying Space Distorting Structure and Function

The liver is a vital structure, and is considered the metabolic warehouse of the body. The image reflects it 24/7, clockwork nature processing churning and producing products for ongoing metabolism. The growth of any tumor in the liver will distort structure and affect function. This image reflects a large tumor throwing a “spanner” in the wheels of production.

Space Occupation in the Liver

The gross pathology specimen shows malignant tissue (white) occupying at least 80% of the normal liver parenchyma (red). The liver has remarkable tolerance for space occupation before showing ill effects, and also has remarkable regenerative capabilities. In this instance the disease was caused by metatsatic disease. Even the liver in this instance could not tolerate the degree of invasion, and the patient finally succumbed to the disease.

12362 liver fx masses dx metastatic carcinoma of the breast + grosspathology Courtesy Ashley Davidoff MD

Hepatic cancer has varied origins including those that arise primarily from liver elements, and those are metastatic deposits.

The tumors that arise from liver elements include

hepatocellular carcinoma

cholangiocarcinoma

hepatoblasoma

liver sarcoma

malignant hemangioendothelioma

Metastatic disease most commonly originates from a primary colon, lung, breast or pancreatic cancer, and less commonly from less common tumors such as gastric , duodenal, carcinoid malignancies. Capsular metastases are most common form primary ovarian carcinoma.

Structural Principles Liver Cancer

Liver cancer arises from a single cell that for whatever reason assumes a different, and aggressive profile with an agenda and a time cycle that does not conform to the norm, but has the abillity to generate new cells of a similarly aggressive nature.

Proliferation of a Malignant Cell with an Aberrant Sense of Time and An Aggressive Agenda

The image represents the life of a single set of cancer cells showing a progressioon of generations as the cell lives, dies and is regenerated. The orange products of the cell are seen in the background of the pink cytoplasm and the purple nucleus. The nucleus of the newest generation . Thecell is seen as a clock that has become distorted and time has become disordered. This process is abnormal and is a forerunner of a malignant process.

Abnormal Programming Multiplication and Space Occupation

The image represents the evolution of a single cancer cell (a) that fails to conform to the normal time cycle. In image a, the normal columnar mucosa is composed of rectangular cells supported by a thin purple basement membrane. One cell becomes aberrant, and is characterized by a large blue nucleus, scanty cytoplasm and a a change in it shape and overall appearance. The cell grows, multiplies, (b,c,d) and then invades the space of other parts of the tissue around it.

The structure of the liver cell and its organization as a tissue is quite unique so that although the end result of space occupation, and uncontrolled proliferation are common to other cancers, it is unique in many of its structural consequences as a result of unique architecture.

Structural Considerations

Normal Liver Histology

The parenchyma of the liver is a glandular epithelium, and the cells are aligned as plates or cords, radially arranged and separated by hepatic sinusoids making up a portal lobule and bounded by portal triads (radicles of the portal venous, hepatic arterial and bile duct systems).

The Cells

The dominant cell of the liver is the hepatocyte. The hepatocytes constitute approximately 70% of the liver by volume. It is therfore not surprising that most the primary liver cancers arise from this cell.

The hepatocyte is structurally characterised by its large size measuring between 20-30 microns, and the absence of a basement membrane, functionally characterised by their remarkable metabolic and regenerative capability. They characteristically respond to injury, whatever its type, by accumulating fat in the cytoplasm, an entity called steatosis.

The cell

The cell is the building block of all biological structure. In this image a few almost hexagonal cells of the liver are attached together. Each cell has a central dark nucleus which is embedded in a pinkish cytoplasm. The nucleus takes up approximately 1/5 to 1/6 of the volume of the cell and usually lie in the center of the cell. Binucleate cells are normal and account for up to 25% of the cells. There is also considerable variation in the size of the nucleus from cell to cell. The red cells seen in the background are about 5 microns, and the liver cell is about 4 to 5 times their size. (Image courtesy of Barbara Banner M.D.) 13440

The Tissue

The liver is a compound tubular serous gland. The cells are aligned in cord formation that branch and anastomose alongside and in parallel with a vascular system called the sinusoids. These plates are arrranged like spokes of a wheel around a central vein which is a tributary of the hepatic veins. Kupffer cells are found within the space of Disse between the plates of cells and the sinusoids.

Cells Align and Combine in Cords of Tissue Separated by VAscular Channels Called Sinusoids

The cells of the liver are organized in cords and plates and are distributed like spokes of a wheel around the central vein. The plates and cords(red overlay in b) are lined by the sinusoids (white channels between the cords) which are the channels which carry blood to and through the liver. Just below the sinusoids, between the wall of the sinusoid and the capsule of the liver there is a space called the space of Disse which carries the lymphatic fluid of the liver. Spindle shaped cells that are macrophages called Kupffer cells (ringed in blue) line the sinusoids and are related and integrated into the space of Disse.

The liver lobule is a structural and functional unit of the liver. At its centre is the central vein and it is bounded by several portal triads consisting of a hepatic arterial tributary, a portal venous branch, and a biliary radicle. The hepatic arteriole, and portal venule bring blood to the lobule and join to form the sinusoid that runs between the plates of hepatocytes. The biliary radicle takes bile away from the smaller branches of bile ductules that lie between the hepatocytes.The lobule is polyhedral in shapeand has a wheel like formation as described above with spokes of hepatocytes and sinusoids radially positioned around the central vein, and supported by connective tissue. It is functionally characterised by its ability to synthesis metabolically active substances and also by its ability to break down products (cataboloic activity), and by its ability to particpate in defense mechanisms and filtering mechanisms of the body.

The primary blood flow to the liver is via the portal vein which receives mesenteric blood flow which enters the lobules as the portal vein radicle in the portal triad. The radicles of the hepatic artery bring oxygenated blood to the liver, and bile ducts take bile to the duodenum via the gallbladder and common bile duct to facilitate fat digestion. Metastatic deposits that are hematogenously spread are therefore brought to the liver as a first stop if they are transported by the mesenteric veins. It is therefore no surprise that the liver is the most common site for metastatic colon carcinoma.

The Liver Lobule

The sinusoids and hepatic cords combine to form a liver lobule which is a functional and structural unit of the liver. At the center of the lobule is the central vein (royal blue) from which emanate many cords of liver tissue. At the periphery of the lobule there are 4-5 groups of portal triads consisting of distal branches of the portal vein (dark blue), hepatic artery (red) and biliary radicle (green). They create the border of the lobule.

(Image courtesy of Ashley Davidoff M.D.) 13009 W

There are 3 zones within a liver lobule. Zone 1 is closest to the periphery of the lobule and portal triad, zone 2 is the intermediate zone, and zone 3 is in the centre of the lobule abutting the terminal hepatic venule. Zone 3 is the most vulnerable since it is furthest away from the oxygenated blood.

Each lobule measures 1-2mm in size, hexagonal in shape, is metabolically very active, and has tremendous regenerative capacity. The cells are exposed to gastrointestinal products of digestion that are absorbed into the blood, and traansported to the liver by the superior mesenteric vein which empties into the portal vein. Alcohol for example is transported to the liver via this system, and when taken in excess for long periods exposes the liver cells to its toxic effects causing cirrhosis, and eventually, in some patients resulting in dysplastic and finally to malignant neoplastic change.

The Cells, The Plates, The Sinusoids and The Kuppffer Cells

The liver cells (purple) are aligned in plates, with bile canaliculi(green) running between them.· The Kupffer cells (yellow nuclii and black cytoplasm) run alonside the hepatocytes, and between the sinusoids (maroon) and the liver cells.· As the blood enters the sinusoids (maroon arrow) the cells absorb the products of digestion (yellow arrow) metabolise the products, and then export the new product back into the blood (orange arrow).· The Kuppffer cell acts as a macrophage and engulfs any foreign material, organisms,·or “debris” in the blood and acts as a defense mechanism.

13062b05b04.8 liver hepatocyte sinusoid Kupffer cell space of Disse bile canaliculus import export excrete transport portal blood hepatic arterial blood metabolism process receive export excrete Davidoff MD Davidoff art

The sinusoids terminate at the central vein, each a part of the liver lobule. They converge with other central veins, to form the 3 major hepatic veins which transport the nutritionally rich blood to the right atrium via the inferior vena cava.

Lobules

There are a multiplicity of lobules, each with a central vein and each delivering the “goods” to venules, which collectively join to form the hepatic veins and then into the IVC. Destination? The heart, from where it will be distributed to the body wide system. (Image courtesy of Ashley Davidoff M.D.)

The Connective Tissue

The mesenteric extension of the lesser omentum to the liver is called the gastrohepatic ligament and it contains extensive lymphatic networks. The liver capsule also extends toward the porta hepatic to surround the portal triad. As they converge on the porta hepatics they create a sheath around the portal triad, and incorporate the lymphatic with them. As the vessels divide they carry with them a sheath of connective tissueenvelope.

Tumor that is within the lymphatics such as that from a primary gastric carcinoma will be swept within the lymphatics into th liver. Additionally it is also the route of spread of cancers that have spread into the peritoneum. Ovarian cancer is the primary and most common malignancy to spread this way.The capsule

The capsule that surrounds the portal triad structurally characterized being the intrahepatic extension of the liver capsule consisting of serosal outer and fibroelastic inner capsule. It also forms a loose capsule around the liver lobule. Functionally characterised as a support and protective barrier for the portal triad and the liver lobule serving to support the fine reticular network within the lobule disease from the peritoneal cavity may spread within the portal triad within the lymphatics, or within its spaces.

The Capsule of the Liver, Gastrohepatic Ligament, and Glissons Capsule

The gastrohepatic ligament (gh)connects the liver and the stomach not only as a ligamentous connection but also with lympfatics, as well as the portal triad ehich run on its free edge. In this diagram only the file duct is shown (green)It extends and connects to the liver capsule (white covering) around the liver, but also into and around the portal triads within the liver. These ligaments, with lymphatics are an important rourte of spread of disease such as gastric malignancy and ovarian malignancy which tends to spread transperitonealy.

Lympahtic Connections Around the Portal Triad and Capsule

The lympatic drainage of the liver and connective tissue are intimately related, and is another map of how cancer of the ovary spreads into and around the liver from the peritoneal cavity.

24776 R W c liver + lymph nodes lymphatics+ lymphatic drainage portal triad + fx normal + anatomy + imaging radiology CTscan

The connective tissue of the liver consists of fine reticular networks that bind the liver cells together in a delicate weave

Reticular Fibers of the Liver

The fine reticular elements of the liver shown as black strands in this reticulin stain weave a fine but binding infrastructure of the liver cells.

13236 liver hepatocyte liver cords sinusoids cytoplasmic granules connective tissue reticulin histopathology histology Courtesy Barbara Banner MD

Segments of the Liver

It is important to be familiar with the surgical anatomy of the liver since accurate positional descriptions of liver lesions are needed for the mapping of surgery, and determining operability and requires universal acceptance so that anatomists, pathologists, radiologists, hepatologists and surgeons are referencing the disease accurately.

There have been numerous methods of dividing and naming the parts of the liver. The earliest methods divided the liver into the left lobe, the quadrate lobe, the right lobe and the caudate lobe. Subsequently, the liver divisions were based on the venous anatomy. The right lobe was separated from the left by the middle hepatic vein. The falciform ligament divided the left lobe into the medial segment (closest to the middle hepatic vein) and the lateral segment. The right lobe was divided by the right hepatic vein into an anterior segment and a posterior segment. The next several diagrams outline the current segmental nomenclature which is still based on the distribution of the hepatic veins: Segment I = caudate lobe Segments II, III & IV = left lobe Segments V, VI, VII & VIII = right lobe

Segments of the liver

This coronal image shows the division of the liver into right and left lobes, by the middle hepatic vein (blue), and the division of the right lobe into its superior and inferior segments and the division of the left by the cfalciform ligament (green) into its segments. (Image courtesy of Ashley Davidoff M.D.)

Segments of the liver

The following cross sectional image is viewed through the superior aspect of the liver with the hepatic venous system in color overlay. The right hepatic vein divides the right lobe into a posterior segment VII and an anterior segment VIII. The left hepatic vein divides the left lobe in the expected location of the falciform ligament into a rightward subsegment IVa and leftward II and III. (Image courtesy of Ashley Davidoff M.D.)

The following image reveals the cross sectional segmental pattern at the level of the porta hepatis.

Segments of the liver

Note that the falciform ligament anteriorly divides the left lobe. (Image courtesy of Ashley Davidoff M.D.)

Segments of the liver

This image demonstrates the royal blue IVC, posterior to the caudate lobe (I), the dark navy blue portal vein anteriorly, the green line and yellow dot indicating the position of the falciform ligament, the thick blue line of the middle hepatic vein and the thin blue line of the right hepatic vein. Since we are seeing the inferior aspect of the liver we are thus seeing segments V and VI of the right lobe, subsegment IVb and segments II and III of the left. (Image courtesy of Ashley Davidoff M.D.)

Segment VIII Liver Lesion

It is usual that in order to accurately locate the lesion that all the axial images have to be reviewed so that the relationship to all the veins is defined.

16487 liver hepatic fx mass fx hypervascular almost isodense HCC hepatoma hepatocellular carcinoma CTscan Courtesy Ashley Davidoff MD

The caudate lobe (also known as segment I) is positioned medial to the right lobe and posterior to the left lobe. It is bounded inferiorly by the porta hepatis, posteriorly by the inferior vena cava, anteriorly by the portal vein and more superiorly and anteriorly by the by the ductus venosus. The caudate lobe is a rather curious structure, situated almost as an appendage to the liver. A unique characteristic is that its venous drainage flows directly and independently to the inferior vena cava below the diaphragm. As previously stated, it belongs neither to the left nor the right lobe, and it is considered as an “independent” segment.

Hepatocellular Carcinoma

Hepatocellular (HCC)·carcinoma is a primary malignancy of hepatic parenchymal cells, characterized by space occupation and malignant proliferation of aberrant liver cells, with a tendency to invade veins,·with a·predisposition to multicentricity·that usually develops in patients with risk factors·of·alcohol abuse, viral hepatitis, and metabolic liver disease.

The disease is often clinically silent in the early stages unless it involves the capsule when it will resultin pain.·Continued clinical attention is paid to to·patients who have a history of alcoholoc cirrhossis, or a history of hepatitis b or c.· These patients are usually followed carefully, and are intermittantly screned for the development of hepatocellular carcinoma (hcc).· A rise in the serum level of alpha fetoprotein is particulalrly concerning.· As the tumor ot tumors advance in the liver, systemic symptoms such as malaise, fatigue, weight loss, fever of unknown origin, and hepatomegaly.··Less common presentations include hepatic rupture with hemoperitoneum.

The diagnosisis made by elevated serum alpha fetoprotein, or by imaging studies which include ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI).··

Surgical resection and liver transplantation remain the mainstay of curative therapy. The results of the various medical treatments (chemotherapy, chemoembolization, ablation, and proton beam therapy) remain disappointing. Untreated HCC carries a poor prognosis and is directly related to tumour stage and degree of cirrhosis.

According to the classification by the International Working Party of the World Congress of Gastroenterology, hepatic nodules in patients with chronic liver diseases are subdivided into regenerative nodules (mono acinus and multi acinus), low-grade dysplastic nodules, high-grade dysplastic nodules, well-differentiated HCC, moderately- differentiated HCC, and poorly-differentiated HCC, in an ascending order of histologic grades, representing a sequence of multistep hepatocarcinogenesis.

Regenerative nodules represent focal proliferation of hepatocytes in response to various injurious stimuli. They can be classified as micronodular (<5 mm) or macronodular (>5 mm). Their blood supply is from the portal vein and hence they show an enhancement pattern similar to the normal liver parenchyma. Some nodules may contain iron (siderotic nodules) and these have a greater propensity towards dysplasia.

Dysplastic nodules are premalignant and contain atypical hepatocytes without definite features of malignancy on histology. According to the severity of the cellular atypia, they can be low grade or high grade and can undergo malignant transformation in a short duration of 4 months. They receive their blood supply from the portal vein and are hypovascular. However, occasionally they can have increased arterial flow.

HCC may be solitary, multifocal or diffusely infiltrative. Small HCC (<3 cm) are usually well differentiated whereas larger and diffuse HCC are poorly differentiated. They receive their blood supply mostly from the hepatic artery although rarely portal venous supply may be noted. Fibrous capsule and fat may be noted in well differentiated HCC thus differentiating them from dysplastic nodules. Fibrous septa, necrosis, hemorrhage and invasion of veins and bile ducts can also be present.

On gross pathology HCC may show 3 different patterns :

Nodular form – single or multiple with or without a capsule
Massive form -appears as an infiltrative mass in noncirrhotic livers
Diffuse form – miliary infiltration of the liver parenchyma .

Cellular Changes

Histologically there are four different architectural types of HCC .

Trabecular type – is the most common type
Pseudo glandular type
Solid
Scirrhous or sclerosing type

Cytologically the cells of HCC exhibit varying degrees of hepatocellular differentiation. Histological criteria in favor of HCC include prominent nuclear atypia, high nuclear to cytoplasmic ratio with nuclear density twice normal, plates 3 or more cell thick , numerous unaccompanied arteries , mitoses in moderate numbers and invasion of stroma or portal tract .

Cause and Predisposing Factors

Cirrhosis from any cause is the seed-bed of HCC. The risk varies according to the aetiology of the cirrhosis.

Hepatitis B Chronic infection with this virus is the most common cause of hepatoma worldwide.
Hepatitis C As potent an oncogenic virus as HBV but less prevalent. Usually requires 25 years of chronic infection to cause tumour.
Alcoholic liver disease Oncogenic potential probably mediated by inflammation and cirrhosis. May be augmented by concurrent viral infection.
Haemochromatosis -Iron overload, Untreated genetic haemochromatosis is an especially severe premalignant state.
Tyrosinaemia HCC occurs in 37% of patients who survive to 2 years of age and may occur in patients who have had successful liver transplants
Oral contraceptives Absolute risk of developing HCC very small.
Anabolic steroids Case-reports suggest a small increased risk for HCC

Genetic

Chromosomal abberations have been frequently reported in HCC.· Amplifications of the chromosomes are noted in 1q, 8q, 6p, and 17q. Among the chromosomes most frequently lost in HCC are 8p, 16q, 4q, 17p, and 13q. These chromosomal regions contain key players in hepatocarcinogenesis such as p53 (chromosome 17p) or Rb (chromosome 13q).

Genes involved in important regulatory pathways are the targets of these mutations. Four main pathways can be distinguished

• The p53 pathway involved in DNA damage response and apoptosis,

•The b-catenin/APC pathway involved in intercellular interactions and signal transduction

•The TGF-b pathway involved in growth inhibition and hepatocyte death

• The RB1 pathway involved in cell cycle control.

Connections between these different pathways are most probable.

Carcinogens

Plant carcinogens: Aflatoxins produced by fungi Aspergillus flavis and A. parasitans are well recognized to cause severe hepatic injury.These fungi grow readily on grains, peanuts, and food products in the humid subtropical and tropical regions.Higher HCC mortality rates have also been found in people who drink pond-ditch water contaminated with the blue-green algal toxin microcystin, the toxin also causes hepatic hemorrhage and necrosis.

Chemical carcinogens :DDT,Nitrites, hydrocarbons, solvents, organochlorine pesticides, primary metals, and polychlorinated biphenyls have been implicated as potential carcinogens.

Pathophysiology and Pathogenesis

Result

Potential Complications

Natural History

03539

03539 liver hepatocytes fx enlarged HCC hepatocellular carcinoma hepatoma histopathology Courtesy Ashley Davidoff MD

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13447 liver HCC hepatocellular carcinoma cytopathology

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48369c03 40 male with hepatitis B liver fx hypervascular lesion seen in early arterial phase only with rapid wasout dx HCC hepatoma hepatocellular carcinoma capillary hemangioma characterisation characterization blood flow CTscan MRI Courtesy Ashley DAvidoff MD

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03503 liver mass fx fat fatty change within the lesion intracytoplasmic fat HCC hepatocellular carcinoma hepatoma histopathology Courtesy Barbara Banner MD

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03760 liver fx hepatic mass echogenic heterogeneous HCC hepatocellular carcinoma hepatoma dx hemochromatosis dx fat in the lesion USscan Courtesy Ashley Davidoff MD

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03762 liver fx hepatic mass fx question capsule lobular contours HCC hepatocellular carcinoma hepatoma dx hemochromatosis iron overload hemosiderosis grosspathology Courtesy Barbara Banner MD

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03763 liver fx hepatic mass fx fat steatosis HCC hepatocellular carcinoma hepatoma dx hemochromatosis iron overload hemosiderosis histopathology Courtesy Barbara Banner MD

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03764 liver fx hepatic mass fx fat fx capsule steatosis HCC hepatocellular carcinoma hepatoma dx hemochromatosis iron overload hemosiderosis histopathology Courtesy Barbara Banner MD

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03765 liver fx hepatic mass fx fat fx positive for iron steatosis HCC hepatocellular carcinoma hepatoma dx hemochromatosis iron overload hemosiderosis histopathology Courtesy Barbara Banner MD

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24008 liver fx mass portal vein fx invasion satellite nodule multicentric dx hepatocellular carcinoma hepatoma HCC grosspathology Courtesy Barbara Banner MD

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16486 liver + fx mass + hypervascular arterial phase HCC hepatocellular carcinoma + imaging radiology CTscan C+

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71 year old male with chronic alcoholism 40417c Courtesy Ashley Davidoff MD code liver left lobe fx mass code spleen fx multiple masses code pancreas pancreatic body fx mass code dx primary HCC hepatoma hepatocellular carcinoma complicated by metatstatic disease to the spleen and pancreas imaging radiology MRI T1 T2 neoplasm malignant carcinoma tumor cancer

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20860 spleen + fx heterogeneous masses nodules water T2 bright nodules masses enhancement dark dx HCC metastasis primary liver irregula cirrhosis mass + hepatocellular carcinoma + imaging radiology MRI T2 neoplasm malignant cancer tumor

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19675 liver mass fx hypervascular mass early arterial phase arteriovenous shunting A-V shunting hepatpoma HCC hepatocellular carcinoma angiogram arteriogaphy angiography Courtesy Ashley Davidoff MD

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03552 liver fx hypervascular mass HCC hepatocellular carcinoma hepatoma angiogram amgiography Courtesy Ashley Davidoff MD

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19681 liver mass fx hypervascular mass early arterial phase hepatpoma HCC hepatocellular carcinoma angiogram arteriogaphy angiography ethiodol injection fx ethiodol accumulation Courtesy Ashley Davidoff MD

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19678 liver fx mass post ethiodol injection fx ethiodol accumulation hepatpoma HCC hepatocellular carcinoma CTscan Courtesy Ashley Davidoff MD

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19543 liver + fx mass + malgnant ethiodol + imaging radiology CTscan neoplasm malignant cancer tumor

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03751 liver fx mass fx capsule HCC hepatocellular carcinoma hepatoma histopathology Courtesy Barbara Banner MD

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03750 liver fx hepatic mass HCC hepatocellular carcinoma hepatoma grosspathology Courtesy Ashley Davidoff MD

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82709c01.8s 60M liver HCC hepatocellular carcinoma portal vein thrombosis hepatic vein thrombosis cavernous transformation of the portal vein gallbladder varicosity ascites CTscan Courtesy Ashley Davidoff MD copyright 2008 CTscan

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03239 liver hepatocellular carcinoma dx HCC infiltating infiltrative grosspathology Courtesy Ashley Davidoff MD

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03240 liver hepatocellular carcinoma hepatocellular carcinoma dx HCC infiltating infiltrative dx HCC

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03486 liver HCC infiltrative infiltrating hepatocellular carcinoma hepatoma Courtesy Ashley Davidoff MD

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03492 liver HCC hepatocellular carcinoma infiltrative infiltrating hepatoma nuclear medicine NM liver spleen technetium scan

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03573 liver fx hepatic mass fx capsule HCC hepatocellular carcinoma hepatoma MRI T1 Courtesy Ashley Davidoff MD

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03274 liver fx mass fx dense dx hemorrhage hemorrhagic hepatocellular carcinoma dx HCC CTscan Courtesy Ashley Davidoff MD

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03271 liver hepatocellular carcinoma dx HCC hemorrhagic nodule grosspathology Courtesy Ashley Davidoff MD

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03463 liver fx mass portal vein fx invasion dx HCC hepatocellular carcinoma hepatoma histopathology Courtesy Barabara Banner MD

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19547 liver + vein + portal invasion portal vein thrombosis multicentric hcc + hepatocellular carcinoma liver fx irregular dx cirrhosis spleen mild enlargement splenomegaly abdomen abdominal ascites imaging radiology CTscan neoplasm primary carcinoma malignant cancer tumor

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22446 liver hepatic artery portal vein fx arterial portal shunting fx retrograde filling of the portal vein fx portal vein thrombosis PVT dx hepatocellular carcinoma HCC hepatoma angiography Courtesy Ashley Davidoff MD

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03427 60 M liver hemachromatosis iron overload fx mass enhancing dx HCC hepatocellular carcinma clear cell Courtesy Ashley Davidoff MD

Natural History

HCC presents in three principal ways

A right-upper- quadrant mass,
A worsening of the general health of a patient with cirrhosis
Asymptomatically as a result of a radiological examination

Diagnosis·

Clinical Approach

Presentation depends on the stage of disease. In countries with systematic screening programs (Taiwan, Hong Kong, Japan and Korea) HCC is often diagnosed at an early stage when patients are asymptomatic or have symptoms due only to the underlying disease. In the United states, there is no systematic screening for HCC, patients usually present at a late stage, often with abdominal pain, palpable RUQ mass, weight loss, weakness, abdominal fullness and swelling – ascites, and nausea. Suspicion for HCC should be heightened when patients with compensated cirrhosis develop signs of decompensation. Jaundice due to obstruction of the intrahepatic ducts by the underlying liver disease or rarely due to hemobilia is relatively uncommon but ominous. Abdominal swelling may occur as a consequence of ascites due to the underlying chronic liver disease or may be due to a rapidly expanding tumor. In fewer than 5% of cases, central necrosis or acute hemorrhage into the peritoneal cavity leads to death. Hematemesis may occur due to esophageal varices from the underlying portal hypertension. Bone pain is seen in 3-12% of patients, but necropsies show bone metastases in ~20% of patients.

The triad of abdominal pain, weight loss and an abdominal mass is the most common clinical presentation in the United States.

Physical Signs Hepatomegaly is the most common physical sign, occurring in 50-90% of patients. Abdominal bruits are noted in 6-25%, and ascites occurs in 30-60% of patients. Ascites should be examined by cytology. Splenomegaly is mainly due to portal hypertension. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors. Fever is found in 10-50% of patients, from unclear cause. The signs of chronic liver disease may be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema. Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins; it should be suspected in patients with tense ascites and a large tender liver.

Paraneoplastic Syndromes Most paraneoplastic syndromes in HCC are biochemical abnormalities without associated clinical consequences. They include hypoglycemia (also caused by end-stage liver failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sex characteristics (gynecomastia, testicular atrophy, and precocious puberty), and porphyria cutanea tarda. Mild hypoglycemia occurs in rapidly growing HCC as part of terminal illness, and profound hypoglycemia may occur, although the cause is unclear. Erythrocytosis occurs in 3-12% of patients, and hypercholesterolemia in 10-40%. A high percentage of patients have thrombocytopenia or leukopenia not caused by cancer infiltration of bone marrow, as in other tumor types.

Patients with HCV infection are more often screened and thus tend to present with signs and symptoms of cirrhosis and earlier stage HCC tumors. Patients with HBV infection or no serological evidence of hepatitis infection tend to present with larger tumors and less cirrhosis.

History

The history is important in evaluating putative predisposing factors, including a history of hepatitis or jaundice, blood transfusion, or use of intravenous drugs. A family history of HCC or hepatitis should be sought, and a detailed social history taken to include job descriptions for industrial exposure to possible carcinogenic drugs as well as contraceptive hormones.

Surveillance for Hepatocellular Carcinoma (HCC)

Ø Patients at high risk for developing HCC should be entered into surveillance programs (Level I). The at-risk groups are identified in the table below.
Ø Patients on the transplant waiting list should be screened for HCC because in the USA the development of HCC gives increased priority for orthotopic liver transplantation (OLT), and because failure to screen for HCC means that patients may develop HCC and progress beyond listing criteria without the physician being aware (Level III).
Ø Surveillance for HCC should be performed using ultrasonography (Level II).
Ø Alphafetoprotein (AFP) alone should not be used for screening unless ultrasound is not available (Level II).
Ø Patients should be screened at 6 to 12 month intervals (Level II).
Ø The surveillance interval does not need to be shortened for patients at higher risk of HCC (Level III).

·Surveillance Is Recommended for the Following Groups of Patients (Level III)

Hepatitis B carriers

Asian males >40 years
Asian females >50 years
All cirrhotic hepatitis B carriers
Family history of HCC
Africans over age 20

For non-cirrhotic hepatitis B carriers not listed above the risk of HCC varies depending

on the severity of the underlying liver disease, and current and past hepatic inflammatory

activity. Patients with high hepatitis B virus (HBV) deoxyribonucleic acid (DNA)

concentrations and those with ongoing hepatic inflammatory activity remain at risk for

HCC.

Non-hepatitis B cirrhosis

Hepatitis C
Alcoholic cirrhosis
Genetic hemochromatosis
Primary biliary cirrhosis
Although the following groups have an increased risk of HCC no recommendations for
or against surveillance can be made because a lack of data precludes an assessment
of whether surveillance would be beneficial.
Alpha1-antitrypsin deficiency
Non-alcoholic steatohepatitis
Autoimmune hepatitis

Ø Nodules found on ultrasound surveillance that are smaller than 1 cm should be followed with ultrasound at intervals from 3 to 6 months (Level III). If there has been no growth over a period of up to 2 years, one can revert to routine surveillance (Level III).
Ø Nodules between 1-2 cm found on ultrasound screening of a cirrhotic liver should be investigated further with two dynamic studies, either computed tomography (CT) scan, contrast ultrasound or magnetic resonance imaging (MRI) with contrast. If the appearances are typical of HCC (i.e., hypervascular with washout in the portal/venous phase) in two techniques the lesion should be treated as HCC. If the findings are not characteristic or the vascular profile is not coincidental among techniques the lesion should be biopsied (Level II).
Ø If the nodule is larger than 2 cm at initial diagnosis and has the typical features of HCC on a dynamic imaging technique, biopsy is not necessary for the diagnosis of HCC. Alternatively, if the AFP is >200 ng/mL biopsy is also not required. However, if the vascular profile on imaging is not characteristic or if the nodule is detected in a non-cirrhotic liver, biopsy should be performed (Level II).
Ø Biopsies of small lesions should be evaluated by expert pathologists. If the biopsy is negative for HCC patients should be followed by ultrasound or CT scanning at 3 to 6 monthly intervals until the nodule either disappears, enlarges, or displays diagnostic characteristics of HCC. If the lesion enlarges but remains atypical for HCC a repeat biopsy is recommended (Level III).

Diagnostic criteria

Ø The presence of a nodule larger than 2 cm with hypervascular characteristics detected by at least two imaging techniques confirms the presence of HCC, with no need for cyto-histopathological confirmation.
Ø AFP > 200 ng/ml plus an arterial enhancing lesion by one of the imaging tests meet criteria for the diagnosis of HCC.

Imaging

Imaging has numerous roles diagnosis, staging, screening and follow up. Several imaging modalities can be used to diagnose HCC including ultrasound, helical CT scanning, and

Ultrasound (US) plays a major role in the diagnosis of HCC, because it provides real-time and non-invasive observation by a simple and easy technique. In addition, US-guided needle puncture methods are frequently required for the diagnosis and/or treatment process of HCC. The development of digital technology has led to the detection of blood flow by color Doppler US,and the sensitivity for detecting tumor vascularity has shown remarkable improvement with the introduction of microbubble contrast agents. Moreover, near real- time 3-dimensional US images are now available. As for the treatment of HCC, high intensity focused ultrasound (HIFU) was developed as a novel technology that provides a transcutaneous ablation effect without needle puncture. The quality of a US examination is however operator dependent.

Sonographicaly the appearance of HCC· is variable. The masses are usually solid and may be hypoechoic , hyperechoic or of mixed echogenicity . These tumors more frequently invade portal or hepatic veins . Portal vein invasion is much more common than hepatic vein involvement,but hepatic vein involvement is more specific. Tumors invading the hepatic vein may extend to the IVC or the right atrium. Tumor invasion into the hepatic duct or common bile duct can be seen in 2-6% of advanced HCC’s. Obstructive jaundice can occur from direct invasion of the biliary tree or by compression by the tumor or lymph nodes.

Doppler sonography : HCC demonstrates internal vascularity (blood flow running into and branching within the tumor) and basket pattern of vascularity (a fine blood flow network surrounding the tumor nodule) .

Contrast Enhanced ultrasound :· On CEUS , the characteristic pattern of HCC is represented by an intense and fast peak of enhancement in the arterial phase , followed by a relatively quick washout staring at the beginning of the portal phase and quickly increasing towards the sinusoidal phase . Chaotic peritumoral and intralesional tortuous “corkscrew”/ “s” shaped vessels may be seen in he arterial phase as well as during the overlap with the portal phase.·Vascular lakes subsequently develop.

Proper technical performance of CT with imaging in the hepatic arterial and portal venous phases, as well as delayed contrast images, is important in detecting hepatocellular carcinoma (HCC). Arterial phase imaging is most useful for the detection of HCC as its predominant blood supply is from the hepatic artery. However, it is less sensitive for the detection of small HCC and for dysplastic nodules which appear isodense to the liver parenchyma due to their predominant blood supply from the portal vein . CT arterio-portography and CT hepatic arteriography are more sensitive for the detection of HCC but the false positive rate is high due to benign hypervascular lesions like arterioportal shunts.Lesions may be missed if early vascular imaging is not performed. It is important to use high injection rates and appropriate bolus timing. Sensitivity of good-quality dual- or triple-phase CT for the detection of patients with tumors is 60-70%. The classical appearance of a HCC on a dynamic CT scan of the liver is that of early arterial phase enhancement followed by a rapid washout on a later phase .

Ø Unenhanced CT typically reveals an iso-hypodense mass. If the mass is large, central areas of necrosis may be seen. Look for signs of cirrhosis or hemochromatosis.
Ø In the hepatic arterial phase, lesions typically are hyperdense (relative to hepatic parenchyma) as a result of hepatic arterial supply. Larger tumors may have necrotic central regions that are typically hypodense during this imaging phase. Look for neovascularity to indicate the presence of inconspicuous lesions.
Ø In the portal venous phase, small lesions may be isodense or hypodense and difficult to see, since the remainder of the liver increases in attenuation. Larger lesions with necrotic regions remain hypodense.
Ø In the delayed-postcontrast phase, small lesions may be inconspicuous on late phases. Delayed phase scans may show a tumor capsule, one of the more specific signs indicating HCC.

CT can also evaluate complications of HCC such as portal venous or hepatic venous invasion. In addition, other complications·such as·bleeding within the tumor and hemoperitoneum can also be identified.

MRI

Magnetic resonance imaging (MRI) is extremely useful in the detection and characterization of regenerating and dysplastic nodules and HCC. The various techniques of MRI are useful and more sensitive than other modalities in the early detection and characterization of HCC in the cirrhotic liver and in differentiating it from dysplastic nodules and pseudolesions.

MR features of focal liver lesions in cirrhosis

Lesion	T1 W image	T2 W image	Contrast enhancement pattern	SPIO uptake	Other features
Regenerative nodule	Variable	Hypointense	Enhances during portal venous phase	Present	Siderosis
Dysplastic nodule	Hyperintense	Hypointense	Enhances during portal venous phase	Present	Siderosis, nodule-in- nodule
HCC (small)	Hypointense	Hyperintense	Enhances during arterial phase	Absent	Nodule-in-nodule
HCC (large)	Heterogeneous	Hyperintense	Enhances during arterial phase	Absent	Fibrous capsule, satellite
·	·	·	·	·	nodules, invasion, fat
Pseudolesion	Variable	Hypointense	Enhances during arterial phase	Absent	·

PET scan

PET scan has been evaluated in the experimental setting, but, to date, its role is uncertain. Routine use of PET scan for diagnosis or staging of hepatocellular carcinoma is not recommended.

Biopsy

Imaging studies such as triple-phase CT and contrast-enhanced MRI have evolved to the extent that biopsy of liver lesions is generally reserved for select ambiguous circumstances.

Ø In general, core biopsy is favored over fine needle biopsy since larger amounts of tissue, often with normal surrounding parenchyma, can be obtained.
Ø Controversy exists regarding the potential risk of tumor seeding along the needle tract. Some studies report a small increase in risk (approximately 1/1000), while others show no difference. Regardless, potential risks and complications should be considered before performing a biopsy.
Ø Biopsy may be omitted in a clinical setting of a growing mass in a cirrhotic liver (>2 cm) noted on 2 coincident imaging techniques with at least one imaging showing contrast enhancement. Likewise, a growing mass in a cirrhotic liver on one imaging modality with an associated AFP level greater than 500-1000 ng/mL is clinically diagnostic of hepatocellular carcinoma. The need for biopsy should be carefully evaluated, especially if the risk for complications is high.
Ø Biopsy is generally obtained percutaneously under ultrasonographic or CT guidance. Prior to obtaining biopsy, large-volume paracentesis may be useful in patients with massive ascites; similarly, platelet transfusion may be necessary in patients with cirrhosis with severe thrombocytopenia (<50,000). Bleeding risk does not correlate with elevations in prothrombin time.
Ø Lesions that are 2-3 cm or smaller may be dysplastic nodules in a cirrhotic background. These are probably premalignant, and obtaining a biopsy is especially important to distinguish them from hepatocellular carcinoma. False-negative rates as high as 30-40% have been reported for biopsied tumors smaller than 2 cm in size.
Ø Using laparoscopic guidance may make obtaining a percutaneous biopsy easier. Laparoscopy allows visualization of the liver to evaluate the extent of cirrhosis if surgery is being contemplated.
Ø Obtaining a biopsy may be unnecessary in patients who will undergo resection regardless of diagnosis.

Staging

The goal of tumor staging is to separate patients into different groups based on their predicted survival to help determine the most appropriate treatment modality. The currently available staging systems for HCC include the pathologic tumor-node-metastasis (pTNM), Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer.

Ø TNM staging criteria for hepatocellular carcinoma
T1 – Solitary tumor without vascular invasion
T2 – Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
T3 – Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
T4 – Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
N0 – Indicates no nodal involvement
N1 – Indicates regional nodal involvement
M0 – Indicates no distant metastasis
M1 – Indicates metastasis presence beyond the liver
Ø Stage grouping
Stage I = T1 + N0 + M0
Stage II = T2 + N0 + M0
Stage IIIA = T3 + N0 + M0
Stage IIIB = T4 + N0 + M0
Stage IIIC = TX + N1 + M0
Stage IVB = TX + NX + M1
Ø CLIP scoring system: Score of 0-2 is assigned for each of the 4 features listed below; cumulative score ranging from 0-6 is the CLIP score.
Child-Pugh stage
Stage A = 0
Stage B = 1
Stage C = 2
Tumor morphology
Uninodular and extension less than 50% = 0
Multinodular and extension less than 50% = 1
Massive and extension greater than 50% = 2
Alpha-fetoprotein
Less than 400 = 0
Greater than 400 = 1
Portal vein thrombosis
Absent = 0
Present = 1

Estimated survival based on CLIP score: Patients with a total CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.

Management

Treatment approach to patients with hepatocellular carcinoma. The initial clinical evaluation is aimed at assessing the extent of the tumor and the underlying functional compromise of the liver by cirrhosis. Patients are classified as having resectable disease, unresectable disease, or as transplantation candidates. Abbreviations: OLTX, orthotopic liver transplantation; TACE, transarterial chemoembolization; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; LN, lymph node. Child’s A/B/C refers to the Child-Pugh classification of liver failure.

Most HCC patients have two liver diseases, cirrhosis and HCC, each of which is an independent cause of death. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Thus patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, transplant surgeon, and medical oncologist, is important for the comprehensive management of HCC patients.

Prognosis

The natural history of HCC is highly variable. Patients presenting with advanced tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of ~4 months, with or without treatment.

Conclusion

HCC is an aggressive tumor with a high case fatality rate. Successful treatment is dependent on early detection through widespread use of surveillance of patients at risk for HCC development.

Cholangiocarcinoma

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16254c02b.8s gallbladder anterior wall liver invasion space occupatopn obstruction bile ducts aggressive gallbladder carcinoma complicated by direct invasion metastasis liver windows narroe windws tumor settings gallbladder fossa GBF CTscan Courtesy Ashley Davidoff copyright 2008

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18126 liver + fx mass + fx calcification + bile duct + cholangiocarcinoma + imaging radiology CTscan splenic early heterogeneous contrast enhancement

Hepatoblastoma

Hepatoblastoma is rthe most common malignant tumor of the liver in the pediatric population

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03347c03.8s 18 month old female presents with abdominal distension and lethargy, and clinica lexam shows an enlarged liver. The grosspathology specimen shows white fibrous bands (f) mixed with dark pink tumor (t) and pockets of marroon hemorrhage(h). liver malignancy hepatoblastoma heterogeneous mass grosspathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

03334.81s

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03347c02.8s 18 month old female presents with abdominal distension and lethargy, and clinica lexam shows an enlarged liver. The histopathology shows fibrous bands in light pink (f) mixed with cellular tumor (t). liver malignancy hepatoblastoma heterogeneous mass histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

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03347c07.8s 18 month old female presents with abdominal distension and lethargy, and clinical exam shows an enlarged liver. The histopathology shows advancing malignant cells and tumor (t in image b) overlaid in pale green, and intermediate zone (i) that has a pushing edge of malignant cells and a larger front of squashed normal liver cells (pseudocapsule) and then beyond and to the right of the image overlaid in red is normal liver (liver). liver malignancy hepatoblastoma heterogeneous mass histopathology space ocupation pressure atrophy pseudocapsule Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

Malignant Hemangioendothelioma

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43346 hx 45M with abdominal mass liver fx situs inversus fx stomach fx displaced fx large exophytic mass dx leiomyosarcoma situs inversus CTscan Courtesy Ashley Davidoff MD

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20921 spleen + fx dense hyperdense parenchyma dx Thorotrast + imaging radiology CTscan C- non contrast liver dense hyperdense parenchyma calcific density calcification calcified infiltrative disease retciculoendothelial system RES

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15762 Courtesy Ashley Davidoff MD code liver metastasis breast dx carcinoma hepar lobatum imaging radiology CTscan DB

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44408 liver applied biology capsule angiomyolipoma histopathology Courtesy Barbara Banner

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16700c02 liver hepatic nodules masses ring enhancement flattened lesion dimple on liver capsule multiple adult malignant hemangioendothelioma T1 weighted with and without gadolinium contrast MRI T1 weighted pre and post contrast Davidoff MD

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16700c004 liver hepatic nodules masses ring enhancement flattened lesion dimple on liver capsule T2 bright multiple adult malignant hemangioendothelioma T1 weighted with gadolinium contrast MRI T1 weighted post contrast T2 ewighted Davidoff MD

Metastases

The Battleground – Tumor vs Healthy Tissue

The histopathology of a surgically resected hepatic metastasis from a primary colon carcinoma shows a mucinous secreting tumor at the bottom of the image labeled “advancing tumor”. The cellular detail is not well seen in the low power view but the columnar epithelial nature, hyperchromicity, and bizarre appearance of squatter tissue in the liver are recognized as malignant characteristics. The white spaces in between the cellular structure, represents mucin in the tumor. The edge of the tumor shows a rounded and aggressive push into the liver where the injured liver in the battlefield is recognized as compressed normal liver with linear areas of hemorrhage·evidenced by a curvilinear line at 11 and 12 oclock of· increased area of redness representing ·extravascular red cells (“layer of “injured liver”). The uppermost layer represents the normal liver which at this time looks healthy but is in jeopardy.

The radial red spokes seen at the edge of the tumor are artifacts of preparation but are indicators of the direction of the battle.

·liver cancer metastasis malignant tumor battlefield mucinous secreting adenocarcinoma colon primary histopathology destruction hemorrhageCourtesy Ashley Davidoff MD copyright 2009 all rights reserved 5star 03028b01.81s

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46587.800 liver bone vertebra fx mass space occupying disease dx liver metastases metastasis dx primary lung carcinoma malignancy cancer CTscan Davidoff MD

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02643c03.8s The post mortem specimen (a) shows a 2cms primary duodenal carcinoma (white arrow) with extensive nodular hepatic metastases occupying 80% of the liver. (b) In image c, the metastasis reflects an overall a blue hue caused by the increased nuclear presence. The image reveals an irregular and advancing threat on the normal liver. The higher power in d, shows a rind of compressed liver that is in the process of destruction and hemorrhage (red patches) in the tumor, in the border, as well as in the normal liver. This image is reminiscent of an advancing enemy in a battlefield with victory apparent for the aggressor. code liver duodenum adenocarcinoma metastases metastasis cancer malignant space occupation pressure atrophy death grosspathology histopathology Courtesy Ashley DAvidoff MD copyright 2009 all rights reserved

40343c

40343c Courtesy Ashley Davidoff MD code pancreas pancreatic body fx mass code liver fx multiple nodules and masses code dx primary adenocarcinoma of the pancrreas complicated by metastasis metastatic disease to the liver imaging radiology CTscan neoplasm malignant tumor cancer

Normal Liver –·(left) ·and Cancer in the Liver (right)

The liver on the left is normal except for gallstones in the gallbladder.· Gallstones are squatters but they usually do not have aggressive tendencies unless they block the outflow of bile.· The liver shown in the right image is from a patient who succumbed to metastatic pancreatic carcinoma.· The normal liver cells have been displaced and have been overridden by metastatic squatters.· The metastases have contributed to the demise of the patient by their relentless displacement of normal tissue, causing progressive impairment of function.·

13456 liver normal anatomy gallbladder stones cholelithiasis grosspathology

13448b01

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02891c03.8s This unfortunate patient presented in pregnancy with metastatic disease to the liver showing rounded discrete metastases in the liver on CTscan (a) confirmed at autopsy to be metastatic pancreatic carcinoma. The lesions in the liver (b) show a bile tinged green halo caused by local cholestasis caused by space occupation and obstruction. In c and d, the metastatic tumor (m) is seen to the left of the images, the middle layer of bile stained injured liver cells caused by cholestsais (ch) is seen as a subtle orange tinged section (c). The bile tinged layer (ch) is digitally enhanced in orange in d. Therelatively normal liver tissue (l) is seen to the right and is enhanced in with pink (d). code liver malignant cancer pancreatic primary pancreas bile tinge cholestasis space occupation bile stain CTscan grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

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45220 liver fx large hepatic mass dx colonic rectosigmoid carcinoma with hepatic metatsasis s/p stent placement CTscan Courtesy Ashley Davidoff MD 45220 45221 45222

Normal Liver and Single Group of Cancer Cells

These two cases represent the microscopic events described in the macroscopic examples above.· The left image shows normal liver cords at high power, while the image on the right shows slightly lower power of the liver cords in pink, and a blue, rounded, space occupying metastasis. ··

13445 11440 liver hepatocytes normal metastasis adenocarcinoma histopathology nodule Davidoff MD

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02986.8s This specimen is from a biopsy of the liver. The medium power view of malignant adenocarcinoma shows groups of columnar cells arranged in rosettes in a bed aof malignant stromal tissue and surrounded by normal liver. Although the nuclii in this case are not particulalrly enlarged the cytoplasm is basophilic, and the appearance is of a “squatter” in the liver, ie tissue that does not belong, is consistent with metastatic adenocarcinoma malignant cancer liver hepatic adenocarcinoma histopathology Courtesy Barbara Banner MD copyright 2009 all rights reserved GW question 5star

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18370 liver colon large bowel liver fx hepatic mass fx fine stippled calcifications calcified mass dx metastattic mucin secreting adenocarcinoma of colon carcinoma metastasis CTscan Courtesy Ashley Davidoff MD

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39484 liver CTscan imaging radiology mass dystrophic calcification calcified neoplasm mass metastasis malignant carcinoma adenocarcinoma cancer tumor

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82313c01.8s 51 year old male with history of rectal carcinoma with extensive hepatic metastases. (orange) The metastases surround gallbladder and by space occupation result in venous and lymphatic congestion causing a thickened edematous gallbladder wall (orange) with a small lumen (green) Tthe portal triad shows surrounding edema (white arrow). This is called periportal tracking which is another sign of venous and lymphatic engorgement. The metastases are calcified confirming the mucinous nature of the tumor. calcified metastasis in gallbladder fossa edema of the wall lymphatics contracted gallbladder CTscan copyright 2008 Courtesy Ashley Davidoff MD gallbladder liver portal triad

03034c.8s

03034c.8s The gross and histopathological specimens are from the autopsy of a patient who died of breast carcinoma that was metastatic to the liver. The right lobe of the liver shows two patterns of metastases. In the posterior aspect of the liver there is diffuse disease, and in the anterior aspect there are innumerable nodules of varying sizes. The left lobe is relatively spared, and the pattern is of a nodular nature. The low power histopathological section shows a diffuse infiltrate of hyperchromatic malignant nuclii in the bottom of the image and relatively normal liver in the upper portion. code liver metastases metastasis breast primary cancer malignant space occupation infiltration infiltrative pattern right lobe left lobe grosspathology histopathology Courtesy Ashley DAvidoff MD copyright 2009 all rights reserved GW question

02939c01.8s

02939c01.8s The series is from a patient who died of metastatic adenocarcinoma. In image a, the ultrasound shows diffuse increased echogenicity in the dome of the right lobe of the liver that suggests diffuse infiltration of metastatic disease. the liver at autopsy showed a combination of diffuse infiltration and discrete nodules. It seems that the discrete nodules in this case become confluent to become infiltrative disease. The histolopathology in d shows discrete metastatic deposits of glandular type metastases separated by spaces within the lesion of mucus consistent with metastatic mucinous adenocarcinoma in a bed of malignant stroma. The distinct blueness and “badness of the malignant tissue is reflective of the hyperchromicity of the nuclii and their dominance in the cell. code liver metastases metastasis discrete diffuse ultrasound grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question

739473

39473 Courtesy Philips Medical Systems liver imaging radiology USscan

24012c01.8s

24012c01.8s The ultrasound of the liver is from a 72 year old patient with metastatic breast carcinoma. There is a region overlaid in green ) that is hyperechoic and diffuse without clear nor rounded borders. No obvious mass or nodule can be defined. This finding represents the less common infiltrating metastatic pattern characteristically, but not exclusively observed in patients with breast carcinoma. code liver cancer malignancy malignant carcinoma metastasis infiltrating infiltrative US USscan ultrasound Courtsy Ashley DAvidoff MD copyright 2009 all rights reserved

20912

20912 liver + fx mass + complex cystic solid metastasis dx carcinoid tumor + imaging radiology CTscan C- mass neoplasm malignant metastasis carcinoma cancer tumor Courtesy Ashley Davidoff MD

02996c02.8s

02996c02.8s The autopsy series is from an elderly female who died with metastatic ovarian carcinoma. The CTscan (a) shows a focal hypodensity at the edge of the right lobe of the liver that was shown to be a metastasis. There is ascites around the spleen. Image b shows a white patch on the liver capsule in the region of the CT finding. Image c shows metastatic disease on the diaphragm characterized by a white rind of malignant tissue. (orange arrow). The histipathology shows three layers of tissue with normal liver at the bottom, the capsule in the middle and the matastatic deposit on the edge of the capsule. liver capsule ovary metastasis malignant primary cancer metastases transpertoneal spread of disease diaphragm Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question

24776 R W c

24776 R W c liver + lymph nodes lymphatics+ lymphatic drainage portal triad + fx normal + anatomy + imaging radiology CTscan

20115c

20115c Courtesy Ashley Davidoff MD code pancreas + dx carcinoma code abdomen fx abdominal ascites spleen stomach liver gastrolienal ligament lesser omentum gastrohepatic ligament masses metastasis abdomen + imaging radiology CTscan primary pancreas neoplasm malignant carcinoma cancer tumor

22993

22993 liver + capsule + spleen fx mass nodule + fx calcification + calcified dx pseudomyxoma peritonei + imaging radiology CTscan

03146c.8s

03146c.8s 56 year old male with gastric carcinoma and T2 weighted MRI that shows diffuse infiltration of metastic disease (areas of increased water (white) are abnormal and the darker areas are normal liver. The liver is almost totally replaced by diffuse metastases. The histopathology shows an infiltrative patternof dark tissue caused by hyperchromatic nuclii and diminished basophilic cytoplasm. The pink cells in between represent the normal liver. code liver metastases metastasis stomach primary gastric metastases to liver hepatic infiltrative malignant malignancy cancer MRI T 2 weighted image histopathology Courtesy Ashley DAvidoff MD copyright 2009 all rights reserved

22359

22359 51 M hepatic bare area liver abdomen ascites fx mass fx stippled calcification calcified fx psammomatous psamomatous calcifications dx metastattic mucinous adenocarcinoma of the rectum CTscan soft tissue windows Davidoff MD 22359 22357.800

16868

16868 diaphragm liver porta hepatis gastrohepatic ligament Glissons capsule + fx calcification + primary ovary + metastasis + imaging radiology CTscan neoplasm malignant carcinoma tumor cancer

20893

20893 spleen + capsule + fx calcification + metastatic primary ovary + carcinoma + imaging radiology CTscan C- liver Glisson’s capsule ligamentum venosum + fx calcification falciform ligament ligamentum teres fx calcium calcified dx metastatic primary ovary neoplasm malignant metastasis metastases cancer tumor abdomen peritoneum peritoneal cavity calcium deposit calcification calcified punctate ascites neoplasm malignant metastasis metastases cancer tumor

03779.800

03779.800 liver metatstasis primary ovarian cancer adenocarcinoma psammomatous calcifications psammoma bodies glandular malignancy histopathology Davidoff MD

20886

03780

03780 liver + fx psammomatous calcification + dystrophic calcification calcium metastatic primary ovary ovarian carcinoma + cytopathology

03028c01

03028c01 The images show a series of 4 images that reveal a metastaic lesion in the liver from a primary colon carcinoma. The lesion is about 2.5cms in size, has rounded pseudopod like advancing edges (best seen in image b – CT and image C MRI), is situated in the superior aspect of the right lobe of the liver and appears to have a complex nature. The through transmission seen in the ultrasound (a), the low density seen in the CT(b) and brightness on T2 (d) suggest complex fluid. The bright central region and bright lobulated rim on T1 (c) suggest mucin and or hemorrhage. liver hepatic mass a= US through transmission b= CT hypodense lesion c = T1 weighted cental intensity rim and matrix of low intensity periphery hyperintense d = T2 weighting = T2 bright fx metastattic colon carcinoma mucin secreting adenocarcinoma with central hemorrhage peripheral hemorrhage USscan CTscan MRIscan Davidoff MD copyright 2009 all rights reserved

03028c02

03028c02 The images show a series of 4 images that reveal a metastaic lesion in the liver from a primary colon carcinoma. The lesion is about 2.5cms in size, has rounded pseudopod like advancing edges (best seen in image a – T1 weighted MRI), is situated in the superior aspect of the right lobe of the liver and appears to have a complex nature. The brightness on T2 weighted series (d) and white area in the histopathology (d) suggest water content made up from mucus. The bright central region and bright lobulated rim on T1 (a) suggest mucin and or hemorrhage. The gross pathology shows central necrosis with hemorrhage (c) and the histopathology shows mucinous tumor with hemorrhage at the the advancing edge. liver hepatic mass a= MRI T1 weighted – T1 weighted cental intensity rim and matrix of low intensity periphery hyperintense b= MRI T2 weighted lesion is wet c = gross pathology shows central necrosis and hemorrhage and peripheral hemnorrhage d = histopathology advancing mucin secreting tumor with destroyed liver and hemorrhage fx metastattic colon carcinoma mucin secreting adenocarcinoma with central hemorrhage peripheral hemorrhage MRIscan liver hepatic mass histopathology grosspathology Courtesy Davidoff MD all rights reserved copyright 2009

16844

16844 Courtesy Ashley DAvidoff MD code pancreas + fx mass endocrine tumor + code liver capsule fx mass dx metastasis code IVC fx stent dx obstruction Budd Chiari imaging radiology CTscan neoplasm tumor carcinoma cancer

46579

46579 liver hepatic vein fx tumor thrombus lung fx consolidation dx infiltrative adenocarcinoma of the lung with metastases to the liver and adrenal and invasion of the hepatic veins malignancy cancer Davidoff MD 46581 46588 46587

03057c01.8s

03057c01.8s The collage consists of a CT scan (a) showing a focal well circumscribed low density liver lesion. Biopsy of this lesion yielded the histopathological specimen (b) that shows hyperchromatic nuclii and spindle shaped cells consistent with metastatic leiomyosarcoma. The cytological aspirate (c) shows spindle shaped nuclii with pleomorphism and hyperchromicity. code malignant cancer sarcoma histopathology CTscan Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

22068

22068 liver focal filling defect lymph nodes retrocrural enlarged dx lymphoma CTscan imaging radiology periportal tracking

03172c01.8s

03172c01.8s This series is from a patient who died with diffuse histiocytic lymphoma and DIC. The CT scan (a) shows hepatosplenomegaly with a low density liver suggestive of steatosis. The grosspathology specimen shows an enlarged liver with punctate hemorrhages. The low power histopathology shows a diffuse inflitration of dark nuclii reminiscent of a malignant infiltration, and the high power shows fatty vacuoles within the cytoplasm of the hepatocytes and an infiltrate of histiocytic appearing cells with increased nuclear cytoplasmic ratio (d). liver fatty change steatosis malignant cancer histiocytic lymphoma DIC metastases metastasis CTscan grosspathology histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved GW question

70248c01

70248c01 liver metastattic small lung carcinoma with diffuse metatstattic disease to the liver )hepatic metastases metastasis before and after treatment 6weeks post chemotherapy successful result size change character change CTscan Davidoff MD 5star

Carcinoma – Extending into the Liver via the Gallbladder Fossa

Direct Invasion into the Liver and Bile Duct Obstruction

The CTscan of this patient shows a normal sized gallbladder (green) associated with a 4-5cms mass (orange) adjacent to the gallbladder, and extending from the gallbladder fossa. There is asssociated biliary obstruction (dark green tubes)· This case represents invasive gallbladder carcinoma with bile duct obstruction. Images c and d show the almost universal association of gallstones in patients with carcinoma.···In this case the stones (white) are in the centre of the gallbladder. (green)

·16254c03.8s gallbladder anterior wall liver invasion space occupatopn obstruction bile ducts aggressive gallbladder carcinoma complicated by direct invasion metastasis liver windows narroe windws tumor settings gallbladder fossa GBF CTscan Courtesy Ashley Davidoff copyright 2008

Dystrophic Calcification – Carcinoma of the Gallbladder Extending into the Gallbladder Fossa

The non-contrast CT of the 75year old female patient, shows dystrophic calcification·in a mass that seems to be part of the wall of the gallbladder.· The·mass extends into the liver.· These findings are consistent with an inoperable gallbladder mucinous adenocarcinoma, metastatic to the liver by direct extension.· Calcification of adenocarcinomas is usually found in the mucinous variant of the disease.

Carcinoma – Extending into the Liver via the Gallbladder Fossa and Additional Metastases

Local Invasion and Separate Liver Mestastasis

Disease Extension Beyond the Liver·

Cholangiocarcinoma with Involvement of the Gallbladder and Bile Duct

The multiple imaging modalities of this patient who is elderly female who presents with obstructive jaundice.··Deformity of the gallbladder by CT is noted, with extension of a mass into the surrounding liver (a,b,c) In addition to a mass in the gallbladder (d), the ultrasound shows a shadowing stone (e).· An ERCP (f), shows a circumferential stricture of the bile duct.·The stricture is in the region of the cystic duct – bile duct junction, with non visualization of the cystic duct suggesting extension of the gallbladder cancer into the cystic duct and bile duct.· Lymph node involvement with bile duct obstruction is a less likely possibility due to the circumferential nature of the stricture.

45132c01

45132c01 elderly female with known sigmoid colon carcinoma liver lungs mediastinum fx FDG positive uptake fx high intensity uptake in a single focus in the dome of the right lobe of the hepatic parenchyma meadiastinal lymph nodes and within the pulmonary parenchyma dx colonic mucinous adenocarcinoma complicated by metastatic lung disease and hepatic metastasis PETscan Courtesy Ashley Davidoff MD 45132 45133 45134 45135 45136 45139 45141

Red Flags

ü Decompensation in patients with compensated cirrhosis
ü The triad of abdominal pain, weight loss and an abdominal mass
ü The presence of a nodule larger than 2 cm with hypervascular characteristics detected by imaging techniques
ü Gross Vascular invasion is a marker of widespread disease.

References

1. Naugler WE and Schwartz JM. Hepatocellular carcinoma . Disease- a-hepatoblastomamonth. 2008 (54); 432-44.
2. Leong TYM and Leong ASY. Epidemiology and carcinogenesis of hepatocellular carcinoma . HPB 2005; 7:5-15.
3. Digumarthy SR, Sahani DV, Saini S . MRI in detection of hepatocellular carcinoma . Cancer Imaging. 2005; 5: 20-24.
4. Schafer DF and Sorrell MF. Hepatocellular carcinoma . Lancet 1999;353: 1253-57
5. http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=9401&nbr=5036
6. http://books.google.com/books?id=OoAkdMgCxV0C&pg=PA91&lpg=PA91&dq=hcc+causes+bile+obstruction&source=bl&ots=h_BDTaU4aB&sig=Mg64P-p7lgJu9TvpvfnHoI2ugpw&hl=en&ei=GKthSumdGYPYtgOi36Fn&sa=X&oi=book_result&ct=result&resnum=9
7. http://online.statref.com.ezproxy.library.tufts.edu/Document/Document.aspx?docAddress=Z-lA2-alKAgqyrbNXcUh1w%3d%3d&offset=6130&SessionId=FAC669MXIJSTVNEK

03347c07.8s

03347c07.8s 18 month old female presents with abdominal distension and lethargy, and clinica lexam shows an enlarged liver. The histopathology shows advancing malignant cells and tumor (t in b) overlaid in pale green, and intermediate zonebands in light pink (f) mixed with cellular tumor (t). liver malignancy hepatoblastoma heterogeneous mass histopathology Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

The intimate relationship between the liver cells and the sinusoids infers that seedlings of malignant cells will aslo be in close proximity to the venous system and if they break off from the mother tumor have access to the rest of the body and the lungs in particular from the primary tumor

breasts, introduction, malignant, primary cancer

Breast Carcinoma Introduction

Carcinoma of the Breast

The Common Vein

Niharika Dixit MD Ashley Davidoff MD

Definition

Breast cancer is a malignant condition of the ductal or glandular epithelium. The causes for the disease are multifactorial and include genetic, environmental,physical (body habitus) and obstetric elements, but 75% of patients have no risk factors except for gender and age. The disease starts out locally as an aberrant cell in the epithelium, grows and multiplies into a nodule or mass and subsequently results in local extension. When the cancer has not yet invaded it is called carcinoma in situ and when the epithelial membrane is breached it is considered truly malignant and invasive. Each tummor has a specific biology. Sometimes the cells are well differentiated, suggesting a lower grade malignancy, some are intermediate, while others are categorized as high grade and poorly differentiated, suggesting a more aggressive disease. the cells also express individual by protein and gene expression characterized best by immunohistochemistry.

The disease is complicated by metastatic disease to regional lymph nodes and distant organs. TNM (status of the tumor,nodes, and metastases)classification is commonly used

The diagnosis may be suspected clinically on finding a new mass in the breast, new nipple or skin retraction, but mammography and MRI are utilized to suggest the diagnosis, and percutaneous biopsy is used to confirm the diagnosis.

The mainstay of treatment is surgery when the tumor is considered localized, usually combined with chemotherapy and radiation therapy. With optimal treatment 10 year disease free survival ranges from 10-98%, depending on type, grade and staging.

Breast Carcinoma

Artistic Rendition

This artistic rendition of a mammogram shows the crab like malignancy (red) invading the breast tissue.

27993b02.62k.8s breast cancer spiculated lesion infiltrating carcinoma space occupation invasion Davidoff art all rights resrved copyright 20

Overview

Breast cancer is the second most common cancer in the world after lung cancer. Although it is 100 times more common in woman, it affects males as well. It constitutes about 10.9 % of all newly diagnosed cancers each year.¹ Breast cancer is the most frequently diagnosed cancer in women in the United States, accounting for an estimated 274,900 new cases (212,920 invasive cancers and 61,980 in situ carcinomas) and 40,970 deaths in 2006. In the United States, the age-specific incidence of breast cancer increases with age, to a lifetime risk of breast cancer of 1 in 8 (to 110 years of age); by age 40, approximately 1 in 250 women will have been diagnosed with breast cancer annually; at 60 years of age, the figure is 1 in 35 women. Breast cancer diagnosis is devastating to any woman; however tremendous strides have been made in screening, treatment and follow up of the disease which has made breast cancer a very treatable disease.

History of the Disease

Breast is likely to be one of the first known cancers, likely because of its external manifestations.. It dates back to 1600 BC in ancient Egypt twhere both recognition of the disease and its treatment begins with cauterization of tumors with an instrument known as “the fire drill.” Although medical practitioners were able to remove these tumors in some cases, they were for the most part unable to stop the disease from taking its course. Writes the ancient Egyptian doctor of breast cancer: “There is no treatment.”

Such was the prevailing wisdom throughout the history of breast cancer. Although cases of breast cancer are documented throughout history, it is not until the 17th century in that European doctors linked the tumors in the breast to the lymph glands in the armpit. In the early 18th century two extremely important figures in the history of breast cancer arose: Jean Louis Petit and Benjamin Bell who performed the first surgeries removing the lymph nodes, breast tissue and breast muscle in order to remove the cancer from the body and fight its spread.

This pioneering work was continued by the surgeon William Stewart Halsted who began performing complete mastectomies in 1882. His procedure is known as the Halsted radical mastectomy, and was popular throughout the 20th century up until the 1970’s and is still common today.

While breast cancer survival rates have gone up somewhat in the last twenty years, the fact remains that this disease is still far too prevalent and resulting in the death of far too many women.

Many great strides have been made in the history of breast cancer treatment but there is still a great amount of work to be done. One in 12 or 13 women will suffer from breast cancer at some time during their lives in the western world. In the United States these numbers can be even higher. One of the most important aspects of the fight against breast cancer is breast cancer awareness. The more knowledge known about the disease and the more done to check for early warning signs, the better is the chance for survival. Continuing research and breakthrough in treatment are a part of the ongoing history of breast cancer

Causes and Predisposing Factors

Genetic:

A personal or family history of the disease, (in mothers or fathers family) particularly if acquired before the age of 40, increasingly raises the risk of the disease. Breast cancer is approximately twice as common among first-degree relatives of breast cancer patients as in those women with no family history of the disease. The two most important breast cancer susceptibility genes, BRCA1 and BRCA2, were identified by linkage analyses in the mid-1990s. Since then, rare germ line mutations in several other genes, such as TP53, PTEN, and ATM, have been shown to confer an increased risk of breast cancer. BRCA1 and BRCA2 account for less than 20% of familial clustering of breast cancer. It is likely that most familial breast cancers have polygenic transmission, where multiple genes are involved and difficult to identify.²

It is more common in Caucasian women, than Asian or African American women. The Jewish Ashkenazi population displays a 10 fold higher frequency of 2 founder mutations (185delAG and 5382insC) therefore screening of such mutations in the above population is indicated.

Reproductive and endocrine risk factors:

Gender is the most important risk factor in the development of breast cancer, which occurs 100 times more frequently in women than in men. This is due to endocrine factors that relate to lifetime exposure to estrogen. Estrogen is itimately involved in every aspect of female reproducrtive physiology including normal sexual development, regulation of menstrual cycles, tand , pregnancy. The longer the exposure to estrogen the greater the risk of pregnancy. Therefore the older the patient the greater the exposure to estrogen and the higher the risk. Additionally, early menarche and late menopause raise the risk by increasing the time of estrogen exposure ( > 30 years menstrual time). On the other hand, diets low in fat and high in fiber decrease the levels of estrogen and lower the risk of breast carcinoma. Age is also an important risk factor for the development of breast cancer, since in essence translates to years of exposure to estrogen.

Protective factors include, longer lactation periods, and moderate levels of exercise. There is some evidence that circulating levels of estrogen are lower in women who excercise. In addition they have less body fat.

Birth Control Pills and Hormone Replacement Therapy

The effect of birth control pills is controversial. Theoretically it should depend on the concentration of estrogen in the pill. The earlier birth control pills had higher levels of estrogen compared to the current OCP’s, and this may relate to the association.

Estrogen in hormone replacement therapy (HRT) in post menopausal women, has been linked to increased risk of both breast and endometrial cancer. As such, there has been a move to recommend discontinuation of HRT in post menopausal women.

Obesity:

There appears to be an association between body mass index (BMI) and breast cancer, which may be accounted for by increased estrogen levels in women with a higher BMI. The BMI is a ratio of weight to height. Obesity after menopause is especially important since the ovaries at this time stop producing estrogen, and if estrogen from fat is still present then it increases lifetime exposure.

Diet:

Alcohol consumption is the best-established dietary factor associated with increased risk for breast cancer, and seems to be related to the amount of alcohol consumed. A proposed explanation is that alcohol increases the amount of circulating estrogen.

Dietary phytoestrogens, are estrogens found in vegetables. They serve as a protective factor since they are much weaker than endogenous estrogen, but compete for estrogen receptors, and thus reduce the effect of the endogenous estrogen theoretically resulting in less cell division.

Ionizing radiations:

Data about risk in women from radiation is derived mainly from epidemiologic studies of patients exposed to diagnostic or therapeutic radiation. Low-dose radiation exposure to the breast is carcinogenic, and risk increases as a linear function of increasing dose. The risk is particularly high in the developing breast (age <20).

Geographic Distribution

The incidence of breast cancer varies significantly among differennt countries, and is highest in Northern European countries and in the United States, intermediate in Southern America and Southern and Eastern Europe, and lowest in Asia (Japan, Singapore and urban China have seen a rise in rates with the advent of Western-style economy). Breast cancer incidence and mortality vary sigificatly within the United States. The incidence of breast cancer appears to be highest in white women from Hawaii (128:100,000) followed by those from San Fransisco and the Northeast.The lowest incidence is found in Utah (98:100,000) and New Mexico

The variation of incidence for African-American woment is relatively small ( 94-106:100,000).

The interaction of many different risk factors in the initiation of breast cancer has lead to the creation and use of risk-assessment models. This helps predict the risk of management and determine the best course of action. The most frequently used model was designed by Gail in 1970 and incorporates age at menarche, number of breast biopsies, age at first live birth and the number of first degree relatives with breast cancer. It is used to predict the risk of developing breast cancer per decade of life. One of the disadvantages of this model is that it doesn’t take into account age at which a family member was diagnosed and whether the disease occurred in both breasts — early onset and bilateral disease suggesting a BRCA mutation carrier

Structural Principles and Changes

Breast tissue consists of glandular, fatty and connective tissue. Each breast overlies the pectoral muscle of chest wall and is tethered to chest wall with tiny connective tissue fibers call ligaments of Cooper. Each breast is divided into about 15-20 lobes which are formed by smaller units called lobules. There are about 20-40 lobules per lobe. The lobules are made from small glandular structures called acini. There are 10-100 acini per lobule. A branching ductal system transports the milk from the acicini into the lobular ducts, which converge to a single lactiferous duct, which brings the milk to the nipple.

Components of the Breast

This CT is from a patient with normal breasts by CT scan. The image on the left shows the CTscan without overlay through the mid chest, and the image on the right shows the parts of the breast overlaid in color to exemplify the parts. The nipple, surrounded by the areola is overlaid in dark pink. The triangular shaped glandular tissue is overlaid in lightpink and is surrrounded anteriorly by the superficial layer of fat, (light yellow), and the deep layer of fat posteriorly (dark yellow). Deep to the deep layer of fat is the chest wall that includes the pectoralis muscle and ribs.

The make up of the breast is extremely varied among patients with some breasts dominated by fat and others dominated by glandular tissue, and yet otyher dominanted fy connective tissue. In this patient fatty tissue dominates.

The Terminal Duct Lobular Unit (TDLU)

The understanding of cancer of the breast requires an understanding of the terminal duct lobular unit (TDLU). In order to understand the terminal duct lobular unit the histology of the breast needs to be understood.

Definition

The terminal duct lobular unit is the functional unit of the breast and is responsible for the production and transport milk to the lactiferous duct.

Structurally, it consists of a lobule of the breast with an extraobular terminal duct. A group of acini group together with an intralobular duct form a lobule, and the lobule empties into an extralobular duct. The TDLU is surrounded by fibrofatty connective tissue. 20-40 TDLU’s combine to form a lobe.

The TDLU is extremely sensitive to hormonal influences, and its appearance varies based on physiologic conditions. It changes within each cycle, enlarges significantly during pregnancy and lactation and finally atrophies in the post menopausal period. Because of its sensitivity to hormonal conditions, it is also subject to aberrances in the hormonal environment.

From a disease standpoint, the TDLU is the site of origin of ductal carcinoma in situ (DCIS), lobular carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, as well as more benign conditions such as fibroadenoma, fibrocystic disease, cysts, apocine metaplasia, adenosis and epitheliosis.

The diagnosis of disease in the TDLU is usually at a pathological level, since in general imaging techniques are not sensitive to the histological subtypes.

Terminal Duct Lobular Unit

Lobule of the Breast at a Histological Level

The TDLU consists of a clump of grape like acini with their respective terminal ductules, all of which empty into an intralobular duct to form a lobule. The lobule empties into an extralobular duct. The extralobular duct and the lobule form the terminal duct lobular unit (TDLU). The acinus is two layers thick. The inner layer is the secretory epithelium of a cuboidal nature and the outer layer is a myoepithelial layer.

42707b03b45b05 breast mammary gland ducts ductules extralobular terminal duct intralobular terminal duct terminal ductule acini acinus alveoli alveolus surface epithelium luminal cell myoepithelial cell lobule terminal ductal lobular unit TDLU drawing anatomy histology normal Courtesy Ashley Davidoff MD

The following section is a review of the applied histology of the breast, and provides a framework of how to understand the various subtypes of carcinoma.

Applied Histology of the Breast

The10-20 lobes of the breast are arranged radially around the breast and the single duct that subtends the lobe, empties independantly on the nipple.

Radially Arranged Lobules Each with a Single Duct Opening Onto the Nipple

The lobules are arranged around the breast in radial fashion, just like the hands on a clock. In this artistic rendition the lobules are seen in teal blue, the acini within the lobules are seen as branching dark pink structures within the lobe. From each lobe, a single duct arises, and opens onto the nipple.

42657b07_800 Courtesy Ashley Davidoff MD breast lobule duct nipple fat glands glandular tissue normal anatomy drawing art Davidoff art

Anatomical Sites and Subsites

1. Nipple

2. Central portion

3. Upper-inner quadrant

4. Lower-inner quadrant

5. Upper-outer quadrant

6. Lower-outer quadrant

7. Axillary tail

Lateral View of Both Breasts Showing Lobules

The lateral view of both breasts against their respective chest walls show the lobules as pink structures within which reside the glandular elements (branching pale pink). The duct subtending the lobule enters the nipple. There are fine white strands of connective tissue that anchor the breast tissue to the skin in front , to other lobes, and the chest wall behind. These are called Cooper’s ligaments.

42707b03b19b breast mammary gland nipple areola ducts Coopers ligaments Cooper’s ligaments pectoralis muscle chest wall adipose tissue layers fat superficial adipose tissue deep retromammary interlobular fat adipose tissue stroma connective tissue parenchyma glandular apparatus mammary apparatus axilla axillary lymph node normal anatomy drawing Courtesy Ashley Davidoff MD

Glandular Makeup of the Breast

The first drawing in a transverse plane (a) shows 4 of the 10 -20 lobes that make up the glandular tissue of the breast, each with their own lactiferous duct that enters the nipple. The second drawing (b) shows a single lobe made up of 20-40 lobules that look like white clumps of grapes on a stalk. The lobules shown in (c) are composed of ovoid sacs or tear drop sacs called acini. Only 3-4 are shown per small stalk (ductule) but there are between 10-100 per “bunch”. Image d is a high powered view of a lobule (the described bunch) and each of the tear dropped shaped “grapes” is called an acinus. or alveolus. Each acinus is an empty sac surrounded by two layers of epithelium. A high powered view of the inner lining (e) is shown consisting of two cell layers. The inner (luminal) layer is cuboidal and is responsible for milk secretion, and the outer lining consists of smooth muscle cells that enable the glands to contract and move the milk out of the acinus and into the ductal system.

code breast normal anatomy histology lobe lobules acini alveoli acinus lactiferous duct extralobular ductule intralobular ductule Davidoff art Courtesy Ashley Davidoff MD copyright 2009 all rights reserved

code breast normal anatomy histology lobe lobules acini alveoli acinus lactiferous duct extralobular ductule intralobular ductule Davidoff art Courtesy Ashley DAvidoff Md copyright 2009 all rights reserved 42707c29.8s

Ductal System of the Breast

This diagram shows the ductal system of the breast. As the milk is secreted by the cells into the acini (ac) its transport is facilitated by smooth muscle contraction into the ductules subtending the acini. Multiple ductules join to form an intralobular terminal duct which advances outside of the lobule into an extralobular terminal duct. This duct, that subserves a single clump of acini, converges with 20-40 other extralobular ducts to form the main duct of the lobe and becomes the lactiferous duct (b). The lactiferous duct (c) has a small fusiform dilatation just before the nipple called the lactiferous sinus which is able to distend, and store milk temporarily before it is needed and expelled.

code breast ducts acinus acini lobule ductules terminal duct intralobular terminal duct extralobular terminal duct lactiferous duct lactiferous sinus Courtesy Ashley Davidoff MD Davidoff art copyright 2009 all rights reserved 42707b03b45b05c01.8s

Microscopic Histology of the Lobule

This histological section shows a terminal duct lobule unit. (TDLU) A lobule is ringed in black and the extralobular terminal duct is noted and labelled. The acini are shown ringed in red but the draining intralobular ducts are not seen The lobules and extralobular terminal ducts join to form a single lactiferous duct which exits at the nipple

Bands of connective tissue, the suspensory ligaments, extend from the interlobular connective tissue to attach to the dermis.

Malignant breast disease

The carcinomas are the most significant lesions of the breast. There are two major types of breast carcinoma that arise from the lobule namely ductal carcinoma and lobular carcinoma. They both arise from the TDLU.

Carcinoma of the breast at this level is divided into the non invasive or “in situ” carcinomas on the one hand and the invasive carcinomas on the other. The “in situ” carcinomas are restricted to the lobule and do not show invasion of the basement membrane while in the invasive group, there is obvious transgression of the basement membrane.

The “in situ” group has variable behavioral patterns and outcomes. These lesions may remain dormant for a lifetime, or may even involute. They do however place the woman at increased risk of developing cancer and should therefore be treated with heightened awareness.

The two types of “in situ” carcinomas are called ductal carcinoma in situ (DCIS), and lobular carcinoma in situ (LCIS), and they are very different. DCIS is common and occurs in 70-95% of women at autopsy and is commonly associated with microcalcifications on mammography. It arises from ductal epithelium. LCIS is less common, clinically and radiologically more elusive, occurs in 1-5% of biopsies, and is rarely associated with microcalcifications on mammography. Once LCIS is identified the risk of developing cancer if untreated is about 30% within 20 years of diagnosis. It is not considered a precancerous disease, but a marker of increased risk.

The two more common invasive carcinomas of the breast are correspondingly called invasive ductal carcinoma and invasive lobular carcinoma and are defined by the transgression of the basement membrane by malignant cells.

The most common site of involvement is the upper outer quadrant since it is the location of “extra” tissue called the axillary tail of Spence. The presence of a larger amount of glandular tissue raises the relative incidence of disease in this quadrant. About 45% of carcinomas arise from this upper outer quadrant. Invasive ductal carcinoma is the most common type of carcinoma.

Spiculated Carcinoma

The appearance of carcinoma on a mammogram can take many forms, one of which is shown above and characterized by its spiculated shape.

13523 breast + fx mass fx spiculated dx carcinoma mammogram mammography Courtesy Carl D’Orsi MD DB

The current favored hypothesis on the evolution of breast cancer describes a progression similar to that in colon cancer ( Knudson’s hypothesis) that includes usual ductal hyperplasia, atypical hyperplasia, carcinoma in situ ( ductal carcinoma in situ and lobular carcinoma in situ) and invasive carcinoma.

Carcinoma in Situ

Each type of breast carcinoma in situ (DCIS and LCIS) has a distinct clinical and biological behavior, and they are discussed separately.

Ductal Carcinoma in Situ (DCIS)

DCIS is a stage zero malignancy of cells confined to the ducts or lobules by the basement membrane. Structurally the disease is characterized by malignant proliferation of epithelial cells cells within the ducts and lobules, with intact myoepithelial cells and basement membrane. The cells are able to spread through the ductal system and lobules, and therefore a single clone of cells can spread within the lobular system almost like sludge or debris in a river with intact river banks. DCIS is the most common type of non invasive cancer of the breast.

Histologically there are 5 architectural types including comedocarcinoma, solid, cribriform, papillary, and micropapillary. The comedocarcinoma shows the highest grade of behaviour, with the most malignant characteristics. There is associated necrosis of the cells giving rise to a cheesy material that can be squeezed like toothpaste out of the ducts. This necrotic debris undergoes dystrophic calcification which manifests as clusters of tubular branching microcalcifications on the mammogram.

Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, and is found in approximately 7% of all biopsied specimens. It is considered a premalignant condition and risk of invasive breast cancer is increased nearly five times in women with DCIS. Such risk is primarily ipsilateral as opposed to LCIS which is more likely to be multifocal and bilateral. Multicentricity is seen in 60-90% of patients with LCIS and in 40-80% of patients with DCIS. LCIS occurs bilaterally in 10-20% of DCIS cases and in 50-70% of LCIS cases.

Before mammography DCIS was primarily diagnosed by physical examination as a palpable lesion. In situ breast cancers constituted approximately 2% of all breast cancers in 1980 and LCIS was more common than DCIS by a ratio of 2:1. Screening mammography revealed a 14 fold increase in the incidence of in situ cancer (45%) and DCIS was diagnosed more frequently than LCIS, mostly because small non specific calcifications associated with DCIS are identifiable, whereas not a characteristic feature of LCIS.

The calcifications seen on mammography arise in the extralobular ducts, and hence tend to be small , clustered, heterogeneous but often rod shaped.

Biopsy of suspicious areas of calcification confirms the diagnosis.

Treatment in general includes excision of the lesion(s) and radiation therapy is often included. However the treatment is individualised taking factors such as age, multicentricity, state of health, and family history into account.

Prognosis is excellent with almost 100% cure rate.

Lobular Carcinoma in Situ (LCIS)

Lobular carcinoma is not truly a carcinoma, but has the risk of developing into a carcinoma. LCIS is considered a marker of increased risk for invasive breast cancer rather a premalignant lesion . Like DCIS, it can be considered a stage zero carcinoma, and malignant appearing cells are seen microscopically within the lobules of the breast, with a basement membrane that is intact, ie not invaded. The complicating statistic is that about 25% of patients with LCIS will develop invasive cancer in their lifetime, either from the lobules or from the ducts.

Lobular carcinoma in situ (LCIS) was first described in 1941 ( Foote and Stewart) and is characterized by three important features:

1) the lesion is a microscopic finding that is not apparent clinically and is usually an incidental finding;

2) the lesion is multicentric in the breast and often bilateral (30%) and

3) both infiltrating ductal and lobular carcinomas may develop after LCIS.

Lobular carcinoma in situ arises from the terminal lobular duct units. LCIS is a risk factor for bilateral breast cancer (approximately 1% per year) and therefore careful clinical followup is appropriate for most women.

Treatment is individualised but ranges from increased surveillance with frequent physical exams per year and mammograms once or twice per year. Tamoxifen reduces the risk of breast cancer ( by approximately 55%)

Bilateral mastectomy is not commonly performed, but patients with a strong family history, or who have unfavorable genetic mutations sometimes choose this option.

Statistics

LCIS lacks clinical and mammographic signs and therefore it’s true incidence is not known. Numerous authors have reviewed breast biopsies in an effort to determine the incidence of LCIS and the results varied from 0.5% ( Page et al) to 3.6% ( Haagensen et al) . Incidence is increasing partly because of criteria that contribute to its definition as a pathologic entity and due to mammography which has resulted in increased utilization of biopsy. LCIS is multicentric in 60-80% of cases and bilateral in at least 26% of cases. LCIS is ten times more frequent in white women than in African-American women. The age at diagnosis is most commonly between 44-47 years ( vs 52-58 years for DCIS) and 25-35% of women with LCIS develop invasive carcinoma ( 65% of invasive carcinomas that develop are infiltrating ductal, not lobular, carcinomas).

Invasive Carcinomas

Invasive (Infiltrating)Ductal Carcinoma

Invasive ductal carcinoma is the most common cell type, comprising 70% to 80% of all cases. It most commonly affects women in their mid to late 50’s but affects women of all ages.

Structurally it is characrterised by its desmoplastic nature inferring that it has a tendency to incite a fibrous response. The cells form well developed glands and nests, with individual cells being relatively large with large pleomorphic nuclii. The cells also vary in size and shape. The cells in the ducts also undergo necrosis resulting in the dystrophic calcifications, as wll as the accumulation a cheesy material. This is called a comedo carcinoma and the cheesy material can be extruded from the ducts. Multifocality of invasive ductal carcinoma is more frequent when there is a lesion that is is larger than 2-2.5cms.

From a clinical and diagnostic perspective, the lesion is hard to palpation because of its fibrous content. The desmoplastic nature also causes fibrosis of the surrounding connective tissue, resulting in a tugging effect on other structures such as the Cooper’s ligament, the skin or the nipple. Retraction on the ligaments of Cooper presents as peau d’orange – a dimpling of the skin that is reminiscent of the dimpling seen in the skin of an orange. New onset of nipple retraction is also an important warning sign of cancer.

From an imaging perspective, invasive ductal carcinoma is very dense on mammography, and between 70-90% are associated with calcifications, usally shaped as linear casts of the ducts, but are sometimes granular, and usually are more than 5 in number. Calcification is dystrophic in nature, commonly associated with necrosis. Those patients who do not show calcifications pathologically usually show malignancies of lower grade. (low nuclear grade and low grade growth pattern).

An associated ductal carcinoma in-situ is frequently present and comedo necrosis may occur in both invasive areas and areas of intraductal carcinoma.

Invasive ductal carcinoma carries the poorest prognosis among various ductal types. Nuclear and histologic grade have shown to be effective predictors of prognosis. In general the prognosis for the most common histological form which is called invasive ductal carcinoma not otherwise specified (“IDC NOS”) is intermediate. The mucinous, papillary, cribriform, and tubular forms have better survival than the rarer types such as the sarcomatoid and inflammatory carcinomas.

Treatment in general depends on the size, but surgery remains the mainstay of therapy.. In general when the lesion is less than 4cms, the mass is excised and the axillary lymph nodes are sampled. Grading, staging after surgery allows the decision for further adjuvant (post surgical) treatment that may include chemotherapy, radiation therapy, and hormonoal therapy.

When the mass is larger than 4cms modified or full mastectomy is performed, and lymph nodes are sampled, and treatment is tailored to the patients individiual situation.

Soft Tissue Mass – Invasive Ductal Carcinoma

The mammogram is from a 45 year old patient with a history of a prior benign biopsy on the left breast now presenting with a hard palpable lump in the right breast. CC view shows subtle asymmetry (red ring). Pathology revealed high grade invasive ductal carcinoma. The patient underwent needle localization and sentinel lymph node dissection followed by radiation therapy and chemotherapy.

43824r01 45 year old with history of a prior benign biopsy on the left breast now with a palpable lump in the right breast. CC view shows subtle asymmetry. Pathology revealed high grade invasive ductal carcionma. The patient underwent needle localization and sentinel lymph node dissection followed by radiation therapy and chemotherapy. fx asymmetry dx invasive ductal carcinoma breast imaging radiology mammogram mammography Courtesy Priscilla Slanetz MD MPH

Invasive Ductal Carcinoma DCIS , Positive Nodes

The mammogram from a 27 year old female who noted a lump in her breast, and shows a left breast a large cluster of pleomorphic calcifications. The patient had a lumpectomy and lymphadenectomy which showed invasive ductal carcinoma, associated with DCIS and positive findings in the lymph nodes.

27975 breast hx 27F left breast lump fx pleomorphic calcification Rx lumpectomy dx intraductal carcinoma with high grade DCIS lymph node positive mammogram mammography Courtesy Priscilla Slanetz MD

Invasive Scirrhous Ductal Carcinoma

The grosspathology specimen following surgical resection, was rock hard an gritty to the feel in the region of multiple well defined foci of white to pale yellow lesions with tan colored central foci. Histopathology showed infiltrating ductal carcinoma. The rock hard nature is characteristic of invasive ductal carcinoma, but the gross appearance is non specific.

13553 breast + dx infiltrating ductal carcinoma + grosspathology Courtesy Frank Reale MD DB

Infiltrating Ductal CArcinoma

The histopathology specimen shows malignant appearing cells within the confines of the duct and a necrotic centre. The nucllii are dark (hyperchromatic) and relatively large compared to the cytoplasm, which are features characteristic of malignancy. However the pathologist indicated that the basement membrane was breached indicating the invasive nature, and inferring a diagnosis of infiltrating ductal carcinoma.

13555 breast + dx infiltrating ductal carcinoma + histopathology Courtesy Frank Reale MD DB

Invasive Carcinomas

Invasive Lobular Carcinoma

Invasive lobular carcinoma is the less common than invasive ductal carcinoma common cell type.

Infiltrating lobular carcinoma is present in 5%-10% of breast cancers. It is characterized by its bilaterality in up to 20% of patients, and may be multicentric as well

Structurally they are poorly circumscribed, and like the invasive ductal may be associated with some fibrosis, but is not as desmoplastic as invasive ductal carcinoma. It has a typical microscopic appearance characterized by small uniform cells organized in strands with one or two layers of cells organized in a single-file (“Iindian file”). They may encircle the ducts, and often preserve the architecture of the ductsThere is little pleomorphism. It typically grow around ducts and lobules. Lobular carcinomas are frequently multifocal and multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges, serosal surfaces the GI tract and the retroperitoneum.

Clinically they may present as poorly defined areas of thickening of the breast and these may be hard to detect clinically. Therefore the patients themselves, may not be able to palate these masses on self examionation, and they therefore may be larger than IDC when presenting. (Harminder)

Unlike DCIS, LCIS is not associated with a mass, nor obvious findings on mammography, the diagnosis is usually made under the microscope as an incidental finding on a biopsy specimen.

Mammographically, the lesion is often ill defined, vague, with calcifications only seen in about 2%. (Hilleren). In addition when observed, it usually underestimates the extent of the disease. As a result of the low sensitivity of mammograpphy, ultrsasound and more increasingly MRI (Qayyum)are being used when clinical suspicion is raised, for preoperative planning to define extent, multicentricty and bilaterality. Lobular carcinoma in situ coexists with invasive lobular carcinoma in most cases (70%-80%).

Treatment in general depends on the size, but surgery remains the mainstay of therapy. Breast conserving surgery followed by radiation therapy is recommennded for early stages I or II. Although there is a higher incidenc e of bilaterality, mirror image biopsy, or prophylactic mastectomy is not recommended.

Invasive Lobular Carcinoma

The patient is an 82 year old presenting for baseline screening mammogram, with a positive family history of breast cancer. Her daughter was diagnosed in her 40’s with breast cancer. The mediolateral oblique ( MLO ) views show an irregular spiculated mass in the upper anterior right breast. Note the vascular and secretory calcifications in both breasts. At pathology invasive lobular carcinoma was diagnosed. Note that in this case the mass was easily identified, by mammography which is not always the case for lobular carcinoma.

breast fx mass fx calcified vascular calcifications ductal calcifications dx lobular carcinoma RX US guided needle loc with surgical excision and XRT breast imaging radiology mammogram mammography

Courtesy Priscilla Slanetz MD MPH 43716r01

MRI – Invasive Lobular Carcinoma

The MRI is from a 54year old female, who had a vague fullness in the left breast. Asymmetric changes showing an enhancing infiltration was shown pathologically to be an invasive lobular carcinoma. MRI is the most sensitive imaging procedure for invasive lobular carcinoma.

42975 Courtesy Priscilla Slanetz MD breast CASE 26: hx 54 year old for screening Dx: Invasive lobular carcinoma MRI DB

Ill defined Mass in the Surical Specimen

Diagnosis Infiltrating Lobular Carcinoima

The grosspathology specimen following surgical resection, was ill define with subtle change in texture to the feel. The lesion is the paler tissue in the specimen and is obviously different from the surrounding yellow fat. Histopathology showed infiltrating lobular carcinoma.

13559 breast + fx mass dx infiltrating lobular carcinoma + grosspathology Courtesy Frank Reale MD0 DB

Histopathology of Invasive Lobular Carcinoma

The histopathology specimen shows features consistent with malignant disease cgharacterized by dark nuclii, and a large nuclear to cytoplasmic nature. All the malignant cells are external to the ducts, beyond the basement membrane making the lesion invasive in nature. The alignment of the cells in columns of cells, in this instance 2-3 layers thick, is characteristic of invasive lobular carcinoma. the formation of cells, sometiimes even only one cell layer thick is called “Indian file”.

13560 breast + fx mass dx infiltrating lobular carcinoma + histopathology Courtesy Frank Reale MD0 DB

Other Less Common Invasive Carcinomas

Inflammatory Carcinoma

Inflammatory Carcinoma is a malignant condition of the breast, accounting for 1-4% of breast cancer cases, characterized by poorly differentiated ductal carcinoma with tumor invasion into dermal lymphatics, and a universally poor prognosis.

Clinically the breast appears inflammed, red, swollen, and painful, with peau d’orange manifestations in the skin, and nipple retraction. A mass is not always apparent, .

Mammographically the breast is less compressible and dense with skin and trabecular thickening.

Biopsy should include a section of the skin to reveal the presence of the malignancy in the dermal lymphatics in order to make the diagnosis. Despite the name, inflammatory cells are not usually present.

Staging of the tumor is based on the size and extent of metastases.

In general inflammatory breast carcinoma is first treated with chemotherapy before surgery is contemplated, and if surgery is performed, then radiation therapy follows. If the tumor is receptor positive, hormonal therapy is added.

CT scan – Inflammatory Carcinoma

This CT scan shows a large mass in the right breast, which was pathologically confirmed to be inflammatory breast carcinoma. The superficial skin cannot be fully appreciated but the most medial aspect overlying the breast is thickened. The blood vessels in the lateral aspect of the breast are enlarged, and a liver lesion in the posterior aspect of the right lobe is a known metastasis.

20044 Courtesy Ashley Davidoff MD code breast fx mass inflammatory carcinoma imaging radiology CTscan C+ DB

Medullary Carcinoma

Medullary carcinoma is a rare cancer of the breast arising from the stromal cells and represents less than 5% or invasive breast cancers. (Meyer) It is characterised structurally by its large size at detection, soft texture, and mobility since it appears to have no significant associated desmoplasia, and has less invasive properties and less commonly metastasizes. The centre of large tumors may be hemorrhagic or necrotic. Pathologically the cells are large,lack glandular morphology and there may be a lymphocytic infiltrate. They all appear be poorly diferentiated, DCIS is usually not seen, and lymphatic and vascular invasion is not seen.

Clinically, medullary carcinoma presents at a slightly younger age (45-55) as a palpable mass, sometimes with a history of explosive growth, commonly in the upper outer quadrant. Rarely, it has been documented in men; it is associated with BRCA-1 mutations in many cases.

It has benign appearing feautures on imaging studies often mimicking benign disease. The mammographic features of medullary carcinoma include the presence of a well defined mass, sometimes lobulated, absent calcifications, often with a complete or incomplete halo. On ultrasound, they are usually large, well defined , oval, round or lobulated, hypoechoic with through transmission. They have similar appearance to fibroadenomas.

Some studies suggest a more favorable prognosis, yet others suggest that the prognosis is the same as other breast malignancies. Overall at 10 years there appears to be no difference in recurrence rates between patients with medullary carcinomas and other subtypes of invasive breast cancer.

Medullary Carcinoma

The histopathological section of the breast shows a medullary carcinoma show cells that are highly pleomorphic with frequent mitotic activity growing in sheets of cohesive cells.

13564 breast medullary carcinoma histopathology Courtesy Frank Reale MD DB

Other less common tumors include the mucinous or colloid carcinoma which is characterized by its slow growing, soft, well circumscribed nature, that presents as a circumscribed mass in older women. It tends to have a more favorable prognosis.

Tubular carcinomas present in women who are younger (mid 40’s) and are characterized histologically by well formed tubules of malignant cells, often multicentric (10-50%), and sometimes bilateral (10-40%). It has uniformly excellent prognosis.

Paget’s Disease of the Nipple

Paget’s disease of the nippple is a malignant disorder of the nipple areolar complex of the breast, with invasion by cells characterized adenocarcinomatous features accounting for

2-3% of breast carcinomas.. The causative factors are multifactoial, and there is often associated DCIS

Historical notes

The first documentation of Paget’s disease was carried out by John of Ardenne in 1307 who described nipple ulceration in a male priest that evolved into breast cancer. In 1874 Sir James Paget documented the association of the ulceration of the nipple with an underlying breast cancer in 15 patients, but erroneously speculated that the skin condition was benign. Such a conclusion was then rectified in 1881 by Thin who concluded that the skin condition was a malignancy.

Pathogenesis

There are two main theories for the origin of Paget’s disease of the nipple: the epidermotropic theory ( Paget cells arise in breast ducts and migrate to the epidermis) and the intraepidermal transformation theory ( Paget cells arise from the terminal portion of the lactiferous duct). The first theory is supported by the fact that more than 97% of patients with Paget’s disease of the nipple have an underlying breast carcinoma.

Clinical presentation

Paget’s disease typically presents as erythema and scaling of the nipple skin that progresses to crusting, skin erosion and ulceration if left untreated. Symptoms may include pruritus, tingling, hypersensitivity, burning or pain. Many diseases must be included when differentiating Paget’s disease from other conditions that lead to erythema and scaling of the skin. The differential diagnosis therefore includes: eczema, contact dermatitis, postradiation dermatitis, and Paget’s disease. Bilateral changes are most consistent with eczema and contact dermatitis. Less common diseases in the differential diagnoses include nipple adenoma and a variety of skin cancers ( melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma).

The diagnosis is obtained in a variety of ways including scrape cytology, shave biopsy, 2mm punch biopsy, wedge incisional biopsy or nipple excision. Immunohistologic staining is useful in the differentiation of Paget’s ( + for keratins- CK-7, CAM-5.2, + for S100) from other malignancies.

Conventional imaging is usually unable to detect the underlying neoplasia’ though recently the utility of MRI to distinguish between supeerficial disease and deep disease has been utilized.. (Echevarria).

The typical histologic appearance of the Paget cell is that of a large pale-staining cell with round or oval nuclei and prominent nucleoli . Paget cells are between the normal keratinocytes of the nipple epidermis ( single cells in superficial layers and clusters near the basement membrane).

Since Paget’s disease presents earlier it tends to have a more favorable prognosis. However prognosis depends on the presence of a breast mass. When present the prognosis worsens, with a survival rate of 40% at 5 years and about 30% at 10 years. In the absence of a mass survival at 5 years is 90-94%, and at 10 years it is 82-90%

Incidence

Paget’s disease is diagnosed pathologically more frequently than it is clinically . Its clinical incidence ranges from 0.5% to 2.8% (mean 1.3%) whereas its pathological incidence is approximately 4%.

Treatment

Treatment of Paget’s disease varies depending on the presence of underlying breast carcinoma or DCIS. Mammogrephic evaluation looking for evidence of breast cancer is therefore part of the routine evaluation of patients with Paget’s disease (bilateral mammograms). If available, preoperative MRI of the breast can identify occult disease. When possible breast conserving surgical intervention should be considered. THe combination of radiation to breast conserving surgery has been shown to decrease recurrence rates. For patients undergoing mastectomy or breast preservation, the decision of evaluation and treatment of axillary nodes should be reserved for invasive breast cancers.

Cystosarcoma Phyllodes (Phyllodes Tumor)

Phylloides is a rare type of breast disease, more commonly benign, but may be malignant, (10-15%) usually presenting in women with an average age of 70, structurally characterised by features of stromal ori rather than epithelial origin and histolgy that is reminiscent of a fibroadenoma., but with a cellular stroma and epithelial lined branching clefts. The benign disease can be locally recurrent afrter resecction which is another characteristic feature of the disease. Its name originates from the Greek words “sarcoma” meaning fleshy, and “phyllo” meaning a leaf, but because it is more commonly a benign tumor, the term Phyllodes tumor is favored over the more malignant sounding name of “sarcoma”

Clinically it presents as a large, well circumscribed, rapidly enlarging mass in a an elderly patient.

On mammography it is a well circumscribed, solid mass, usually in the 5cms range, and resembles a fibroadenoma. However fibroadenoma presents in young premenopausal patients, and the phylloides tumor is seen in post menopausal elderly patients. On ultrasound the tumor is seen as well circumscribed, and may have cystic spaces in the matrix.

The treatment includes wide local excision with a margin of at least 2cms on lesions <5cms, and a 5cms margin on lesions >5cms. Nodal resection is reserved for those patients where nodes are large enough to raise clinical suspicion. Chemotherapy and radiation therapy are not used in the treatment of phyllodes tumors. Hormonal intervention also has no role.

Well Circumscribed Mass – Phyllodes Tumor

The mammogram is from a 36 year old female who presented with a palpable mass. There is an obvious well circumscribed mass with round borders. In a patient od tgis age fibroadenoma would have been the most likely diagnosis. However the pathology showed cystosarcoma phyllodes.

28249 breast hx 36F fx mass dx cystosarcoma phylloides mammogram mammography Courtesy Priscilla Slanetz MDDB

Magnified View of the Well Circumscribed Phyllodes Tumor

28251 breast hx 36F fx mass dx cystosarcoma phylloides mammogram mammography Courtesy Priscilla Slanetz MD DB

Gross Pathology of the Phyllodes Tumor

The gross pathology specimen shows a 5cms, well circumscribe mass with white fibrous bands and a lobular pattern. Histopathology was consistent with Phyllodes tumor.

11090 breast mass cystosarcoma phylloides 5 cms grosspathology Courtesy Frank Reale MD

Histopathology of the Phyllodes Tumor

The histological section shows findings characteristic of the Phyllodes tumor. The cells have a stromal and fusiform shape that resemble fibroblasts. In this section there is a high degree of cellular atypia.

13537 breast dx cystosarcoma phylloides carcinoma histopathology Courtesy Frank Reale MD DB

Summary of the Pathological Characteristics of breast Carcinoma

Intraductal carcinoma of the breast (DCIS)	Tumor cells fill ducts, tumor cell necrosis results in cheese-like consistency
Invasive ductal carcinoma	Most common type, characterized by tumor cells arranged in cords, islands, and glands embedded in a dense fibrous stroma; abundant fibrous tissue results in firm consistency
Paget disease of breast	Eczematoid lesion of the nipple or areola; neoplastic Paget cells, characteristic large cells surrounded by a clear halo-like area, invade the epidermis; underlying ductal carcinoma almost always present
Lobular carcinoma in situ (LCIS)	Clusters of neoplastic cells fill intralobular ductules and acini; may lead to invasive carcinoma many years later (in the same or contra lateral breast); often bilateral at the time of diagnosis
Invasive Lobular Carcinoma	One or two layers of cells organized in a single-file (“Iindian file”). May encircle the ducts, and often preserve the architecture of the ducts. Grow around ducts and lobules. Lobular carcinomas are frequently multifocal and multicentric
Medullary carcinoma	Cellular with scant stroma; soft, fleshy consistency; characteristic lymphocytic infiltrate, prognosis better than that for invasive ductal carcinoma
Mucinous carcinoma	Pools of extracellular mucus surrounding clusters of tumor cells; gelatinous consistency; prognosis better than for invasive ductal carcinoma
Inflammatory carcinomas	Lymphatic involvement of skin by underlying carcinoma, causing red, swollen, hot skin resembling an inflammatory process; peau d’orange, poor prognosis

Clinical Approach

The approach to the patient with suspected breast cancer should always follow solid clinical principles that include a directed history, and thorough directed clinical examination. These are followed by investigation with imaging, and documentation by biopsy. Once the diagnosis is established, grading and staging of the disease is necessary with the initial goal of establishing whether surgery is indicated.

History Related to the Primary Site

The most common symptom associated with breast cancer is a lump or alteration in the shape of breast. The breast cancer by itself may be painless unless there is a superimposed infection or bony lesion. There may be a change in the nipple in the form of nipple retraction, or nipple discharge. The inflammatory breast cancer may present with pain and redness.

Questions in the clinical history that are relevant include how long the patient has noted the mass, how big the mass is, where it is located, and whether it feels hard or soft. Its relationship to the menstrual cycle, and the presence of associated symptoms such as pain, nipple retraction, nipple discharge, itching, or skin changeare relevant questions.

Directed history probing the possibility of metastatic disease includes symptoms of back pain, bone pain, breathing dificulties, local neurological symptoms, or jaundice. Weight loss, malaise, weakness and fever reflect systemic manifestations of cancer.

The overall risk of the patient is probed by finding out the genetic links of the patient. The incidence is 4 times higher in patients who have a mother or sister with the disease. The risk is also much higher in patients who have family members with a history of both breast and ovarian cancer. The risk is higher in Jewish Ashkenazi women, but lower in African American, Japanese, and Taiwanese women. The patients who have ataxia telangiectasia have a 4 times increased risk. Inherited breast cancer though, only makes up a quarter of all breast cancer cases.

Other diseases that have increased risk include patients with a previous history of breast disease that include breast carcinoma, DCIS. LCIS, complex fibroadenoma, radial scar, sclerosing adenosis, ovarian carcinoma, or endometrial carcinoma.

It is important to ask questions that relate to both lifetime exposure to estrogen, as well as hormonal therapy that incorporates estrogen. The onset of menarche and menopause, obstetric history, and duration of breastfeeding have relevance to the disease. Directed questioning on the use of estrogen containing oral contraception, and hormone replacement therapy both raise the risk.

Signs

The exam for a patient who has suspected breast cancer should include an exam of both breasts.The directed clinical exam explores the size of the mass, its texture, mobilty, and symmetry. Evaluation of the nipple, and overlying skin looking for tethering, inversion, and peau d’orange follows. Nodal assessment in the subpectoral region, axilla, and supraclavicuar area is the next step.

Systemic evaluation for metastases should include evaluation of the sclera for jaundice, neurological exam for focal motor or sensory deficit, the lungs for pleural effusion, and the spine for focal back pain.

Investigations.

Lab Tests

Lab tests are not very helpful in breast cancer. A high calcium level may be seen in bony metastatic disease. Low blood count may be seen due to bone marrow involvement

Imaging

Imaging forms the epicenter of breast cancer management.

Imaging Strategies

All women are recommended to undergo breast cancer screening in form of annual mammogram once they are above 40 yrs of age. After treatment for breast cancer women should continue to undergo annual mammogram except for the women who have undergone bilateral mastectomies. The most important imaging is mammogram however ultrasound may be requested in women with dense breasts or cystic lesions. The MRI may be recommended in women with high risk features such as history of breast cancer in the past , family history or presence of mutations that confers high risk of breast cancer.

Mammography:

Aim:

Mammography is an x-ray technique designed to detect cancers at an earlier stage than physical examination. Earlier detection translates into earlier stage cancer, and hence, improved long-term prognosis. Most cancers detected by mammography are non-palpable and are ductal carcinoma in situ, which is highly curable.

Indications: Current screening guidelines are based on a patient’s individual risk. For the average woman, annual mammography starting at age 40 years is recommended. If the patient is high-risk (i.e. has a first degree relative diagnosed with breast cancer), she should begin screening a decade prior to the relative’s age at diagnosis or 40 years, whichever is soonest. Women who are known carriers of the BRAC-1/BRCA-2 mutations often begin screening in their 30’s as they have an 80% lifetime risk of developing breast cancer (10-12% lifetime risk for average patients). Nearly 40% of women treated with mantle radiation for Hodgkin’s disease prior to the age of 25 years will develop breast cancer by age 45, so these women begin annual screening mammography in their 30’s as well.

Diagnostic mammograms are indicated if a patient has a specific problem, such as pain, lump, thickening, or nipple discharge. This examination is performed on symptomatic patients over the age of 30 years and is usually combined with an ultrasound targeted to the area of concern.

Contraindications: The benefits of any imaging test should always outweigh the risks. In general, there are no true contraindications to mammography. However, mammography is not performed on women who are in the first trimester of pregnancy (unless there is substantial clinical suspicion for breast cancer) or who have an active mastitis. As patients must be able to sit or stand upright, bedridden patients can not undergo the examination.

Advantages: In multiple randomized screening studies, mammography has been shown to reduce breast cancer mortality by up to 30%. This mortality reduction even applies to women in their 40’s, and more recent studies suggest that these women may benefit even more with reductions up to 45%.

Disadvantages: For the rare patient, the breast compression associated with mammography is extremely painful and can not be tolerated. If this is the case, the patient is asked to take motrin or ibuprofen an hour prior to her appointment and to schedule the study during the first week of the menstrual cycle (if applicable).

Method

Patient Preparation: Patients are requested not to wear antiperspirants or powders on the day of the study as the metals in these compounds can appear similar to microcalcifications. Deodorants are usually do not interfere with the images. Patients are also asked to bring all of their prior outside mammograms with them to their appointment as the radiologist will need these as they interpret the current study.

Technique: The patient is asked to undress from the waist up and put on a gown. The technologist takes the patient into a mammography room and reviews the patient information sheet for accuracy and completeness. Each breast is then positioned for the craniocaudad (CC) and mediolateral oblique (MLO) views. The patient waits until the technologist determines that the images are of good quality. She then can leave the center. The radiologist will interpret the screening study later that day. If the patient has a symptom, she will wait at the center until the radiologist reviews the films, as there may be a need for additional mammographic views or possibly even an ultrasound.

Results: Recall for additional imaging from a screening examination ranges from 3-12% depending upon the center. The positive predictive value of biopsy for most centers ranges between 20-40%.

The false negative rate of mammography is approximately 5-15%, depending upon the experience of the interpreting radiologist. Double reading (i.e. two radiologists interpret every screening study) and/or the use of computer-aided detection (CAD) can help reduce the false negative rates by up to 40-60%.

Conclusions: Mammography is a safe, effective tool for the early detection of breast cancer and reduces mortality from breast cancer by up to 30%.

Ultrasound of the Breast

Aim:

Ultrasound uses sound waves to image the breast. This modality is predominantly designed to differentiate a cystic mass from a solid mass. In addition, ulrasound can be used to guide percutaneous procedures, such as fine needle aspiration, core needle biopsy, or percutaneous excision.

Indications:

Ultrasound is indicated to: 1) Evaluate a palpable abnormality on physical exam (focal pain, lump, thickening); 2) Evaluate a mammographic finding (focal mammographic lesion); 3) Evaluate focal pain persistent for greater than 3 months; or 4) To guide a percutaneous procedure such as a core biopsy or fine needle aspiration (FNA). Although there are a few studies using ultrasound to screen for breast cancer, this is not widely embraced as the modality is highly operator dependent. In addition, there are no large randomized studies showing that screening ultrasound reduces mortality from breast cancer.

Contraindications:

There are no known contraindications to breast ultrasound.

Advantages:

Ultrasound is a safe technology with no known side effects. It does not require breast compression. Although usually performed with the patient supine or supine oblique, it can be performed in the upright position in wheelchair bound patients. It offers a means to better characterize palpable and mammographic findings and provides a mechanism to biopsy lesions percutaneously.

Disadvantages:

Ultrasound is highly operator dependent. Despite standard planes to image abnormalities, the detection of an abnormality depends on the skill of the operator. Although there are features on ultrasound which favor benign disease from malignancy, ultrasound can not reliably differentiate solid lesions, and therefore, biopsy is often necessary.

Method

Patient Preparation:

There is no particular preparation for this examination, except that we do ask patients to bring all previous breast imaging studies with them to their appointment.

Technique:

Usually, the patient is asked to lie down on a stretcher. With their arm above their head and in a supine or supine oblique position, the technologist or radiologist places gel on the skin and scans the patient with a linear 12-17MHz transducer in the radial and antiradial planes. Images are usually acquired in both planes if an abnormality is identified and only in one plane if the study is normal. If there is a palpable abnormality, the patient is asked to put their finger on the spot prior to scanning.

Results:

Ultrasound has high specificity for the diagnosis of simple cysts.

Well Defined Mass

The mammogram shows a well defined mass in the breast, which cannot be further characterized. It could be cystic ,in which case no further workup would be necessary, or it could be solid. Ultrasound is extremely helpful in this situation.

mmamogram28239 breast fx mass fx well circumscribed dx simple cyst mammogram mammography Courtesy Priscilla Slanetz MD DB

Ultrasound Showing a Cyst

The ultraound shows a well defined mass in the breast, which is anechoic with through transmission visible as a column of white behind the black cyst. Since this is a simple cyst no further workup is necessary.

28241 breast fx anechoic through transmiision dx cyst USscan Courtesy Priscilla Slanetz MD DB

Ultrasound Showing a Solid Lesion – Fibroadenoma

The ultraound in this instance shows a solid lesion, meaning that there are echoes within the lesion. Biopsy is therefore necessary. This case represented a fibroadenoma.

This a an Us of a solid lesion of the breast. In his case the lesion was a fibroadenoma22260 Courtesy Ashley Davidoff MD code breast fx mass fx solid imaging radiology USscan DB

28241 breast fx anechoic through transmiision dx cyst USscan Courtesy Priscilla Slanetz MD DB

Ultrasound Showing a Solid Lesion – Invasive Ductal Carcinoma

The ultraound in this instance shows a hypoechoic lesion, with irregular ill defined borders and no through transmission, and in fact shadowing or blackness is behind the lesion. This is not a cyst and biopsy is therefore necessary. This case represented an invasive ductal carcinoma.

42933 Courtesy Priscilla Slanetz MD breast Case 16 51 yo screening fx mass Dx: invasive ductal carcinoma USscan Carcinoma typically ill-defined, irregular, spiculated or microlobulated hypoechoic acoustic shadowing taller than wide (transverse to AP ratio < 1.4) Ultrasonographic Analysis of Breast Masses DB

Conclusions:

Ultrasound is a safe modality to evaluate a palpable abnormality or a suspicious mammographic finding. It can reliably differentiate cysts from solid masses.

MRI of the Breast

Aim:

Magnetic resonance imaging (MR) of the breast uses a high-field magnet to image the breast. Multiplanar imaging with different sequences prior to and following contrast administration permits evaluation of the breast tissue. Interpretation of MR studies entails a combination of lesion morphology and enhancement pattern. Lesions that demonstrate early rapid uptake of contrast with a plateau or delayed washout over time are most suspicious for malignancy and warrant biopsy. Gradual uptake of the contrast over time favors a benign process.

Indications:

Current indications for this study are as follows: 1) To determine the integrity of silicone breast implants; 2) To determine disease extent in a newly diagnosed breast cancer patient, particularly younger patients with dense tissue; 3) To identify the breast primary in patients with positive axillary lymph nodes and negative physical exams; 4) To differentiate scar from recurrence in selected patients previously treated for breast cancer; 5) To further characterize an incompletely evaluated suspicious mammographic finding; 6) To monitor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer; and 7) To screen high-risk women, particularly BRCA-1 and BRCA-2 known carriers.

Contraindications:

The standard contraindications to MR imaging apply. In addition, as intravenous gadolinium is given for almost all studies, an allergy to gadolinium would preclude this examination. Relative contraindications include pregnant women as the safety of gadolinium to the fetus is unknown.

Advantages:

MR imaging of the breast is a highly sensitive test with sensitivities approaching 100% for the detection of invasive carcinoma.

Disadvantages:

The specificity is variable depending upon the specific sequences employed and the experience of the interpreting radiologist. In addition, the imaging sequences are not standardized across sites in the U.S..

Method

Patient Preparation:

Patients must be screened for contraindications to MR imaging. Premenopausal patients and cycling postmenopausal patients should be imaged between days 5-15 of the menstrual cycle in order to control for hormonal fluctuations.

Technique:

The patient lies prone on the scanner with her breasts pendent and in mild compression in the dedicated breast coil. An intravenous line is placed through which contrast will be administered. Every center utilizes different sequences for imaging the breasts. In general, most centers acquire images in the sagittal and/or axial plane prior to and following contrast administration. During the contrast injection, dynamic imaging is performed such that images of the entire breast volume are acquired every 1-2 minutes for up to 8-10 minutes following the start of the injection. Using CAD software (Confirma or DynaCad), the enhancement curves can be generated. The entire study usually takes approximately 30 minutes to perform. The radiologist then interprets the images by looking at the lesion morphology and its enhancement pattern.

Results:

MR imaging of the breasts is a highly sensitive test with sensitivities approaching 100% for the detection of invasive carcinoma. Its sensitivity for ductal carcinoma in situ ranges between 10-90% depending upon the center and its sequences. Specificity for this study ranges between 75-90%, once again depending on the specific sequences employed. The false negative rate of MR is unknown.

Conclusions:

MR imaging of the breast serves as a useful adjunct to other breast imaging modalities and for screening high-risk women, particularly known carriers of BRCA-1 and BRCA-2. MR-guided percutaneous core needle biopsy is now available at most centers permitting minmally invasive diagnosis of suspiciously enhancing lesions detected only on MR imaging.

PET Scan

PET scan is not usually recommended for the work up of breast carcinoma. It is limited by the size of the tumor and tumors less than 1cms may not be identified. While it is sensitive and able to detect invasive ductal carcinoma, it is not sensitive to in situ carcinomas and less sensitive to lobular carcinoma.

Reporting the Findings on Imaging Studies

Breast Imaging Reporting and DataSystem (BI-RADS)

BI-RADS is a standardized method of reporting mammography studies allowing for a quality assurance mechanism, consistency and clarity of the reports. It was developed by the American College of Radiology as a standard for rating the liklihood of cancer by setting up levels of suspicion. BI-RADS system takes into account presence of a discrete nodule, calcifications, and architectural distortion of focal asymmetric densities.The radiologists scores the findings from 1-6 providing the referring physician a standardized report on the liklihood of cancer in their patient.

BI-RADS Scores

Category	Assessment	Criteria
0	Incomplete	The mammogram or ultrasound does not provide enough information to make a clear diagnosis; follow-up imaging is necessary
1	Negative	routine screening recommended
2	Benign	A definite benign findingis present; routine screening recommended
3	Probably Benign	Findings that have a high liklihhood of being benign six-month short interval follow-up, then every 6-12 months for 1-2 years
4	Suspicious Abnormality	Not characteristic of breast cancer, biopsy should be considered
5	Highly Suspicious of Malignancy	Lesion that has a high probability of being malignant biopsy needed
6	Known Biopsy Proven Malignancy	Lesions known to be malignant that are being imaged prior to definitive treatment; assure that treatment is completed

Diagnosis

Once an abnormality is detected in the breast by palpation or imaging studies, the gold standard for diagnosis is hitospathological exam of a biopsy specimen. The optimal method to do biopsy is decided upon size, depth and nature of abnormality. Cystic lesion may be aspirated under ultrasound guidance. Fine needle aspiration may be done which may help in diagnosis. Core biopsy is an excellent method, the lesion may be studies in greater detail as well as staining is possible for hormone receptors. It may be done by stereotactic guidance or needle localization. Rarely when a lesion is not accessible incisonal biopsy may be needed.

Biopsy

Histopathological examination of breast biopsy of the suspicious lesions remains the gold standard of diagnosis. This is most commonly performed using imaging guidance. In the event that usual techniques are indeterminate or fail then surgical biopsy is performed.

The image guided techniques include ultrasound, stereotactic (X-ray using specially designed mammography equipment), and MRI.

Ultrasound is the most commonly performed because it allows real time visualization of the needle and the lesion, and avoids radiation. Stereotactic guidance is used when calcifications are present since it is more sensitive than ultrasound to identify this important aspect of the lesion. MRI is performed when the lesion cannot be seen by ultrasound or mammography. Surgery is performed when the above techniques fail.

Percutaneous breast biopsy is usually performed as an outpatient using imaging guidance, commonly by ultrasound, but mammography and MRI are also utilized.

Aim

The aim of the procedure is to obtain sufficient tissue to diagnose malignancy and to characterize the tissue relating to its specific histopathological type, grade and hormonal receptor status.

Indications

Based on the BI-RADS system the lesions for biopsy are most commonly those designated as BI-RADS score 4 or 5. There will be some uncommon situations where a biopsy for a category 3 lesion is indicated, (eg inability to obtain mammographic follow up, anxiety about the lesion, planned pregnancy, planned breast cosmetic surgery) but the goal is to avoid biopsy of benign disease.

Since many lesions identified by mammography are impalpable, and are seen only by mammography or ultrasound, image guided biopsy is utilized. Ultrasound guided procedures are most widely used since they are real time inferring that the needle can be observed as it is advanced into the lesion. Ultrasound also avoids radiation, and is relatively inexpensive. However when microcalcifications are present, tor when the lesion cannot be seen by ultrasound then stereotactic biopsy is employed. MRI guided procedures are used when the the lesion can only be seen by MRI.

Contraindications

There are no absolute contraindications and only relative contraindications. Obviously if the lesion cannot be definitely seen it cannot be biopsied. In patients who cannot come off anticoagulation, there is a relative contraindication to the procedure, but this circumstance is rarely encountered.

Advantages

The risks of the procedure are low, and the need to diagnose the disease, evaluate the type, and grade the tumor are essential to treatment planning.

Disadvantages

There are no disadvantages other than the innate concerns of radiation in the case of stereotactic method, and the risk of bleeding, infection and low seeding the tumor.

Method

Patient Preparation

The procedure, the technique, and the risks and benefits need to be explained to the patient in a quiet and confident manner and informed consent is necessary.

Aspirin prophylaxis should be stopped a week before the procedure, and any other anticoagulation should be discontinued to enable the INR to be below 1.5. The patient does not have to be NPO

Equipment

There are a variety of needles and cutting devices that are used. Cytological apsirates are no longer used by radiologists, who only use only core technique. The cutting needles which are used for obtaining a core are usually 14 gauge. More recently use of the vacuum assisted devices (VAD) are being utilized , since they are able to obtain larger samples of tissue. The 9 French cutting needleincreases the yield of invasive carcinoma in a DCIS environment, because the larger sample size. In general these are used for the stereoscopic and MRI guided procedures.

Technique

All of the procedures require sterile technique, and local anesthesia.

Whichever technique is used the principles include;

find the shortest distance to the lesion and transgress the least amount of tissue

biopsy it,

mark the biopsy site with a clip,

prove that the appropriate tissue was acquired by specimen X-ray for microcalcifications, or post procedure mammogram to prove that the lesion has disappeared.

Fine needle aspirate

Fine needle (FNA) using a 21 gauge needle is the least invasive and most commonly used needle and has a sensitivity of 50-95%% and a specificity of 95-100%. As stated radiologists do not use this technique due to the limited amount of information that it provides.

A slow back and forth motion in the lesion observing the needle in real time, until some material is seen in the bottom of the barrel of the syringe.

The aspirate is transferred onto glass slides, and is spread by a second glass slide in order to ensure that the material thinly distributed. This is best done by an attending cytopathology technologist. Staining techniques are individualized by the preference of specific pathology laboratories.

Core Biopsy

Core biopsy specimens may be obtained in a variety of ways. A 14 gauge trucut needle using a spring loaded firing device, facilitates needle penetration of hard fibrous elements in the tumor which may otherwise be difficult to penetrate. The volume of tissue is larger than the aspirate, and the architecture of the tumor can be appreciated. Once the specimen is obtained the material is transferred to formalin. If the lesion was known to contain calcifications then specimen radiographs are obtained to ensure accuracy of sampling.

A pressure dressing is usually applied for 24 hours after the procedure to prevent or limit bleeding.

Vaccuum Assisted Device

The VAD is usually an 11 gauge percutaneous system that is vaccum driven used in stereotactic biopsies and in MRI. It is particulalrly helpful in the DCIS environment where a small pocket of invasive carcinoma may be present. In this instance the larger the sample the more likely one is able to identify invasive disease.

On occasion it is used to excision benign lesions that are less than 15mm in size. The purpose is to avoid surgery for benign disease.

Results

The fine needle procedures appear to be adequate if the only question is the presence or absence of malignancy. It requires cytopathologists, who are experienced in the technique. It proves to be inadequate for treatment planning since detailed information of the architecture grade, and histologic type is needed, that can only be provided by core specimens. The Tru Cut needle which is a well known core biopsy needle has a sensitivity that ranges between 64%-84%, and the 14gauge Biopty cut has a sensitivity of 88-98%. Both have specificity of 100%.

Complications

The complications of the procedure include bleeding and infection. Hematomas have become more frequent as the sizes of the needles have increased in size. The MRI guided procedures are particulalrly prone to hematoma because while the patient is in the scanner the ability to identify bleeding or to compress bleeding if it is present is restricted, since the patient is out of reach and observation while in the gantry.

Conclusion

Biopsy of an equivocal finding in the breast is an essential and key step in the diagnosis and management of breast carcinoma. The histopathological type, grade, and hormone receptor status are necessary before embarking on a treatment program. Ultrasound and core biopsy technique are favored in most cases, while stereotactic biopsy is favored when microcalcifications are present, or the lesion cannot be seen by ultrasound. MRI guided procedures are utilized when it is the only modality able to visualize suspicious areas. Needles have become larger so that current sized needles range from 9 gauge to 14gauge, though some institutions use 18 gauge for the cores and 21 gauge for cytology. Surgical excisional biopsy is used for lesions that reveal equivocal pathological findings such as atypical intraductal hyperplasia, or in breasts that are less than 25mms when compressed.

Microcalcifications Identified on Mammography

A cluster of suspicious pleomorphic calcifications are identified on a mammogram. These could represent either DCIS, or invasive carcinoma. A sterotactic biopsy is indicated, and a specimen radiograph of the biopsy follows.

28171 breast fx calcification mammogram mammography Courtesy Priscilla Slanetz MD DB

Specimen Biopsy Confirms That Correct Tissue has Been Biopsied

Microcalcifications Present

28173 breast fx calcification pathology Courtesy Priscilla Slanetz MD DB

Cytopathology Specimen Infiltrating Ductal Carcinoma

This cytopathology specimen shows cells with high nuclear to cytoplasmic ratio characteristic of malignant tissue. Further characterization is difficult due to the limited amount of tissue that the pathologist has to work with.

13552 breast + dx infiltrating ductal carcinoma + cytopathology histopathology Courtesy Frank Reale MD DB

Evaluation of Regional Nodes – The Axilla

The clinical examination of the axilla is not a sensitive nor specific procedure, and in the patient who is being prepared for surgery one of the key issues is to determine whether the regional nodes are positive for disease.

Preoperative evaluation with ultrasounded guided biopsy of suspicious nodes is a recent innovation that provides the surgeon with critical information. A negative biopsy is not usually helpful, though a positive biopsy may avoid extensive surgery.

Alternatively sentinel node imaging oof axillary nodes allows directed intraoperative sampling of lymph nodes by directing the surgeon to the node or nodal group that will most likely contain disease.

Prognostic Indicators

The prognosis and treatment of breast cancer are intimately related and multifactorial . At the simplest level, tumor size in the absence of nodal disease is an independent predictor. The prognosis detriorates with increasing size.

If the nodes are negative, then the averahge 10 year survival is 60-70%. If the nodes are positive the 10 year survival decreases to 20-30%.

Treatment Strategies

Treatment strategies are dependent on many factors primary of which, is the stage at diagnosis. The surgeon’s recommendation is based on the biopsy results and the extent of the disease.

The patients are divided into two broad groups at this stage; Those with disease that appears to be localized to the breast, and those that have definite disease that has spread beyond the breast. This broad division translates in to two therapeutic groups. The first group, where extent of disease is unknown, require surgery and evaluation of axillary nodes. The second, is the group that have locally inoperable disease or have spread beyond the breast and are inoperable. When the disease presents with obvious extension beyond the breast, where the skin regional lymph nodes or distant metastases are present, then surgery is not recommended.

We will follow the course taken by the first group of patients first andf then consider the therapeutic options available to the second group.

Surgical Options

In the absence of known regional involvement, surgery is the primary treatment since early stage patients can be cured by surgery alone.

The goal of surgery is;

complete resection of the tumor with negative margins and

regional pathologic staging of the tumor by establishing nodal involvement.

Resection of the Primary Tumor

The resection of the primary tumor may be by lumpectomy or mastectomy and is tailored according to the lesion, the breast size, the location of the tumor, the possibility of changing any of these factors preoperatively with chemotherapy, the patient’s needs and the skill of the surgeon and skill and experience of the overall team.

Breast conserving surgery in form of lumpectomy and radiotherapy lends itself best to small size tumors which are localized . It requires that the tumor is excisable with resulting negative margins and an acceptable cosmetic result. Thus a small lesion in a small breast may not be amenable for breast conserving therapy since the cosmetic result would not be acceptable. On the other hand a large lesion in close proximity to the skin or the chest wall may not be amenable for breast conserving therapy either. Sometimes such a lesion may be treated with chemotherapy before the surgery and if significant reduction in size is attained, then breast conserving surgery could become possible.

Lumpectomy infers resection of the tumor, ideally resulting in a 1cms disease free margin. Contraindication to lumpectomy includes multicentric diseasae, repeated positive margins, or a large primary tumor. Radiotherapy (XRT) is sometimes used as an adjunct to breast conserving surgery to prevent local recurrence, usually reserved for patients with invasive ductal carcinoma or DCIS, tumor size <3cms, negative surgical margins and negative nodes.

A total mastectomy is the complete removal of breast tissue, without necessarily removing any lymph nodes.

A radical mastectomy is the removal of the breast tissue with en bloc removal of the pectoralis muscle and and axillary nodes.

A modified radical mastectomy is a total mastectomy with axillary node dissection.

Each of these surgeries is in some way dependant on the local disease, and the suspicion or knowledge of nodal disease. Either way nodal involvement has to be established pathologically, and there are multiple mechanisms of trying to establish involvement.

Other Surgery

Breast reconstruction surgery:

Reconstruction of breast after mastectomy is done either at time of surgery or months after primary surgery. Some women choose not to undergo reconstruction.

Prophylactic mastectomy:

Some women choose to undergo prophylactic mastectomy of opposite breast at the primary surgery of affected breast. Some young patients with high risk mutations and strong family history may choose to undergo prophylactic mastectomy.

Bilateral ovary removal:

Some women may undergo ovary removal to reduce the amount of circulating estrogen thus reducing risk.

Nodal Evaluation

Anatomy of the Lymph Nodes

The breast has a very rich supply of lymphatics, with the dominant flow being toward the axilla. The lymphatics originate in the lobules, and they accompany the veins and ductal systems coursing toward the nipple and areola. An extensive network develops in the subareolar region called the subareolar plexus.

There are about 35 nodes that drain the breast and they are basically divided into 4 regions. The axillary nodes are the largest group and they drain about 75% of the breast. The other major groups include the parasternal group, the infraclavicular group, and the supraclavicular group.

Lymphatic supply of the breast

There are 4 basic groups of lymph nodes the largest of which are the axillary group (1) which account for 75% of the lymphatic drainage. The other groups are the infraclavicular (2), supraclavicular (3), and parasternal (4) groups of nodes. Davidoff MD. 78378pb06l05

Subgroups of the axillary system of nodes

There are subgroups of the axillary nodes that mostly lie alongside the veins described above. The first of these is called the anterior pectoral group (aka low axillary nodes), consists of about four nodes, and are distributed alongside the lateral thoracic vessels on the lateral border of the pectoralis muscles. The nodes that lie along the axillary vein are called the central axillary nodes. The nodes that lie alongside the subclavian vein are called the subclavian nodes.

There is a set that is not necessarily associated with any specific vein that lies deep to both pectoral muscles under the breast. This group is called the deep fascial system and they drain into set of nodes between the pectoral muscles called Rotter’s nodes. Subsequently some of these nodes will drain into the subclavian nodes and some will drain medially into the internal mammary system which finally drains into the mediastinal nodes.

The other regions described including the infraclavicular, supraclavicular and internal mammary lymphatic drainage are less dominant sites.
Even more uncommon is drainage to the infradiaphragmatic nodes.

It should also be noted that there are intramammary lymph nodes that sometimes masquerade as a breast mass since they have features. On mammography they are typically reniform in shape, have a fatty or radiolucent notch, are less than 1 cm in size and are usually in upper outer quadrant. Cyrlak describes a case of an enlarged intramammary node that turned out to be a site of metastatic involvement of breast carcinoma.

Applied Anatomy

Lymph nodes

This is a CT scan of a 62year normal female that shows axillary nodes on the right. These nodes are considered “level 1” lymph nodes in surgical terminology (yellow). They lie lateral to the pectoral muscles. On the left the nodes in orange are level 2 nodes and they lie deep to both pectoral muscles. They belong to the group called the deep fascial system. Courtesy Ashley Davidoff MD 43843 43843b02

The staging and hence the management of breast carcinoma depends to a large extent on whether the lymph nodes of the breast are involved. Most of the search for disease is directed to the axillary group of nodes. Clinical examination is the first step, mammographic findings the second, sentinel node evaluation using radiopharmaceuticals the third, and surgery and microscopic evaluation the fourth. In cancers involving the medial breast tissue, when the axillary nodes are negative the internal mammary chain is involved in only about 15% of cases, and in lateral cancers the internal mammary nodes are only involved in about 5% of cases.

Lymph nodes

This mammogram reveals large and dense nodes in left axilla. This patient had leukemic involvement of these nodes. Courtesy Priscilla Slanetz MD MPH 43000

The sentinel node is defined as the first lymph node to drain a region of the breast and in the setting of breast carcinoma would be the first node to contain metastatic disease.

The Sentinel Node Evaluation

If the nodes are clinically negative then the approach is to evaluate the sentinel node which is the node or group of nodes that drain from the breast to the axilla. Sentinel node identification is evaluated by injecting a small dose of low level radioactive technetium 99 and isosulfan blue dye into the skin in the region of the tumor prior to surgery. A period of between 1-8 hours allows the blue dye and tracer to be taken by the lymphatic system to the regional nodes. A hand held gamma ray counter allows the surgeon to identify the sentinel node. A small incision is made over the radioactivity and between 1 and 3 nodes are removed and given to the pathologist. By this means only limited dissection of the lymph nodes is attained with reasonable certainty that if the sentinel nodes are negative then nodes more distal are negative. If it the sentinel node is positive the tumor is upstaged and further dissection of the lymph nodes is required. In the past all axillary nodes would have been removed with consequent morbidity, including significant swelling of the arm from lymphedema and consequent cellulitis.

Axillary Node Evaluation

Surgical approach to lymph node dissection and resection requires dividing the nodes into 3 levels, going in general from lateral to the breast, to deep and under the breast and pectoral muscles, to deep and medial to the breast. More specifically, a level I dissection is bordered by the axillary vein superiorly, the lateral border of the pectoralis major and minor muscles medially, and the latissimus dorsi muscle laterally. A level II dissection includes nodes below the pectoralis minor muscle, and a level III includes nodes medial to the pectoralis minor muscle and below the costoclavicular ligament. In general if a patient requires lymph node dissection, resecting nodes from Level I and II is considered adequate. Level III nodes are only removed if they are suspicious .

It is now reasonable to discuss staging disease in both groups of patients. Those who were subjected to surgery who now are post op with knowledge of nodal status, and those that were considered inoperable due to extensive inoperable local disease or due to known regional or distant disease.

Staging

Cancer stage is based on the size of the tumor, whether the cancer is invasive or non-invasive, whether lymph nodes are involved, and whether the cancer has spread beyond the breast.

Stage 0

Stage 0 is used to describe non-invasive breast cancers, such as DCIS and LCIS. In stage 0 the cancer is contained and there is no evidence of cancer spreading to normal surrounding tissue.

Stage I

Stage I describes invasive breast cancer wherein there is evidence of cancer cells are invading the surrounding normal tissue

the tumor measures up to 2 centimeters, and
no lymph nodes are involved

Stage II

Stage II is divided into subcategories known as IIA and IIB.

Stage IIA describes invasive breast cancer in which:

no tumor can be found in the breast, but cancer cells are found in the axillary lymph nodes (the lymph nodes under the arm), OR
the tumor measures 2 centimeters or less and has spread to the axillary lymph nodes, OR
the tumor is larger than 2 centimeters but not larger than 5 centimeters and has not spread to the axillary lymph nodes

Stage IIB describes invasive breast cancer in which:

the tumor is larger than 2 but no larger than 5 centimeters and has spread to the axillary lymph nodes, OR
the tumor is larger than 5 centimeters but has not spread to the axillary lymph nodes

Stage III

Stage III is divided into subcategories known as IIIA, IIIB, and IIIC.

Stage IIIA describes invasive breast cancer in which either:

No tumor is found in the breast. Cancer is found in axillary lymph nodes that are clumped together or sticking to other structures, or cancer may have spread to lymph nodes near the breastbone, OR
the tumor is 5 centimeters or smaller and has spread to axillary lymph nodes that are clumped together or sticking to other structures, OR
the tumor is larger than 5 centimeters and has spread to axillary lymph nodes that are clumped together or sticking to other structures

Stage IIIB describes invasive breast cancer in which:

the tumor may be any size and has spread to the chest wall and/or skin of the breast AND
may have spread to axillary lymph nodes that are clumped together or sticking to other structures, or cancer may have spread to lymph nodes near the breastbone
Inflammatory breast cancer is considered at least stage IIIB.

Stage IIIC describes invasive breast cancer in which:

there may be no sign of cancer in the breast or, if there is a tumor, it may be any size and may have spread to the chest wall and/or the skin of the breast, AND
the cancer has spread to lymph nodes above or below the collarbone, AND
the cancer may have spread to axillary lymph nodes or to lymph nodes near the breastbone

Stage IV

Stage IV describes invasive breast cancer in which:

the cancer has spread to other organs of the body — usually the lungs, liver, bone, or brain

“Metastatic at presentation” means that the breast cancer has spread beyond the breast and nearby lymph nodes, even though this is the first diagnosis of breast cancer. The reason for this is that the primary breast cancer was not found when it was only inside the breast. Metastatic cancer is considered stage IV.⁸

Additional staging information

Terms such as “early” or “earlier” stage, “later,” or “advanced” stage breast cancer are not medically precise but are often used by medical professionals loosely.

following is the break up of early versus advanced.⁸

Early stage

Stage 0
Stage I
Stage II
Some stage III

Later or advanced stage

Other stage III
Stage IV

TNM

TNM (status of Tumor, Nodess and Metastases), is another method of defining and classifying breast carcinoma.

Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic classification.

Primary tumor (T) . ⁹

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Intraductal carcinoma, lobular carcinoma in situ, or Paget disease of the nipple with no associated invasion of normal breast tissue
- Tis (DCIS): Ductal carcinoma in situ
- Tis (LCIS): Lobular carcinoma in situ
- Tis (Paget): Paget disease of the nipple with no tumor.
T1: Tumor not larger than 2.0 cm in greatest dimension
- T1mic: Microinvasion not larger than 0.1 cm in greatest dimension
- T1a: Tumor larger than 0.1 cm but not larger than 0.5 cm in greatest dimension
- T1b: Tumor larger than 0.5 cm but not larger than 1.0 cm in greatest dimension
- T1c: Tumor larger than 1.0 cm but not larger than 2.0 cm in greatest dimension
T2: Tumor larger than 2.0 cm but not larger than 5.0 cm in greatest dimension
T3: Tumor larger than 5.0 cm in greatest dimension
T4: Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below
- T4a: Extension to chest wall, not including pectoralis muscle
- T4b: Edema (including peau d’orange) or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast
- T4c: Both T4a and T4b
- T4d: Inflammatory carcinoma

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed (e.g., previously removed)
N0: No regional lymph node metastasis
N1: Metastasis to movable ipsilateral axillary lymph node(s)
N2: Metastasis to ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident lymph node metastasis
- N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
- N2b: Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis
N3: Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or, metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
- N3a: Metastasis in ipsilateral infraclavicular lymph node(s)
- N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
- N3c: Metastasis in ipsilateral supraclavicular lymph node(s)

* [Note: Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible pathologically.]

Pathologic classification (pN)*

- dissection but not clinically apparent** (If associated with more than three positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to reflect increased tumor burden.)

Distant metastasis (M)

MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

AJCC Stage Groupings

Stage 0

Tis, N0, M0

Stage I

T1*, N0, M0

Stage IIA

T0, N1, M0
T1*, N1, M0
T2, N0, M0

Stage IIB

T2, N1, M0
T3, N0, M0

Stage IIIA

T0, N2, M0
T1*, N2, M0
T2, N2, M0
T3, N1, M0
T3, N2, M0

Stage IIIB

T4, N0, M0
T4, N1, M0
T4, N2, M0

Stage IIIC**

Any T, N3, M0

Stage IV

Any T, Any N, M1

Management After Staging

Following are the modalities that are employed in management of breast cancer

The treatment may be in either of the following sequences in most cases.

surgery → radiation → possible hormonal therapy
surgery → chemotherapy → radiation → possible hormonal therapy
Chemotherapy, targeted therapy, or hormonal therapy → surgery → radiation → possible hormonal therapy.
Chemotherapy – possibly radiation for palliation

Chemotherapy:

Chemotherapy is recommended on the basis of findings after surgery, relating to tumor size and lymph node involvement. In addition to stage of disease hormonal receptor status as well as Her 2 neu status. Chemotherapy affects rapidly dividing cancer cells and therefore may also affect cells of blood, hair, and gastrointestinal tract. The most common side effects of chemotherapy are hair loss, low blood counts, nausea and vomiting. Monoclonal antibody against Her 2 neu is used if the receptor is positive in tissue. Anti hormone medications are used in case hormone receptors are positive.

Chemotherapy has played a major role in cancer treatment for half a century. The cancer drugs work by killing the rapidly dividing cells. Since the cancer cells are rapidly dividing they are affect other rapidly dividing cells and tissues. However there are certain normal cells in the body that have very rapid turnover and are affected by chemotherapy such as bone marrow and gastrointestinal epithelium and hair follicles. Therefore patients receiving chemotherapy may suffer decrease blood cell counts, hair loss and diarrhea. Unlike radiation and surgery which are much more localized, chemotherapy can target cancer cells that have escaped from the original tumor site and may cause metastasis.

Chemotherapy may be used for following goals depending upon staging and type of cancer.

Cure of the cancer by eliminating all cancer cells in the body, even when cancer is widespread
Prolong life by controlling cancer growth and spread
Relieve symptoms and enhance quality of life
In conjunction with radiation they can act as radiosensitizers, making cancer cells more susceptible to radiation
Following surgery to enhance results. This is called as adjuvant therapy.
Prior to surgery or radiation making disease more amenable to treatment and is called as neoadjuvant therapy.

Radiation:

Radiation therapy is important in all stages of breast cancer. It is important from stage 0-III for treatment of breast cancer. Radiation attempts to destroy the cancer cells left behind after lumpectomy or mastectomy. It may have a role in palliation in stage IV. Side effects of radiation are usually limited to the localized to the area of radiation.

Hormonal therapy:

Hormonal therapy is used in patient with hormone receptor positive cancers. Hormonal therapy medicines treat hormone-receptor-positive breast cancers in two ways:

by lowering the amount of the hormone estrogen in the body
by blocking the action of estrogen in the body

The estrogen is produced primarily by ovaries in a woman’s body and therefore women who are premenopausal may undergo bilateral ovary removal. There are two drug classes which are used for hormonal therapy.

Selective estrogen receptor blocker, blocks the selected estrogen receptors in breast tissue but may bind and activate estrogen receptors in other part of the body.

Aromatase inhibitors, block production of estrogen. Since they cannot inhibit estrogen production in ovaries, they are therefore are only effective in postmenopausal women.

Targeted Therapies:

There are three types of targeted therapies

Trastuzumab: It is a monoclonal antibody that blocks her 2 Neu a receptor found in some breast cancer. Blocking the receptors helps block the proliferation of cancer cells.

Lapatinib: It is also a her 2 neu receptor blocker.

Avastin: It is a vascular endothelial growth factor block which prevents the proliferation of blood vessels on which cancer cells depend to multiply.

Principles of Treatment of Breast Cancer

Principles of treatment relate to the staging of tumor:

Stage 0:

Refers to non invasive cancer or DCIS. DCIS is optimally treated with mastectomy. Breast conserving surgery i.e. lumpectomy and radiation is also an option. Lymph node dissection is usually not done. However sentinel lymph node biopsy can be carried out. Tamoxifen may be used for chemoprevention in hormone receptor positive tumor

Stage I:

Most stage one breast cancers are treated with mastectomy. Although a majority of breast cancer may be treated by lumpectomy and followed by radiation. Tumors larger than 1 cm have higher recurrence rate. Hormone treatment is recommended in cancers which are hormone receptor positive to reduce recurrence. Tamoxifen reduces recurrence risk by 40-50%. Recurrence score may be calculated using gene based prognostic score and a recommendation if chemotherapy is needed or not is made.

Stage II:

Stage II breast cancers are treated by mastectomy or breast conserving therapy as appropriate with sentinel axillary lymph node dissection or extensive axillary lymph node dissection as appropriate. Chemotherapy confers a higher absolute risk reduction and therefore recommended. Radiation is recommended following mastectomy to patients who have 4 or more positive lymph nodes. Hormone therapy is recommended for hormone receptor positive tumor.

Stage III:

Patients with stage III breast cancer can be classified into two general categories. Some have large tumors, without skin involvement or fixation to deeper tissues, which are clearly operable. Others have neoplasms that are considered inoperable because skin involvement or fixation to the underlying chest wall precludes total resection with clean margins. Some stage III tumors can be treated as stage II. Inoperable stage III tumors may require chemotherapy/radiation followed by radiation. Hormonal therapy is recommended upfront if chemotherapy cannot be administered. Radiation therapy is considered a cornerstone of local therapy.

Stage IV:

Metastatic disease should be considered and approached as a chronic illness. The goals of therapy are to palliate symptoms, prolong life, and, if possible, achieve a long term, disease-free state. The options are from cytotoxic chemotherapy, hormonal therapy and targeted therapy depending on Her 2 positive status. Patient who are in poor general health or have other serious medical condition may be treated with hormonal therapy if cancer is hormone receptor is positive or supportive measure.

The treatment of breast cancer is complex and needs to be tailored to each patient, and a multidisciplinary approach by an oncology team is extremely useful.

Oncology Team

The team of subspecialists consist of the following members.

The radiologist is responsible for interpreting the mammogram, ultrasound or MRI, and then in the patient with the non palpable mass is instrumental in the biopsy of the abnormality. In the staging evaluation of metatstattic disease, evaluation by CTscan, MRI, PET scan, or bone scan is in the pervue of the radiologist.

The pathologist particpates both preoperatively as well as postoperatively. In the preoperative patient grading of the tumor, identifying the type of breast cancer, hormone receptor status, as well as Her 2 neu status. During and after surgery evaluation of the margins of the primary tumor and involvement of the nodes enables the post operative staging and prognostication of the tumor.

Surgeons help in deciding which type of breast surgery would be most apprpriate for a given situation, and then executing the surgery in the operating room and deciding which nodes to evaluate or remove.

The radiation oncologist: particpates in the control of local and regional disease as well as palliation of symptoms in advanced and metastatic disease.

The oncologists coordiate the care, integrate the care and direct chemotherapy including the type of chemotherapy, and the utility of hormonal therapy or targeted therapy. Oncologists usually monitor patient on long term basis to assess recurrence and prompt management of recurrent disease.

Nurses provide care to the patient thorough all the steps of treatment in the operating room, in administering chemotherapy in oncology unit, and as confidants and support for those who need it. Nurses undergo special training to assist in the OR and to administer chemotherapy.

Multiple other technologists are involved with the patient care, including radiology technologists, radiation therapy technologists, and lab technologists. Patients often develop important and intimate relationships with the technologists and nurses.

Social workers deal with issues such as financial hardships, transport and providing assistance in placement to rehabilitation centers or hospice.

Nutritionists help in supporting nutritional status of the patients especially with side effects associated with treatment such as mucositis.

Hospice nurses: Help in care of end of life issues in patients who are dying due to their disease

Psychological Aspects

Diagnosis of breast cancer is devastating news for most patients, and runs deep and profound. Along with dealing with a potentially life threatening disease most women worry about the effect of treatment on their appearance. It is important to address these issues at the outset as well as periodically during duration of treatment. If required an appointment should be made to seek assistance from a psychologist or psychiatrist. Support groups are extremely helpful allowing the patient to express deep feelings that are common to many woman with the same disease allowing for some cathartic and therapeutic beneficial effects.

Critical illness leaves no aspect of life untouched. Diagnosis of cancer, as well as stress associated with cancer, is trying for most patients. The initial period is dominated by medical aspects of obtaining diagnostic information and undertaking primary or adjuvant therapy. Fear anxiety and pain are common at this stage. Coping with therapy requires all the adaptive energies of most patients. Following treatment, there is an extended period when patients adjust to the follow up after acute treatment. Providing psychosocial support to patients during these phases is essential.

Families and friends are an important source of psychological support. Social workers are also an important source of support to patients. For patient in terminal stages of cancer patient may have fear, pain and felling of helplessness and loss of control over their lives. It is important allow patients to take control of their lives and treatment decisions. Patients also worry about being a burden on their families. Therefore it is important to allow the patients to make decisions about where they want to be treated.

Family

Breast cancer not only affects the patients but also their families. A number of patients may have young families and may find it difficult to talk to their young children about their diagnosis. Many sources such as American cancer society may be resources that patient can refer to. It is important to prepare the family members such as spouses and young children as to how the treatment will affect daily routine.

Family members undergo considerable psychological turmoil when a loved one is diagnosed with cancer. The distress may at times be considerable enough to affect the patient. The best way to deal with these issues is to educate and provide support to family members as sometimes they may be the primary caregiver of the patients. Some patients may not like the family members to be involved in their care.

Social

Diagnosis of cancer affects all aspects of a patient’s life. A number of patients continue to work full time during treatment while others choose to take time off. Most patient struggle with the impact of their diagnosis and worry about their appearance and economic impact of the treatment. Patients can and should continue their normal life as much as possible.

Their every day life is affected and they may have questions such as …. Will I lose my hair? Will my appearance change? How will my social life be impacted? Will I be able to go out and enjoy a meal in the restaurant?

Most patients are able to work through their diagnosis and treatment. The ability to adapt to the disease, depends on the patient’s age and performance status prior to beginning the therapy. The patient may feel conscious about hair loss while going out in public, therefore an effort should be made to address this issue at the outset. The oncology nurse will usually go over with the patient about wigs and uses. Most patients are able to go out and spend time with the family and friends however if they are neutropenic but it is recommended that they avoid crowded places and certain foods. Patients undergoing transplant may be asked to make lifelong dietary changes for example; to eat only well done meats.

It is important to address issues such as fertility, future pregnancy and contraception

Nutritional

Nutrition is important as good nutrition help keeps the body strong so that treatment can be administered in a timely fashion. A nutritionist may help in formulating a healthy diet — one with a variety of foods that includes lots of fruits and vegetables and regular protein — which gives the reserves of nutrients that patients need to keep their strength up while being treated for breast cancer. These reserves also help rebuild body’s tissues and keep immune system strong to help fight off infection. Plus, a healthy diet can help in managing treatment side effects. There is evidence that some cancer treatments actually work better in people who are eating enough calories and protein. During the breast cancer treatment, it’s more important than ever that patients eat a healthy diet.

Patients may lose weight and appetite secondary to the cancer. Challenges to nutrition are as a result of chemotherapy induced nausea, vomiting , mucositis and diarrhea and radiation induced mucositis and diarrhea . Patients may become severely dehydrated and their nutrition may suffer severely. It is important to take a good nutritional history as well as history of any adverse effect that may severely impact oral intake. A focused exam should include looking for mucositis. Patients may do well with nutritional shakes and soft diet while these symptoms abate. A nutritional consult is often helpful in determining the available options.

New Advances

The field of cancer is changing everyday. There are new and improved drugs that are coming out, or in pipeline;

Targeted therapy: These drugs target a particular abnormality or receptor in the cancer cell, and therefore normal cells may be spared from chemotherapy.

Radioimmunotherapy: radioactive ligands such as iodine are tagged on to antibody targeting a specific molecule and thus allow for targeted radiation and immunotherapy

Defining risk and response in the patients: Scientists are looking for parameters that may predict if a tumor will respond to a particular chemotherapy and therefore allowing the patient to be treated only if they have responsive disease.

End of Life Issues

End of life issues are major part of caring for a cancer patient. It is important to help a patient and family understand their prognosis and help them cope with their terminal illness.

Hospice: Hospice care is a philosophy about care of people who are nearing the end of their lives. Hospice care is designed to relieve pain, or other symptoms, and provide as much quality time as possible with family and friends. The focus of hospice care is no longer on curing or treating the underlying disease. The goal of hospice care is to provide the highest quality of life for whatever time remains.

It is important to emphasize to the patient that by discussing hospice you are not abandoning them. Instead you are helping them focus on care and spending time with the family.

There are tow types of hospice care: home hospice and residential hospice in an institution. Any one of these may be chosen depending upon patient’s family situation and social support.

A hospice care team consists of following:

Doctor: provides a treatment plan tailored to the patient and as well as performs a supervisory role.

Hospice nurses are trained professional who are expert in providing pain and symptom relief to a terminally ill patient.

Home health aides: provide care to a patient.

Prognosis

The prognosis of breast cancer varies depending upon type of cancer, age and performance status of the patient, high risk features in histopathological profile.

The following is stagewise overall prognosis

Stage 0 -DCIS

Is usually cured by definitive surgery and recurrence risk is low

Early stage breast cancer:

For cancer less than 2 cm and lymph node negative as well as intermediate grade pathology, 10 year survival is 85-89%. Cancer that are less than 2 cms with high grade features 10 year survival is 70-78 %

Advanced or late stage breast cancer;

Cancers that are large in size with lymph node involvement prognosis varies a lot from 35-78% depending on the size, grade of the lesion and lymph node involvement

Metastatic breast cancer: prognosis is poor in metastatic stage, it is not curable and only 23% of women are alive at 5 years.

Conclusion

Breast cancer represents a significant challenge in terms of diagnosis, prognosis as well as treatment. There are multiple variables that determine the aggressiveness of the disease. In a particular the treatment of one patient may be different than another woman with similar stage and there are multiple algorithms defining optimal treatment in a certain patient. Though breast cancer is serious disease, the treatment options have increased over last few years. Chemotherapy side effects are less and radiation is much more precise. Breast cancer is a disease that can be cured in early stages and can be controlled in advanced stages. Women may continue to lead their lives even with breast cancer.

Red Flags

The following conditions should warrant concern and a comprehensive emergency room evaluation in the oncology patient, as they may be signs of a life-threatening condition:

Fever

New or sudden chest, back or abdominal pain

Night sweats and extreme fatigue

Pre-syncope or syncope

Severe eye or headache

Change in mental status, including but not limited to confusion and lethargy.

Focal weakness.

Productive cough

Hemoptysis

Tachypnea .

Tachycardia,

Bony pain

Fall with or without head trauma

References.

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Questions (20 MCQ)

1) Which of the following is correct?

Breast cancer

a) Is the most common cancer in the world
b) Is the most common cancer in men
c)Is not as common as lung cancer
d) Is only a cancer of women
e) Is not really a true cancer

2) Which of the following is correct?

a)Family history is only important after the age of 40
b)Family history on both the mothers side and fathers side are importnt
c)Genetics plays a dominant role in breast cancer
d)Breast cancer is highest in African American women
e)Breast cancer is as frequent in first degree relatives as the general population

3) Regarding the hormonal aspects of breast cancer

a)Progesterone exposure is most important factor
b)Estrogen exposure plays only a small part in hormonal theories
c)Hormonal replacement therapy has no relevance to the development of breast cancer and is recommended for all post menopausal women.
d)Gender is the most important risk factor in the development of breast cancer and occurs 100 more frequent in men than women.
e)The shorter the exposure to estrogen the higher the likelihood of breast cancer

4) Regarding diet and breast cancer?

a)Vegetables have no estrogens and have no beneficial effect
b)Vegetables have phytoestrogens which compete with the bodies estrogens and reduce risk of cancer
c)Alcohol helps prevent breast cancer
d)Obesity helps prevent breast cancer
e)Anorexia helps prevent breast cancer

5) The terminal duct lobular unit(TDLU)

a)Is the same as the breast lobule?
b) Is the support tissue of the breast?
c)Is the most metabolically active unit of the breast?
d)Is present in the breast only when the patients cancer is terminal
e)Is the place where cancerous sarcomas arise

6) Which of the following is correct?

a) There are 10-20 lobules in the mature breast
b)There are 10-20 acini in the pregnant breast
c)There are 10-20 TDLU’s in the lactating breast
d)There are 10-20 ductules in the breast
e)The there are 10-20 lobes in the breast

7) Regarding the anatomy of the breast?

a)There are 10-20 ducts in each breast opening separately on the nipple
b)The axillary tail of Spence represents the suspensory ligaments in the breast
c)Cooper’s ligaments are seen only in the breasts of women from Cooper’s town
d)Cooper’s ligaments are really extra areas of glandular tissue in the axilla
e)All breasts consists dominantly of glandular tissue

8) Regarding in situ disease of the breast?

a)DCIS and LCIS have the same behavioral patterns
b)DCIS is associated with calcifications on mammography
c)LCIS is associated with calcifications on mammography
d)Calcifications are best seen on ultrasound
e)The basement membrane is invaded in the in situ carcinomas

9) Which of the following is correct?

a)DCIS occurs in 70-95% of women at autopsy
b)LCIS arises from the supportive tissue
c)DCIS arises from the supportive tissue
d)DCIS is multicentric and more often involves the other breast
e)These lesions are both always active and never involute, always becoming invasive cancer

10) Invasive Ductal Carcinoma

a) Is not associated with calcifications on mammography
b)Is only associated with calcifications in the phyllodes subtype
c)Is only malignant when calcifications are present
d)Is the most common form of breast carcinoma
e)Is usually a very soft tumor

11) Invasive Ductal Carcinoma

a)Is really a type of sarcoma and is also called a Phyllodes tumor
b)Is an in situ carcinoma
c)Can undergo necrosis and a cheesy material can be extruded from the ducts
d)Does not undergo necrosis and peau d’orange is extruded from the ducts
e)Nipple retraction never occurs

12) Invasive Ductal Carcinoma

a)Is the least common breast carcinoma and carries the worst prognosis
b)Is the least common breast carcinoma and carries the best prognosis
c)Is the most common breast carcinoma and carries the best prognosis
d)Is the most common breast carcinoma and carries the worst prognosis

13) Invasive Lobular Carcinoma

a)Is always palpable clinically
b)Has a desmoplastic, fibrotic nature and always feels hard to palpation
c)Is characterized by tubular and pleomorphic calcifications
d)Is characterized by its bilaterality
e)Is the most common form of breast cancer

14) Regarding invasive lobular carcinoma?

a)Ultrasound is the most sensitive imaging modality
b)CT scan is the most sensitive imaging modality
c)Mammography is the most sensitive imaging modality
d)MRI is the most sensitive imaging modality
e)PET scan is the most sensitive imaging modality

15) Inflammatory breast carcinoma?

a)Is diagnosed by finding malignant cells in the skin biopsy
b)Is diagnosed by finding inflammatory cells in the skin biopsy
c)Is not really a carcinoma but an inflammatory condition of the breast
d)Is treated with surgery and then steroids to reduce the inflammation
e)Is treated with surgery and then antibiotics to reduce the inflammation

16) Regarding mammography

a)Is being superseded by MRI as the study of choice for breast cancer
b)Annual mammography is recommended for all women starting age 40
c)Is safe in the first trimester of pregnancy
d) Has no effect on cancer mortality
e)False negative rate is unacceptably high

17) Regarding ultrasound

a) Annual ultrasound is recommended for all women starting age 40
b)Has no place in breast cancer evaluation
c)Is used to guide core biopsy of a lesion
d)Is unable to distinguish between a cyst and a solid lesion
e)Is contraindicated in pregnancy

18) Regarding surgery

a)All patients with breast cancer should have the lesion surgically removed
b)Patients with stage IV disease require surgery
c)Cancer of the breast is an aggressive disease and therefore requires radical mastectomy
d)Cancer of the breast is not such an aggressive disease and therefore only requires lumpectomy
e)The goal of surgery is complete resection of the tumor, and establishing the involvement of regional nodes

19) Regarding chemotherapy?

a)Always precedes surgery
b)Sometimes used to follow surgery to enhance results
c)Is only effective in treating macroscopic disease
d)Is only effective in treating local disease at both the macroscopic and microscopic level
e)Cannot relieve symptoms or enhance the quality of life and in fact does the oppposite

20) Regarding radiotherapy

a)Is used for local control of disease that may have been left behind after surgery
b)Is not used in stage IV disease
c)Is used prophylactically in the spine and liver which are common sites for metastases
d)There are usually no local side effects
e)Side effects are commonly systemic and include nausea, vomiting, and loss of hair