Linda A. Murakata

Primary carcinoma of the gallbladder is an uncommon, aggressive malignancy that affects women more frequently than men. Older age groups are most often affected, and coexisting gallstones are present in the vast majority of cases. The symptoms at presentation are vague and are most often related to adjacent organ invasion. Therefore, despite advances in cross-sectional imaging, early-stage tumors are not often encountered. Imaging studies may reveal a mass replacing the normal gallbladder, diffuse or focal thickening of the gallbladder wall, or a polypoid mass within the gallbladder lumen. Adjacent organ invasion, most commonly involving the liver, is typically present at diagnosis, as is biliary obstruction. Periportal and peripancreatic lymphadenopathy, hematogenous metastases, and peritoneal metastases may also be seen. The vast majority of gallbladder carcinomas are adenocarcinomas. Because most patients present with advanced disease, the prognosis is poor, with a reported 5-year survival rate of less than 5% in most large series. The radiologic differential diagnosis includes the more frequently encountered inflammatory conditions of the gallbladder, xanthogranulomatous cholecystitis, adenomyomatosis, other hepatobiliary malignancies, and metastatic disease.

A diverse spectrum of benign tumors and tumorlike lesions arises from the gallbladder and bile ducts, and despite their diversity, these lesions share common embryologic origins and histologic characteristics. Although these lesions are relatively uncommon, their importance lies in their ability to mimic malignant lesions in these locations. Benign neoplasms are derived from the epithelial and nonepithelial structures that compose the normal gallbladder and bile ducts. The epithelium gives rise to adenomas, cystadenomas, and the unusual condition of biliary papillomatosis. Granular cell tumors, neurofibromas, ganglioneuromas, paragangliomas, and leiomyomas are examples of benign tumors that may originate from nonepithelial structures. Tumorlike lesions are more commonly found in the gallbladder and include xanthogranulomatous cholecystitis, adenomyomatous hyperplasia, cholesterol polyps, and heterotopias. In the clinical setting of a patient with nonspecific abdominal complaints or symptoms of biliary obstruction, the discovery of a gallbladder or bile duct polyp or mass, gallbladder wall thickening, or biliary stricture is most often indicative of malignancy. However, the differential diagnosis should include benign tumors and tumorlike lesions. The preoperative determination of a benign lesion may significantly alter therapy and patient prognosis.

Caroli's Disease: Radiologic Spectrum with Pathologic CorrelationAngela D. Levy1 2, Charles A. Rohrmann, Jr.1 3, Linda A. Murakata4 and Gael J. Lonergan1 2Audio Available | Share

Morphologic differentiation of clear cell hepatocellular carcinoma (HCC-CC) from clear cell renal carcinoma (RCC-CC) may not be possible without the aid of immunohistochemical stains. We performed a battery of immunohistochemical stains on 10 previously diagnosed HCC-CCs, and 10 RCC-CCs, in order to determine which single or combination of immunostains would be most useful in diagnosis. We concluded that a positive Hepatocyte immunostain (DAKO) is sufficient for a diagnosis of HCC-CC if enough tissue is available. This immunostain distinguishes HCC-CC from other clear cell malignancies with sensitivity of 90% and specificity of 100%, when biopsy material is adequate. Other tests were much less sensitive, although several had specificity of 100%. A negative immunostain does not exclude the diagnosis of HCC-CC (negative predictive value 91%, especially in small biopsy material) and should be followed by additional immunostains such as pCEA for demonstration of tumor canaliculi, ubiquitin for Mallory bodies, and several epithelial cell markers that are typically positive in RCC-CC (epithelial membrane antigen, Leu M-1, pancytokeratin) and negative in HCC-CC.

Adenocarcinomas of the extrahepatic bile ducts (EBD) are uncommon neoplasms that are morphologically heterogenous and associated with a poor prognosis. Papillary carcinomas of the EBD, however, appear to follow a much less aggressive clinical course.The authors reviewed the clinical records of nine patients with papillary carcinoma of the EBD, analyzed the microscopic features, and selected immunohistochemical reactivity (p53 and MIB-1) that might correlate with patient survival.Six patients were male and three were female, with a mean age of 65 years (range, 48-83 years). The clinical presentation of disease in these patients was similar to that reported for conventional adenocarcinoma of EBD. According to their cell phenotypes, these papillary carcinomas were classified as biliary type (7 cases) and intestinal type (2 cases). Most were located in the common bile duct and were well differentiated (7 cases). Five showed minimal expansile invasion into the ductal wall and four were noninvasive. Five patients were treated with a Whipple operation, three underwent segmental resections, and one underwent a left hepatic lobectomy. One patient died of unrelated causes 16 years after a Whipple operation, and another died of postoperative complications. The remaining 7 patients are alive and disease free 1-13 years after surgery.Noninvasive and minimally invasive papillary carcinomas of the EBD are associated with excellent long term prognosis regardless of their cytologic features or their immunohistochemical reactivity to p53 and MIB-1. These tumors should be distinguished from biliary papillomatosis, intraductal papillary mucinous carcinomas of the pancreas extending into the bile ducts, papillary adenomas, and papillary hyperplasia.

Hepatocyte paraffin 1 (Hep Par 1) is a monoclonal antibody considered almost specific for normal and neoplastic hepatocytes, that can be used on formalin-fixed paraffin-embedded tissues. Hep Par 1 reactivity has been demonstrated consistently in hepatocellular carcinomas and hepatoblastomas but only rarely in cholangiocarcinomas and metastatic tumors to the liver. Although its role as a marker of hepatocytic differentiation in primary liver tumors has been studied extensively, Hep Par 1 expression has not been explored in extrahepatic lesions, especially rare adenocarcinomas with hepatoid morphologic features. We studied 7 hepatoid adenocarcinomas of the gastrointestinal tract (6 gastric and 1 from the gallbladder) for Hep Par 1 immunoreactivity. Focal Hep Par 1 expression was seen in 6 of 7 tumors. These hepatoid adenocarcinomas also showed reactivity for alpha-fetoprotein and carcinoembryonic antigen. The presence of Hep Par 1 reactivity in extrahepatic hepatoid adenocarcinomas underscores the fact that Hep Par 1 expression is not unique to primary hepatocellular neoplasms. Adenocarcinomas with hepatoid features must be considered in the differential diagnosis of Hep Par 1–positive lesions.

Prominent eosinophilic infiltrates are an unusual finding in the pancreas. Eosinophilic pancreatitis is one rare etiology of pancreatic eosinophilia, but other described causes of eosinophilic infiltrates have also included pancreatic allograft rejection, pancreatic pseudocyst, lymphoplasmacytic sclerosing pancreatitis (LPSP), inflammatory myofibroblastic tumor, and histiocytosis X. In this study we describe the clinicopathologic features of three new cases of eosinophilic pancreatitis and conduct a retrospective 18-year institutional review of the myriad disease processes associated with pancreatic eosinophilia. In the files of the Johns Hopkins Hospital, <1% of all pancreatic specimens had been noted to show increased numbers of eosinophils. Eosinophilic pancreatitis itself was a rare etiology for pancreatic eosinophilia, with only one in-house case over the 18-year study period and two additional referral cases. Other disease processes associated with prominent eosinophilic infiltrates were more common and included pancreatic allograft rejection (14 cases), LPSP (5 of 24 total LPSP cases evaluated), inflammatory myofibroblastic tumor (4 cases), and systemic mastocytosis (1 case). Patients with eosinophilic pancreatitis showed two distinct histologic patterns: 1) a diffuse periductal, acinar, and septal eosinophilic infiltrate with eosinophilic phlebitis and arteritis; and 2) localized intense eosinophilic infiltrates associated with pseudocyst formation. All three patients with eosinophilic pancreatitis had peripheral eosinophilia, and all had multiorgan involvement. One patient with LPSP also had marked peripheral eosinophilia, and 5 of 24 LPSP cases demonstrated prominent eosinophilic infiltrates in the gallbladder, biliary tree, and/or duodenum. Notably, not all of these patients with LPSP with prominent eosinophils in other organs had increased eosinophils in the pancreas itself. These results emphasize the infrequent nature of pancreatic eosinophilia and its multiple potential disease associations. True eosinophilic pancreatitis, although a fascinating clinicopathologic entity, is one of the rarest causes of pancreatic eosinophilia.

We describe a morphologically distinctive carcinoid tumor of the gallbladder that occurred in a 38-year-old man with von Hippel-Lindau (VHL) disease. The carcinoid tumor was composed predominantly of lipid-containing clear cells arranged in nests and tubules with pagetoid spread into the biliary epithelium and was interpreted as metastatic renal cell carcinoma. The neoplastic cells showed diffuse immunoreactivity for chromogranin, synaptophysin, cytokeratins (cytokeratin 7 and AE1/AE3) and, unexpectedly, for inhibin, but were negative for monoclonal carcinoembryonic antigen, serotonin and a variety of peptide hormones. This clear cell carcinoid tumor of the gallbladder was histologically similar to the recently described clear cell endocrine pancreatic tumor associated with VHL. Four cases of the latter tumor, which were also inhibin positive showed, in addition, focal and variable reactivity for the pancreatic hormones. Two classical carcinoid tumors of the gallbladder, two renal cell carcinomas associated with VHL and 11 of 13 sporadic endocrine pancreatic tumors (not associated with VHL) did not show immunoreactivity for inhibin. Inhibin appears to be an immunohistochemical marker for gallbladder clear cell carcinoid and clear cell endocrine pancreatic tumors associated with VHL and is a useful tool to distinguish these tumors from metastatic renal cell carcinoma. However, the basis for the inhibin positivity in these endocrine tumors is unknown.

Carcinomas of the extrahepatic bile ducts are uncommon neoplasms that are morphologically heterogeneous and associated with a poor prognosis. We have previously shown that the noninvasive and minimally invasive papillary carcinomas of the extrahepatic bile ducts behave as in situ carcinomas and are associated with a better prognosis. We reviewed the clinical records of 13 patients with invasive papillary carcinomas of the extrahepatic bile ducts and analyzed the microscopic features and selected immunohistochemical reactivity (p53, Mib-1, and Dpc4) that might correlate with patient survival. In addition, we present the updated SEER (Surveillance, Epidemiology, and End Results) data of the National Cancer Institute for the invasive extrahepatic bile duct carcinomas compiled from 1975 to 1998. The 13 patients with papillary carcinoma had a male to female ratio of 1:1, and their ages ranged from 33 to 89 years. Painless jaundice and abdominal pain were the most common complaints. Five tumors were located in the distal portion, one in the mid portion, and six in the proximal portion of the common bile duct. One papillary carcinoma arose in the right hepatic duct. The Whipple procedure was performed in six patients, common bile duct resection in six, and right hepatic lobectomy in one. The cell phenotype of the papillary carcinomas was biliary in nine and intestinal in three. One tumor had both biliary and intestinal phenotypes. Four tumors dedifferentiated (two to undifferentiated small cell carcinomas, one to small [oat] cell carcinoma, and one to giant cell carcinoma). Two papillary carcinomas extended into the pancreas and three into the liver. Only one patient had lymph node metastases at presentation. Follow-up was available in 10 patients. Six patients died of disease from 2 weeks to 2 years and 1 month after surgery. Four patients are alive with no evidence of disease from 4 months to 8 years and 8 months after surgery. Of 174 invasive papillary carcinomas compiled by the SEER program, 71 were confined to the ductal wall, and 61 had regional lymph node metastases. Papillary carcinomas confined to the ductal wall have better 10-year relative survival rates than adenocarcinomas limited to the wall (21% versus 12%). Likewise papillary carcinomas with lymph node metastasis have better prognosis than adenocarcinoma with nodal metastases (10-y survival rate of 12% versus 5%). Currently, the histologic type and the stage of the disease are the most important prognostic factors in these papillary carcinomas. Separation of invasive and noninvasive or minimally invasive papillary carcinoma is critical in estimating the patient outcome. Our findings suggest that there is no correlation between p53, Ki-67, and Dpc4 expression in these tumors and survival of the patients.

A variable proportion of bile duct adenomas of the liver are still confused with metastatic well-differentiated adenocarcinoma by surgeons and pathologists. We present here three examples of previously undescribed primary hepatic bile duct tumors that were composed almost entirely of clear cells that closely mimicked metastatic renal cell carcinoma. They were interpreted as atypical bile duct adenomas and occurred in two males and one female whose ages ranged from 25 to 64 years. All three tumors were incidental findings and measured from 0.8 to 1.1 cm. The clear neoplastic cells showed mild nuclear atypia and no mitotic activity. They were arranged in tubules and nests that focally infiltrated the hepatic parenchyma. For comparison, a case of clear cell cholangiocarcinoma and 13 conventional bile duct adenomas were examined. The clear cell cholangiocarcinoma was larger (6.0 cm) and had the tubular pattern of conventional cholangiocarcinoma and an abundant desmoplastic stroma. The clear cells of this tumor exhibited greater nuclear atypia and increased mitotic activity. All three atypical bile duct adenomas expressed cytokeratin (CK) 7, p53 protein, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA); they were negative for CK20, vimentin, Hep Par 1, chromogranin, and prostatic specific antigen (PSA) and exhibited less than 10% of Ki-67-positive nuclei. One atypical bile duct adenoma displayed luminal immunoreactivity for villin. With the exception of Ki-67 reactivity, the 13 conventional bile duct adenomas and the clear cell cholangiocarcinoma had essentially a similar immunohistochemical profile as that of the atypical clear cell bile duct adenomas. The absence of an extrahepatic primary tumor, the histologic features, the immunohistochemical profile, and the fact that all patients are symptom-free 2 months to 18 years after wedge liver biopsy support the interpretation of atypical clear cell bile duct adenoma. The differential diagnosis with clear cell hepatocellular carcinoma and metastatic clear cell carcinomas is discussed.

This is the first report of inhibin-α expression in granular cell tumors. A Medline search of the literature revealed no case reports of granular cell tumors in any location of the body being tested for inhibin-α immunohistochemically, by enzyme-linked immunosorbent assay, by radioimmunoassay, or by immunoprecipitation. Seventeen cases of previously diagnosed granular cell tumors of the gallbladder and extrahepatic bile ducts with hematoxylin and eosin-stained sections, and S-100 protein immunostain were retrieved from the archives of the Armed Forces Institute of Pathology. All cases were reviewed for diagnostic accuracy and then immunostained for inhibin-α (with endogenous biotin blocking). All 17 (100%) cases were diffusely positive for inhibin-α immunostain. Previous studies of inhibin-α-positive lesions reported in the literature include sex cord stromal tumors (granulosa cell tumors, luteinized thecomas, Leydig cell tumors), placental and gestational trophoblastic lesions, and adrenal cortical tumors. This study adds the granular cell tumor to the list of inhibin-positive lesions and should prove helpful in differential diagnosis of these lesions.

Although metaplastic changes can occur in the extrahepatic bile ducts, a detailed morphologic study of these lesions has not been done. We examined the bile duct mucosa in 42 pancreaticoduodenectomy specimens, 32 with neoplastic lesions and ten with inflammatory lesions of the extrahepatic bile ducts, to assess the prevalence and type of metaplastic lesions. For comparison, the common bile ducts from 10 autopsy cases were reviewed. Twenty of the 42 total cases (48%), 13 of the 32 neoplastic cases (40%), and 7 of the 10 inflammatory cases (70%) had metaplastic changes. Pyloric gland metaplasia was the most common type (16/20 cases; 80%), whereas intestinal metaplasia was seen in 1/20 cases (5%). A combination of pyloric gland and intestinal metaplasia occurred in 2/20 cases (10%), and squamous metaplasia plus the above-mentioned two types of metaplasia was seen in 1/20 cases (5%). None of the normal common bile ducts obtained from ten autopsies had metaplastic changes. Endocrine cells were identified in nine (56%) of 17 metaplastic lesions. In contrast, endocrine cells within the intramural glands were seen in only 2 of the 10 normal common bile ducts. Although a significant proportion of carcinomas (6/13 cases) was in close proximity to areas of metaplasia, we were unable to find dysplastic foci within the metaplastic glands or the metaplastic surface epithelium. Reactive atypical cells involved the surface biliary epithelium and intramural glands and were associated with inflammation and metaplastic changes. The presence of goblet, mucinous, squamous, and reactive atypical cells in association with hyperplasia of intramural glands in frozen sections or small biopsy specimens may be mistaken for malignancy; hence, recognition of these lesions is of diagnostic importance.

Foreign body giant cell (FBGC) reaction to silicone material in the lymph nodes of patients with silicone breast implants has been documented in the literature, with a number of case reports dating back to 1978. Many of these case reports describe histologic features of silicone lymphadenopathy in regional lymph nodes from patients with multiple sets of different types of implants, including single lumen smooth surface gel, single lumen textured surface gel, single lumen with polyethylene terephthalate patch, single lumen with polyurethane coating, and double lumen smooth surface. Only one other case report described a patient with highly-cohesive breast implants and silicone granulomas of the skin. In this article, we describe a patient with a clinical presentation of systemic sarcoidosis following highly cohesive breast implant placement. Histopathologic analysis and Confocal Laser Raman Microprobe (CLRM) examination were used to confirm the presence of silicone in the axillary lymph node and capsular tissues. This is the first report where chemical spectroscopic mapping has been used to establish and identify the coexistence of Schaumann bodies, consisting of calcium oxalate and calcium phosphate minerals, together with silicone implant material.

Vascular embolization is a well-established practice for the treatment of tumors and vascular lesions. Rounded beads (microspheres) of various materials (collagen, dextran and trisacryl-polymer-gelatin) were developed to solve problems encountered with earlier versions of embolic material. We performed histochemistry, Fourier transform infrared microspectroscopy and scanning electron microscopy with energy dispersive X-ray analysis on two uterine and one hepatic specimen with unidentified intravascular foreign material, and examined a reference embolization product for comparison. The hematoxylin and eosin stained tissue sections showed multiple foci with unidentified intravascular foreign material and fibrous obliteration of vessel lumens. Only one case had a clinical history of previous embolization but without specifying the material used. One case was submitted for identification of a ‘parasite’. The material stained positively with Sirius red and mucicarmine, variably with Masson's trichrome stain and Movat pentachrome, and did not stain centrally with periodic acid Schiff with diastase. Infrared spectrophotometric analysis of the material from all three cases demonstrated the spectrum of acrylic polyamide plastic. A control sample of EmboGold™ exhibited infrared microspectroscopic spectra similar to the three tissue specimens. Analysis by scanning electron microscopy with energy dispersive X-ray analysis demonstrated some differences in elemental composition between the tissue sections and the selected reference material. To our knowledge, this is the first report of infrared spectrophotometric analysis with scanning electron microscopy with energy dispersive X-ray analysis of an acrylic polyamide plastic embolization product both in vitro and in human histologic tissue sections. In cases lacking appropriate clinical information, identification by these methods and/or a panel of special stains may assist pathologists unfamiliar with this material's light microscopic appearance.

To compare proliferating cell nuclear antigen (PCNA) immunoexpression in hyperplastic polyps, adenomas, and inflammatory cloacogenic polyps of the human colon and rectum using paraffin wax embedded tissue.The monoclonal antibody PC10 was used to demonstrate PCNA immunoreactivity in 88 polypoid lesions from 68 patients. Cases in which immunoexpression was completely absent were excluded, leaving 32 hyperplastic polyps, 31 adenomas, and seven inflammatory cloacogenic polyps for analysis. Labelling indices for the upper and lower third of each lesion and for adjacent normal mucosa were calculated.The upper third labelling indices for adenomas were substantially higher than those for hyperplastic polyps or normal mucosa, whereas those for the upper thirds of hyperplastic polyps and normal mucosa did not differ greatly. The differences between the lower third samples were not significant. In 16 (50%) hyperplastic polyps positive cells persisted onto the luminal surface. Some adenomas showed the most intense staining and the highest labelling indices in the upper third, with strong staining of surface cells; this pattern was not seen in the other lesions. The inflammatory cloacogenic polyps did not show a consistent pattern of immunoexpression.Differences in cell kinetics between adenomas, hyperplastic polyps, and normal mucosa may be shown in formalin fixed, paraffin wax embedded tissue using PC10 as a marker of proliferative activity. PCNA expression also persists into the upper portions of hyperplastic polyps. Assuming that hyperplastic polyps are hypermature lesions with a slower rate of cell migration, this finding suggests that there may be an alteration in PCNA protein metabolism.

Hepatocellular carcinoma (HCC), cholangiocarcinoma (Chca) and benign bile ductule proliferations represent uncommon but important differential diagnoses in liver masses, especially if the patient has no known primary malignancy. The glucose transporter protein Glut-1 is commonly expressed in adenocarcinomas but its expression in HCC, Chca, and benign bile ductules has not been systematically investigated. Forty-two cases of Chca, 27 cases of benign bile ductule proliferations and 19 cases of HCC were stained with Glut-1. Cases were evaluated for a membranous staining pattern in tumor cells and the results compared. Twenty-one of 42 (50%) Chca stained with Glut-1 while no HCC or benign bile ductule proliferations did, neither did benign hepatocytes or portal triad structures. Glut-1 is a highly specific but insensitive stain for Chca. It may prove to be a helpful part of a diagnostic panel used to evaluate liver lesions.

The distinction between cholangiocarcinoma, hepatocellular carcinoma and liver metastasis is important but at times difficult solely on microscopic appearances. The Das-1 immunostain exhibits specificity for colonic epithelium. However, its staining of cholangiocarcinomas and hepatocellular carcinomas has not been extensively studied. We evaluated the staining properties of the Das-1 immunostain in cholangiocarcinoma and hepatocellular carcinoma. Forty-four cholangiocarcinomas, 16 hepatocellular carcinomas, 17 colon adenocarcinomas metastatic to the liver and 3 benign biliary tumors were studied. The cases were stained with the Das-1 antibody following deparaffinization and rehydration. The slides were evaluated for membranous and/or cytoplasmic staining in a blinded fashion. The percentage of tumor cells exhibiting strong staining was estimated. Of the intra-hepatic cholangiocarcinomas, 4 of 36 (11%) and 2 of 16 (13%) hepatocellular carcinomas were positive for Das-1, though typically only in rare cells. In comparison, 7 of 8 (88%) extra-hepatic cholangiocarcinomas, 13 of 17 (77%) of metastatic colon carcinomas and 3 of 3 (100%) benign tumors of the biliary tract were strongly positive in a diffuse pattern. The Das-1 immunostain may play a useful role in evaluating liver malignancies.

We describe two primary malignancies occurring simultaneously. The coexistence of chondrosarcoma and malignant lymphoma, small lymphocytic type (MLSL) (WDLL) is a rare occurrence. In this case, the untreated malignant lymphoma appears to have increased the aggressiveness of the chondrosarcoma through its adverse effect on the host's immune system.