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Background
This is a rare adenocarcinoma arising from within biliary tract. They are classically divided into intra- and extra-hepatic tumors. Carcinomas arising within the extrahepatic ducts usually present with signs and symptoms of obstruction caused by both narrowing of the ductal lumina by the infiltrative carcinoma and by luminal protrusion by the tumor. Classically, these tumors present with painless progressive jaundice.
OUTLINE
LABORATORY/
RADIOLOGICCHARACTERIZATION RADIOLOGIC CT features of intraductal intrahepatic cholangiocarcinoma.
Lee JW, Han JK, Kim TK, Kim YH, Choi BI, Han MC, Suh KS, Kim SW.
Department of Radiology and the Institute of Radiation Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744 Seoul, Korea.
AJR Am J Roentgenol 2000 Sep;175(3):721-5 Abstract quote
OBJECTIVE: The objective of this report was to describe the CT features of intraductal intrahepatic cholangiocarcinoma.
CONCLUSION: Segmental or lobar dilatation of the intrahepatic bile ducts associated with or without intraductal polypoid mass, amorphous structures, or both with slight hyperattenuation are common CT findings of intraductal intrahepatic cholangiocarcinoma. The size of the intraductal mass determines the visibility on CT.
LABORATORY The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis.
Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Am J Gastroenterol 2000 Jan;95(1):204-7 Abstract quote
OBJECTIVES: The diagnosis of cholangiocarcinoma is often difficult, making management approaches problematic. A reliable serum tumor marker for cholangiocarcinoma would be a useful additional diagnostic test. Previous studies have demonstrated that elevated serum concentrations of CA 19-9, a tumor-associated antigen, have good sensitivity and specificity for cholangiocarcinoma in patients with primary sclerosing cholangitis. However, the value of this tumor marker for cholangiocarcinoma unassociated with primary sclerosing cholangitis is unclear. Thus, the aims of this study were to determine the usefulness of a serum CA 19-9 determination in the diagnosis of de novo cholangiocarcinoma.
METHODS: We prospectively measured serum CA 19-9 concentrations in patients with cholangiocarcinoma (n = 36), nonmalignant liver disease (n = 41), and benign bile duct strictures (n = 26). Serum CA 19-9 concentrations were measured by an immunoradiometric assay (CIS Bio International) without knowledge of the clinical diagnosis.
RESULTS: The sensitivity of a CA 19-9 value >100 U/ml in diagnosing cholangiocarcinoma was 53%. When compared with the nonmalignant liver disease and the benign bile duct stricture groups, the true negative rates were 76% and 92%, respectively. Patients with unresectable cholangiocarcinoma had significantly greater mean CA 19-9 concentrations compared to patients with resectable cholangiocarcinoma.
CONCLUSIONS: These data suggest that the serum CA 19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION General VARIANTS Klatskin Tumors Tumors arising at the junction of the hepatic ducts
Usually slow growing behavior and infrequent distant metastasis
HISTOLOGICAL TYPES CHARACTERIZATION General Malignant infiltrating glands which may or may not be mucin secreting
Usually prominent desmoplastic stromal host response
Paul S. Furmanczyk, MD, etal.
Interpreting biliary brush cytology (BBC) findings in primary sclerosing cholangitis (PSC) is problematic.
In our study, BBC findings and CA19-9 serum levels were evaluated for their effectiveness in diagnosing cholangiocarcinoma in patients with PSC. We reviewed 107 biliary brushings from 51 patients with PSC and concurrent CA19-9 levels between January 1995 and March 2004 at the University of Washington Medical Center, Seattle. A portion of the brushings were evaluated and scored according to specific cytologic criteria; statistical analysis showed which criteria were most predictive in diagnosing malignancy: nuclear/cytoplasmic ratio, prominent nucleoli, nuclear membrane irregularities, and discohesion were significant predictive features.
Sensitivity and specificity of BBC were 62.5% and 100%, respectively. Sensitivity and specificity of CA19-9 at a cutoff of 186 IU/mL were 100% and 94%, respectively. BBC is a specific and relatively sensitive method of detecting cholangiocarcinoma, even in patients with PSC, especially when certain cytomorphologic features are identified. Combining biliary cytology and CA19-9 levels might have an important diagnostic role in PSC.VARIANTS CARCINOMATOUS ARTERIOPATHY
Carcinomatous arteriopathy as an unusual feature of pulmonary spread of cholangiocarcinoma arising in caroli disease.Wang HL.
Department of Pathology, The University of Chicago Hospitals, Chicago, Ill
Arch Pathol Lab Med 2002 Jun;126(6):717-20 Abstract quote Carcinomatous arteriopathy is a rare and distinct form of pulmonary spread of solid malignant tumors characterized by fibrointimal proliferation of small pulmonary arteries and arterioles initiated by tumor emboli.
Although it has been reported in many types of adenocarcinomas, no case of carcinomatous arteriopathy induced by cholangiocarcinoma has been described in the literature.
We report a unique case of cholangiocarcinoma that arose in Caroli disease. Postmortem examination revealed extensive pulmonary vascular spread in the form of carcinomatous arteriopathy.
COMBINED (HCC with cholangiocarcinoma)
Combined Hepatocellular-Cholangiocarcinoma: A Histopathologic, Immunohistochemical, and In Situ Hybridization Study
Satish K. Tickoo, M.D.; Sui Y. Zee, M.D.; Sam Obiekwe, M.D.; Hong Xiao, B.S.; Jonathan Koea, M.D.; Christian Robiou, M.D.; Leslie H. Blumgart, M.D., F.A.C.S.; William Jarnagin, M.D.; Marc Ladanyi, M.D.; David S. Klimstra, M.D.
Am J Surg Pathol 2002; 26(8):989-997 Abstract quote
Combined hepatocellular-cholangiocarcinoma (CHC) forms a small but significant proportion of primary liver carcinomas. However, its diagnostic features are not well established, and this has possibly contributed to the variability in its reported clinical outcome in the literature. Many such tumors with features intermediate between hepatocellular carcinoma and cholangiocarcinoma (CC) may have been considered CC in the past based on positivity for "biliary differentiation" cytokeratins and the lack of availability of highly sensitive and specific hepatocellular markers. The utility of in situ hybridization for albumin mRNA, a recently available sensitive and specific hepatocellular marker, has not been reported in CHC.
We investigated 27 CHCs with regard to their histomorphologic spectrum and association of these morphologies with immunohistochemical staining for different cytokeratins (CK7, CK19, and CK20; AE1; Cam 5.2), epithelial membrane antigen, polyclonal carcinoembryonic antigen and alpha-fetoprotein, and in situ hybridization for albumin mRNA. All 27 tumors contained areas morphologically intermediate between hepatocellular carcinoma and CC (transitional-type tumors), and in each case such areas formed at least 25% of the tumor. Nine (33%) tumors showed areas with "antler-like" morphology, a feature not previously described in CHC. Twenty-two of 23 tumors (96%) showed positive signals on in situ hybridization for albumin mRNA. Positivity for both hepatocellular (albumin mRNA) and biliary (keratin immunohistochemical profile) markers confirmed the light microscopic impression of biphenotypic differentiation in these tumors. Immunohistochemical positivity for all cytokeratins (except CK7) and epithelial membrane antigen, as well as the expression of albumin mRNA by in situ hybridization, did not show significant differences between hepatocellular carcinoma and CC-like areas.
Based on the cytokeratin profile and results on polyclonal carcinoembryonic antigen/alpha-fetoprotein alone, many such tumors would be classified as CC. However, the positivity for albumin mRNA by in situ hybridization proves that such an interpretation would not have been accurate. Clinically, CHCs showed many differences from pure hepatocellular carcinoma, including the absence of cirrhosis (0 of 27), rarity of serum hepatitis B or C marker positivity (4 of 27), and normal to only mildly elevated serum alpha-fetoprotein levels (median 187 ng/mL). The tumor followed an aggressive clinical course, with overall 3-and 5-year survival rates of 30% and 18%, and in the resected cases of 38% and 24%, respectively.
INTRADUCTAL PAPILLARY NEOPLASMS Microsatellite Instability in Intraductal Papillary Neoplasms of the Biliary Tract
Susan C. Abraham, M.D., Jae-Hyuk Lee, M.D., Ph.D., John K. Boitnott, M.D., Pedram Argani, M.D., Emma E. Furth, M.D. and Tsung-Teh Wu, M.D., Ph.D.
Division of Gastrointestinal/Liver Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (SCA, JKB, PA); Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (EEF); and Department of Pathology, University of Texas M.D. Anderson Cancer Center (JHL, TTW), Houston, Texas
Modern Pathology 2002;15:1309-1317 Abstract quote Intraductal papillary neoplasms of the biliary tree are unusual lesions characterized by solitary or diffuse growth along the intra- and/or extrahepatic biliary tract. Biliary papillary neoplasms bear some clinicopathologic similarity to intraductal papillary mucinous neoplasms of the pancreas. Like intraductal papillary mucinous neoplasms of the pancreas, biliary papillary neoplasms can be purely intraductal lesions or can give rise to invasive adenocarcinomas.
We recently studied the genetic alterations present in a series of biliary papillary neoplasms and noted the presence of allelic shifts in some biliary tumors during allelic loss assays on chromosomes 5q and 18q. This suggested that microsatellite instability might play a role in the molecular pathogenesis of biliary papillary neoplasms. Genomic DNA was extracted from 17 intraductal papillary neoplasms, 6 associated invasive cholangiocarcinomas, and corresponding normal tissues, and microsatellite instability testing was performed using the 5 microsatellite loci recommended by the 1997 National Cancer Institute–sponsored consensus conference (D2S123, D5S346, D17S250, Bat-25, and Bat-26). High-level microsatellite instability was considered to be present when at least two of five microsatellite loci showed allelic shifts, and low-level microsatellite instability, when only one locus was shifted, as per the National Cancer Institute criteria.
We also determined the methylation status of the DNA mismatch repair gene hMLH1 by bisulfite treatment of genomic DNA, followed by methylation-specific PCR. High-level microsatellite instability was present in 2 of 17 (11.8%) biliary papillary neoplasms, including 1 case of purely intraductal tumor and 1 case with both intraductal and invasive cholangiocarcinoma components. In both cases there was extensive microsatellite instability, with allelic shifts in five of five and four of five microsatellite markers, respectively.
Low-level microsatellite instability was present in 6 of 17 (35.3%) biliary papillary neoplasms, including 2 cases of purely intraductal tumor and 4 cases with both intraductal and invasive cholangiocarcinoma components. Interestingly, the pattern of allelic shifts was frequently not identical between the intraductal and invasive cholangiocarcinoma components; although the same microsatellite markers were shifted, alleles of differing lengths were generated in the intraductal and invasive components of the neoplasms with high-level microsatellite instability and of two neoplasms with low-level microsatellite instability. None of the biliary papillary neoplasms (0 of 10 cases with adequate DNA for evaluation) showed methylation of hMLH1.
These results indicate that microsatellite instability is a relatively frequent event in papillary neoplasms of the biliary tree but is not associated with hMLH1 promoter hypermethylation. The finding that alleles of differing lengths were frequently generated between the intraductal and invasive components of those tumors with microsatellite instability suggests that there is significant genetic heterogeneity within these neoplasms.
NEUROENDOCRINE
Hum Pathol. 2005 Jul;36(7):732-40. Abstract quote
Neuroendocrine differentiation is known to be one of the prognostic factors in many carcinomas. However, the characteristics of neuroendocrine differentiation are not well elucidated in extrahepatic bile duct (EBD) carcinomas.
One hundred ninety-four cases of EBD carcinomas were analyzed using immunohistochemistry with synaptophysin and chromogranin. The tumors were graded as degree 0, 1, and 2 when the positive tumor cells were 5% or less, 6% to 25%, and 26% or more, respectively.
Immunohistochemical results were compared with clinicopathologic variables and survival rate. Synaptophysin and chromogranin were positive in 54 (27.8%) and 74 (38.1%) cases, respectively. Thirty-four cases (17.5%) were positive for both synaptophysin and chromogranin, 20 (10.3%) and 40 cases (20.6%) were positive only for synaptophysin and for chromogranin, respectively, and 100 cases (51.6%) were negative for both markers. There was a significant survival difference between overall synaptophysin-positive (median, 27 months) and synaptophysin-negative (38 months) groups (P < .05). However, there was no survival difference between chromogranin-positive and chromogranin-negative groups.
There was a significant survival difference between the dual-positive expression to synaptophysin and chromogranin group (median, 21 months) and the dual-negative expression group (median, 35 months; P < .05). In summary, synaptophysin expression was an important prognostic factor because synaptophysin-positive cases showed a worse prognosis than synaptophysin-negative cases. The more tumor cells expressed chromogranin, the poorer the survival.
Therefore, immunohistochemical studies for neuroendocrine differentiation may be helpful in routine pathological examinations for evaluating the survival and the prognosis of patients with EBD carcinomas.PAPILLARY
Invasive papillary carcinomas of the extrahepatic bile ducts: a clinicopathologic and immunohistochemical study of 13 cases.Hoang MP, Murakata LA, Katabi N, Henson DE, Albores-Saavedra J.
Division of Anatomic Pathology, The University of Texas Southwestern Medical Center (MPH, JA-S), Dallas.
Mod Pathol 2002 Dec;15(12):1251-8 Abstract quote 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.
SYNCHRONOUS (Hepatocellular and cholangiocarcinoma)
Synchronous hepatocellular carcinoma and cholangiocarcinoma arising in two different dysplastic nodules.Kwon Y, Lee SK, Kim JS, Ro JY, Yu E.
Departments of Pathology and Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
Mod Pathol 2002 Oct;15(10):1096-101 Abstract quote We present the first reported case of explant cirrhotic liver that had synchronous cholangiocarcinoma and hepatocellular carcinoma arising in two different high-grade dysplastic nodules.
The patient was a 55-year-old woman who had hepatitis B virus-associated liver cirrhosis for 3 years. The moderately differentiated cholangiocarcinoma occurred in high-grade dysplastic nodule with a 1.7-fold cell density compared with that of cirrhotic nodule. The hepatocellular carcinoma arose in a nodule-in-nodule pattern within a peripherally low-grade and centrally high-grade dysplastic nodule and had a 2.7-fold cell density compared with that of cirrhotic nodule. By immunohistochemistry, the tumor cells of the cholangiocarcinoma as well as bile ductular cells in dysplastic nodule were diffusely positive for cytokeratin 7, whereas hepatocellular carcinoma cells and dysplastic hepatocytes were negative for cytokeratin 7. The c-kit-positive hepatic progenitor cells were singly scattered between hepatocytes, and their number was highest in cirrhotic nodule and decreased in dysplastic nodule, whereas they were absent in cholangiocarcinoma and hepatocellular carcinoma arising in dysplastic nodules. Proliferation indices were progressively increased in cirrhotic nodule, dysplastic nodule, and cholangiocarcinoma or hepatocellular carcinoma, sequentially.
These observations indicate that cholangiocarcinoma as well as hepatocellular carcinoma can develop in dysplastic nodule and that hepatic progenitor cells might play a role in the early stage of cholangiocarcinogenesis and hepatocarcinogenesis.
SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY/
OTHERCHARACTERIZATION GENERAL
Seung-Mo Hong, MD, PhD, etal.
Although CDX2-mediated intestinal metaplasia and its association with gastric and esophageal carcinoma have been well described, its function in extrahepatic bile duct (EBD) carcinoma remains unclear. CDX2 and MUC2 expression were examined in 193 EBD carcinomas, and observed in 37.3% and 42.0%, respectively.
Both CDX2 and MUC2 were observed in 27.4%. CDX2 (P < .001) and MUC2 (P < .001) were correlated with histologic subtypes and present, respectively, in all intestinal-type adenocarcinomas and mucinous carcinomas, 12 (71%) and 13 (76%) of 17 papillary carcinomas, 2 (40%) and 2 (40%) of 5 adenosquamous carcinomas, and 28.4% and 33.5% of adenocarcinomas, not otherwise specified. CDX2 was observed more frequently in tumors with papillary growth (P = .03) and no vascular invasion (P = .04), whereas MUC2 was more common in cases with low stage (P = .01) and no vascular invasion (P < .001).
Patients with CDX2+/MUC2+ tumors had significantly better overall survival in univariate but not multivariate analysis than patients with other tumors (P < .05). Expression of CDX2 and MUC2 supports that intestinal differentiation is present in specific subtypes of EBD carcinomas, and their expression status correlates with patients' overall survival.
- Immunohistochemical Staining in the Diagnosis of Pancreatobiliary and Ampulla of Vater Adenocarcinoma: Application of CDX2, CK17, MUC1, and MUC2.
Chu PG, Schwarz RE, Lau SK, Yen Y, Weiss LM.
From the *Division of Pathology and double daggerMedical Oncology, City of Hope National Medical Center, Duarte, CA; and daggerDepartment of Surgery, UMDNJ, Robert Wood Johnson University Hospital, New Brunswick, NJ.
Am J Surg Pathol. 2005 Mar;29(3):359-367. Abstract quote
Pancreatobiliary and ampulla of Vater adenocarcinomas frequently metastasize to regional lymph nodes, liver, or lung and are difficult to diagnose because they lack specific immunohistochemical markers.
We studied the expression of cytokeratin 7 (CK7), cytokeratin 17 (CK17), cytokeratin 20 (CK20), CDX2, mucin 1 (MUC1), mucin 2 (MUC2), and mucin 5AC (MUC5AC) in 46 cases of pancreatic ductal carcinoma, 18 ampulla of Vater adenocarcinomas, and 24 intrahepatic cholangiocarcinomas. The expression of MUC1 and CK17 was restricted to pancreatic ductal carcinoma (41 of 46, 89%; 38 of 46, 83%, respectively), the ampullary carcinoma of pancreatobiliary origin (6 of 6, 100%; 5 of 6, 83%, respectively), and intrahepatic cholangiocarcinoma (20 of 24, 83%; 17 of 24, 71%, respectively). More than 50% of cases of pancreatobiliary adenocarcinomas showed diffuse cytoplasmic CK17 positivity. In contrast, less than 5% cases (8 of 184) of extra-pancreatobiliary nonmucinous adenocarcinomas expressed CK17, and only 3 of them showed diffuse CK17 positivity. The expression of MUC2 and CDX2 was restricted to the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin (9 of 11, 82%; 11 of 11, 100%, respectively). MUC2 was rarely expressed in pancreatic ductal carcinoma (1 of 46, 2%) and was negative in the ampullary carcinoma of pancreatobiliary origin and in intrahepatic cholangiocarcinoma. A heterogeneous CDX2 staining pattern was seen in 1 of 6 cases of the ampullary carcinoma of pancreatobiliary origin (17%), 5 of 24 intrahepatic cholangiocarcinomas (21%), and 10 of 46 (22%) pancreatic ductal carcinomas.
In contrast, all 11 cases of the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin showed homogeneous CDX2 nuclear positivity.
We concluded that CK17 is a useful marker in separating pancreatobiliary adenocarcinomas from extra-pancreatobiliary nonmucinous adenocarcinomas, including adenocarcinomas from the colon, breast, gynecologic organs, stomach, lung, prostate, thyroid, kidney, and adrenal gland, and malignant mesothelioma. MUC1+/CK17+ can be used as positive markers for pancreatic ductal carcinomas, the ampullary carcinoma of pancreatobiliary origin, and cholangiocarcinomas with positive predictive values of 76%, 83%, and 58%, respectively. MUC2+/CDX2+ can be used as positive markers for the intestinal-type adenocarcinoma of duodenal papillary origin with a positive predictive value of 82%.
Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays.
Swierczynski SL, Maitra A, Abraham SC, Iacobuzio-Donahue CA, Ashfaq R, Cameron JL, Schulick RD, Yeo CJ, Rahman A, Hinkle DA, Hruban RH, Argani P.
Hum Pathol 2004;35:356-366 Abstract quote
Using global gene expression analyses, multiple novel tumor markers overexpressed in infiltrating ductal adenocarcinomas of the pancreas have recently been identified. However, the expression of these markers in morphologically similar adenocarcinomas of the biliary tree has not been investigated.
The purpose of the present study was 3-fold. First, we used 8 markers that have been shown to be overexpressed in whole tissue sections of pancreatic adenocarcinomas to validate tissue microarrays (TMAs) created from a series of pancreatic adenocarcinomas (n = 68). The labeling patterns of 6 epithelial markers (fascin, mucin 4, 14-3-3sigma, prostate stem cell antigen, topoisomerase IIalpha, and cdc2/p34) were concordant with previously published studies on whole tissue sections, yet required far fewer slides and reagents. Mesothelin, an epithelial marker, and heat shock protein 47, a marker of peritumoral desmoplasia, showed lower levels of expression in the TMAs when compared with whole tissue sections. Second, we examined the previously unknown expression of the same 8 novel tumor proteins in cancers of the biliary tree by using TMAs created from a series of intrahepatic cholangiocarcinomas, gallbladder adenocarcinomas, and adenocarcinomas of the distal common bile duct (n = 38). Each of the 8 markers was overexpressed in the biliary cancers, ranging from 14% demonstrating at least focal labeling with prostate stem cell antigen to 100% labeling with cdc2/p34. Most of the markers showed lower frequencies of expression in the biliary tract carcinomas in comparison to the pancreatic adenocarcinomas. In addition, expression patterns varied with location in the biliary system (intrahepatic versus gallbladder versus distal common bile duct). These differences were statistically significant (P < 0.05) for mesothelin, mucin 4, and heat shock protein 47. Finally, the expression of selected markers in neoplastic progression of gallbladder cancer was examined. Two markers, fascin and mesothelin, showed up-regulation of expression with transition from carcinoma in situ to invasive adenocarcinoma, implicating a role for these markers in neoplastic progression.
The results of this study indicate that TMA technology provides valid and cost-effective means to screen large numbers of novel tumor markers, even in tumors such as pancreatic and biliary adenocarcinomas that characteristically have abundant desmoplastic stroma. In addition, novel tumor markers of pancreatic adenocarcinomas show similar, yet not identical, expression patterns in biliary carcinomas.
Therefore, these markers are potentially useful in developing diagnostic tests and treatment paradigms for tumors involving the biliary system.Cytokeratin 7 and 20 Expression in Cholangiocarcinomas Varies Along the Biliary Tract But Still Differs From That in Colorectal Carcinoma Metastasis
Anne Rullier; Brigitte Le Bail, M.D., Ph.D.; Rabia Fawaz; Jean Frédéric Blanc, M.D.; Jean Saric, M.D.; Paulette Bioulac-Sage, M.D.
From Service d'Anatomie et Cytologie Pathologiques, Hôpital Pellegrin (A.R., B.L.B., P.B.-S.), Fédération d'HépatologieGastro-Entérologie, Hôpital Saint-André, CHU Bordeaux (J.F.B., J.S.); Laboratoire de Pathologie/Groupe de Recherche pour l'Etude du Foie-EMI-HU 99.17, Université Victor Ségalen, Bordeaux 2 (A.R., B.L.B., R.F., J.F.B., P.B.-S.), France.
Am J Surg Pathol 2000;24:870-876 Abstract quote
In the liver, the immunostaining of cytokeratins (CK) 7 and 20 has been used to distinguish usual peripheral cholangiocarcinomas (CC) and colorectal carcinoma metastasis (CRM). However, other subtypes of CC are not infrequent and may be particularly difficult to distinguish from CRM by histology and even immunohistochemistry.
Therefore, 48 CC from different locations, either peripheral (n = 19), or nonperipheral, that is, from the large intrahepatic bile ducts, the hilum, and the extrahepatic bile ducts (n = 29), and with different cytoarchitectural patterns were tested for CK7 and CK20 and compared with 31 CRM. CC were positive for CK7 and CK20 in 96% and 70%, respectively, whatever the architecture and differentiation of the tumor.
The labeling index (LI) of CK7 in CC was always high, whereas it was low or moderate for CK20. CK20-positive phenotype was significantly more frequent in nonperipheral than in peripheral CC (82% vs 47%; p = 0.007). CRM were all positive for CK20 with a high LI, and mostly negative (81%) for CK7.
In conclusion, (1) the CK immunoprofile of CC varies according to the location of the tumor in the biliary tract, peripheral CC being more often CK7+/CK20-, and nonperipheral ones CK7+/CK20+; and (2) a decision tree based on CK20 LI and CK7 positivity allows the distinction of CRM and CC, even for the nonperipheral type.
Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.Lau SK, Prakash S, Geller SA, Alsabeh R.
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
Hum Pathol 2002;33:1175-1181 Abstract quote Distinguishing hepatocellular carcinoma (HCC) from cholangiocarcinoma (CC) and metastatic adenocarcinoma (MA) involving the liver can be problematic, often requiring the use of immunohistochemistry to facilitate diagnosis. Hep Par 1, a monoclonal antibody with expression confined primarily to benign and malignant hepatocytes, has recently become commercially available.
We evaluated Hep Par 1 along with other immunohistochemical markers used to differentiate HCC, CC, and MA, including AE1/AE3, CAM 5.2, B72.3, monoclonal carcinoembryonic antigen (mCEA), polyclonal CEA (pCEA), alpha-fetoprotein (AFP), factor XIIIa, inhibin, CD10, villin, MOC-31, cytokeratin (CK) 7, CK 19, and CK 20, to determine the markers most useful in differentiating these entities. Forty-two cases of HCC, 9 cases of CC, and 56 cases of MA (24 colon, 15 pancreas, 8 ovary, 5 breast, and 4 stomach) were studied. Hep Par 1 was sensitive and specific for HCC, with 38 of 42 (90%) cases staining positively, whereas reactivity was observed in only 8 of 56 (14%) MAs and 0 of 9 CCs.
Though limited somewhat by poor sensitivity, a bile canalicular pattern of staining with pCEA, CD10, and villin was specific for HCC and was not observed in the other tumors. Lack of mCEA and MOC-31 immunoreactivity was also characteristic of HCCs. CK 19 positivity favored CC over HCC, but was not useful in differentiating CC from MA.
Expression of AFP, although observed in only about one third of the cases, favored HCC over CC and MA. CK 7 and CK 20 were also useful in this differential diagnosis, particularly when dealing with MA of colonic origin. AE1/AE3, CAM 5.2, B72.3, inhibin, and factor XIIIa were noncontributory in differentiating these entities.
CLAUDIN-4
- Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas.
Lodi C, Szabo E, Holczbauer A, Batmunkh E, Szijarto A, Kupcsulik P, Kovalszky I, Paku S, Illyes G, Kiss A, Schaff Z.
12nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Mod Pathol. 2006 Mar;19(3):460-9 Abstract quote.
The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target.
The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers.
Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%).
In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.THYROID TRANSCRIPTION FACTOR (TTF-1)
Jun-Yi Lei, MD, PhD, Patricia A. Bourne, P. Anthony diSant'Agnese, MD, and Jiaoti Huang, MD, PhD
The cytoplasmic staining of thyroid transcription factor (TTF)-1 was analyzed in 86 liver resection specimens, including 40 hepatocellular carcinoma (HCC), 4 metastatic HCC, 20 cholangiocarcinoma, 2 combined hepatocellular-cholangiocarcinoma (CHC), and 20 metastatic carcinoma (MC), with immuno-histochemical stains to TTF-1, cytokeratin (CK)19, hepatocyte paraffin 1, a-fetoprotein, polyclonal carcinoembryonic antigen, CK7, and CK20. TTF-1 cytoplasmic staining was identified in 93% of HCCs (37/40), 100% of metastatic HCCs (4/4), 10% of cholangiocarcinomas (2/20), and 5% of MCs (1/20). CK19 was positive in all cholangiocarcinomas and MCs but only in 5% of HCCs (2/40) and none of the metastatic HCCs (0/4). TTF-1 cytoplasmic staining positively correlates with differentiation and the trabecular growth pattern of HCC.
The results suggest TTF-1 cytoplasmic staining, together with CK19, might serve as a useful marker for the diagnosis of primary and metastatic HCC and for the differential diagnosis of HCC from cholangiocarcinoma and MC. The mechanism of TTF-1 cytoplasmic staining is explored.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Primary biliary malignant lymphoma clinically mimicking cholangiocarcinoma: A case report and review of the literature Ann Diagn Pathol 2001;5:25-33
Case Report:
We describe an unusual case of a diffuse large B-cell lymphoma arising in the extrahepatic bile ducts with local extension to involve the intrahepatic bile ducts. The patient presented solely with obstructive biliary symptoms. The clinical presentation, radiographic studies, and gross findings at surgery suggested that this patient had a Klatskin tumor (cholangiocarcinoma arising at the junction of the left and right hepatic ducts).Conclusion:
While rare, the difference in initial patient management emphasizes the importance of including malignant lymphoma in the differential diagnosis of obstructive biliary lesionsMetaplastic Lesions of the Extrahepatic Bile Ducts: A Morphologic and Immunohistochemical Study
Mai P. Hoang, M.D., Linda A. Murakata, M.D., Alvaro L. Padilla-Rodriguez, M.D. and Jorge Albores-Saavedra, M.D.
Division of Anatomic Pathology (MPH, JA-S), The University of Texas Southwestern Medical Center, Dallas, Texas; Department of Hepatic and Gastrointestinal Pathology (LAM), Armed Forces Institute of Pathology, Washington, D.C.; and Pathology Unit (ALP-R), General Hospital, Mexico City, Mexico
Mod Pathol 2001;14:1119-1125 Abstract quote
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.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS GENERAL
- Analysis of extrahepatic bile duct carcinomas according to the New American Joint Committee on Cancer staging system focused on tumor classification problems in 222 patients.
Hong SM, Kim MJ, Pi DY, Jo D, Cho HJ, Yu E, Ro JY.
Department of Pathology, Asan Medical Center, University of Ulsan Medical College, Seoul, Korea.
Cancer. 2005 Jun 15; [Epub ahead of print] Abstract quote
BACKGROUND: Although the sixth edition of the American Joint Committee on Cancer (AJCC) staging system for extrahepatic bile duct carcinoma was updated, the system has a problem on T classification due to its ambiguous definition of T1 as "tumor confined to bile duct histologically" and T2 as "tumor invading beyond the bile duct."
METHODS: The authors considered the outermost part of the muscle layer or fibrous tissue as within the extrahepatic bile duct and considered the area starting from large clusters of adipose tissue as beyond the extrahepatic bile duct. After designing a precise definition of the extrahepatic bile duct wall, they analyzed the new AJCC staging system in 222 patients with of extrahepatic bile duct carcinomas. Then, other clinicopathologic variables for prognosis were evaluated using univariate and multivariate analyses.
RESULTS: The 5-year survival rates for patients with tumors that were classified as T1, T2, T3, and T4 were 53.1%, 29.7%, 24.9%, and 0%, respectively. There was a significant difference in survival between patients with T1 tumors and T2 tumors (P < 0.05), but not between patients with T2 tumors and T3 tumors. Significant prognostic factors included depth of invasion (P < 0.005), lymph node metastasis (P < 0.005), and patient age (P < 0.05).
CONCLUSIONS: Based on a proposed histologic definition, depth of invasion was practical for evaluating the prognosis of patients with middle and upper extrahepatic bile duct carcinomas. Therefore, the authors recommended changing the current pT1 and pT2 classifications to more precise pathologic terminology.Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system.
Burke EC, Jarnagin WR, Hochwald SN, Pisters PW, Fong Y, Blumgart LH.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, New York 10021, USA.
Ann Surg 1998 Sep;228(3):385-94 Abstract quote
OBJECTIVES: To determine the resectability rate for hilar cholangiocarcinoma, to analyze reasons for unresectability, and to devise a presurgical clinical T-staging system.
METHODS: Ninety patients with hilar cholangiocarcinomas seen between March 1, 1991, and April 1, 1997, were evaluated. Accurate patterns of disease progression and therapy were evaluable. Disease was staged in 87 patients using extent of ductal tumor involvement, portal vein compromise, and liver atrophy.
RESULTS: In 21 patients, disease was deemed unresectable for cure at presentation. In 39 patients, disease was found to be unresectable at laparotomy, 23 secondary to nodal (N2) or distant metastases. Unresectability was the result of metastases in 52% and of locally advanced disease in 28%. Thirty patients (33%) had resection of all gross disease, and 25 of these (83%) had negative histologic margins. Twenty-two patients underwent partial hepatectomy. The 30-day mortality rate was 7%. Projected survival is greater than 60 months in those with a negative histologic margin, with a median follow-up of 26 months. A presurgical T-staging system allows presurgical selection for therapy, predicts partial hepatectomy, and offers an index of prognosis.
CONCLUSIONS: In half the patients, unresectability is mainly the result of intraabdominal metastases. Presurgical imaging predicts unresectability based on local extension but is poor for assessing nodal metastases. In one third of patients, disease can be resected for cure with a long median survival. Curative resection depends on negative margins, and hepatic resection is necessary to achieve this. The T-staging system correlates with resectability, the need for hepatectomy, and overall survival.
BETA-CATENIN Altered Expression of ß-Catenin without Genetic Mutation in Intrahepatic Cholangiocarcinoma
Keishi Sugimachi, M.D., Ken-ichi Taguchi, M.D., Shin-ichi Aishima, M.D., Shinji Tanaka, M.D., Ph.D., Mitsuo Shimada, M.D., Ph.D., Kiyoshi Kajiyama, M.D., Ph.D., Keizo Sugimachi, M.D., Ph.D., FACS and Masazumi Tsuneyoshi, M.D., Ph.D.
Department of Anatomic Pathology (KSKT, SA, MT) and Department of Surgery and Science (ST, MS, KK, KS) Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Mod Pathol 2001;14:900-905 Abstract quote
ß-catenin which has a role in E-cadherin mediated cell-to-cell adhesion, and is also involved in Wnt signaling pathways as a downstream signaling molecule accumulating in the cytoplasm and nucleus constitutively activates Tcf/LEF-associated transcription of oncogenic genes.
We examined the expression pattern and the genetic alteration of ß-catenin to determine the role of ß-catenin in cancer formation and/or progression in intrahepatic cholangiocarcinoma (ICC). ß-catenin expression was immunohistochemically examined in 71 surgically resected ICC samples, and correlation between the expression pattern and clinicopathologic factors was investigated. Mutation analysis of ß-catenin exon 3, which included the responsible element for Wnt signaling was done in 55 samples, using PCR-SSCP and direct sequence methods.
Immunohistochemical analysis revealed the reduced membranous expression of ß-catenin in 58 (82%) ICCs and aberrant nuclear expression in 11 (15%) ICCs. The membranous expression was preserved in 62% of the papillary adenocarcinomas, and was frequently reduced in tumors with a poorer histological differentiation (84%), with a significant difference (P = .01). Genetic analysis showed that none of the 55 ICCs examined carried mutations in ß-catenin exon 3.
The present study indicates that reduced membranous expression of ß-catenin is associated with non-papillary ICCs which have a more malignant behavior, and that nuclear translocation of ß-catenin results in oncogenic events. Mutations in ß-catenin exon 3 do not appear to be responsible for nuclear translocation of ß-catenin in ICCs.
CADHERINS Significant Correlations of E-Cadherin, Catenin, and CD44 Variant Form Expression With Carcinoma Cell Differentiation and Prognosis of Extrahepatic Bile Duct Carcinomas
Tetuo Mikami, MD
Makoto Saegusa, MD
Hiroyuki Mitomi, MD
Nobuyuki Yanagisawa, MD
Masaaki Ichinoe, MD
Isao Okayasu, MDAm J Clin Pathol 2001;116:369-376 Abstract quote
To clarify the relation between alteration of expression of cell adhesion molecules and progression of extrahepatic bile duct carcinomas, 55 cases were immunohistochemically examined for E-cadherin, alpha-catenin, beta-catenin, and CD44, with additional reverse transcription–polymerase chain reaction and Southern blotting hybridization (RT-PCR/SBH) assays.
Levels of E-cadherin, alpha-catenin, and beta-catenin proteins were lower in carcinomas than in normal mucosa, while CD44 variants 3 and 6 were up-regulated. Well-differentiated carcinoma showed higher expression of E-cadherin and alpha-catenin than moderately to poorly differentiated types. Macroscopically papillary lesions had higher expression of E-cadherin than their nonpapillary counterparts. RT-PCR/SBH for CD44 revealed the CD44 variant form to be more prevalent in carcinoma than in normal mucosa, correlating with the immunohistochemical results, and with more exon variety.
The Cox proportional hazards test identified histologic type and E-cadherin expression as prognostic factors. Among the examined molecules, E-cadherin was especially related to papillary mass formation and a good prognosis.
HISTOPATHOLOGY
- Hong SM,
- Cho H,
- Moskaluk CA,
- Yu E.
*Department of Pathology, University of Virginia Health System, Charlottesville, Virginia daggerDepartment of Statistics, Korea University double daggerDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Tumor staging of extrahepatic bile duct (EBD) carcinoma is problematic for a number of reasons, including definitional problems with the current T classification of the American Joint Committee on Cancer staging system and the common occurrence of severe desmoplastic stromal reaction around the advancing edges of these tumors.
To address these problems we evaluated the depth of invasion in 222 cases of EBD carcinoma by measuring the distance between the basal lamina of the adjacent normal epithelium to the most deeply infiltrating tumor cells, and compared this evaluation to time of survival and other clinical and pathologic parameters. A complex pattern of survival time versus the depth of invasion was observed by censored local regression. The recursive-partitioning technique was coupled with the log-rank test to identify 2 significant cutoff points for the depth of invasion, 5 and 12 mm, which segregated patients into 3 groups with statistically significant decreasing length of median survival (<5 mm, 61 mo; 5 to 12 mm, 23 mo; >12 mm, 17 mo, P<0.001).
On the basis of the present data, we propose that a measurement of the depth of invasion should be performed in cases of EBD carcinoma, and that the T classification of EBD carcinoma should be changed to incorporate this measurement: T1 (<5 mm), T2 (5 to 12 mm), and T3 (>12 mm).
- Reconsideration of the histologic definitions used in the pathologic staging of extrahepatic bile duct carcinoma.
Hong SM, Presley AE, Stelow EB, Frierson HF Jr, Moskaluk CA.
Department of Pathology, University of Virginia Health System, Charlottesville, VA.
Am J Surg Pathol. 2006 Jun;30(6):744-9. Abstract quote
The histologic boundaries of the extrahepatic bile ducts (EBDs) are not well defined, despite the fact that pathologic staging of carcinomas arising in these structures requires the determination of extent of tumor invasion in this area. Perhaps in part, because the smooth muscle band in the EBD wall is not well formed throughout the length of these structures, a previous definition of the outer portion of the bile duct wall included "loose, richly vascularized connective tissue, interlaced with large nerve fibers."
We have experienced difficulty in the application of these criteria in staging EBD carcinomas, which requires the histologic determination of the extent of the EBD wall. To systematically study the histologic features of EBD tissue boundaries, 34 EBD specimens obtained from autopsy were analyzed with attention to the distribution of blood vessels and nerve fibers along the length of this system. The EBD specimens were divided into lower, middle, and upper portions, and the locations of blood vessels and nerve fibers were then analyzed separately at each location.
We defined the fibromuscular wall as the dense concentric arrangement of collagen and smooth muscle fibers surrounding the EBD mucosa. The location of blood vessels and nerve fibers was categorized as either (1) within, (2) junctional to, or (3) outside of the fibromuscular wall. Blood vessels and nerve fibers are located predominantly outside of the fibromuscular wall and are usually surrounded by adipose tissue throughout the entire EBD, however, their distribution in this location is not consistent.
Because of these histologic features, we propose that the bile duct wall is more precisely defined as occurring between the mucosa and the outermost boundary of dense fibromuscular tissue, without consideration of the presence or absence of blood vessels and nerve fibers.
- Histological characteristics of tumor cells and stromal cells in vessels and lymph nodes are important prognostic parameters of extrahepatic bile duct carcinoma: A prospective study.
Hasebe T, Konishi M, Iwasaki M, Endoh Y, Nakagohri T, Takahashi S, Kinoshita T, Ochiai A.
Hum Pathol. 2005 Jun;36(6):655-64. Abstract quote
Summary Extrahepatic bile duct carcinomas (EHBDCs) consist of primary tumors, tumors in vessels, and tumors in lymph nodes.
The purpose of this study was to prospectively investigate whether the histological characteristics of tumor cells and tumor stromal cells in vessels and lymph nodes were significantly associated with the outcomes of 60 EHBDC patients as compared with the histological characteristics of tumor cells and tumor stromal cells in primary tumors. Multivariate analyses, using the Cox proportional hazard regression model, showed that in EHBDCs without nodal metastasis, blood vessel tumor emboli with an angiomatous stroma significantly increased the hazard ratios (HRs) of tumor recurrence and death ( P < .05).
In EHBDCs with nodal metastasis, the presence of tumor necrosis in the nodal tumors significantly increased the HRs of tumor recurrence and initial distant organ metastasis ( P < .05). In EHBDCs located in the distal to middle portion of the extrahepatic bile duct, blood vessel tumor emboli with an angiomatous stroma significantly increased the HRs of tumor recurrence, initial distant organ metastasis, and death ( P < .05). Severe nuclear atypia of the tumor cells in lymph vessels significantly increased the HRs of tumor recurrence and initial distant organ metastasis ( P < .05).
In EHBDCs located in the hilar portion of the extrahepatic bile duct, the presence of nodal tumors with more than 4 mitotic figures significantly increased the HRs of tumor recurrence and initial distant organ metastasis ( P < .05). Several histological characteristics of tumor cells and tumor stromal cells in vessels and lymph nodes have significant effects on tumor progression of EHBDCs.
Mod Pathol. 2005 Jul;18(7):969-75. Abstract quote
Pancreatic invasion of the extrahepatic bile duct (EBD) carcinomas is known to have a poor outcome. We hypothesized that EBD carcinoma showing shallow invasion to the pancreas may have a better outcome than the usual deep pancreatic invasion.
We divided 87 cases of the distal EBD carcinomas into superficial and deep pancreatic invasion groups according to degrees of the pancreatic invasion. The superficial pancreatic invasion group included cases with tumor abutting the pancreatic lobule or pancreatic parenchymal invasion equal to or less than 1 mm from the uppermost portion of the pancreatic lobule or tumors invading into the fibroadipose tissue between pancreatic lobules without parenchymal invasion. The deep invasion group consisted of tumors with more than 1 mm pancreatic parenchymal invasion. The cases with superficial pancreatic invasion showed significantly better survival rate than those with deep pancreatic invasion (P<0.001).
Therefore, we recommend that a specific remark on the pathology report about the presence or absence of parenchymal invasion and the depth of invasion of the pancreas is required for managing patients and determining the prognosis. We also recommend that the current pT3 stage of distal EBD carcinomas be subdivided into superficial (pT3a) and deep pancreatic invasion (pT3b).KERATINS
The utility of keratin 903 as a new prognostic marker in mass-forming-type intrahepatic cholangiocarcinoma.Aishima S, Asayama Y, Taguchi K, Sugimachi K, Shirabe K, Shimada M, Sugimachi K, Tsuneyoshi M.
Departments of Anatomic Pathology and of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mod Pathol 2002 Nov;15(11):1181-90 Abstract quote The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development.
We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80% of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10%), 6 (20%), and 1 (3%) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74%), 66 (90%), and 61 (84%) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively.
On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P <.0001), in those with medullary-type stromal reaction (P =.0327), in those without perineural invasion (P =.0001), and in those without lymph node metastasis (P =.0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively).
Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor.
In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.
METASTASIS Hematogenous metastasis to lungs, bones (vertebrae), adrenals, brain, occurs in about 50% of cases
Lymph nodes metastasis to perihilar, peripancreatic, and para-aortic nodes above and below diaphragm occur in about 50%
- The Number of Metastatic Lymph Nodes in Extrahepatic Bile Duct Carcinoma as a Prognostic Factor.
Hong SM, Cho H, Lee OJ, Ro JY.
From the *Department of Pathology, daggerDivision of Biostatistics and Epidemiology, University of Virginia Health System, Charlottesville, VA; and double daggerDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Am J Surg Pathol. 2005 Sep;29(9):1177-1183. Abstract quote
The number of lymph nodes with metastases is known to be an important prognostic factor in carcinomas of many organs. The insufficient sampling of lymph nodes has also been associated with worse outcome in several types of carcinoma. However, the prognostic significance of lymph node dissection is not well characterized in extrahepatic bile duct (EBD) carcinomas.
For 209 patients with EBD carcinoma, the total number of retrieved lymph nodes and the number of metastatic lymph nodes were evaluated, and other clinicopathologic variables were correlated with patient survival. The number of retrieved lymph nodes was not significantly correlated with survival in this study. The presence of metastasis to lymph nodes significantly decreased survival of patients with EBD carcinoma. The patients with 5 or more metastatic lymph nodes had significantly worse survival than those with 4 or less metastatic lymph nodes.
To evaluate the prognosis of the patients with EBD carcinomas more precisely, the number of metastatic lymph nodes as well as the status of metastasis to lymph nodes should be examined and reported.
Based on the present data, we propose that nodal classification should be divided into N1 (metastasis in 1 to 4 regional lymph nodes) and N2 (metastasis in 5 or more regional lymph nodes).
SURVIVAL Mean is 6-18 months What constitutes long-term survival after surgery for hilar cholangiocarcinoma?
Klempnauer J, Ridder GJ, Werner M, Weimann A, Pichlmayr R.
Clinic of Abdominal and Transplantation Surgery, Hanover Medical School, Germany.
Cancer 1997 Jan 1;79(1):26-34 Abstract quote
BACKGROUND: Hilar cholangiocarcinomas are rarely considered to be resectable and specific data regarding long-term survival are not available.
METHODS: A retrospective single center experience from 1971 and 1995 details long-term survival among 339 patients who underwent surgery for adenocarcinoma of the hepatic duct bifurcation. Tumor removal was accomplished by resection of the bile duct bifurcation either alone (33 patients), in combination with hepatic resection (77 patients), or combined with hepatic and vascular resection (41 patients). Thirty-two patients underwent total hepatectomy and liver transplantation. In 188 patients the tumor was unresectable and palliative internal or external biliary drainage was established. The resectability rate was 49.2% and rose to 54% after inclusion of liver transplantation. The clinicopathologic features of 32 5-year survivors were compared with patients whose survival was less than 5 years.
RESULTS: Thirty-two patients survived longer than 5 years after surgical treatment of hilar cholangiocarcinoma; 22 of these patients (69%) were still alive at last follow-up. Twenty-six long-term survivors had primarily undergone resection; 4 received liver transplants. There was 1 long-term survivor beyond 5 years after both exploratory laparotomy and subsequent percutaneous transhepatic drainage, and palliative hepatojejunostomy. Long-term survival after resection was significantly associated with less advanced tumor stages. Lymph node involvement and residual tumor were the primary prognostic factors both in a multivariate analysis after resection and in the cohort of long-term survivors. Nevertheless, long-term survivors were still at a significant risk to die from tumor recurrence.
CONCLUSIONS: Radical resection offers the best possibility of prolonged survival with a good quality of life for patients with hilar cholangiocarcinoma.
Clinicopathological features and outcome of hepatic resection for intrahepatic cholangiocarcinoma in Japan.
Isaji S, Kawarada Y, Taoka H, Tabata M, Suzuki H, Yokoi H.
First Department of Surgery, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan.
J Hepatobiliary Pancreat Surg 1999;6(2):108-16 Abstract quote
As a result of an increasing number of studies on the surgical treatment of intrahepatic cholangiocarcinoma (ICC), knowledge of its biological characteristics has been accumulating.
We analyzed the clinicopathological features and outcome of 36 of 48 surgical patients with histologically proven ICC (75.0%) who underwent hepatic resection between March 1979 and July 1998.
According to tumor location, 12 patients had the central type and 24, the peripheral type. The incidence of portal vein tumor thrombus and lymph node metastasis was higher in the central type than in the peripheral type. All 12 patients with the central type had stage IV disease, and none of them underwent complete resection, whereas 12 of the 24 patients with peripheral type tumors had stage IV disease; complete resection was achieved in 12 of the 24 patients with peripheral type tumors (50%). O
utcome after resection was significantly poorer in the patients with the central type. The macroscopic type of lesion in the resected specimens was the mass-forming type in 15 patients (41.7%), the mass-forming + periductal-infiltrating type in 15 patients (41.7%), the periductal-infiltrating type in 3 patients (8.3%) and the intraductal growth type in 3 patients (8.3%). The macroscopic tumor type was associated with mode of tumor spread and outcome. All 3 patients with the intraductal growth type are alive without tumor recurrence 26-138 months after surgery. The survival rate was much higher in the patients with the mass-forming type than in those with the mass-forming + periductal-infiltrating type. Importantly, the outcome in the 17 patients who underwent resection for stage IV-B disease and who accounted for 47.2% of patients with resection in the present series was very poor, almost the same as that in the 12 patients who did not undergo resection.
By selecting patients based on the biological characteristics of the tumor and taking into account patients' quality of life, complete surgical resection can be performed safely and is associated with long-term survival.
TENASCIN
Tenascin expression at the invasive front is associated with poor prognosis in intrahepatic cholangiocarcinoma.
Aishima S, Taguchi K, Terashi T, Matsuura S, Shimada M, Tsuneyoshi M.
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Mod Pathol. 2003 Oct;16(10):1019-27. Abstract quote
Tenascin and decorin are components of the extracellular matrix (ECM) that are implicated in cell proliferation in tumors. Here, we propose that abnormal expression of stromal ECM may play an important role in the progression of intrahepatic cholangiocarcinoma, which is characterized by desmoplastic reaction.
To explore this hypothesis, we performed immunohistochemical analysis in order to examine the expression and distribution of tenascin and decorin in 75 cases of intrahepatic cholangiocarcinoma. In the intratumoral stroma, positive staining for tenascin was observed in 51 (68%) cases, and positive staining for decorin was observed in 61 (81%) cases. However, at the invasive front, positive staining for tenascin was found in 23 (31%) cases, and positive staining for decorin was found in 6 (8%) cases. Decorin staining was not correlated with aggressive behavior of intrahepatic cholangiocarcinoma, whereas intratumoral tenascin staining was correlated with lymphatic permeation and proliferative activity measured by Ki67. Tenascin staining at the invasive front was associated with tumor size, lymphatic permeation, lymph node metastasis, and proliferative activity and appeared to be a useful prognostic factor by univariate analysis, although it was not an independent prognostic factor.
These results indicate that tenascin plays a role in tumor progression in cases of intrahepatic cholangiocarcinoma and that tenascin expression, especially at the invasive front, may be a useful marker in evaluating an unfavorable prognosis in patients with intrahepatic cholangiocarcinoma.TREATMENT Surgical resection Carcinoma of the extrahepatic bile ducts. The University of California at San Francisco experience.
Schoenthaler R, Phillips TL, Castro J, Efird JT, Better A, Way LW.
Department of Radiation Oncology, University of California at San Francisco.
Ann Surg 1994 Mar;219(3):267-74 Abstract quote
OBJECTIVE: The authors investigated the combined experience of a single institution in treating bile duct carcinoma during the modern era.
SUMMARY BACKGROUND DATA: Bile duct carcinomas are notoriously difficult to cure, with locoregional recurrence the rule, even after radical resection. Adjuvant efforts have included various radiation modalities, with limited success. Recently, charged-particle radiotherapy has also been used in these patients.
METHODS: The authors performed a retrospective chart analysis of 129 patients with bile duct adenocarcinomas treated between 1977 and 1987 through the University of California at San Francisco, including 22 patients treated at Lawrence Berkeley Laboratory with the charged particles helium and neon. The minimum follow-up was 5 years. Survival, outcome, and complication results were analyzed.
RESULTS: Sixty-two patients were treated with surgery alone (S), 45 patients received conventional adjuvant x-ray radiotherapy (S + X), and 22 were treated with charged particles (S + CP). The median survival times were 6.5, 11, and 14 months, respectively, for the entire group, and 16, 16, and 23 months in patients treated with curative intent. There was a survival difference in patients undergoing total resection compared with debulking (p = 0.05) and minor resections (p = 0.0001). Patients with microscopic residual disease had increased median survival times when they were treated with adjuvant irradiation, most markedly after CP (p = 0.0005) but also with conventional X (p = 0.0109). Patients with gross residual disease had a less marked but still statistically significant extended survival (p = 0.05 for S + X and p = 0.0423 for S + CP) after irradiatio
CONCLUSIONS: The mainstay of bile duct carcinoma management was maximal surgical resection in these patients. Postoperative radiotherapy gave patients with positive microscopic margins a significant survival advantage and may be of value in selected patients with gross disease.
Surgical management of intrahepatic cholangiocarcinoma: a 31-year experience.
Lieser MJ, Barry MK, Rowland C, Ilstrup DM, Nagorney DM.
Department of General Surgery, Mayo Clinic, Rochester, MN 55902, USA.
J Hepatobiliary Pancreat Surg 1998;5(1):41-7 Abstract quote
Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant primary tumor of the liver. It is, though, a rare tumor and little is known regarding its natural history, clinicopathologic characteristics, or the outcomes of surgical therapy.
We reviewed the experience of 61 patients with ICC seen by the surgical service at the Mayo Clinic over a 31-year period. Patient demographic and clinical data were recorded, as were survival statistics. Pathologic data were also obtained and patients stratified according to the TNM classification. Twenty-eight patients were resected for cure. Overall, 45 patients died of ICC. Of the patients resected for cure, survival at 3 years was 60%. No pathologic condition was found to be associated with the development of ICC. Overall survival correlated with stage of the tumor. Among patients resected for cure, stage did not correlate with survival.
Prognosis for patients with ICC remains poor; resection, though, appears to prolong survival.
Resection of intrahepatic cholangiocarcinoma: a Western experience.
Valverde A, Bonhomme N, Farges O, Sauvanet A, Flejou JF, Belghiti J.
Department of Hepato-biliary and Digestive Surgery, Beaujon Hospital, University Paris VII, Clichy - Paris, France.
J Hepatobiliary Pancreat Surg 1999;6(2):122-7 Abstract quote
We analyzed the results of an aggressive surgical approach to intrahepatic cholangiocarcinoma.
Between 1990 and 1997, 30 of 42 patients with intrahepatic cholangiocarcinoma underwent resection with curative intent. Mean tumor size was 10 +/- 5 cm, and the tumors were classified as TNM type III, IVa, and IVb in 63%, 34%, and 3% of the patients, respectively. All patients underwent hepaticoduodenal lymphadenectomy. Fifteen patients received adjuvant radio- and chemotherapy. The overall survival rates at 1, 2, and 3 years were 86%, 63%, and 22%, respectively, and the median survival time was 28 months. Tumor recurrence was the main cause of death. Three patients survived for more than 5 years, including 2 patients with no evidence of recurrence. Factors influencing survival were: presence of satellite nodules (P = 0.007) and lymph node invasion (P = 0.05). The width of the resection margin and the use of an adjuvant therapy had no impact on survival.
Complete surgical resection may offer a chance for long-term survival in selected patients and may improve the quality of life of patients with more advanced disease.
Resection of hilar cholangiocarcinoma--a European and United States experience.
Saldinger PF, Blumgart LH.
Hepatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
J Hepatobiliary Pancreat Surg 2000;7(2):111-4 Abstract quote
Improvements in preoperative imaging, patient selection, and refined operative techniques have allowed a more radical surgical approach to hilar cholangiocarcinoma.
A total of 269 patients with histologically proven cholangiocarcinoma were treated during a 20-year period under the direction of one surgeon (LHB) over three separate time periods in different institutions: 131 patients at the Hepatobiliary Unit of Hammersmith Hospital, London, England, from January 1977 to September 1985; 48 patients at Inselspital, University of Bern, Switzerland, between October 1986 and October 1990; and 90 patients at Memorial Sloan-Kettering Cancer Center, New York, between March 1991 and April 1997. An increase in the use of concomitant hepatectomy was noted over these time periods, paralleled by an increase in achieving negative margins and in survival.
Hilar cholangiocarcinoma should not be considered an incurable disease, but patients should be aggressively evaluated for possible curative resection before any intervention is performed. Good long-term results can be achieved and cure is possible provided a complete tumor resection with negative margins is obtained.
Surgery for hilar cholangiocarcinoma: French experience in a collective survey of 552 extrahepatic bile duct cancers.
Launois B, Reding R, Lebeau G, Buard JL.
Department of Digestive Surgery and Transplantation Unit, Clinique Chirurgicale, Hopital Pontchaillou, Rue Henri Le Guilloux 35033 Rennes Cedex, France.
J Hepatobiliary Pancreat Surg 2000;7(2):128-34 Abstract quote
Five hundred and fifty-two cases of primary carcinoma of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded) collected from 55 surgical centers were reviewed retrospectively.
Three hundred seven patients (56%) had upper-third lesions (proximal carcinoma), whereas 71 (13%) and 101 (18%), respectively, had middle-third and lower-third bile duct carcinomas. The remaining patients had diffuse lesions. Resectability rates were 32% for upper-third localization compared with 47% and 51% for middle-third and lower-third localization, respectively. The operative mortality rate for proximal carcinomas was significantly lower with resection (16%) compared with palliative surgery (31%) (P<0.05). Overall 1 year survival (operative deaths excluded) was 68% after tumor resection compared to 31% after palliative surgery (P<0.001). Long-term results after surgical resection correlated with local and regional extension of the disease.
The results of this study show that resection of extrahepatic bile duct carcinomas, particularly in an upper-third localization, is often associated with worthwhile long-term survival.
A single center experience with extrahepatic cholangiocarcinomas.
Johnson SR, Kelly BS, Pennington LJ, Hanto DW.
Department of Surgery, Division of Transplantation, University of Cincinnati College of Medicine.
Surgery 2001 Oct;130(4):584-92 Abstract quote
Background. Few large Western series on cholangiocarcinoma have been reported in the literature. We reviewed 40 consecutive cases of extrahepatic cholangiocarcinomas referred to a single center.
Methods. From 1992 until 2000, 40 patients with extrahepatic cholangiocarcinomas were evaluated. The charts of all patients were reviewed to evaluate predictors of survival. Survival was calculated with the Kaplan-Meier method.
Results. Forty patients were referred for management of extrahepatic cholangiocarcinomas. Tumors were located in the distal common duct in 3 (7.5%), mid duct in 5 (12.5%), and at the bifurcation in 32 (80%). Surgical resection was attempted in 32 (80%) patients and was curative in 9 (22.5%), palliative in 11 (27.5%), and diagnostic in 12 (30%). Mean survival for all patients was 21.1 +/- 5.1 months and on the basis of tumor stage was 71.4 +/- 15.4, 39.7 +/- 10.6, 19.2 +/- 2.9, 3.9 +/- 1.8, and 6.9 +/- 1.3 months for stages I, II, III, IVA, and IVB, respectively. Mean survival was 51.1 +/- 13.5 months versus 10 +/- 1.8 months in those with curative and noncurative resections, respectively. The presence of a portal mass was associated with a reduction in mean survival from 28.4 +/- 7.2 months to 6.0 +/- 1.9 months.
Conclusions. Extrahepatic cholangiocarcinoma remains a dismal disease with only a 22.5% chance of a curative surgical resection, achieving a 5-year survival rate of 44.4%. Only the absence of a portal mass was predictive of a possible curative resection and long-term survival.
Surgical treatment and outcomes in carcinoma of the extrahepatic bile ducts: the University of Rochester experience.
Blom D, Schwartz SI.
Department of Surgery, University of Southern California, Los Angeles, USA.
Arch Surg 2001 Feb;136(2):209-15 Abstract quote
HYPOTHESIS: To our knowledge, few individual surgeons and only a handful of institutions have gained a meaningful experience with the treatment of adenocarcinoma of the extrahepatic bile ducts or cholangiocarcinoma. The purpose of this study was to critically evaluate the experience of a single center in the treatment of these tumors. DESIGN: Retrospective cohort study with a median follow-up of 48 months.
SETTING: Department of surgery at a university referral center.
PATIENTS: Seventy-seven patients with biopsy-confirmed adenocarcinoma of the extrahepatic bile ducts evaluated and treated between January 1980 and February 1998.
MAIN OUTCOME MEASURES: Prognostic variables, resectability rates, morbidity, and survival.
RESULTS: Thirty-eight male and 39 female patients were studied (median age, 71 years). Twenty-three patients (30%) underwent curative resections, 32 patients (41%) underwent palliative surgery, and 22 patients (29%) received nonoperative therapies. The 30-day perioperative morbidity rate was 18%, and mortality was 6%. Overall median survival was 11 months; 4 months for patients receiving nonoperative therapy; 8 months for patients receiving palliative surgery; and 72 months for curative resection. Five-year survival rates were 23%, 0%, 10%, and 55%, respectively. Curative resection was the only prognostic variable to have a statistically significant effect on survival.
CONCLUSIONS: Curative resection could be achieved in approximately one third of patients who had cholangiocarcinoma, and should be the goal of treatment. Survival is significantly improved in those patients who are considered to have resectable tumors and who undergo removal of all gross disease. Palliative surgical treatments also revealed a survival advantage over nonoperative therapies.
Extrahepatic bile duct carcinoma: a western experience with 118 consecutive patients.
Doglietto GB, Alfieri S, Pacelli F, Mutignani M, Costamagna G, Carriero C, Di Giorgio A, Papa V.
Department of Digestive Surgery, Catholic University, Rome, Italy.
Hepatogastroenterology 2000 Mar-Apr;47(32):349-54 Abstract quote
BACKGROUND/AIMS: This study was designed to evaluate the effectiveness of a diagnostic and therapeutic approach adopted in 118 consecutive patients affected by primary malignancy of the extrahepatic bile duct.
METHODOLOGY: After diagnostic procedures were performed (ultrasound examination, endoscopic retrograde cholangiopancreatography and computed tomography scan) 25 patients underwent surgical resection. For the remaining 93 patients considered unresectable for cure, stenting by endoscopic means was almost always the only palliative treatment performed.
RESULTS: The morbidity and mortality rates were 28% and 8% for patients treated with surgical resection and the curative and overall 3-year survival rate was 30% and 22% respectively. The procedure related morbidity and mortality rates were 13% and 4% for patients endoscopically treated and the median survival rate was 7.3 months. The quality of life evaluated in 68 patients out of 93 was good in 57% of cases, fair in 19% and poor in the remaining 22%.
CONCLUSIONS: The results of the present study demonstrate the safety and efficacy of endoscopic stenting in the palliative treatment of extrahepatic bile duct cancer while potential cure can only be achieved by radical surgical resection.
Orthotopic liver transplantation after extended bile duct resection as treatment of hilar cholangiocarcinoma. First long-terms results.
Jonas S, Kling N, Guckelberger O, Keck H, Bechstein WO, Neuhaus P. Chirurgische Klinik,
Virchow Klinikum der Humboldt Universitat, Berlin, Germany.
Transpl Int 1998;11 Suppl 1:S206-8 Abstract quote
Although the surgical treatment of hilar cholangiocarcinoma represents the only potentially curative option, survival figures remain low over the long term. After hilar and partial hepatic resections for hilar cholangiocarcinoma, loco-regional tumor recurrence appears as the primary site of failure.
From April 1992 to April 1996, 14 patients underwent extended bile duct resections. Extended bile duct resections combine total hepatectomy, partial pancreatoduodenectomy, and liver transplantation in an attempt to eradicate the entire biliary tract without dissecting the hepatoduodenal ligament. The postoperative 60-day mortality rate was 14% (n = 2). The rate of curative resections was 93% (13 of 14 extended bile duct resections). One- and 4-year survival rates after curative resections were 56% and 30%, respectively. The rate of curative resections increased by combining total hepatectomy, partial pancreatoduodenectomy, and liver transplantation, i.e., extended bile duct resection. However, survival figures have not improved accordingly.
Therefore, this extended surgical procedure has to be implemented with caution and possibly not without modifications (e.g., multimodal treatment).
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Cancer 1992;70:1498-1501
Ann Surg 1998;64:921-925
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