Search

Simple mucinous cysts of the pancreas have an epithelial lining resembling pancreatic intraepithelial neoplasia but may have a clinical presentation similar to premalignant mucinous neoplasms such as intraductal papillary mucinous neoplasms. Whether the epithelial lining shares genomic alterations with other pancreatic preinvasive neoplasms such as PanIN and intraductal papillary mucinous neoplasm has not been determined. We performed targeted sequencing analysis using a custom-designed MiSeq panel including the full coding regions of 18 pancreatic cancer genes on 13 clinically and pathologically well-characterized simple mucinous cysts. We detected 59 mutations in 15 genes in the cohort, with a median of 4 mutations per cyst (range = 0-16 mutations per cyst). The mutated genes and rate of detected mutations were as follows: KMT2C (MLL3) (62%), KRAS (15%), BRAF (8%), RNF43 (8%), CDKN2a (8%), TP53 (15%), and SMAD4 (8%). No GNAS mutations were detected. Four cases (31%) had no mutations detected. These findings place the majority of simple mucinous cysts of the pancreas in the spectrum of early, low-grade mucinous neoplasia, albeit with a different spectrum of genomic alterations compared with PanIN and intraductal papillary mucinous neoplasm., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The last 50 years have witnessed an explosion in our understanding of the pathology of pancreatic diseases. Entities known to exist 50 years ago have been defined more precisely and are now better classified. New entities, previously not recognized, have been discovered and can now be treated. Importantly, new tools have been developed that have unraveled the fundamental biological drivers of a number of pancreatic diseases. Many of these same tools have also been applied clinically, supplementing the tried and true hematoxylin and eosin stained slide with a plethora of new, highly sensitive and specific tests that improve diagnostic accuracy and delineate best treatments. As exciting as these many advances are, our knowledge of pancreatic pathology remains incomplete, and there is much to be learned., (Copyright © 2019. Published by Elsevier Inc.)

Mutations of Hepatocyte-Nuclear-Factor-1-Homeobox-A (HNF1A) gene and loss of Liver-Fatty-Acid-Binding-Protein (LFABP) are well documented in hepatocellular adenoma. However, the role of HNF1A mutations in hepatocellular carcinoma remains to be determined. In this study, all hepatocellular neoplasms evaluated by our institutional Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Clinical Targets assay or the Cancer Genome Atlas sequencing, and cases reported in the literature, were queried for HNF1A mutations. Together, 11 of 672 (1.6%) hepatocellular carcinomas harbored HNF1A mutations. The single case from our institution (n = 153) was extremely well differentiated, arising in a background of adenomatosis. Both the adenoma and carcinoma component contained the same 2 somatic HNF1A mutations (p. E32* and L214Q), with loss of LFABP. From the literature, 2 of 146 (1.4%) hepatocellular carcinomas had HNF1A mutations, and both arose in a background of adenomatosis. Information on pre-existing adenoma for the remaining cases (8/373, from The Cancer Genome Atlas) was not available. HNF1A mutations in carcinomas were associated with negative viral hepatitis status (p = .004), mutually exclusive with catenin beta-1 (CTNNB1) hotspot mutations, and trended to occur more in females (p = .06) and without cirrhosis (p = .03). Grade was not associated with HNF1A status (p = .28). Somatic HNF1A mutations occur in approximately 1% to 2% of hepatocellular carcinoma, often in a background of adenomatosis. Our findings suggest that malignant transformation of HNF1A-mutated hepatocellular adenoma occurs, albeit infrequently. Hepatocellular adenomas with HNF1A mutation or adenomatosis with loss of LFABP warrant thorough sampling and examination., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Colorectal medullary carcinoma, recognized by the World Health Organization as a distinct histologic subtype, is commonly regarded as a specific entity with an improved prognosis and unique molecular pathogenesis. A fundamental but as yet unaddressed question, however, is whether it can be diagnosed reproducibly. In this study, by analyzing 80 colorectal adenocarcinomas whose dominant growth pattern was solid (thus encompassing medullary carcinoma and its mimics), we provided a detailed description of the morphological spectrum from "classic medullary histology" to nonmedullary poorly differentiated histologies and demonstrated significant overlapping between categories. By assessing a selected subset (n=30) that represented the spectrum of histologies, we showed that the interobserver agreement for diagnosing medullary carcinoma by using 2010 World Health Organization criteria was poor; the κ value among 5 gastrointestinal pathologists was only 0.157 (95% confidence interval, 0.127-0.263; P=.001). When we arbitrarily classified the entire cohort into "classic" and "indeterminate" medullary tumors (group 1, n=19; group 2, n=26, respectively) and nonmedullary poorly differentiated tumors (group 3, n=35), groups 1 and 2 were more likely to exhibit mismatch repair protein deficiency than group 3 (P<.001); however, improved survival could not be detected in either group compared with group 3. Our findings suggest that the diagnosis of medullary carcinoma, as currently applied, may only serve as a morphological descriptor indicating an increased likelihood of mismatch-repair deficiency. Additional evidence including a more objective classification system is needed before medullary carcinoma can be regarded as a distinct entity with prognostic relevance. Until such evidence becomes available, caution should be exercised when making this diagnosis, as well as when comparing results across different studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant. We collected a retrospective series of 578 stage I or II CRCs. All patients underwent surgery with curative intent and without neoadjuvant or adjuvant therapy. ARID1A expression was analyzed by immunohistochemistry using tissue microarray. We found ARID1A loss in 49 of 552 analyzable tumors (8.9%). Compared with the ARID1A-retained group, cases with ARID1A loss were associated with female sex (P<.001), mismatch-repair protein deficiency (P<.001), poor differentiation (P<.001), lymphovascular invasion (P=.001), and higher pT stage (P=.047). However, at a median follow-up of 49months, ARID1A loss did not correlate with overall, disease-specific, or recurrence-free survival. This is the first systematic analysis to evaluate the prognostic significance of ARID1A in stage I/II CRCs, and our data indicate that ARID1A loss lacks prognostic significance in this population despite its association with other adverse features. Such data are clinically relevant, as efforts are ongoing in identifying markers that can detect the small but significant subset of early stage CRCs that will have a poor outcome., Competing Interests: ☆ Competing interests: All authors do not have any conflicts of interest to declare., (Copyright © 2016 Elsevier Inc. All rights reserved.)

AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Choledochal cysts (CDCs) are believed to represent a risk factor for the development of neoplasia. However, the frequency and morphology of neoplastic changes have not been systematically studied, especially in North America. Our aims were to study the frequency and morphology of preneoplastic/neoplastic changes of CDCs. Thirty-six cysts were subjected to clinicopathological analyses. Metaplasia was found in 14 of 35, of which 9 had biliary intraepithelial neoplasia (BilIN). Of the 14 with metaplasia, 13 showed pyloric gland; 5, intestinal; and 2, squamous. BilINs included 6 BilIN-1, 2 BilIN-2, and 2 BilIN-3. Carcinoma was identified in 5 cases of which 3 were associated with metaplasia and BilIN. Only 1 of 18 cases without metaplasia had BilIN, and none had carcinoma (P = .0008). There was a trend toward more BilIN and carcinoma with intestinal rather than with pyloric gland metaplasia. All cases with metaplasia or/and BilIN were negative for MUC1. All cases with intestinal metaplasia were positive for CK20, CDX2, and MUC2, whereas cases with pyloric gland were positive for MUC6. MUC1, CEA, and B72.3 were positive only in carcinoma. There was a trend toward increasing p53 and Ki-67 from metaplasia to BilIN to carcinoma. Four of 5 patients with carcinoma died, and one was alive with disease. All others were free of disease except for one who developed new cysts. CDCs are associated with a high rate of BilIN (28.5%) and carcinoma (14.3%). CDCs show a sequence of tumor progression from metaplasia to BilIN and carcinoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Carcinoma ex pleomorphic adenoma is a rare salivary gland neoplasm, especially when the malignant component is only intracapsular/minimally invasive. Moreover, only few studies have assessed the behavior of carcinoma ex pleomorphic adenoma according to the histologic subtype. Forty-three cases of carcinoma ex pleomorphic adenoma were identified over a 27-year period and subjected to a detailed histopathologic analysis. There were 13 intracapsular/minimally invasive and 30 widely invasive carcinomas. There were 15 myoepithelial carcinomas, 25 salivary duct carcinomas, 2 adenocarcinomas not otherwise specified, and 1 carcinosarcoma. There was a trend toward a higher frequency of myoepithelial carcinomas in widely invasive tumors (13/30, 43%) than in intracapsular/minimally invasive (2/13, 15%) carcinoma ex pleomorphic adenoma (P = .095). Adequate follow-up was available for 38 patients. Vascular invasion and distant metastases correlated with decreased disease-free survival and disease-specific survival (P < .05), whereas the extent of invasion and the presence of a high mitotic rate or atypical mitoses correlated with decreased disease-free survival only (P < .05). There was a trend toward worse disease-free survival and disease-specific survival in patients with myoepithelial carcinoma (P = .08). Within the intracapsular/minimally invasive carcinoma ex pleomorphic adenoma group, both myoepithelial carcinoma (2/2, 100%) had metastatic disease, whereas only 1 of 11 nonmyoepithelial carcinoma relapsed (P = .038). Vascular invasion, high mitotic rate, and histologic subtype were found to correlate with recurrence in carcinoma ex pleomorphic adenoma. Patients with intracapsular/minimally invasive tumor have a more favorable outcome than patients with widely invasive neoplasm, but intracapsular/minimally invasive carcinoma ex pleomorphic adenoma can recur and cause death. The presence of myoepithelial carcinoma subtype increases the risk of recurrence in carcinoma ex pleomorphic adenoma, especially within the group of intracapsular/minimally invasive tumors., (Copyright 2010 Elsevier Inc. All rights reserved.)

The patients with autoimmune pancreatitis usually present with jaundice and a pancreatic head mass, presumed to have pancreatic cancer, and they often undergo pancreatic resection. Elevated serum IgG4 levels (>135 mg/dL) help to distinguish autoimmune pancreatitis from pancreatic cancer. However, when the biopsy from a pancreatic mass shows dense chronic inflammation and fibrosis and the serum IgG4 level is not available, it presents a diagnostic dilemma whether it represents autoimmune pancreatitis or peritumoral pancreatitis. We performed IgG4 immunohistochemistry on 25 cases of autoimmune pancreatitis-lymphoplasmacytic sclerosing pancreatitis, 7 cases of autoimmune pancreatitis with granulocytic epithelial lesions, 8 cases of nonspecific pancreatitis, 15 cases of pancreatitis associated with pancreatic ductal adenocarcinoma, and 5 biopsies of pancreatic adenocarcinoma with variable inflammation. The distribution of IgG4-positive cells was noted in each case. Eighty-four percent (21/25) of autoimmune pancreatitis-LPSP cases showed diffuse and dense staining for IgG4, with more than 50 positive plasma cells per high-power field (range, 50-150 cells/hpf) in the highest density area. Most (5/7) cases of autoimmune pancreatitis-granulocytic epithelial lesions were negative for IgG4. Thirty-nine percent of nonspecific pancreatitis and peritumoral pancreatitis cases stained positive for IgG4, but the distribution was focal and none of the cases showed more than 50 IgG4-positive cells/hpf in the highest density area of IgG4 staining. IgG4-positive cells in peritumoral pancreatitis and nonspecific pancreatitis cases were closely associated with malignant glands and areas of acute inflammation in some cases. Using a cutoff of 50 IgG4-positive cells/hpf, the sensitivity of IgG4 staining for classical autoimmune pancreatitis-LPSP versus other types of pancreatitis was 84%, the specificity was 100%, and the P value was significant (<.0001). Hence, we conclude that diffuse and dense staining (>50 positive cells/hpf) for IgG4 is specifically seen in autoimmune pancreatitis-LPSP, and IgG4 staining along with the histologic features and serum IgG4 levels may be very helpful in diagnosing autoimmune pancreatitis., (Copyright 2010 Elsevier Inc. All rights reserved.)

Folate receptor alpha (FRalpha) has emerged as a potential cancer therapy target with several folate-linked therapeutic agents currently undergoing clinical trials. In addition, FRalpha expression in tumors may offer prognostic significance. Most studies on FRalpha expression used reverse transcriptase polymerase chain reaction or cytofluorimetric assays. The applicability of such methods to paraffin-embedded tissues is limited. The aims of this study were to assess the feasibility of immunohistochemistry in detecting FRalpha expression and to assess the patterns and clinical significance of FRalpha expression in colorectal tissues. We used tissue microarrays containing 152 normal colorectal mucosa samples, 42 adenomas, 177 primary, and 52 metastatic colorectal carcinomas. Our results showed that staining for FRalpha on colorectal tissues was simple and easy to read. FRalpha positivity was more frequent in carcinomas (33% in primaries and 44% in metastases) than in normal mucosa or adenoma (7% in both) (P < .001). Positive staining in primary carcinomas correlated with younger age (n = 130) (P = .008), presence of distant metastasis (n = 130) (P = .043), and non-high-frequency microsatellite instability status (as detected by the standard polymerase chain reaction method using the 5 National Cancer Institute-recommended markers) (n = 77) (P = .006). Positive staining in primary carcinomas also correlated with a worse 5-year disease-specific survival (P = .04) on univariate but not multivariate analysis. Thus, our data show that there is selective expression of FRalpha in some colorectal cancers, providing a foundation for investigating the use of folate conjugates for imaging and therapy of colorectal tumors. Furthermore, our results suggest that a possible association exists between FRalpha expression and the microsatellite instability status in colorectal carcinoma. The significance of such an association as well as the prognostic value of FRalpha expression deserves further exploration.

alpha-methylacyl-coenzyme A racemase (AMACR) is a recently discovered biomarker that is shown to be overexpressed in some prostatic carcinomas and associated with prostatic cancer progression. Given that AMACR plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids from red meat and dairy products, and that consumption of red meat may increase risk of developing colon cancer as suggested by epidemiological studies, it is plausible to explore the function of AMACR in colorectal carcinoma. A few previous studies have indeed observed overexpression of AMACR in 45% to 69% of the colorectal carcinomas. However, the clinical and pathologic characteristics of such AMACR expressers have not been investigated. In this study, the immunohistochemical expression pattern of AMACR of 163 patients with primary colorectal carcinoma treated primarily with surgical resection was analyzed and correlated with tumor pathologic features (tumor location, histologic type, grade, pathologic stage, lymph node and distant metastasis) and patient outcome (disease-specific survival). The results showed variable positive staining for AMACR in 123 (75%) of 163 tumors, and moderate to strong staining in 63 (39%) of 163. Lack of staining or low-intensity staining appeared to correlate significantly with mucinous histology (P < .001), poor tumor differentiation (P = .021), and presence of lymphovascular invasion (P = .032). Patients whose tumors showed lack of staining or low-intensity staining also had a significantly worse 5-year disease-specific survival (P < .012), as did patients whose tumors had lymphovascular invasion, or were of high American Joint Committee on Cancer (AJCC) stage. On multivariate analysis, AMACR staining and AJCC staging remained independent predictors for patient outcome. Thus, our data suggest that AMACR expression in colorectal carcinoma correlates with certain tumor pathologic characteristics (histologic type, differentiation, and lymphovascular invasion) and patient outcome. Additional confirmatory studies are needed to establish the significance of AMACR as a prognostic marker for colorectal carcinoma. Further investigation on interaction between AMACR and other known colorectal cancer development pathways may provide new insights on colorectal carcinogenesis.

A pulmonary carcinoid tumorlet (PCT) is a nodular proliferation of neuroendocrine cells smaller than 0.5 cm. On computed tomographic (CT) imaging, these nodules are nonspecific in appearance and can mimic metastatic disease. Cases of multiple PCTs diagnosed between 1992 and 2003 in patients with history of breast cancer were identified through a search of the pathology files. The clinical information was abstracted from the medical records. We identified 12 women with a history of breast cancer and biopsy-proven PCTs, who were treated at our institution in a period of 12 years. Only 3 women were smokers. The mean age at diagnosis of the breast cancer was 62.8 years. The breast cancer was invasive carcinoma in 10 cases (9 ductal and 1 lobular) and ductal carcinoma in situ and malignant phyllodes tumor in 1 case each. Six women received radiotherapy; 5, chemotherapy; and 4, hormonal treatment, alone or in combination. Pulmonary carcinoid tumorlets were identified within 5 months from diagnosis of the breast malignancy in 7 patients and at follow-up (range, 57-162 months) in the remaining 5. In all cases, the PCTs consisted of multiple pulmonary nodules that were radiologically interpreted as suspicious for pulmonary metastases. Misdiagnosis of metastatic carcinoma was rendered intraoperatively by frozen section analysis in 3 cases. None of the patients had known metastatic disease at the time of diagnosis of PCTs. Three patients subsequently developed recurrent disease, including 2 with extramammary spread. Pulmonary carcinoid tumorlets are radiologic and histologic mimickers of pulmonary metastases in patients with a history of breast cancer. Consideration should be given to the possibility of PCTs in patients with breast cancer with pulmonary nodules, even if multiple.

Hepatic amyloid deposition in the form of globular inclusions is a rare occurrence. Only 24 such cases have been reported to date. Its clinical and pathological significance are undefined. Unawareness of such a pattern can cause diagnostic confusion. We herein describe a case of globular hepatic amyloid in a patient with a B-cell lymphoma and chronic hepatitis C. The findings in our case support the literature data in that (1) it is often an incidental finding during workup for other coexisting conditions and (2) its morphology is peculiar but can be recognized with ease if one is aware of its existence. Our case also provides new insights into this condition. First, it represents the first nonautopsy case to demonstrate that globular hepatic amyloid is an indication of systemic amyloidosis, thus emphasizing the clinical importance of the recognition of this condition. Second, in our case, there was a coexisting B-cell lymphoma, the constituent cells of which showed immunoglobulin lambda light chain restriction, and patient's serum lambda light chain was elevated. However, light chain restriction was not demonstrated in the globular inclusions, and there was no evidence of monoclonal gammopathy by serum electrophoresis. Whether immunoglobulin light-chain abnormality played a causal role in this condition is to be determined.

Five cases of pancreatic neoplasms accompanied by production of alpha-fetoprotein (AFP) and serum elevation of this marker are presented, and the better-documented cases of this phenomenon from the literature are reviewed. Four of the cases originated in the orthotopic pancreas, whereas the fifth arose in the pancreatic component of a mediastinal teratoma. The patients were children or young adults. AFP production in pancreatic tumors is closely linked to acinar differentiation, most cases representing either pancreatoblastoma or acinar cell carcinoma. The distinction between these 2 tumors may be difficult because of the many morphologic and immunohistochemical features they share.

For a tumor classification scheme to be useful, it must be reproducible and it must show clinical significance. Classification of neuroendocrine lung tumors is a difficult problem with little information about interobserver reproducibility. We sought to evaluate the classification of typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell carcinoma (SCC) tumors as proposed by W.D. Travis et al (Am J Surg Pathol 15:529, 1991). Forty neuroendocrine tumors were retrieved from the Armed Forces Institute of Pathology (AFIP) files and independently evaluated by five lung pathologists and classified as TC, AC, LCNEC, or SCC (pure SCC, mixed small cell/large cell, and combined SCC). A single hematoxylin and eosin-stained slide from each case was reviewed. Each participant was provided a set of tables summarizing the criteria for separation of the four major categories. Agreement was regarded as unanimous if all five pathologists agreed, a majority if four agreed, and a consensus if three or more pathologists agreed. The kappa statistic was calculated to measure the degree of agreement between two observers. A consensus diagnosis was achieved in all 40 cases (100%), a majority agreement in 31 of 40 (78%), and unanimous agreement in 22 of 40 (55%) of cases. Unanimous agreement occurred in seven of SCC (70%), seven of TC (58%), four of AC (50%), and four of LCNEC (40%). A majority diagnosis was achieved in 11 of 12 (92%) of TC, 9 of 10 (90%) of SCC, 6 of 8 (75%) of AC, and 5 of 10 (50%) of LCNEC. Most of the kappa values were 0.70 or greater, falling into the substantial agreement category. The most common disagreements fell between LCNEC and SCC, followed by TC and AC, and AC and LCNEC. The highest reproducibility occurred for SCC and TC, with disagreement in 8% and 10% of the diagnoses, respectively. For TC, 10% of the diagnoses rendered were AC. For AC, 15% of the diagnoses were rendered as TC, with 2.5% called LCNEC and 2.5% called SCC. For LCNEC, 18% and 4% of the diagnoses were called SCC and AC, respectively. For SCC, 4% of the diagnoses were called AC and 4% were called LCNEC. Thus, using the classification scheme tested, a consensus diagnosis can be achieved for virtually all neuroendocrine lung tumors with substantial agreement between experienced lung pathologists. Classification of NE tumors is most reproducible for classification of TC and SCC but less reproducible for AC and LCNEC. These results indicate a need for more careful definition and application of criteria for TC versus AC and SCC versus LCNEC.

Cholangiocarcinomas may be extrahepatic or intrahepatic; the latter are further divided into hilar and peripheral types. Peripheral cholangiocarcinomas often resemble adenocarcinomas arising in other organs. Although clear cell changes may occur in hepatocellular carcinoma and extrahepatic cholangiocarcinoma, peripheral cholangiocarcinomas with clear cell change are rare. In such cases, an extrahepatic primary carcinoma must be excluded. We present a patient with a large, clear cell papillary carcinoma in the liver. Extensive workup of the patient for other possible primary sites including kidneys, adrenals, thyroid, prostate, or urinary bladder failed to indicate any other neoplasm. The patient is alive without evidence of disease 30 months after complete resection. The histological, immunohistochemical, and electron microscopic results were most consistent with a neoplasm in the cholangiocarcinoma family. To the best of our knowledge, a clear cell papillary peripheral cholangio carcinoma has not been described previously. This neoplasm may be related to the recently described clear cell carcinomas of the gallbladder and extrahepatic bile ducts.