Synchronous renal cell carcinoma and clear cell hepatocellular carcinoma mimicking metastatic disease

Double carcinomas of hepatocellular and renal cell carcinoma (RCC) are extremely rare, and among the reported cases, none of the hepatocellular carcinomas show clear cell change. We report a case of synchronous double primary clear cell tumor in the liver and the kidney of a 70-year-old male. The renal mass was a renal cell carcinoma of mixed clear and granular cell types, and the hepatic mass was a hepatocellular carcinoma with extensive clear cell change that mimicked a metastatic renal cell carcinoma. A simple battery of immunohistochemical stains composed of hepatocyte antigen, and CD10 was performed to make a definite diagnosis.     

Expression of alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: astudy of 761 cases

Alpha-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids. It has recently been shown that AMACR is highly expressed in prostate cancer and that it may be an important diagnostic marker for prostate carcinoma. However, little is known about expression of AMACR in normal tissues and other malignant tumors. In this study, we investigated expression of AMACR in 539 malignant tumors and 222 normal human tissues of various types by immunohistochemical analysis. mRNA levels of AMACR in normal organs and in selected tumors were assessed by real time PCR. In normal tissue, high expression of AMACR mRNA was identified in liver, kidney and salivary gland, while AMACR protein was detected in liver (hepatocytes), kidney (tubular epithelial cells), lung (only bronchial epithelial cells), and gallbladder (only mucosal epithelial cells). High expression of AMACR mRNA was found in prostate, liver, and kidney cancers but rarely in stomach and bladder cancers. A high percent of adenocarcinomas arising from these organs express AMACR, including 17 of 21 (81%) of hepatocellular carcinomas and 18 of 24 (75%) of renal cell carcinomas. In addition, carcinomas arising from tissues normally not expressing AMACR were also positive for the antigen, including 17 of 18 (94%) prostate carcinomas, 9 of 29 (31%) of urothelial carcinomas, and 4 of 15 (27%) of gastric adenocarcinomas. Two hundred and fifty cases of adenocarcinomas from lung, breast, pancreas, bile duct, adrenal gland, salivary gland, ovary, thyroid and endometrium were negative or rarely positive for AMACR. Neuroendocrine carcinomas rarely expressed AMACR. Melanomas, squamous cell carcinomas, basal cell carcinomas, soft tissue tumors (including epithelioid sarcomas and synovial sarcoma), thymomas, and germ cell tumors were negative for AMACR. Our data provide important baseline information for using AMACR in clinical practice and also are valuable in furthering understanding of the pathogenic role of AMACR in malignant neoplasms.     

Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition

Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma.     

Small cell carcinoma arising from the outer urethral orifice: A case report examined by histologic, ultrastructural and immunohistochemical methods

A case of small cell carcinoma arising In the outer urethral orifice is presented. The resected tumor showed a proliferation of small round or fusiform neoplastic cells in the submucosa. Tumor cells were arranged in sheets or a trabecular manner and possessed markedly hyper-chromatic nuclei with a high N: C ratlo, closely resembling small cell carcinoma of the lung. Characteristically, pagetoid lntraepithellal spreading could be identified. However, there was no evidence of in sku transitional cell carcinoma and adene or squamous cell carcinoma components anywhere. Ultrastructurally, each tumor cell contained only a few membrane-bound cored granules measuring 60–100 nm, which were compatible with neurosecretory granules, and desmosomellke Intercellular attachments, but lacked aggregated microfilaments. By immunohistochemical examination, tumor cells were positive for eplthelial markers, such as cytokeratln and epithellal membrane antlgen, and neuron specific enolase, but negative for any other neuro-endocrine markers. Extensive systemic examinatlon falled to show the primary site to be other than the outer urethral oritlce. These findings lndicate that the current tumor is a small cell carclnoma with neume-ndocrine differentiation arising from the outer urethral orifice.     

Fine-needle aspiration biopsy of renal collecting duct carcinoma

The fine-needle aspiration biopsy (FNA) findings in a case of collecting duct (ducts of Bellini) carcinoma of the kidney are described. The cytologic smears were modestly cellular and contained individual and small clusters of round to oval cells with small to moderate amounts of well-defined cytoplasm. The nuclei were large and hyperchromatic with prominent single nucleoli and focal chromatin clearing. The findings were distinct from those of the usual clear or granular cell renal-cell carcinomas and were more similar to adenocarcinomas arising in the breast, ovary, or pancreas. Because collecting duct carcinomas need to be distinguished from metastatic deposits and are believed to have a poorer prognosis than the majority of renal-cell carcinomas, preoperative diagnosis may have important therapeutic implications. The distinction of collecting duct carcinoma from the more common variants of renal-cell carcinoma and transitional-cell carcinoma is discussed. Diagn Cytopathol 1994; 11:74–78. © 1994 Wiley-Liss, Inc.     

Co-expression of cytokeratin and vimentin intermediate-sized filaments in renal cell carcinomas

Summary The expression of intermediate-sized filaments (IF) was examined by immunocytochemical methods in 40 primary renal cell carcinomas and compared with the IF distribution in the normal adult human kidney. All tumours stained positively with cytokeratin IF antibodies. Co-expression of cytokeratins and vimentin was observed in 21/40 (52,5%) renal carcinomas. Double immunofluorescence labelling demonstrated that in most of these cases tumour cells contained both cytokeratin and vimentin type IF. In normal human kidneys, cells of the various tubular segments disclosed a positive reaction with cytokeratin antibodies in a different intensity and intracellular localization. Co-expression of cytokeratin and vimentin IF in normal adult human kidneys has never been observed. From a histogenetic point of view, co-expression of cytokeratins and vimentin in renal cell carcinoma obviously represents an atavistic phenomenon since vimentin is re-expressed by these tumour cells during neoplastic transformation. This finding indicates the metanephric origin of the renal parenchyma. In surgical pathology the possibility of very rare co-expression of cytokeratin and vimentin IF within tumour cells should be considered, particularly in the differential diagnosis of clear cell carcinomas.Dedicated to Prof. Dr. K. Goerttler on the occasion of his 60th birthday     

Immunohistochemical detection of breast specific antigens and cytokeratins in metastatic breast carcinoma in the liver

The present study was performed to evaluate the diagnostic reliability of antibodies to breast carcinoma-specific antigen and antibodies to cytokeratin catalogue in a metastatic hepatic lesion. Immunohistochemical examinations using antibodies to gross cystic disease fluid protein-15 (GCDFP-15), BCA-225 (a glycoprotein secreted by T47D breast carcinoma cell line) and BRST-5 (a glycoprotein identified in SK-BR-7 breast carcinoma cell line), anti-cytokeratin monoclonal antibodies of MA904, AE3, CAM5.2, PKK1 and cytokeratin 19, and polyclonal anti-keratin antibodies were done. These were on 15 cases of primary breast carcinoma, eight cases of metastatic breast carcinoma in the liver, five cases of cholangiocarcinoma, eight cases of hepatocellular carcinoma and 11 cases of metastatic adenocarcinoma of another primary tumor in the liver. Results showed that GCDFP-15 antigen was most reliable: it was 100% positive in both primary and metastatic breast carcinomas unrelated to histological subtypes, and 100% negative in primary or other metastatic carcinomas in the liver. BCA-225 antigen was detected in high amounts in breast carcinomas (100%, 23/23), but it was positive in cholangiocarcinomas (80%, 4/5) and another metastatic carcinoma in the liver (64%, 7/11). BRST-5 was specifically positive in breast carcinomas but the positivity was low (13%, 3/23). Cytokeratin 19 and keratin were useful to discriminate hepatocellular carcinomas (0%, 0/8) from breast carcinomas (87%, 20/23; 96%, 22/23), but they were also positive in cholangiocarcinomas (100%, 5/5) and other metastatic carcinomas in the liver (91%, 10/11). AE3, CAM5.2 and PKK1 showed highly positive immunoreactivity for breast carcinomas, cholangiocarcinomas and other metastatic carcinomas in the liver, and hepatocellular carcinoma cells were sometimes stained (50%, 4/8; 88%, 7/8; 38%, 3/8). MA904 showed negative immunoreactivity for all cases examined. A discussion was made on the specificity of the antibodies available for a histologic differential diagnosis.     

肾脏黏液性管状和梭形细胞癌临床病理学观察

目的 探讨肾脏黏液性管状和梭形细胞癌的临床病理学特征、免疫表型及鉴别诊断。方法 应用常规病理、免疫组化方法观察1例肾脏黏液性管状和梭形细胞癌并复习相关文献。结果 肿物与周围肾组织分界清楚，组织学特点是排列呈管状的上皮样细胞，片状的梭形细胞和黏液性间质，无明显核的异型性，缺乏坏死。免疫组化：CK、EMA、vimentin阳性，SMA、desmin、S-100蛋白、HMB45等阴性。结论 肾脏黏液性管状和梭形细胞癌是WHO新确定的一类罕见的低度恶性肾上皮性肿瘤，预后较好，要与后肾腺瘤、肉瘤样癌和集合管癌等疾病相鉴别。     

New trends of immunohistochemistry for making differential diagnosis of breast lesions

Immunohistochemistry is widely used for pathological diagnosis of breast lesions. Other than hormone receptors and HER2/neu analysis for primary breast carcinomas, several markers may be useful for differential diagnoses, although in limited situations. To decide the malignant potential of intraductal proliferative lesions, analysis for the staining pattern of cytokeratins may be a good reference. Most ductal carcinoma in situ cases are diffusely positive for luminal cell markers (CK8, CK18, CK19), but negative for basal cell markers (CK5/6 and CK14). However, usual ductal hyperplasia may show the mosaic staining patterns for any of these markers, which may indicate a heterogeneous cell population in benign lesions. Myoepithelial markers (α-SMA, myosin, calponin, p63, CD10) are almost consistently positive for benign papillomas but they do not completely distinguish intraductal papillary carcinomas. Preservation of myoepithelial layer is the diagnostic key when looking at benign sclerosing lesions, including carcinoma with pseudoinvasive structures. E-cadherin is mostly positive for ductal carcinomas but negative for lobular carcinomas. Some of the lobular carcinomas are positive for 34βE12, but they are consistently negative for CK5/6. Comparison with histopathological findings of hematoxylin and eosin is essential to make proper diagnosis in the individual case.     

Undifferentiated carcinoma of the prostate with small cell features: immunohistochemical subtyping and reflections on histogenesis

 To investigate the histogenesis of undifferentiated carcinoma of the prostate with small cell features we analysed the expression of neuroendocrine (NE) markers, the androgen receptor (AR), and prostatic-specific antigen (PSA) in 19 undifferentiated carcinomas of the prostate. The proliferative activity (MIB-1/Ki67) of the tumours was examined, and the clinical data reviewed. The results identified two groups: carcinomas in group 1 were positive for PSA and AR and negative for NE markers. The mean MIB-1 labelling index (LI) was 34.8% and the mean serum PSA value 56.4 ng/ml. Two of the 7 patients died within 12 months after tumour diagnosis. The tumours in group 2 were NE differentiated small cell carcinomas (SCC), which were negative for PSA and AR. The mean MIB-1 LI was 82.6% and the mean serum PSA value 7.1 ng/ml. Seven of the 10 patients died between 2 and 12 months after tumour diagnosis. Positive staining for NE markers in combination with negative staining for PSA and AR and a high MIB-1 LI substantiated the diagnosis of a NE-SCC. We suggest that this tumour has a stem cell origin and does not derive from a dedifferentiated adenocarcinoma or from benign NE cells of the prostatic epithelium. This clear distinction of NE-SCC from NE-negative undifferentiated carcinoma is in accordance with the differing biological behaviour and response to therapy of the two tumour entities. Received: 12 November 1998 / Accepted: 28 January 1999     

Pleomorphic carcinoma of the breast with expression of macrophage markers: report of two cases

Pleomorphic ductal carcinoma of the breast is a rare variant included in the morphological group of infiltrating ductal carcinoma. The pleomorphic carcinoma is composed predominantly of epithelial and multinucleated tumor giant cells. We report here two cases presenting a lesion composed microscopically of a proliferation of large pleomorphic cells with a predominance of multinucleated giant cells. These lesions were negative for estrogen receptor, progesterone receptor and Her2-neu (triple-negative phenotype). Basal markers (cytokeratin 5/6, cytokeratin 17 and epidermal growth factor receptor [EGFR]) were present, accompanied by the presence of histiocyte marker CD163 in most neoplastic giant cells. High-grade pleomorphic breast carcinomas with the triple-negative phenotype and expression of basal markers might be included in the basal subtype. This is the first report about the co-expression of macrophage marker CD163, with tumor (P53) or epithelial markers (CAM5.2), as indicated by double immunohistochemistry in pleomorphic ductal carcinoma of the breast.     

Metastatic squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers

Squamous cell carcinoma with pseudoangiosarcomatous features is a rare but well-recognized variant of squamous cell carcinoma. These tumors exhibit complex anastomosing channels lined by neoplastic cells, histologically mimicking a vasoformative mesenchymal tumor. Immunohistochemically, the published cases expressed epithelial markers and were consistently negative for vascular markers. Squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers has never been reported. Herein, we report two cases of metastatic poorly-differentiated squamous cell carcinoma with pseudoangiosarcomatous morphologic features which showed immunoreactivity for vascular markers (CD31, Fli-1, and ERG). One case (left thigh skin squamous cell carcinoma with abdominal wall metastasis) showed strong and diffuse positivity for vascular markers, and the final diagnosis was confirmed with electron microscopy. The second case (squamous cell carcinoma of unknown primary site with bone metastasis) showed patchy positivity for both squamous and vascular markers. This is the first report of squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers, which resembles angiosarcoma both morphologically and immunohistochemically, and may represent a potential diagnostic pitfall. It is of crucial importance for pathologists to be aware of metastatic squamous cell carcinoma with such unique features, so that misdiagnosis and inappropriate treatment will be avoided.     

Expression of bcl-2 oncoprotein in renal cell tumours

Expression of bcl-2 is associated with inhibition of apoptosis and extension of cell survival. The importance of apoptosis in relation to the development and progression of renal cell neoplasia remains undefined so far. In order to determine the expression of bcl-2 oncoprotein in normal and neoplastic renal cells, 37 renal tumours were investigated by immunolabelling, including 13 clear cell carcinomas, ten tubulopapillary carcinomas, four chromophobic renal cell carcinomas, and ten oncocytomas. Twenty-six samples of adjacent normal renal tissue served as controls. bcl-2 expression was correlated with cell proliferation activity as estimated by Ki67 antigen expression, and p53 protein expression in the tumour samples. The results demonstrate that in the normal kidney, positive bcl-2 immunostaining was present in glomerular parietal epithelial cells, in distal tubular cells, and in sparse proximal tubule cells. Renal cell tumours showed heterogeneous bcl-2 expression according to the tumour cell type. While the majority of carcinomas of clear cell type were usually negative or contained sparsely distributed positive cells, all tubulopapillary carcinomas were consistently positive for bcl-2. In oncocytomas and chromophobic carcinomas, there was a low percentage of bcl-2 immunoreactive tumour cells; some nuclear bcl-2 positivity was detected in one chromophobic tumour. These findings indicate variable bcl-2 oncoprotein expression in different types of renal cell tumours, with the highest level of expression in tubulopapillary carcinomas. No clear relationship was found between nuclear grade, cell proliferation activity, and level of bcl-2 expression. p53 protein was detected in only one tubulopapillary carcinoma.     

Differential diagnosis of epithelioid and clear cell tumors in the liver

A tumor composed of large eosinophilic cells in the liver raises concern for hepatocellular carcinoma, which is typically composed of such cells. However, there are other tumors, both primary and metastatic, that may be composed predominantly of large epithelioid cells. Distinction of these tumors from hepatocellular carcinoma and from each other is of obvious importance for patient management. Similarly, a clear cell tumor anywhere in the body triggers suspicion for renal cell carcinoma. However, other tumors, including hepatocellular carcinoma can rarely be composed entirely of cell cells and the distinction of these from one another, and of primary from metastatic disease is vital. As with the latter, accurate diagnosis is essential for patient management. Using illustrative examples, this article discusses differential diagnosis of liver tumors comprised predominantly of epithelioid cells or clear cells.     

囊性肾细胞癌3例报道及文献复习

目的探讨囊性肾细胞癌的病理形态学特征及鉴别诊断。方法对3例囊性肾细胞癌进行光镜观察及免疫组化标记,并复习文献。结果肿瘤有确切的瘤体,由厚的假纤维包膜围绕,切面见大小不等的囊腔。镜下见囊腔被覆无明显异型的透明细胞,纤维性囊壁间隔中可见透明细胞巢。免疫表型:透明细胞CK、EMA强阳性,CD68、M ac387阴性,K i-67、p53弱阳性。结论囊性肾细胞癌少见,预后好,术前易与多囊肾、囊性变肾细胞癌和囊性肾瘤等混淆。本瘤的特征是囊性区显著,囊腔内衬单层或数层异型小的透明细胞,囊壁之间可见透明细胞巢。     

Endometriosis-related pathology: a discussion of selected uncommon benign,premalignant and malignant lesions

Endometriosis is an extremely common condition and, in most cases, establishing a histological diagnosis is straightforward, although a variety of benign alterations may result in problems with interpretation. In this review, I discuss selected uncommon variants of endometriosis or benign alterations that may result in diagnostic problems. The topics covered include the contentious issue of so-called atypical endometriosis, stromal endometriosis, polypoid endometriosis, and the association of endometriosis with florid mesothelial hyperplasia. The propensity of endometriosis to undergo neoplastic transformation (especially to endometrioid and clear cell carcinoma) is well known. Selected issues relating to the various neoplasms that can arise in endometriosis are discussed, with a particular concentration on unusual variants of endometrioid carcinoma that result in a disproportionately high number of issues in referral practice. The propensity of ovarian endometrioid carcinomas to show an unexpected (‘aberrant’) immunophenotype with positive staining with ‘intestinal’ markers and negative staining with Mullerian markers is also discussed. Uncommon tumour types that may arise in endometriosis, namely seromucinous neoplasms, mesonephric-like carcinomas, and somatically derived yolk sac tumours, are also covered.     

Multiple expression of tissue markers in mucoepidermoid carcinomas and acinic cell carcinomas of the salivary glands

Summary The distribution of various tissue antigens was studied in mucoepidermoid carcinomas (n=74) and acinic cell carcinomas (n=38) by means of immunocytochemistry. Mucoepidermoid carcinomas were generally positive for cytokeratin and showed double expression for cytokeratin and vimentin in 31.1% and triple expression for cytokeratin, vimentin and GFAP in 24.1%. CEA was studied using new monoclonal antibodies which distinguish between epitopes that are present on CEA alone and those which are present on nonspecific cross reacting antigens as well. The monospecific CEA antibody was completely negative in mucoepidermoid carcinomas, while nonspecific cross reacting antigens (NCAs) were positive in mucoepidermoid carcinomas to a varying degree. Alpha 1-antichymotrypsin, a marker formerly thought to be specific for tissues for histiocytic origin, was positive in 85.1% of mucoepidermoid carcinomas. Twenty three percent of mucoepidermoid carcinomas showed focal infiltration by S-100 positive dendritic stromal cells, tumour cell being negative. Leu-M 1 antigen was positive in 58.1% of mucoepidermoid carcinomas. Acinic cell carcinomas were generally positive for cytokeratin and in single cases showed double expression for cytokeratin and vimentin and triple expression for cytokeratin, vimentin and GFAP. Monospecific CEA antibody positivity could be demonstrated in 24.2% of acinic cell carcinoma, while nonspecific cross reacting antigens (NCAs) were positive in acinic cell carcinomas to a varying degree. Alpha 1-antichymotrypsin was positive in 97.4% of acinic cell carcinomas. 2.5% of acinic cell carcinomas showed focal infiltration by S-100 positive dendritic stromal cells, 2.5% of acinic cell carcinomas were positive for S-100 protein with no dendritic stromal cells present. Leu-M 1 antigen was positive in 86.8% of acinic cell carcinomas. For S-100 protein and Leu-M 1, no correlation with the clinical course, as reported previously for other tumours, could be observed.Supported by the Deutsche Forschungsgemeinschaft (DFG), the Hamburger Landesverband für Krebsbekämpfung und Krebsforschung, and the Hamburger Stiftung zur Förderung der KrebsbekämpfungProf. Dr. Dres. h.c. W. Doerr on the occasion of his 75th birthday