Composite distal nephron-derived renal cell carcinoma with chromophobe and collecting duct carcinomatous elements

Chromophobe renal cell carcinoma (RCC) and collecting duct carcinoma (CDC) are derived from the collecting duct epithelia, although their morphology, molecular biologic characteristics and clinical behaviors are quite different. Herein is presented a case of RCC possessing the chromophobe RCC and CDC elements occurring in a 64 year-old Japanese woman. The patient was referred to Yokohama City University Hospital with complaints of persistent back pain and fever. Radiologic examinations revealed a left renal tumor, and radical nephrectomy was performed. The patient died with multiple metastases, 8 months after the operation. The resected tumor showed an invasive growth, and its cut surface was heterogenous with hemorrhage and necrosis. Histologically, the tumor was composed of chromophobe elements with dedifferentiation, and CDC elements. The chromophobe and CDC elements had obvious histological transition. Lectin histochemistry and immunohistochemistry confirmed that this tumor was derived from the distal nephron. c-KIT, p53 and Ki67 antigen showed differential localization between the chromophobe and CDC elements, even in the transitional areas. Along with the previous reports, the present case seemed to be composite RCC derived from the collecting duct, which might present clues to elucidate carcinogenesis in the distal nephron.     

Triple synchronous neoplasms in one kidney: report of a case and review of the literature

We report the case of a patient with three synchronous but histologically different primary renal tumors that were all in the same kidney. Two tumors were different subtypes of renal cell carcinoma (RCC), and the third was a variant form of angiomyolipoma. The patient was a 62-year-old man who was receiving antihypertensive drugs and came to our hospital for a regular check-up. Ultrasonography performed during the visit revealed a left renal mass, but the patient had no related symptoms. Subsequent computed tomography revealed two round, high-density masses, one in the mid-portion and the other in the lower pole of the left kidney, and multiple cysts in the right kidney and the liver. The mass in the mid-portion measured 3.3 x 3.0 x 2.8 cm, and the mass in the lower pole measured 1.7 x 1.1 x 0.9 cm. A left radical nephrectomy was performed. On gross examination, an additional ovoid nodule (0.6 cm in the greatest dimension) was found in the lower pole. Microscopically, the largest tumor consisted of a broad alveolar arrangement of large round cells with abundant eosinophilic or clear cytoplasm, distinct cell borders, and perinuclear halos, features consistent with chromophobe RCC. The smallest tumor was a conventional (clear-cell) RCC. The third tumor was composed solely of atypical epithelioid cells with prominent nucleoli and yellowish-brown to black pigments. The tumor cells were positive for melanin (Fontana-Masson stain), the melanoma marker HMB45, vimentin, smooth-muscle actin, and the macrophage marker CD68 and were negative for cytokeratin. This tumor was considered a pigmented epithelioid type of angiomyolipoma. The histologic, histochemical, and immunohistochemical features in this case confirmed the presence of three synchronous primary tumors, a chromophobe and a clear-cell type RCC and a pigmented epithelioid angiomyolipoma, all of which were in the same kidney. This case is the first of its type reported in the literature.     

Chromophobe renal cell carcinoma: an immunohistochemical study of 21 Japanese cases.

Chromophobe renal cell carcinoma (RCC) is a newly established category of RCC composed histologically of characteristic "chromophobe" tumor cells. Although ultrastructural and immunohistochemical studies showed that these tumor cells present several features similar to those found in the intercalated cells of the collecting duct, immunohistochemical studies using antibody panels on a large number of cases are limited. We performed an immunohistochemical study of 21 Japanese cases of chromophobe RCC, along with cases of clear RCC and renal oncocytoma, to find hallmarks useful for precise differential diagnosis of these tumors. Chromophobe RCC was positive for epithelial membrane antigen but negative for vimentin. Cytokeratins did not show constant immunoreactivity in the three types of renal tumors. Furthermore, all of the chromophobe RCCs and renal oncocytomas were positive for E-cadherin but not for N-cadherin, whereas all of the clear RCCs were negative for E-cadherin, and 58% were positive for N-cadherin. The Ki-67 labeling indices were significantly lower in cases classified as (pT1) or Grade 2 chromophobe RCC than in cases of clear RCC. Immunoreaction for E-cadherin was demonstrated to be useful for distinguishing chromophobe RCC from clear RCC, and a low Ki-67 labeling index might indicate a favorable prognosis, as reported in several previous studies.     

Chromophobe renal cell carcinoma with sarcomatoid change. A case report

Chromophobe renal cell carcinoma (RCC) is a newly established entity of renal neoplasm with histological and molecular biological features different from those of common RCCs. Chromophobe RCC shows characteristically cloudy and reticular cytoplasm and cellular features resembling distal nephron. Its prognosis has been reported to be more favorable than that of common RCCs. Recently, however, several cases have been reported which showed sarcomatoid change to present poor prognosis. Here we present a case of chromophobe RCC with sarcomatoid change which was once resected surgically. The surgically resected tumor was histologically composed of chromophobe epithelial cell sheets and sarcomatoid elements. The former showed positivity for colloid iron staining, and was immunohistochemically positive for E-cadherin and epithelial membrane antigen (EMA), whereas the latter was positive for vimentin instead of colloid iron and E-cadherin. EMA was focally positive in the sarcomatoid element. The patient died with systemic metastases 14 months after the operation. Histologically, the metastatic tumors were composed only of sarcomatoid element lacking epithelial element. Based on these findings and previous reports, this case supports the existence of a tumor progression pathway from chromophobe to sarcomatoid RCC. It is necessary to perform careful postoperative investigation of chromophobe RCC due to its possible histological progression to the sarcomatoid subtype.     

Chromophobe renal cell carcinoma

Chromophobe renal cell carcinoma (RCC) is a recently established subtype of RCC, which has rarely been reported in Japan. In this communication, the authors report two Japanese cases of chromophobe RCC together with the immunohistochemical findings. The tumors were composed of sheets and cribriform glands formed by tumor cells with cloudy and reticular cytoplasm. Ultrastructurally, the cytoplasm was filled with numerous microvesicles. The tumor cells were positive for cytokeratin, epithelial membrane antigen, and Tamm-Horsfall protein. Occasionally, LeuM1-positive cells were also noted. Vimentin was negative, unlike the usual RCC. Reactivity for peanut agglutinin was more frequent than that to Lotus tetragonolobus agglutinin. The results of this study suggest that the tumor cellq possessed phenotypes similar to the distal nephron rather than to the proximal tubular cells.     

Renal cell carcinoma metastatic to the nasal cavity

Metastatic renal cell carcinoma of the nasal cavity is very rare. A 76-year-old man presented with epistaxis and admitted to our hospital. His past histories were right radical nephrectomy for renal cell carcinomas at the age of 68 years and brain infarction at the age of 75 years. Laryngoscopic examination revealed a red polyp of the right nasal cavity. Imaging modalities including CT and MRI also revealed a tumor measuring 2 x 3 x 2 cm. Angiography showed that the tumor is very hypervascular. Clinical diagnosis was angiogenic tumors including hemangioma, sinonasal hemangiopericytoma, and paraganglioma. A blood data showed anemia and low platerets, and bone marrow biopsy revealed myelodysplastic syndrome. A coiling embolization of the feeding artery was performed, and the tumor reduced markedly. The tumor was resected almost entirely. Pathologically, the tumor was 2 x 1.5 x 1.5 cm red tumor. The tumor cells had clear cytoplasm, and arranged in a trabecular pattern lined by a layer of endothelial cells. Atypia is mild. Immunohistochemically, the tumor cells were positive for pancytokeratin (AE1/3, CAM5.2), RCC ma, CD10, and Ki-67 (labeling=20%), but negative for CD34, factor-VIII-related antigen, CEA, EMA, melanosome (HMB45), S100 protein, p53, and HepPar-1. The pathological diagnosis was made without knowledge of kidney status. A pathological diagnosis of metastatic renal cell carcinoma of clear cell type (grade 1) was made. The patient is now free from tumor, and palliative chemoradiation is considered.     

Kidney-specific cadherin, a specific marker for the distal portion of the nephron and related renal neoplasms.

Renal cell neoplasms are presumably derived from different cell types of the nephron. Clear cell and papillary renal cell carcinoma (RCC) are thought to be of proximal tubular origin, whereas oncocytoma and chromophobe RCC are derived from intercalated cells of distal nephron. A few molecules, such as RCC marker and CD10, have been shown to be markers for clear cell RCC and papillary RCC. Such markers are not yet available for renal tumors presumably of the distal nephron. The expression of kidney-specific (Ksp) cadherin, a recently cloned gene thought to be transcribed exclusively in the kidney, was studied in normal human kidney, as well as in 105 primary renal neoplasms, including 42 clear cell RCC, 30 papillary RCC, 13 chromophobe RCC, and 20 oncocytomas. The expression patterns were compared with those of RCC marker. The Ksp-cadherin expression was noted preferentially in distal convoluted tubules with a basolateral membrane stain in normal kidney. All 13 chromophobe RCC and 19 of 20 oncocytomas showed diffuse and strong immunoreactivity for Ksp-cadherin, while only 14% clear cell RCC and 13% papillary RCC showed focal positivity. The RCC marker expression was detected in 85%, 98%, 15% and 0% of clear cell RCC, papillary RCC, chromophobe RCC, and oncocytoma, respectively. A few clear cell RCC and papillary RCC showed dual expression of both RCC marker and Ksp-cadherin, which appear to have distinct histologic features. These results demonstrated high sensitivity and specificity of Ksp-cadherin for distal convoluted tubules, which can be used as adjunct for diagnosis of chromophobe RCC.     

Cutaneous metastasis of renal cell carcinoma: a report of two cases

Cutaneous metastasis of renal cell carcinoma (RCC) is very rare. The author herein report two cases of RCC with cutaneous metastasis. Case 1: is a 75-year-old man with right lumbago. Imaging modalities including CT and MRI revealed a right renal tumor. Nephrectomy was performed. Pathological diagnosis of the renal tumor was RCC of clear cell type (Fuhrman's grade II). He denied follow-up. Nine years later, he (at the age of 84 years), a neck skin tumor emerged. Clinical diagnosis was hemangioma. Imaging modalities including CT and MRI showed several tumors in both lungs. The resection of the neck tumor was performed. The tumor was composed of clear cell type arranged in a trabecular pattern. Immunohistochemically, the tumor cells were positive for pancytokeratins, cytokeratin 18, CD10, Ki-67 (labeling=13%), but negative for CD34, factor-VIII-related antigen, CEA, EMA, melanosome (HMB45), S100 protein, p53, and HepPar-1. Metastatic RCC was diagnosed. Despite interferon therapy, he died of 6 months after the second admission. Case 2 is a 66-year-old man with gross hematuria. Imaging modalities revealed left renal tumor. A nephrectomy was performed. The pathological diagnosis was RCC of clear cell type (grade II). The tumor was invasive into the renal pelvis. He was treated by chemoradiation, but metastases of lungs, skin (thigh), and lib emerged, and died of cachexia 9 months after the admission. Necropsy of the skin tumor was performed. The skin tumor was composed of clear cells arranged in a trabecular pattern. Immunohistochemically, the tumor cells were positive for pancytokeratins (AE1/3, CAM5.2), CD10, p53, and Ki-67 (labeling=20%), but negative for CD34, factor-VIII-related antigen, CEA, melanosome (HMB45), S100 protein, and HepPar-1. A diagnosis of RCC (grade II) was diagnosed.     

Acquired cystic disease-associated renal cell carcinoma with sarcomatoid change and rhabdoid features

Acquired cystic disease (ACD)–associated renal cell carcinoma (RCC) is a recently described entity. To the best of our knowledge, there are no reports of ACD-associated RCC with sarcomatoid and rhabdoid changes. In this article, we present the first case of such a tumor. A 56-year-old Japanese man has received long-term hemodialysis and had a history of right renal cancer. Following the discovery of metastatic cancer in the thoracic wall, detailed imaging studies revealed a mass in the left kidney. The histologic examination of the left renal tumor showed ACD-associated RCC with sarcomatoid change and rhabdoid features. Immunohistochemically, intracytoplasmic globular inclusions in rhabdoid cells were positive for vimentin and cytokeratin CAM5.2. The G-band karyotype showed the following changes: 46, X, +X. −Y[1]/43, idem, add(2)(q31), −6, −9, −14, −15, +16, −22, +mar1[6]/46, XY[2]/abnormal cell[11]. In conclusion, pathologists and urologists should be aware that rhabdoid features may occur in ACD-associated RCC and that the loss of chromosomes 9 and 14 may occur during the process of sarcomatoid change in ACD-associated RCC.     

Composite renal cell carcinoma and angiomyolipoma: a study of the histogenetic relationship of the two lesions

The purpose of the present study was to investigate the possible histogenetic relationship of renal cell carcinoma (RCC) and angiomyolipoma (AMYL) occurring in the same renal nodule by examining two cases of composite RCC and AMYL in patients without stigmata of tuberous sclerosis and by reviewing the medical literature of similar cases. Case 1 represents an epithelioid variant of AMYL with multiple additional nodules of typical AMYL in a surgically removed kidney. The patient subsequently developed a lesion consisting of a mixture of epithelioid variant of AMYL and RCC 24 months later in the retroperitoneum and, an additional 4 months later, in the liver. The RCC cells resembled mononucleated epithelioid cells of the epithelioid AMYL except that they were focally reactive with epithelial membrane antigen (EMA) in the retroperitoneum and focally reactive with both EMA and cytokeratin (CK) in the liver. Case 2 consisted of a typical AMYL admixed with a chromophil cell RCC. A review of the medical literature revealed seven additional cases with histopathological findings similar to this case. All cases had multiple foci of typical AMYL. Immunostaining results are available in five tumors. Chromophil RCC showed variable reactivity with CK and EMA. In addition, RCC in the two cases in the present study also displayed a positive reaction with mucin staining and a positive reactivity with carcinoembryonic antigen. There appears to be a spectrum of histopathological and immunohistochemical changes from the epithelioid variant of AMYL through a mixed epithelioid AMYL/RCC to chromophil RCC in three successive specimens in case 1. Moreover, the intimate admixture of AMYL and RCC and the similar expression of epithelial markers of RCC in the two cases in the present study, as well as other cases in the literature, suggest that some RCC develop from the same precursor cell as AMYL or from a component of AMYL.     

Histopathologic approaches to the infiltrative renal mass

Most renal masses are round or oval, well-circumscribed, and demonstrate a well-defined interface from the normal renal parenchyma. However, a small subset of renal tumors exhibits an infiltrative pattern, with a poorly-defined interface with the renal parenchyma and entrapment of normal structures. These infiltrative renal malignancies generally show more aggressive clinical course and are associated with a poorer prognosis compared to the more typical renal neoplasms. Main differential diagnoses for a renal mass with infiltrative histology would include urothelial carcinoma, fumarate hydratase (FH)-deficient renal cell carcinoma (RCC), medullary RCC, metastatic cancer from another organ, and rare patterns of clear cell or papillary RCC. Non-epithelial processes may include lymphoma and various infectious, inflammatory, immune-mediated, and vascular mimics. Collecting duct carcinoma is extremely rare in modern practice and is essentially a diagnosis of exclusion once the previous considerations are thoroughly argued against. The aim of this review is to familiarize pathologists with the spectrum of entities that can present as infiltrative masses in the kidney, and to highlight the most relevant immunohistochemical or other tools to facilitate accurate diagnoses and appropriate patient management.     

Clear cell papillary renal cell carcinoma: a review

The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.     

Evaluation of Morphologically Unclassified Renal Cell Carcinoma with Electron Microscopy and Novel Renal Markers: Implications for Tumor Reclassification

Despite progress in the classification of renal cell carcinomas (RCC), a subset of these carcinomas remains unclassified (RCC-U). Patients with RCC-U usually present at a late stage and have a poor prognosis. Several studies have attempted to extract new classifications of newly recognized renal carcinomas from the group of RCC-U. However, to date, no studies in the literature have attempted to characterize the RCC-U with unrecognizable cell types beyond the morphologic evaluation on H&E-stained sections. The purpose of this study was to evaluate this group of RCC-U using electron microscopy and novel renal markers. Ten cases of such RCC-U were identified for this study. At the ultrastructural level, they did not show typical morphology that resembled any of the well-studied, recognizable subtypes of RCC. However, they did reveal features of renal tubular epithelial differentiation. The histologic, ultrastructural, and immunophenotypic features indicated that these tumors are poorly differentiated renal epithelial tumors, possibly derived from the proximal nephron, with an immunohistochemical profile similar to high-grade clear cell RCC. It is, therefore, proposed that this group of renal carcinomas be renamed “poorly differentiated renal cell carcinoma, not otherwise specified.” The current study showed that PAX-8 and carbonic anhydrase IX are reliable markers for this novel group of renal carcinoma, and that electron microscopy is an important adjunct in the evaluation of new and unusual renal entities.     

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。     

Xp11.2 translocation renal neoplasm with features of TFE3 rearrangement associated renal cell carcinoma and Xp11 translocation renal mesenchymal tumor with melanocytic differentiation harboring NONO-TFE3 fusion gene

Xp11.2 translocation/TFE3 rearrangement-associated renal cell carcinoma (RCC) and Xp11 translocation renal mesenchymal tumor are distinct tumor entity. To broaden the spectrum of Xp11 neoplasms, we investigated a novel tumor exhibiting morphologies overlapping Xp11.2 translocation/TFE3 rearrangement-associated RCC and the mesenchymal counterpart with melanocytic differentiation by immunohistochemistry, fluorescence in situ hybridization (FISH) and RNA sequencing, as well as literature review. Histologically, the tumor was composed of three different types of tumor cells, including a large proportion of clear cells, small round cells, and a few spindle cells, presenting a relatively clear border in the majority area. The nuclei of all tumor cells showed extensively and strong positive expressions of TFE3. Whereas, the clear cells positively expressed the RCC-related markers including PAX8, RCC marker and CD10, and negatively expressed HMB45; On the contrary, the small round cells and spindle cells positively expressed melanocytic marker HMB45, and negatively expressed PAX8, RCC marker and CD10. The ki67 index was higher in the small round cells and spindle cells than that in the clear cells. FISH revealed the rearrangement of TFE3 gene in all the three types of cells. The NONO-TFE3 fusion gene was detected in all tumor cells by RNA sequencing. This unique Xp11 translocation-associated neoplasm might represent a distinct entity overlapping Xp11 translocation RCC and the mesenchymal counterpart with melanocytic differentiation, broadening the spectrum of Xp11 neoplasms. The patient died of tumor recurrence and lung metastasis after seven months after the surgery suggesting those tumors have an unfavorable prognosis.     

Expression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers

The expression patterns of 7075 genes were analyzed in four conventional (clear cell) renal cell carcinomas (RCC), one chromophobe RCC, and two oncocytomas using cDNA microarrays. Expression profiles were compared among tumors using various clustering algorithms, thereby separating the tumors into two categories consistent with corresponding histopathological diagnoses. Specifically, conventional RCCs were distinguished from chromophobe RCC/oncocytomas based on large-scale gene expression patterns. Chromophobe RCC/oncocytomas displayed similar expression profiles, including genes involved with oxidative phosphorylation and genes expressed normally by distal nephron, consistent with the mitochondrion-rich morphology of these tumors and the theory that both lesions are related histogenetically to distal nephron epithelium. Conventional RCCs underexpressed mitochondrial and distal nephron genes, and were further distinguished from chromophobe RCC/oncocytomas by overexpression of vimentin and class II major histocompatibility complex-related molecules. Novel, tumor-specific expression of four genes-vimentin, class II major histocompatibility complex-associated invariant chain (CD74), parvalbumin, and galectin-3-was confirmed in an independent tumor series by immunohistochemistry. Vimentin was a sensitive, specific marker for conventional RCCs, and parvalbumin was detected primarily in chromophobe RCC/oncocytomas. In conclusion, histopathological subtypes of renal epithelial neoplasia were characterized by distinct patterns of gene expression. Expression patterns were useful for identifying novel molecular markers with potential diagnostic utility.     

Tubulocystic renal cell carcinoma with poorly differentiated foci is indicative of aggressive behavior: clinicopathologic study of two cases and review of the literature

Tubulocystic renal cell carcinoma (TCRCC) is a rare, recently characterized RCC subtype with distinctive clinicopathologic and genetic characterizations as well as typical behaviors in an indolent fashion. However, sporadic case reports in the literature have indicated that TCRCC with sarcomatoid differentiation or poorly differentiated (PD) foci could behave aggressively. Herein, we reported two cases of TCRCC with PD foci indentified from our consultative service. Both patients were male and aged 66 y and 47 y, respectively. The first patient experienced radical nephrectomy while the other was treated by partial nephrectomy. Macroscopically, both tumors were described as partly cystic and solid with the greatest diameter measuring of 12-cm and 4.5-cm, respectively. Histologically, both lesions had classic areas of TCRCC occupying most part of the tumor with small papillary RCC component. In case one, PD foci were scatteredly distributed and mixed with TCRCC and papillary RCC components, while in the other case the PD foci were adjacent to the areas of TCRCC. In both tumors, the PD foci were composed of irregular, often angulated, small tubules lined by atypical eosinophilic cells and surrounded by desmoplastic stroma, resembling collecting duct carcinoma. Immunohistochemistry, in both tumors, both TCRCC component and PD foci showed the similar immunoprofiles, i.e., labeling strongly and diffusely with PAX8, AMACR and Vimentin, and focally with CK34βE12 but not with renal cell carcinoma marker or P63. In case one, the tumor invaded extensively into the adjacent renal parenchyma and focally into both renal sinusal and perirenal adipose tissues. The patient had metastasis in the pelvic cavity at the time of diagnosis and succumbed to the disease without further treatment 3 months later. The other case was organ confined but with focal positive renal parenchymal margin. The patient subsequently underwent radical nephrectomy and was in a good status without evidence of tumor recurrence or metastasis at a follow-up of 8 months.