Chromophobe renal cell carcinoma, oncocytic variant: a proposal of a new variant giving a critical diagnostic pitfall in diagnosing renal oncocytic tumors

In chromophobe renal cell carcinoma (RCC), two forms of typical and eosinophilic variants have been reported to date. We have previously reported a new variant of chromophobe RCC, namely an oncocytic variant. However, little is known on the histological features of this variant. In this article, we report such five cases. Macroscopically, the tumor was well demarcated, but unencapsulated. The cut surface of the tumor showed brown in color, but neither hemorrhage nor necrosis was seen. Microscopically, the tumor consisted of predominant tubular configuration with or without various proportion of solid-sheet pattern. In one tumor, tumor cells microscopically invaded branches of renal vein. In addition, the constituting cells were characterized by the oncocytic cytoplasm, trivial to minimal variation in tumor size, indistinct to slightly distinct cell border, centrally located round nuclei and the absence of perinuclear halo. These characteristics entirely resembled renal oncocytoma. However, neoplastic cells immunohistochemically showed the diffuse and strong labeling for cytokeratin 7 and mitochondrial antigen in all cases. In addition, in fluorescence in situ hybridization (FISH) study the loss of more than four chromosomes among chromosomes 7, 10, 13, 17 and 21 was confirmed in all tumors and the diagnosis of chromophobe RCC was rendered. In conclusion, we propose a new variant, namely an oncocytic variant, of chromophobe RCC morphologically resembling renal oncocytoma and biologically showing characteristics of chromophobe RCC, and this recognition is practically crucial in the differential diagnosis from renal oncocytoma.     

Acquired cystic disease-associated renal cell carcinoma with gain of chromosomes 3, 7, and 16, gain of chromosome X, and loss of chromosome Y

Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) has been recently described. To date, there are no reports on genetic findings of G-band karyotype of ACD-associated RCC. In this article, we report the first report of G-band karyotype of ACD-associated RCC. A 66-year-old Japanese man was found to have a left renal tumor during the follow-up of hemodialysis consequent to chronic renal failure. Left nephrectomy was performed. Histological examination of three tumors in the left kidney showed the cribriform or microcystic growth pattern of neoplastic cells with eosinophilic cytoplasm, and many oxalate crystals were observed. The G-band karyotype of ACD-associated RCC showed 49, X, +X, −Y, +3, +7, +16. These chromosomal abnormalities resemble those of sporadic papillary RCC that has been previously reported. Finally, we suggest that this tumor may show a close relationship between ACD-associated RCC and papillary RCC, but a large-scale study will be needed to clarify the relationship between ACD-associated RCC and papillary RCC.     

Progesterone receptor reactivity in renal oncocytoma and chromophobe renal cell carcinoma

Aims:  To investigate the reactivity for oestrogen and progesterone receptors (ER and PR) in renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC).
Materials and methods:  Thirty-eight RO, 25 CHRCC, 20 papillary RCC with oncocytic cytoplasm and 10 clear cell RCC with dominant eosinophilic cytoplasm were submitted for immunohistochemistry for ER, PR, CD117 and RCC.
Results:  All cases of RO and CHRCC displayed moderately positive reactivity for PR. The nuclear reactivity ranged from 60% to 90% in RO and from occasional cells to 70% in CHRCC. In CHRCC, reactivity tended to be more prevalent in areas of tumour cells with eosinophilic cytoplasm. Progesterone reactivity was focal in areas. All RO and most CHRCC were reactive for CD117 and neither RO nor CHRCC was reactive for RCC. CD117 reactivity tended to be more intense in CHRCC than in RO. Negative reactivity for CD117 and positive reactivity for RCC were observed in almost all RCC, as reported in the literature.
Conclusions:  PR can be used in combination with CD117 and RCC in the differential diagnosis of RO and eosinophilic variant of CHRCC with other RCC with oncocytic or eosinophilic cytoplasm.     

Fine‐needle aspiration findings of Xp11 translocation renal cell carcinoma metastatic to a hilar lymph node

Xp11 translocation renal cell carcinoma (RCC) is a specific type of renal cell carcinoma recently placed under the “MiT family translocation RCC” at the last 2013 ISUP Vancouver classification of renal neoplasia. This tumor contains variable proportions of clear cells and could easily mimic papillary RCC, clear cell type, and clear cell papillary RCC. Given the small number of published cytologic findings of this tumor, it could easily present as a diagnostic pitfall. We describe a case of a 23‐year‐old man with a history of prior nephrectomy who presented with multiple mediastinal lymphadenopathies on imaging surveillance follow‐up. Fine‐needle aspiration of the lymph node showed tumor cells with voluminous clear to eosinophilic cytoplasm, well‐defined cell borders and hyperchromatic nuclei arranged in papillary architecture. Review of the prior nephrectomy specimen showed papillary cores surrounded by cells with voluminous clear to finely granular eosinophilic cytoplasm and distinct cell borders. Immunohistochemical stains performed on the nephrectomy specimen showed tumor positivity for CD10, E‐cadherin, a‐methylacyl coenzyme A racemase, and TFE3 supporting the diagnosis of Xp11 translocation renal cell carcinoma. Although this tumor was initially described predominantly in children, it could also occur in adults, as seen in this case. Familiarity with the cytologic findings of this tumor, use of immunohistochemical stains, or cytogenetic test to determine the type of gene fusion will be extremely useful in arriving at the correct diagnosis. Diagn. Cytopathol. 2017;45:456–462. © 2017 Wiley Periodicals, Inc.     

Pediatric renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion

Renal cell carcinoma (RCC) in children and young adults is rare and pathologically problematic. RCC can be either hereditary or sporadic and has a guarded prognosis because appropriate management has not been established. A case of RCC in an 11-year-old is reported. The clinical presentation was a right abdominal mass, hematuria, urinary tract infection, and wasting. Radio-logically, the mass was found within the right kidney with calcification and paraaortic lymphadenopathy. The postsurgical diagnosis was Wilms' tumor stage T4N2M0. On gross inspection, the tumor was ill defined, extending across Gerota's fascia and into the ureter lumina. Microscopically, the tumor consisted of malignant epithelial cells with clear and eosinophilic cytoplasm in nested, papillary, and alveolar configuration. Hyaline nodules, psammoma bodies, vascular invasion, capsular invasion, and extension into the ureter were also found. Immunohistochemically, the cells showed strong nuclear immunoreactivity for TFE3. We concluded that this case was an RCC associated with Xp11.2 translocation/TFE3 fusion, Fuhrman grade 3, stage IV.     

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.     

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.     

Coexistent loss of INI1 and BRG1 expression in a rhabdoid renal cell carcinoma (RCC): implications for a possible role of SWI/SNF complex in the pathogenesis of RCC

In this study, we analyzed the immunohistochemical and molecular profiles of an unusual RCC showed coexistent absence of INI1 and BRG1 expression, rhabdoid morphology, and poor prognosis. Histologically, the tumor had rhabdoid features, which were demonstrated by large round to polygonal cells with eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm varying from abundant to scanty. Immunohistochemically, the tumor were positive for BRM, PBRM1, ARID1A, CD10, CKpan, Vimentin, carbonic anhydrase IX (CA-IX), and P504S (AMACR) but negative for INI1, BRG1, HMB45, melan A, CK7, CD117, Ksp-cadherin, TFEB, TFE3, and Cathepsin K. We detected all three exons status of the VHL gene of the tumor and observed 1 somatic mutations in 1st exon. Chromosome 3p deletion, coupled with polysomy of chromosome 3 was also found. Based on these findings, it is further indicated that in some cases, rhabdoid RCC may arise from clear cell RCC. SWI/SNF chromatin remodeling complex may be an attractive candidate for being the “second hit” in RCCs and may play an important role during tumor progression. The role of SWI/SNF complex in rhabdoid RCC should be further studied on a larger number of cases.     

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.     

Cytologic findings of acquired cystic disease-associated renal cell carcinoma: a report of two cases

Renal tumors may arise in the setting of end-stage renal cell disease. The risk is 100 times that of the normal population with an incidence ranging from 3-7%. The most common malignant tumor to arise in the setting of acquired cystic disease of the kidney is the acquired cystic disease-associated renal cell carcinoma (ACD-associated RCC). The cytomorphologic features of ACD-associated RCC, which has not been described previously, show moderately cellular specimens composed of clusters of cells with papillary configuration. The cells ranged from polygonal to columnar and contained abundant eosinophilic granular cytoplasm. The nuclei were round and centrally located, and the chromatin was finely granular with prominent central nucleoli that corresponded to Fuhrman's grade 3 nucleolar size. The main differential diagnosis is type 2 papillary renal cell carcinoma, from which it can be distinguished based on clinical findings only at this moment.     

Analysis of lectin binding in benign and malignant thyroid nodules

The lectin binding properties of ten cases each of adenomatoid nodule, follicular adenoma, and papillary carcinoma and five cases of microinvasive follicular carcinoma were examined histochemically and compared with adjacent normal thyroid tissue. Wheat germ agglutinin, concanavalin A, Ulex europaeus agglutinin I, peanut agglutinin, soybean agglutinin, Dolichos biflorus agglutinin, Ricinus communis agglutinin, and Helix pomatia agglutinin were employed. All the lectins but Ulex europaeus agglutinin I, peanut agglutinin, and Helix pomatia agglutinin were bound to thyroid parenchymal cells, colloid and stromal cells, but none uniquely to thyroid parenchymal cells. Helix pomatia agglutinin binding was present in stromal cells but not in parenchymal cells. Ulex europaeus agglutinin I binding to parenchymal cells was weakly positive only in five cases of papillary carcinoma. The binding in adenomatoid and neoplastic cells and their colloid was stronger than in adjacent normal thyroid tissue in all cases examined. Wheat germ agglutinin and concanavalin A binding was most intense among the lectins examined. In papillary carcinoma, lectin binding was observed mostly in the apical cytoplasm of carcinoma cells, whereas a diffuse surface binding pattern was predominant in follicular adenoma and carcinoma, adenomatoid nodules and normal thyroid gland. No consistent differences in lectin binding were found between follicular adenoma and carcinoma, or between adenomatoid nodules and follicular neoplasia.     

Renal oncocytoma with and without intravascular extension into the branches of renal vein have the same morphological, immunohistochemical and genetic features

We attempted to investigate the clinicopathological correlation of renal oncocytoma (RO) with renal vein extension. We identified seven ROs with extension into the branches of renal vein. The age of seven patients ranged from 61 to 82 years. Five cases were identified; incidentally, two patients had gross hematuria. After surgery, all patients were alive and free of tumors with follow-up of 1 to 5 years (mean=3.6). Oncocytomas measured from 2.2 to 7.5 cm. Renal vein extension was grossly suspected in 5/7 cases and histologically confirmed in all seven cases. Tumor cells were positive for cytokeratins, mitochondrial antigen, epithelial membrane antigen, and parvalbumin; 5/7 tumors were focally positive for cluster of differentiation 117. Ultrastructurally, the cytoplasm was packed by mitochondria. Molecular genetic analysis did not detect abnormal numbers of chromosomes 1, 2, 6, 7, 10, 17, and XY by fluorescence in situ hybridization, loss of heterozygosity on 3p, and mutation of Von Hippel-Lindau gene in all cases. Array comparative genomic hybridization analysis of two cases did not show any major genetic changes. Conclusions are: (1) renal oncocytomas may have intravascular extension to the branches of the renal vein; (2) renal oncocytomas with intravascular extension to the branches of the renal vein have the same morphological, immunohistochemical, and cytogenetic findings as have their counterparts without evidence of intravascular invasion; (3) the absence of metastases suggests an overall benign behavior of this tumor, but this has to be substantiated by further studies with a long-term follow-up; (4) in a renal tumor with granular cytoplasm showing renal vein extension, it is necessary to carefully exclude renal cell carcinomas (RCC) such as chromophobe RCC, oncocytic variant of papillary RCC, and granular variant of clear cell RCC.     

Renal epithelial neoplasms: the diagnostic implications of electron microscopic study in 55 cases

Several unsettled histogenetic, nosologic and diagnostic considerations for renal epithelial tumors may have ultrastructural ramifications. Yet, a comprehensive electron microscopic study of renal epithelial neoplasms, in light of the recent classification, is not available. The ultrastructural findings from fifty-five renal epithelial neoplasms [31 clear cell renal cell carcinomas (RCC), 11 papillary RCC, 5 chromophobe RCC, 3 sarcomatoid RCC and 5 oncocytomas] were correlated with their light microscopic appearance. Clear cell RCC showed long microvilli similar to the brush border of the normal proximal tubules, with abundant cytoplasmic lipid and glycogen. Papillary RCC showed variably sized microvilli, and small amounts of cytoplasmic lipid, but no glycogen. Chromophobe RCC showed many cytoplasmic vesicles and abnormal mitochondria, with rare short and stubby microvilli. Renal oncocytoma showed many mitochondria with a few vesicles in the apical portion of the cytoplasm and rare short and stubby microvilli. The eosinophilic cell variants of clear cell RCC, papillary RCC and chromophobe RCC showed ultrastructural features similar to those of their respective prototypes, except for an increased numbers of mitochondria in the cytoplasm. One sarcomatoid clear cell RCC showed skeletal muscle differentiation. Two types of cytoplasmic inclusions, i.e. hyaline globules and granules similar to those in the Paneth cells (PC-like granules) were identified only in clear cell RCC, which displayed distinctive ultrastructural features. The current EM study demonstrates distinctive ultrastructural features of renal epithelial neoplasms. The findings lend additional support to the current classification of the pertinent tumor types, facilitate the differential diagnoses, and provide insights into the possible histogenesis of renal epithelial neoplasms.     

Chromophobe renal cell carcinoma: clinical, pathological and molecular biological aspects

Chromophobe renal cell carcinoma (RCC), a newly established subtype of renal neoplasm, is composed of tumor cells with characteristically cloudy, weakly eosinophilic and reticular cytoplasm. The tumor should be distinguished from the common clear cell RCC, because of the unique clinicopathological and molecular biological features. The tumor does not show gender bias. Patient ages are similar to those of clear cell RCC, but might occur in the 20- to 40-year-old age group. Grossly, the tumor tends to be beige in color, which is different from the yellowish color of common RCC. Electron microscopy and immunohistochemistry indicate the intercalated cell of the collecting duct as the cellular origin. Cytogenetic study shows non-random multiple chromosome loss, with mitochondrial DNA rearrangement. Alteration of the von Hippel-Lindau (VHL) gene, a cancer suppressor gene relating with clear cell RCC, has not yet been observed. In order to adopt the most appropriate treatment, including gene therapy, recognition and correct pathological diagnosis of chromophobe RCC are extremely important.     

Fine-needle aspiration of a Xp11.2 translocation/TFE3 fusion renal cell carcinoma metastatic to the lung: report of a case and review of the literature

A 57-yr-old woman presented to the National Cancer Institute (NCI) with a history of nephrectomy for a clear cell renal cell carcinoma (RCC), Fuhrman grade 3 of 4 diagnosed 1 yr prior to admission to the NCI. A CT scan done upon admission revealed multiple bilateral lung masses. A CT-guided fine-needle aspiration (FNA) of one of the lung masses revealed a cellular specimen composed primarily of follicular structures surrounding dense hyalinized central cores. The cells in the follicular structures displayed bland nuclei and had granular to vacuolated cytoplasm. Papillary structures were also appreciated. Immunocytochemical studies showed tumor cells that were strongly vimentin and TFE3 positive. Focal staining for AE1/AE3 and CD10 was observed, as was negative staining for EMA. A surgical biopsy specimen reflected the FNA findings and demonstrated a similar immunoprofile. These findings correspond to the recently described Xp11.2 translocation/TFE3 fusion renal cell carcinoma. To our knowledge, this is the first report describing the cytologic features of an Xp11.2 translocation/TFE3 fusion RCC.     

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.     

Oncocytic renal cell carcinoma with immunohistochemical properties of renal oncocytoma

Renal oncocytoma (RO) is a characteristic benign renal tumor. The existence of malignant RO is controversial and anecdotal, partly due to a lack of specific markers for RO. With recent advances in immunohistochemistry, RO can be distinguished from other renal neoplasms with routine stains and with the aid of immunostaining. We report two cases of renal neoplasms with similar histopathological appearances. They were characterized by oncocytic cytoplasm, numerous intra-cytoplasmic vacuoles, uniform round to oval hyperchromatic nuclei with remarkably thick nuclear membranes and prominent nucleoli. The tumor cells were closely packed and disposed in an alveolar pattern. The neoplastic cells were diffusely reactive for CD117 and progesterone receptor, and diffusely or focally reactive for cytokeratin AE1/AE3, and focally reactive for cytokeratin 7, CD10, and racemase. The cells were non-reactive for renal cell carcinoma (RCC) antigen, vimentin, S100, and neuroendocrine markers. One tumor showed lymph node metastasis. Due to the remarkable cytological atypia, lymph node metastasis, and similar immunological features of RO, these two tumors likely represent a distinct subtype of RCC related to RO.