Tumour-to-tumour metastasis: a rare cause of apparent intratumoural heterogeneity in conventional clear cell renal cell carcinoma

Tumour-to-tumour metastasis is a rare phenomenon and few case reports exist that describe tumor-to-tumor metastases to and from clear cell renal cell carcinoma.¹ In order for metastases to become established, tumour cells must be shed, survive in circulation, and implant, grow, and establish vascularity in a distant site - which in our case was within another primary tumour.² Tumours are, by definition, environments that promote growth of neoplastic cells. Clear cell renal cell carcinoma, in particular, provides a unique pro-tumour environment, in part due to its molecular characteristics, affording metastatic tumours the opportunity to survive and grow.³ We describe a case of metastatic breast carcinoma that was found within a conventional clear cell type renal cell carcinoma. Further, this case illustrates the potential for sampling errors with percutaneous biopsies of renal masses and highlights the need for pathologists to consider the rare possibility of tumour-to-tumour metastasis when confronted with tumours showing striking morphologic heterogeneity.     

转移性透明细胞性肾细胞癌42例临床病理分析

目的探讨转移性透明细胞性肾细胞癌(clear cell renal cell carcinoma,CCRCC)的临床病理学特征、诊断及鉴别诊断。方法回顾性分析42例转移性CCRCC的临床病理资料,并复习相关文献。结果 42例转移性CCRCC中,男性35例,女性7例;转移部位依次为肺19例,骨8例,淋巴结及软组织各3例,肾上腺、皮肤及脑各2例,肝、小肠及鼻腔各1例。42例转移性CCRCC中,31例于肾原发灶手术切除后3周~11年出现转移,4例原发灶与转移灶同时发现;28例转移灶为单发,14例为多发性。34例转移性CCRCC仍具有原发性CCRCC的组织学形态,4例出现多灶状坏死,6例呈肉瘤样分化。Fuhrman细胞核分级:Ⅰ级4例、Ⅱ级13例、Ⅲ级18例、Ⅳ级7例。17例间质小血管呈簇状增生。免疫组化标记42例转移性CCRCC中CD10、vimentin、CAⅨ、PAX8、RCC和EMA阳性例数分别为39例(92.9%)、40例(95.2%)、38例(90.5%)、38例(90.5%)、31例(73.8%)和38例(90.5%)。结论转移性CCRCC具有独特的临床病理学特征,结合临床病史及肿瘤组织形态学特点,联合免疫组化标记vimentin、EMA、CD10、CAⅨ、PAX8等有助于诊断及鉴别诊断。     

Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma

Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the ‘seed and soil’ hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously reported that constitutive VEGF‐A expression in tumour xenografts facilitates this type of metastatic seeding by promoting shedding of multicellular tumour tissue fragments, surrounded by vessel wall elements, into the circulation. After transport through the vena cava, such fragments may be trapped in pulmonary arteries, allowing them to expand to symptomatic lesions. Here we tested whether this process has clinical relevance for clear cell renal cell carcinoma (ccRCC), a prototype tumour in the sense of high constitutive VEGF‐A expression. To this end we collected and analysed outflow samples from the renal vein, directly after tumour nephrectomy, in 42 patients diagnosed with ccRCC. Tumour fragments in venous outflow were observed in 33% of ccRCC patients and correlated with the synchronous presence or metachronous development of pulmonary metastases (p < 0.001, Fisher's exact test). In patients with tumours that, in retrospect, were not of the VEGF‐A‐expressing clear cell type, tumour fragments were never observed in the renal outflow. These data suggest that, in ccRCC, a VEGF‐A‐induced phenotype promotes a release of tumour cell clusters into the circulation that may contribute to pulmonary metastasis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

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.     

肾透明细胞癌伴同侧肾上腺皮质腺瘤内转移1例及文献复习

目的：探讨1例肾透明细胞癌(clear-cell renal cell carcinoma,clear-cell RCC)伴同侧肾上腺皮质腺瘤内转移的临床病理特征及转移机制。方法：观察1例肾透明细胞癌转移至同侧肾上腺皮质腺瘤的临床表现、组织学特征、免疫组织化学特点,并复习相关文献。结果：患者,男性,63岁,右季肋部不适半月余入院。术后结果显示右肾透明细胞癌。单纯性孤立性肾囊肿。右肾上腺皮质腺瘤,瘤内见转移的肾透明细胞癌、直径约3 mm。结论：肾透明细胞癌转移至同侧肾上腺皮质腺瘤是非常罕见的现象。     

多囊性肾透明细胞癌的病理学诊断

目的：探讨多囊性肾透明细胞癌的临床病理特点。方法：对1例多囊性肾透明细胞癌进行了免疫组化染色,并进行文献复习。结果：本例右肾肿物18年。大体见肿物由多发不等的囊腔组成。镜下囊内壁主要由单层立方或柱状上皮被覆,部分为多层并有乳头形成。瘤细胞胞质透亮,无明显异型性。癌细胞免疫表型cytokeratin、CEA和vimentin呈阳性表达。本例诊断为多囊性肾透明细胞癌。结论：多囊性肾透明细胞癌是一种罕见的肾癌病理类型。临床上主要采用根治切除术。本瘤的生物学行为属于低度恶性肿瘤。     

Spindle and cuboidal renal cell carcinoma,a tumour having frequent association with nephrolithiasis: report of 11 cases including a case with hybrid conventional renal cell carcinoma/ spindle and cuboidal renal cell carcinoma components

AIMS: We present the largest series of an unclassified subtype of renal cell carcinoma, which seems to be a distinct morphological entity and which is sometimes designated as spindle and cuboidal renal cell carcinoma. METHODS AND RESULTS: Eleven cases of spindle and cuboidal renal cell carcinoma were found among 7000 primary renal cell tumours in Pilsen's routine and consultation files. The patients were five men and six women. They ranged in age from 22 to 65 years (mean 56.8). Microscopically, the tumours were composed of two main populations of cells. First, the preponderant type of cells was formed by flattened, spindle cells with sparse cytoplasm. The second cell type was a small cuboidal cell with clear to light eosinophilic cytoplasm. Spindle-shaped cells were arranged in a fascicular pattern often reminiscent of low-grade smooth muscle tumours. Solid areas of spindle cells were also present. Small cuboidal cells formed sparse tubular structures lined by a row of single cells. In addition to all previous published cases of spindle and cuboidal renal cell carcinoma we observed an association of nephrolithiasis in our cases. It was seen in 3/11 of our patients. A previously unreported feature is the occurrence of a conventional renal cell carcinoma component in one of our cases. Seven of our patients are currently well without signs of recurrence or metastasis, one had metastasis in a regional lymph node at the time of nephrectomy, one died of an unrelated condition, and two were lost to follow-up. CONCLUSIONS: We present 11 cases of spindle and cuboidal renal cell carcinoma, which is believed to be a distinctive morphological entity. Our cases were histologically, immunohistochemically and ultrastructurally similar to the previously reported cases of spindle and cuboidal renal cell carcinoma. In contrast to all previously reported cases of spindle and cuboidal renal cell carcinoma, we observed an association with nephrolithiasis in three of our cases; moreover, one of our tumours had a conventional renal cell carcinoma component and another revealed a metastatic focus in a regional lymph node. None of our patients died of the disease. This study confirms that spindle and cuboidal renal cell carcinoma has a low malignant potential.     

FNAC aided diagnosis of clear cell sarcoma of kidney: Report of two cases in infants

Clear cell sarcoma of kidney (CCSK) is a rare aggressive malignant renal neoplasm with a high metastatic potential. Its outcome has however, improved with the advent of doxorubicin based neoadjuvant chemotherapy. Here, we present two cases of CCSK in infants diagnosed on cytology followed by nephrectomy. The first case presented in the neonatal period and had the unusual histological finding of islands of cartilage. The second case presented at the age of eight months. The possibility of CCSK should, therefore, be considered in the differential diagnoses of renal masses in infants as well as neonates. Diagn. Cytopathol. 2017;45:761–765. © 2017 Wiley Periodicals, Inc.     

miR-27a promotes cell proliferation and metastasis in renal cell carcinoma

miR-27a has been reported to exhibit abnormal expression in renal cell carcinoma (RCC), but the role of miR-27a in RCC remains unknown. In our study, up-regulation of miR-27a was validated by Real-time PCR analysis in 133 RCC samples. Overexpression of miR-27a promoted cell migration, invasion and proliferation in vitro, while its low expression exerted opposite effects. Kaplan-Meier analysis demonstrated that the patients with high expression of miR-27a had a worse overall and relapse-free survivals compared with those with low expression of miR-27a. Cox proportional hazards analyses showed that miR-27a expression was an independent prognostic factor for RCC patients. Collectively, our findings illustrate the promoting-cancer effect of miR-27a in RCC, suggesting that miR-27a could be a potential therapeutic target for RCC. Additionally, Kaplan-Meier analyses and Cox proportional regression analysis suggest that miR-27a may be a potential biomarker for predicting the survival of RCC patients.     

Cytology diagnosis of metastatic clear cell renal cell carcinoma,synchronous to pancreas,and metachronous to thyroid and contralateral adrenal: Report of a case and literature review

Renal cell carcinoma metastases to pancreas, thyroid, and contralateral adrenal gland are decidedly uncommon. Clear cell renal cell carcinoma (CCRCC) is the most frequent subtype. Cytology diagnosis may be challenging. A 74‐year‐old male with remote history of vocal cord malignancy and hypertension presented with abdominal pain. Computed tomography (CT) revealed 8.4 cm left renal mass highly suspicious for renal cell carcinoma, a 1.8 cm mass within vessels near left adrenal and a 2.5 cm mass in pancreatic tail. Right pulmonary middle lobe showed two small nodules. Metastatic CCRCC was diagnosed on preoperative transgastric, endoscopic ultrasound guided fine‐needle aspiration cytology of pancreatic tail mass. Left radical nephrectomy and distal pancreatectomy and splenectomy confirmed CCRCC (pT3bNxM1), with metastases in adrenal and pancreatic tail. The 3p deletion identification in pancreatic tumor suggested CCRCC origin. Follow‐up positron emission tomography‐CT (PET‐CT) scan revealed left thyroid lower pole mass. Thyroid ultrasound showed three clustered 6 mm nodules in left mid pole. Ultrasound‐guided fine needle aspiration (US‐FNA) biopsies, 4‐month post‐nephrectomy, were consistent with metastatic renal cell carcinoma in lower, and atypia of undetermined significance in mid poles respectively. Left lobectomy and isthmus and pyramidal lobe resections confirmed metastatic renal cell carcinoma. One year post‐radical nephrectomy, contralateral adrenal lesion noted on PET‐CT was interpreted as metastatic CCRCC on CT‐guided core biopsy with touch imprints. Rapid on‐site evaluation was implemented, and immunoprofile typical of CCRCC substantiated cytomorphology at all three sites. Previously reported cases of renal cell carcinoma metastases to organs as in the described case are reviewed as well. Diagn. Cytopathol. 2017;45:161–167. © 2016 Wiley Periodicals, Inc.     

Metastatic risk stratification of clear cell renal cell carcinoma patients based on genomic aberrations

Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut‐off values were determined by receiver‐operator curve (ROC)‐curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T‐category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10^?5, P = 5×10^?6 and P = 3.57×10^?8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as “low” or “intermediate risk.” We present a new tool for individual risk stratification by combining genetic alterations with clinico‐pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ‐confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.     

Cell heterogeneity in clear cell renal cell carcinoma

The aim of this study was to define the histological spectrum, frequency and significance of nonconventional tumour cells in clear cell renal cell carcinomas (CCRCC). Fifty‐one totally sampled CCRCC were studied histologically to evaluate the spectrum of cell morphology variability, its frequency and significance, and their correlation with tumour grade and stage, and other histological parameters of aggressive behaviour like necrosis. Aside from conventional clear/eosinophilic granular cells, three additional cellular types were identified and considered in this study: small clear cells, syncytial cells and rhabdoid cells. Small clear cells were detected in 11 cases (21.5%), syncytial cells in 8 (15.6%) and rhabdoid cells in 5 (9.8%). The presence of syncytial and rhabdoid cells statistically correlated with grade (p = 0.003 and p = 0.006) and stage (p = 0.049 and p = 0.05) in CCRCC. Necrosis correlated with stage (p = 0.018) and grade (p = 0.004), but not with syncytial, rhabdoid or small clear cells. The presence of syncytial and rhabdoid cells in CCRCC is a relatively frequent event that significantly correlates with high‐grade tumours and high stage status.     

多囊性肾细胞癌1例报道及文献复习

目的：阐明多囊性肾细胞癌的病理形态学特征及鉴别诊断要点。方法：报道1例多囊性肾细胞癌,结合文献对本病的临床病理特征进行探讨。结果：肿瘤由厚的假纤维被膜环绕,瘤体全部由大小不等的囊腔及无膨胀性实性结节的薄的间隔构成,囊腔被覆透明细胞,异形性小,间隔内含聚集的透明细胞上皮巢,结论：多囊性肾细胞癌是一种罕见的有低度恶性倾向的肿瘤,术前影像学,细胞学检查及术后的肉眼特征均与囊性肾瘤,囊性部分分化性肾母细胞瘤相似,最重要的是本瘤缺乏肉眼所见的膨胀性实性结节,显微镜下的关键特征是间隔内可见聚集的透明细胞巢。     

Papillary renal cell carcinoma with clear cell cytomorphology and chromosomal loss of 3p

AIMS: Cytogenetic studies on renal cell carcinomas (RCCs) have disclosed a correlation between chromosome aberrations and histomorphological features. Nevertheless, it is still controversial whether the cytomorphology of the tumour cells (clear cell, chromophilic, chromophobe) or their growth pattern (nonpapillary, papillary) is more discriminative for the combined histomorphological-cytogenetic classification of RCCs. METHODS AND RESULTS: Three RCCs with papillary growth pattern and clear cell cytomorphology were analysed by classical cytogenetics using standard G-banding techniques. Each tumour displayed clonal aberrations leading to loss of terminal 3p chromosomal segments. Monosomy 14 was also consistently found. Trisomy 17 was not observed in any of the tumours. CONCLUSIONS: This series of three RCCs consisting of clear cells with papillary architecture revealed chromosomal aberrations characteristic for the conventional (clear cell) RCC. Irrespective of the predominant papillary growth pattern, none of the cases were characterized by trisomy of chromosomes 3q, 7, 8, 12, 16, 17 and 20 and loss of Y chromosome which are widely regarded as the most consistent genetic alterations for papillary RCC. Therefore, our cytogenetic findings provide evidence that papillary clear cell RCCs should be classified according to their cytomorphology rather than their growth pattern even when papillary architecture is prominent.     

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.     

Cytohistological study of clear cell carcinoma of kidney with special reference to nuclear grading and tumor size

Several prognostic indicators have shown to predict patients' survival in clear cell carcinoma of kidney. Among these, Fuhrman nuclear grading and tumor size are believed to be two important prognostic factors. The aim of this study was to evaluate the efficacy of fine needle aspiration cytology (FNAC) to classify the clear cell renal cell carcinoma (CRCC) according to nuclear grade and tumor size. A total of 24 patients (15 males, 9 females) suffering from CRCC were included in this study over a period of 5 years (January, 2005 to December, 2009). A preoperative cytologic diagnosis was made by computed tomography guided FNAC and histologic correlation was made after surgery. Cytologic diagnoses were nuclear grade 1 or G1 (four cases), nuclear grade 2 or G2 (11 cases), nuclear grade 3 or G3 (six cases) and nuclear grade 4 or G4 (three cases). Radical nephrectomies were done during surgery and most of the specimens were from right side (18/24). Upper pole was commonly involved by the tumor (19/24). Low nuclear grade lesions (G1 and G2) were commonly seen with tumor size up to 5 cm and high nuclear grade lesions (G3 and G4) were common when tumor was >5 cm in size. After cytohistologic correlation, diagnostic accuracy of FNAC was found to be 87.5% in this study. FNAC has high diagnostic accuracy in CRCC and highly dependable procedure to classify these tumors according to its nuclear grade. Both the nuclear grading and tumor size can be used to predict the clinical outcome in these patients. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.