A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma

Succinate dehydrogenase (SDH), which is located on the mitochondrial inner membrane, is essential to the Krebs cycle. Mutations of the SDH gene are associated with many tumors, such as renal cell carcinoma, wild type gastrointestinal stromal tumors (WT GISTs) and hereditary paragangliomas/pheochromocytomas. Herein we present a rare case diagnosed as a WT GIST complicated with a renal chromophobe cell tumor and detected a novel germline heterozygous mutation (c.2T>C: p.M1T) in the initiation codon of the SDHA gene. We also conduct a preliminary exploration for the mechanism of reduced expression of SDHB without mutation of SDHB gene. Our case enriches the mutation spectrum of the SDH gene. After reviewing previous studies, we found it to be the first case diagnosed as a WT GIST complicated with a synchronous renal chromophobe cell tumor and identified a novel germline heterozygous mutation. It was also the second reported case of a renal cell carcinoma associated with an SDHA mutation.     

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.     

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。     

肾癌患者血清中miR-126的异常表达及其临床意义

目的：检测miR-126在肾癌病人血清中的表达状况,同时研究miR-126与肾癌患者临床病理特征之间的关联,为进一步的深入研究奠定基础。方法：收集35例新诊断肾癌患者术前血清样本,另外收集35例健康体检者血清样本作为对照,利用实时荧光定量PCR技术检测miR-126在肾癌患者血清中的表达情况,利用SPSS19.0软件分析肾癌病人临床病理特征和miR-126表达量两者之间的关系。结果：与对照组比较,肾癌组患者血清中miR-126表达量明显低于健康体检组,差异具有统计学意义(P<0.05),在35例肾癌血清样本中,出现31例miR-126下调(88.57%),而4例则表现为上调(11.43%)。肾癌病人的性别、年龄、肾癌组织类型、肾肿瘤大小、TNM分期和肾癌患者血清中miR-126表达量无相关性(P>0.05)。结论：miR-126在肾癌患者血清中低表达,提示其可能与肾癌的发生和发展相关。     

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.     

Coexistence of multiple myeloma and clear cell renal cell carcinoma: a case report and review of literature

Coexistence of multiple myeloma (MM) and renal cell carcinoma (RCC) is an extremely rare condition. Nevertheless, there is a higher than expected incidence of co-occurrence of these two malignancies. Several case series, in the recent past, have postulated an association between MM and RCC. Population-based data analyses have revealed a bi-directional association between these two malignancies. However, the cause still remains speculative up to date. Here, we aim to describe a patient with MM and clear cell renal cell carcinoma (CCRCC) one after another for the second time from China. Clinical implications are discussed with a critical review of existing literature and we expect to draw much more awareness among clinicians regarding such association.     

A case of a novel entity: eosinophilic solid and cystic renal cell carcinoma

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is a relatively newly described entity characterized by specific morphological features and a consistent immunohistochemical profile. The vast majority of cases are sporadic, but tumours with identical histological appearances have been reported in patients with tuberous sclerosis complex (TSC). The distinction between a sporadic or syndrome associated ESC-RCC is not possible without, at a minimum, exploring the patient's clinical context and family history. We present a case of a young female patient who presented with bilateral renal tumours, one of which has been diagnosed as ESC-RCC, and is awaiting genetic testing to exclude underlying TSC.     

Chromophobe renal cell carcinoma with osseous metaplasia containing fatty bone marrow element: a case report

A 27-year-old woman presenting with epigastric pain and dyspepsia was found to have a calcified mass in the upper-middle right kidney. Gross examination of the nephrectomy specimen revealed a 6.5 x 5 x 4 cm renal tumor with dense calcification and ossification. Histopathological examination of the tumor showed solid, trabecular sheets and nesting of polygonal epithelial cells with abundant cytoplasm and prominent cell border and mature bony tissue enclosing fatty marrow. Renal cell carcinoma is frequently associated with calcification, but ossification is extremely rare. To our knowledge, we report the fourth case of a chromophobe renal cell carcinoma with extensive calcification and ossification.     

Thyroid metastasis of clear cell renal carcinoma: Report of a case

Renal cell carcinoma can recur many years after diagnosis and nephrectomy metastasizing even in uncommon sites, including thyroid gland. Thyroid metastases are extremely rare, the most frequent site of origin are renal tumors. Metastases in thyroid gland appear as painless nodules or masses, “cold” at scintiscan. We report the case of a 67‐year‐old male patient affected by clear cell renal carcinoma, diagnosed by fine‐needle aspiration cytology procedures, and treated with anticancer medical therapy, who noticed after some months a mass in the neck‐thyroid region requiring deeper medical investigations. By this way, thyroid fine‐needle aspiration cytology reported a lesion made of malignant epithelial cells compatible with metastases of renal carcinoma (clear cell). Clinical and pathological data, together with immunostaining, supported the diagnosis of metastatic clear cell renal carcinoma. The diagnosis of metastatic disease, although difficult clinically and pathologically, should be suspected in patients with a clinical history of cancer, particularly in case of renal cell carcinoma, but fine‐needle aspiration cytology can provide the clue for diagnosis. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Synchronous clear cell renal cell carcinoma and clonal plasmacytoid cell infiltration: A case report and literature review

Recent studies of tumor microenvironments have revealed that clonal B cells reacting to tumor-derived antigens play an important role in anti-tumor immunity. We report a case of a 72-year-old Japanese man with a complaint of fever for 1 month. Computed tomography revealed a 48 mm mass in his right kidney. The patient underwent a right nephrectomy and histology revealed clear cell renal cell carcinoma (ccRCC) of Fuhrman Grade 4 with rhabdoid morphology. Focally, marked plasmacytoid cell infiltration was detected in the carcinoma. These plasmacytoid cells were immunohistochemically positive for immunoglobulin (Ig) G, and kappa light chain restriction was confirmed using mRNA in situ hybridization. Programmed death-ligand 1 (PD-L1) immunostaining and RNA in situ hybridization of transforming growth factor beta (TGF-β) revealed that both PD-L1 and TGF-β were highly expressed in the area with clonal plasmacytoid cell infiltration. The patient developed bone metastasis 3 months after surgery, and plasmacytoma was not detected during the observation period. We identified a potential link between an immunosuppressive microenvironment and clonal B cell proliferation. The latter posed a differential diagnosis problem between reactive and neoplastic clonal B cell proliferation vis-à-vis a plasmacytoma complicating carcinoma.     

Chromophobe renal cell carcinoma with liposarcomatous dedifferentiation - report of a unique case

Sarcomatous transformation of chromophobe renal cell carcinoma (CRCC) is a well recognized phenomenon. Of the published cases with sarcomatous transformation of CRCC, none have shown liposarcomatous differentiation. Out of a cohort of 250 cases of CRCC, 19 (7.6%) showed sarcomatous differentiation. In one case (female, age 46 years), the sarcomatous component of the tumor displayed histological features of a pleomorphic liposar-coma. Light microscopic examination revealed a biphasic pattern with a chromophobe renal cell carcinoma(CRCC) and a high-grade sarcomatous component containing large pleomorphic lipoblasts. In several areas both components were intermingled. The conventional CRCC component showed classic histological features with calcifications, medium-sized polygonal cells arranged in solid-alveolar structures with raisinoid nuclei, pale-eosinophilic flocculent cytoplasm with perinuclear haloes. In addition, a microcystic-adenomatous component had luminal spaces filled with erythrocytes. The CRCC was positive with Hale''s colloidal iron-stain whereas the sarcomatous component was negative. The CRCC component was diffusely positive for cytokeratin 7, parvalbumin and racemase but negative for cy-tokeratin 20, vimentin, CD10, carboanhydrase IX and S100-protein. The pleomorphic liposarcomatous component displayed immunereactivity for CD10, vimentin, racemase and focally for carboanhydrase IX. The proliferative activity (Mib-1/Ki-67) was 5% in the CRCC and 30% in the pleomorphic liposarcomatous component. No immunereactivity for MDM2 or CDK4 was detected.This is the first reported case of a sarcomatoid CRCC where the sarcomatous component displayed features of a pleomorphic liposarcoma. The patient died from widespread metastatic disease 12 months after nephrectomy.     

The treatment of primary and metastatic renal cell carcinoma (RCC) with image-guided stereotactic body radiation therapy (SBRT)

Purpose:

Brain metastases from renal cell carcinoma (RCC) have been successfully treated with stereotactic radiosurgery (SRS). Metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high-dose radiation in a few fractions. This paper reports the authors’ initial experience with image-guided SBRT in treating primary and metastatic RCC.

Materials and methods:

The image-guided Brainlab Novalis stereotactic system was used. Fourteen patients with 23 extra-cranial metastatic RCC lesions (orbits, head and neck, lung, mediastinum, sternum, clavicle, scapula, humerus, rib, spine and abdominal wall) and two patients with biopsy-proven primary RCC (not surgical candidates) were treated with SBRT (24-40 Gy in 3-6 fractions over 1-2 weeks). All patients were immobilised in body cast or head and neck mask. Image-guidance was used for all fractions. PET/CT images were fused with simulation CT images to assist in target delineation and dose determination. SMART (simultaneous modulated accelerated radiation therapy) boost approach was adopted. 4D-CT was utilised to assess tumour/organ motion and assist in determining planning target volume margins.

Results:

Median follow-up was nine months. Thirteen patients (93%) who received SBRT to extra-cranial metastases achieved symptomatic relief. Two patients had local progression, yielding a local control rate of 87%. In the two patients with primary RCC, tumour size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There were no significant treatment-related side effects.

Conclusion:

Image-guided SBRT provides excellent symptom palliation and local control without any significant toxicity. SBRT may represent a novel, non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC.     

Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity

Inherited renal cell carcinoma (RCC) is associated with multiple familial cancer syndromes but most individuals with features of non‐syndromic inherited RCC do not harbor variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbor mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC ≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been prescreened for pathogenic variants in the major RCC genes. We detected pathogenic or likely pathogenic (P/LP) variants of potential clinical relevance in 16.1% (19/118) of individuals, including P/LP variants in BRIP1 (n = 4), CHEK2 (n = 3), MITF (n = 1), and BRCA1 (n = 1). Though the power to detect rare variants was limited by sample size the frequency of truncating variants in BRIP1, 4/118, was significantly higher than in controls (P = 5.92E‐03). These findings suggest that the application of genetic testing for larger inherited cancer gene panels in patients with indicators of a potential inherited RCC can increase the diagnostic yield for P/LP variants. However, the clinical utility of such a diagnostic strategy requires validation and further evaluation and in particular, confirmation of rarer RCC genotype‐phenotype associations is required.     

Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma

Renal cell carcinoma (RCC) treatment has improved in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10–15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells, and generally in the tumor cell compartment. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined. Two RCC tissue microarrays were used; a discovery cohort consisting of 64 patients and a validation cohort of 314 patients. VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay (PLA), and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells, and general tumor cell expression) was determined by immunofluorescent staining. Expression of NRP1 in perivascular tumor cells was explored as a marker for RCC survival in the two RCC cohorts. Results were further validated using a publicly available gene expression dataset of clear cell RCC (ccRCC). We found that VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 expression was associated with a reduced tumor vessel density and size. When exploring NRP1 as a biomarker for RCC prognosis, perivascular NRP1 and general tumor cell NRP1 protein expression correlated with improved survival in the two independent cohorts, and significant results were obtained also at the mRNA level using the publicly available ccRCC gene expression dataset. Only perivascular NRP1 expression remained significant in multivariable analysis. Our work shows that perivascular NRP1 expression is an independent marker of improved survival in RCC patients, and reduces tumor vascularization by forming complexes in trans with VEGFR2 in the tumor endothelium. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

A case of renal cell carcinoma unclassified with medullary phenotype without detectable gene deletion

Renal cell carcinoma unclassified with medullary phenotype (RCCU‐MP) is a rare variant of renal medullary carcinoma (RMC) characterized by loss of SMARCB1 (INI1 / SNF5 / BAF47) protein expression in patients without sickle cell trait. Here, we report a case of RCCU‐MP in a Japanese patient who had experienced colon cancer 13 years ago, gastric cancer 11 years ago and lung cancer 9 years ago and had received hemodialysis for 15 years. This is the first report of RCCU‐MP in Japan. The patient was not of African descent, and did not have SCT or any other hereditary blood abnormality typical of RMC. The tumor was located in the left kidney, and was composed histologically of rhabdoid cells with marked lymphocyte infiltration; it was immunohistochemically negative for SMARCB1. We were, however, unable to detect mutation in the SMARCB1 gene, reduced messengerRNA expression, or deletion or translocation of chromosome 22, where the SMARCB1 gene is located. These results suggest that RCCU‐MP may not involve the hemizygous loss of this gene noted in typical RMC cases.     

Renal adenomatosis associated with carcinoma of the lower urinary tract: A case report with immunohistochemical study

A case of renal adenomatosis of the left kidney associated with a carcinoma of the ipsilateral ureter in a 49-year-old man is examined. One hundred and eight adenomas, which were smaller than 15 mm in diameter, and a single microcarcinoma, which measured 1 mm in diameter, were found in the kidney. Further, there were more than 800 hyperplastic lesions which could be classified into three groups: (i) 792 of distal origin; (ii) 24 of proximal origin; and 10 of collecting duct origin. The serial sections obtained from 19 paraffin blocks were stained using Leu M1 as the proximal marker and epithelial membrane antigen (EMA) as the distal/collecting marker to assist in determining the origins. Ten of the small adenomas (15 lesions), which did not exceed 3 mm in diameter, were predominantly positive for EMA and five were predominantly positive for Leu M1. Further, hyperplastic lesions of distal and collecting duct origins were diffusely positive for EMA and sporadically positive for Leu M1. The lesions of proximal origin were predominantly positive for Leu M1 and sporadically positive for EMA. These findings suggest that a progression from hyperplasia and a direct transition from a single tubule to adenoma occurred multifocally in different segments of the nephrons throughout the left kidney.