Hybrid Renal Cell Carcinomas Containing Histopathologic Features of Chromophobe Renal Cell Carcinomas and Oncocytomas Have Excellent Oncologic Outcomes

Background

Modern histopathology is able to differentiate chromophobe renal cell carcinomas (cRCCs), oncocytomas, and chromophobe–oncocytic hybrid RCCs; however, the true frequency and clinical courses of these tumors remain unclear.

Objective

To determine the clinical course of hybrid RCC.

Design, setting, and participants

Ninety-one surgically treated tumors, originally classified as oncocytoma or cRCC, were slide reviewed and reclassified by an experienced uropathologist. Immunohistochemical cytokeratin-7 (CK7) staining was used to distinguish oncocytoma (CK7 positive in <10% of the cells) and hybrid RCCs (CK7 positive in >10% of the cells).

Interventions

Radical tumor nephrectomy or nephron-sparing surgery.

Measurements

Recurrence-free and tumor-specific survival.

Results and limitations

Overall, 16 tumors (17.6%) were hybrid RCCs, 32 tumors were cRCCs, and 43 tumors were pure oncocytomas. Perinephric tissue invasion (pT3a) was found in one pure oncocytoma and in two hybrid RCCs. The pathologic stage for cRCC was pT1 in 50% of tumors (n = 17), pT2 in 23.5% of tumors (n = 8), and pT3a in 26.5% of tumors (n = 9). Low-grade RCC was found in 76.5% of tumors (n = 26), and vascular invasion was found in 11.8% of tumors (n = 4). After a mean follow-up of 50 mo, no oncocytomas or hybrid RCCs were found, but two cRCCs had recurred. The 3-yr tumor-specific survival rates for patients with oncocytoma, hybrid RCCs, and cRCC were 100%, 100%, and 97%, respectively.

Conclusions

Hybrid RCCs are more common than expected. The survival rate is 100% for both hybrid RCCs and oncocytomas. Hybrid RCCs may be candidates for active surveillance, and surgery may be unnecessary. CRCCs should be treated because a small proportion of these tumors exhibit aggressive clinical courses.     

肾嫌色细胞癌的临床研究

目的 探讨肾嫌色细胞癌的临床特点,提高肾嫌色细胞癌的诊断和治疗水平.方法 针对1例肾嫌色细胞癌的临床资料,结合相关文献进行分析.结果 病理结果示为肾嫌色细胞癌.免疫组化:CK部分细胞(+),CD10(-),CK8(+),RCC(-),vimentin(-),Ki-67(＜5%+),Hale胶状铁染色(+).结论 肾嫌色...     

Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics

According to the current World Health Organization (WHO), renal cell carcinomas (RCCs) that primarily affect adults are classified into 8 major subtypes. Additional emerging entities in renal neoplasia have also been recently recognized and these are discussed in further detail by Mehra et al (Emerging Entities in Renal Neoplasia, Surgical Pathology Clinics, 2015, Volume 8, Issue 4). In most cases, the diagnosis of a RCC subtype can be based on morphologic criteria, but in some circumstances the use of ancillary studies can aid in the diagnosis. This review discusses the morphologic, genetic, and molecular findings in RCCs previously recognized by the WHO, and provides clues to distinction from each other and some of the newer subtypes of RCC. As prognosis and therapeutic options vary for the different subtypes of RCC, accurate pathologic distinction is critical for patient care.     

同侧肾脏同时发生透明细胞型与乳头状肾细胞癌

目的探讨同侧肾脏发病并且相对独立的透明细胞型和肾乳头状细胞癌的临床病理特点及免疫表型,提高对该肿瘤的认识和诊断水平。方法本研究回顾了2例病理诊断为透明细胞型合并肾乳头状细胞癌的临床资料,通过光镜和免疫组织化学染色,针对肾细胞癌相关蛋白标志物[包括 Vimentin、CD10、CK（AE1/AE3）、CK7、CK8/18、PAX2、PAX8、CAⅨ、AMACR]进行了观察和分析。结果2例患者为男性,年龄分别为70、63岁。2例患者的两处独立肿瘤均位于左侧肾脏,镜下观察均可见两处独立肿瘤,肿瘤间隔有正常肾脏组织,分别为乳头状肾细胞癌及透明细胞型肾细胞癌,且免疫组化显示2例患者肿瘤的表型一致。结论单侧肾脏肾透明细胞癌合并肾乳头状细胞癌是一种少见的临床现象,这种现象的存在以及类似的免疫组化表型提示透明细胞型肾细胞癌和乳头状肾细胞癌在发生过程中可能存在着内部的联系。     

Clinical Trials for Specific Renal Cancer Subtypes—The Time Will Come!

Renal cell cancer is a heterogeneous group of cancers with different histological phenotypes. Recent 2016 WHO classification acknowledges the genetic background of most renal cancer subtypes, whereas treatment for metastasized renal cell carcinoma (RCC) considers only clear cell and non–clear cell RCCs. Clear cell RCCs are characterized by the presence of at least three tumor suppressor genes on chromosome 3p. Owing to inactivation of von Hippel–Lindau (VHL), clear cell renal cancer produces the hypoxia-inducible factor–responsive vascular endothelial growth factor (VEGF). Other specific gene alterations have been identified in non–clear cell renal cancers, for example, PTEN, p53, and FLCN in chromophobe carcinomas; TFE3, TFEB, and MITF in translocation carcinomas; or MET and FH in variants of papillary RCC. Current treatments target VEGF or VEGF receptor using tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors. Renal cancer immunotherapy using immune checkpoint inhibitors is currently tested in early clinical phases. We review current clinical trials on the basis of the molecular background of specific renal cancer subtypes.     

Chromophobe renal cell carcinoma showing oncocytoma-like hyalinized and edematous stroma: A case report and review of the literature

A case of chromophobe renal cell carcinoma (CRCC) with abundant hyalinized and edematous stroma mimicking oncocytoma is presented. This stromal architecture in the current case has not been reported on CRCC to our knowledge. A further interesting finding is entrapped non-neoplastic tubules in the hyalinized and edematous stroma composing the tumor. These histological features, such as abundant hyalinized and edematous stroma containing non-neoplastic tubules, may be analogous to oncocytoma. We reported a unique case of CRCC and studied with light microscopy and immunohistochemistry.     

肾嫌色细胞癌(附15例报告)

目的　提高肾嫌色细胞癌的诊治水平和对此类型肾癌的认识。　方法　回顾性分析15例肾嫌色细胞癌的临床资料。男 10例 ,女 5例。年龄 4 7～ 74岁 ,平均 5 7岁。均行根治性肾切除术。　结果　术后病理证实为肾嫌色细胞癌。病理分期 :pT1N0 M0 6例 ,pT2 N0 M0 5例 ,pT3bN0 M0 2例 ,pT1N2 M0 1例 ,pT2 N2 M0 1例。病理分级 :G2 10例 ,G3 5例。 11例获随访 ,随访 2～ 31个月 ,平均19个月 ,1例死于心脏病 ,1例局部复发 ,9例无瘤生存。　结论　肾嫌色细胞癌是一种具有特殊形态的少见肾癌类型。肾根治性切除术是治疗肾嫌色细胞癌的首选方法。与同期、同级的其他类型肾癌相比 ,肾嫌色细胞癌预后较好。     

A Phase 2 Trial of Sunitinib in Patients with Advanced Non–clear Cell Renal Cell Carcinoma

Background

Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non–clear cell renal cell carcinoma (nccRCC).

Objective

To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.

Design, setting, and participants

This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥20% sarcomatoid histology, performance status 0–2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.

Intervention

Patients received sunitinib 50 mg daily on a 4-wk on, 2-wk off schedule.

Outcome measurements and statistical analysis

Primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS).

Results and limitations

Fifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4–5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4–5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5–NA). Median OS for all patients was 16.8 mo (95% CI, 10.7–26.3). Treatment-emergent adverse events were consistent with sunitinib's mechanism of action. The nonrandomized design and small number of patients are limitations of this study.

Conclusions

The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.     

Histologic variants of renal cell carcinoma: does tumor type influence outcome?

Each histologic type of renal cell carcinoma (RCC) has different pathologic and clinical parameters; however, the independent role of histologic type in outcome prediction remains contested. Most studies show relevance for outcome of each histologic type when correlated with survival by univariate analysis, whereas few studies show differences in outcome once other key prognostic factors, such as stage and grade, are considered. These studies highlight the challenges to prove outcome relevance. Despite the contested independent value of type for outcome prediction, separation of RCC into types is well accepted and can be substantiated on clinical, pathologic, molecular, and general outcome differences.     

Diagnosis of Renal Cell Carcinoma: A Clinician’s Perspective

Renal cell carcinoma (RCC) is a heterogeneous disease. A rigorous diagnostic assessment by a pathologist with close communication with the clinician provides more accurate prognostication and informed treatment decisions. In the localized setting, an accurate prognostic assessment directs patients to potential adjuvant clinical trials. For patients with advanced disease, the pathologic assessment may have a direct impact on the systemic therapy algorithm. Additionally, it provides the basis for continuous efforts in biomarker development. In rare histologic subtypes, the interaction between clinicians and pathologists provides an opportunity to offer patients specific clinical trials. Molecular characterization platforms may identify targets for therapeutic intervention.     

Chromophobe renal cell carcinoma in an 18-year-old female

Renal cell carcinoma (RCC) in young adults is uncommon. Whether they have different clinicopathologic characteristics and outcomes from those in older patients is still a conflicting matter. In this article we present an uncommon subtype of RCC which is chromophobe RCC (chRCC) in a female aged less than 20 years.     

Neoplasia papilar de polaridad inversa: un nuevo subtipo de tumor renal de buen pronóstico

IntroductionPapillary renal cell neoplasm with reverse polarity (PRNRP) has recently been recognized as an entity separate from the traditional classification of papillary renal cell carcinomas, due to its specific histopathological, immunophenotypic and molecular characteristics, as well as its indolent behavior.Material and methodsWe provide 6 new cases and a review of the literature published until the present time, which comprises a total number of 104 cases.ResultsOur PRNRP cases correspond to 5 men and one woman aged between 47 and 91 years. In 5 of the 6 cases, the PRNRP was an incidental finding in nephrectomy specimens. Nephrectomy had been indicated due to the presence of another renal tumor, except for one case, in which surgical intervention was indicated due to PRNRP. Our cases present mass sizes between 2 and 13 mm, as well as papillary histology with a monolayered lining of eosinophilic cells with low-grade nuclei in apical location. Immunohistochemically, they show a constant positivity for GATA3 and negativity for vimentin. KRAS mutations were identified in 50% of our cases. After a follow-up ranging between one and 60 months, 5 of the cases were still alive without recurrences or metastases, and one died from urothelial carcinoma.ConclusionsOur cases agree with the clinical and pathological characteristics described in the PRNRP cases published to date. With the present study, we provide the first series of national cases corroborating the existence of well-defined and constant diagnostic criteria that allow PRNRP to be considered as a distinctive entity.     

Gallbladder Metastasis of Renal Cell Carcinoma: Report of Two Cases

We report two extremely rare cases of metastasis to the gallbladder from renal cell carcinoma. In both men, aged 63 and 80 years, a pedunculated polypoid gallbladder tumor was incidentally found 27 and 8 years after surgery for renal cell carcinoma, respectively. The tumors showed hypervascularity on diagnostic imaging. A histopathological examination showed no tumor cells in the gallbladder mucosa, but clear cell carcinoma was predominantly observed below the mucosal layer. Furthermore, based on various specific and immunohistochemical studies as well as the electron-microscopic findings, the patients were pathologically diagnosed to have gallbladder metastasis of renal cell carcinoma. Received: February 16, 2001 / Accepted: September 11, 2001     

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management

BackgroundClear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior.ObjectiveTo comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes.Design, setting, and participantsWe identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients.Outcome measurements and statistical analysisNonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes.Results and limitationsA higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034).ConclusionsCCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management.Patient summaryWe explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.     

肾嫌色细胞癌临床特征分析

目的 探讨肾嫌色细胞癌的临床特点并分析其预后.方法 对1998年1月至2008年1月期间收治的29例肾嫌色细胞癌患者的临床资料包括临床表现、影像学检查、治疗方法、Ptnm分期和生存期随访等,进行回顾性分析.结果 所有29例患者均缺乏典型的临床症状,术前影像学检查亦未发现特异性表现.23例患者行根治性肾切除术,6例行保留肾单位手术(NSS),病理分期:Pt1n0m0 11例,Pt2n0m0 8例,pT3aN0M0 5例,Pt1nm0 3例,Pt2n1m0 2例.26例患者获得随访,随访24～144个月,平均90个月;3例死于心脑血管疾病,6例局部复发后4例再次手术,1例远处转移,21例无瘤生存.与同期肾透明细胞癌患者相比,累积5年生存率两者分别为83.9%和63.8%,差异无统计学意义(P＞0.05),累积10年生存率分别为77.9%和49.9%,差异具有统计学意义(P＜0.01).结论 肾嫌色细胞癌是一种少见的具有特殊形态的肾细胞癌病理亚型,主要通过病理学予以鉴别诊断,手术切除是治疗初发或复发的肾嫌色细胞癌的首选方法,其预后较好.

Abstract：

Objectives To explore the clinical, pathological features and prognosis of patients with chromophobe renal cell carcinoma. Methods From January 1998 to January 2008, clinical data of 29 patients with chromophobe renal cell carcinoma including clinical manifestations, imaging examinations,treatment models, pTNM stages and follow-up results, were summarized to investigate its features and prognosis. Results All cases had no obvious clinical and preoperative imaging presentation. There were 23 patients underwent radical nephrectomy, and 6 cases underwent nephron sparing surgery. Postoperative pathological findings confirmed the diagnosis of chromophobe renal cell carcinoma. Macroscopically, the cut surface of the tumors were generally beige in color. Histologically, it showed polygonal chromophobe cells and small round eosinophilic cells with eccentric hyaline degeneration. These tumor cells had a clear and sharp membrane, lightly stained abundant cytoplasm with a fine reticular translucent pattern and irregular nuclei. And a perinuclear halo was often seen in these cells. Histochemically, the tumor cells generally show a diffuse and strong reaction for CK-8 with a negative expression of Vimentin. The pTNM stages of the tumor were as follows, pT1N0M0 in 11 cases, pT2N0M0 in 8 cases, pT3aN0M0 in 5 cases, pT1N1M0 in 3 cases,pT2N1M0 in 2 cases. Twenty-six cases of patients were followed up (24 to 144 months, with an average of 90 months), 3 cases died of cardio-cerebrovascular disease, and local recurrence involved in 6 cases with reoperation in 4 cases, as well as distant metastasis in 1 case. Twenty-one cases survived with tumor-free.The statistical results indicated that the survival rates of the patients with chromophobe renal cell carcinoma in five years and ten years were 83.9%, 77.9%, respectively, compared with renal cell carcinoma of the same stage 63. 8% and 49. 9% at the same periods, and there is no difference in the survival rate of five years( P ＞ 0. 05 ) but significant difference in that of ten years ( P ＜ 0. 01 ). Conclusions Chromophobe renal cell carcinoma is a morphologically uncommon subtype of renal cell carcinoma with the good prognosis. Definite diagnosis depends on its typical pathological feature. Radical nephrectomy is the first choice for the treatment of chromophobe renal cell carcinoma.     

Distinguishing Benign Renal Tumors with an Oncocytic Gene Expression (ONEX) Classifier

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors.Patient summaryRenal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer.     

Variants and Variations in Epithelial Renal Cell Tumors in Adults: The Pathologist's Point of View

Context and ObjectivesThe Vancouver consensus conference of the International Society of Urological Pathology provided the foundation for the 2016 World Health Organization (WHO) classification of the renal tumors.The aim of this contribution is to review some of the major changes and additions to tumor variants and variations in the current classification of the renal cell neoplasms in adults.Evidence acquisition and Evidence synthesisSeveral publications report no recurrence or metastasis in patients with multilocular cystic renal cell carcinoma (RCC). Multilocular cystic renal neoplasm of low malignant potential is now the term recommended by the WHO for this lesion.A similar recommendation has been made in the current literature for hybrid oncocytic/chromophobe tumors (ie, oncocytic neoplasia of uncertain malignant potential) and for clear cell papillary renal cell carcinoma (ie, neoplasm of low malignant potential). Some of the latter tumors were referred to as renal angioadenomatous tumors.Papillary RCC has traditionally been subdivided into type 1 and type 2 papillary RCCs. Recent molecular studies suggest that type 2 papillary RCCs may not constitute a single well-defined entity. There are newly recognized epithelial renal tumor entities in the 2016 WHO classification such as succinate dehydrogenase-deficient RCC.Conclusions and Patient summaryThere are some additional variations in the tumor types that are not included in the WHO classification, however, worth knowing, such as clear cell RCC with hemangioblastoma-like features and unclassified RCC with medullary phenotype.     

p63 Immunohistochemistry Differentiates Salivary Gland Oncocytoma and Oncocytic Carcinoma from Metastatic Renal Cell Carcinoma

Metastatic renal cell carcinoma (RCC) can pose diagnostic challenges in the head and neck often resembling benign and malignant oncocytic lesions. Immunohistochemical panels have been reported to help with this differential but are not entirely specific or sensitive. We have noticed that p63 routinely stains salivary gland oncocytomas but not metastatic RCC. Nineteen oncocytomas, 9 cases of oncocytosis, 9 oncocytic carcinomas and 16 head and neck metastatic RCC were studied. Morphologic features evaluated were cytoplasmic character (clear versus oncocytic), Fuhrman nuclear grade, mitotic rate, growth pattern, presence of lumens/blood lakes and stromal characteristics. Tumors were stained with antibodies to p63, renal cell carcinoma marker (RCCm), CD10, and vimentin. Eight benign oncocytic tumors (29%) had clear cell features while 6 metastatic RCC (37%) had oncocytic features. Median Fuhrman nuclear grade was 2 in oncocytoma and oncocytosis and 3 both oncocytic carcinoma and metastatic RCC. Mitotic rates were only significantly different between benign oncocytic tumors and metastatic RCC. All oncocytomas had lumina compared to half of metastatic RCC, all of which also demonstrated blood lakes. Seven benign oncocytic tumors (25%) and 5 oncocytic carcinomas (56%) had RCC-like vascular stroma. All primary salivary gland tumors were positive for p63, predominately in basal cell-type distribution. None of the metastatic RCC was positive. RCCm was entirely specific but lacked sensitivity for metastatic RCC while CD10 and vimentin showed variable sensitivity and specificity. While clinical history and morphology usually are adequate, demonstration of p63 staining can definitively exclude metastatic RCC from the differential diagnosis of similar appearing tumors in salivary glands, namely oncocytoma and oncocytic carcinoma, with 100% specificity and sensitivity. While RCCm, CD10, and vimentin performed adequately, they were significantly less reliable than p63 with both false positives and false negatives. The results of this study were presented at the 96th Annual Meeting of the United States and Canadian Academy of Pathologists in San Diego, CA, March 2007.     

A rare case of synchronous association of chromophobe renal cell carcinoma with urothelial carcinoma of urinary bladder

Introduction

Chromophobe renal cell carcinoma accounts for 3–5% of all RCCs. However, its association with urothelial carcinoma of urinary bladder has never been reported. We report a case of synchronous association of chromophobe RCC with low grade urothelial carcinoma of urinary bladder.