Christopher G. Przybycin

Succinate Dehydrogenase (SDH)-deficient Renal Carcinoma: A Morphologically Distinct Entity: A Clinicopathologic Series of 36 Tumors From 27 Patients

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.

Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with characteristic tumors involving multiple organ systems. Whereas renal angiomyolipoma (AML) is common in TSC, renal cell carcinoma (RCC) is rarely reported. Fifty-seven RCCs from 13 female and 5 male TSC patients were reviewed. Age at surgery ranged from 7 to 65 years (mean: 42 y). Nine patients (50%) had multiple synchronous and/or metachronous RCCs (range of 2 to 20 RCCs) and 5 had bilateral RCCs (28%). Seventeen patients (94%) had histologically confirmed concurrent renal AMLs, including 15 with multiple AMLs (88%) and 9 (50%) with AMLs with epithelial cysts. None of the 15 patients with available clinical follow-up information had evidence of distant metastatic disease from 6 to 198 months after their initial surgery (mean: 52 mo). The 57 RCCs exhibited 3 major distinct morphologies: (1) 17 RCCs (30%) had features similar to tumors previously described as “renal angiomyoadenomatous tumor” or “RCC with smooth muscle stroma”; (2) 34 RCCs (59%) showed features similar to chromophobe RCC; and (3) 6 RCCs (11%) showed a granular eosinophilic-macrocystic morphology. Distinct histologic changes were also commonly present in the background kidney parenchyma and included cysts or renal tubules lined by epithelial cells with prominent eosinophilic cytoplasm, nucleomegaly, and nucleoli. Immunohistochemically, all RCCs tested showed strong nuclear reactivity for PAX8 and HMB45 negativity. Compared with sporadic RCCs, TSC-associated RCCs have unique clinicopathologic features including female predominance, younger age at diagnosis, multiplicity, association with AMLs, 3 recurring histologic patterns, and an indolent clinical course. Awareness of the morphologic and clinicopathologic spectrum of RCC in this setting will allow surgical pathologists to better recognize clinically unsuspected TSC patients.

Chromophobe renal cell carcinoma: a clinicopathologic study of 203 tumors in 200 patients with primary resection at a single institution.

Despite multiple studies, many clinicopathologic issues about chromophobe renal cell carcinoma (RCC) remain contentious; for example, its biological behavior-whether better or similar to papillary RCC, the incidence of sarcomatoid features, and whether pathologic features such as necrosis, nuclear grade, and tumor stage predict worse outcome. We studied 203 consecutive primary chromophobe RCCs resected at our institution in an attempt to answer these and other questions. The tumors showed significant progressive decrease in size and stage (P=0.047 and 0.001) from 1980 to 2000. Five patients had metastasis at presentation, and further disease-specific events (recurrence/metastasis/death due to disease) occurred in 8 more. Only 4 of 203 tumors had sarcomatoid features. Over median follow-up of 6.1 years (range, 0.1 to 18 y), 5-year and 10-year disease-specific events occurred in 3.7% (95% CI, 1.5%, 7.4%) and 6.4% (95% CI, 2.7%, 12.2%) patients. Outcomes showed significant association with tumor size, small-vessel invasion, sarcomatoid features, and microscopic necrosis (P⩽0.05 each). pT stage or nodal metastasis tended to show some association, without reaching statistical significance (P=0.05 and 0.06, respectively). A modified tumor grading scheme, somewhat similar to that proposed recently, mitotic index, cytologic eosinophilia, and architecture, were not significantly associated with outcome. In conclusion, sarcomatoid differentiation is quite uncommon in chromophobe RCC. Tumor size, small-vessel invasion, sarcomatoid differentiation, and microscopic necrosis are the only features that are significantly associated with adverse outcome. On the basis of this long follow-up on a large number of cases, chromophobes seem to have better clinical outcomes than those reported for clear cell and papillary RCCs.

Rhabdoid Differentiation Is Associated With Aggressive Behavior in Renal Cell Carcinoma: A Clinicopathologic Analysis of 76 Cases With Clinical Follow-up

Rhabdoid differentiation has been associated with aggressive behavior in carcinomas from different organ systems. A recent consensus statement of the International Society of Urological Pathology (ISUP), in addition to proposing a nucleolar grading system (ISUP grade) for renal cell carcinoma (RCC) to replace the Fuhrman system, recommended reporting the presence of rhabdoid differentiation in RCC and considering tumors with rhabdoid differentiation to be ISUP grade 4. Although it has been shown that rhabdoid differentiation is associated with increased grade and stage of RCC, it has not been fully demonstrated whether it has an adverse effect independent of this association with increased grade and stage. We provide the largest clinicopathologic analysis of RCC with rhabdoid differentiation to date (76 cases), including characterization of metastatic disease. In addition, by constructing a multivariable model including tumor grade, stage, necrosis, and distant metastasis to compare a series of 49 clear cell RCC with rhabdoid differentiation with a cohort of 41 clear cell RCCs without rhabdoid differentiation, we demonstrate that the presence of rhabdoid differentiation in clear cell RCC confers an increased risk of death (hazard ratio=5.25; 95% confidence interval, 2.1-14.3) independent of these other adverse prognostic factors. These findings underscore the significance of rhabdoid differentiation in RCC as an adverse prognostic factor and support the recent reporting and grading recommendations of the ISUP.

Eosinophilic, Solid, and Cystic Renal Cell Carcinoma: Clinicopathologic Study of 16 Unique, Sporadic Neoplasms Occurring in Women

A unique renal neoplasm characterized by eosinophilic cytoplasm and solid and cystic growth was recently reported in patients with tuberous sclerosis complex (TSC). We searched multiple institutional archives and consult files in an attempt to identify a sporadic counterpart. We identified 16 morphologically identical cases, all in women, without clinical features of TSC. The median age was 57 years (range, 31 to 75 y). Macroscopically, tumors were tan and had a solid and macrocystic (12) or only solid appearance (4). Average tumor size was 50 mm (median, 38.5 mm; range, 15 to 135 mm). Microscopically, the tumors showed solid areas admixed with variably sized macrocysts and microcysts that were lined by cells with a pronounced hobnail arrangement. The cells had voluminous eosinophilic cytoplasm with prominent granular cytoplasmic stippling and round to oval nuclei with prominent nucleoli. Scattered histiocytes and lymphocytes were invariably present. Thirteen of 16 patients were stage pT1; 2 were pT2, and 1 was pT3a. The cells demonstrated a distinct immunoprofile: nuclear PAX8 expression, predominant CK20-positive/CK7-negative phenotype, patchy AMACR staining, but no CD117 reactivity. Thirteen of 14 patients with follow-up were alive and without disease progression after 2 to 138 months (mean: 53 mo; median: 37.5 mo); 1 patient died of other causes. Although similar to a subset of renal cell carcinomas (RCCs) seen in TSC, we propose that sporadic “eosinophilic, solid, and cystic RCC,” which occurs predominantly in female individuals and is characterized by distinct morphologic features, predominant CK20-positive/CK7-negative immunophenotype, and indolent behavior, represents a novel subtype of RCC.

Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens.

Many hereditary tumor syndromes are associated with neoplasms of the kidney. It is becoming increasingly well recognized that a given familial tumor syndrome may be very heterogenous in clinical appearance and that unrecognized patients may present initially for the treatment of a renal mass. It is therefore important for surgical pathologists to be aware of the specific gross and microscopic findings in the kidney that suggest a possible syndromic association. In this review, we detail the histologic features of syndromic-associated renal neoplasms, describe the presence of characteristic changes in the background renal parenchyma, and provide an update on associated extrarenal manifestations for each of the following syndromes: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma (RCC), hereditary leiomyomatosis-RCC, Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, germline succinate dehydrogenase mutation, hereditary nonpolyposis colorectal cancer syndrome, hyperparathyroidism-jaw tumor syndrome, PTEN hamartoma syndrome, constitutional chromosome 3 translocation, and familial nonsyndromic clear cell RCC. We also include a synopsis of renal medullary carcinoma because of its association with hereditary hemoglobinopathies.

Signal integration and gene induction by a functionally distinct STAT3 phosphoform.

ABSTRACT Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr705 phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr705 phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr714 and Ser727 by glycogen synthase kinase 3α and -β (GSK-3α/β). Both Thr714 and Ser727 are required for STAT3-dependent gene induction in response to simultaneous activation of epidermal growth factor receptor (EGFR) and protease-activated receptor 1 (PAR-1) in endothelial cells. In this combinatorial signaling context, preventing formation of doubly phosphorylated STAT3 by depleting GSK-3α/β is sufficient to disrupt signal integration and inhibit STAT3-dependent gene expression. Levels of doubly phosphorylated STAT3 but not of Tyr705-phosphorylated STAT3 are remarkably elevated in clear-cell renal-cell carcinoma relative to adjacent normal tissue, suggesting that the GSK-3α/β–STAT3 pathway is active in the disease. Collectively, our results describe a functionally distinct, noncanonical STAT3 phosphoform that positively regulates target gene expression in a combinatorial signaling context and identify GSK-3α/β–STAT3 signaling as a potential therapeutic target in renal-cell carcinoma.

Renal neoplasms with overlapping features of clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma a clinicopathologic study of 37 cases from a single institution

Clear cell papillary renal cell carcinoma (CCPRCC) was recently included in the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia as a subtype of RCC that is morphologically, immunohistochemically, and genetically distinct from both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma. In our clinical practice we have observed tumors with overlapping histologic features of CCPRCC and CCRCC; therefore, our aim was to describe the morphologic, immunohistochemical, and clinical characteristics of these tumors. We examined a large series of consecutive nephrectomies diagnosed as CCRCC and found 37 tumors with morphologic overlap between CCRCC and CCPRCC, identifying 2 patterns. Pattern 1 tumors (N=19) had areas diagnosable as CCRCC admixed with foci having a prominent linear arrangement of nuclei away from the basement membrane imparting a resemblance to CCPRCC; however, other morphologic features commonly seen in CCPRCC (such as branching acini and cystic spaces with papillary tufts) were not typical and, when present, were focal or poorly developed. Pattern 2 (N=18) tumors had 2 discrete areas, one area with an appearance strongly resembling CCPRCC and the other with higher grade nuclei and features diagnosable as CCRCC, sometimes including rhabdoid differentiation, sarcomatoid differentiation, necrosis, and high-stage disease. Four (21%) of the pattern 1 tumors had grade 3 nuclei in the CCRCC-like areas, and 4 were high stage (pT3a). Of the 16 immunostained pattern 1 tumors, all expressed cytokeratin 7 (CK7) at least focally in the CCPRCC-like areas, strongly and diffusely in 9 (56%) cases; 12 (75%) showed negative to focal and/or weak CK7 expression in the CCRCC-like areas. CD10, &agr;-methylacyl-CoA-racemase, high–molecular-weight cytokeratin, and carbonic anhydrase IX (CA IX) had no significant differential expression between these foci. No cup-like staining pattern was seen with CA IX. Two (11%) patients with pattern 1 tumors developed metastases, and 1 (5%) subsequently died of disease. Eleven (61%) pattern 2 cases had the International Society of Urological Pathology grade 3 nuclei in the CCRCC-like areas, and 7 (39%) were grade 4 (4 of these cases had rhabdoid features; 1 was also sarcomatoid). Of the 16 immunostained pattern 2 tumors, 8 (50%) showed strong diffuse CK7 expression in the CCPRCC-like areas, and 9 (56%) showed complete lack of CK7 expression in the CCRCC-like areas. CD10, &agr;-methylacyl-CoA-racemase, and high-molecular-weight cytokeratin did not have significant differential expression. Membranous expression of CA IX, typically strong and diffuse, was identified in both the CCPRCC-like and CCRCC-like areas in all cases tested (with a cup-like pattern at least focally in the CCPRCC-like areas of 10 [63%] pattern 2 cases). Five (28%) patients with pattern 2 tumors had distant metastases, 3 (17%) of whom subsequently died of disease. Renal cell carcinomas with areas resembling both CCRCC and CCPRCC occur. Some can have high-grade and high-stage foci, and aggressive clinical outcomes are seen. Given this malignant potential, we would presently diagnose such cases as CCRCC. These 2 patterns of renal neoplasia underscore the need for caution in diagnosing CCPRCC on limited sampling, reserving the diagnosis for those tumors that strictly fulfill both morphologic and immunohistochemical criteria.

Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases from a Single Institution

Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (P<0.001). When a recursive partitioning approach was applied to our data, patients of a given ISUP grade could be further prognostically separated according to the presence or absence of necrosis and could be divided into 3 statistically significant prognostic groups: (1) non-necrotic ISUP grade 1 to 3 tumors, (2) ISUP grade 1 to 3 tumors with necrosis and ISUP grade 4 tumors with <10% necrosis, and (3) ISUP grade 4 tumors with >10% necrosis. In conclusion, our study shows that tumor necrosis adds additional prognostic information to ISUP grade and that quantification of necrosis can further stratify patients with ISUP grade 4 tumors.

A genomic algorithm for the molecular classification of common renal cortical neoplasms: development and validation.

PURPOSE Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms. MATERIALS AND METHODS Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization. RESULTS The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved. CONCLUSIONS In a clinical diagnostic setting the implementation of genome based molecular classification could serve as an ancillary assay to assist in the histological classification of common renal neoplasms.