Mechanistic target of rapamycin kinase (mTOR) is a member of the phosphatidylinositol-3-hydroxide kinase (PI3 K)-related protein kinase family that functions as a central regulator of cell growth, metabolism, proliferation, and survival. The role of the TSC-mTOR signaling pathway in kidney tumors has been implicated in some hamartoma syndromes; however, with the advent and wide utilization of molecular studies, a growing number of kidney tumors have been linked to somatic or germline mutations involving genes that encode for this pathway, including eosinophilic solid and cystic renal cell carcinoma, low-grade oncocytic tumor, eosinophilic vacuolated tumor, renal cell carcinoma with fibromyomatous stroma and angiomyolipoma, among others. Herein, we review the contemporary developments of mTOR pathway-related renal neoplasia, focusing on the clinicopathologic features of the tumor entities.

Renal cell carcinoma with fibromyomatous stroma (RCC-FMS) is a recent provisional entity already recognised in the 2016 WHO Classification of Cancer of the Urinary Tract and Male Genital Organs 4th Edition as renal cell carcinoma with (angio)leiomyomatous stroma, histologically defined as a tumour characterised by clear cells intertwined in a conspicuous vascular stroma. In the casuistry taken into consideration, another proposed variant, thyroid-like follicular carcinoma of the kidney (TLFCK), endowed with a morphology mimicking thyroid parenchyma, was examined. The aim of this work was to parse the theoretical system, experimental data and diagnostic impact of these new entities proposed in the field of renal neoplasms.

An analysis of 120 cases of kidney tumours from the Department of Surgical, Medical, Molecular and Critical Area at the University of Pisa was run. Subsequently, all samples were reassessed by two pathologists with expertise in uropathology, whose revaluation provided a histomorphological study combined with subsequent and coherent immunohistochemical analyses of CK7, CD10, CAIX, CK34betaE12, CD117, vimentin, TTF-1 and thyroglobulin. These analyses were performed using the Ventana Benchmark Automated Staining System (Ventana Medical Systems, Tucson, AZ, USA) and Ventana reagents.

On the one hand, the data, thus brought to light, did not show an immunohistochemical profile consistent with that proposed for RCC-FMS. However, it should be emphasised that the morphological background also unearthed a poor specificity for RCC-FMS. This was specifically due to a stromal component which was, in any case, evident, although characterised by a wide range of presentation, in clear cell renal cell carcinoma (ccRCC). This latter is, indeed, the reference background for this theorised variant. On the other hand, a thyroid-like pattern was highlighted in 11 cases, more specifically in 10 ccRCCs and in one oncocytoma, presenting itself as a type of neoplastic appearance rather than as the peculiar morphological pattern of a standalone cancer.

In the light of these results, RCC-FMS and TLFCK appear to be more appropriately variants of already categorised neoplastic entities rather than new independent neoplasias.

Renal cell carcinoma (RCC) with haemangioblastoma-like characteristics is a type of RCC reported in recent years. RCC with (angio) leiomyomatous stroma (RCCLMS) was included as a provisional entity of the 2016 World Health Organization (WHO) classification. RCC with haemangioblastoma-like characteristics and leiomyomatous stroma is extremely rare. This is the first report of a rare tumour harbouring TSC2 and SETD2 variations.

The patient was a 38-year-old woman who presented with discomfort in the area of her right kidney. Ultrasound and enhanced CT showed a right renal mass, and clear cell renal cell carcinoma (CCRCC) was suspected; hence, robot-assisted laparoscopic nephron-sparing partial nephrectomy was performed. Gross examination revealed a well-circumscribed tumour measuring 2.0 cm × 1 cm × 0.7 cm under the renal capsule adjacent to the stripping edge that was greyish yellow and greyish red in colour. Histologic examination showed that the tumour consisted of three different structures: a CCRCC-like region, a haemangioblastoma-like region, and a focal leiomyomatous stroma component. Based on immunohistochemistry, the CCRCC-like region was diffusely strongly positive for AE1/AE3, vimentin, CAIX, PAX8, PAX2, CK7, and CAM5.2, partly positive for HNF1α, and negative for CD10, α-inhibin, NSE, S-100, CD34, and TFE3. The haemangioblastoma-like area was diffusely positive for vimentin, CAIX; partly positive for PAX8, PAX2, α-inhibin, and S-100; mostly positive for NSE; and slightly positive for HNF1α; the CD34 staining highlighted the complex capillary network. The Ki67 index was approximately 1-2% in the two above areas, and the leiomyomatous stroma was strongly positive for SMA. The whole-exon sequencing (WES) showed TSC2 and SETD2 variations. There was no progression after 18 months of follow-up.

We report for the first time a unique case of RCC with haemangioblastoma-like features and leiomyomatous stroma accompanied by rare molecular abnormalities. Whether this is a new tumour entity or a variant of clear cell carcinoma remains to be determined. The biological behaviour and clinical characteristics need to be further examined.

In the 2016 World Health Organization (WHO) classification of renal tumors, renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma) was classified as an emerging or provisional entity of renal cell carcinoma (RCC). We report a rare case of RCC FMS in a 62-year-old male patient with hypertension, type II diabetes mellitus, and early chronic kidney disease. He was referred to the Department of Urology for an incidental finding of a 2-cm-long left renal nodule on a routine abdominal ultrasound. A laparoscopic right partial nephrectomy was performed. Histopathology and immunohistochemistry studies confirm the diagnosis of RCC FMS. The purpose of this work is to review and discuss newly acquired data and evidence on the clinical, pathological, immunohistochemical, molecular, and prognostic aspects of this unusual entity in the hopes of assisting pathologists in accurate diagnosis.

Renal cell carcinoma (RCC) with fibromyomatous stroma (FMS) was included as an "emerging/provisional" entity in the 2016 World Health Organization (WHO) classification as a "RCC with (angio) leiomyomatous stroma." It has been debated whether RCCFMS represents a separate entity or a group of RCCs with overlapping morphologies. Accordingly, various names have been used to refer to the RCCs that exhibited clear cells and prominent smooth muscle and fibromatous stroma. Recent studies have demonstrated that RCCFMS indeed represents a distinct entity with subtle but distinguishable features that can be separated from other RCCs that exhibit clear cells, as well as tubulopapillary morphology and smooth muscle/fibromatous stroma, such as clear cell RCC and clear cell papillary RCC. Microscopically, the epithelial component forms tumor nodules composed of elongated and frequently branching tubules, lined by clear or mildly eosinophilic cells containing voluminous cytoplasm. Focal papillary morphology is also frequently present. Diffuse CK7 positivity is typical and is required for the diagnosis. Molecular analysis of these tumors demonstrated recurrent mutations involving the TSC/mTOR pathway. A subset of tumors with similar morphology has shown mutations involving ELOC (previously referred to as TCEB1), typically associated with monosomy 8. Finally, in addition to the more common RCCFMS that are sporadic, essentially identical tumors have been found in patients with tuberous sclerosis complex, suggesting the existence of hereditary and sporadic counterparts of this tumor. It is currently debated whether TSC/mTOR and ELOC mutated RCCFMS should be grouped together, based on their shared and overlapping morphology and common CK7 reactivity, despite the differing molecular alterations. This review outlines evidence supporting the recognition of RCCFMS as a novel subtype of RCC with morphologic, immunohistochemical, and molecular characteristics distinct from clear cell RCC and clear cell papillary RCC.

The notochord is the defining structure of all chordate embryos. It is a midline structure ventral to the ectoderm, neural plates, and neural arch. Remnants of the notochord ultimately give rise to the nucleus pulposus. The function of the notochord is to organize the surrounding structures. Chordoma is a rare malignant bone tumor arising from remnants of the notochord. These tumors are indolent and can present as incidental or locally advanced involving adjacent structures. These tumors typically present at the skull base and sacral spine but more rarely can be seen on the cervical and thoracic spine. Rare cases of chordoma invading the brachial plexus have been recorded. Surgical resection is the mainstay of treatment for chordomas. We would like to discuss a novel presentation of a chordoma as a Pancoast tumor, and aim to highlight the clinical importance of accurate diagnosis and planning therapy along with poor prognosis of incomplete surgical resection.

Renal cell carcinoma with (angio) leiomyomatous stroma (RCCLMS) is included as a provisional entity in the 2016 World Health Organization (WHO) classification of renal epithelial neoplasia; however, debate remains whether it represents a distinct entity or a heterogenous group of renal cell carcinomas (RCCs) with overlapping morphology. Also, its relationship to similar tumors occurring in the setting of tuberous sclerosis complex (TSC) is not fully addressed. We analyzed the clinicopathologic, immunohistochemical, and molecular characteristics of 23 sporadic RCCs associated with smooth muscle stroma and classified them into 2 groups, independent of molecular results: (1) RCCLMS (n=18) and (2) clear cell renal cell carcinoma (CCRCC) (n=5). The classification of a case as "RCCLMS" was based on morphologic comparison with 5 "index" RCCs from 3 patients with TSC showing similar features and the presence of diffuse CK7 expression. To investigate mutational and copy number alterations, a 170-gene solid tumor panel was utilized to sequence 14 RCCLMSs and control of 5 CCRCCs. Also, 4 RCCLMSs, suspicious for chromosome 8 monosomy, were further evaluated by a broader 479 gene sequencing panel that included ELOC (also referred to as TCEB1). Clinical information and follow-up data were obtained from electronic medical records. The mean age of patients with RCCLMS was 52 years (range, 33 to 69) with male:female ratio of 1:2. Macroscopically, all tumors were solitary and predominantly (82%) tan/red, circumscribed, and solid. The average tumor size was 2.3 cm (range, 1.1 to 4.5). Microscopically, the distinctive feature included tumor nodules of elongated and frequently branching tubules lined by cells with voluminous clear to mildly eosinophilic cytoplasm (100%), separated by focal to prominent smooth muscle stroma. Additional frequently identified features included: biphasic pattern of collapsed acini surrounding tubules with voluminous cytoplasm (50%), focal papillary architecture (39%), peritumoral lymphoid aggregates (39%), and hemosiderin-laden macrophages (33%). All 11 (100%) RCCLMSs with available staging information were pT1; 78% were WHO/International Society of Urologic Pathology (ISUP) grade 2 and 22% grade 3. Immunophenotypically, RCCLMSs were characterized by diffuse CK7, CAM5.2 and CD10 reactivity (100%). All patients with available follow-up (n=10) were alive and without disease progression after a mean and median follow-up of 25.2 (range: 1 to 58) and 25 months, respectively. The molecular results showed recurrent mutations in all RCCLMS: TSC1 (4), TSC2 (4), MTOR (6), and/or ELOC (2). Five control CCRCCs demonstrated primary alterations in VHL gene, while all 14 RCCLMS cases tested had intact VHL gene. Of 2 RCCLMSs with confirmed monosomy 8, 1 showed a hotspot ELOC mutation without TSC/MTOR mutations, and 1 showed a previously undescribed 3-bp in-frame ELOC deletion, along with a truncating TSC1 mutation. In conclusion, RCCLMS, as defined herein, harbors recurrent mutations of TSC1/TSC2, MTOR, and/or ELOC, consistent with hyperactive MTOR complex. Our findings argue that these tumors represent the sporadic counterpart to morphologically identical tumors occurring in TSC patients. Finally, the data support that RCCLMS is a novel subtype of RCC with unique morphologic, immunohistochemical, and molecular characteristics that is distinct from CCRCC and clear cell-papillary RCC.

Thirty-one cases of low-grade renal cell carcinoma (RCC) with clear cells and tubulopapillary/papillary architecture were analyzed retrospectively with immunohistochemical and genetic markers to gain more experience with the differential diagnosis of such cases. All samples coexpressed CK7 and CA9; the TFE3 or TFEB reactions were negative; the CD10 and the AMACR stainings were negative in 27 cases and 30 cases, respectively. The FISH assays for papillary RCC, available in 27 cases, and deletion of chromosome 3p, available in 29 cases, gave negative results. The results for 3p deletion, VHL gene mutation or VHL gene promoter region hypermethylation testing, along with the diffuse CD10-positivity in 2 cases confirmed 21 cases as clear cell papillary RCC (CCPRCC; CK7+, CA9+; no 3p loss, no VHL abnormality) and 10 cases as clear cell RCC (CCRCC; CK7+, CA9+; no 3p loss, VHL abnormality mutation/hypermethylation present). In CCPRCCs, the representative growth pattern was branching tubulo-acinar, commonly accompanied by cyst formation. The linear nuclear arrangement or cup-shaped staining of CA9 did not necessarily indicate CCPRCC, and the absence of these did not exclude the diagnosis of CCPPRC. One tumor infiltrated the renal sinus; the others exhibited pT1 stage; and metastatic outcome was not recorded. The CCRCC cases were in pT1 stage; 6 exhibited cup-shaped staining of CA9, and 1 displayed lymph node metastasis at the time of surgery. Distant metastatic disease was not observed. In summary, the VHL abnormalities distinguished the subset of CCRCC with diffuse CK7-positivity and no 3p loss from cases of CCPRCC.

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of kidney neoplasms. Renal cell carcinoma with leiomyomatous stroma (RCCLS) is an extremely rare histopathological entity based on available literature data. Herein, we report a 31-year-old male with incidentally detected synchronous bilateral renal masses who was eventually found to harbor RCCLS after being operated sequentially via nephron-sparing surgery.

Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p loss, for which whole-slide images were reviewed. Of the 418 tumors in the published Cancer Genome Atlas clear cell renal cell carcinoma database, 387 had VHL mutation, copy number loss for chromosome 3p, or both (93%). Of the remaining, 27/31 had whole-slide images for review. One had 3p loss based on karyotype but not sequencing, and three demonstrated VHL promoter hypermethylation. Nine could be reclassified as distinct or emerging entities: translocation renal cell carcinoma (n=3), TCEB1 mutant renal cell carcinoma (n=3), papillary renal cell carcinoma (n=2), and clear cell papillary renal cell carcinoma (n=1). Of the remaining, 6 had other clear cell renal cell carcinoma-associated gene alterations (PBRM1, SMARCA4, BAP1, SETD2), leaving 11 specimens, including 2 high-grade or sarcomatoid renal cell carcinomas and 2 with prominent fibromuscular stroma (not TCEB1 mutant). One of the remaining tumors exhibited gain of chromosome 7 but lacked histological features of papillary renal cell carcinoma. Two tumors previously reported to harbor TFE3 gene fusions also exhibited VHL mutation, chromosome 3p loss, and morphology indistinguishable from clear cell renal cell carcinoma, the significance of which is uncertain. In summary, almost all clear cell renal cell carcinomas harbor VHL mutation, 3p copy number loss, or both. Of tumors with clear cell histology that lack these alterations, a subset can now be reclassified as other entities. Further study will determine whether additional entities exist, based on distinct genetic pathways that may have implications for treatment.

Accumulating evidence suggests that renal cell tumors represent a group of histologically and molecularly heterogeneous diseases, even within the same histological subtype. In accordance with the increased understanding of the morphological, immunohistochemical, molecular, and epidemiological characteristics of renal cell tumors, the World Health Organization (WHO) classification of renal cell tumors has been modified. This review provides perspectives on both new and current subtypes of renal cell tumors, as well as on the emerging/provisional renal cell carcinomas in the new 2016 WHO classification, which focuses on features of their molecular pathological epidemiology. The WHO classification will require additional revisions to enable the classification of renal cell tumors as clinically meaningful subtypes and provide a better understanding of the unique characteristics of renal cell tumors.

While clear cell, papillary and chromophobic renal cell carinoma (RCC) represent the most common malignant renal neoplasms, the evaluation and classification of rare renal carcinomas has currently come into focus. One of these is the leiomyomatous RCC, which shows morphologic similarities to clear cell RCCs, however exhibiting additional, atypical smooth muscle differentiation. We report the clinical case of a patient simultaneously presenting with leiomyomatous and papillary RCC and discuss new tumor entities of RCC.

Clear cell papillary renal cell carcinoma (ccpRCC) and renal angiomyoadenomatous tumor (RAT) share morphologic similarities with clear cell (ccRCC) and papillary RCC (pRCC). It is a matter of controversy whether their morphologic, immunophenotypic, and molecular features allow the definition of a separate renal carcinoma entity. The aim of our project was to investigate specific renal immunohistochemical biomarkers involved in the hypoxia-inducible factor pathway and mutations in the VHL gene to clarify the relationship between ccpRCC and RAT. We investigated 28 ccpRCC and 9 RAT samples by immunohistochemistry using 25 markers. VHL gene mutations and allele losses were investigated by Sanger sequencing and fluorescence in situ hybridization. Clinical follow-up data were obtained for a subset of the patients. No tumor recurrence or tumor-related death was observed in any of the patients. Immunohistochemistry and molecular analyses led to the reclassification of 3 tumors as ccRCC and TFE3 translocation carcinomas. The immunohistochemical profile of ccpRCC and RAT samples was very similar but not identical, differing from both ccRCC and pRCC. Especially, the parafibromin and hKIM-1 expression exhibited differences in ccpRCC/RAT compared with ccRCC and pRCC. Genetic analysis revealed VHL mutations in 2/27 (7%) and 1/7 (14%) ccpRCC and RAT samples, respectively. Fluorescence in situ hybridization analysis disclosed a 3p loss in 2/20 (10%) ccpRCC samples. ccpRCC and RAT have a specific morphologic and immunohistochemical profile, but they share similarities with the more aggressive renal tumors. On the basis of our results, we regard ccpRCC/RAT as a distinct entity of RCCs.

Clear cell-papillary renal cell carcinoma (CC-Pap RCC) is a recently described renal tumor initially reported in the setting of end-stage renal disease (ESRD). It has unique morphologic and immunohistochemical features that differentiate it from the more common clear cell RCC and papillary RCC. Recently, these tumors have also been described in a sporadic setting. We studied 64 cases of CC-Pap RCC not associated with ESRD (57 CC-Pap RCCs and 7 cases with features of renal angiomyoadenomatous tumors [RAT] including 5 initially diagnosed as such). The morphologic features of all cases and the immunohistochemical profile of 59 cases were studied along with the clinical and molecular features of 30 and 12 cases, respectively. All the tumors were well circumscribed with a mean tumor size of 2.6 cm and showed a wide array of architectural patterns, usually mixed, including tubular (77%), papillary (62%), tubulocystic (52%), and compact nested (21%). Seventy-three percent of the cases showed areas in which the tumor nuclei had a distinct orientation away from the basement membrane. Ninety-two percent of the cases had a low Fuhrman nuclear grade (nuclear grade 2%-86%, and nuclear grade 1%-6%); however, 8% cases showed foci of Fuhrman nuclear grade 3. In 4 cases, epithelial tumor comprised <5% of the tumor; >95% of the tumor was cystic or hyalinized. The stroma varied from being minimal to occasionally prominent myxoid to hyalinized and rarely with organized amianthoid fibers or well-defined smooth muscle bundles. Pathologic stage was reliably assigned in 60 cases, of which 93.3% (56 cases) were pT1, 3.3% (2 cases) were pT2, and 3.3% (2 cases) were pT3a with extension into the perinephric fat. One case had coagulative necrosis; sarcomatoid change and vascular invasion was not identified. The tumors showed a fairly typical immunoprofile characterized by positivity for CK7 (100%), HMCK (96%), CAIX (94%), and vimentin (100%) with negativity for AMACR, RCC, and TFE3; CD10 was positive in 24%. None of the cases tested showed recurrent chromosomal imbalances by virtual karyotyping, fluorescence in situ hybridization, or 3p loss of heterozygosity analysis. VHL gene mutations were, however, noted in 3 cases (2 in exon 1 and 1 in exon 3). Clinical follow-up information was available in 47% of the patients, with a mean and median follow-up of 47 and 37 months, respectively (range, 18 to 108 mo). One case occurred in the setting of VHL syndrome and multiple benign cysts. None of the cases showed local recurrence, metastasis, or death due to disease. Morphology, immunophenotype, and molecular studies did not vary between typical cases, those with prominent smooth muscle (so-called RAT), and historically published data on cases occurring in ESRD. Our analysis confirms that CC-Pap RCC is a unique subtype of adult renal epithelial neoplasia in which tumors are frequently small, are of low nuclear grade and pathologic stage, and have extremely favorable short to intermediate range prognosis. Tumors occurring sporadically, with prominent smooth muscle stroma (so-called RAT), and occurring in ESRD are in the spectrum of the same category of tumors.

Papillary architecture is one of the most common morphological patterns in renal cell neoplasms. Many renal cell neoplasms can also exhibit, diffusely or focally, papillary growth pattern. This article reviews all the renal cell neoplasms with papillary or pseudopapillary architecture, with an emphasis on recently described new histological types. New insights into the "old" entities, including their immunohistochemical and genetic features, will also be discussed.

The classification of renal cell neoplasia is morphologically based; however, this has evolved over the last 35 years with the incorporation of genetic characteristics into the diagnostic features of some tumors. The 2013 Vancouver classification recognized 17 morphotypes of renal parenchymal malignancy and two benign tumors. This classification included the newly established entities tubulocystic renal cell carcinoma (RCC)), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, microphthalmia transcription factor family translocation RCC and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition to these newly described forms of RCC there are a number of novel tumors that are currently recognized as emerging entities. These are likely to be incorporated into subsequent classifications and include thyroid-like follicular RCC, succinate dehydrogenase B mutation-associated RCC, ALK translocation RCC, tuberous sclerosis complex-associated RCC, and RCC with (angio) leiomyomatous stroma.

Rare renal epithelial neoplasms have been recognized to have an angioleiomyoma or leiomyoma-like proliferation of stromal smooth muscle; however, the nature of these tumors and their relationships to other renal cell carcinomas are poorly understood. We analyzed 23 such tumors for their clinicopathological, immunohistochemical, and cytogenetic features using fluorescence in situ hybridization. Twelve showed a homogeneous combination of features and were reclassified as renal cell carcinoma with angioleiomyoma-like stroma. These were composed of neoplastic glandular structures lined by cells with mixed clear, pale, and eosinophilic cytoplasm forming occasional papillary tufts. The stroma resembled smooth muscle and often extended away from the epithelial component, entrapping perinephric fat or non-neoplastic renal elements. Immunohistochemistry showed the epithelium to have reactivity for: carbonic anhydrase IX, CD10, vimentin, cytokeratin 7, cytokeratin 34βE12, and PAX8 but not α-methylacyl-coA-racemase. The stroma labeled for smooth muscle (smooth muscle actin 3+, desmin 1+, caldesmon 3+) but not epithelial antigens. Neither component showed substantial reactivity for HMB45, melan-A, cathepsin K, or TFE3 protein. An interrupted, conspicuous layer of CD34-positive endothelial cells rimmed the epithelium, imparting a two-cell layer pattern resembling myoepithelial or basal cells. Chromosome 3p deletion and trisomy 7 and 17 were uniformly absent. Follow-up was available for three patients, none of whom experienced malignant behavior. Eleven tumors were excluded from this category and considered to be clear cell renal cell carcinoma with a reactive proliferation of smooth muscle (n=4) or tangential sectioning of the pseudocapsule (n=2), renal cell carcinoma unclassified (n=4), or clear cell papillary renal cell carcinoma (n=1). In summary, renal cell carcinoma with angioleiomyoma-like stroma is a distinct neoplasm with characteristic morphological, immunohistochemical, and molecular features, unrelated to clear cell renal cell carcinoma. The immunoprofile overlaps partly with that of clear cell papillary renal cell carcinoma, though morphology and reactivity for CD10 are points of contrast.

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.

Renal cell carcinoma with prominent smooth muscle stroma is a rare neoplasm composed of an admixture of epithelial cell with clear cytoplasm arranged in small nest and tubular structures and a stroma composed of smooth muscle. In the epithelial component, loss of chromosome 3p detected by fluorescence in situ hybridization (FISH) has been reported and on this basis these neoplasms have been viewed as variants of clear cell renal cell carcinoma. To test the validity of this classification, we have evaluated the chromosome 3 and VHL status of three of these tumors using FISH, array comparative genomic hybridization, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification analysis. None of the tumors showed deletion of chromosome 3p, VHL mutation, a significant VHL methylation, or changes in VHL copy number and all three tumors demonstrated a flat profile in the comparative genomic hybridization analysis. We conclude that renal cell carcinoma with smooth muscle stroma should be considered as an entity distinct from clear cell renal cell carcinoma.

Several entities have been individualized recently within the family of renal neoplasms with papillary features. Clear cell papillary renal cell carcinoma (CCPRCC) was first described in patients with end-stage renal disease, but is also observed in patients with normal renal function. The objective of this study was to document the clinicopathological and immunohistochemical characteristics of CCPRCC, with a special emphasis on cyclin D1 expression.

The patients were 25 men and 17 women, mean age 60.7 years. Seventeen patients had a chronic renal disease. All tumours were stage pT1, with a mean diameter of 2 cm. Six tumours were multifocal. Tumours cells were mainly cuboidal, with clear cytoplasm and low-grade nuclei apically aligned. In all cases, Fuhrman nuclear grade was one or two. No necrosis or vascular invasion was seen. During follow-up (10-72 months), no metastasis or death related to the disease was observed. Immunohistochemistry showed strong and diffuse cytokeratin 7 immunoreactivity in all cases, but no labelling for AMACR or TFE3. There was diffuse nuclear cyclin D1 immunoreactivity in 83% of cases.

CCPRCC is now a well-characterized entity. This tumour is an indolent and very low-grade neoplasm. Here we report the first study, to our knowledge, demonstrating the overexpression of cyclin D1 immunostaining by this tumour.

This study was undertaken to determine the incidence and the clinicopathologic characteristics of those tumors that qualify as clear cell papillary renal cell carcinoma (CCPRCC) by the current definitions. From January 1, 2003 to April 30, 2013, a total of twenty-eight CCPRCC were identified (28/648, 4.3%). CCPRCC showed variable architectural patterns including cystic, papillary, tubular, and acinar. Irrespective of the architecture, the tumors were composed of cuboidal or columnar cells with clear cytoplasm, small vesicular, round or oval nuclei, and inconspicuous nucleoli. Variably thick bundles of smooth muscle actin-positive soft tissue encircled the whole tumors, forming a continuous pseudocapsule. CCPRCC strongly expressed PAX8, CA-IX, CK7, cytokeratin 34betaE12, and vimentin, and were negative for RCC, P504s/AMACR, and TFE3. On ultrastructural examination, CCPRCC showed short microvilli, cytoplasmic interdigitations, nuclear pseudoinclusions, and stromal myofibroblasts. To the best of our knowledge, this is first comprehensive ultrastructural study of CCPRCC in the literature. The major differential diagnostic considerations are clear cell renal cell carcinoma, multilocular cystic renal cell carcinoma, papillary renal cell carcinoma with clear cell changes, and Xp11.2 translocation renal cell carcinoma. CCPRCC seems to have a favorable prognosis. In the current series, none of the patients had local recurrence or metastatic disease.

Clear cell papillary renal cell carcinoma is a recently recognized renal neoplasm, composed of cells with clear cytoplasm lining cystic, tubular, and papillary structures. These tumors have immunohistochemical and genetic profiles distinct from clear cell renal cell carcinoma and papillary renal cell carcinoma. We studied morphologic and immunohistochemical features (cytokeratin 7 (CK7), carbonic anhydrase IX (CAIX), CD10, alpha-methylacyl-CoA racemase, smooth muscle actin, desmin, estrogen and progesterone receptors) in 55 tumors from 34 patients, 8 of whom had end-stage renal disease. These tumors comprised 3% of all adult renal cell carcinoma resections over a period of 3 years. The patients' ages ranged from 33 to 87 years (mean 61). Multiple tumors (2-8) were present in 9 patients. Other renal tumors were present concurrently in four patients and subsequently in two patients, including: oncocytoma, clear cell renal cell carcinoma, and multilocular cystic renal cell carcinoma. Sizes ranged from 0.2 to 7.5 (mean 2.0) cm; 87% were Fuhrman grade 2, and 96% were stage pT1a. Papillary architecture was usually limited to focal branching papillae (51% of 55 tumors) or small, blunt papillae (35%). Large areas of extensively branched papillae were present in only 14% of tumors. Almost all tumors (98%) included cysts, and 18 tumors were extensively (≥90%) cystic. Immunoprofile showed CK7+, AMACR-, CD10-, CAIX+ in the tubular and papillary components of all tumors; however, CD10 labeled the apical cell membrane of cyst epithelium in 59%. The stroma was focally actin positive (94%), with infrequent desmin expression (13%). Estrogen receptor and progesterone receptor were negative. During a median follow-up period of 56 months, no patient developed local recurrence, distant or lymph-node metastasis, or cancer death. Branched tubules, small papillae, and the immunohistochemical and molecular profiles aid in distinguishing these tumors from clear cell renal cell carcinoma and multilocular cystic renal cell carcinoma.

The diagnosis of primary renal cell carcinomas (RCCs) with both papillary architecture and cells with clear cytoplasm can be diagnostically challenging for practicing pathologists. The 4 main neoplasms in the differential diagnosis are clear cell RCC, papillary RCC, clear cell papillary RCC, and Xp11 translocation RCC. Accurate diagnosis has both prognostic and therapeutic implications.

To highlight the helpful cytomorphologic, immunohistochemical, and cytogenetic features of each of these entities to enable reproducible classification.

Published peer-reviewed literature was reviewed, accompanied by the authors' personal experiences.

Key morphologic clues and a focused immunohistochemical panel, including CK7, α-methylacyl coenzyme A racemase (AMACR), TFE3, cathepsin K, and carbonic anhydrase IX (CAIX), now allow most resected RCCs with papillary architecture and clear cells to be accurately classified. In other cases, cytogenetic and molecular findings can establish the diagnosis. Despite these tools, some RCCs with papillary architecture and clear cells do not fit into any of the described entities and currently remain unclassified.

Renal cell carcinoma (RCC) in adults comprises a heterogeneous group of tumours with variable clinical outcomes that range from indolent to overtly malignant. The application of molecular genetic techniques to the study of renal neoplasms has resulted in an improved classification of these entities and a better understanding of the biologic mechanisms responsible for tumour development and progression. The current 2004 World Health Organisation classification of adult renal epithelial neoplasms has expanded rapidly with new categories recently incorporated.

To review and evaluate the evidence implicating pathologic features and classification of RCC in adults as a tool to approach patients' prognosis and modulate current therapy.

Members of Committee 3: Pathology, under the auspices of the International Consultation on Urological Diseases and the European Association of Urology (ICUD-EAU) International Consultation on Kidney Cancer, performed a systematic review using PubMed. Participating pathologists discussed pathologic categories and diagnostic features of RCC in adults.

We reviewed and discussed articles and the personal experiences of participating uropathologists.

The conclusions reached by the ICUD-EAU 2010 International Consultation on Kidney Cancer emphasise the appropriate pathologic diagnosis of RCC in adults as a tool to approach patients' prognosis and modulate current therapy. Further emphasis should be placed on defining risk groups of RCC and diagnostic features of unusual tumours such as familial RCC, translocation RCC, and tubular mucinous and spindle cell carcinoma. A number of recently described entities and morphologic variants of classical categories deserves recognition because they can be important in differential diagnosis and therapy.

Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as "clear cell tubulopapillary renal cell carcinoma," constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.

Recently, renal angiomyoadenomatous tumor (RAT) has been identified. However, there are no descriptions about clear cell renal cell carcinoma (RCC) with focal RAT-like features. A 33-year-old Japanese man was found to have a tumor in the left kidney. Macroscopically, the tumor extended into the perinephric fat tissue, and the cut surface showed the yellowish color. The histologic examination of the tumor consisted of 2 components of clear cell RCC and RAT-like area. The RAT-like area showed the admixture of epithelial cells with basophilic or clear cytoplasm and stromal component containing leiomyomatous stroma, fine capillary network, and pericytic network. Immunohistochemically, epithelial neoplastic cells in RAT-like area were diffusely positive for CD10 and RCC Ma. G-band karyotype showed the structural abnormality of chromosome 3 and both components of clear cell RCC and RAT-like area revealed the identical VHL gene mutation. Finally, pathologists should pay attention to the presence of clear cell RCC focally resembling RAT.

Major consensus conferences held over a decade ago laid the foundations for the current (2004) WHO classification of renal carcinoma. Clear cell, papillary and chromophobe carcinomas account for 85-90% carcinomas seen in routine practice. The remaining 10-15% of carcinomas consist of rare sporadic and hereditary tumors, some of which had been long recognized, but many of which only emerged as distinct entities in the decade leading up to the WHO publication. Collecting-duct carcinoma is a rare, often lethal form of carcinoma. Medullary carcinoma associated with sickle cell trait, has emerged as a distinctive tumor showing some overlapping features with upper tract urothelial carcinoma. Mucinous tubular and spindle-cell carcinoma and tubulocystic carcinoma were earlier considered as patterns of low-grade collecting-duct carcinoma, but are now recognized as separate tumor entities. Carcinomas associated with somatic translocations of TFE3 and TFEB comprise a significant proportion of pediatric renal carcinomas. Oncocytoid renal carcinomas in neuroblastoma survivors was recognized as a unique tumor category in the WHO classification. Renal carcinoma associated with end-stage renal disease is now recognized as having distinct morphological patterns and behavior. In addition there is a group of rare recently described carcinomas, including clear cell papillary carcinoma, oncocytic papillary renal cell carcinoma, follicular renal carcinoma and leiomyomatous renal cell carcinoma. It behooves the surgical pathologist to not only be capable of diagnosing the common forms of renal cancer, but also to be aware of the rare types of renal carcinoma, many of which have emerged in recent years.