Molecular and morphologic interrogation has driven a much-needed reexamination of renal cell carcinoma (RCC). Indeed, the recently released 2016 World Health Organization classification now recognizes 12 distinct RCC subtypes, as well as several other emerging/provisional RCC entities. From a clinical perspective, accurate RCC classification may have important implications for patients and their families, including prognostic risk stratification, targeted therapeutics selection, and identification for genetic testing. In this review, we provide a conceptual framework for approaching RCC diagnosis and classification by categorizing RCCs as tumors with clear cytoplasm, papillary architecture, and eosinophilic (oncocytic) cytoplasm. The currently recognized 2016 World Health Organization classification for RCC subtypes is briefly discussed, including new diagnostic entities (clear cell papillary RCC, hereditary leiomyomatosis and RCC-associated RCC, succinate dehydrogenase–deficient RCC, tubulocystic RCC, and acquired cystic disease–associated RCC) and areas of evolving RCC classification, such as transcription elongation factor B subunit 1 (TCEB1)–mutated RCC/RCC with angioleiomyoma-like stroma/RCC with leiomyomatous stroma, RCC associated with anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement, thyroidlike follicular RCC, and RCC in neuroblastoma survivors. For each RCC subtype, relevant clinical, molecular, gross, and microscopic findings are reviewed, and ancillary studies helpful for its differential diagnosis are presented, providing a practical approach to modern RCC classification.

During the past several decades, considerable advances have been made in our understanding of the molecular pathogenesis of genitourinary tumors. In perhaps no tumor type has this been more evident than renal cell carcinoma (RCC), which has expanded from 4 subtypes in the 1997 Heidelberg classification1  to 12 recognized subtypes and several provisional entities in the recent 2016 World Health Organization (WHO) Classification of Tumours of the Urinary System and Male Genital Organs2,3  (Table). Although these insights have improved our ability to identify molecularly distinct RCC entities from within a group of morphologically heterogeneous tumors, RCC classification may also carry significant clinical implications for patients, including prognostic risk stratification, selection of targeted therapeutics, and identification for subsequent genetic testing (with associated familial ramifications). Herein, we present a conceptual approach to RCC diagnosis by categorizing RCC subtypes as tumors with clear cytoplasm, papillary architecture, or eosinophilic (oncocytic) cytoplasm. We also provide a morphologic, molecular, and taxonomic update to our evolving understanding of RCC, with current WHO annotations. Although many RCC subtypes can demonstrate overlapping features (as discussed below), these categories provide a practical framework for approaching differential diagnoses in RCC classification.

Summary of 2016 World Health Organization Updates for Renal Cell Carcinoma (RCC) Classification, Including Emerging/Provisional Entities

Summary of 2016 World Health Organization Updates for Renal Cell Carcinoma (RCC) Classification, Including Emerging/Provisional Entities
Summary of 2016 World Health Organization Updates for Renal Cell Carcinoma (RCC) Classification, Including Emerging/Provisional Entities

RCC WITH CLEAR CYTOPLASM

Tumors that demonstrate cytoplasmic clarity constitute most RCCs and, as such, present the most-common differential diagnosis for practicing pathologists. Despite increasing recognition of morphologically similar, but molecularly distinct, entities, clear cell RCC (CCRCC) remains the most-common subtype of RCC.3  Clear cell RCC shows a moderate male predilection, and although the age range is broad, it typically occurs as a solitary, solid, and/or cystic cortical mass in older patients. The classic morphologic features of CCRCC include abundant optically clear cytoplasm; nested, trabecular, and/or alveolar architecture; and a branching (“racemose”) network of thin-walled vessels (Figure 1, A). Although these classic features are seen in most low-grade tumors, the morphologic spectrum of high-grade CCRCC includes granular to eosinophilic cytoplasm, papillary/pseudopapillary architecture, and sarcomatoid/rhabdoid features. Clear cell RCC is associated with sporadic alterations in, and subsequent loss of heterozygosity of, the von Hippel-Lindau tumor suppressor (VHL) gene.4  Genetic predisposition to the development of CCRCC (termed VHL syndrome) is associated with germline VHL mutations, and patients with the VHL gene often develop numerous, bilateral CCRCCs beginning at an early age5 ; they may also develop paragangliomas, pancreatic tumors, hemangioblastomas, endolymphatic sac tumors, and papillary cystadenomas of the epididymis/broad ligament.6  Typically, CCRCC expresses pancytokeratin, epithelial membrane antigen, CD10, and carbonic anhydrase IX (CA-IX; diffuse, complete membranous staining; Figure 1, B); α-methylacyl-coenzyme A racemase (AMACR) expression is variable, CK7 expression is usually negative or focal, and CCRCC is typically negative for CD117 expression.3,7,8  From a practical standpoint, pancytokeratin, CA-IX, and CK7 are probably the most helpful immunohistochemical markers because strong, unambiguous staining of pancytokeratin and CA-IX, coupled with negative CK7 expression, is consistent with CCRCC.9  Pancytokeratin staining can be patchy or even absent in a subset of CCRCCs, especially high-grade CCRCCs; in these cases, the presence of an unequivocal low-grade component and/or strong and diffuse, complete membranous CA-IX expression supports the diagnosis of CCRCC. In general, CA-IX expression is retained in the sarcomatoid component of high-grade CCRCC, however, it may be patchy or negative, and patchy, membranous CA-IX expression may be seen adjacent to foci of necrosis in non-CCRCC tumors. If possible, in cases with equivocal CA-IX expression, additional tumor sampling to identify a low-grade or nonnecrotic area of tumor may be the key to diagnosis.

Figure 1.

Renal cell carcinoma (RCC) with clear cytoplasm. A and B, Clear cell RCC (CCRCC) example showing a predominantly nested architecture with scattered cytoplasmic eosinophilia and increased nuclear atypia; carbonic anhydrase IX (CA-IX) expression is strong and diffuse in a complete membranous pattern (B). C and D, Clear cell papillary RCC (CCPRCC) example shows a predominantly tubular architecture with linearly arranged, apically oriented, low-grade nuclei; CA-IX expression is strong and diffuse in a basolateral (“cuplike”) membranous pattern (D). E and F, MiT family translocation RCC (t-RCC) example with CCPRCC-like areas, including prominent papillary architecture and apically oriented, low-grade nuclei; the CA-IX immunostain is essentially negative (F), and subsequent fluorescent in situ hybridization demonstrated a TFE3 gene rearrangement (hematoxylin-eosin, original magnification ×200 [A, C, and E]; original magnification ×200 [B, D, and F].

Figure 1.

Renal cell carcinoma (RCC) with clear cytoplasm. A and B, Clear cell RCC (CCRCC) example showing a predominantly nested architecture with scattered cytoplasmic eosinophilia and increased nuclear atypia; carbonic anhydrase IX (CA-IX) expression is strong and diffuse in a complete membranous pattern (B). C and D, Clear cell papillary RCC (CCPRCC) example shows a predominantly tubular architecture with linearly arranged, apically oriented, low-grade nuclei; CA-IX expression is strong and diffuse in a basolateral (“cuplike”) membranous pattern (D). E and F, MiT family translocation RCC (t-RCC) example with CCPRCC-like areas, including prominent papillary architecture and apically oriented, low-grade nuclei; the CA-IX immunostain is essentially negative (F), and subsequent fluorescent in situ hybridization demonstrated a TFE3 gene rearrangement (hematoxylin-eosin, original magnification ×200 [A, C, and E]; original magnification ×200 [B, D, and F].

Prognostically, the 2 most important entities in the differential diagnosis of CCRCC are multilocular cystic renal neoplasm of low malignant potential and clear cell papillary RCC (CCPRCC) because these tumors have an indolent clinical course. Prior to the 2016 WHO classification, multilocular cystic renal neoplasm of low malignant potential was known as multilocular cystic RCC3; although these tumors share some molecular alterations with CCRCC,10  the name was changed to reflect the fact that, when correctly diagnosed and classified using strict morphologic criteria (as described below), there have been no reports of recurrence or metastasis with long-term clinical follow-up.1113  Multilocular cystic renal neoplasm of low malignant potential has a similar demographic profile to CCRCC and, as the name implies, is a grossly cystic cortical mass composed of numerous multiloculated cysts.13  These cysts are lined by cells that have clear cytoplasm and small, round nuclei with inconspicuous nucleoli (International Society of Urological Pathology nuclear grade 1 or 2); thin, fibrous septae separate the cysts and contain scattered “nonexpansile” nests of clear cells. There are no reliable immunophenotypic differences between a multilocular cystic neoplasm of low malignant potential and a low-grade, predominantly cystic CCRCC14 ; therefore, this differential diagnosis is resolved purely on morphologic grounds, with a key discriminating feature being the lack of expansile nests of tumor cells within fibrous septae of multilocular cystic neoplasm of low malignant potential. Before rendering a diagnosis of multilocular cystic neoplasm of low malignant potential, it is strongly recommended that all tissue from the specimen be submitted for evaluation, and in challenging cases, intramural or extramural consultation may be helpful.

Clear cell papillary RCC is a newly recognized RCC entity in the 2016 WHO classification.3  Although originally described in patients with end-stage renal disease,15  CCPRCC is now recognized to occur more commonly as a sporadic tumor in patients without significant intrinsic kidney disease.1618  CCPRCC has been reported across a large age range and, in contrast to RCC in general, has no significant sex predilection. Similar to multilocular cystic renal neoplasm of low malignant potential, CCPRCC has a very good prognosis, with essentially none to very rare reports of recurrence or metastasis with long-term clinical follow-up.19  Interestingly, in contrast to multilocular cystic renal neoplasm of low malignant potential, CCPRCC does not share common molecular alterations with CCRCC, suggesting that it is truly a distinct molecular entity from these tumor subtypes.16  Clear cell papillary RCC typically presents as a small, circumscribed, solid and/or cystic cortical mass. As the name implies, the tumor is composed of cells with optically clear cytoplasm and often demonstrates papillary architecture, although the morphologic spectrum of CCPRCC is relatively broad and comprises tumors with predominantly cystic, solid, acinar, and tubular architecture (Figure 1, C). One of the unifying morphologic features (and, often, key to diagnosis) for CCPRCC is the presence of apical- to mid-oriented, linearly-arranged, relatively low-grade nuclei; although there may be considerable overlap with low-grade CCRCC, the presence of areas with these characteristic morphologic features should prompt consideration of, and immunohistochemical workup for, CCPRCC. Fortunately, the immunophenotype of CCPRCC is distinctly different from CCRCC. Typically, CCPRCC is strongly and diffusely positive for CK7. Usually, CA-IX is also strongly and diffusely positive but shows a unique basolateral (“cuplike”) membranous staining pattern, with a relative lack of staining at the apical membrane (Figure 1, D); this is in contrast to CA-IX expression in CCRCC, which is strong and diffuse in a complete membranous pattern. In addition, in contrast to CCRCC, CCPRCC often shows high–molecular-weight cytokeratin (ie, CK34BE12) expression and is typically negative for AMACR and CD10 expression. Finally, CCPRCC-like tumors can rarely occur in patients with VHL, and although they may be morphologically similar to sporadic CCPRCC, according to one study,20  these tumors show the immunophenotype and molecular features of CCRCC.

From a genetic perspective, perhaps the most important entity in the differential diagnosis of CCRCC is MiT family translocation RCC (t-RCC) because these tumors have distinct molecular alterations from CCRCC and, therefore, may or may not respond to conventional vascular endothelial growth factor (VEGF)-based targeted therapies for CCRCC. In addition, differentiating between CCRCC and t-RCC may be essential for clinical trial enrollment of patients with advanced disease.21,22  Translocation RCC is associated with recurrent gene fusions involving transcription factor binding to IGHM enhancer 3 (TFE3; located on band Xp11) or transcription factor EB (TFEB; located on band 6p21), which are both members of the MiT family of transcription factors.2325  These tumors were formerly classified as Xp11 translocation carcinoma; however, the name has been changed in the 2016 WHO classification to reflect the possibility of non-TFE3 fusion partners in the MiT family (ie, TFEB).3  Although the age range is broad, in contrast to CCRCC, t-RCC most commonly occurs in younger patients26 ; indeed, it is the most-common RCC subtype in children,27  including a predisposition in those with prior cytotoxic chemotherapy and/or a history of prior malignancy.28  The morphologic spectrum of t-RCC is extremely varied, however, “classic” morphologic appearances of Xp11- and t(6;11)-associated t-RCC have been described23 : Xp11-associated t-RCC is composed of tumor cells with abundant pale-to-granular (eosinophilic) cytoplasm and large, irregular nuclei with prominent nucleoli lining papillary/pseudopapillary structures with conspicuous, admixed psammomatous calcifications, whereas t(6;11)-associated t-RCC has a biphasic appearance, including large cells with clear-to-granular (eosinophilic) cytoplasm and small cells with eosinophilic cytoplasm and hyperchromatic nuclei within basement-membranelike material. The varied morphologic spectrum of t-RCC, however, cannot be understated and includes tumors showing areas of overlap with common RCC subtypes, including CCRCC, RCC with eosinophilic (oncocytic) cytoplasm, and papillary RCC (PRCC). In fact, recent studies describe Xp11-associated t-RCC demonstrating morphologic overlap with CCPRCC29,30  (Figure 1, E). Therefore, a high level of suspicion for t-RCC is appropriate in children and younger patients, as well as in older patients who have tumors with unusual or mixed morphologies. Immunohistochemistry may be helpful in the workup of tumors for which the differential diagnosis includes t-RCC because these tumors are generally negative for, or show only patchy expression of, epithelial markers (ie, pancytokeratin, epithelial membrane antigen, among others). In addition, t-RCC is typically negative for CA-IX (Figure 1, F) and shows variable expression of melanocytic markers (ie, HMB-45, Melan-A, among others) and the osteoclastic protein cathepsin K.21  Although immunohistochemistry may be useful as part of the initial workup, fluorescence in situ hybridization for TFE3 and/or TFEB rearrangements is the most sensitive and specific method to confirm the diagnosis of t-RCC.22 

Finally, several other RCC entities with clear cells have been described, including transcription elongation factor B subunit 1 (TCEB1)–mutated RCC, RCC with leiomyomatous stroma, and RCC with angioleiomyoma-like stroma.3133  These tumors appear to show some overlapping morphologic and immunohistochemical features of CCRCC and CCPRCC but do not share common molecular alterations with CCRCC. TCEB1-mutated RCCs harbor recurrent hotspot mutations in the TCEB1 gene and were identified as tumors without VHL alterations in The Cancer Genome Atlas CCRCC data set.31  Although only a few TCEB1-mutated RCC cases have been described, they appear to be circumscribed tumors composed of cells with abundant clear cytoplasm showing varied architectural patterns and arranged in multiple, distinct nodules with intervening thick fibromuscular bands; these tumors typically express CK7 (patchy to moderate) and CA-IX (diffuse, complete membranous staining), show variable CD10 expression, and are negative for high–molecular-weight cytokeratin expression. Similar to TCEB1-mutated RCC, RCC with leiomyomatous stroma and RCC with angioleiomyoma-like stroma are recently described RCC entities with only a few reported cases32,33 ; however, these tumors appear to show some overlapping morphologic features with each other, as well as with TCEB1-mutated RCC. Both RCC with leiomyomatous stroma and RCC with angioleiomyoma-like stroma are circumscribed tumors composed of cells with voluminous clear-to-granular (eosinophilic) cytoplasm showing varied architectural patterns and embedded in prominent fibromuscular stroma. In addition, RCC with angioleiomyoma-like stroma appears to have an intimately associated proliferation of slitlike endothelial cells (imparting an angioleiomyoma-like appearance). Whether these 3 tumor types represent distinct molecular entities or comprise a morphologic spectrum of TCEB1-mutated RCC is currently unknown and awaits further interrogation.

RCC WITH PAPILLARY ARCHITECTURE

The phenomenon that papillary architecture is not unique to PRCC is well recognized. Indeed, RCC with papillary architecture comprise a diverse set of tumors with distinct morphology, molecular alterations, and clinical outcome, and these tumors present a frequent differential diagnosis for practicing pathologists. Papillary RCC is the most common type of RCC with papillary architecture and the second most common RCC subtype overall34 ; it has a similar age distribution as CCRCC and typically presents as one or more cortically based, solid and cystic masses. Grossly, PRCC is usually well circumscribed and encapsulated and has a friable appearance with central necrosis and hemorrhage. Historically, PRCC has been subclassified into 2 morphologic subtypes (type 1 and type 2),35,36  although recent molecular studies have established that tumors previously described as type 2 PRCC, in fact, comprise a heterogeneous group of molecularly distinct RCC subtypes (see below).37  Type 1 PRCC is typically composed of cuboidal cells with moderate amphophilic cytoplasm, slightly enlarged and irregular nuclei, and variably prominent nucleoli, lining papillary structures with true fibrovascular cores that frequently contain foamy histiocytes (Figure 2, A), although tumor cells can show clear or oncocytic cytoplasm and can demonstrate solid papillary growth.35,36  These tumors typically strongly and diffusely express CK7 and AMACR and are essentially uniformly negative for CA-IX expression (except for focal positivity in the papillary tips). CD10 expression can be variable but is usually positive. From a molecular standpoint, type 1 PRCCs often show chromosome 7 and/or 17 gains, and somatic-activating mutations in the MET oncogene are present in a subset of sporadic cases (approximately 15%). Genetic predisposition to the development of type 1 PRCC, termed hereditary papillary RCC syndrome, is associated with germline MET mutations, and patients with hereditary papillary RCC often develop numerous (hundreds) of bilateral type 1 PRCCs.38,39  In general, type 1 PRCC has a more favorable prognosis than CCRCC; a subset of patients, however, has high-grade and/or locally advanced tumors, and a subset of tumors may metastasize. Papillary adenomas are unencapsulated renal tumors that are morphologically and immunophenotypically identical to PRCC. In the past, a cutoff of 0.5 cm was used to distinguish between papillary adenoma and PRCC; recent data with long-term follow-up, however, indicate that tumors up to 1.5 cm with low-grade nuclei (International Society of Urological Pathology nuclear grades 1 or 2) have completely indolent behavior.40  Therefore, the 2016 WHO classification has increased the cutoff for PRCC to greater than 1.5 cm.3  Type 2 PRCC, on the other hand, is typically composed of cells with abundant eosinophilic (oncocytic) cytoplasm, large pleomorphic pseudostratified nuclei, and prominent nucleoli, lining papillary structures with true fibrovascular cores (with or without foamy histiocytes). Similar to type 1 PRCC, type 2 PRCC typically expresses AMACR and is negative for CA-IX expression, although CK7 expression is variable and may be completely negative. As previously mentioned, from a molecular standpoint, type 2 PRCC represents a heterogeneous group of molecularly distinct tumors and is currently considered to be a diagnosis of exclusion; other RCC entities with papillary architecture (ie, hereditary leiomyomatosis and RCC [HLRCC]–associated RCC, collecting duct carcinoma [CDC], among others) should be ruled out before rendering a diagnosis of type 2 PRCC.

Figure 2.

Renal cell carcinoma (RCC) with papillary architecture. A, Type 1 papillary RCC example with low-grade, cuboidal cells lining papillary structures with true fibrovascular cores containing foamy histiocytes. B, Mucinous tubular and spindle cell carcinoma example with epithelioid to spindled cells arranged in tubules within mucinous stroma. C, Hereditary leiomyomatosis and renal cell carcinoma–associated RCC (with corresponding fumarate hydratase [FH] immunohistochemistry in [D]) example with large, irregular nucleoli and prominent “inclusion-like,” orangiophilic macronucleoli with perinucleolar clearing. D, Cytoplasmic FH expression is lost by immunohistochemistry (retained in admixed blood vessels). E, Acquired cystic disease–associated RCC example with intracytoplasmic and/or intercytoplasmic lumina (cribriform/“sievelike” appearance) and intratumoral calcium oxalate crystals. F, Collecting duct carcinoma example with hobnail cells, enlarged irregular nuclei, and prominent nucleoli, arranged in infiltrating nests with stromal desmoplasia (hematoxylin-eosin, original magnification ×200 [A, B, C, E, and F]; original magnification ×200 [D]).

Figure 2.

Renal cell carcinoma (RCC) with papillary architecture. A, Type 1 papillary RCC example with low-grade, cuboidal cells lining papillary structures with true fibrovascular cores containing foamy histiocytes. B, Mucinous tubular and spindle cell carcinoma example with epithelioid to spindled cells arranged in tubules within mucinous stroma. C, Hereditary leiomyomatosis and renal cell carcinoma–associated RCC (with corresponding fumarate hydratase [FH] immunohistochemistry in [D]) example with large, irregular nucleoli and prominent “inclusion-like,” orangiophilic macronucleoli with perinucleolar clearing. D, Cytoplasmic FH expression is lost by immunohistochemistry (retained in admixed blood vessels). E, Acquired cystic disease–associated RCC example with intracytoplasmic and/or intercytoplasmic lumina (cribriform/“sievelike” appearance) and intratumoral calcium oxalate crystals. F, Collecting duct carcinoma example with hobnail cells, enlarged irregular nuclei, and prominent nucleoli, arranged in infiltrating nests with stromal desmoplasia (hematoxylin-eosin, original magnification ×200 [A, B, C, E, and F]; original magnification ×200 [D]).

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, relatively recently described RCC subtype, which may demonstrate significant morphologic and immunophenotypic overlap with type 1 PRCC.4143  Mucinous tubular and spindle cell carcinoma occurs across a broad age range and usually presents as a solid, well-circumscribed, solitary cortical mass; in contrast to CCRCC and PRCC, however, MTSCC shows a moderate female predilection. Typically, MTSCC is composed of bland epithelioid-to-spindled cells with moderate, pale-to-granular (eosinophilic) cytoplasm, small slightly irregular nuclei, and inconspicuous nucleoli, arranged predominantly in tubules within variable mucinous stroma (Figure 2, B), although tumors with focal papillary architecture, conspicuous high-grade nuclei, and sarcomatoid features have been described. Similar to type 1 PRCC, MTSCCs usually strongly and diffusely express CK7 and AMACR; although these tumors typically are negative for CD10 expression, lack of CD10 staining alone is not diagnostic of MTSCC. Despite overlapping morphologic and immunophenotypic features with type 1 PRCC, recent molecular interrogation of MTSCC has documented characteristic chromosomal losses, recurrent somatic mutations in Hippo signaling pathway genes, and lack of chromosome 7/17 gains and MET mutations, indicating that MTSCC is indeed a molecularly distinct RCC subtype.44,45  Finally, similar to type 1 PRCCs, MTSCCs are typically indolent tumors, however, a small subset of patients with MTSCC may develop metastases.

Hereditary leiomyomatosis and RCC–associated RCC is a newly recognized RCC entity in the 2016 WHO classification.3  It is a relatively uncommon RCC subtype that has morphologic and immunophenotypic overlap with type 2 PRCC.46  Hereditary leiomyomatosis and RCC is associated with germline mutations in the Krebs cycle gene fumarate hydratase (FH), which predisposes patients to the development of multiple characteristic tumors, including cutaneous and uterine leiomyomata and RCCs.47,48  Although HLRCC-associated RCC occurs across a large age range, it may present with advanced disease in relatively young patients. In contrast to some other syndrome-associated RCC, HLRCC-associated RCC often occurs as a single, solid, and/or cystic mass, and even relatively small lesions may be associated with metastatic disease. Hereditary leiomyomatosis and RCC–associated RCC typically is composed of cells with abundant eosinophilic cytoplasm, large irregular nucleoli, and prominent “inclusion-like” orangiophilic macronucleoli with perinucleolar clearing, and lining papillary structures with true fibrovascular cores without foamy histiocytes (Figure 2, C), although tubular, acinar, cystic, and/or solid growth patterns may predominate.46  The morphologic spectrum of these tumors is expanding, however, because recent studies have documented cases of HLRCC-associated RCC with low-grade oncocytic morphology,49  as well as tubulocystic-like morphology with dedifferentiated features.50  The immunophenotype of these tumors has not been well delineated, but HLRCC-associated RCCs are typically negative for CK7, CK20, and high–molecular-weight cytokeratin.46  Recently, immunohistochemistry for FH and S-(2-succino)cysteine have been shown to be useful for detecting HLRCC-associated RCCs.5153  In these tumors, loss of heterozygosity at the FH locus results in loss of cytoplasmic FH protein expression in most cases (Figure 2, D); in addition, loss of the FH protein function leads to accumulation of aberrantly succinated proteins, which can be detected as increased cytoplasmic/nuclear S-(2-succinyl)cysteine expression.54  Together, these 2 immunostains have a high sensitivity and specificity for detecting HLRCC-associated RCCs.51,52  In general, HLRCC-associated RCC has an aggressive clinical course, with frequent metastasis and subsequent death.48  As such, the identification of patients with HLRCC-associated RCC is important because these patients (and their families) should undergo genetic evaluation and counseling. Therefore, it is important to have a high sensitivity for recognizing possible cases of HLRCC-associated RCC.

Acquired cystic disease (ACD)–associated RCC is a newly recognized RCC entity in the 2016 WHO classification.3  It is the most-common RCC subtype in patients with end-stage renal disease and ACD (usually in the setting of long-term hemodialysis or peritoneal dialysis)15,55 ; although CCPRCC and PRCC are also common, ACD-associated RCC accounts for more than one-third of tumors in these patients.15  These tumors are usually well circumscribed and cystic and/or solid, and they are often multifocal and sometimes bilateral. Typically, ACD-associated RCC is composed of cells with abundant eosinophilic cytoplasm, large irregular vesicular nuclei, and prominent nucleoli, arranged in several architectural patterns, including papillary, tubular, acinar, and solid, although tumors with sarcomatoid and/or rhabdoid features have been described.15,56  The unifying characteristic features, however, are the presence of intracytoplasmic and/or intercytoplasmic lumina, which bestow a cribriform/sievelike appearance, and intratumoral calcium oxalate crystal deposition (Figure 2, E). The molecular basis for ACD-associated RCC is not fully understood, however, these tumors often show variable chromosomal gains, including chromosomes 7 and 17 (which are more classically associated with PRCC).5658  Indeed, ACD-associated RCC can show overlapping morphologic and immunophenotypic features with PRCC, and although these tumors frequently express AMACR and CD10, ACD-associated RCC is usually negative for CK7 expression.5658  In general, ACD-associated RCC is an indolent tumor; however, a subset of patients with ACD-associated RCC may develop metastatic disease.15 

Collecting duct carcinoma is an uncommon RCC subtype that arises from the distal collecting system of the kidney and has an aggressive clinical course.5961  Although the age range is large, these tumors usually occur in older patients, and there is a slight male predominance. Typically, CDC presents as a large, medullary-based, poorly defined, firm, white mass, with frequent extrarenal extension and regional lymph node involvement. These tumors are typically composed of cuboidal-to-hobnail cells with moderate eosinophilic cytoplasm, enlarged irregular nuclei, and prominent nucleoli, arranged in infiltrating nests with prominent tubular and acinar appearance, frequent intraluminal mucin, focal papillary architecture, and stromal desmoplasia (Figure 2, F), and adjacent renal intratubular dysplasia may be present. Usually, CDC expresses CK7 and high–molecular-weight cytokeratin and is typically negative for AMACR and CD10 expression.7,8,62,63  Given the broad differential diagnosis for CDC, which includes type 2 PRCC, HLRCC-associated RCC, invasive urothelial carcinoma, primary adenocarcinoma of the renal pelvis, metastatic adenocarcinoma, and renal medullary carcinoma (RMC), the 2016 WHO classification recommends adhering to the following diagnostic criteria: a medullary location, tubular morphologic features, presence of desmoplastic stroma, high-grade cytology, an infiltrative growth pattern, and, importantly, the absence of other RCC subtypes.3  Renal medullary carcinoma is a rare, aggressive RCC subtype, which has many features that overlap with CDC, but it occurs in younger patients with hemoglobinopathies (most commonly sickle cell trait), and these tumors often have an abundant associated neutrophil-predominant inflammatory infiltrate.64,65  Renal medullary carcinoma is strongly associated with biallelic inactivation of SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily b, member 1 (SMARCB1; also known as INI-1),66  and loss of nuclear INI-1 expression and corresponding nuclear overexpression of POU class 5 homeobox 1 (POU5F1; also known as OCT3/4) is characteristic of RMC.62,64,67,68  Interestingly, similar to type 2 PRCC, recent molecular profiling indicates that CDC likely represents a molecularly heterogeneous group of tumors with overlapping morphologic features, and a subset of cases shows alterations in FH or SMARCB1/INI-1.69  Renal cell carcinoma with CDC-like features and accompanying cytoplasmic FH loss by immunohistochemistry should be classified as either FH-deficient RCC or HLRCC-associated RCC (after constitutional genotyping for FH aberrations) because CDC-like morphology has been reported in a few patients with HLRCC. Similarly, given the strong association between RMC and SMARCB1/INI-1 inactivation, tumors with CDC-like morphology and nuclear INI-1 loss by immunohistochemistry should be noted,70  and the possibility of a clinically occult hemoglobinopathy should be raised with the patient's treating physician.64  Regardless, both CDC and RMC have dismal prognoses, with frequent metastatic dissemination and subsequent death.61,71,72 

Renal cell carcinoma associated with anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement is a provisional RCC entity in the 2016 WHO classification.3  ALK gene rearrangement is present in approximately one-half of anaplastic large cell lymphomas and is the most common gene fusion in lung cancer.73,74  Interestingly, ALK gene rearrangements have been very rarely identified in RCC (<1% of all tumors) and occur in children and adults with and without hemoglobinopathy.7580  ALK-rearranged RCCs in young patients with hemoglobinopathy often show a medullary location, are composed of spindled-to-polygonal cells with eosinophilic cytoplasm and intracytoplasmic vacuoles, and are positive for ALK expression (with concomitant retained nuclear INI-1 staining). At the genomic level, these tumors typically harbor ALK fusions with vinculin (VCL), whereas other reported ALK-rearranged RCCs show variable fusion partners (and morphology). Because of their relative rarity, there are limited data regarding the natural history and overall prognosis of ALK-rearranged RCCs; however, tumors with VCL-ALK rearrangement may demonstrate relatively indolent clinical behavior.76  Crizotinib, an ALK protein inhibitor, has been approved by the US Food and Drug Administration for the treatment of patients with ALK-rearranged lung cancer73  and may be helpful therapeutically in metastatic cases of RCC associated with ALK gene rearrangement.

Finally, several RCC subtypes, including CCRCC, t-RCC, and CCPRCC, can show focal-to-diffuse papillary architecture. In these cases, the key to diagnosis is recognition of a conventional component in other areas of the tumor, judicious use of immunohistochemistry, examination of the gross specimen, and/or clinicopathologic correlation. For example, high-grade CCRCC and t-RCC will often show papillary/pseudopapillary features and, therefore, may enter the differential diagnosis of type 2 PRCC. However, CCRCC typically shows strong and diffuse CA-IX expression (in a complete membranous pattern), and t-RCC often expresses melanocytic markers and will usually be negative for epithelial markers. Similarly, although type 1 PRCC may have cells with cytoplasmic clearing,36  it will not have the typical morphologic appearance or CA-IX expression pattern found in CCPRCC.

RCC WITH EOSINOPHILIC (ONCOCYTIC) CYTOPLASM

Although relatively less common than RCC with clear cytoplasm or RCC with papillary architecture, RCC with eosinophilic (oncocytic) cytoplasm is nonetheless an important differential diagnosis for practicing pathologists, and these tumors comprise a diverse group of renal neoplasms with unique morphology, molecular alterations, and clinical outcomes. Chromophobe renal cell carcinoma (ChRCC) is the most-common type of RCC with eosinophilic cytoplasm and the third most-common RCC subtype overall81,82 ; it can occur across a large age range but is most frequently seen in relatively older patients, and it usually presents as a large, well-circumscribed, unencapsulated, solid, tan-brown mass with or without a central scar. Classically, ChRCC is composed of cells with abundant pale-to-eosinophilic cytoplasm, enlarged irregular (“raisinoid”) nuclei with compact chromatin, wrinkled nuclear membranes, conspicuous perinuclear clearing (ie, “koilocytic atypia”), frequent binucleation, and variably prominent nucleoli, arranged in large nests and trabeculae with an associated incomplete branching network of thin-walled vessels (Figure 3, A). In contrast, the eosinophilic variant of ChRCC shows a predominance of cells with moderate eosinophilic cytoplasm and slightly enlarged, irregular nuclei arranged in small, tightly packed nests or acini; the “raisinoid” nuclei and perinuclear clearing typically seen in classic ChRCC are not usually prevalent but are generally seen focally in the eosinophilic variant (Figure 3, B). Chromophobe RCC strongly and diffusely expresses CD117 in a membranous pattern and is negative for CA-IX expression; CK7 expression is typically diffuse in classic ChRCC but may be patchy, focal, or even negative in the eosinophilic variant.7,8,83,84  Classic ChRCC is associated with multiple chromosomal losses, and recent molecular data indicate frequent mutations in tumor protein p53 (TP53) and phosphatase and tensin homolog (PTEN), as well as telomerase reverse transcriptase (TERT) promoter alterations85,86 ; the molecular basis of the eosinophilic variant has not been fully explored, but these tumors typically show fewer chromosomal losses.85  Genetic predisposition to the development of ChRCC, particularly so-called hybrid oncocytic/chromophobe tumors that show overlapping features of oncocytoma and ChRCC, is seen in patients with Birt-Hogg-Dubé syndrome, which is associated with germline folliculin (FLCN) mutations; these patients often develop multiple, bilateral, oncocytic renal neoplasms, including ChRCC, hybrid oncocytic/chromophobe tumors, and oncocytoma, and may also have characteristic skin (ie, fibrofolliculomas, trichodiscomas) and lung (ie, subpleural cystic blebs) findings.87,88  Typically, ChRCC has better overall prognosis than other common renal tumors, including CCRCC and PRCC, although a small subset of tumors may show sarcomatoid features and/or metastasize.81,82 

Figure 3.

Renal cell carcinoma (RCC) with eosinophilic (oncocytic) cytoplasm. A, Classic chromophobe RCC (ChRCC) example with abundant pale-to-eosinophilic cytoplasm, irregular (“raisinoid”) nuclei, and perinuclear clearing (ie, “koilocytic atypia”), arranged in large trabeculae with an associated incomplete branching vascular network. B, Eosinophilic variant of ChRCC example with eosinophilic cytoplasm and subtle perinuclear clearing, arranged in small, tightly packed nests and acini. C, Succinate dehydrogenase–deficient RCC (with corresponding SDHB immunohistochemistry in [D]) example with “neuroendocrine-like” nuclei and eosinophilic cytoplasm with scattered, pale-to-eosinophilic inclusions. D, Cytoplasmic SDHB expression is lost by immunohistochemistry (retained in admixed blood vessels). E, Tubulocystic RCC example with hobnail cells with eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli, and lining variably sized tubules and cysts. F, Thyroidlike follicular carcinoma of the kidney showing eosinophilic cytoplasm and forming follicular structures with intraluminal secretions (reminiscent of follicular thyroid tumors) (hematoxylin-eosin, original magnification ×200 [A, B, C, E, and F]; original magnification ×200 [D].

Figure 3.

Renal cell carcinoma (RCC) with eosinophilic (oncocytic) cytoplasm. A, Classic chromophobe RCC (ChRCC) example with abundant pale-to-eosinophilic cytoplasm, irregular (“raisinoid”) nuclei, and perinuclear clearing (ie, “koilocytic atypia”), arranged in large trabeculae with an associated incomplete branching vascular network. B, Eosinophilic variant of ChRCC example with eosinophilic cytoplasm and subtle perinuclear clearing, arranged in small, tightly packed nests and acini. C, Succinate dehydrogenase–deficient RCC (with corresponding SDHB immunohistochemistry in [D]) example with “neuroendocrine-like” nuclei and eosinophilic cytoplasm with scattered, pale-to-eosinophilic inclusions. D, Cytoplasmic SDHB expression is lost by immunohistochemistry (retained in admixed blood vessels). E, Tubulocystic RCC example with hobnail cells with eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli, and lining variably sized tubules and cysts. F, Thyroidlike follicular carcinoma of the kidney showing eosinophilic cytoplasm and forming follicular structures with intraluminal secretions (reminiscent of follicular thyroid tumors) (hematoxylin-eosin, original magnification ×200 [A, B, C, E, and F]; original magnification ×200 [D].

Succinate dehydrogenase (SDH)–deficient RCC is a newly recognized RCC entity in the 2016 WHO classification.3  It occurs predominantly in patients with germline mutations in one of the SDH genes: SDHA, SDHB (most commonly), SDHC, and SDHD. These tumors usually arise in younger patients but have a large age range, and they may present multifocally and/or bilaterally as well-circumscribed, solid, tan-brown masses.8991  Patients with germline mutations in 1 of the 4 SDH genes may also have paragangliomas and gastrointestinal stromal tumors. Succinate dehydrogenase-deficient RCC is typically composed of cells with moderate eosinophilic cytoplasm, variably sized round nuclei with even (“neuroendocrine-like”) chromatin, and inconspicuous nucleoli arranged in solid sheets of small nests with numerous admixed intratumoral mast cells and occasional entrapped benign renal tubules, although high-grade cytologic features have been described rarely. The characteristic feature, however, is the presence of pale-to-eosinophilic cytoplasmic vacuoles and rare-to-occasional cytoplasmic inclusions (Figure 3, C). Succinate dehydrogenase–deficient RCC is typically negative for CD117 and CK7 expression, which along with the morphology helps distinguish it from ChRCC. Immunohistochemistry with SDHA and SDHB is useful (and, perhaps, even required) for the diagnosis of SDH-deficient RCC; loss of cytoplasmic SDHA staining indicates a mutation in SDHA, whereas loss of cytoplasmic SDHB staining signifies a mutation in either SDHB, SHDC, or SDHD (Figure 3D). Most SDH-deficient RCCs are low-grade neoplasms with an indolent clinical course, however, a distinct subset of patients with dedifferentiation or presence of coagulative necrosis may develop metastatic disease and/or late recurrences. Genetic evaluation and counseling should be recommended for all patients with SDH-deficient RCC.

Tubulocystic RCC is a newly recognized RCC entity in the 2016 WHO classification.3  It is a rare, often incidentally discovered, RCC subtype, which typically occurs in older patients and shows a slight male predominance.9294  These tumors usually present as a solitary, well-circumscribed renal masses and have a characteristic multicystic (“spongelike”) gross appearance. Classically, tubulocystic RCC is composed of cuboidal-to-hobnail cells with abundant eosinophilic cytoplasm, enlarged irregular vesicular nuclei, and prominent nucleoli (International Society of Urological Pathology nuclear grade 3), lining variably sized tubules and cysts with intervening fibrotic stroma (Figure 3, E), although admixed areas of morphologically reminiscent of PRCC may be present in a subset of cases.94,95  Similar to PRCC, tubulocystic RCC typically expresses CK7, AMACR, and CD10 and often demonstrates gains of chromosomes 7 and 17.94  Overall, tubulocystic RCC is an indolent tumor, with only rare reports of metastasis.92  Recent data indicate that tubulocystic-like morphology may be seen in patients with HLRCC-associated RCC,50,51  and cases with dedifferentiated tubulocystic morphology may actually represent a subset of HLRCC-associated RCC.50,96 

Thyroidlike follicular carcinoma of the kidney is a provisional RCC entity in the 2016 WHO classification.3  These rare tumors are typically well circumscribed and encapsulated and are composed of cells with medium eosinophilic cytoplasm that form follicular structures with intraluminal secretions (reminiscent of follicular thyroid tumors) (Figure 3, F).97  Thyroidlike follicular carcinoma of the kidney is generally positive for PAX8, and although it does not usually express PAX2, the absence of thyroid transcription factor-1 and thyroglobulin expression helps to rule out metastatic thyroid carcinoma. Little is known about the molecular pathogenesis of these tumors, and only very rare metastases have been reported.

Renal cell carcinoma in neuroblastoma (NB) survivors is a provisional RCC entity in the 2016 WHO classification.3  Patients with NB have a well-documented increased risk of RCC compared with the general population,98  and tumors that arise in these patients demonstrate diverse morphologic features, including: (1) oncocytoid appearance, and (2) an appearance similar to the classic morphology of Xp11 or t(6;11) t-RCC.99,100  Although our understanding of the pathogenesis of these tumors is still evolving, fluorescence in situ hybridization demonstrates TFE3 or TFEB rearrangements in a subset of tumors with morphologic similarity to t-RCC, suggesting that at least some RCC in NB survivors may be therapy-related.

Finally, several RCC subtypes, including CCRCC, t-RCC, PRCC, HLRCC-associated RCC, and ACD-associated RCC, can show focal-to-diffuse eosinophilic (oncocytic) cytoplasm. Similar to RCC with papillary architecture, in these cases, the key to diagnosis is a multifaceted approach that involves correlation of available clinical data with gross, microscopic, and immunohistochemical findings. For example, high-grade CCRCC, t-RCC, and PRCC (including HLRCC-associated RCC) may enter the differential diagnosis of CDC. Strong and diffuse CA-IX expression (in a complete, membranous pattern) with concomitant lack of CK7 expression is consistent with CCRCC, whereas lack of epithelial markers and expression of melanocytic markers suggests t-RCC. In some cases, type 2 PRCC may be difficult to distinguish from CDC; the anatomic location and gross appearance may be clues to diagnosis, and FH immunohistochemistry may be helpful to rule out HLRCC-associated RCC. Finally, although ACD-associated RCC may enter the differential diagnosis of some RCCs with eosinophilic cytoplasm (ie, tubulocystic RCC), the characteristic clinical setting and morphologic features (ie, sievelike cytoplasmic lumina and calcium oxalate crystals) should facilitate its distinction from other tumors.

CONCLUSIONS

The expanding number of recognized and emerging/provisional RCC entities in the 2016 WHO classification requires surgical pathologists (both general and subspecialty) to integrate clinical, radiologic, gross, and microscopic findings to successfully navigate challenging differential diagnoses in RCC classification because accurate classification has important clinical implications for patients and their families. In routine clinical practice, categorizing RCC subtypes as tumors with clear cytoplasm, papillary architecture, and eosinophilic (oncocytic) cytoplasm may provide a conceptual framework for approaching RCC with unusual morphologic features.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.

Competing Interests

Presented in part at the New Frontiers in Pathology meeting; University of Michigan; October 22–24, 2015; Ann Arbor, Michigan.