Residency · Residency · Pathology

Renal Tumor Pathology

Overview

The WHO classification of renal tumors has expanded dramatically with the recognition of molecularly defined entities. Clear cell renal cell carcinoma remains the most common, but emerging entities defined by gene fusions, metabolic enzyme deficiency, and specific molecular alterations have transformed the diagnostic landscape. Accurate classification has direct implications for prognosis and therapy selection.

Clear Cell Renal Cell Carcinoma (ccRCC)

General Features

Clear cell RCC is the most common subtype, accounting for approximately 70 to 75 percent of all renal cell carcinomas. It is driven by VHL gene inactivation at chromosome 3p25, with biallelic loss through mutation, deletion, or methylation occurring in over 90 percent of cases. VHL loss leads to HIF accumulation, which drives VEGF and PDGF expression and promotes angiogenesis. The tumor is associated with von Hippel-Lindau syndrome (germline VHL mutation), which presents with bilateral or multifocal ccRCC, hemangioblastomas, pheochromocytoma, and pancreatic neuroendocrine tumors.

Histology

The architecture consists of nests, sheets, and alveolar or acinar arrangements of cells with clear cytoplasm, a result of glycogen and lipid that dissolve during tissue processing. A prominent delicate sinusoidal vasculature creates a characteristic "chicken-wire" capillary network. Architectural patterns include solid, alveolar, acinar, tubular, and cystic configurations. In high-grade areas the cytoplasm may become eosinophilic and granular. Rhabdoid and sarcomatoid differentiation are aggressive features that can develop in any case.

IHC Profile

The immunohistochemical profile includes positivity for PAX8, CA-IX (diffuse membranous, box-like pattern), CD10, and vimentin. CK7 is usually negative, though focal positivity may occur in low-grade tumors. CA-IX with strong diffuse membranous staining is the most sensitive marker for ccRCC.

Grading (WHO/ISUP)

The WHO/ISUP nucleolar grading system assigns Grade 1 when nucleoli are inconspicuous at 400x, Grade 2 when nucleoli are visible at 400x but inconspicuous at 100x, Grade 3 when nucleoli are visible at 100x, and Grade 4 when there is extreme pleomorphism, sarcomatoid or rhabdoid differentiation, or tumor giant cells. This grading system applies to ccRCC and papillary RCC but uses a different system for chromophobe.

Papillary Renal Cell Carcinoma (pRCC)

General Features

Papillary RCC is the second most common subtype at approximately 10 to 15 percent of cases. Characteristic cytogenetic findings include gains of chromosomes 7 and 17 with loss of Y. MET mutations are found in hereditary papillary RCC (Type 1), while FH loss and CDKN2A deletion occur in some Type 2 tumors.

Histologic Subtypes

Type 1 papillary RCC features papillae lined by small cells with scant pale cytoplasm arranged in a single layer, with foamy macrophages in papillary cores and psammoma bodies; it carries a better prognosis. Type 2 shows papillae lined by large cells with abundant eosinophilic cytoplasm, pseudostratified nuclei, and higher nuclear grade, conferring a worse prognosis. Type 2 is now recognized as a heterogeneous category that likely represents multiple distinct entities.

IHC Profile

The immunoprofile includes PAX8, CK7 (especially strong in Type 1), AMACR, CD10, and vimentin positivity. CA-IX is negative or only focal, which distinguishes papillary RCC from the diffuse pattern seen in ccRCC.

Chromophobe Renal Cell Carcinoma

General Features

Chromophobe RCC accounts for approximately 5 percent of renal cell carcinomas and arises from intercalated cells of the collecting duct. It exhibits multiple chromosomal losses involving chromosomes 1, 2, 6, 10, 13, 17, and 21. It is associated with Birt-Hogg-Dube syndrome, caused by germline FLCN mutation, which predisposes to chromophobe RCC, oncocytoma, fibrofolliculomas, and lung cysts.

Histology

The tumor is composed of large polygonal cells with prominent cell borders giving a "plant cell-like" appearance. The cytoplasm is pale and finely reticular with perinuclear clearing (halo). Binucleation is common, and the nuclei show a characteristic raisinoid wrinkling and irregularity. Hale colloidal iron stain demonstrates diffuse cytoplasmic staining, which helps distinguish chromophobe from oncocytoma. An eosinophilic variant exists that may closely mimic oncocytoma.

IHC Profile

Chromophobe RCC is positive for PAX8, KIT (CD117), CK7 (diffuse), and E-cadherin. CA-IX is negative. Vimentin is negative, which helps distinguish it from ccRCC.

Prognosis

The prognosis is generally excellent and metastasis is uncommon. Sarcomatoid differentiation is rare but confers a poor prognosis when present.

Oncocytoma

General Features

Oncocytoma is a benign renal neoplasm accounting for approximately 5 percent of renal tumors. It must be distinguished from chromophobe RCC (eosinophilic variant) and eosinophilic ccRCC. On gross examination it may show a central stellate scar, though this feature is not always present.

Histology

The tumor is composed of round, uniform cells with abundant granular eosinophilic cytoplasm reflecting their mitochondria-rich nature. Architecture is nested, organoid, or tubulocystic. Nuclei are round and regular, though degenerative nuclear atypia may occur and should not be graded. There is no necrosis, no mitotic activity, and no vascular invasion. The stroma is characteristically edematous or myxoid.

IHC Profile

Oncocytoma is positive for PAX8 and CD117, and negative for vimentin. The key distinguishing marker is CK7: diffuse CK7 positivity indicates chromophobe RCC, while negative or only rare focal CK7 staining supports oncocytoma.

Emerging/Molecularly Defined Entities

TFE3-Rearranged RCC (Xp11 Translocation RCC)

This MiT family translocation tumor involves various gene partners (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3) and occurs in younger patients, where it may mimic ccRCC or papillary RCC. It shows papillary architecture with clear to eosinophilic cells and psammoma bodies. TFE3 IHC demonstrates strong nuclear staining, with break-apart FISH available for confirmation. The tumor is positive for PAX8 and CD10, with cathepsin K positivity in some fusions, and is CK7-negative with variable melan-A expression.

TFEB-Altered RCC

TFEB-altered RCC involves TFEB amplification or TFEB::VEGFA fusion. It shows a biphasic pattern with large eosinophilic cells nested around smaller cells. TFEB IHC is positive in nuclei. Melanocytic markers are expressed, including HMB-45 and melan-A.

FH-Deficient RCC (Hereditary Leiomyomatosis and RCC)

This aggressive tumor results from fumarate hydratase (FH) loss due to germline FH mutation in the HLRCC syndrome. It often presents at advanced stage. The morphology is variable but characteristically papillary with prominent eosinophilic nucleoli showing perinucleolar clearing, described as "cherry-red" nucleoli with a halo, which is the hallmark feature. FH IHC shows loss of cytoplasmic staining, and 2SC (S-(2-succinyl)cysteine) IHC is positive due to accumulated substrate, representing the most sensitive and specific marker. Recognition is critical because screening of family members for FH mutations is essential and active surveillance is contraindicated; immediate surgical excision is required.

SDH-Deficient RCC

SDH-deficient RCC results from SDH subunit mutations (SDHB most commonly). It shows solid, nested architecture with eosinophilic cytoplasm containing flocculent cytoplasmic inclusions. SDHB IHC demonstrates loss of granular cytoplasmic staining. Behavior is indolent in most cases though metastatic potential exists. Family members should be screened for paraganglioma and pheochromocytoma.

Clear Cell Papillary RCC (now: Clear Cell Papillary Renal Cell Tumor)

This entity has been reclassified as a tumor of low malignant potential rather than a carcinoma. It shows papillary or tubular architecture with clear cells whose nuclei are aligned away from the basement membrane in a characteristic linear nuclear arrangement. It is diffusely CK7-positive and CA-IX-positive, but the CA-IX pattern is cup-shaped and non-circumferential, distinguishing it from the box-like pattern of ccRCC. There are no VHL alterations or 3p loss. Prognosis is excellent and conservative management may be appropriate.

Grading and Staging Essentials

The WHO/ISUP grading system (Grades 1-4) is applied to ccRCC and papillary RCC but is not applied to chromophobe RCC. Sarcomatoid and rhabdoid differentiation should be reported as a percentage; their presence automatically assigns Grade 4 and is associated with poor prognosis regardless of the underlying subtype. Staging is determined by tumor size (pT1a 4 cm or less, pT1b 4-7 cm, pT2a 7-10 cm, pT2b greater than 10 cm), renal vein invasion (pT3a), and IVC involvement (pT3b/c). Renal sinus fat invasion classifies as pT3a and is commonly under-recognized, requiring adequate sampling of the sinus region.

<image>A medical illustration comparing the three major RCC subtypes. Panel A (Clear cell RCC): Nests of cells with optically clear cytoplasm (glycogen/lipid dissolved) arranged around a delicate sinusoidal capillary network, with CA-IX IHC inset showing diffuse strong membranous (box-like) staining. Panel B (Papillary RCC Type 1): Papillary architecture with fibrovascular cores containing foamy macrophages and hemosiderin, lined by a single layer of small cuboidal cells with scant basophilic cytoplasm, CK7 IHC inset showing diffuse positivity. Panel C (Chromophobe RCC): Large polygonal cells with prominent cell borders, pale reticular cytoplasm with perinuclear halos, and raisinoid wrinkled nuclei, Hale colloidal iron inset showing diffuse blue cytoplasmic staining.</image>

<image>A medical illustration of emerging molecularly defined renal tumors. Panel A (FH-deficient RCC): Papillary architecture with large cells containing prominent eosinophilic nucleoli with perinucleolar clearing (cherry-red nucleoli with halo, arrow), FH IHC showing loss of cytoplasmic staining in tumor with retained staining in stromal cells. Panel B (TFE3-rearranged RCC): Papillary/nested architecture with voluminous clear to eosinophilic cytoplasm and psammoma bodies, TFE3 IHC showing strong nuclear positivity. Panel C (SDH-deficient RCC): Solid nested architecture with eosinophilic cytoplasm containing flocculent vacuolar inclusions, SDHB IHC showing loss of granular cytoplasmic staining. Panel D (Clear cell papillary renal cell tumor): Papillary/tubular architecture with clear cells showing characteristic linear nuclear arrangement (nuclei aligned away from the basement membrane), CK7 IHC showing diffuse positivity.</image>

<image>A medical illustration of oncocytoma versus chromophobe RCC. Panel A (Oncocytoma): Nests and tubules of uniform cells with abundant granular eosinophilic cytoplasm, round regular nuclei without wrinkling, edematous stroma, CK7 IHC showing negative/rare focal staining. Panel B (Chromophobe RCC, eosinophilic variant): Similar eosinophilic cells but with raisinoid nuclear wrinkling, prominent cell borders, and perinuclear halos, CK7 IHC showing diffuse positive staining. Panel C: Comparison table of key IHC differences: CK7 (focal/negative in oncocytoma vs. diffuse in chromophobe), Hale colloidal iron (negative/apical in oncocytoma vs. diffuse in chromophobe), vimentin (negative in both), CD117 (positive in both).</image>

Clinical Pearls

CA-IX staining pattern distinguishes the two most common clear cell renal neoplasms: diffuse circumferential (box-like) membranous staining is characteristic of ccRCC, while cup-shaped incomplete membranous staining suggests clear cell papillary renal cell tumor. FH-deficient RCC must be recognized because it is highly aggressive and is associated with germline FH mutations (HLRCC syndrome); the hallmark histologic feature is prominent eosinophilic nucleoli with perinucleolar clearing, and FH IHC loss with 2SC positivity confirms the diagnosis.

CK7 is the single most useful marker for distinguishing oncocytoma (negative or focal) from chromophobe RCC eosinophilic variant (diffuse positive). This distinction matters because oncocytoma is benign while chromophobe, though generally indolent, can rarely metastasize. Sarcomatoid and rhabdoid differentiation can occur in any RCC subtype and independently confer poor prognosis; their presence and percentage should always be reported, as they automatically assign WHO/ISUP Grade 4.

Renal sinus fat invasion (pT3a) is frequently under-recognized because the renal sinus fat is not encapsulated and can be difficult to distinguish from perinephric fat; adequate sectioning of the renal sinus region is essential for accurate staging. In young patients with aggressive papillary or unclassified RCC, TFE3 and TFEB translocation RCC should always be considered, as these may express melanocytic markers (HMB-45, melan-A) and can be confirmed by break-apart FISH or NGS fusion analysis.

References

• WHO Classification of Tumours Editorial Board. Urinary and Male Genital Tumours. 5th ed. IARC; 2022.
• Moch H, et al. The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. Eur Urol. 2022;82(5):489-502.
• Ricketts CJ, et al. The Cancer Genome Atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018;23(1):313-326.
• Trpkov K, Hes O. New and emerging renal entities: a perspective post-WHO 2016 classification. Histopathology. 2019;74(1):31-59.
• Amin MB, et al. AJCC Cancer Staging Manual. 8th ed. Springer; 2017.

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