Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2022, Case 32, and is clear cell renal cell carcinoma of the kidney. The information provided in this case was accurate and correct at the time of publication in 2022. Any changes in terminology since the time of publication may not be reflected in this case. 

Sections of the mass show nests of epithelioid clear cells with large, pleomorphic nuclei and prominent nucleoli with intermingled thin-walled vessels and extensive necrosis. Also noted are occasional spindle cells with marked pleomorphism admixed with round or polygonal tumor cells with abundant eosinophilic cytoplasm and eccentrically placed nuclei. These morphologic findings, combined with the gross appearance and staining pattern, are consistent with a diagnosis of clear cell renal cell carcinoma (CCRCC) with sarcomatoid and rhabdoid differentiation.

CCRCC is the most common subtype of renal cell carcinoma (RCC), frequently found incidentally in patients in their 60s to 70s with a slight female predominance. If symptomatic, patients may experience hematuria or flank pain. Grossly, CCRCC tends to have a golden yellow appearance with possible areas of hemorrhage, necrosis, and cystic change. Histologically, the tumor cells classically form compact nests or sheets of clear cells with distinct cell membranes. Eosinophilic cells are not unusual in higher-grade tumors. Also present is a characteristic chicken-wire vascular pattern, with delicate thin-walled vessels intermingling with the tumor cells.

While TNM staging is the most accurate predictor of prognosis for RCC, the World Health Organization/International Society of Urologic Pathology (WHO/ISUP) grading system is used to provide prognostic distinction among CCRCC of the same clinical stage. Grades 1, 2, and 3 are based on nucleolar prominence, with inconspicuous nucleoli at 400x magnification defining grade 1, conspicuous and eosinophilic nucleoli at 400x with additional visibility at 100x defining grade 2, and conspicuous and eosinophilic nucleoli at 100x defining grade 3. Grade 4 is reserved for cases showing extreme nuclear pleomorphism, multinucleated giant cells, or rhabdoid or sarcomatoid differentiation. Rhabdoid and sarcomatoid differentiation are associated with aggressive behavior and a worse prognosis proportional to the percentage of tumor involved. On gross examination, areas with sarcomatoid or rhabdoid differentiation have a distinct tan-gray fleshy appearance. Extensive sampling of such heterogeneous areas within the tumor is critical to ensure any grade 4 tumor is identified.  

Due to the significant morphologic overlap that can occur in subtypes of RCC, immunohistochemistry plays a key role in accurately subtyping renal tumors. CAIX is the most specific IHC marker for CCRCC available, with a distinct box-like membranous staining pattern. CK7 negativity can aid in the diagnosis of CCRCC; however, CK7 can be focally positive in high-grade tumors.

Genetic analysis can also aid in distinguishing among subtypes of RCC. The loss of 3p is classic for CCRCC. Alteration of the VHL gene on 3p due to mutations, promoter hypermethylation, or loss of heterozygosity is the most common finding. This leads to hyperactivation of HIF and the upregulation of gene expression involved in tumorigenesis. The 3p locus also contains multiple other tumor suppressor genes that may be affected. Unsurprisingly, CCRCC is one of the manifestations of von Hippel–Lindau syndrome, and bilateral, multifocal, or early onset tumors may warrant additional genetic testing. Importantly, VHL alteration has not been shown to have prognostic significance or direct correlation to pathologic features in CCRCC.  

Conversely, BAP1 mutations in CCRCC have been shown to be associated with a more aggressive clinical picture, so the presence of multiple morphologic features commonly identified in BAP1-mutated CCRCC, such as papillary, tubulopapillary, or nested architectural patterns; prominent eosinophilic cytoplasmic globules; and high-grade nuclei, may be reason to perform genetic testing. BAP1 loss can also be detected by immunohistochemistry, although recent studies show it is not entirely sensitive. It is also crucial to keep in mind that RCC can have a high degree of intratumoral genetic heterogeneity, especially in cases with sarcomatoid or rhabdoid differentiation. These patterns are thought to be part of a dedifferentiation process, as evidenced by reports demonstrating gene expression patterns mimicking the original tumor subtype within the dedifferentiated areas along with sarcomatoid- or rhabdoid-specific mutations (TP53 mutation is common).  

Chromophobe renal cell carcinoma (ChRCC) is also in the differential. The cytologic features include a mixture of clear and eosinophilic cells in its classic form. Binucleation and perinuclear halos are characteristic of ChRCC, as are thick-walled hyalinized vessels. Additionally, the majority of the RCC subtypes can show sarcomatoid or rhabdoid differentiation. CD10, a marker of proximal tubules, is negative in ChRCC, as this subtype originates from the intercalated cells of the distal collecting ducts. CK7 and C-KIT are diffusely positive in ChRCC.

Clear cell papillary renal cell tumor (CCPRCT) is an important diagnostic consideration that demonstrates a combination of clear cells, occasional papillary formation, and a lack of the characteristic foamy macrophages and psammomatous calcifications seen in papillary RCC. This is a crucial entity to distinguish from a low-grade CCRCC, as there are no documented adverse outcomes associated with this diagnosis. This indolent behavior has prompted a terminology change in the most recent WHO monograph, dropping “cancer” and replacing it with “tumor.” In CCPRCT, CAIX stains in a cup-shaped basolateral pattern. However, CAIX staining patterns can be unreliable, as staining can be box-like in CCPRCT and a cup-shaped luminal pattern can occasionally be present in pseudopapillary areas of CCRCC. In CCPRCT, CK7 tends to be strongly positive, and CD10 and AMACR are negative. Additionally, it is not unusual for CCPRCT to have no cytogenetic abnormalities.

Epithelioid angiomyolipoma (EAML) is a rare variant of angiomyolipoma that consists of at least 80% epithelioid cells with a carcinoma-like growth pattern. Unlike the classic benign angiomyolipoma, this variant can exhibit malignant behavior, albeit with significant variability in presentation and prognosis. Grossly, it can have a similar appearance to CCRCC, with a tan-yellow to hemorrhagic cut surface, necrosis, and infiltrating borders. It may involve the renal veins and has the potential to metastasize. Histologically, the large atypical eosinophilic epithelioid tumor cells growing in nests and sheets can closely mimic those of high-grade CCRCC. EAML and CCRCC can be distinguished by PAX8 and cytokeratins (both positive in CCRCC and negative in EAML) or with cathepsin K and melanocytic markers, which are positive in EAML.  

Papillary renal cell carcinoma (PRCC) demonstrates diffuse papillary architecture with true fibrovascular cores, frequently distended by foamy histiocytes. The epithelial cells can range from clear to eosinophilic, with varying nuclear grades. These tumors were previously subdivided into type 1 and type 2 based on their morphology; however, this is no longer recommended as “type 2” tumors show diverse molecular alterations suggesting they do not belong to the same diagnostic subtype. CK7 is often positive in PRCC, but may be lost in tumors with more eosinophilia. AMACR positivity is usually seen in PRCC and is uncommon but variable in the other RCC subtypes. 

1. Which of the following pathologic features is most commonly seen in clear cell renal cell carcinoma (CCRCC)? 
    
   1. Large eosinophilic cells forming papillae  
   2. Psammomatous calcifications  
   3. Thick-walled hyalinized vessels  
   4. Thin-walled vessels in a chicken-wire pattern
   5. Tumor size of 5 cm or less
2. What is the genetic abnormality most commonly associated with CCRCC? 
    
   1. Loss of 3p
   2. Loss of 22q
   3. Polysomy of chromosome 7
   4. Polysomy of chromosome 17
   5. Single copy loss of chromosome 3
3. What is the most reliable immunohistochemical indicator specific to a diagnosis of CCRCC? 
    
   1. CAIX positivity with a box-like membranous staining pattern
   2. CAIX positivity with a cup-shaped luminal staining pattern
   3. CK7 strong and diffuse positivity  
   4. CKIT positivity  
   5. PAX8 positivity  

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1. Thin-walled vessels in a chicken-wire pattern (d)
2. Loss of 3p (a)
3. CAIX positivity with a box-like membranous staining pattern (a)