Resident Program - Case of the Month

February 2022 – Presented by Dr. Sohrab C. Kadivar

Discussion

In the category of epithelial tumors of the kidney, renal clear cell carcinoma (RCCC) is the most commonly occurring tumor. RCCC is understood to develop in the cell lining of the proximal convoluted tubule, and often seen to develop as a solitary lesion in the renal cortex. It is most frequently associated with VHL protein loss of function, which leads to accumulation of hypoxia inducible transcription factor alpha (HIF1-alpha). This accumulation results in transcription and subsequent accumulation of hypoxia associated genes (e.g. VEGF, PDFG-beta, TGF-alpha, etc).

Risk factors include smoking, obesity, chronic hypertension, and a family history of renal cancer. Additionally, there is a known association with acquired adult cystic kidney disease, which itself is common in end stage renal disease patients undergoing long term hemodialysis.

Patients commonly present with gross hematuria and flank pain, as seen in our case. Additionally, anemia, weight loss, and -- in late stages -- fever can be seen. Diagnosis is most commonly initiated radiologically, with approximately 70% of cases first being identified incidentally on imaging. While definitive diagnosis can be made by biopsy, partial or total nephrectomy is more commonly employed. This is, in part, due to resection of RCCC that is graded as stages 1-3 being curative, and systemic chemotherapy is known to have limited efficacy.

Classic histologic features of RCCC include nested architecture, or sheets of cells contained within a distinct membrane. Architectural subtypes can be solid, alveolar, acinar, microcystic, or macrocystic. Alveolar subtype is defined by nesting pattern, acinar is tubular, and microcystic features extravasated erythrocytes and occasionally eosinophilic deposits.

Cellular cytoplasm is cleared out, and in cases of high grade tumors, or areas of hemorrhage or necrosis, cytoplasm can be granular and eosinophilic. High grade features include rhabdoid differentiation, which is defined by high grade malignant cells featuring homogeneous eosinophilic cytoplasm. Occasionally, these cells will also have globular eosinophilic intracytoplasmic nuclear inclusions. Sarcomatoid features also represent high grade differentiation, and can occur in any RCCC architectural subtype.

Immunohistochemical staining for RCC will show PAX8, CD10, and vimentin positivity, while CK7, CK20, CD117, Cathepsin K, and Inhibin would be expected to be negative (note however that high grade differentiation could feature CK7 positivity).

Differential diagnoses that are important to consider when making a diagnosis of RCCC include papillary RCC with cytoplasmic clearing, which is defined by classic papillary architecture, and papillary RCC type 2 which features large lining cells with eosinophilic cytoplasm. Another differential is chromophobe renal cell carcinoma which most commonly features clear to eosinophilic cytoplasm (note that chromophobe RCC will stain positively for CK7).

References

• WHO Classification of Tumours Editorial Board. World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed., vol 8 Lyon: International Agency for Research on Cancer; 2016.
• Nezami BG, MacLennan G. Clear cell. PathologyOutlines.com website. Accessed February 10th, 2022.