Case 1109 - A Male in His 70s with a Large Kidney Mass

Genitourinary Pathology

Contributed by Kotaro Takeda, MD and Gabriela Quiroga-Garza, MD

Clinical History

The patient is a male in his 70s who presents with a newly detected large right renal mass. He had gross hematuria. Computed tomography shows a 12.5 cm solid mass at the upper pole of the right kidney with no evidence of metastasis or other primary tumors. He has no significant past medical history. Subsequently, laparoscopic right radical nephrectomy is performed.

Gross Examination

The right kidney has a 12.5 x 11.9 x 6.8 cm ill-defined, tan-yellow, lobulated, focally necrotic and hemorrhagic mass at the upper to mid pole (Figure 1). The tumor apparently involves the renal sinus adipose tissue. The tumor pushes against the renal capsule and abuts renal capsular and hilar parenchymal resection margins.

Figure 1
Figure 1. Gross picture of bivalved right kidney. A 12.5 x 11.9 x 6.8 cm ill-defined mass is present at the upper to mid pole. The tumor involves the renal sinus.

Microscopic Examination

The renal cell carcinoma shows predominantly high-grade histologic features with tumor cells with voluminous pale eosinophilic cytoplasm, enlarged nuclei with prominent nucleoli (conspicuous at x100 magnification, WHO/ISUP Nuclear Grade 3) arranged in tubulopapillary and solid architecture (Figure 2A-2C). Some tumor cells have small eosinophilic granules in the cytoplasm (Figure 2C). Tumor necrosis, mitotic figures, renal vein branch invasion and renal sinus invasion are identified. The tumor in some area (approximately 10 % of tumor) shows a classic clear cell renal cell carcinoma morphology with a nested growth pattern, clear cytoplasm, and relatively low-grade nuclear atypia (Figure 2D).

Immunohistochemical stains show that tumor cells are immunoreactive for carbonic anhydrase IX (CAIX) (box-like membranous, Figure 3A), CD10 (diffuse, Figure 3B), P504S/alpha-methylacyl-CoA racemase (AMACR) (diffuse, Figure 3C), and cytokeratin AE1/AE3, while negative for cytokeratin 7 (Figure 3D), cathepsin-K and HMB45. Tumor cells show a loss of BAP1 nuclear expression.

Molecular testing is performed. The VHL mutational analysis identified VHL gene mutation (p.V165D, c.494T>A). The UPMC Oncomine test identified one gene mutation in BAP1 gene (p.Y129Ifs*14, c.383dupG) with variant allele frequency of 30%, suggesting somatic mutation. No other significant gene mutations and copy number alterations are identified. Microsatellite status is stable.

 

Figure 2
Figure 2. Histology of the renal tumor (H&E stains). (A) The renal cell carcinoma with tubulopapillary architecture (x20). (B) Tumor cells with voluminous eosinophilic to pale cytoplasm, enlarged nuclei with prominent nucleoli (x100). (C) Tumor cells with eosinophilic cytoplasmic granules and prominent nucleoli (x400). (D) Classic clear cell renal cell carcinoma morphology with nested growth pattern, clear cytoplasm, and low-grade cytologic atypia (x100).

 

Figure 3
Figure 3. Immunohistochemical stains for the renal tumor (x200). The tumor cells are immunoreactive for carbonic anhydrase IX (A), CD10 (B), P504S/alpha-methylacyl-CoA racemase (AMACR) (C), while negative for cytokeratin 7 (D).

Multiple Choice Questions

1. BAP1 is involved in the regulation of what processes?

  1. Chromatin remodeling
  2. DNA damage repair
  3. Cell cycle control and proliferation
  4. Regulated cell death
  5. All of the above
Answer

5. The function of BAP1 is widespread and complex. BAP1 utilizes its deubiquitinating activity to regulate different proteins involved in chromatin remodeling, DNA damage repair, cell cycle control and proliferation, regulated cell death and cell differentiation.

2. BAP1 gene is located in which chromosome?

  1. Chromosome 1p
  2. Chromosome 3p
  3. Chromosome 7q
  4. Chromosome 10q
  5. Chromosome 21p
Answer

2. BAP1 gene is located at chromosome 3p21.1 in close proximity to VHL gene. VHL gene is located at chromosome 3p25.

3. BAP1 gene alterations are commonly found in:

  1. Renal cell carcinoma
  2. Uveal melanoma
  3. Malignant mesothelioma
  4. Cutaneous melanoma
  5. All of the above
Answer

5. BAP1 gene alterations are observed in a variety of malignant tumors. Malignant neoplasms associated with BAP1 alterations include uveal melanoma, malignant mesothelioma, and cutaneous melanoma and clear cell renal cell carcinoma.

4. What percentage of clear cell renal cell carcinoma has BAP1 abnormality?

  1. 1%
  2. 10%
  3. 40%
  4. 70%
  5. 90%
Answer

2. BAP1 abnormality is found in approximately 10% of sporadic ccRCC. BAP1-mutated ccRCC is associated with advanced tumor stage, higher tumor grade and poor prognosis.

 5. What is the differential diagnosis of BAP1-mutated clear cell renal cell carcinoma?

  1. Papillary renal cell carcinoma
  2. Fumarate hydratase (FH)-deficient renal cell carcinoma
  3. Succinate dehydrogenase (SDH)-deficient renal cell carcinoma
  4. Xp11 translocation renal cell carcinoma
  5. All of the above
Answer

5. Given the significant overlap of histologic features between BAP1-mutated clear cell renal cell carcinoma and other high-grade renal cell carcinoma, a wide differential diagnosis must be considered including type 2 papillary renal cell carcinoma, fumarate hydratase (FH)-deficient renal cell carcinoma, succinate dehydrogenase (SDH)-deficient renal cell carcinoma and Xp11 translocation renal cell carcinoma.

DIAGNOSIS AND DISCUSSION