A 67-year-old man presents with a mass in the left kidney found incidentally following a low-dose chest computed tomography (CT) scan to screen for lung cancer. He is otherwise asymptomatic. Diagnostic imaging confirms a well-demarcated, exophytic, 5.3 cm mass located in the superior pole of the left kidney. The mass shows heterogeneous attenuation and enhancement postcontrast. There are no other lesions or adenopathy. The patient undergoes a partial nephrectomy. Grossly, the mass is tan-brown and sharply circumscribed, but no capsule is apparent.

Master List of Diagnoses

  • Chromophobe renal cell carcinoma
  • Clear cell renal cell carcinoma, eosinophilic variant
  • Oncocytic papillary renal cell carcinoma
  • Oncocytoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 38, and is oncocytoma of the kidney.

Criteria for Diagnosis and Comments

The provided sections show nests of oncocytic cells in a vaguely nodular and dispersed pattern with intermixed hyalinized stroma. The cells are polygonal with indistinct cell borders and granular eosinophilic cytoplasm. The nuclei are predominantly round and regular with a single nucleolus and even chromatin. Scattered binucleation is identified. Foci of cells toward the periphery have a higher nucleus to cytoplasm ratio (some authors have referred to these cells as oncoblasts), but they transition to more typical oncocytes. These features are diagnostic of renal oncocytoma. Some sections show cell clusters with marked cytologic atypia, which is not uncommon in benign renal oncocytomas and can be seen in up to 30% of these tumors. This atypia is thought to be degenerative. While this type of atypia is accepted, “red flag” features such as tumor necrosis, extensive papillary architecture, atypical mitotic figures, and sarcomatoid dedifferentiation should direct the pathologist away from benign oncocytoma for a diagnosis.

Renal oncocytoma accounts for 3% - 5% of primary epithelial neoplasms of the kidney. Patients with renal oncocytoma are most commonly in their 7th decade and present with an incidentally found renal mass. In some studies, they are more common in women, but others report the ratio as even. Grossly, they are typically well-circumscribed and unencapsulated. Oncocytomas are classically described as mahogany brown with a central stellate scar, though this is present in only one-third of oncocytomas. They can often be multifocal and bilateral (13%). Interestingly, gross extension into perirenal adipose can be present.

The most common mimicker of renal oncocytoma is the eosinophilic variant of chromophobe renal cell carcinoma (CRCC). Distinction between these two entities is of great importance, as CRCC, while having a better prognosis than other renal cell carcinomas, is still a malignant neoplasm with metastatic potential. Both CRCC and oncocytoma are thought to arise from intercalated cells of the collecting ducts. CRCC generally presents in the 6th decade, affecting men and women equally. CRCC can usually be distinguished easily on H&E, but the eosinophilic variant, which accounts for 20% - 40% of cases, shows histologic overlap with renal oncocytoma. Clues to the diagnosis of CRCC include perinuclear halos, thick cell membranes, and hyperchromatic nuclei with irregular membranes. An additional challenge to the diagnosis is the existence of tumors with hybrid features of oncocytoma and CRCC.

In instances where differentiating renal oncocytoma from CRCC is difficult on H&E, ancillary studies may be helpful, though no single test has been shown to be sensitive and/or specific. Historically, Hale’s colloidal iron has been used to distinguish the two; renal oncocytoma shows apical staining of the cells and CRCC shows diffuse cytoplasmic staining. Hale’s colloidal iron staining quality varies with technique, and assessment is variable, making the interpretation of this histochemical stain unreliable. While there is no perfectly sensitive and specific stain, a meta-analysis suggested an immunohistochemical panel that can help distinguish the two. Four stains were identified as being informative: CK7, S100A1, Caveolin-1, and claudin-7. The majority of renal oncocytomas were negative for CK7 (may show focal positivity), claudin-7 and Caveolin-1, and positive for S100A1. CRCC are diffusely positive for CK7 and Claudin-7, negative for S100A1, and show diffuse peripheral staining for Caveolin-1.

Other entities in the differential include the oncocytic variant of papillary renal cell carcinoma (PRCC) and eosinophilic variant of clear cell (conventional) renal cell carcinoma. PRCC can be distinguished from oncocytoma due to its papillary architecture and generally higher-grade nuclei. Classic papillary features, such as papillary growth with fibrovascular cores and foamy macrophages, are frequently found elsewhere within the tumor. Clear cell renal cell carcinoma (RCC) cells that are eosinophilic or granular are more likely to be higher Fuhrman grade, and adequate sampling may show more classic clear cell features, such as polygonal or cuboidal cells with clear cytoplasm. Immunohistochemical staining for RCC and vimentin is also usually positive, in contrast to oncocytoma. Both of these entities are malignant, and frequently demonstrate necrosis and hemorrhage on histology. Appropriate sampling of these tumors is essential for an accurate diagnosis.

Multiple genomic abnormalities have been identified in renal oncocytomas, as well as CRCC, but none are specific enough to help differentiate them. Sporadic oncocytomas most frequently show loss of material from chromosome 1. Loss of chromosome Y and translocations involving chromosome 11 have also been found in multiple instances.

As renal oncocytomas are considered benign, excision is regarded as curative. Watchful waiting has been proposed for these lesions, but differentiating oncocytomas from renal cell carcinomas via CT or magnetic resonance imaging is difficult, especially in smaller masses, as there are no specific features. Biopsy has been suggested, but many pathologists may feel uncomfortable differentiating definitively a renal oncocytoma from CRCC on a small biopsy or ruling out a hybrid oncocytoma and CRCC tumor.

Oncocytic renal tumors are associated with two inherited syndromes: Succinate Dehydrogenase (SDH)-associated kidney cancer and Birt-Hogg-Dube syndrome (BHDS). SDH acts within the Krebs cycle and the mitochondrial respiratory chain, and mutations in SDH are associated with increased risk of mainly pheochromocytomas and paragangliomas, but also oncocytomas, clear cell RCC, and CRCC.

The better known oncocytic renal tumor syndrome is BHDS. This syndrome is uncommon, with an incidence of approximately 1 in 200,000 people, but is likely underdiagnosed due to the frequently mild presentation and inconstant symptoms. BHDS is caused by multiple different mutations in the folliculin (FLCN) gene on chromosome 17. These patients usually present with skin findings (fibrofolliculomas, trichodiscomas, and acrochordons) in their 20s and 30s, and renal tumors (hybrid oncocytoma-CRCC, CRCCs, and less commonly oncocytomas, clear cell RCC, and papillary RCC) around age 50. Pulmonary cysts are quite common, found in 77% - 89% of syndromic patients, with subsequent pneumothorax in 33% - 38% of those patients. The most common renal tumor is the hybrid oncocytoma-CRCC, and recognizing it should prompt the pathologist to suspect BHDS.

  1. Which staining pattern is most consistent with renal oncocytoma?

    1. CK7 negative, S100A1 negative, caveolin-1 positive (diffuse peripherally)
    2. CK7 negative, S100A1 positive, claudin-7 negative
    3. CK7 positive, caveolin-1 positive (diffuse peripherally), claudin-7 positive
    4. CK7 positive, S100A1 negative, claudin-7 positive
    5. S100A1 positive, caveolin-1 negative, claudin-7 positive
  2. Which findings are most likely present in a patient with a hybrid oncocytic tumor (mixed oncocytoma and chromophobe renal cell carcinoma)?

    1. Angiomyolipoma, periungual fibroma, facial angiofibroma, pancreatic, and renal cysts
    2. Breast and thyroid cancer, mucocutaneous papules, hamartomas, and lipomas
    3. Fibrofolliculoma, trichodiscoma, lung cysts, and pneumothorax
    4. Hemangioblastoma, pheochromocytoma, neuroendocrine tumor, endolymphatic sac tumor
    5. Leiomyomatosis
  3. Which feature should definitively preclude a diagnosis of oncocytoma?

    1. Atypical mitotic figures
    2. Bilateral tumors
    3. Binucleation
    4. Invasion into surrounding adipose tissue
    5. Marked nuclear atypia

References

  1. Abrahams NA, Tamboli P. Oncocytic renal neoplasms: diagnostic considerations. Clin Lab Med. 2005;25(2):317-339.
  2. Dal Sasso AA, Belém LC, Zanetti G, et al. Birt-Hogg-Dube syndrome. State-of-the-art review with emphasis on pulmonary involvement. Respir Med. 2015;109(3):289-296.
  3. Hass NP, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014;21(1):81-90.
  4. Ng KL, Morais C, Bernard A, et al. A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma. J Clin Pathol. 2016;69(8):661-671.
  5. Ng KL, Rajandram R, Morais C, et al. Differentiation of oncocytoma from chromophobe renal cell carcinoma (RCC): can novel molecular biomarkers help solve an old problem? J Clin Pathol. 2014;67(2):97-104.
  6. Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urologic Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol. 2013;37(10):1469-1489.
  7. Yusenko, MV. Molecular pathology of renal oncocytoma: a review. Int J Urol. 2010; 17(7):602-612.

Authors

Carrie L Robinson, MD, LT MC USN
Attending Pathologist
Naval Hospital Pensacola
Pensacola, FL

Justin M Wells, MD, MAJ MC USA, FCAP
Surgical Pathology Committee
Walter Reed National Military Medical Center
Bethesda, MD


Answer Key

  1. CK7 negative, S100A1 positive, claudin-7 negative (b)
  2. Fibrofolliculoma, trichodiscoma, lung cysts, and pneumothorax (c)
  3. Atypical mitotic figures (a)