Metanephric adenoma is a rare renal tumor (<1% of all epithelial neoplasms in the kidney) that most commonly arises in females (F:M, 2:1) during adulthood (peak incidence during the fifth decade), although a wide age range is reported. Tumors are essentially benign, and while diagnosis is relatively straightforward on surgical resection specimens, the diagnosis on fine needle aspiration biopsy may be more challenging. Recent studies have demonstrated that the majority of metanephric adenomas harbor BRAF V600E mutations, and are positive for BRAF V600E-specific immunohistochemical antibody, which has high diagnostic utility in challenging small specimens.


Grossly, metanephric adenoma is often a single, well-circumscribed, unencapsulated mass, with reported sizes ranging from subcentimeter to larger than 20.0 cm (mean, 5.5 cm). Tumors are frequently tan-yellow with a solid cut surface, with occasional hemorrhage, central necrosis, cystic degeneration, and calcifications. Histologically, tumors are comprised of a proliferation of compact tubules (occasionally collapsed) arranged back-to-back and separated by a modest amount of fibrous stroma (which is often not evident on aspirate smears). Foci of solid and sheetlike growth and papillary or glomeruloid architecture with psammomatous calcifications may occasionally be present. The tumor cells comprise a uniform population that is cytologically bland, with small round-to-ovoid nuclei and inconspicuous nucleoli and scant cytoplasm. Mitotic figures are rare. On immunohistochemistry, metanephric adenoma expresses WT1 and is typically negative for cytokeratin, EMA, and AMACR (although focal staining may be seen).


Over the past few years, studies have found that metanephric adenomas (90%) harbor the BRAF V600E missense mutation. BRAF is a serine/threonine kinase in the MAPK signaling pathway, which is involved in the regulation of cellular proliferation, differentiation, and survival. The exon 15 V600E mutation mimics phosphorylation of the BRAF activation site, which leads to constitutive pathway activation. This specific mutation has been described in a wide spectrum of benign and malignant tumor types. Other neoplasms harboring BRAF V600E mutations include melanoma, papillary thyroid carcinoma, colonic adenocarcinoma, hairy cell leukemia, Langerhans cell histiocytosis, Erdheim-Chester disease, ameloblastoma, pleomorphic xanthoastrocytoma, and papillary craniopharyngioma. An immunohistochemical antibody specific for the BRAF V600E protein (clone VE1) became commercially available in 2011, and immunoreactivity (present as cytoplasmic staining) has proven to have nearly perfect concordance with V600E mutation status in nearly all tumor types tested that harbor the mutation. BRAF V600E immunohistochemistry has been shown to be a highly sensitive and specific marker for metanephric adenoma in comparison to most renal epithelial neoplasms (including oncocytoma, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC), which has high utility with the increase in minimally invasive biopsy techniques for renal masses.


In small biopsies, the differential diagnosis of metanephric adenoma includes Wilms tumor, low-grade papillary renal cell carcinoma RCC, clear cell papillary (tubulopapillary) (CCPRCC), and metastatic tumors. Wilms Tumor is by far the most common alternative diagnostic consideration to metanephric adenoma, especially in pediatric patients. Wilms Tumor is typically triphasic and most cases can be easily distinguished with the presence of a blastemal, stromal (mesenchymal), and epithelial component. However, some examples may be epithelial-predominant and may closely resemble metanephric adenoma; furthermore, Wilms Tumor also shows diffuse nuclear WT1 nuclear staining. Wilms tumor may exhibit features indicative of malignancy, including larger hyperchromatic nuclei and mitotic activity. However, BRAF V600E is not expected in Wilms Tumor and will be discriminatory in challenging specimens.


Low-grade papillary RCC may also show morphologic overlap with metanephric adenoma; papill ary RCC is more likely to have foamy macrophages (some within papillary cores) and cytoplasmic hemosiderin deposition. Papillary RCC are positive for EMA, CK7, and AMACR, and negative for WT1 and BRAF V600E. Papillary RCC are frequently associated with trisomies of chromosome 7, 16, and 17, and cytogenetic analysis may also be helpful.


CCPRCC may also show morphologic overlap with metanephric adenoma on aspirate smears given its characteristic low nuclear grade and variable acinar and papillary architecture. However, tumor cells in CCPRCC tend show a distinctive apical orientation of tumor nuclei and abundant clear cytoplasm, which may be prominent on cell block sections. CCPRCC is positive for CK7 and EMA and can be distinguished by immunohistochemistry (although BRAF V600E has not been studied in this tumor type).


Lastly, metastatic tumors may come into consideration when encountering metanephric adenoma in an adult; most metastatic carcinomas demonstrate cytologic feature s of malignancy. In the context of a WT-1 positive tumor in an adult female, a metastatic serous carcinoma may be considered, however correlation with clinical data to identify either an adnexal, uterine, or peritoneal mass (and/or evidence of carcinomatosis) is helpful. The differential diagnosis depends on the clinical suspicion and would require appropriate use of ancillary studies, and may include melanoma (positive for S-100, Melan-A, HMB-45; but may be positive for BRAF V600E), neuroendocrine carcinoma (positive for cytokeratin, synaptophysin, chromogranin), and adenocarcinoma from lung, upper gastrointestinal, pancreaticobiliary tract, and lower gastrointestinal primary sites (requiring the use of markers such as CK7, CK20, TTF-1, CK7, SMAD4, CDX-2).