Kidney tumor

• Extremely uncommon (~40 cases reported)
• Resembles well differentiated thyroid follicular neoplasms
• Encapsulated mass with thyroid-like follicles (macro and microfollicles) containing inspissated, eosinophilic colloid-like material
• Negative for TTF1 and thyroglobulin
• Most have low malignant potential

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• Follicular-like architecture with variably sized follicles, with micro and macrofollicles, containing inspissated, eosinophilic colloid-like material
• Follicles are lined by a single layer of cuboidal or low columnar epithelium with moderate amphophilic to eosinophilic cytoplasm, round nuclei, mostly inconspicuous to occasionally prominent nucleoli
• Majority of tumors show pure follicular architecture, with some variations including branching, resulting in focal papillary-like pattern (Mod Pathol 2021;34:1167)
• Papillary areas appear to be broken interfollicular septa rather than true papillae (Pathology 2018;50:24)
• May be cystically dilated (Diagn Pathol 2014;9:186)
• May have focal tightly packed follicles without secretions, imparting a somewhat solid appearance
• Few cases demonstrate nuclear grooves or ground glass nuclear appearance (Pathology 2018;50:24)
• Lymphocytic infiltrate may be present intratumorally or around periphery and macrophages may be present in background (Diagn Pathol 2013;8:108)
• Calcifications may be seen (Pathology 2018;50:24)
• Necrosis and lymphovascular invasion are absent in most tumors
• Sarcomatoid differentiation has been reported (Int J Surg Pathol 2019;27:678, Int J Surg Pathol 2021;29:327, Histopathology 2022;80:745)

Contributed by Maria Tretiakova, M.D., Ph.D.

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• Follicular architecture is not unique to thyroid-like follicular renal cell carcinoma (RCC) and may be seen in other RCC subtypes, such as papillary RCC, clear cell RCC, FH deficient RCC, tubulocystic RCC, SDHB deficient RCC, microcystic chromophobe RCC, atrophic kidney-like tumor / lesion (provisional entity) and mixed epithelial and stromal tumor (Mod Pathol 2021;34:1167, Am J Surg Pathol 2018;42:1585)
• Papillary RCC:
  • Will demonstrate ordinary papillary renal cell carcinoma areas
• Atrophic kidney-like tumor / lesion (provisional entity):
  • Atrophic / flattened epithelium with occasional hobnailing within follicles, more pronounced microcalcifications, entrapped benign atrophic renal tubular structures and morphologic similarity to glomerulocystic change
  • Will demonstrate WT1 positive / PAX8 negative / CK7 negative IHC profile (Mod Pathol 2021;34:1921, Am J Surg Pathol 2018;42:1585)
• Metastatic thyroid carcinoma (Case Rep Pathol 2015;2015:701413, Mol Clin Oncol 2021;15:268):
  • Very rare to have metastatic disease to kidney; usually obvious thyroid primary with widely disseminated metastases
  • Thyroglobulin+ or TTF1+
  • Most follicular and follicular variant of papillary thyroid carcinomas have RAS or BRAF mutations, respectively (Mod Pathol 2021;34:1921)
  • Thyroid carcinomas can have a Hürthle (oncocytic) phenotype, which could be a potential pitfall for eosinophilic / oncocytic renal neoplasms; these more commonly metastasis to the lung and bone (Thyroid 2010;20:429, Nucl Med Mol Imaging 2017;51:256)
• Metastatic follicular carcinoma arising in struma ovarii in women:
  • If this metastasizes, usually goes to bone (Pathologica 2020;112:224, Int J Gynecol Pathol 2009;28:405, J Clin Neurosci 2010;17:269)
• Chronic pyelonephritis and end stage kidney disease:
  • May be considered due to presence of colloid-like hyaline casts in atrophic, microcytic tubules resembling thyroid (thyroidization)
  • Differentiated by clinical history, lack of mass formation and histologic differences (inflammation, demonstration of normal constituents, such as glomeruli and tubules, with chronic injury pattern resulting in fibrosis, atrophy, etc.)
• Well differentiated neuroendocrine tumor (carcinoid):
  • Rare
  • Patterns are insular, cords, nests or ribbons but not follicular
  • Neuroendocrine histology
  • Positive for neuroendocrine markers synaptophysin and chromogranin
• Urothelial carcinoma with cystitis cystica pattern:
  • Arises from the renal pelvis
  • GATA3 positivity (Mod Pathol 2021;34:1921)
• Oncocytoma:
  • Areas of classical oncocytoma with nests of oncocytic cells embedded in loose myxoid stroma

A 42 year old woman undergoes a left radical nephrectomy for a 4 cm renal mass. Which of the following is most consistent with a diagnosis of thyroid-like follicular renal cell carcinoma?

1. Grossly well circumscribed renal tumor with microscopic follicular growth and inspissated colloid-like material
2. Immunohistochemistry demonstrates tumor cells to be negative for PAX8 and CK7 and positive for WT1
3. Poor clinical prognosis after diagnosis with high mortality rate
4. Will demonstrate NRAS and HRAS or BRAF mutations by sequencing

A. Grossly well circumscribed renal tumor with microscopic follicular growth and inspissated colloid-like material. Thyroid-like follicular renal cell carcinoma usually presents asymptomatically over a wide age range with female predominance. On gross, the tumor is well circumscribed tan to brown, solid to cystic mass. Microscopically, it demonstrates follicular-like architecture with micro and macrofollicles, filled with inspissated colloid-like material. The follicles are lined by cuboidal cells with moderate amount of amphophilic to eosinophilic cytoplasm, oval nuclei with uniform chromatin and inconspicuous nucleoli. This entity typically has an indolent clinical behavior. Immunohistochemical profile is typically PAX8+ / CK7+ / WT1- / TTF1- / thyroglobulin-, in contrast to atrophic kidney-like tumor / lesion and metastatic thyroid carcinoma, the 2 closest morphologic mimics. The tumor will be negative for NRAS, HRAS and BRAF mutations, in contrast to metastatic thyroid carcinoma.

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Reference: Primary thyroid-like follicular carcinoma

A 65 year old woman undergoes a right radical nephrectomy for a 3 cm renal mass. The tumor displays follicular architecture with inspissated colloid-like material without papillary-like nuclear features or papillary growth. By immunohistochemistry, the tumor cells are positive for TTF1 and thyroglobulin. This patient will likely have which of the following?

1. An intact thyroid with no nodules
2. No evidence of other metastatic foci on PET / CT
3. PAX8 IHC negativity
4. RAS mutation

D. RAS mutation. The question describes a metastatic follicular carcinoma of the thyroid. These patients will typically have evidence of prior thyroid surgery or an obvious thyroid primary with widely metastatic disease. The most common somatic mutations to occur in follicular thyroid carcinoma are RAS point mutations (most often codon 61 of NRAS and codon 61 of HRAS) followed by PPARG gene fusions (e.g., PAX8::PPARG). RAS mutations are found in almost half of conventional follicular carcinomas. They stabilize the protein in its active guanosine triphosphate (GTP) bound form, leading to constant stimulation of the downstream signaling pathways, particularly MAPK and PI3K / AKT cascades. Both metastatic thyroid-like follicular renal cell carcinoma and metastatic follicular carcinoma of the thyroid will demonstrate PAX8 positivity and therefore this stain should not be used to distinguish between these entities.

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Reference: Primary thyroid-like follicular carcinoma