Kidney tumor

• Commonly organ confined, more favorable clinical outcome and lower metastatic risk than clear cell RCC (Clin Genitourin Cancer 2019;17:373)
• Metastatic disease in 5 - 10% of cases (Clin Genitourin Cancer 2019;17:373)
• Recurrence free survival at 5 years is 94.9% (91.7% at 10 years) (Clin Genitourin Cancer 2019;17:373)
• Overall cancer survival at 5 years is 92.3% (82.1% at 10 years) (Clin Genitourin Cancer 2019;17:373)
• Larger tumor size and sarcomatoid transformation significantly associated with adverse recurrence free and overall cancer survival rates (Clin Genitourin Cancer 2019;17:373)

• Most are incidentally discovered on imaging performed for other reasons
• Computed tomography (CT) scan is the most common imaging modality for diagnosis and staging (Crit Rev Oncol Hematol 2021;160:103287)
• According to the 5th edition of WHO, the following diagnostic criteria are listed as
  • Essential: large pale cells with prominent cell membranes and perinuclear halos; groups of CK7 positive cells
  • Desirable: absence of vimentin expression (except in sarcomatoid differentiation)

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• Poor prognostic factors
  • Large tumor size (> 7 cm)
  • Higher clinical T category and pathologic TNM staging
  • Sarcomatoid transformation, tumor necrosis, vascular invasion
  • Male sex (Clin Genitourin Cancer 2019;17:373)
• Tumor grading is not prognostically relevant and not recommended
• Histologic diversity of ChRCC does not impact survival outcome (Ann Diagn Pathol 2022;60:151978)

• Surgery, cryoablation and targeted systemic chemotherapy for metastatic disease with antiangiogenic, tyrosine kinase (TK) and mTOR inhibitors (Urol Oncol 2020;38:137, Crit Rev Oncol Hematol 2021;160:103287)

Contributed by AFIP and @katcollmd on Twitter

Contributed by Maria Tretiakova, M.D., Ph.D., Timothy Isaac Miller, M.D., M.A., Miruna C. Popescu, M.D., Ankur Sangoi, M.D., Daniel Anderson, M.D., M.B.A. and @katcollmd on Twitter

Images hosted on other servers:

Images hosted on other servers:

• CAIX: significant positive staining may be noted in sarcomatoid component of ChRCC (Hum Pathol 2022;119:85)
• Vimentin: except scar area and sarcomatoid component (Int J Surg Pathol 2024;32:83, Int J Surg Pathol 2024;32:11)
• AMACR
• CD10: rarely positive (focally), more so in sarcomatoid component of ChRCC (Int J Surg Pathol 2024;32:11)
• Cathepsin K: helpful in the distinction from epithelioid angiomyolipoma and MiT family RCC; diffuse positive staining in both chromophobe RCC and oncocytoma, with lesser intensity in ChRCC, has been reported with the EPR19992 clone (Mod Pathol 2012;25:100, Mod Pathol 2009;22:1016, Int J Surg Pathol 2021;29:600)
• GATA3: 30% positive in conventional epithelial component, 50% positive in sarcomatoid component of ChRCC (Am J Surg Pathol 2022;46:1171)
• HMWCK
• Cyclin D1: helpful to distinguish from oncocytoma (81% positive) (Pathol Res Pract 2015;211:303)

AFIP images

• Variable copy number alterations (CNAs), most commonly loss of chromosomes 1, 2, 6, 7, 10, 13, 17 and 21 (86%, mainly classic ChRCC) (Asian J Urol 2022;9:1)
• Additional reported losses of chromosomes 3, 5, 8, 9, 11 and 18 (12 - 58%) (Asian J Urol 2022;9:1)
• Chromosomal gains of 4, 7, 15, 19 and 20 also reported (mainly in classic and sarcomatoid ChRCC) (Adv Anat Pathol 2021;28:8)
• Eosinophilic ChRCC less frequently shows the characteristic chromosomal losses of classic ChRCC and may even have diploid karyotype; no chromosomal gains reported to date (Adv Anat Pathol 2021;28:8)
• Doubled hypodiploidy is a common phenomenon in eosinophilic ChRCC (Hum Pathol 2020;104:18)
• Other rare subtypes of ChRCC (excluding sarcomatoid) show variable CNAs, more often losses than gains (Asian J Urol 2022;9:1)
• Classic ChRCC shows lower tumor mutation burden (TMB) than other RCC subtypes, most commonly involving TP53 (32 - 64%), PTEN (9 - 45%) and TERT promoter (6 - 12%); loss of CDKN2A is also frequently seen (Asian J Urol 2022;9:1)
• Mutations in MTOR, TSC1, TSC2 have been reported in a minority of ChRCC, especially eosinophilic subtypes and associated with a worse prognosis (Mod Pathol 2020;33:2580)
• ChRCC also displays somatic mutations in mitochondrial DNA (Asian J Urol 2022;9:1)
• Recurring RB1 mutations are found in 27% of tumors and suggest that subclonal RB1 mutations can drive the evolution to high grade, nonsarcomatoid ChRCC (Mod Pathol 2024;37:100472)

• Clear cell renal cell carcinoma (versus both classic and eosinophilic ChRCC):
  • Optically clear cytoplasm instead of finely reticulated
  • No raisinoid nuclei, no perinuclear halos, no prominent cell borders
  • Negative for CD117 / KIT, CK7, Hale colloidal iron
  • Positive for CAIX, vimentin (especially when higher grade and mostly eosinophilic)
• Oncocytoma (versus eosinophilic ChRCC):
  • Uniform, round, regular nuclei (no koilocytic-like nuclear atypia)
  • Only occasional binucleation
  • No perinuclear halos, no prominent cell membranes
  • CK7 negative or positive only in scattered, isolated cells (beware of increased staining in central scar area)
  • Hale colloidal iron negative or apical bar
  • Positive for cyclin D1, S100A1
• Hybrid oncocytic chromophobe tumor (HOCT):
  • Seen in 3 distinct scenarios: renal oncocytosis, Birt-Hogg-Dubé (BHD) syndrome or sporadic (GUPS recommendation to call sporadic hybrid tumors oncocytic renal neoplasm of low malignant potential)
  • Presence of multiple, bilateral tumors is a clue
  • Tumors with oncocytic cells with mixed morphology between oncocytoma and ChRCC
  • Tumors with distinct areas with more typical renal oncocytoma-like and ChRCC-like areas (mosaic alternating pattern)
  • Variably positive for CK7
  • Positive for CD117 / KIT
  • Variable (apical bar to diffuse) Hale colloidal iron
  • Sporadic cases exhibit different mutational patterns than in oncocytoma or ChRCC; syndromic cases with FLCN (BHD) gene mutations (Mod Pathol 2019;32:1698)
• Low grade oncocytic tumor (LOT) (versus eosinophilic ChRCC):
  • Solid sheets with abrupt transition to edematous areas with loosely arranged cords and strands of oncocytic cells (boats in a bay pattern)
  • Uniform, round / oval, low grade nuclei without nuclear membrane irregularities (no raisinoid nuclei)
  • Patchy, usually subtle perinuclear halo
  • No prominent, plant cell-like cell borders
  • Diffusely positive for CK7 and GATA3
  • Negative for CD117 / KIT
• Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) (versus eosinophilic ChRCC):
  • Solid and (micro)cystic components
  • Variably high grade, mild pleomorphic nuclei
  • Usually abundant granular eosinophilic cytoplasm, sometimes centrally condensed with more flocculent pale periphery
  • Fine to coarse basophilic cytoplasmic stippling / inclusions (leishmaniasis-like)
  • Cystic areas lined by monolayered, hobnailed, frequently multinucleated cells
  • Foamy macrophages and lymphocytic aggregates are common
  • Positive for CK20
  • Negative for CK7 (may be focally positive but always CK20 > CK7)
  • Negative for CD117 / KIT
• High grade papillary renal cell carcinoma (PRCC) (versus eosinophilic ChRCC):
  • No raisinoid nuclei, no perinuclear halos, no prominent cell borders
  • Negative for CD117 / KIT and CK7 (or focal, as in eosinophilic ChRCC)
  • Positive for AMACR, vimentin, CD10
• SDH deficient renal cell carcinoma:
  • Characteristic univacuolated cytoplasm with pale eosinophilic, flocculent material
  • Uniform round / oval nuclei without nuclear membrane irregularities
  • No perinuclear halos, no prominent cell borders
  • Loss of SDHB
  • Negative for CD117 / KIT, CK7
• MiT family renal cell carcinoma (especially TFEB altered RCC):
  • TFEB altered RCC (and especially TFEB amplified RCC) most closely resembles eosinophilic ChRCC
  • If present, biphasic pattern with smaller cells clustered around basement membrane hyaline material and larger peripheral epithelioid cells may be helpful
  • No prominent cell borders, no perinuclear halos
  • Positive for TFEB (must be strong, nuclear and cytoplasmic)
  • Variably positive for cathepsin K, MelanA, HMB45
  • Negative for CD117 / KIT
• Epithelioid angiomyolipoma:
  • Epithelioid to plump spindled cells with prominent nucleoli, intranuclear pseudoinclusions, variable cell discohesion with eosinophilic cytoplasm, sometimes ganglion cell-like appearance
  • Negative for PAX8 and CK
  • Positive for HMB45, MelanA and cathepsin K (beware of diffusely positive EPR19992 clone in ChRCC) (Int J Surg Pathol 2021;29:600)
  • Variably positive for SMA
  • Positive for TFE3, GPNMB, TRIM63 RNA ISH
• Oncocytic adrenal cortical carcinoma (versus eosinophilic ChRCC):
  • Upper kidney pole localization
  • Patchy prominent anisonucleosis (endocrine atypia)
  • No raisinoid nuclei, no perinuclear halos, no prominent cell borders
  • Nuclei frequently looked pushed to the side of the cell (sometimes even with a rhabdoid appearance)
  • Negative for PAX8, CK7, CD117 / KIT, Hale colloidal iron
  • Positive for SF1, inhibin, calretinin, MelanA, vimentin, synaptophysin

Which of the following is true about chromophobe renal cell carcinoma (ChRCC)?

1. Binucleation is pathognomonic
2. Cellulose deposition explains plant-like prominent membranes
3. Cytoplasmic clearing is due to high concentration of lipids
4. Multinucleation is an unfavorable prognostic feature
5. Perinuclear halos are due to accumulation of cytoplasmic microvesicles

E. Perinuclear halos are due to accumulation of cytoplasmic microvesicles. The presence of cytoplasmic microvesicles is a unique and consistent ultrastructural feature of ChRCC. Microvesicles are often concentrated in perinuclear location, corresponding to perinuclear halos on light microscopy. These vesicles lack affinity for H&E stain, resulting in cells with clear, reticular or flocculent cytoplasmic appearance on light microscopy (chromophobe). The origin is uncertain but likely related to defective mitochondria. Answer A is incorrect because binucleation may also be seen in other renal cell tumors, including oncocytoma, one of the main differential diagnoses of ChRCC. Answer B is incorrect because the term plant cell-like is only a descriptive term, it does not relate to accumulation of cellulose in the cellular membrane. Answer C is incorrect because the cytoplasmic clearing in ChRCC is due to accumulation of microvesicles, not lipid. Answer D is incorrect because multinucleation, while part of the WHO / ISUP grading system, does not apply to chromophobe RCC. Multinucleated cells are commonly seen in ChRCC and unlike in clear cell or papillary RCC, have no proven prognostic significance.

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Reference: Chromophobe

What is the best statement describing chromophobe renal cell carcinoma (ChRCC)?

1. Can be reliably distinguished from clear cell RCC by CK7, CD117 / KIT, CAIX and vimentin
2. Classic autosomal dominant genetic correlation is Birt-Hogg-Dubé syndrome, which is associated with a mutation of the HOGG gene on chromosome 3p
3. Sarcomatoid dedifferentiation is a very common phenomenon
4. Typically shows gains of chromosomes 1, 2, 6, 7, 10, 13, 17 and 21
5. WHO / ISUP grading system is a useful prognostic indicator

A. Can be reliably distinguished from clear cell RCC by CK7, CD117 / KIT, CAIX and vimentin. ChRCC is typically diffusely positive for CD117 / KIT and CK7, while negative for CAIX and vimentin. In contrast, clear cell RCC is typically CAIX positive, may be vimentin positive especially with increasing grade, it is usually negative for CK7 (except predominantly cystic tumors) and is negative for CD117 / KIT. Answer B is incorrect because Birt-Hogg-Dubé is caused by an autosomal dominant mutation of the Folliculin gene (FLCN) at 17p11.2 leading to premature truncation and loss of function of the folliculin protein. Von Hippel-Lindau (VHL) syndrome, also autosomal dominant, is caused by a mutation of the VHL tumor suppressor gene (3p25-26). Depending on the subtype, VHL is associated with clear cell renal cell carcinoma, CNS and retinal hemangioblastomas, visceral cysts in the kidney, pancreas and epididymis, endolymphatic sac tumors, pancreatic neuroendocrine tumors, paragangliomas and pheochromocytomas. Answer E is incorrect because, unlike in clear cell RCC and papillary RCC, the WHO / ISUP grading system has no prognostic value in ChRCC. Answer C is incorrect because sarcomatoid transformation, although being a significant poor prognostic indicator in chromophobe RCC, is observed in ~ 5% of cases. Answer D is incorrect because chromophobe RCC typically shows multiple losses of whole chromosomes, most often 1, 2, 6, 7, 10, 13, 17 and 21.

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Reference: Chromophobe

Which of the following is the most likely immunohistochemical profile of the renal neoplasm shown above?

1. CK7+, KIT+, vimentin-, CAIX-
2. CK7+, KIT+, vimentin-, CAIX+
3. CK7+, KIT+, vimentin+, CAIX-
4. CK7-, KIT+, vimentin-, CAIX-
5. CK7-, KIT-, vimentin+, CAIX+

A. CK7+, KIT+, vimentin-, CAIX-. The image shown is chromophobe renal cell carcinoma (ChRCC), eosinophilic subtype. Histologic clues to the diagnosis of ChRCC are the raisinoid nuclei, perinuclear clearing / halos and prominent, plant cell-like borders. Furthermore, at least 80% of the cells have an eosinophilic cytoplasm, thus making it the eosinophilic variant of ChRCC. The immunoprofile of ChRCC is typically CK7+, CD117 / KIT+, vimentin- and CAIX-. The other entity to consider is oncocytoma but in this case the degree of nuclear pleomorphism (with enlarged, wrinkled and oval nuclei) favors ChRCC. Answer D is incorrect because CK7-, KIT+, vimentin-, CAIX- would be the immunohistochemical profile most typical of oncocytoma, although vimentin can be focally positive in both ChRCC and oncocytoma in the central scar area. Answer E is incorrect because it is the immunoprofile most typical of clear cell renal cell carcinoma; while high grade clear cell RCC may be predominantly eosinophilic, the perinuclear clearing and raisinoid nuclei are still most characteristic of ChRCC. Answer B is incorrect because CAIX is almost always negative in ChRCC while positivity is more characteristic of clear cell RCC. Answer C is incorrect because ChRCC is typically negative for vimentin. Positive vimentin staining is more characteristic of clear cell RCC, especially when higher grade and mostly eosinophilic.

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Reference: Chromophobe

Which of the following is true regarding eosinophilic chromophobe RCC compared to classic ChRCC?

1. Classic ChRCC is more likely to have a brown coloration grossly
2. Classic ChRCC typically has smaller cells than eosinophilic ChRCC
3. Eosinophilic ChRCC must have 100% eosinophilic cells
4. No differences in cytogenetics have been found between eosinophilic and classic ChRCC
5. The prognosis of eosinophilic ChRCC is the same as classic ChRCC

E. The prognosis of eosinophilic ChRCC is the same as classic ChRCC. Studies have shown no difference in prognosis between the different histologic subtypes and morphologic patterns of ChRCC and classic ChRCC. Answer D is incorrect because a recent study showed that eosinophilic ChRCC frequently has less chromosomal instability compared with classic ChRCC and is often characterized by doubled hypodiploidy (Cancers (Basel) 2019;11:1492, Hum Pathol 2020;104:18). Answer A is incorrect because the gross brown coloration of chromophobe RCC correlates with the amount of eosinophilic cells. In this sense, eosinophilic ChRCC is more likely to be brown in coloration grossly. Answer B is incorrect because the eosinophilic cells of eosinophilic ChRCC are typically smaller compared with those of classic ChRCC. Answer C is incorrect because, by definition, eosinophilic ChRCC only needs to have at least 80% eosinophilic cells.

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Reference: Chromophobe