Chromophobe renal cell carcinoma: Novel molecular insights and clinicopathologic updates

doi:10.1016/j.ajur.2021.11.010

Asian Journal of Urology, 2022, 9 (1): 1-11 doi: 10.1016/j.ajur.2021.11.010

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Chromophobe renal cell carcinoma: Novel molecular insights and clinicopathologic updates

Reza Alaghehbandan^a,*(

),Christopher G. Przybycin^b,Virginie Verkarre^c,Rohit Mehra^d,e,f,**(

)

^a Department of Pathology, Faculty of Medicine, University of British Columbia, Royal Columbian Hospital, Vancouver, BC, Canada
^b Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
^c Department of Pathology, Georges Pompidou European Hospital, AP-HP, Paris University, INSERM UMR 970, PARCC, Paris, France
^d Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
^e Michigan Center for Translational Pathology, Ann Arbor, MI, USA
^f Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA

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Abstract

Chromophobe renal cell carcinoma (ChRCC) is the third most common renal cell carcinoma (RCC) subtype, which predominantly occurs in sporadic setting. ChRCCs are considered to originate from the intercalated cell of distal tubules with two main morphological variants, classic and eosinophilic. Most ChRCCs carry a favorable clinical outcome. Histology alone is limited in predicting the behavior of ChRCCs that do not have overtly aggressive morphologic findings such as necrosis and sarcomatoid features. Along with positive CD117 expression, classic ChRCCs generally express diffuse and uniform CK7, while eosinophilic variant demonstrates more heterogeneous CK7 expression (rare or patchy). Multiple losses of chromosomes 1, 2, 6, 10, 13, 17, and 21 are considered to be the genetic hallmarks of classic and eosinophilic ChRCCs, while chromosomal gains are known to be associated with sarcomatoid ChRCCs. TP53 and PTEN are the two most frequently mutated genes in ChRCCs. The major challenge in the differential diagnosis of ChRCCs includes considerations around the eosinophilic variant (of ChRCCs), where it may share overlapping features with oncocytoma or other recent emergent oncocytic tumors. Most eosinophilic ChRCCs share expression of the recently described biomarkers, LINC01187 and FOXI1, with classic ChRCCs, however, a subset of eosinophilic-like ChRCCs with lower biomarker expression have been demonstrated to harbor MTOR gene mutations. Overall, the morphologic features of ChRCCs and genetic profile with combinations of chromosomal losses and gains suggest this tumor entity to represent a distinct, yet heterogeneous group of renal neoplasms.

Key words： Renal cell carcinoma Chromophobe Immunohisto-chemistry RNA in situ hybridization Next-generation sequencing Oncocytic tumors Molecular

Received: 24 August 2021 Available online: 20 January 2022

Corresponding Authors: Reza Alaghehbandan,Rohit Mehra E-mail: reza.alagh@gmail.com;mrohit@med.umich.edu

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Reza Alaghehbandan,Christopher G. Przybycin,Virginie Verkarre, et al. Chromophobe renal cell carcinoma: Novel molecular insights and clinicopathologic updates[J]. Asian Journal of Urology, 2022, 9(1): 1-11.

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http://www.ajurology.com/EN/10.1016/j.ajur.2021.11.010 OR http://www.ajurology.com/EN/Y2022/V9/I1/1

Classic and sarcomatoid ChRCCs. (A) Classic ChRCC H & E stain; (B) Sarcomatoid ChRCC H & E stain; (C) Membranous staining for CD117; (D) High-level nuclear LINC01187 expression. All images are at 200×. ChRCC, chromophobe renal cell carcinoma; H & E, hematoxylin and eosin.

Eosinophilic variant of ChRCC. (A) Eosinophilic variant of ChRCC H&E stain; (B) Predominantly membranous staining for CD117; (C) The nuclear staining for FOXI1 in eosinophilic variant of ChRCC; (D) High-level nuclear LINC01187 expression; (E) Another example of eosinophilic variant of ChRCC H & E stain; (F) With negative CD117 expression and MTOR gene mutation (data not shown). All images are at 200×. ChRCC, chromophobe renal cell carcinoma; H & E, hematoxylin and eosin.

Distribution of chromosomal losses and gains in classic, eosinophilic and sarcomatoid ChRCC. ChRCC, chromophobe renal cell carcinoma.

Molecular aberrations and mutation summary for ChRCC including a comparison with CCRCC and PRCC.

Renal tumor subtype	Clinical feature	Morphologic feature	Ancillary feature	Molecular aberration
ChRCC	- Majorityindolent, 3%-10% metastasis; mostly sporadic; rare hereditary setting (TSC, BHD, and Cowden)	- Large pale cells with prominent cell membranes, +/- admixed with granular eosinophilic cytoplasm and wrinkled nuclei with perinuclear haloes, solid/large alveolar architecture with incomplete vascular septa	- CD117+;usually diffuse CK7+ (sometimes focal or negative); positive expression of LINC01187 and FOXI1; vimentin-	- Multiple chromosomallosses and gains; TP53 and PTEN gene mutations; other less common mutations
Eosinophilic variant of ChRCC	- Similar to ChRCC	- Granulareosinophilic cytoplasm, perinuclear haloes, and nested architecture	- CD117+; more focal CK7+; expression of LINC01187 and FOXI1; vimentin-; SDHB retained	- Diploidormultiple chromosomal losses
Oncocytoma	- Benignandmostly sporadic	- Granulareosinophilic cytoplasm, central “archipelagos”, uniform round nuclei with minimal atypia and no mitotic activity	- CD117+;focalto negative CK7; positive for LINC01187 and FOXI1	- Diploid or hypodiploid (-1, X, Y, 14, 21); 11q13 (CCND1 locus) rearrangement; mutation in mitochondrial gene
Hybrid oncocytic tumor	- Exceptionalmetastases; usually associated with BHD	- Features of oncocytoma and ChRCC in the same tumor	- Variable;generally CD117+; CK7 focal to patchy	- Germline mutations in FLCN encoding folliculin
Low-grade oncocytic RCC, unclassified or oncocytic renal neoplasm of low malignant potential	- Presumably indolent	- Resembles oncocytoma with greater nuclear atypia and absence of diagnostic features of another oncocytic neoplasm	- GenerallyCD117+; CK7 variable	- Unknown
ESC-RCC^a	- Established, metastatic potential; sporadic or germline	- Solid and cystic architecture, abundant cytoplasm with coarse basophilic granules	- Usually CK20+; CK7- or focal; CD117-; vimentin+	- TSC1/TSC2 somatic or germline mutations
LOT^a	- Indolent^band mostly sporadic	- Solidarchitecturewith edematous areas, monomorphic round to oval nuclei with delicate perinuclear haloes	- CK7+diffusely; CD117-; vimentin-; SDHB retained	- Disomicordel 19p13, 19q13, 1p36; MTOR gene mutations in borderline tumor or closely similar tumor
EVT^a	- Indolent^b;sporadic or germline	- Solid/nested growth, oncocytic cytoplasm with large vacuoles, and prominent nucleoli	- CD117+;CK7-or focal+; vimentin-; cathepsin-K+; CK20-; SDHB retained	- TSC2/MTORgene mutations; loss of chromosomes 1 and 19, LOH of 16p11.2-11.1; 7q31.31
SDH-deficient RCC	- Established metastatic potential; germline	- Eosinophilic cytoplasm with vacuoles containing eosinophilic to pale flocculent material	- Loss of SDHB; CD117-; CK7-	- Germline mutations in one of the SDH genes
ALK-RCC	- Established metastatic potential	- Eosinophilic cytoplasm, variable and admixed architecture, mucinous/myxoid background	- ALK+; SDHB and FH retained	- Rearrangementof ALK with various partners

Clinical, histologic, immunophenotypic, and molecular summary of ChRCC, eosinophilic variant, and overlapping entities.

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