1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA) 2.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)l
Chromophobe renal cell carcinoma (ChRCC) is the third most common type of RCC characterized by chromosomal aneuploidy, TP53, PTEN, and mitochondrial gene mutations. 1-3
Chromophobe renal cell carcinoma arises from the intercalated cells of the collecting duct. Most tumors are sporadic, but ChRCC has been diagnosed in patients with genetic syndromes, mainly Birt-Hogg-Dube’ syndrome OMIM:135150, rarely BAP1 tumor predisposition syndrome OMIM:614327, hereditary paraganglioma/ pheochromocytoma OMIM:185470 and OMIM:602690, Cowden syndrome OMIM:158350, and tuberous sclerosis OMIM:191100) and {omim.
Patients with ChRCC often present at an earlier stage (mostly pT1) compared with other RCC subtypes. Most patients are asymptomatic at diagnosis, with most cases detected as an incidental renal mass. However, a small subset of ChRCC will transform into a high grade carcinoma; these tumors are typically larger and patients may present with pain, a mass and hematuria.
A well-circumscribed well circumscribed mass with solid, homogeneous, and pale tan to dark brown cut surfaces (Fig.1). Necrosis is usually only seen with high grade transformation.
Figure 1. A well circumscribed brown/mahogony mass with areas of degeneration is present in the central protion of the kidney.
Most ChRCC are comprised of eosinophilic to clear cells with prominent cell borders, round to oval shaped nuclei with irregular nuclear borders and scattered multinucleated tumor cells (Fig.2),. Perinuclear halos are a common finding. The growth pattern is is typically solid with long linear vessels (the latter are sometimes hyalinized); however rare cases may demonstrate tubular growth. Significant nuclear atypia, sarcomatoid differentiation, necrosis and increased mitoses are seen in cases with high grade transformation
Figure 2. Histologically, the tumor demonstates tumor cells with prominent cell borders, irregular shaped nuclei, and hyalinized long linear vessels.
The classic immunoprofile includes strong and diffuse CK7 and KIT expression, and an absence of CA9.
The clinical course of ChRCC is less aggressive as compared to ccRCC. However, high grade and sarcomatoid changes are a sign of aggressive behavior and poor prognosis. A small fraction of patients present with metastatic disease at the time of diagnosis, with liver and lung, been the most reported common sites of metastases.
ChRCC is characterized by a unique genetic profile with multiple chromosome losses, mainly chrs.1, 2, 6, 10, 13, 17, 21 in the majority of the cases (Fig. 3), but additional chromosome losses can be observed, e.g. chrs 3, 5, 8, 9, 11, and 18.4,5
Fig.3 GTG-banding karyotype showing the most frequent chromosome losses in chromophobe RCC: 2, 6, 10, 13, 17, 21 and Y.
The comparative genomic hybridization profiles showed that the classic ChRCC group had more chromosomal losses (Fig.4) but fewer chromosomal gains than the ChRCC group with sarcomatoid features.6
Fig.4 Microarray profile showing loss of chromosomes 1, 2, 6, 10, 13, and 17
A low somatic mutation rate has been identified in ChRCC with TP53, PTEN as the most frequently mutated genes, with higher mutation rates in ChRCC patients with metastatic disease and with sarcomatoid features. Loss of the CDKN2A gene or its expression, by either deletion of 9p21.3 or hypermethylation is also frequently observed TERT promoter was altered by chromosomal rearrangements resulting in a novel mechanism for increased TERT expression Less common mutations have been noted in MTOR, NRAS, TSC1 and TSC2. 4,7-9 There are increased mitochondrial genome copy numbers and increased utilization of the Kreb’s cycle and electron transport chain for ATP generation in ChRCC.
Paola Dal Cin ; Michelle S. Hirsch
Chromophobe renal cell carcinoma
Atlas Genet Cytogenet Oncol Haematol. 2023-09-27
Online version: http://atlasgeneticsoncology.org/solid-tumor/209207