Kidney: Chromophobe renal cell carcinoma

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Written2001-10Paola Dal Cin
Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Updated2016-11Paola Dal Cin, Michelle S. Hirsch
Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA

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1. Identity

ICD-Morpho 8317/3 Renal cell carcinoma, chromophobe type
Atlas_Id 5124
Phylum Urinary system: Kidney::Chromophobe renal cell carcinoma
WHO/OMS Classification Urinary system

2. Classification

    Chromophobe renal cell carcinoma (ChRCC) is a distinct subtype of renal cell carcinoma, possibly originating from the the distal nephron.

3. Clinics and Pathology

Epidemiology ChRCC comprise ~5% of all renal cell carcinomas. Most tumors are sporadic, with a slight male predilection.
  • ChRCC tumors can vary in size and have a tan to brown cut surface. The growth pattern is often solid with sheets of cells divided by vascular septae, some of which may have perivascular hyalinized stroma. ChRCC tumor cells have pale cytoplasm and distinct cell membranes. Small eosinophilic cells with granular appearance may be present. Nuclei may appear atypical, but are usually small with wrinkled nuclear membranes and multinucleation (Fig1A). ChRCC grading is complicated by the nuclear atypia, and Fuhrman nuclear grading should not be used. Prognosis is generally favorable with low grade, low stage tumors; but increased cytologic atypia, increased mitotic activity, necrosis, and vascular invasion are poor prognostic indicators. Sarcomatoid differentiation and high tumor stage are also predictors of poor outcome.
  • Special stains and immunohistochemistry can be used to distinguish ChRCC from other renal epithelial neoplasms. The presence of Hale's colloidal iron in the cytoplasm of tumor cells is supportive of ChRCC (an apical staining pattern is more supportive of oncocytoma) (Fig.1B). Immunohistochemical expression of CK7 (patchy to diffuse) combined with the absence of S100A1, HNF1beta (nuclear), and CD10 is consistent with a ChRCC.
  • Occasionally composite oncocytic tumors with features of both oncocytoma and ChRCC tumors have been described, and are most commonly seen in patients with Birt-Hogg-Dube' syndrome and/or oncocytosis.
    Fig. 1A: ChRCC (H&E stain) is comprised of sheets of tumor cells with well-defined cell borders, round to raisonoid nuclei, and perinuclear halos. Long linear, parallel vessels are common in ChRCC.
    Fig 1B: A Hale's colloidal iron stain is positive (blue) in the cytoplasm of ChRCC tumor cells.

    4. Cytogenetics

    Chromophobe RCCs generally have a tendency to grow very slowly in vitro in comparison to all other type of renal tumors. This may be a reason why cytogenetic reports are scarce and usually few metaphases of poor quality were available for investigation. A low chromosome number ranging between 32-39, without discernible structural changes was the most frequent cytogenetic finding. Chromosomes 1, 2, 6, 10, 13, 17 and 21 were most frequently lost (Fig.2). Endoreduplication of the cells with hypodiploid karyotype has been observed. It is of interest, the presence of an hypodiploid clone can be disclosed by a DNA index of 0.86. The low chromosome number has been confirmed by other techniques such as flow cytometry, comparative genomic hybridization (CGH), restriction fragment length polymorphism (RFLP) analysis, and polymorphic microsatellite markers.
    Fig.2. GTG-banded karyotype showing combination of monosomies 1, 2, 6, 8, 10, 13, 15, 17 and 22, and loss of the Y-chromosome

    5. Genes involved and Proteins

  • High resolution DNA-microarray analysis excluded the occurrence of small specific alteration confirming that this combination of monosomies occurs exclusively in chromophobe subtype of RCC. The most commonly mutated genes in chRCC are TP53 and PTEN, combined with chromosome 17 and 10 deletions (Haake et al 2016).
  • Whole genomes sequencing identified a number of genomic rearrangements in the TERT promoter region, these same tumors displayed elevated TERT gene expression, suggesting a functional role for these gene fusions.
  • Gene NameTERT (telomerase reverse transcriptase)
    Location 5p15.33
    Note Structural rearrangements in the TERT promoter region and TERT upregulation are found in a subset of chromophobe RCCs.
    Protein Telomerase encodes a catalytic subunit of the telomerase enzyme, which functions to maintain telomere ends. Telomerase is upregulated in a variety of tumors and plays a role tumor cell immortalization.

    Gene NamePTEN (Phosphatase and Tensin homolog deleted on chromosome Ten)
    Location 10q23.31
    Note PTEN mutations are found in approximately 20% of chromophobe RCCs1.
    Protein PTEN mutations frequently co-occur with loss of chromosome 10 resulting in complete loss of function. PTEN is a tumor suppressor that functions as a protein and lipid phosphatase and negatively regulates the PI3K-AKT/PKB signaling pathway.

    Gene NameTP53 (Tumour protein p53 (Li-Fraumeni syndrome))
    Location 17p13.1
    Note Approximately 32% of chromophobe RCCs have a TP53 mutation.
    Protein TP53 encodes a tumor suppressor protein, which plays a regulatory role in many cellular processes including DNA repair, growth arrest, apoptosis, senescence and metabolism. Mutations in TP53 are found in a broad range of tumor types.

    6. Bibliography

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    World Health Organization Classification of Tumours of the Urinary Systems and Male Genital Organs
    Moch, H., Humphrey, P.A., Ulbright, T.M., Reuter, V.E. eds (4th edition); IARC Press, Lyon 2016; 11-76.
    ICGC Breast Cancer Consortium
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    ; ICGC MMML-Seq Consortium ; ICGC PedBrain
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    Papillary adenoma.
    Eble J, Delahunt B, Moch H, Martignoni G, Amin MB, Srigley JR, Argani P, Tan PH, Cheville J, Tickoo SK.
    In: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Moch, H., Humphrey, P.A., Ulbright, T.M., Reuter, V.E. eds; IARC Press, Lyon 2016, 42-43.
    Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas
    Haake SM, Weyandt JD, Rathmell WK
    Mol Cancer Res 2016 Jul;14(7):589-98
    PMID 27330105
    Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics
    Hirsch MS, Signoretti S, Dal Cin P
    Surg Pathol Clin 2015 Dec;8(4):587-621
    PMID 26612217
    FISH analysis in chromophobe renal-cell carcinoma
    Iqbal MA, Akhtar M, Ulmer C, Al-Dayel F, Paterson MC
    Diagn Cytopathol 2000 Jan;22(1):3-6
    PMID 10613963
    Low chromosome number in chromophobe renal cell carcinomas
    Kovacs A, Kovacs G
    Genes Chromosomes Cancer 1992 Apr;4(3):267-8
    PMID 1382570
    Binucleated cells in a human renal cell carcinoma with 34 chromosomes
    Kovacs G, Soudah B, Hoene E
    Cancer Genet Cytogenet 1988 Apr;31(2):211-5
    PMID 3349439
    Specific loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe renal cell carcinomas revealed by comparative genomic hybridization
    Speicher MR, Schoell B, du Manoir S, Schröck E, Ried T, Cremer T, Störkel S, Kovacs A, Kovacs G
    Am J Pathol 1994 Aug;145(2):356-64
    PMID 7519827
    Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P; ISUP Renal Tumor Panel
    The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia Am J Surg Pathol
    PMID 24025519
    The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct
    Störkel S, Steart PV, Drenckhahn D, Thoenes W
    Virchows Arch B Cell Pathol Incl Mol Pathol 1989;56(4):237-45
    PMID 2565618
    Tan PH, Cheng L, Rioux-Leclercq N, Merino MJ, Netto G, Reuter VE, Shen SS, Grignon DJ, Montironi R, Egevad L, Srigley JR, Delahunt B, Moch H; ISUP Renal Tumor Panel
    Renal tumors: diagnostic and prognostic biomarkers Am J Surg Pathol
    Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining
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    PMID 9537468

    7. Citation

    This paper should be referenced as such :
    Paola Dal Cin, Michelle S Hirsch
    Kidney: Chromophobe renal cell carcinoma
    Atlas Genet Cytogenet Oncol Haematol. 2017;21(12):472-474.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Dal, Cin P. Kidney: Chromophobe renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2002;6(1):47-48.

    8. External links

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