Kidney: Chromophobe renal cell carcinoma

2016-11-01   Paola Dal Cin, PhD , Michelle S. Hirsch, MD 

1.Department of Pathology, Brigham, Womens Hospital, 75 Francis Street, Boston, MA 02115, USA

Classification

Classification

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

Clinics and Pathology

Epidemiology

ChRCC comprise ~5% of all renal cell carcinomas. Most tumors are sporadic, with a slight male predilection.

Pathology

  • 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 Hales 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.
    • Atlas Image
    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.
    Atlas Image
    Fig 1B: A Hales colloidal iron stain is positive (blue) in the cytoplasm of ChRCC tumor cells.

    Cytogenetics

    Atlas Image
    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

    Cytogenetics morphological

    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.

    Genes Involved and Proteins

    Note

  • 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 name

    TERT (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 description

    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 name

    PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten)

    Location

    10q23.31

    Note

    PTEN mutations are found in approximately 20% of chromophobe RCCs1.

    Protein description

    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 name

    TP53 (Tumour protein p53 (Li-Fraumeni syndrome))

    Location

    17p13.1

    Note

    Approximately 32% of chromophobe RCCs have a TP53 mutation.

    Protein description

    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.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    239455922013Signatures of mutational processes in human cancer.Alexandrov LB et al
    273301052016Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas.Haake SM et al
    266122172015Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics.Hirsch MS et al
    106139632000FISH analysis in chromophobe renal-cell carcinoma.Iqbal MA et al
    13825701992Low chromosome number in chromophobe renal cell carcinomas.Kovacs A et al
    33494391988Binucleated cells in a human renal cell carcinoma with 34 chromosomes.Kovacs G et al
    75198271994Specific loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe renal cell carcinomas revealed by comparative genomic hybridization.Speicher MR et al
    240255192013The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.Srigley JR et al
    25656181989The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct.Störkel S et al
    95374681998Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining.Tickoo SK et al

    Citation

    Paola Dal Cin, PhD ; Michelle S. Hirsch, MD

    Kidney: Chromophobe renal cell carcinoma

    Atlas Genet Cytogenet Oncol Haematol. 2016-11-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5124/kidney-chromophobe-renal-cell-carcinoma

    Historical Card

    2001-10-01 Kidney: Chromophobe renal cell carcinoma by  Paola Dal Cin 

    Department of Pathology, Brigham, Womens Hospital, 75 Francis Street, Boston, MA 02115, USA