Kidney tumor
Adult renal cell carcinoma - rare
TCEB1 mutated


Topic Completed: 6 January 2020

Minor changes: 27 October 2020

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: TCEB1[TIAB] OR monosomy 8[TIAB]) renal cell carcinoma

Maria Tretiakova, M.D., Ph.D.
Page views in 2019: 448
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Cite this page: Tretiakova M. TCEB1 mutated. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneytumortceb1mutatedrcc.html. Accessed November 26th, 2020.
Definition / general
  • Renal cell carcinoma (RCC) composed of clear cells separated by thick fibromuscular bands and associated with mutation of TCEB1 gene
Essential features
  • Low grade clear cells with voluminous cytoplasm
  • Transecting thick fibromuscular septae imparting multilobular appearance
  • Biallelic inactivation of TCEB1 gene: mutation with concurrent monosomy 8 or loss of heterozygosity at 8q21
  • Lack VHL mutations, hypermethylation or loss of heterozygosity at 3p (Histopathology 2019;74:31, Mod Pathol 2015;28:845, Histopathology 2019;74:60)
Terminology
  • Transcription Elongation Factor B (TCEB1) mutated renal cell carcinoma
  • Monosomy 8 renal cell carcinoma
ICD coding
  • ICD10: C64 - malignant neoplasm of kidney, except renal pelvis
Epidemiology
Sites
  • Solitary kidney mass
  • Renal cortex
Pathophysiology
  • TCEB1 located at chromosome 8q21.11 and encodes 112-residue protein elongin C, subunit 1 of transcription factor B (SIII) complex
  • Elongin C is part of VHL complex responsible for proteosomic degradation (ubiquitination) of hydroxylated HIF
  • Loss of Elongin C leads to HIF1α stabilization, accumulation, activation of hypoxia inducible growth factors and tumor development
  • Downregulate other genes in ubiquitination complex including POLR2E, POLR2C, CDK7, TCEA1 and TCEB2
  • Increase the POL II transcription elongation past template encoding arresting sites (Nat Genet 2013;45:860, Mod Pathol 2015;28:845)
Etiology
  • Hotspot mutations in TCEB1 gene always accompanied by loss of chromosome 8 (loss of heterozygosity at 8q or monosomy 8)
  • TCEB1 mutations and VHL abnormalities are mutually exclusive (Nat Genet 2013;45:860)
Clinical features
  • Vast majority are incidental: pT1a
  • Rare tumors are pT3a
Prognostic factors
  • No recurrence or metastasis reported to date
Case reports
  • Not available at this time
Treatment
  • Surgical: partial or radical nephrectomy
Gross description
Microscopic (histologic) description
  • Clear cell tumor with multinodular appearance at low power due to transecting thick fibrous or fibromuscular bands
  • Variable architecture combining solid, alveolar, nested patterns with occasional cystic and tubulopapillary features
  • Cells with predominantly clear voluminous cytoplasm, prominent cell membranes and low nucleolar grade (WHO / ISUP grade 1 or 2)
  • No necrosis, lymphovascular invasion or heavy inflammatory infiltrate (Mod Pathol 2015;28:845, Histopathology 2019;74:31)
Microscopic (histologic) images

Contributed by Maria Tretiakova, M.D., Ph.D.
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TCEB1 mutated RCC

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CAIX

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CK7

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CD10

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Clear cell RCC with TCEB1-like features

Positive stains
Negative stains
Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:
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TCEB1 mutations and HIF accumulation

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TCEB1 mutated RCC with monosomy 8

Sample pathology report
  • Left kidney, mass, partial nephrectomy:
    • Renal cell carcinoma with clear cell features, unclassified (see synoptic report and comment)
    • Comment: The carcinoma is morphologically consistent with clear cell renal cell carcinoma but contains prominent fibromuscular stroma. The immunohistochemical stains demonstrate that the neoplastic cells are positive for CAIX, variably positive for CK7 and CD10 but negative for TFE3. The tumor histology and variable CK7 positivity raise the possibility of a recently described TCEB1 mutated renal cell carcinoma. Molecular characterization can be attempted to confirm the histologic impression.
Differential diagnosis
Board review style question #1
    Which is true about TCEB1 mutated renal cell carcinoma?

  1. Definitive diagnosis is based on documenting either TCEB1 mutation or absence of chromosome 8 (monosomy 8)
  2. Morphologically identical to clear cell renal cell carcinoma with prominent fibromuscular stroma
  3. Multiple reports indicate relatively high incidence of this tumor type
  4. TCEB1 and TFEB genes belong to the same family of transcription factors
  5. Typically pursue aggressive course
Board review answer #1
B. TCEB1 mutated renal cell carcinoma is a distinct genomic entity of RCC with clear cell phenotype, mutations of TCEB1 gene with concurrent loss of heterozygosity at chromosome 8. Histologically these tumors are similar to conventional clear cell renal cell carcinoma but contain thick traversing fibromuscular bands transecting the tumor parenchyma and imparting multinodular appearance. Based on peculiar stromal prominence, these tumors were included into the 2016 World Health Organization Classification as a provisional entity of RCCs with (angio)leiomyomatous stroma. Grossly tumors are unifocal, small, well circumscribed and often encapsulated with tan nodular cut surface. On microscopy, neoplastic cells have voluminous clear cytoplasm, low grade nuclei and could be arranged in several architectural patterns in various combinations: solid alveolar, nested, cystic or tubulopapillary. Immunostaining shows a characteristic pattern: diffuse membranous box-like expression of CAIX, diffuse HIF1α, strong CK7 in the majority but not 100% of tumors cells, patchy and weak CD10, negative HMWCK, GATA3 and TFE3. Virtually all reported cases are incidental low stage indolent tumors with no recurrences or metastases.

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Reference: TCEB1 mutated renal cell carcinoma
Board review style question #2
    Which immunohistochemical results will raise concern of TCEB1 mutated renal cell carcinoma in 45 year old patient with 3 cm encapsulated tumor having prominent stroma and clear cell morphology, shown here?

  1. HMWCK-, CD10-, TFE3+, RCC+
  2. HMWCK-, CK7-, CAIX+, CD10+
  3. HMWCK-, CK7+, CAIX+, CD10-
  4. HMWCK+, CK7+, CAIX+, GATA3+
Board review answer #2
C. The microscopic image shows a clear cell tumor with solid alveolar and microcystic areas with abundant fibromuscular stroma separating tumor into nodules. These features are often seen in conventional clear cell renal cell carcinoma but also raise a suspicion of rare indolent tumor entity of renal cell carcinoma with (angio)leiomyomatous stroma including TCEB1 mutated RCC. From the above panels, only answer B is consistent with TCEB1 mutated RCC; but definitive diagnosis requires molecular studies confirming mutation of TCEB1 gene and loss of heterozygosity at 8q21/monosomy 8.

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Reference: TCEB1 mutated renal cell carcinoma
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