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MiT Family Translocation Renal Cell Carcinoma

Definition

  • Renal carcinoma associated with gene fusions in MiT family transcription factors TFE3 or TFEB

Alternate/Historical Names

  • Juvenile renal cell carcinoma
  • Xp11/TFE3 translocation carcinoma

Diagnostic Criteria

  • Presence of translocation of TFE3 or TFEB
    • May be demonstrated by classical cytogenetics, PCR or FISH
    • Demonstration may not be required in every case
    • Most common abnormalities are t(6;11) between TFEB and Alpha/MALAT1
      • Immunohistochemistry showing strong nuclear staining for TFEB is highly specific for t(6;11)
    • Less common is fusion Xp11 of TFE3 and ASPL
      • Immunohistochemistry showing strong nuclear staining with antibody to the C terminus of TFE3 is highly sensitive and specific for Xp11
    • Break apart FISH may be useful and less sensitive to fixation effects
  • Xp11 and t(6;11) tumors can overlap morphologically
    • Compoed of cells with abundant to voluminous cytoplasm
      • Clear to granular eosinophilic cytoplasm
      • Sharp cell borders
    • Pleomorphic and polymorphic growth patterns
      • Frequent papillary, pseudopapillary, alveolar and nested patterns
      • Bbiphasic appearance with clusters of small cells centered on hyaline cores may be seen
        • Collections of small cells should suggest a t(6;11) carcinoma
    • Patterns and cells may vary according to the precise translocation involved
    • Large vesicular nuclei
      • Prominent round nucleoli
      • Mitotic figures frequent
    • Features frequently present
      • Psammoma bodies may be abundant
      • Intracytoplasmic hyaline droplets
    • May coontain melanin pigment and express melanocytic markers
  • Negative to weak keratn and EMA staining
  • Most cases reported in children and young adults
    • Under-recognized in adults
      • Two studies find an incidence of 1-5% in adults (Zhong, Sukov)
      • If possible, fresh tumor tissue should be sent for cytogenetics in all renal tumor patients under 40 years of age and in older patients in which an unusual tumor is discovered at frozen section

 

Kurt Schaberg MD
John P Higgins MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 11/21/16

Supplemental studies

Immunohistology

Keratin weak to neg
EMA, CK7 neg
AMACR/racemase/P504S pos
CD10 pos
PAX8 pos
CA9 typically neg
Cathepsin K variable
CD117 neg
TFE3 or TFEB

pos

MelanA, HMB45 Variable, frequently weak
  • Lack of, or minimal, cytokeratin and EMA expression may be the most helpful immunophenotypic findings

Molecular Genetic Study

  • Classical cytogenetics, PCR and FISH can demonstrate translocations involving TFEB or TFE3
    • FISH is more sensitive than immunohistochemistry (Green 2013)

 

Differential Diagnosis

  • Translocation carcinoma should be considered in the following situations
    • Any clear or papillary renal carcinoma in a patient under 35
    • Any carcinoma combining papillary with clear cell features
    • Any carcinoma with nests of cells with voluminous cytoplasm
    • Any carcinoma with large numbers of psammoma bodies
  • Immunohistochemistry can be useful in such cases
  • FISH or PCR may be required to make the diagnosis

Immunohistochemistry for the differential diagnosis of renal MiT translocation carcinomas
  CD10 Racemase CK7 EMA CD117
MiT Translocation Ca >90% >90% neg neg neg
Clear Cell Ca >90% 0-20% neg >90% neg
Papillary Ca >90% >90% >90% >90% neg
Chromophobe Ca neg neg >90% >90% >90%
Nuclear staining for TFE3 and/or TFEB (if available) appears to be sensitive and specific for translocation carcinoma

MiT Family Translocation Renal Cell Carcinoma Clear Cell Papillary Renal Cell Carcinoma
Frequently occurs under age 20 Mean age 60
Typically high grade nuclear features Low grade nuclear features, nuclei linear, apical
Voluminous cytoplasm Moderate amount of clear cytoplasm
TFEB or TPF3 immunostain or FISH positive Lacks TFEB or TPF3 translocations
CK7 and other keratins negative to weak, CD10 pos, Racemase/AMACR pos CK7 strong pos, CD10 neg, Racemase/AMACR neg
Variable expression of melanocytic markers Melanocytic markers neg
CA9 negative CA9 basolateral positive

MiT Family Translocation Renal Cell Carcinoma Papillary Renal Cell Carcinoma
Frequently occurs under age 20 Mean age 60
Mixed papillary and clear cell areas Clear cell areas focal to absent
Voluminous cytoplasm Moderately abundant cytoplasm at most
Typically high grade nuclear features May have any grade nuclear features
TFEB or TPE3 immunostain or FISH positive Lacks TFEB or TPE3 translocations
CK7 & EMA negative to weak CK7 & EMA frequently strong positive (but may be negative)

MiT Family Translocation Renal Cell Carcinoma Clear Cell Renal Cell Carcinoma
Frequently occurs under age 20 Mean age 60
Frequently papillary Papillary pattern not prominent
Typically high grade nuclear features Variable nuclear grrade
Voluminous cytoplasm Moderate amount of clear cytoplasm
TFEB or TPF3 immunostain nuclear positive, CA9 negative Lacks TFEB or TPF3 staining, CA9 positive
Keratins and EMA negative to weak Keratins and EMA generallly positive
Variable expression of melanocytic markers Melanocytic markers neg
Translocations involving TFE3 or TFEB Often VHL mutation or chromosoome 3p loss
Psammoma bodies may be promiinent Psammoma bodies rare

Grading / Staging

Grading

  • Use WHO/ISUP grading, but significance is unclear (see below)
    • Most cases grade 3

Staging

  • Use TNM for renal cell carcinoma

  • WHO/ISUP grading system for clear cell and papillary renal cell carcinomas
  • Grade 1 Nucleoli are absent or inconspicuous and basophilic at 400x magnification
    Grade 2 Nucleoli are conspicuous and eosinophilic at 400x and visible but not prominent at 100x
    Grade 3 Nucleoli are conspicuous and eosinophilic at 100x
    Grade 4 Extreme nuclear pleomorphism, multinucleate giant cells, and/or rhabdoid and/or sarcomatoid differentiation
  • Sarcomatoid differentiation may be seen in many types of renal carcinomas (de Peralta-Venturina; Cheville)
    • It no longer refers to a type of carcinoma
    • It is considered an adverse prognostic factor
      • Prognosis may be worse than simple grade 4 carcinoma
    • Defined as a spindle cell component measuring at least one low power (40x) field with either
      • Adjacent carcinoma, or
      • Evidence of epithelial differentiation in the spindle cells
    • Spindle cells usually show moderate to marked atypia
      • Frequent patterns include fibrosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma
      • Occasional cases have low grade atypia in spindle component
      • No clinical significance to type of differentation or degree of atypia
    • May arise in setting of many types of carcinoma
      • Clear cell RCC (reported 5-8% incidence of sarcomatoid foci, in our experience it is less frequent)
      • Papillary RCC (2-3% incidence)
      • Chromophobe RCC (9% incidence)
      • Collecting duct carcinoma (39% incidence)

Staging

  • Use TNM for renal cell carcinoma

Clinical

  • Mean age reported about 25
    • Most studies have focused on renal tumors arising in young people
    • Has been reported at all ages
      • Clearly has been under-recognized in the past in adults
  • Behavior uncertain
    • Frequently presents with metastases
    • Initial reports suggested relatively indolent behavior
    • Later reports describe more aggressive behavior, especially in adults
  • A few cases have been reported following chemotherapy for other processes

Classification / Lists

Renal epithelial neoplasms

Bibliography

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