Renal medullary carcinoma

2021-10-29   Paola Dal Cin , Michelle S. Hirsch 

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)

Classification

Definition

Renal medullary carcinoma (RMC) is rare and highly malignant neoplasm that most often occurs in teenagers or young adults with sickle cell trait or other associated hemoglobinopathy.  The existence of RMC without a concomitant hemoglobinopathy is a controversial subject, and most consider the latter an Unclassified RCC with Medullary Features and SMARCB1/INI1 loss.

Clinics and Pathology

Epidemiology

African descent increases risk 1,2. It occurs in approximately 1 in 20,000 individuals with sickle cell trait or other associated hemoglobinopathy RMC is the third most common kidney malignancy among male adolescents and young adults 3.

Clinical features

Young male patient of African or Mediterranean descent, with hematuria and/or flank pain and/or a palpable mass, and weight loss 4.

Macroscopic apperances

Poorly circumscribed mass arises predominantly from the right kidney occupying most of the renal medulla with extension into the renal cortex 5.

Histopathology

A characteristic reticular or cribriform pattern with a striking desmoplastic stromal response and a robust mixed inflammatory infiltrate.

Tumors with SMARCB1-translocation were more likely to show reticular and cribriform pattern versus those with other growth patterns (64% vs 17%, respectively), whereas tumors with SMARCB1 homozygous loss were significantly enriched for a solid growth pattern.

Immunohistochemistry

Loss of SMARCB1 protein expression (Fig. 1) is a key diagnostic feature of these tumors, Aberrant expression of OCT3/4 may also be present.  Secondary loss of SMARCB1 expression has been found in other RCC types 6.


Fig. 1 Renal medullary carcinoma: the absence (loss) of SMARCB1 protein expression is clear in on the tumor cells, in contrast inflammatory, endothelial and stroma cells are positive.

Genetics

Cytogenetics

The most common molecular alteration was inactivating translocation of one SMARCB1 allele and deletion (-22,/del22q) of the second allele.  Less frequent is  deletion of both SMARCB1 alleles, representing an important molecular mechanism in patients with sickle cell trait 8,9,10,11; this is a relatively unique mechanism that has not been well described in other [[SMARCB1-deficient neoplasms]] 12.
RMC also has recurrent focal copy number alterations in chromosomal fragile sites, such as amplifications (11q14.3, NOTCH2, chr.2) and deletions (chr.4 and 22), in addition to 22q11.23 loss.  Chromosome 8q gain was noted with significantly upregulated genes in that chromosome arm 11.

Mutations

SMARCB1 somatic mutations are detected uncommonly, as well as recurrent mutations.

Note

By gene expression profiling, RMC may be closely related to collecting duct carcinoma, but is clearly distinct from malignant rhabdoid tumor of the kidney; the latter shares etiology of SMARCB1 inactivation 11

Promiscuity

SMARCB1 loss has also been identified in a variety of other malignant neoplasms 13,14,15

Cytogenetics

Prognosis and treatment

Very poor prognosis; metastatic disease (liver, lungs, bone and adrenal glands) frequent at the time of presentation. Resistant to conventional chemotherapy, and a fatal outcome often occurs within a few months 4,5.

Given the presence of SMARCB1 alterations, targeted therapies utilized for the management of other SMARCB1-deficient neoplasms may prove to be helpful/increase survival 7.

Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
1302872232019Updated Recommendations on the Diagnosis, Management, and Clinical Trial Eligibility Criteria for Patients With Renal Medullary Carcinoma.Msaouel P et al
2308551712019Renal Medullary Carcinoma.Elliott A et al
3294401902018A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma.Msaouel P et al
4306564882019Renal Medullary Carcinoma: a Report of the Current Literature.Blas L et al
5278601492017Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study.Shah AY et al
6279842372017Rhabdoid and Undifferentiated Phenotype in Renal Cell Carcinoma: Analysis of 32 Cases Indicating a Distinctive Common Pathway of Dedifferentiation Frequently Associated With SWI/SNF Complex Deficiency.Agaimy A et al
7308604822019Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition.Hong AL et al
8264335722016Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.Calderaro J et al
9285589872017Genomic Characterization of Renal Medullary Carcinoma and Treatment Outcomes.Carlo MI et al
10309800402019Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma: morphologic and molecular analysis of 20 cases.Jia L et al
11323593972020Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma.Msaouel P et al
12219343992011INI1-deficient tumors: diagnostic features and molecular genetics.Hollmann TJ et al
13269411812016Gene of the month: SMARCB1.Kalimuthu SN et al
14292806802018SMARCB1-deficient Tumors of Childhood: A Practical Guide.Pawel BR et al
15319821812020SMARCB1 (INI1)-deficient thyroid carcinoma: A novel entity expanding the spectrum of tumors with INI1 loss.Agarwal S et al

Citation

Paola Dal Cin ; Michelle S. Hirsch

Renal medullary carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2021-10-29

Online version: http://atlasgeneticsoncology.org/solid-tumor/208910/renal-medullary-carcinoma