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Diagnosis: SMARCB1-Deficient Renal Medullary Carcinoma

The following text taken from: WHO Classification of Tumours Editorial Board. Urinary and male genital tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022.

Renal medullary carcinoma is a high-grade adenocarcinoma with SMARCB1 (INI1) deficiency, typically centred in the renal medulla and occurring mainly in patients with sickle cell trait.

Age at diagnosis of SMARCB1-deficient renal medullary carcinoma ranges from childhood to the seventh decade of life. There is a male predominance (M:F ratio: 2:1). Most reported cases of renal medullary carcinoma have been in patients of African ancestry. Almost all patients have had sickle cell trait or haemoglobin SC disease, but a few have had sickle cell disease. A few patients have been reported to have tumours morphologically identical to renal medullary carcinoma but without any haemoglobinopathy. Such tumours have previously been termed “unclassified renal cell carcinoma with medullary phenotype”.

Among patients with renal medullary carcinoma (and in the general population), there are many more individuals with sickle trait than with sickle cell disease. The two conditions confer a similar risk (about 1/40 000 over a 10-year period) of developing renal medullary carcinoma.

In renal medullary carcinomas, the hypoxic and hypertonic environment of the renal medulla, exacerbated by microvascular occlusion by sickle-shaped erythrocytes, may promote the DNA double-strand breaks that are prerequisites for the translocations and deletions that inactivate SMARCB1. About three quarters of these tumours occur in the right kidney; this predilection may be accounted for by the greater length of the right renal artery, which results in less blood flow and relative hypoxia in the right kidney.

Renal medullary carcinomas are usually large and poorly circumscribed, ranging from 40 to 120 mm (mean: 70 mm). Smaller tumours are often centred in the renal medulla. The cut surface of the tumour is frequently tan or grey-white and often shows necrosis.

Renal medullary carcinoma cells typically grow as infiltrating cords, nests, microcysts, sheets, and tubules. Round empty spaces from individual cell necrosis are common, and when numerous, they can impart a cribriform, adenoid cystic carcinoma–like appearance. There is usually a pronounced myxoid desmoplastic reaction with a chronic inflammatory cell infiltrate. The carcinoma cells may show marked nuclear pleomorphism, and they may have vesicular chromatin, prominent nucleoli, and eosinophilic cytoplasm, imparting a rhabdoid appearance. Mitotic figures are numerous. Sickle-shaped erythrocytes are very frequent, both in the vessels within the tumour and in non-tumoural renal parenchyma. By immunohistochemistry, renal medullary carcinomas demonstrate loss of SMARCB1 (also known as INI1, SNF5, or BAF47) protein. Renal medullary carcinomas typically label diffusely for PAX8, broad spectrum cytokeratins, EMA, and vimentin. There is variable labelling for CK7, high-molecular-weight cytokeratin, CEA, and p53. OCT3/4 is strongly positive in about 50% of cases, which creates a potential diagnostic pitfall with metastatic germ cell tumours when young patients present with extensive retroperitoneal nodal involvement.

The main differential diagnostic considerations for renal medullary carcinoma in children are the VCL::ALK fusion RCCs that also occur in patients with sickle cell trait, and renal rhabdoid tumours that occur almost exclusively in very young patients. In adults, the differential diagnosis is mainly high-grade invasive urothelial carcinoma or collecting duct carcinoma. Clinical evidence of sickle cell trait and young age at presentation are typical of renal medullary carcinoma, whereas the presence of in situ urothelial carcinoma or GATA3 positivity favour urothelial carcinoma. The differential diagnosis also includes other renal cancer subtypes with secondary SMARCB1 (INI1) deficiency (e.g. clear cell RCC with sarcomatoid differentiation, collecting duct carcinoma with secondary SMARCB1 loss, or fumarate hydratase [FH]-deficient RCC with secondary SMARCB1 loss. Secondary SMARCB1 deficiency does not constitute a distinct entity, and these tumours should be reported according to their underlying morphological or genetic (e.g. FH-deficient) subtype. Secondary SMARCB1 deficiency has been reported in only a few studies. It is more common among dedifferentiated and undifferentiated or sarcomatoid RCC, but such tumours are probably underreported because SMARCB1 is not evaluated in the majority of poorly differentiated and undifferentiated adult RCCs.

Some unclassified RCCs with a medullary phenotype show complete loss of SMARCB1 but no association with haemoglobinopathies. These tumours can be regarded as subtypes of SMARCB1-deficient RCC with medullary-like features or phenotype.

The most common genetic abnormality is inactivation of the SMARCB1 gene at 22q11.23 by chromosome translocations or deletions. SMARCB1 is commonly lost by mutation and deletion in rhabdoid tumour of the kidney. In medullary carcinoma, loss of SMARCB1 protein expression arises through concurrent hemizygous loss and translocation, or by homozygous loss.

See the chapter: Renal Neoplasms of our Tutorial (this chapter has only Spanish version).

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