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Internal Medicine

Renal medullary carcinoma (RMC)

Rare, aggressive malignant neoplasm found almost exclusively in patients with sickle cell trait, or, less frequently, sickle cell disease.

  • Also named as “seventh sickle cell nephropathy”
  • Extremely rare tumor and comprises < 0.5% of all renal carcinomas.

WHO Classification of Tumours of the Urinary System and Male Genital Organs:

High-grade renal adenocarcinoma with histologic and immunophenotypic findings consistent with those of medullary carcinoma occurring in a patient with no evidence of a hemoglobinopathy is best categorized as unclassified renal cell carcinoma (RCC) with medullary phenotype.

Pathophysiology

Arise from the renal papillae or calyceal epithelium and may be triggered by chronic medullary hypoxia as a result of sickled red cells in individuals with HbS and is suggested by strong expression of vascular endothelial growth factor and hypoxia-inducible factor.

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The renal cortex is isosmotic to plasma, whereas the renal medulla becomes progressively more hypertonic up to ∼1,200 mOsm/L in the inner medulla. In addition, the medulla becomes progressively more hypoxic with a partial pressure of oxygen (pO2) as low as 7 mm Hg in the inner medulla. These extreme conditions result in RBC sickling even in patients with sickle cell trait. Furthermore, the high NaCl concentration in the inner medulla produces DNA DSBs and simultaneously inactivates DNA repair pathways that would have otherwise repaired these lesions. | Msaouel, P., Tannir, N. M., & Walker, C. L. (2018). A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma. Clinical Cancer Research, 24(9), 2044 LP – 2049. https://doi.org/10.1158/1078-0432.CCR-17-3296

SMARCB1/INI1 loss:

Loss of SMARCB1/INI1 in the switch/sucrose nonfermentable (SWI/SNF) complex, a key mediator of chromatin remodelling and modulation of transcriptional activity.

  • Biallelic loss of SMARCB1/INI1 is a hallmark feature in several childhood cancers:
    • Malignant rhabdoid tumour of the kidney
    • Atypical teratoid/rhabdoid tumour
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Proposed steps in RMC pathogenesis. There are 4 predisposing conditions that interact together: sickle hemoglobinopathy, hypoxia in the renal inner medulla, hypertonicity in the renal medullary interstitium, and presence of LCRs and palindromic AT-rich repeats (PATRR) within the 22q11.2 locus. The hypoxic microenvironment facilitates the sickling of RBCs resulting in recurrent regional ischemia and microinfarctions in the renal inner medulla, which reduce the osmolarity in the medullary interstitium. This subsequently reactivates pathways that repair DSBs previously induced by hypertonicity (increased NaCl). However, the chronic hypoxia within the renal inner medulla will favor a switch to the more error-prone aNHEJ repair pathways that are more likely to produce translocations and deletions, particularly in genomic regions such as 22q11.2, which is susceptible to DSB-mediated rearrangements due to the presence of LCRs and PATRRs. Together, these events will result in inactivating translocations and/or deletions of SMARCB1, the tumor suppressor that is always inactivated in RMC. Anatomical differences in blood perfusion will produce more frequent regional ischemia in the right kidney and thus increase the risk of developing RMC in the right versus the left kidney. | Msaouel, P., Tannir, N. M., & Walker, C. L. (2018). A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma. Clinical Cancer Research, 24(9), 2044 LP – 2049. https://doi.org/10.1158/1078-0432.CCR-17-3296
  • RMC occurs in the right kidney (> 75% cases)

Metastasis:

  • M/C sites: Liver & lungs > bone & adrenal glands

Clinical features

Most patients having metastatic disease at the time of presentation

Commonly presents as a young male patient of African/Mediterranean descent, with hematuria and/or flank pain

  • Gross hematuria
  • Flank pain
  • Weight loss
  • Palpable flank mass
  • Lymphadenopathy
  • Constitutional symptoms

Case study:

Diagnosis

Fine-needle aspiration cytology:

  • Features of a high-grade carcinoma with loosely cohesive groups of cells in a background of scattered individual cells.

Management

jop.2017.020909f2
Renal medullary carcinoma (RMC) treatment algorithm. This flowchart represents diagnostic criteria and considerations in treating patients with RMC. *If performance status and surgical planning permit consideration. †Treatment with vascular endothelial growth factor–directed therapies or mammalian target of rapamycin inhibitors is not beneficial; single-agent chemotherapy is not encouraged. RPLND, retroperitoneal lymph node dissection. | Beckermann, K. E., Sharma, D., Chaturvedi, S., Msaouel, P., Abboud, M. R., Allory, Y., … Rathmell, W. K. (2017). Renal Medullary Carcinoma: Establishing Standards in Practice. Journal of Oncology Practice, 13(7), 414–421. https://doi.org/10.1200/JOP.2017.020909

Poor prognosis:

  • Highly aggressive cancer and resistant to conventional chemotherapy
  • Average length of survival after diagnosis: 4 months

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