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renal medullary carcinoma

Friday 18 November 2005

Definition: Renal medullary carcinoma (RMC) is a rare aggressive renal tumor that classically afflicts young black patients with sickle cell trait.

The tumor shows overlapping pathologic and clinical characteristics with collecting duct carcinoma and urothelial carcinoma, which often results in a diagnostic conundrum.

Images

- Renal medullary carcinoma

- Metastatic renal medullary carcinoma in lymph node.

Digital cases

- HPC:248 : Bellini type renal cell carcinoma.

When the tumor presents in a metastatic site in the absence of a history of renal tumor, germ-cell tumor is often a primary diagnostic consideration, given the young age of most patients.

Renal medullary carcinoma was recognized as a novel form of renal malignancy in a series published by Colonel Davis of the Armed Forces Institute of Pathology in 1995. This study was based upon retrospective analysis of tumors coded as renal pelvic carcinoma from patients aged less than 40 years.

Where race had been recorded, all patients were black and all had sickled erthrocytes on histological examination.

On this basis the tumor, which was termed medullary carcinoma on morphologic grounds, was designated the seventh sickle cell nephropathy (the others being gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine and pyelonephritis); since the original study over 160 cases have been reported.

Patient age at diagnosis ranges from 5 to 69 years with a mean age of 19 years. There is a male predominance with a male/female ratio of 2:1, although for patients @<@10 years the male/female ratio is 5:1.

Where ethnicity was reported the overwhelming majority of patients were African American, whereas 15 patients were Hispanic/Brazilian.

Medullary carcinoma has only rarely (@<@10 cases) been reported in Caucasians. Virtually all patients have sickle cell trait/disease although the tumor has been reported from a patient with a normal blood profile.26

Virtually all patients are symptomatic at diagnosis, with pain and hematuria predominating, whereas other presenting symptoms are abdominal mass, dysuria and weight loss.

Medullary carcinoma more commonly occurs in the right kidney (>75%) and is generally a solitary, poorly circumscribed mass. On sectioning the tumor is tan or gray–white, with macroscopic evidence of necrosis and hemorrhage.

Microscopy

Microscopic examination shows an infiltrative poorly differentiated carcinoma consisting of solid sheets with poorly formed vacuoles.

The tumor may also form cords, and occasionally vacuolated nests, microcysts, tubules and areas resembling yolk sac tumors or sarcomatoid carcinoma may be seen. There is usually a pronounced desmoplastic reaction with an associated chronic active inflammatory cell infiltrate and areas of necrosis are often present.

Tumor cells have an eosinophilic/granular cytoplasm and there is usually a marked degree of nuclear pleomorphism with prominent nucleoli. Mitotic figures are common and cells resembling those seen in rhabdoid dedifferentiation in renal cell carcinoma may also be identified.32 Sickle-cell erythrocytes are a frequent finding within the tumor and adjacent renal tissue.

Ultrastructure

Ultrastructural studies show variable findings and no consistent features were reported from one study.24 Recently it has been noted that tumor cells contain large intracytoplasmic vesicles lined by long slender microvilli. Condensed fibrillary electron-dense deposits were also present. Prominent desmosomes were identified, whereas glycogen and lipids were universally absent.

The immunohistochemical expression of medullary carcinoma has been reported from several studies.24, 25, 31 All tumors show positive and diffuse expression for cytokeratin AE1/AE3, low molecular weight cytokeratin, EMA, vimentin, HIF and VEGF. Cytokeratin 7 and carcinoembryonic antigen was focally expressed in all cases, whereas there was a variable expression of high molecular weight cytokeratin, Ulex europeaus agglutinin-1 and TP53. There was no expression of Her-2neu.

Genetics

Genetic studies on medullary carcinoma are limited. On CGH no gains or losses were found in eight of nine tumors studied, whereas one case showed loss of chromosome 22. Gene expression profiling showed 487 genes to be expressed differently from that of other types of renal tumor, with an expression most closely resembling urothelial carcinoma.

In three cases FISH analysis showed amplification of the ABL gene, with increased expression of ABL protein in two cases. In this series no evidence of BCR-ABD translocation was detected, in contradiction to the report of Stahlschmidt et al34 based on a single case.

Differential diagnosis

The differential diagnosis for medullary carcinoma is high-grade invasive urothelial carcinoma and collecting-duct carcinoma. As noted above urothelial carcinoma appears closely related to medullary carcinoma on the basis of genetic profile.

Clinical evidence of sickle cell trait and young patient age are seen with medullary carcinoma, whereas cytokeratin 20 positivity and the presence of adjacent urothelial carcinoma in situ are often seen in urothelial carcinoma. The infiltrative elements of medullary carcinoma may show tubules that resemble collecting-duct carcinoma and this has been considered to be evidence that these two tumors are related. Sickle cell trait is not associated with collecting-duct carcinoma, which is usually positive for high molecular weight cytokeratin and Ulex europeaus agglutinin-1, and may be negative for EMA.

INI1 also helps to differentiate medullary carcinoma from collecting duct carcinoma.

Prognosis

Medullary carcinoma has a poor prognosis.

Metastatic disease is seen at presentation in 95% of patients with metastases encountered, in descending frequency, in lymph nodes (retroperitoneal and mediastinal), lungs, liver and adrenal glands.

Metastases to breast, bone and contralateral kidney at the time of diagnosis have also been reported. In a published series post-presentation survival for patients ranged from 1 day to 68 weeks with a mean survival of approximately 18 weeks. Three patients with organ-confined disease were alive 9 months, 2 years and 8 years post-nephrectomy.

One patient with pleural, mediastinal and retroperitoneal metastases was alive 85 weeks post-diagnosis, following nephrectomy and post-operative cisplatin, gemcitabene and paclitaxel chemotherapy, with tandem autologous bone marrow transplantation.

Immunochemistry

OCT3/4 is an immunohistochemical marker that is routinely used in clinical practice and is widely considered to be a specific marker for germ-cell tumor.

Caution must be exercised in interpreting the presence of OCT3/4 staining in a poorly differentiated neoplasm, especially at a metastatic site as a germ-cell tumor, as this may represent a potential diagnostic pitfall.

Cytogenetics

- t(10;16)(q22;q22) (10573578)
- t(9;22)(q34;q11) (10573578)

Molecular biology

- BCR/ABL rearrangement (10573578)

Gene expression profiling: 14983493

See also

- renal tumors

  • renal carcinomas

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma are rare aggressive neoplasms of putative distal nephron origin. First described in 1949, case reports and review articles constitute a major source of information on collecting duct carcinoma, whereas Davis and colleagues and the pediatric tumor registry have contributed the seminal works on renal medullary carcinoma.

Differential clinical features between collecting duct carcinoma and renal medullary carcinoma included proclivity for younger male individuals of African ancestry with hemoglobin abnormalities and a shorter median survival of 17 weeks (vs. 44 wk for collecting duct carcinoma) for renal medullary carcinoma.

The markedly overlapping clinical features, histology, immunophenotype, metastasis patterns, and uniformly aggressive outcome in collecting duct and renal medullary carcinomas suggest that renal medullary carcinoma is a distinctive clinicopathologic subtype within the entity of collecting duct carcinoma.

The extremely poor prognosis and ongoing clinical trials with specific therapeutic protocols argue for their accurate distinction from other renal cell carcinoma subtypes.

See also

- renal cell carcinomas

Reference

- Carcinoma of the Collecting Ducts of Bellini and Renal Medullary Carcinoma: Clinicopathologic Analysis of 52 Cases of Rare Aggressive Subtypes of Renal Cell Carcinoma With a Focus on Their Interrelationship. Gupta R, Billis A, Shah RB, Moch H, Osunkoya AO, Jochum W, Hes O, Bacchi CE, de Castro MG, Hansel DE, Zhou M, Vankalakunti M, Salles PG, Cabrera RA, Gown AM, Amin MB. Am J Surg Pathol. 2012 Sep;36(9):1265-1278. PMID: 22895263

- Expression of OCT3/4 in Renal Medullary Carcinoma Represents a Potential Diagnostic Pitfall. Rao P, Tannir NM, Tamboli P. Am J Surg Pathol. 2012 Apr;36(4):583-8. PMID: 22301499

- Yang XJ, Sugimura J, Tretiakova MS, Furge K, Zagaja G, Sokoloff M, Pins M, Bergan R, Grignon DJ, Stadler WM, Vogelzang NJ, Teh BT. Gene expression profiling of renal medullary carcinoma: potential clinical relevance. Cancer. 2004 Mar 1;100(5):976-85. PMID: 14983493

- Hakimi AA, Koi PT, Milhoua PM, Blitman NM, Li M, Hugec V, Dutcher JP, Ghavamian R. Renal medullary carcinoma: the Bronx experience. Urology. 2007 Nov;70(5):878-82. PMID: 18068443

- Vargas-Gonzalez R, Sotelo-Avila C, Coria AS. Renal medullary carcinoma in a six-year-old boy with sickle cell trait. Pathol Oncol Res. 2003;9(3):193-5. PMID: 14530815

- Stahlschmidt J, Cullinane C, Roberts P, Picton SV. Renal medullary carcinoma: prolonged remission with chemotherapy, immunohistochemical characterisation and evidence of bcr/abl rearrangement. Med Pediatr Oncol. 1999 Dec;33(6):551-7. PMID: 10573578

- Adsay NV, deRoux SJ, Sakr W, Grignon D. Cancer as a marker of genetic medical disease: an unusual case of medullary carcinoma of the kidney. Am J Surg Pathol. 1998 Feb;22(2):260-4. PMID: 9500230

- Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995 Jan;19(1):1-11. PMID: 7528470