Case 1 -

Renal Medullary Carcinoma Athanase Billis MD School of Medicine University of Campinas (Unicamp), Brazil

Clinical History: A 25-year-old black male was hospitalized due to macroscopic hematuria. A computerized tomography (CT) revealed a 7cm solid, expansile mass in the lower pole of the right kidney. The patient underwent a radical nephrectomy. Three metastatic nodules in the liver were seen during the surgical procedure. After surgery, hemoglobin electrophoresis showed 41.8%HbS and 0.5% HbF. A bone scintigraphy showed several metastatic lesions. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathologic Findings: The tumor measured 7.8cm in maximum diameter and was located in the lower pole of the right kidney. The cut surface was white-yellowish with focal hemorrage. The adrenal gland showed a whitish irregular area in the medulla. Twenty retroperitoneal lymph nodes were dissected. The microscopic findings were characteristic of this tumor. The prevalent arrangement was a reticular pattern of growth in which tumor cell aggregates formed spaces of variable size reminiscent of the yolk sac testicular tumors of reticular type. Other areas included adenoid cystic appearance, microcystic arrangement usually with micropapillations, tubular, trabecular and solid patterns. Cytologically the cells showed dark eosinophilic cytoplasm, and nuclei with conspicuous and sometimes very prominent nucleoli. The tumor diffusely infiltrated the renal parenchyma as seen in urothelial carcinomas but there was no histologic resemblance to this kind of neoplasia. Stromal desmoplasia was prominent and composed a considerable bulk of the tumor showing several appearances: dense, loose, mucoid and myxoid. A peculiar finding was presence of focal suppurative necrosis typically resembling microabscesses within epithelial aggregates. Sickled cells were seen in blood vessels. The tumor cells were positive for 35βH11 (low molecular weight cytokeratin) and vimentin; negative for 34βE12 (high molecular weight cytokeratin); and, positive in a single focus for CK7. Electron microscopy from the paraffin blocks disclosed two tumoral cell types: one with electron dense cytoplasm rich in microfilaments and another one with clear cytoplasm and few organelles. Intracytoplasmic lumens with short microvilli and intercellular junctions were seen. The adrenal gland was invaded by the tumor and 18/20 lymph nodes dissected showed metastases. Diagnosis: Renal medullary carcinoma Discussion: In 1995, Davis, Mostofi and Sesterhenn [1], reported 34 cases of a very aggressive neoplasm with a microscopic morphology highly predictive of finding sickled erythrocytes in the tissue. The authors labeled this tumor renal medullary carcinoma and considered it as the seventh sickle cell nephropathy. Berman [2], in 1974, enumerated the six nephropathies seen in patients with sickle cell disease or trait: gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate the urine and pyelonephritis. All of them can be attributed to the vascular stagnation associated with the sharp-pointed sickle cells or the reduced oxygen pressure and interstitial hypertonicity of the renal medulla that are associated with them. Renal medullary carcinoma is a rare, rapidly growing tumour of the renal medulla associated almost exclusively with sickle cell trait [3]. Only one of the 34 patients reported by Davis, Mostofi and Sesterhenn [1] had sickle cell disease. Over a period of 22 years the Armed Forces Institute of Pathology had collected only 34 cases [1] and over the next 5 years only 15 more had been described [4]. The incidence of sickle cell trait in Brazil is 6.7% in African-Brazilians, 5.4% in mulattos (persons of mixed white and black ancestry), and 0.21% in whites [5]. Considering the large black population at risk, the tumor is very rare. Clinical Features The tumor is seen in young people with sickle cell trait and exceptionally with sickle cell disease, between ages 10 and 40 (mean age 22 years) and chiefly in males by 2:1 [3]. In the series of Davis, Mostofi and Sesterhenn [1], most of the carcinomas were on the right side. The most frequent symptoms are gross haematuria and flank or abdominal pain. Considering that the tumor has a predilection for the right kidney it is interesting that the benign bleeding associated with sickle cell disease (Berman's first sickle cell nephropathy) occurs on the left side. Morphologic Features, Immunoprofile, Genetic Analysis and Pathogenesis Generally, the tumor arises centrally in the kidney, is poorly circumscribed and ranges in size from 4-12cm. Hemorrhage and necrosis are common [1]. The microscopic findings of the case previously described are characteristic of this tumor. Electron microscopy may disclose intracytoplasmic lumens with short microvilli, lipid vacuoles and intercellular junctions [6, 7] but no finding is specific for this tumor. Keratin AE1/AE3 is nearly always positive as is EMA but typically less strong and CEA is usually positive. Some studies showed strong expression for low molecular weight cytokeratin (CAM 5.2) but negative high molecular weight cytokeratin [6, 7]. Of the 15 tumors analyzed by Swartz et al. [7], cytokeratins 7 and 20 and CEA were heterogeneous and variable, and Ulex was focally positive in a minority of cases. Of nine tumors analyzed for genetic gains and losses using comparative genomic hybridization, eight showed no changes and one showed loss of chromosome 22 [7]. Yang et al. [8] analyzed the gene expression profiles of 2 renal medullary carcinomas from patients with sickle cell trait using microarrays containing 21,632 cyclic DNA (cDNA) clones and compared them with gene expression profiles of 64 renal tumors. Based on global gene clustering with 3583 selected cDNAs, the authors found a distinct molecular signature of renal medullary carcinoma, which clustered closely with urothelial (transitional cell) carcinoma of the renal pelvis, rather than renal cell carcinoma (RCC). This finding of a significant difference in the gene expression patterns of renal medullary carcinoma compared with RCC suggests that this tumor should not be treated as a conventional RCC but rather as a special malignancy. Medullary renal carcinoma probably originates in or near the renal papillae. This origin is suggested by accumulated radiographic and pathologic findings in individuals with sickle cell disease and sickle cell trait. Curiously, most of the spontaneous bleeding is from the left kidney, and most of the carcinomas are on the right. Positivity for vascular endothelial growth factor (VEGF) and hypoxia induced factor (HIF) suggests that chronic hypoxia secondary to the hemoglobinopathy may be involved in the pathogenesis of medullary carcinoma [7]. Mostofi et al. [9] studied 22 patients with sickle cell trait and unilateral hematuria. They observed epithelial proliferation of the terminal collecting ducts in 12 cases and of the adjacent papillary mucosa in 14. Davis, Mostofi and Sesterhenn [1] hypothesized that renal medullary carcinomas may originate in such areas of cellular activity. Of interest is a case of this tumor associated with invasive pelvic urothelial carcinoma reported by Figenshau et al. [10]. The authors speculated whether the finding represents a collision tumor or dedifferentiation of the pelvic urothelial carcinoma. Differential Diagnosis The main differential diagnosis is carcinoma of the collecting ducts of Bellini (or collecting duct carcinoma of the kidney) [11]. The peculiar histology of the renal medullary carcinoma precludes the diagnosis of usual collecting duct carcinoma. The latter shows a predominantly tubulopapillary pattern, the inflammatory infiltrate is not prominent, and dysplastic lesions are seen in the adjacent collecting ducts. Both tumors involve young patients with a wider variation of age for the collecting duct carcinoma [12]. The overlap of immunohistochemical findings between these tumors favors the possibility that they may represent a spectrum of the same neoplasm [13]. It is now regarded that renal medullary carcinoma may be a more aggressive variant of collecting duct carcinoma [14]. Prognosis The prognosis is very poor. Metastases are both lymphatic and hematogenous with lymph nodes, liver and lungs most often involved. In the series of Davis, Mostofi and Sesterhenn [1], 25/33 (75%) patients had metastases to one or more lymph nodes; the tumor extended to the adrenal gland in eight, to the perinodal retroperitoneal tissue in nine, to the peritoneum in two, and in six and seven patients, respectively, it had metastasized to the liver and lungs. The mean duration of survival after surgery has been 15 weeks [3]. Chemotherapy may prolong survival by a few months [15] but generally, chemotherapy and radiotherapy has not altered the course of the disease [4]. References: Davis CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995;19:1-11. Berman LB. Sickle cell nephrophathy. JAMA. 1974;228:1279. Davis CJ. Renal medullary carcinoma. In: Eble JN, Sauter G, Epstein JI et al. eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC Press;2004:162-192. Khan A, Thomas N, Costello B, et al. Renal medullary carcinoma: sonographic, computed tomography, magnetic resonance and angiographic findings. Eur J Radiol. 2000;35:1-7. Chapadeiro E, Maciel R, Jamra M, et al. Linfonodos.Baço.Medula Óssea e Sangue.Tumores do Sistema Hemolinfático.Timo. In: Bogliolo Patologia. 4a ed. Rio de Janeiro:Editora Guanabara Koogan;1987:651-652. Rodriguez-Jurado R, Gonzalez-Crussi. Renal Medullary Carcinoma. J Urol Pathol. 1996;4:191-203. Swartz MA, Karth J, Schneider DT et al. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology. 2002;60:1083-1089. Yang XJ, Sugimura J, Tretiakova MS, et al. Gene expression profiling of renal medullary carcinoma: potential clinical relevance. Cancer. 2004;100:976-985. Mostofi FK, Vorder Bruegge CF, Diggs LW. Lesions in kidney removed for unilateral hematuria in sickle cell disease. Arch Pathol.1957;63:336-351. Figenshau RS, Basler JW, Ritter JH, Siegel CL, Simon JA, Dierks SM. Renal medullary carcinoma. J Urol. 1998;159:711-713. Srigley JR, Eble JN. Collecting duct carcinoma of kidney. Semin Diagn Pathol. 1998;15:54-67. Polascik TJ, Bostwick DG, Cairns P. Molecular genetics and histopathologic features of adults distal nephron tumors. Urology. 2002;60:941-946. Dimashkieh H, Choe J, Mutema G. Renal medullary carcinoma. A report of 2 cases and review of the literature. Arch Pathol Lab Med. 2003;127:135-138. Eble JN. Renal medullary carcinoma: a distinct entity emerges from the confusion of collecting duct carcinoma. Advances Anat Pathol. 1996;3:233-238. Pisani P, Bray F, Parkin DM. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer. 2002;97:72-81.