Final diagnosis: Renal medullary carcinoma
Discussion: Renal medullary carcinoma was first described in 1995 by Davis et al, as a highly aggressive primary renal neoplasm arising almost exclusively in young patients with sickle cell trait. This malignancy is extremely rare with an estimated incidence of 0.5% of renal carcinomas.1 The mean age of presentation is 26 years (wide age range: 5 - 69 years)2,3 with slight male predominance (M:F ratio of 2:1)and predilection to the right side.3 It usually arises in the renal medulla where multiple factors can promote red blood cells sickling including: low partial oxygen pressure, low pH, and a hyperosmolarity.4,5 Although the cell of origin is uncertain, it is believed to arise from renal papillae or calyceal epithelium.6
The clinical presentation is nonspecific and most commonly presents in the form of hematuria and flank pain. Radiographic evaluation by CT scan reveals a tumor located deep within the renal parenchyma with an infiltrative growth pattern, as opposed to growth by expansion typical of Wilms’ tumor and renal cell carcinoma.7 The majority of patients present with lymph nodes and visceral metastases7 with lung being the most common site for visceral metastases. The tumor is highly aggressive and resistant to different treatment modalities. The survival is usually measured in months.8
Grossly, these tumors are poorly circumscribed, lobulated, grey tan, arising from the renal medulla, with extension into the calyces and renal pelvis. Hemorrhage and necrosis are common. The size ranges from 4 to 12 cm, mean 5.9 cm. Satellite nodules in the cortex and extension into the perinephric and sinus fat can be present.1,3
There are only a few case reports and case series describing the cytologic findings in renal medullary carcinoma. The smears have been described as consisting of pleomorphic tumor cells that are predominantly arranged in loosely cohesive groups, with rare single cells that occasionally have an eccentrically placed nucleus. The nuclei are shaped irregularly and often have prominent nucleoli. The cytoplasm ranges between dense to vacuolated and containing multiple, small vacuoles and large vacuoles that displaces and indents the nucleus.9,10
Histologically, renal medullary carcinoma consists of high grade tumor cells with nuclear pleomorphism, hyperchromasia and prominent nucleoli. The cytoplasm is eosinophilic and the cells can show rhabdoid morphology. Intracytoplasmic mucin production is common. Architecturally, they can be arranged in reticular, microcystic, adenoid cystic-like, tubular, glandular, tubulopapillary and solid patterns. The background shows desmoplastic stroma with abundant neutrophilic and lymphocytic infiltrates. Sickled erythrocytes (drepanocytes) may be pathognomonic. 1, 3, 11 By immunohistochemistry, the tumor cells are variably positive for PAX8. Polyclonal CEA, CK7, CAM5.2, and Ulex europaeus agglutinin-1 are positive in more than half of the cases. Loss of SMARCB1, and the common acquisition of OCT3/4 expression are diagnostically helpful.3,12
The main differential diagnosis based on histology is the collecting duct carcinoma. These tumors have cytologically high grade cells arranged in tubular, tubulopapillary, or tubulocystic fashion with desmoplastic stroma and a predominately lymphocytic infiltrate; a picture that can markedly overlap with renal medullary carcinoma. However; in our case, the history (age and sickle cell trait), the arrangement of cells (diffuse sheets), presence of predominantly neutrophilic infiltrate, and the loss of SMARCB1/INI1 expression all favor the diagnosis of renal medullary carcinoma.
List of References
1. Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995;19:1–11
2. Kathryn E. Beckermann, Deva Sharma, Shruti Chaturvedi, Pavlos Msaouel, Miguel R. Abboud, Yves Allory, Franck Bourdeaut, Julien Calderaro, Aguirre A. de Cubas, Vimal K. Derebail, Andrew L. Hong, Rakhi P. Naik, Gabriel G. Malouf, Elizabeth A. Mullen, Victor E. Reuter, Charles W.M. Roberts, Cheryl L. Walker, Christopher G. Wood, Michael R. DeBaun, Hendrik Van Poppel, Nizar M. Tannir, and W. Kimryn Rathmell. Renal Medullary Carcinoma: Establishing Standards in Practice. Journal of Oncology Practice 2017 13:7, 414-421
3. Liu, Qingyan; Galli, Susanna; Srinivasan, Ramaprasad; Linehan, William Marston; Tsokos, Maria; Merino, Maria J. Renal Medullary Carcinoma: Molecular, Immunohistochemistry, and Morphologic Correlation. Am J Surg Pathol. 2013; 37(3): 368–374.
4. Chauhan PM, Kondlapoodi P, Natta CL. Pathology of sickle cell disorders. Pathol Annu 1983;18:253–276.
5. Kersting U, Dantzler DW, Oberleithner H, Silbernagl S. Evidence for an acid pH in rat renal inner medulla:
Paired measurements with liquid ion-exchange microelectrodes on collecting ducts and vasa recta.
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6. Swartz Mia A, Karth John, Schneider Dominik T, Rodriguez Ronald, Beckwith J Bruce, Perlman Elizabeth J. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology. 2002 Dec;60(6):1083–1089.
7. Avery RA, Harris JE, Davis CJJ, et al: Renal medullary carcinoma: clinical and therapeutic aspects of a newly described tumor. Cancer 78: 128–132, 1996.
8. Maroja Silvino, Marina Cavalcanti et al. “Renal Medullary Carcinoma Response to Chemotherapy: A Referral Center Experience in Brazil.” Rare Tumors 5.3 (2013): e44. PMC. Web. 28 Nov. 2017
9. Assad, L., Resetkova, E., Oliveira, V. L., Sun, W., Stewart, J. M., Katz, R. L. and Caraway, N. P. (2005), Cytologic features of renal medullary carcinoma. Cancer, 105: 28–34. doi:10.1002/cncr.20764
10. Qi J, Shen PU, Rezuke WN, Currier AA, Westfall PK, Mandavilli SR. Fine needle aspiration cytology diagnosis of renal medullary carcinoma: a case report. Acta Cytol. 2001; 45: 735–739.
11. Gupta R, Billis A, Shah RB, et al. 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. Am J Surg Pathol 2012;36:1265–1278.
12. Rao P, Tannir NM, Tamboli P. Expression of OCT3/4 in renal medullary carcinoma represents a potential diagnostic pitfall. Am J Surg Pathol 2012;36:583–588.