Clinical Practice

Clinical Practice Renal Medullary Carcinoma: A Case Report and Literature Review Michael Dinerman, MD

Abstract Presented is a fatal case of renal medullary cancer (RMC) diagnosed in a woman with sickle cell trait. The patient was a 19-year-old adolescent who presented with right-sided flank pain. She complained of weight loss, fatigue, dyspnea, and a non-productive cough. The metastatic tumor demonstrated an aggressive and fatal course. Literature review of the pathology, histology, and metastatic potential of the tumor follows. No therapy has hitherto contributed to a prolonged disease-free survival. Int Pediatr. 2005;20(1):40-43.

Key words: Renal Medullary Carcinoma (RMC), sickle cell trait, kidney tumor

From the Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia. Address reprint requests to Michael Dinerman, MD, Emory University School of Medicine, Department of Pediatrics, 1608 Briarcliff Road #3, Atlanta, GA , 30306. Copyright © 2005 Miami Children’s Hospital

Introduction

C

ancer is the second leading cause of death among children between 1 and 14 years of age in the US. The American Cancer Society predicted that an estimated 35 710 new cases and 12 480 deaths of kidney and renal pelvis cancer occurred in 2004.1 Renal cell carcinoma, the most common type of kidney cancer in adults, accounts for about 85% of all kidney tumors. By comparison, Wilms tumor is the most common kidney tumor in the pediatric population.2-4 Renal medullary carcinoma (RMC), by contrast, is a tumor seldom described in the literature. Presented is a case of RMC and a review of the presentation, pathology and clinical course of the disease. Case Report The patient was a 19-year-old woman with sickle cell trait referred to Miami Children’s Hospital from the Dominican Republic. She presented with right sided flank pain of several weeks duration. She complained of weight loss, fatigue, mild shortness of breath, chest and back discomfort, and a non-productive cough. Medical history was notable only for sickle cell trait. She denied headache, nausea, hematuria, dysuria, visual complaints, and bone pain. Family history, likewise, was remarkable only for sickle cell trait. Ten days prior to admission, chest radiographs showed a bilateral pleural effusion (Fig. 1). Physical examination showed a 57 kg female who appeared acutely ill and malnourished. She was afebrile with normal vital signs. Crackles and diminished breath sounds were heard near the right lung base. Pulse oximetry readings were normal. Complete blood count (CBC) showed a

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Clinical Practice Renal Medullary Carcinoma

white count 8.3 x 103/mm2 (71% neutrophils, 2% bands, 21% lymphocytes, 6% monocytes), Hb 13.3 g/dL, Hct 39.4%, platelets 435 000/ mm3. Westergren sedimentation rate was 45 mm/hr. Laboratory investigations showed fibrinogen of 623 mg/dL; ALP of 52 IU/L; LDH of 334 IU/L; and CPK of 40 IU/L. Urinalysis, electrolytes, coagulations studies, and liver profiles were normal. Analysis of a pleural effusion performed in another institution prior to admission showed glucose of 91 mg/dL, protein of 4.4 g/dL, and LDH of 543 IU/L. Cultures of the blood, urine, and pleural fluid were sterile. Abdominal computerized tomography (CT) scan showed a mass in the upper pole of the right kidney (Fig. 2). The tumor invaded the Gerota’s fascia with right renal vein infiltration, extension into the retroperitoneum, and retrocrural spread through the diaphragmatic hiatus. Chest scan showed a large right pleural effusion with atelectasis of the right lung, accompanied by left mediastinal shift. Numerous pleural nodular densities were present along the lower pleural surface which extended to the right hemidiaphragm (Fig. 3). A pleural effusion and a layer of hemorrhage and nodularity along the parietal pleura were confirmed by spinal magnetic resonance imaging (MRI). Additionally, a Gallium scan showed extensive uptake in the right renal, paraaortic, and right lower chest region, along the pleural and diaphragmatic surface, accompanied by mediastinal involvement. On admission, the patient underwent thoracentesis and four liters of serosanguinous fluid were removed. An additional 1.5 L of pleural fluid were drained in the following two weeks. Pathologic examination of the pleural effusion showed tumor cells typical of RMC. Histologic examination revealed keratin positive, stratified sheets and tubules separated by desmoplastic, hyalinized stroma, with characteristic reticular, adenoid and yolk-sac features. RMC was diagnosed and the patient was treated with combination chemotherapy, initiated seven days after admission. Doxorubicin (30 mg/m2) was given on day 1,


Fig 1 - Anterior-posterior view of chest radiograph shows a right pleural effusion.

Fig 2 - Axial abdominal CT scan demonstrates a mass in the right upper pole of the kidney.

cisplatin (70 mg/m2) on day 2, methotrexate (30 mg/m2) and vinblastine (3 mg/m2) on day 1, 15, and 22. Interestingly, the patient developed mild tremor in the upper extremity which acutely deteriorated over the two weeks of hospitalization into distressing hemi-choreiform movements. The tremors rendered the patient incapable of ambulating without substantial assistance. Her disability was acutely unresponsive to treatment with hydroxyzine, diphenhydramine, lorazepam, clonazepam, and risperidone, but the tremors subsided over time. The hospital admission was uncomplicated by respiratory failure, seizures, uremia, infection, or neutropenia. Ultimately, the patient was discharged in stable condition 30 days after admission to Miami Children’s Hospital. Subsequent medical follow-up was sought at an outside institution for personal and social reasons. During my last communication

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Fig 3 - Axial abdominal CT scan illustrates the tumor with involvement of the periaortic and juxta cava lymph nodes.

with a family member, notification was that she had died with widespread metastases. Discussion RMC was first described in 1995 by Davis and The Armed Forces Institute of Pathology (AFIP) in the largest reported series in the literature.5 In this retrospective review, all 33 patients were black, all with presumed sickle cell trait, and their ages ranged from 11 to 39. Prevalence was higher for males than females (3 to 1 between the ages of 11 and 24 years). The tumors occurred equally beyond that age. RMC presented with a combination of weight loss, hematuria, cough, shortness of breath, hematemesis, flank pain, and abdominal mass. In this series, the neoplasm occupied the deep renal parenchyma. The bulk of the tumor lay in the renal medulla, and multiple satellite nodules lay in the cortical tissue. The gross size of the tumor ranged from 4 to 12 cm. The malignancy was described as lobulated, firm, rubbery, and tan to gray. Pathological studies showed hemorrhage and significant necrosis. A reticular growth pattern with small gland and cystic for mation was described. The specimens contained poorly differentiated spindle and rhabdoid cells, in which large pale vesicular nuclei and marked nucleoli were found. Prominent inflammation and stromal desmoplasia was noted. The cells

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stained positive for vimentin, cytokeratin, and epithelial membrane antigen.6 Sickle erythrocytes were universally present on careful inspection.5 The cellular origin of RMC is presumably the caliceal epithelium.6,7 Infiltration extends into the collecting system, renal pelvis, and sinus. Infiltrative spread by direct local invasion may extend into renal hilar nodes, renal veins, and renal sinus fat. Metastases sites include liver, lung, adrenal glands, retroperitoneum, inferior vena cava, omental and pulmonary hilar nodes, and peritoneum. Each tumor contains lymphatic or vascular extension.5 In 1974, Ber man repor ted six nephropathies identified with sickle cell disease including: (1) necrotic papillae, (2) gross hematuria, (3) nephrotic syndrome, (4) renal infarction, (5) pyelonephritis, and (6) hyposthenuria.8,9 Davis, in turn, designated RMC the seventh sickle cell nephropathy.5 Regarding sickle cell nephropathy, the radiographic changes consist of calyceal blunting (sickle-cell caliectasis), enlarged calyces, and renal enlargement.9 The histologic changes may include scarring, obliteration of the tubular elements in the medullary pyramids, increased vascularity of the juxta-medullary glomeruli, ischemia, and glomerular obliteration.10 The patient of our report was known to be sickle trait positive, rather than homozygous sickle cell disease (HB SS). To date, RMC has not been proven to have a hereditary origin. Yet, certain types of renal tumors have been shown to be inherited, including von Hippel-Lindau disease,11 familial clear cell carcinoma,12 familial papillary renal carcinoma,13 and tuberous sclerosis. With respect to RMC, one cytogenetic study showed the tumor metaphases (n = 2) were triploid, with numerous structural and numerical anomalies. Further, the karyotype showed anomalies of chromosome 3, including monosomy and a translocation of t(3;8)(p21;q24). 12 Chromosome 11 was monosomic; each cell examined. Chromosome 11, as sug gested by the investigator, may be involved in the



pathogenesis of RMC, as the gene for betaglobin is found at chromosome 11p.14 With respect to prognosis, no therapy to date, including irradiation, surgery, and chemotherapy, has resulted in a prolonged disease-free survival. Clinical reports show numerous treatment failures including cyclophosphamide, cisplatin, carboplatin, doxorubicin, etoposide, and alpha-interferon. Neither interleukin-2, topotecan, 5-fluorouracil, methotrexate, nor paclitaxel showed demonstrable benefit. RMC was uniformly fatal in the cases reported by the GU Pathology Department of the AFIP. Mean survival of life was 15 weeks from surgery, with a range from 3 to 52 weeks. The longest reported survival was 15 months in a diagnosed 12-yearold patient with sickle cell trait and disseminated lung and liver metastases.15 Conclusion While improvements in the survival rates of many childhood cancers have evolved over the past decade, RMC remains tumor associated with an aggressive course and high mortality rate. To date, the prevention, pathogenesis, and optimal intervention remain unknown. Based on a thorough review of the literature, substantial efforts are clearly warranted to reduce the morbidity and mortality of this aggressive malignancy.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Merten DF, Yang SS, Bernstein J. Wilms’ tumor in adolescence. Cancer 1976;37:1532-8. Shah K, Wassan S, Lott S. Wilms tumor in adolescence. J Urol 1979;121:365-6. Abrams HJ, Buchbinder MI, Sutton AP. Renal carcinoma in adolescents. J Urol 1979;121:92-4. Davis CJ, Mostofi FK, Sesterhenn IA: Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol 1995;19:1-11. Figenshau RS, Basler JW, Ritter JH, et al. Renal Medullary Carcinoma. J Urol 1998;159:711-13. Mostofi FK, Vorder Bruegge CF, Diggs LW. Lesions in kidneys removed for unilateral hematuria in sickle cell disease. Arch Path 1957;63:336-51. Ber man, LB. Sickle cell nephropathy. JAMA 1974;228:1279. Friedrichs P, Lassen P, Canby E, et al. Renal medullary carcinoma and sickle cell trait. J Urol 1997;157:1349. Bernstein J, Whitten CF. A histologic appraisal of the kidneys in sickle cell anemia. Arch Path 1960;407-18. Latuf FM, Tory K, Gnarra J, et al. Identification of the von Hippel Lindau disease tumor suppressor gene. Science 1993;260:1317-20. Zbar BH, Brauch H, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987;327:721-24. Zbar B, Tory K, Merino M, et al. Hereditary papillary renal cell carcinoma. J Urol 1994;151:561-66. Avery RA, Harris JE, Davis CJ, el al. Renal medullary carcinoma: clinical and therapeutic aspects of a newly described tumor. Cancer 1996;78:128-32. Pirich LM, Chou P, Walterhouse DO. Prolonged survival of a patient with sickle cell trait and metastatic renal medullary carcinoma. J Pediatric Hematology/ Oncology 1999;21(1);67-9.

References 1.

American Cancer Society, Inc. Cancer facts and figures 2004. Available at: http://www.cancer.org/docroot/ STT/stt_0.asp. Accessed November 15, 2004.


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