Correspondence *SUNY Downstate Medical Center, Department of Urology, 445 Lenox Road, Box 79, Brooklyn, NY 11203, USA

Email kumaran@alumni.duke.edu

The case

A 36-year-old black male with known SICKLE-CELL DISEASE (genotype HbSC), asthma, and dyslipidemia presented with a 4-month history of shortness of breath on exertion, chest pain radiating to the shoulder, lethargy, and recent fever. He had no history of renal insufficiency, vaso-occlusive crisis or chest syndrome secondary to his sickle-cell disease, and the rest of his medical history revealed no significant findings. Physical examination revealed mild respiratory distress. Chest X-ray and CT showed bilateral lower lobe infiltrates and a small right pleural effusion. The patient was diagnosed with bilateral pneumonia with right pleural effusion, treated with antibiotics, and discharged.

Four months later the patient again presented with shortness of breath on exertion and epigastric chest pain. Physical examination revealed weight loss of nearly 7 kg since his last visit. Chest X-ray revealed patchy left-lower-lobe infiltrates and left pleural effusion. He was admitted for pneumonia and acute chest syndrome secondary to vaso-occlusive crisis and discharged.

One month later, he presented once again, this time with a 5-day history of hematuria, left abdominal pain, left-eye blurriness, lethargy, and loss of appetite. Physical examination revealed gross hematuria and mild left-lower-quadrant tenderness to palpation. There was no organomegaly or costovertebral tenderness. Laboratory results revealed mild anemia and mildly elevated creatinine. Urinalysis found no infections. Abdominal ultrasound revealed an enlarged, diffusely echogenic right kidney with extensive lymphadenopathy (Figure 1A). A contrast enhanced CT scan confirmed that there was a large, heterogeneous, infiltrating mass in the lower pole of the right kidney, and extensive retroperitoneal lymphadenopathy encasing the renal arteries, veins, aorta, and inferior vena cava (Figure 1B). There was no direct invasion into these vessels. An MRI of the brain, including both orbits, was ordered to evaluate for metastatic disease; the results revealed no abnormalities. Given the likelihood of extensive retroperitoneal metastatic disease, the patient was not considered a candidate for surgery. The remaining clinical course was notable for rapid deterioration. The patient developed respiratory arrest from pulmonary embolism and died 2 days after admission.

Figure 1 Imaging of the renal mass.

Left panel: renal sonogram showing enlarged right kidney with infiltrating mass in lower pole and extensive lymphadenopathy. Right panel: contrast-enhanced CT confirming large heterogeneous infiltrating mass in the lower pole of the right kidney and extensive retroperitoneal lymphadenopathy (arrows).

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During autopsy, multiple thrombi ranging in size from 0.5 cm to 1.2 cm were found in the pulmonary arteries. The lung parenchyma was unremarkable, with the exception of alveolar capillary congestion secondary to sickled red blood cells. A large antemortem thrombus found in the lumen of the right popliteal vein was assumed to be the source of the fatal lung embolism. Examination of the lung and popliteal thrombi revealed clots composed of fibrin and red blood cells, with distinct lines of Zahn, and did not include tumor cells. The right kidney weighed 480 grams and had a bulging and dull capsular surface and an 8 cm 8 cm 5.5 cm yellow tan, firm mass in the middle and lower pole (Figure 2). No intrarenal satellite tumors were observed. The para-aortic lymph nodes adjacent to the right kidney were massively enlarged and matted. Finally, there was no gross invasion into the inferior vena cava, renal vein, renal artery or aorta.

Figure 2 Gross pathology of renal mass.

Section of the right kidney (480 g) showing 8 cm 8 cm 5.5 cm yellow tan firm mass in the lower half. Enlarged para-aortic lymph node shown (arrow).

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Microscopic evaluation revealed sheet-like, jagged nests of highly atypical polygonal cells with pleomorphic nuclei and prominent nucleoli suggestive of RENAL MEDULLARY CARCINOMA (Figure 3A). Prominent areas of lymphoplasmacytic infiltrates were seen at the junction between the normal kidney tissue and the tumor (Figure 3B), as were regions of necrosis and increased mitotic activity. Sickled red blood cells were seen in congested blood vessels.

Figure 3 Histology of renal mass.

Left panel: histologic specimen showing sheet-like, jagged nests of highly atypical polygonal cells with pleomorphic nuclei and prominent nuclei. Right panel: junction of tumor and normal renal parenchyma. Note a sclerotic glomerulus (circle) and lymphocytic infiltration at the tumor demarcation (arrows).

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On the basis of the aggressiveness of the tumor, the clinical presentation and the pathological review, the patient was diagnosed with renal medullary carcinoma.

Discussion of diagnosis

Renal medullary carcinoma is a rare and fatal disease that is remarkable for its almost exclusive association with young, black patients with sickle-cell trait and, in some cases, sickle-cell disease.

Berman described six nephropathies associated with sickle-cell disease: hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis.¹ Davis et al. studied 34 patients with renal medullary carcinoma and found a uniform association with black patients with sickle-cell disease or sickle-cell trait.² On the basis of this association, they dubbed renal medullary carcinoma the 'seventh sickle-cell nephropathy'. The patients in this study were 11–39 years of age, had a mean survival after diagnosis of 15 weeks, and all presented with metastatic disease at time of diagnosis. The aggressiveness of the tumor was exemplified in our patient, who died within 2 days of diagnosis. Coogan et al. described three cases of patients with sickle-cell trait who had a similar clinical presentation and outcome.³

Sickle-cell nephropathies are thought to be due to the hostile environment of the renal medulla, which is characterized by hypoxia, acidosis and hypertonia.⁴ These conditions facilitate hemoglobin-S polymerization and red-blood-cell sickling, thus leading to vaso-occlusion. This vaso-occlusion makes the renal medulla particularly susceptible to decreased oxygen delivery, and is thought to be a cause of the nephropathies described in patients with sickle-cell disease and sickle-cell trait.

There are few theories accounting for the association between sickle-cell disease and sickle-cell trait and the development of renal medullary carcinoma. Swartz et al. postulate that chronic renal medullary hypoxia due to vaso-occlusion in sickle-cell-disease and sickle-cell-trait patients leads to proliferation of vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF), which together support angiogenesis and tumor growth.⁵ HIF is a transcription factor that induces numerous genes in the presence of hypoxia. HIF induces VEGF in the renal medulla, which, in turn, promotes the neovascular expansion necessary for tumor progression. This theory is further supported by Mostofi et al., who showed that patients with sickle-cell disease have increased cellular growth in the distal collecting ducts.⁴ In this setting of increased cell growth, rapid cellular expansion is promoted and sustained with the increased expression of HIF and VEGF.

Although most reported cases of renal medullary carcinoma have occurred in patients with sickle-cell trait, this might be due to the much higher prevalence of sickle-cell trait compared with sickle-cell disease. To our knowledge, this is one of the first reported cases of renal medullary carcinoma in an individual with sickle-cell disease.

Renal medullary carcinoma is associated with nonspecific signs and symptoms, rapid progression of symptoms, and a high fatality rate. This often leads to a delay in diagnosis and treatment, as was seen in this case. The patient's initial presentation was atypical, in that he complained of shortness of breath and chest pain. These symptoms were due to pleural effusions which are likely to have been the result of metastatic disease. He eventually died from a pulmonary embolism probably caused by the hypercoagulability associated with malignancy. Though hypercoagulability is known to be associated with malignancy, this is the first documented case of a patient dying as a result of hypercoagulability secondary to renal medullary carcinoma. The most common cause of death in patients with renal medullary carcinoma is metastatic spread. If cases such as this were detected earlier, it is possible that the tumor could be identified before metastatic spread, and the disease might be more amenable to surgical management. When the patient later presented with the more typical signs of hematuria, abdominal pain, and weight loss, with probable metastatic spread, the disease had progressed beyond the point of surgical management.

The most common presenting symptoms for renal medullary carcinoma are hematuria, flank pain and weight loss. Since hematuria is very common in patients with sickle-cell trait or sickle-cell disease, many patients do not receive a full work-up following an episode. Such patients should receive the traditional work-up for hematuria, including urine cytology (although only one case with positive urine cytology has ever been reported),⁶ renal sonogram and CT of the abdomen and pelvis. On imaging, renal medullary carcinoma has been found to be centrally located in the renal pelvis. Using reports in the literature and our experience as a reference point, the mass is likely to appear infiltrating, and might preserve the reniform shape of the kidney.⁷ However, diagnosis should consider the combination of demographic (sickle-cell) status, clinical presentation, and radiologic findings, including that of a mass in the renal pelvis.

In our case, the diagnosis was made at autopsy when lymphocytic infiltration was seen at the tumor demarcation. This finding represents the histologic hallmark of renal medullary carcinoma.

Differential diagnosis

The differential diagnosis for an infiltrating lower-pole renal mass includes renal medullary carcinoma, collecting-duct carcinoma, transitional-cell carcinoma of the renal pelvis, renal-cell carcinoma, metastatic disease and lymphoma. It is important to realize that any of these conditions can cause a mass in the renal pelvis. It is, therefore, important to use demographic and clinical presentation information to narrow down the differential diagnosis. Most importantly, sickle-cell status should be obtained. If the patient does not know their status, hemoglobin electrophoresis should be performed. In this case, the patient had documented sickle-cell disease.

Treatment

None of the current treatments available for renal cancers, including radical nephrectomy, radiotherapy and chemotherapy, has been shown to change the outcome or slow the progression of this disease.

Yang et al. demonstrated that renal medullary carcinoma is molecularly distinct from renal cell carcinoma, and should, therefore, be treated differently. They found that DNA topoisomerase II , macrophage stimulating 1 receptor (a tyrosine kinase), and angiogenesis-related genes were overexpressed in renal medullary carcinoma. On the basis of their findings, the authors suggest that chemotherapy agents that act by antagonizing the proteins expressed by these genes might be effective as first-line chemotherapy.⁸ DNA-topoisomerase-II- inhibitors—such as dactinomycin, doxorubicin, and etoposide—are known to be effective in Wilms' tumor, another renal carcinoma in which DNA topoisomerase II is overexpressed.

Selby et al. reported the case of a patient with sickle-cell trait who received a full urologic work-up after presenting with hematuria. CT revealed a medullary mass without any evidence of extrarenal involvement. The patient underwent radical nephrectomy and a pathology report confirmed the diagnosis of renal medullary carcinoma. After two years of follow-up, there was no clinical or radiologic evidence of recurrence or metastatic disease, and the patient remained asymptomatic.⁹ This example underlines the importance of imaging studies in patients with sickle-cell trait or disease presenting with hematuria, and illustrates the potential benefit of early diagnosis.

Conclusion

Given the aggressive and fatal course of this disease, renal medullary carcinoma should be considered in any young black patient presenting with the traditional signs. At the very least, such patients should be assessed for sickle-cell disease or sickle-cell trait, if their status is unknown, and hemoglobin electrophoresis should be performed. Additional investigations for sickle-cell-disease and sickle-cell-trait patients presenting with hematuria should include renal ultrasound and contrast-enhanced CT.¹⁰ Special consideration should be given to patients who have been diagnosed with papillary necrosis or renal infarction and are not responding to standard treatment. The combination of demographic and clinical information, along with radiological features, could lead to a diagnosis of renal medullary carcinoma. Given the extremely high fatality rate of this disease, and the evidence suggesting that early detection prolongs survival, it might be prudent to subject such patients to a more aggressive work-up at the onset of symptoms.

References

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Subject areas under which this article appears: Urologic oncology (nonprostatic)