|Year : 2000 | Volume
| Issue : 2 | Page : 92-97
Renal medullary carcinoma in sickle cell anemia: A review
Rubica Wadhera, Sakti Das, Hari Siva T Gurunadha Rao
Department of Urology, University of California Davis School of Medicine, Sacramento, California, USA
Dept. of Urology, University of California Davis School of Medicine 4860 Y Street Suite 2100, Sacramento, CA 95817
Keywords: Hemoglobin; Sickle Cell Disease; Hematuria; Papillary Necrosis; Renal Medulla; Desmoplasia.
|How to cite this article:|
Wadhera R, Das S, Gurunadha Rao HT. Renal medullary carcinoma in sickle cell anemia: A review. Indian J Urol 2000;16:92-7
| Introduction|| |
In the United States of America, up to 8% of people with African ancestry may be heterozygous for hemoglobin AS (sickle cell trait) and 1 in 400 live births have the homozygous disease (sickle cell anemia).  Current estimates suggest that at present there are about 17500 African American individuals afflicted with sickle cell disease. In 1974, Berman described 6 nephropathies seen in patients with sickle cell disease or sickle cell trait attributable to vascular stagnation, reduced oxygen pressure and renal medullary hypertonicity.  They were gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate the urine and pyelonephritis. In 1995, Davis et al described a rare tumor of kidney that notably occurred in young African American patients with sickle cell disease or sickle cell trait, which they proposed to call as the `seventh sickle cell nephropathy'  This tumor is a rare, very aggresive, resistant to immunotherapy and chemotherapy and universally fatal, with death often occurring within one year of diagnosis.
| Origin and Genetics|| |
The relatively young age of the patients with renal medullae carcinoma prompted the search for some unknown genetic factor likely to be involved in the pathogenesis. Cytogenetic testing performed on tumor tissue revealed monosomy of chromosome 11 in 4 out of 6 successfully karyotyped abnormal cells.  Interestingly, since all the patients had sickle cell trait and that the gene for beta globin is found at the terminal portion of short arm of chromosome 11, it appears likely that the chromosome 11 may be involved in the development of renal medullary carcinoma or that renal medullary carcinoma gene is susceptible to the altered gene product of sickle cell trait. Deletions in short arm segment 11p15 have been described in other neoplasms like hereditary and spontaneous cases of Wilms' tumor, rhabdomyosarcoma and bladder and breast cancer. The Hp segment is thought to contain a suppressor gene. Abnormalities were also noted on chromosome 3.  Another possible mechanism in the etiopathogenesis of renal medullary carcinoma in sickle cell trait is vascular sludging in the vasa recta of renal medulla with focal ischemia in the medullary tips, leading to papillary necrosis which ultimately may result in neoplastic degeneration . 
| Clinical Features|| |
This tumor is seen in young patients usually between 11 and 39 years.  Before the age of 25 years, males are predominantly affected (male to female ratio being 3 to 1) and thereafter both sexes are equally affected. The most common presenting symptoms of renal medullary carcinoma are gross hematuria (60%) and abdominal or flank pain (48%).  Most of these tumors occur on the right side. The initial clinical manifestations may be protean including fever of unknown origin, fatigue, back pain, weight loss, cough, breathlessness, palpable abdominal mass, enlarged lymph nodes, leukocytosis, elevated levels of SGOT, SGPT, LDH. The average duration of symptoms before diagnosis is 4.7 months.  Although this cancer usually occurs in people of African ancestry, Srigley and Eble reported renal medullary carcinoma in a woman from India who had sickle cell trait.  Davis et al refer to a 31-year-old white female with no evidence of sickled erythrocytes, who had a renal tumor indistinguishable from renal medullary carcinoma. 
| Pathology|| |
On gross examination, the bulk of renal medullary carcinoma occupies the renal medulla and adjacent soft tissues. , Most cases, at the time of presentation, also involve the renal cortex as multiple satellite nodules. These nodules are, in fact, tumors in venous and lymphatic channels. The size of the lesion ranges from 4 to 12 cm. The tumor is poorly circumscribed, occupying most of the renal parenchyma, with extension to renal pelvis and peripelvic soft tissue  . The lesions are poorly defined and involve most of the renal parenchyma with extension into the collecting system. Small multifocal nodules and extension into the perirenal soft tissues are characteristic. It is gritty to rubbery in consistency, tan to grey in color with multiple variable areas of hemorrhage and necrosis. Most of them are mucoid, a few being cavitary. The necrosis in most of the cases is suppurative, ischemic or comedo in nature. The growth pattern is often infiltrative. 
Microscopically, the lesion arises from the calyceal epithelium. Mostofi et al observed epithelial proliferation of the terminal collecting ducts in adjacent papillary mucosa which they believed was a proliferation of transitional cells rather than columnar ductal cells.  Based on these findings some authors postulated that renal medullary carcinoma arises from regions of increased cellular growth. Whether such cases (where there is an associated transitional cell carcinoma in the region adjacent to the tumor) represent a collision tumor or dedifferentiation of the pelvic transitional cell carcinoma is open to debate.  The most characteristic pattern of the tumor is loose reticular with areas of small gland and cyst formation, resembling the familial yolk sac testicular tumors of reticular type.  While foci of mucoid, myxoid or edematous changes, stromal desmoplasia and inflammatory elements are prominent in all cases, a few foci of collagen are also noted. The other histologic patterns seen are more compact adenoid cystic type, rhabdoid and spindle cell variants usually with vesicular nuclei and prominent nucleoli.  Focal micropapillae are present in the intervening solid and cystic areas. Adsay et al (1998) reported the tumor cells as having round nuclei, amphophilic cytoplasm and vesicular chromatin.  In some cells, the nuclei are pushed to the periphery by abundant, dense cytoplasm, giving the cells a rhabdoid or plasmacytoid appearance. Mixed histological patterns are occasionally seen.  Sickled erythrocytes are easily identified microscopically. Occasionally the tumor contains transitional cell epthelium and arises from the pelvicalyceal system with invasion of adjacent renal medulla and renal cortex. Based on these findings, some authors feel that renal medullary carcinoma should be considered as a dedifferentiated, high grade transitional cell carcinoma of the kidney. 
| Diagnostic Studies|| |
The tumors can be assessed by ultrasonography, excretory urography and computed tomography.  The tumor usually involves the central portion of kidney. Sonography shows a centrally located solid space occupying lesion of kidney with heterogeneous echogenicity. Tumors are not well visualized on excretory urography with occasional evidence of a mass lesion in the kidney with distortion of adjacent calyx. Computed Tomography (CT) reveals infiltrative and indistinct masses that usually arise in the central region of the kidney with invasion into the renal sinus fat. CT shows contrast enhancement of the lesion in all patients along with retroperitoneal lymphadenopathy (Davidson et al, 1995).  CT may show the mass as arising from the calices and extending through the renal medulla and cortex. Occasionally the lesion masquerades as an invasive transitional cell carcinoma of the renal pelvis / calyces. Retrograde pyelography may reveal multiple filling defects in the pelvicalyceal system. Ureteroscopy may reveal a sessile mass lesion in the pelvicalyceal system.  Angiographically, the tumor is hypovascular.  Malignant cells can be seen in the urine on cytological examination as the cells have poor cohesion and the tumor is in or adjacent to the renal pelvis. 
| Metastatic Spread|| |
The tumor shows local spread as well as distant metastases. Locally, it involves central renal parenchyma renal pelvis and sinus and extends to regional lymph nodes (78%), inferior vena cava, liver, adrenal gland and retroperitoneal soft tissue. Many patients have extensive perinephric and renal vein involvement. Distant metastastis may include lymph nodes, lungs (27%), adrenal gland (24%), liver (18%), lungs (with diffuse lymphangitic pulmonary failure), pulmonary hilar lymph nodes, bone and genitourinary tract  . Larson et al described a case where they found extensive involvement of the genital tract with metastases seen on a cervical smear and vaginal biopsy and malignant cells in the urine specimen. 
| Differential Diagnosis|| |
A distinctive feature of this neoplasm is that it arises in the medullary portion of the kidney  . Other renal neoplasms with central location and infiltrative pattern such as transitional cell carcinoma invading renal parenchyma, perirenal and/or renal lymphoma with trans-sinus invasion, undifferentiated or sarcomatoid variants of renal cell carcinoma, collecting duct carcinoma or squamous cell carcinoma metastasizing to the kidney might post a diagnostic dilemma. But renal medullary carcinoma can be differentiated by the typical clinical (race, age and sickle cell trait) and radiologic findings as described above.  Wilms' tumor and renal cell carcinoma, rare in the 2nd to 4th decades of life, can be distinguished from the renal medullary carcinoma by their cortical location and expansive growth.  Renal medullary carcinoma typically has a fair amount of inflammatory infiltrate and reactive stromal elements, unlike most types of renal cell carcinoma. Renal medullary carcinoma is thought to be distinct from Bellini's duct or collecting duct carcinoma of the kidney. Histologically the features of collecting duct carcinoma overlap more with renal cell carcinoma, and collecting duct tumors do not stain positive for low molecular weight cytokeratin, vimentin and epithelial membrane antigen (EMA).  Transitional cell carcinoma may also present with a positive urine cytology, but it rarely occurs at such a young age as renal medullary carcinoma. Renal cell carcinoma rarely sheds into urine, except when poorly differentiated, advanced and extending into the renal pelvis.  A severe form of acute pyelonephritis may also simulate the infiltrative histologic appearance of the medullary carcinomas.  However, the clinical presentation is distinctive.
| Management|| |
Radical nephrectomy with retroperitoneal lymphadenectomy is recommended in operable cases.  A wide variety of therapeutic modalities, viz., chemotherapy, radiotherapy and immunotherapy including cyclophosphamide, ifosfamide, etoposide, cisplatin, carboplatin, doxorubicin, interferon, paclitaxel and combination chemotherapy with M-VAC (Methotrexate, Vinblastine, Doxorubicin and Cisplatin) have all been tried without success. Investigational agents that are being tried include topotecan, doxorubicin, filgrastim, interleukin-2 and alpha-interferon with 5-fluorouracil, isotretinoin, paclitaxel. Palliative radiation therapy has little or no response.  To date, no regimen has been shown to have a significant effect on the clinical course of this disease and no patient is reported to have survived the disease. Follow-up information is available on 19 out of 33 patients.  The survival from the time of surgery was 352 weeks (mean 15 weeks). Coogan et al reported a case of a 23-year-old African American male who died 17 months following surgery, because of widespread metastatic disease.  To date, this is the longest survival reported from the time of surgery for this fatal neoplasm.
| Discussion|| |
Renal medullary carcinoma is an extremely rare neoplasm. Most of the patients have evidence of advanced disease at presentation. The diagnosis is.often made after nephrectomy. It is a very aggressive tumor with a universally fatal outcome despite a variety of treatment regimens including surgery, radiotherapy, chemotherapy and immunotherapy. This tumor has peculiar demographic characteristics in that the majority of patients are of African American ancestry with an age range of 11 to 39 years and have evidence of sickle cells in their pathologic specimens. The tumor occupies renal medulla and the adjacent tissues with satellite nodules in cortex.
The relative young age and presence of sickle cell hemoglobinopathy in almost all of the patients has raised the suspicion of some yet unidentified genetic component involved in the pathogenesis of this otherwise rare tumor. The tumor has extremely rapid growth potential and poor prognosis. Clinically this tumor is extremely aggressive and has been fatal in all 39 cases in the literature. ,, Davis et al reported a mean survival of 15 weeks postoperatively.  Surgery alone does not seem to alter the disease course. Numerous patients have received adjuvant therapy but none has responded to regimens of cyclophosphamide, doxorubicin, vinblastine and cisplatin. Investigational agents have been tried, including topotecan, filgrastim, interferon-alpha, pacitaxel, interleukin-2 and 5-fluorour acil. 
Since the most common presenting symptom of this tumor is hematuria, a thorough work-up is warranted for all patients of sickle cell anemia presenting with hematuria. A high index of suspicion combined with accurate interpretation by a clinician, cytopathologist and a radiologist are essential for an earlier diagnosis of this rare tumor. This may be the only hope for survival of patients of sickle cell anemia with renal medullary carcinoma, which, to date, seems to have uniformly dismal prognosis.
| Conclusions|| |
Renal medullary carcinoma is a newly described tumor that has been termed the seventh sickle cell nephropathy. To date its rapid and aggressive clinical course has not been changed by any available treatment modality. This tumor should be included in the differential diagnosis in any patient with sickle cell disease or trait who presents with hematuria. A high index of suspicion and earlier diagnosis may be the only opportunity to alter the course of this uniformly fatal cancer.
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