Renal medullary carcinoma is a rare tumor that is most common in young black men with sickle cell disease or trait. Patients often present with advanced disease at the time of diagnosis, and their prognosis is poor, even with aggressive therapy. The clinical and pathologic features of renal medullary carcinoma have been described in several articles, but reports describing the cytologic features are rare.
In the current report, the authors describe the cytologic features of three cases of renal medullary carcinoma. The patients were young black men with sickle cell trait ages 20 years, 33 years, and 33 years.
All three patients presented with hematuria, flank pain, and a renal mass. The cytologic specimens from all three patients showed primarily cohesive groups of cells with vacuolated cytoplasm that often displaced or indented the nuclei. The nuclei often had irregular membranes, coarse or vesicular chromatin, and prominent nucleoli. Both of the two patients who were tested with fluorescence in situ hybridization were negative for the bcr/abl rearrangement.
Renal medullary carcinoma is a rare and highly aggressive tumor that occurs predominantly in young black men with sickle cell disease or trait. It was described first as a distinct entity by Davis et al.1 and was named because of its predominant medullary location. The most common presenting symptoms of this disease are hematuria, abdominal pain, and weight loss. Renal medullary carcinoma should be included in the differential diagnosis of patients with sickle cell trait or disease and hemoglobin SC disease who present with hematuria or a renal mass. The origin of this tumor is still unknown, but it has been suggested that renal medullary carcinoma may arise from the calyceal epithelium or the distal portion of the collecting duct.1 Several reports describe the histologic findings1–10 for this unusual tumor, but case reports that focus on the cytologic features are rare.11, 12 We describe the cytologic findings in three cases of renal medullary carcinoma, all of which occurred in young black men with sickle cell trait and the clinical findings are summarized in Table 1.
Table 1. Summary of Clinical Findings in Renal Medullary Carcinoma
HBDZ: hemoglobinopathies; AS: sickle cell trait; FNA: fine-needle aspiration; DOD: died of disease; LTF: lost to follow-up.
Hematuria, back pain
Renal pelvic washings; kidney FNA
Kidney core biopsy
Hematuria, back and flank pain
Liver core biopsy
Hematuria, back pain
Kidney touch imprints
A black man age 33 years from Nigeria developed sudden left flank pain and hematuria. A computed tomography (CT) scan of the abdomen showed a 5-cm, left upper pole renal mass with a central extension. Cystoscopy was performed, and no macroscopic lesions were identified. Left renal pelvic washings revealed atypical cells that were suspicious for malignancy. A CT scan of the chest revealed multiple bilateral pulmonary nodules. Although the patient denied a family history of sickle cell disease, a laboratory work-up showed that the patient was a carrier of the trait. A renal ultrasound-guided, fine-needle aspiration (FNA) biopsy and a core biopsy were performed, and the samples revealed a poorly differentiated carcinoma consistent with renal medullary carcinoma. Initially, the patient declined any further procedure or therapy. However, 2 months later, he agreed to undergo angioembolization of his left kidney as a palliative procedure. The patient died 10 months after his initial diagnosis.
A black man age 33 years presented with a 1-month history of macroscopic hematuria and increasing left flank pain and back pain. CT scans of the abdomen and pelvis revealed numerous, low-density lesions in the liver and an infiltrating, low attenuation in the posterior half of the left kidney. On CT scan, the differential diagnoses of the kidney lesion were infarct or severe pyelonephritic changes. The patient tested positive for the sickle cell trait. A CT-guided FNA biopsy and core biopsy of the liver were performed, and the results were interpreted as metastatic high-grade carcinoma consistent with renal medullary carcinoma. The patient received chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. His disease initially had appeared stable on CT; however, he developed lymphangitic spread in the lungs. Seven months after the initial diagnosis, the patient developed respiratory distress and died of his disease.
A black man age 20 years with sickle cell trait presented with back pain, hematuria, and loss of appetite. A CT scan of his abdomen revealed a mass in the midpole of the left kidney, a left hepatic lobe lesion, and a splenic nodule. In addition, a chest CT scan revealed a suspicious lung nodule. The patient underwent a biopsy at another institution (those results were not available for review) followed by three courses of chemotherapy and a left radical nephrectomy. The tumor was tan-brown and firm and measured 6.0 cm × 5.7 cm × 4.0 cm. It involved the medulla with invasion into the renal pelvis and extended into the cortex and perinephric fat. A touch imprint of the tumor was made, and a final diagnosis was renal medullary carcinoma. The nephrectomy slides, including touch imprints of the tumor, were reviewed at our institution, and we concurred with the diagnosis. A CT scan of the chest revealed multiple lesions in the lungs consistent with metastatic disease. Postoperatively, the patient received doxorubicin and ifosfamide. Seven months later, lung lesions appeared to have regressed except for a persistent right posterior chest wall opacity. The patient underwent a left thoracotomy with excision of an interlobar lymph node and right chest mass, both of which were negative for disease. Subsequently, the patient was lost to follow-up.
The FNA biopsy sample from Case 1 (Figs. 1–3) and the touch imprints from Case 3 (Fig. 4) of the kidney tumors were moderately cellular. In Case 1, the neoplastic cells were intermingled with glomeruli and benign proximal tubules. In both cases, tumor cells were arranged predominantly in loosely cohesive groups (Fig. 3) with scattered, single cells in the background. The tumor cells were identified readily as malignant with high nuclear-to-cytoplasmic ratios, irregular nuclear membranes, coarse chromatin, and one prominent or several smaller nucleoli. In Case 3, the nuclei were vesicular and had membrane grooves. The cytoplasm often was vacuolated, containing either several small vacuoles or a single, large vacuole that displaced or indented the nucleus regardless of prior therapy (Figs. 3, 4). A few fragments of fibrous connective tissue also were present in all three cases. FNA biopsy of the liver metastasis from Case 2 showed groups of malignant cells intermingled with benign hepatocytes (Fig. 5). The tumor cells in the liver metastasis (Cases 2) were similar cytomorphologically to those seen in Cases 1 and 3.
The renal pelvic washings from Case 1 revealed large atypical cells arranged in sheets, loosely cohesive clusters, and rare single cells. The nuclei had irregular membranes, coarse chromatin, and occasional nuclei (Fig. 6). The cytoplasm ranged from finely vacuolated to dense. Necrotic cellular debris was present in the background. The case was suspicious for malignancy, and the differential diagnosis included transitional cell carcinoma, renal cell carcinoma, and (less likely) lithiasis.
In Case 1, immunohistochemical studies performed on a cell block with limited material showed that the tumor cells stained positive for cytokeratin 7 and Ulex europaeus and were negative for cytokeratin 20, carcinoembryonic antigen, and p53.
DNA image analysis was performed on the renal pelvic washings from Case 1 and revealed diploid and tetraploid cell populations with a 2.9% proliferation index and no cells with a DNA content > 5c. Cytogenetic analysis using fluorescence in situ hybridization (FISH) did not detect bcr/abl rearrangement in either of the cases tested (Cases 1 and 3). Ultrastructural analysis was attempted in Case 1; however, insufficient material was present for classification.
Renal core biopsy (Case 1), liver core biopsy (Case 2), and surgical excision (Case 3) of the kidney showed poorly differentiated carcinomas. The tumor in the nephrectomy specimen had a reticular pattern with areas of gland formation, small solid nests, and cells with a microcystic pattern (Figs. 7, 8). The desmoplastic stroma contained prominent vascular proliferation and scattered inflammatory cells. Many of the tumor cells were vacuolated; and, in some instances, they indented the nuclei. The nuclei had irregular nuclear membranes, vesicular-to-coarse chromatin, and prominent nucleoli.
Immunohistochemical studies performed on the core biopsy sample from Case 1 showed that tumor cells stained positive for U. europaeus lectin, high-molecular-weight cytokeratin, and cytokeratin 7. Cells were stained only rarely for vimentin and were negative for cytokeratin 20.
Most renal cell carcinomas occur in patients ages 50–70 years, but they also have been reported in younger patients. Hartman et al.13 studied renal tumors that occurred in patients ages 10–20 years and found that 50% of patients had renal cell carcinoma, and 50% of patients had Wilms tumor. In 1995, Davis et al.1 described a rare tumor of the kidney that tended to occur in young black patients with sickle cell trait or disease and hemoglobin SC. The patients usually presented with hematuria, abdominal pain, and weight loss. Davis et al.1 referred to this disease as the “seventh sickle cell nephropathy” as an addition to the description by Berman14 of the six nephropathies seen in patients with sickle cell disease or trait: hematuria, papillary necrosis, nephritic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis. These tumors were designated as renal medullary carcinomas due to their dominant medullary location. In 2003, Dimashkieh et al.10 reviewed the literature and summarized the findings of 55 cases of renal medullary carcinoma. Those authors found that the average age at tumor presentation was 21 years, and the male-female ratio was 2.2:1.0. Hemoglobulinopathies were found in 53 of the 55 cases (50 patients had hemoglobin AS, 2 patients had hemoglobin SC, and 1 patient had hemoglobin SS disease). The right kidney was involved 3 times more commonly than the left kidney, and the mean tumor size was 6.1 cm. In the series of 33 cases reported by Davis et al.,1 all tumors extended beyond the renal capsule, and most patients had lymph node metastases at the time of presentation. Although clinical follow-up was not available in all patients, those patients who were followed had a mean survival of only 15 weeks after diagnosis. Avery et al.5 described six patients who presented with advanced renal medullary carcinoma who had short survival despite aggressive therapy.
Renal medullary carcinomas are firm, lobulated, and tan to gray, and they have variable areas of hemorrhage and necrosis. Histologically, a variety of growth patterns have been described, including reticular, solid, tubular, trabecular, cribriform, sarcomatoid, and micropapillary.1–7 Davis et al.1 noted that most renal medullary carcinomas had areas of poorly differentiated cells with solid sheets of tumor cells. The tumor cells in the solid areas contained vesicular nuclei with prominent nucleoli and amphophilic cytoplasm. The cytoplasm was vacuolated in some tumors, whereas it had a squamoid appearance in others. In addition, some authors have reported that it is not uncommon for some renal medullary carcinoma cells to have a rhabdoid appearance.1, 3, 4 Other findings include stromal desmoplasia and mixed inflammatory infiltrate.2
There are only rare case reports describing the cytologic findings of renal medullary carcinoma.11, 12 Larson et al.12 reported on a black woman age 18 years who presented with macroscopic hematuria. Malignant cells that were identified in her urine and cervical smear specimens initially were interpreted as transitional cell carcinoma. In both specimens, the malignant cells had dense cytoplasm with distinct borders. The nuclei had irregular membranes, clumped chromatin, and nucleoli. The renal pelvic washings in our case showed similar findings as well as some tumor cells with finely vacuolated cytoplasm. Qi et al.11 reported a case in which FNA of a renal tumor revealed findings similar to ours. Pleomorphic tumor cells were arranged predominantly in groups, and some of the single cells had an eccentrically placed nucleus. The nuclei were shaped irregularly and often had prominent nucleoli. The cytoplasm was vacuolated and contained multiple, small vacuoles and large vacuoles that displaced and indented the nucleus.
Cytologically, the differential diagnoses of renal medullary carcinoma include other high-grade carcinomas, such as transitional cell carcinoma, renal cell carcinoma, and collecting duct carcinoma, in addition to rhabdoid and Wilms tumors in young patients. High-grade transitional cell carcinoma, collecting duct carcinoma, and renal medullary carcinoma have overlapping cytomorphologic features, including glandular differentiation. The presence of cercariform cells is consistent with transitional cell carcinoma. Collecting duct carcinoma can be more challenging to differentiate, because it can have pleomorphic nuclei with dense or vacuolated cytoplasm, similar to renal medullary carcinoma.15
Renal medullary carcinoma may contain cells with rhabdoid features similar to those seen in rhabdoid tumor; however, the latter contains a monotonous population of rhabdoid cells.16 Furthermore, rhabdoid tumors usually present in the first 3 years of life, unlike renal medullary carcinoma, which usually occurs in older patients, although the age range is broad.1, 10, 16–18 Anaplastic Wilms tumor, which also occurs at a young age, exhibits extreme polymorphism, nuclear hyperchromasia, and variations in the presence of the three cellular components (blastema, epithelial, and mesenchyme).19
Immunohistochemical studies may be helpful in differentiating renal medullary carcinoma in some patients; therefore, a cell block preparation or core biopsy is recommended. Transitional cell carcinoma can be differentiated by positive staining for thrombomodulin; however, lack of positive staining does not exclude transitional cell carcinoma. Moreover, high-molecular-weight cytokeratin 34BE12 was positive in all high-grade transitional cell carcinomas studied by Varma et al20 and was negative in all renal medullary carcinomas studied by Swartz et al.7
To date, there are insufficient data in the literature to reach a conclusion about the ability of immunomarkers to differentiate between renal medullary carcinoma and collecting duct carcinoma2, 6, 21, 22 because they have overlapping immunoprofiles (Table 2). Collecting duct carcinomas typically are positive for cytokeratin 34BE12 and U. europaeus,22 whereas renal medullary carcinomas are negative for cytokeratin 34BE12 and show variable staining for U. europaeus.2, 7 In the current study, Case 1 was positive for U. europaeus. Many renal medullary carcinomas probably were classified as collecting duct carcinomas prior to the report by Davis et al.1 The clinical history of sickle cell trait or disease is a key factor in distinguishing between these entities.
Table 2. Comparison of Immunohistochemical Studies in Adult Renal Tumors
In children, tumor cells that stain positive for S-100 protein and neuron-specific enolase may suggest a rhabdoid tumor.23 In anaplastic Wilms tumor, the diversity of cell lines and the degree of differentiation results in variable immunoprofiles; however, positivity for CD56, WT-1, and desmin suggest the diagnosis of Wilms tumor.24
To date, no genetic abnormality has been associated with renal medullary carcinoma. Avery et al.5 reported monosomy of chromosome 11 in 1 patient, and Stahlschmidt et al.3 described a patient with the bcr/abl rearrangement, as seen in chronic myelogenous leukemia; the treatment of the latter has been enhanced by the development of imatinib, a specific inhibitor of the bc1/ab1 tyrosine kinase. Neither of our cases (Cases 1 and 3) that were tested for bcr/abl had this rearrangement on FISH analysis. Swartz et al.7 performed comparative genomic hybridization tests in nine cases of renal medullary carcinoma and produced negative results in eight cases. Yang et al.25 analyzed the gene expression profiles of two cases of renal medullary carcinoma and compared the results with other subtypes of renal cell carcinoma and transitional cell carcinoma. The authors found that genes analyzed in medullary carcinoma did not cluster with those of clear cell or papillary renal cell carcinoma; however, there was close clustering with transition cell carcinoma. Further studies will be needed to determine whether these findings have clinical significance.
In summary, we report the cytologic features of renal medullary carcinoma occurring in three young black men with sickle cell trait. The presenting symptoms were macroscopic hematuria and flank pain. Imaging studies showed large renal masses with distant metastases. Cytologically, the tumor cells were similar to those seen in a high-grade epithelial malignant neoplasm. The cytologic features of renal medullary carcinoma are not specific; however, in the proper clinical setting, a diagnosis of renal medullary carcinoma can be rendered.