Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases

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1 Human Pathology (2011) 42, Original contribution Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases Qiusheng Si MD, PhD a, Jane Dancer MD a, Melissa L. Stanton MD a, Pheroze Tamboli MD a, Jae Y. Ro MD, PhD b, Bogdan A. Czerniak MD, PhD a, Steven S. Shen MD, PhD b, Charles C. Guo MD a, a Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA b Department of Pathology, The Methodist Hospital and Weill Medical College of Cornell University, Houston, TX 77030, USA Received 20 January 2011; revised 8 March 2011; accepted 16 March 2011 Keywords: Kidney; Small cell carcinoma; Urothelial carcinoma; Neuroendocrine differentiation Summary Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma Elsevier Inc. All rights reserved. 1. Introduction Small cell carcinoma (SmCC) is a distinct histologic phenotype that can arise from a variety of organs [1-3]. SmCCs of various origins share similar histologic features: M. D. Anderson is supported in part by Cancer Center Support Grant CA from the National Institutes of Health. Corresponding author. address: ccguo@mdanderson.org (C. C. Guo). poorly differentiated carcinoma cells with finely granular nuclei, inconspicuous nucleoli, scant cytoplasm, nuclear molding, and poorly defined cellular borders. SmCCs also frequently express neuroendocrine markers such as synaptophysin, chromogranin, and CD56. In addition, SmCC is most commonly associated with paraneoplastic syndromes such as inappropriate antidiuretic hormone secretion, cerebellar degeneration, and Lambert-Eaton myasthenic syndrome [4]. Clinically, SmCC represents one of the most aggressive carcinomas. Most patients with SmCC present with widespread /$ see front matter 2011 Elsevier Inc. All rights reserved. doi: /j.humpath

2 Small cell carcinoma of kidney metastases, which makes it difficult to eradicate the disease by surgery. Although SmCC responds to chemotherapy and radiation treatments, patients usually die of the disease in a relatively short time after diagnosis. More than 90% of SmCCs occur in the lungs, but the disease is also found in various extrapulmonary sites including the genitourinary tract, gastrointestinal tract, breast, cervix, skin, salivary glands, and larynx [5-16]. The genitourinary tract is the most common extrapulmonary site, with approximately 900 new cases diagnosed every year in the United States [15]. Most SmCCs in the genitourinary tract occur in the prostate and urinary bladder [9-13]. SmCC of the kidney is extremely rare, with only a few cases reported in the literature [17-21]. To better understand this rare disease, we studied the clinical and pathologic features of 14 cases of renal SmCC from 2 institutions. To our knowledge, the current study presents the largest series of patients with this extremely rare renal malignancy seen in the literature to date. 2. Materials and methods With the approval of the institutional review board, we retrospectively reviewed the surgical pathology report databases for patients with SmCC of the kidney who were treated at The University of Texas MD Anderson Cancer Center or The Methodist Hospital in Houston, Texas, from 1987 through Eighteen patients with SmCC in the kidney, including the renal pelvis and renal parenchyma, were identified, but 4 of them were excluded from the study because they had lung SmCC and their renal lesions were considered to represent a metastasis from the primary lung disease. All patients with renal SmCC underwent radical nephrectomy. For each radical nephrectomy specimen, the tumor was extensively sampled for histologic examination with at least 1 tissue section per centimeter of the largest tumor dimension, and 2 or more tissue sections were routinely submitted from the pelvicalyceal regions. The hematoxylineosin stained slides from all patients were available for review in this study. The reviewed pathologic parameters included tumor size, location, stage, necrosis, lymphovascular invasion, non-smcc tumor components, and other histologic changes. Demographic and clinical information, including patient age and sex, symptoms at presentation, treatment, follow-up time, and clinical outcome, was obtained from the patients' charts. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections using polymeric biotin-free horseradish peroxidase on a Leica Microsystems Bond Max stainer (Leica Microsystems, Bannock, IL). Sections were routinely heated for epitope retrieval, and commercially available antibodies were used as described in Table 1. Peroxidase activity was visualized by staining with 3,3 - diaminobenzidine. Optimal dilutions and incubation times Table 1 Primary antibodies used for immunohistochemical analyses Antibody Clone Vendor Dilution Cytokeratin AE1/AE3 Polyclonal Dako, Carpentaria, CA 1:100 Synaptophysin Monoclonal (27G12) Leica Microsystems 1:600 Chromogranin Monoclonal Millipore, Billerica, 1:4000 (LK2H109-2) MA CD56 Monoclonal Invitrogen 1:100 (123C3) Carlsbad, CA CD99 Monoclonal Invitrogen Prediluted (O-13) TTF-1 Monoclonal (8G763/1) Dako 1:200 were determined using standard techniques. In each staining series, positive and negative controls were included with the tumor samples. 3. Results 3.1. Patient demographics and clinical findings We identified a total of 14 cases of renal SmCC that accounted for less than 1% of all renal tumors treated at our hospitals during the period studied. Of the 14 patients, 8 were women and 6 were men (Table 2). Their mean age at diagnosis was 59 years (range, years). Notably, 4 patients were younger than 40 years, ranging from 22 to 39 years. The most common symptoms at presentation were hematuria (n = 6) and abdominal pain (n = 5). In addition, 2 patients presented with a flank mass; 1 patient's renal mass was found on a computed tomography scan performed as a follow-up for bladder carcinoma. Eight tumors were found in the left kidney and 6 in the right. All patients were treated with radical nephrectomy Pathologic findings 1793 On gross examination, the radical nephrectomy specimens showed a unifocal tumor in all cases. The tumor was located centrally around the renal pelvis in 5 cases and was located peripherally in renal parenchyma in 9 cases. The tumor usually had an ill-defined border, and the cut surfaces were soft and friable with areas of necrosis. The mean tumor size was 7.1 cm (range, cm). Microscopically, the tumors showed sheets or large nests of small tumor cells infiltrating the renal parenchyma (Fig. 1A). The tumor cells were round or oval with scant cytoplasm and indistinct cell borders (Fig. 1B). The nuclei were hyperchromatic with evenly distributed chromatin, inconspicuous nucleoli, and abundant mitotic figures (Fig. 1C). Nuclear molding

3 1794 Q. Si et al. Table 2 Case Age (y) Pathologic and clinical features of primary SmCC of the kidney Sex Presenting symptoms Size (cm) Confined to kidney LVI Non-SmCC components Metastasis Follow-up (mo) 1 71 F N/A N/A No Yes UC No DOD (18) 2 74 M Flank pain, hematuria 6.0 No Yes No Liver, bone, LN DOD (4) 3 71 M Hematuria 4.7 No No UC No DOD (17) 4 68 M Flank mass 9.0 No No No LN DOD (13) 5 39 F N/A N/A No Yes No No DOD (15) 6 69 F N/A N/A No No UC No DOD (5) 7 32 F Flank pain, hematuria N/A No No No Liver DOD (15) 8 66 F N/A 6.1 No No No No N/A 9 75 F N/A N/A No No No No DOD (12) M Flank pain, hematuria 9.4 Yes No No No ANED (137) F Flank pain 14.0 No Yes UC LN DOD (18) M Flank pain, hematuria 6.0 No Yes No LN ANED (5) F Hematuria 6.0 No No UC No DOD (31) M Flank mass 3.5 No Yes Carcinoid LN DOD (23) Abbreviations: ANED, alive with no evidence of disease; DOD, died of disease; F, female; LN, lymph node; LVI, lymphovascular invasion; M, male; N/A, not available; UC, urothelial carcinoma. and smudging features were common (Fig. 1D). Tumor necrosis, ranging from 10% to 50%, was present in all cases (Fig. 1D). Immunohistochemical studies were performed in 12 cases. On immunostains, SmCC cells were positive for cytokeratin AE1/AE3 (11/12; Fig. 1F), synaptophysin (8/9; Fig. 1G), chromogranin (6/9; Fig. 1H), and CD56 (3/4) and negative for CD99 (0/2) and thyroid transcription factor 1 (TTF-1) (0/1). Although SmCC was pure in 9 cases, it was admixed with high-grade urothelial carcinoma in 5 cases (Fig. 2A). The urothelial carcinoma component accounted for 10% to 60% of the 5 tumors. In 1 case, the tumor had focal areas with carcinoid features (Fig. 2B). The tumor invaded through the renal parenchyma into the perinephric adipose tissue in 13 cases and was confined to the kidney in 1 case. Lymphovascular invasion was identified in 6 cases (6/14). The tumor also invaded the renal vein (n = 2) and the paraspinal skeletal muscle (n = 1). Metastasis to lymph nodes was present in all 5 patients who underwent lymph node dissection Patient outcomes Follow-up data were available for 13 patients with a mean follow-up time of 24 months from diagnosis (range, months) (Table 2). Among 8 patients whose treatment records were available, all patients received standard chemotherapy for SmCC of the lung protocol after surgery, and 1 also received neoadjuvant chemotherapy. Nevertheless, 11 patients died of disease after a mean of 15 months (range, 4-31 months). Among the 2 alive patients, 1 had a limited follow-up time of 5 months, and the other, who had an organconfined tumor, was alive without evidence of disease 137 months after surgery. 4. Discussion Renal SmCC is an extremely rare malignancy. We identified 14 cases of renal SmCC from the pathology files, which accounts for less than 1% of all renal tumors treated at our 2 institutions in the period studied. We found that renal SmCC affected patients at various ages, including younger than the age of 40 years. There were more women than men in our series despite the striking male predominance usually found for SmCCs of other genitourinary organs [9,10]. Patients with renal SmCC commonly presented with abdominal pain and/or hematuria, similar to those with renal cell and urothelial carcinomas; this makes it difficult to distinguish among these cancers based upon clinical presentation alone. Although renal SmCC shares similar morphological and immunohistochemical features with SmCC of other organs, renal SmCC often coexists with urothelial carcinoma, suggesting a potential association between SmCC and urothelial carcinoma in the kidney. The current study also found renal SmCC to be extremely aggressive. Among the 14 patients in our study, 13 had a tumor that spread out of the kidney and invaded Fig. 1 SmCC of the kidney. A, The tumor consists of a sheet of poorly differentiated tumor cells that invade the renal parenchyma. B, The tumor cells are characterized by hyperchromatic nuclei, scant cytoplasm, and indistinct cell borders. C, The tumor cells have numerous mitoses. D, The tumor cells show nuclear molding and smudging features. E, The tumor has focal necrosis. The tumor cells are positive for cytokeratin AE1/AE3 (F), synaptophysin (G), and chromogranin (H).

4 Small cell carcinoma of kidney 1795

5 1796 Q. Si et al. Fig. 2 A, SmCC coexists with high-grade urothelial carcinoma. B, SmCC shows focal carcinoid feature with acinar structures. the perinephric adipose tissue at the time of diagnosis, and only 1 patient had a tumor confined to the kidney. In addition, 6 patients had developed metastasis by the time of surgery. Despite treatment with combined surgery and chemotherapy, most patients died of the disease in a short period. Only 1 patient had a long-term survival of 137 months. Interestingly, this surviving patient had SmCC confined to the kidney, suggesting that patients with an organ-confined SmCC may achieve a long-time survival if treated early. We did not find any association between patient overall survival and patient age, sex, tumor size, or coexistence of high-grade urothelial carcinoma. The presence of even a small amount of SmCC was indicative of a dismal prognosis. Previous reports also found renal SmCC to be characterized by extremely aggressive behavior. Majhail et al [21] reviewed 22 cases of renal SmCC reported in the literature and found a median survival time of only 8 months despite surgery and chemotherapy. The authors divided the renal SmCC into limited and extensive stages: at a limited stage, the renal SmCC was confined to the kidney or had only local extension into the renal vein, adrenal gland, perinephric tissue, or regional lymph nodes; at an extensive stage, the renal SmCC had spread beyond these structures (including distant metastasis). However, Majhail et al did not observe any significant association between tumor stage and overall patient survival. One possible reason for this lack of association might have been a high incidence of occult metastatic disease in patients. Another reason might be that the definition of limited disease was too broad and included disease that should have been considered extensive. Nevertheless, Majhail et al found that patients responded better to platinum-based chemotherapy than to other forms of chemotherapy, with a median survival of 20 months compared with just 8 months' median survival among those who did not receive platinum-based regimens. Although the carcinogenesis of SmCC in the genitourinary tract remains unclear, several hypotheses have been proposed [22-25]. Because immunohistochemical and electron microscopic analyses of SmCC cells frequently reveal neuroendocrine features, it is possible that they may arise from the neuroendocrine precursor Kulchitsky cells in the urinary tract [23]. We observed a focal area of carcinoid differentiation in 1 case, supporting a potential neuroendocrine origin for renal SmCC. Another theory suggests that SmCC may develop through metaplasia of high-grade urothelial carcinoma, as urothelial carcinoma frequently exhibits squamous and glandular metaplasias [24]. In the present study, 5 cases of renal SmCC also contained a high-grade urothelial carcinoma component, suggesting that some renal SmCCs may evolve from urothelial carcinomas of the renal pelvis and calyces. Finally, recent stem cell studies have led to the new hypothesis that SmCC may arise from multipotent cancer stem cells that are capable of differentiating into various cell types including SmCC and urothelial carcinoma [25]. Nonetheless, it is reasonable to postulate that the oncogenesis of renal SmCC may involve multiple pathways. Renal SmCC may be located in the renal parenchyma or the renal pelvis [17,26]. SmCC in the renal pelvis often coexists with urothelial carcinoma or urothelial carcinoma in situ, suggesting a close relationship between SmCC and urothelial carcinoma. Comparative genomic hybridization analysis in the urinary bladder demonstrated that SmCC not only carried the genomic alterations that were characteristic of urothelial carcinoma but also acquired additional genetic alterations, suggesting that SmCC may evolve from a preexistent urothelial carcinoma [26]. Renal SmCC has also been reported to coexist with papillary renal cell carcinoma [27]. Fluorescence in situ hybridization analysis found that renal SmCC has amplification of the Myc gene, a genetic alteration frequently seen in papillary type 2 renal cell carcinoma, suggesting a similar molecular pathway [17]. Nonetheless, there was no significant difference in the clinical course of pure SmCCs and those mixed with other carcinomas. As noted, the presence of even very limited SmCC was indicative of a dismal prognosis. None of our cases was associated with renal cell carcinoma.

6 Small cell carcinoma of kidney Because lung SmCC is far more common than renal SmCC, metastasis from a primary lung SmCC should always be considered when evaluating an SmCC in the kidney. During our database search, 4 cases of primary lung SmCC with metastasis to the kidney were found and excluded from the study. Only 1 of the 4 excluded patients had a previously known history of lung SmCC; the other 3 were diagnosed with primary lung SmCC only after the kidney metastasis was found. Because SmCCs of various origins share similar morphological features, it is difficult to distinguish them based on morphological evaluation alone. Although the expression of TTF-1 has been used to support a pulmonary origin for SmCCs [28], this protein has also been found in SmCC cells from extrapulmonary SmCC including those arising from the urinary tract [13,29]. Therefore, TTF-1 alone cannot be used to distinguish between origins in the lung and kidney for SmCCs. Although certain clinical features such as the presence of lung lesions found by radiographic study would suggest metastasis from a lung origin, the coexistence of urothelial carcinoma or urothelial carcinoma in situ would support a renal origin for SmCC. A spectrum of neuroendocrine tumors with diverse biologic behaviors have been reported in the kidney [30-31]. Renal SmCC should be differentiated from the other renal neuroendocrine tumors including carcinoid tumor and large cell neuroendocrine carcinoma (LCNEC) [30]. A renal carcinoid tumor that usually shows nest, trabecular, and organoid growths of uniform medium-sized cells with oval finely granular nuclei and lightly eosinophilic cytoplasm has a low mitotic rate (b2 per 10 high-power fields) and lacks coagulation necrosis. Although carcinoid tumor is considered to be a low-grade neuroendocrine tumor, patients with renal carcinoma tumors frequently develop metastasis to lymph nodes and distant organs [31]. LCNEC has a typical carcinoid growth pattern, a high mitotic rate (N2 per 10 highpower fields), coagulation necrosis, and immunohistochemical positivity for at least 1 neuroendocrine marker. In contrast to SmCC, LCNEC has large carcinoma cells with a low nuclear to cytoplasmic ratio and finely granular chromatin. Like SmCC, LCNEC is a rapidly progressing disease, and patients often die of disease shortly after diagnosis despite multimodal treatment [30]. Renal SmCC should be distinguished from other small blue cell tumors in the kidney including poorly differentiated urothelial carcinomas, Wilms tumors, lymphomas, and Ewing sarcomas or primitive neuroectodermal tumors [32-35]. Poorly differentiated urothelial carcinomas usually lack neuroendocrine markers such as synaptophysin, chromogranin, and CD56 [32]. Lymphomas are characterized by discohesive malignant cells permeating the nephron structures, and the malignant cells are positive for leukocytecommon antigens but negative for cytokeratin [33]. Wilms tumors primarily affect children and have a triphasic pattern of blastema, epithelial, and stromal cells and are positive for WT- 1 on immunostaining [34]. Ewing sarcomas or primitive neuroectodermal tumors often have neuroectodermal differentiation, and their tumor cells are positive for CD99, negative for cytokeratin, and have a characteristic t(11;22)(q24;q12) chromosomal translocation [35]. In summary, SmCC of the kidney is an extremely rare tumor that should be differentiated from metastases from the lung and other organs. Renal SmCC affects patients of various ages and appears to be more common in women. Its clinical presentations are similar to those of renal cell carcinoma or urothelial carcinoma, and it is histologically and immunohistochemically indistinguishable from its pulmonary or other extrapulmonary SmCC counterparts. Although renal SmCC often coexists with urothelial carcinoma, the presence of urothelial carcinoma does not appear to affect its clinical outcome. Most patients present at an advanced stage with widespread metastases and will have a dismal prognosis despite multimodal therapy. However, if the disease is found and treated early, long-term survival may be possible for patients with an organ-confined tumor. References 1797 [1] Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002;26: [2] Lee SS, Lee J, Ryu M, et al. Extra-pulmonary small cell carcinoma: single center experience with 61 patients. 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