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Collecting Duct Carcinoma of the Kidney: an Immunohistochemical BMC Urology BioMed Central Research article Open Access Collecting duct carcinoma of the kidney: an immunohistochemical study of 11 cases Andrea Vecchione1,2, Tommaso Prayer Galetti3, Marina Gardiman4, Hideshi Ishii5,6, Enrico Giarnieri1,2, Francesco Pagano3, Leonard G Gomella1, Carlo M Croce5 and Raffaele Baffa* Address: 1Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA, 19107, USA, 2University of Rome "La Sapienza", Ospedale Santo Andrea, Rome, Italy, 3Department of Urology, University of Padova, Via Giustiniani 25, Padova, Italy, 4Department of Pathology, University of Padova, Via Gabelli 3, Padova, Italy, 5Department of Microbiology/Immunology, Kimmel Cancer Center, Thomas Jefferson University, 220 10th South Street, Philadelphia, PA, 19107, USA and 6Jichi Medical School, Center for Molecular Medicine, Division of Stem Cell Regulation/Molecular Hematopoiesis, 3311-1 Yakushiji, Minami-Kawachi, Tochigi, 329-0498, Japan Email: Andrea Vecchione - [email protected]; Tommaso Prayer Galetti - [email protected]; Marina Gardiman - [email protected]; Hideshi Ishii - [email protected]; Enrico Giarnieri - [email protected]; Francesco Pagano - [email protected]; Leonard G Gomella - [email protected]; Carlo M Croce - [email protected]; Raffaele Baffa* - [email protected] * Corresponding author Published: 09 September 2004 Received: 20 March 2004 Accepted: 09 September 2004 BMC Urology 2004, 4:11 doi:10.1186/1471-2490-4-11 This article is available from: http://www.biomedcentral.com/1471-2490/4/11 © 2004 Vecchione et al; licensee BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Collecting duct carcinoma (CDC) is a rare but very aggressive variant of kidney carcinoma that arises from the epithelium of Bellini's ducts, in the distal portion of the nephron. In order to gain an insight into the biology of this tumor we evaluated the expression of five genes involved in the development of renal cancer (FEZ1/LZTS1, FHIT, TP53, P27kip1, and BCL2). Methods: We studied eleven patients who underwent radical nephrectomy for primary CDC. All patients had an adequate clinical follow-up and none of them received any systemic therapy before surgery. The expression of the five markers for tumor initiation and/or progression were assessed by immunohistochemistry and correlated to the clinicopathological parameters, and survival by univariate analysis. Results: Results showed that Fez1 protein expression was undetectable or substantially reduced in 7 of the 11 (64%) cases. Fhit protein was absent in three cases (27%). The overexpression of p53 protein was predominantly nuclear and detected in 4 of 11 cases (36%). Immunostaining for p27 was absent in 5 of 11 cases (45.5%). Five of the six remaining cases (90%) showed exclusively cytoplasmic protein expression, where, in the last case, p27 protein was detected in both nucleus and cytoplasm. Bcl2 expression with 100% of the tumor cells positive was observed in 4 of 11 (36%) cases. Statistical analysis showed a statistical trend (P = 0.06) between loss and reduction of Fez1 and presence of lymph node metastases. Conclusions: These findings suggest that Fez1 may represent not only a molecular diagnostic marker but also a prognostic marker in CDC. Page 1 of 8 (page number not for citation purposes) BMC Urology 2004, 4:11 http://www.biomedcentral.com/1471-2490/4/11 Background To improve our understanding of the biology of CDC and Renal cancer accounts for 3% of adult malignancies. An to explore the possibility that different genes may be estimated 35,710 new cases are expected to occur in the involved in the etiology and prognosis of this neoplasm, U.S. in the current year and 12,480 patients will die of this we analyzed by immunohistochemistry eleven cases of disease [1]. The majority of renal cancers arises from the CDC for the expression of five genes (Fez1, Fhit, p53, p27, proximal tubular epithelium, with a characteristic clear or and bcl2) often involved in the development of many granular cell appearance by light microscopy, and is common cancers. These findings were correlated with referred to as renal cell carcinoma (RCC). conventional clinical-pathological features including clin- ical outcome. Recent evidence suggests that solid renal parenchymal tumors arising in the distal portion of the nephron, such Methods as oncocytomas, chromophobe renal cell carcinomas and Patients collecting duct carcinomas represent an heterogeneous Eleven patients with primary CDC (two women and nine group of neoplasm from both clinical and biological per- men; age range 40 to 84 years, mean 62) underwent radi- spectives [2]. Collecting duct carcinoma (CDC), also cal nephrectomy between 1983 and 2000 in the Depart- known as Bellini duct carcinoma, is a rare but highly ment of Urology, University of Padua, Italy. Tissue aggressive renal neoplasm arising from the distal portion specimens from these tumors were registered in the of the nephron, and represents approximately 2% of all Department of Pathology at the same institution. All the RCCs [3,4]. Clinically, CDC appears as a renal mass eleven patients had an adequate clinical follow up and often accompanied by flank pain and hematuria and is were included in our study. Eight of the 11 patients had frequently mistaken for RCC or transitional cell carci- metastatic disease, five with lymph node metastasis and noma of the renal pelvis [3,5,6]. CDC, however, can be five with distant metastases at the time of surgery. None of identified based on gross, microscopic, histochemical, these eleven patients received any systemic therapy before and immunohistochemical features. Macroscopically, surgery. Samples were fixed in 10% buffered formalin for CDCs are often located at the confluence of the medulla routine histological processing and were stained with and renal pelvis, and show a characteristic gray-white-tan hematoxylin and eosin. color, with absence of foci of necrosis and hemorrhage [7]. Histologically, CDC presents a tubulo-papillary mor- Pathological study phology, often accompanied by desmoplasia, atypia in Immunohistochemical reactions using anticytokeratin collecting ducts, and intratubular spread [7], features (Keratins 5, 8, 10, an 18) monoclonal antibodies, and rarely seen in RCC. Ulex Europaeus Lectin, polyclonal antibody were per- formed as previously described [15]. The tumors were Histochemically, CDC cells contain intracytoplasmic classified histologically according to standardized criteria mucicarminophilic material, where RCCs do not [7]. [3,5-7] and staged according to the guidelines of the CDCs are also positive by immunohistochemical staining tumor-node-metastasis (TNM) classification of malignant with high-molecular-weight keratin and lectin, proteins tumor [16]. typically expressed in the epithelium of the distal tubules [8,9]. Conversely, almost all other renal carcinomas Immunohistochemistry express antigens widely expressed in the cells of the prox- Paraffin sections containing non-neoplastic kidney as well imal tubules, such as low molecular weight cytokeratins as neoplastic areas were deparaffinized according to and vimentin [9]. Although little is known about the standard procedures followed by rehydration through genetic profile of CDCs, a DNA flow cytometry study has graded ethanol series, and mounted on positively charged demonstrated aneuploidy in 90% of these tumors [5], and slides. Immunostaining was performed as previously cytogenetics has shown frequent monosomy of chromo- described [17]. Briefly for Fez1, Fhit, p53, and p27 immu- somes 1, 6, 8, 14, 15, and 22 [10,11]. nostaining, slides were immersed in citrate buffer [0.01 M sodium citrate (pH6.0)] and heated in a microwave oven Loss of heterozygosity (LOH) analysis in six CDCs at 600 W (three times for 5 min each) to enhance antigen revealed allelic loss at chromosomes 8p and 13q in 50% retrieval. For retrieval of Bcl2 oncoprotein, we used the of the tumors, and rarely at the short arm of chromosome target retrieval solution, high pH from DAKO (Carpinte- 3 [12,13]. This data suggests that distinct genetic altera- ria, CA, USA) per manufacturers instructions. The primary tions from those observed in RCC, in which 3p LOH is antibodies used in this study were: anti-Fez1 rabbit poly- common [14], occur in the development of this rare renal clonal antibody [17], anti-Fhit rabbit polyclonal antibody tumor. (Zymed Laboratories, San Francisco, CA) at 1:1,000 dilu- tion, anti-p53, anti-p27, anti-Bcl2 (DAKO, Carpinteria, CA, USA) at dilution of 1:25, 1:50, and 1:40 respectively, Page 2 of 8 (page number not for citation purposes) BMC Urology 2004, 4:11 http://www.biomedcentral.com/1471-2490/4/11 as specified by the manufacturers. The primary antibodies thelium of the collecting ducts in the adjacent renal were omitted and replaced with pre-immune serum in the medulla, which was the most convincing feature support- negative controls. Sections were reacted with biotinylated ing a collecting duct origin of these tumors. Metastases, anti-rabbit or anti mouse antibodies and streptavidin- when available for examination, were histologically simi- biotin-peroxidase (Histostain-SP
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