A Collision Tumor of Papillary Renal Cell Carcinoma and Oncocytoma. Case Report and Literature Review

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1 AJCP / Case Report A Collision Tumor of Papillary Renal Cell Carcinoma and Oncocytoma Case Report and Literature Review Rajen Goyal, MD, 1 Anil V. Parwani, MD, PhD, 2 Lan Gellert, MD, PhD, 1 Omar Hameed, MD, 1 and Giovanna A. Giannico, MD 1 From the 1 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, and 2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Key Words: Collision tumor; Oncocytoma; Papillary renal cell carcinoma Am J Clin Pathol November 2015;144: ABSTRACT Objectives: The most common renal neoplasms include clear cell, chromophobe, and papillary renal cell carcinomas (PRCCs) and oncocytomas. While lesions containing hybrid features of different tumor types, such as hybrid oncocytic tumors, have been well documented in the literature, the finding of a collision tumor of two distinct tumor types PRCC and oncocytoma is extremely rare. Methods: We present a case of PRCC associated with an oncocytoma. Our discussion includes a review of the available literature on this rare type of collision tumor. Results: Prosection of a partial nephrectomy performed in a 78-year-old man for painless gross hematuria and nocturia revealed a cm well-delineated orange to yellow-tan mass harboring a white-tan cm mass. Histologic diagnosis of PRCC associated with an oncocytoma was rendered. By immunohistochemistry, focal CK7 expression was present in the oncocytoma, while strong diffuse positive CK7 expression was present in the PRCC component. Fluorescence in situ hybridization (FISH) revealed trisomy 17 in 39.3% of PRCC tumor nuclei but no significant chromosomal aberration in oncocytoma. Conclusions: In view of this and previously reported cases, thorough sectioning and examination, especially in large oncocytomas, is recommended to exclude the presence of an associated malignancy. To our knowledge, trisomy 17 by FISH has not been previously reported in these extremely rare tumors. Despite the emergence of several recently recognized entities within the World Health Organization classification of renal tumors, papillary renal cell carcinoma (PRCC) and oncocytoma are among the most well-understood and common renal tumors. 1 PRCC is the second most common subtype of renal cell carcinoma (RCC), comprising 11% to 18.5% of all RCCs. It occurs across a broad age range, from 30 to 80 years, and is more commonly associated with multifocality compared with other malignant renal tumor subtypes PRCC is subdivided into types 1 and 2, with type 1 having a better overall survival. 11 PRCC commonly shows trisomy or gains of chromosomes 7 and 17 and loss of chromosome Y However, anomalies in chromosomes 1, 5, 6, 8, 11, 15, 18, and 22 are more frequently associated with type 2 PRCC Immunohistochemical studies helpful in the diagnosis of this tumor include cytokeratin 7 (CK7; diffusely positive in the majority of type 1 PRCCs) and alphamethylacyl-coa racemase (AMACR) (diffuse granular cytoplasmic positivity) PRCC, similar to clear cell RCC, is thought to arise from proximal renal tubular epithelial cells, 7 with PRCC having better prognosis, clinical outcome, and survival Oncocytomas became a recognized entity through the work of Klein and Valensi 22 and comprise 3% to 7% of renal tumors. 2,23 Most occur across a broad age range and present asymptomatically. 5,24 The disease-specific survival is nearly 100%. 25 These tumors appear to originate from collecting duct intercalated cells. 23 Cytogenetic abnormalities include loss of chromosomes 1 and Y, 23,26 and more recent data show these tumors may also harbor translocations between chromosomes 6 and Am J Clin Pathol 2015;144:

2 Goyal et al / Renal Collision Tumor The presence of concurrent RCC within the same kidney as an oncocytoma has been described and most commonly involves clear cell RCC and chromophobe RCC. 28,29 However, the occurrence of PRCC and oncocytoma within the same tumor mass is extremely rare and poorly understood In this report, we present a unique case of PRCC associated with an oncocytoma with trisomy 17 identified by fluorescence in situ hybridization (FISH) in the PRCC component, as well as review the limited literature available on this rare type of collision tumor. Case Report A 78-year-old man with multiple medical conditions, including diabetes, chronic renal insufficiency, and atrial fibrillation, sought treatment in November 2011 for a several-day history of painless gross hematuria and nocturia. Renal ultrasound performed at an outside hospital identified bilateral lower pole renal masses. He was subsequently referred to our institution for further care. Computed tomography (CT) of the abdomen revealed a cm lobulated solid complex mass with some calcification within the inferior pole of the right kidney and a cm solid mass within the inferior pole of the left kidney. The patient subsequently underwent a right hand assisted laparoscopic partial nephrectomy, which was well tolerated at the time. However, his postoperative course over several months was complicated by persistent right-sided urine leak and ureteral stricture, requiring routine chronic right ureteral stent exchanges. His contralateral renal mass is under active surveillance. There was no evidence of tumor recurrence or metastasis and no growth in the size of his contralateral renal mass at the 28-month follow-up. Materials and Methods The fresh tissue was formalin fixed, paraffin embedded, sectioned, and stained with H&E. Immunohistochemistry for CK7 (Clone RN7, Leica Biosystems, Buffalo Grove, IL) was performed on a Leica-Bond immunostainer (Leica Biosystems, Nussloch, Germany). FISH was performed to assess for abnormalities in chromosomes 1 (probe CEP1), 2 (probe CEP2), 7 (probe CEP7), and 17 (probe CEP17). Briefly, formalin-fixed, paraffin-embedded tissue blocks were serially sectioned at 5-μm intervals. H&E sections were used to determine the area of the tissue to be targeted for analysis. FISH slides were deparaffinized in xylene twice for 10 minutes, dehydrated twice with 100% ethanol, and then pretreated using the Vysis Paraffin Pretreatment Kit (Abbott Molecular, Des Plaines, IL). Slides were digested for 36 minutes in protease solution (0.5 mg/ml) at 37 C. FISH was performed using CEP1 (1p11.1-q11.1), CEP2 (2p11.1-q11.1), CEP7 (7p11.1-q11.1), and CEP17 (17p11.1-q11.1) centromere probes labeled using Spectrum Green (Abbott Molecular) and Spectrum Orange (Abbott Molecular). The slides were hybridized using dual-color probes for CEP1 with CEP7 and CEP2 with CEP17. The target slide was denatured in 70% formamide at 75 C for 5 minutes and dehydrated in 70%, 85%, and 100% ethanol. Slides were incubated with probe overnight at 42 C in a humidified chamber. Posthybridization washes were performed using 0.4 saline sodium citrate/0.3% Igepal (Sigma, St Louis, MO) at 72 C for 2 minutes, followed by a room temperature 2 saline sodium citrate/0.1% Igepal wash for 30 seconds. Slides were air-dried in the dark and counterstained with 4,6-diamidino-2-phenylindole (DAPI)/antifade (Abbott Molecular). Analysis was performed using a Leica DM5500 B fluorescence microscope (Leica Microsystems) and CytoVision Workstation (Applied Imaging, Santa Clara, CA) equipped with a Chroma Technology filter set with single- and dual-band excitors for Spectrum Orange, Spectrum Green, and DAPI (UV 360 nm) (Abbott Molecular). Only individual and well-delineated cells were scored. Overlapping cells were excluded from the analysis. Approximately 60 tumor cells were analyzed in the targeted region. Using established criteria, chromosomal gains were considered significant if present in greater than 20% of cells. Gains were considered artifactual if seen in less than 20% of cells. Chromosomal losses were considered significant if present in greater than 30% of cells. The loss was considered indeterminate if present in 20% to 30% of cases. The loss was considered artifactual if seen in less than 20% of cases. 34 Normal kidney was used to determine the cutoffs. None of the control kidneys in our study demonstrated trisomic cells. Results The resection specimen consisted of a cm well-delineated orange to yellow-tan mass with focal areas of cystic change and calcifications. Within this mass was another well-delineated white-tan area measuring cm. H&E-stained sections showed a tumor predominantly consisting of diagnostic histologic features of oncocytoma circumscribed nested aggregates of round to polygonal cells with abundant granular eosinophilic cytoplasm and round nuclei with no mitoses. Foci of the tumor also showed nests of oncocytic tumor cells embedded within loose edematous stroma. The smaller 1-cm white-tan area consisted of variably sized papillae and tubules lined by cuboidal tumor cells with relatively scant cytoplasm and 812 Am J Clin Pathol 2015;144:

3 AJCP / Case Report A B C variably conspicuous nucleoli meeting sufficient diagnostic criteria for PRCC, Fuhrman grade 2. The rendered final diagnosis was PRCC associated with an oncocytoma. A fibrous band coursed and mostly separated the two tumor components at their respective interface Image 1. There was no tumor necrosis or mitoses on submitted sections. By immunohistochemistry, focal CK7 expression was present in the oncocytoma, while strong diffuse positive CK7 expression was present in the PRCC component. FISH analysis demonstrated trisomy 17 in 39.3% of PRCC tumor nuclei but no significant chromosomal aberration in oncocytoma Image 2. Also, there were monosomies of chromosomes 1 and 2. There was no difference between the tumor types on analysis of copies of chromosomes 1, 2, and 7 (13.3% of PRCC nuclei and 12% of oncocytoma nuclei showed three copies of chromosome 7). As expected, the oncocytoma-specific regions also demonstrated monosomies in chromosomes 1, 2, and These FISH data support the morphologic findings and immunohistochemical results that these two separate tumor components coexisted within the same lesion and likely represent a collision tumor. Discussion We describe the clinical, histologic, and molecular features of a rare collision tumor comprising two common and distinct tumor types. The majority of this tumor consisted of an oncocytoma with an unequivocal PRCC, as confirmed by A B Image 2 Fluorescence in situ hybridization using CEP17 (chromosome 17) probe highlights increased signals per tumor nucleus in the papillary renal cell carcinoma component (A) compared with oncocytoma tumor nuclei (B). immunohistochemical and molecular analyses, demonstrating focal CK7 expression in the oncocytoma, strong diffuse CK7 expression in the PRCC component, and trisomy 17 by FISH in the PRCC component. The rendered diagnosis was that of a PRCC associated with an oncocytoma with features of a collision tumor. The term collision tumor refers to coexistent but independent tumors that are histologically distinct.35 Collision tumors are believed to result from two Am J Clin Pathol 2015;144: Image 1 A, Oncocytoma component with typical nests and tubules of oncocytic cells with abundant granular eosinophilic cytoplasm (H&E, 200). B, Interface between oncocytoma and papillary renal cell carcinoma (PRCC). A papillary focus containing cells with granular eosinophilic cytoplasm was present within the PRCC component at the tumor-tumor interface (H&E, 40). C, PRCC component with classic histology papillae lined by cuboidal tumor cells with scant cytoplasm (H&E, 100).

4 Goyal et al / Renal Collision Tumor Table 1 Summary of Clinicopathologic Findings in Reported Cases of PRCC-Oncocytoma Composite Tumors Study Age, y/ Sex Presentation Roswell et al 30 75/M Normocytic anemia, bilateral renal masses Floyd et al 31 73/F Lethargy, hypercalcemia, renal mass Sejben et al 32 68/M Abdominal pain, renal mass Location of Resected Collision Tumor Left kidney lower pole Left kidney lower pole Right kidney upper pole separate but adjacent neoplasms (biclonal malignant transformation) and are different from composite tumors, which are thought to arise through a multidirectional differentiation of a single neoplasm 36,37 and involve coexistence of two discrete and histogenetically distinct cell types arising from a common source. 35 Collision tumors have been reported in numerous sites, such as lungs, gastrointestinal tract, genitourinary tract, meninges, lymph nodes, and adrenal glands. 38,39 In the kidney, collision tumors have previously been described However, only rare cases of collision tumor, including PRCC and oncocytoma, have been reported. Review of the literature reveals only four such cases Table Including the current case, all patients were at least 68 years of age and had no common presentation. In these collision tumors, the PRCC represented the smaller component and, if reported, showed a low Fuhrman grade. Interestingly, two patients had bilateral renal masses, one of which was reported to have an oncocytoma contralateral to the collision tumor, while the other (current case) is currently under active surveillance of the contralateral 4.9-cm renal mass. Based on no interval change at 28-month follow-up, this was also clinically felt to represent a benign lesion. Of the four previously reported cases, gains in chromosome 7 were identified in one, chromosomal analysis was not performed in two, and no abnormal copies of chromosome 7 or 17 were identified in another The current case showed PRCC with trisomy 17 by FISH analysis a finding that, to our knowledge, has not been previously reported in these extremely rare tumors. Based on the pathologic descriptions of previously reported cases, our case is similar to others in that the PRCC component within the oncocytoma was well delineated and distinct on both gross and microscopic examination and was exclusively composed of papillary structures The two patients with available Oncocytoma Size, cm PRCC Size, cm Fuhrman Grade FISH Trisomy 7 in PRCC Follow-up/ Outcome follow-up (albeit of short duration) had no evidence of tumor recurrence or metastasis, an outcome consistent with the small size and low grade of their tumors. Our case adds new data and information to the slowly growing list of tumors comprising coexisting PRCC and oncocytoma with regard to morphologic findings and FISH results. Since both PRCC and oncocytoma are thought to have different cellular origins, interesting questions emerge regarding how these coexisting tumors may form within the same mass and how they may be possibly related. Although both tumors present across a broad age range, PRCC and oncocytoma differ on several clinicopathologic parameters, including clinical behavior, prognosis, cell of origin, histologic features, immunophenotype, and molecular characteristics. Features of PRCC include putative origin from proximal renal tubular epithelial cells, architectural features of papillary to tubular structures with variable cytonuclear features (depending on subtype), immunophenotypical expression of CK7 and AMACR, and gains in chromosomes 7 and 17 with loss of Y. 7,12-15,19,20 In contrast, distinguishing features for oncocytoma are its putative origin from collecting duct intercalated cells, architectural features of nests and tubules of round-polygonal cells with abundant granular eosinophilic cytoplasm, immunophenotypical lack or focal expression for CK7, and loss of chromosomes 1 and Y. 5,19,23,25 The stark differences between these two tumor types complicate the difficulty in assessing and understanding how these two could biologically arise in association with each other in the same mass lesion. Several hypotheses have been formulated to explain the histogenesis of collision tumors, including coincidental origin from different cell lines, differentiation of the same stem cell into phenotypically different tumors, induction by a carcinogenic agent acting on different cell lines, and alteration in the microenvironment, such as angiogenesis and inflammation, by the primary tumor that could NA NA NA NA Negative for trisomies 7 and 17 in PRCC NED at 8 months Vasuri and Fellegara 33 69/M NA NA 3.5 NA NA NA NA Current case 78/M Painless gross hematuria, bilateral renal masses Right kidney inferior pole Trisomy 17 in PRCC NED at 28 months FISH, fluorescence in situ hybridization; NA, not available; NED, no evidence of disease; PRCC, papillary renal cell carcinoma. 814 Am J Clin Pathol 2015;144:

5 AJCP / Case Report possibly induce growth of a second primary tumor. In our case, the cancer stem cell hypothesis, 35,44,45 based on the observation that tumors, similar to adult tissues, arise from cells that exhibit the ability to self-renew and give rise to differentiated tissue cells, capable of initiating a heterogeneous tumor, could be applicable to explain the origin of two tumors with a different histogenesis. In summary, we describe an unusual case of a collision tumor composed of an oncocytoma and a PRCC arising in the setting of bilateral renal masses and demonstrating trisomy 17 by FISH in the PRCC component, supporting the collision tumor histogenesis. Given the propensity of oncocytomas to harbor other malignant neoplasms (collision or otherwise), we agree with prior recommendations 32 suggesting, particularly in large oncocytomas, careful sectioning and examination of such tumors to exclude the presence of an associated malignancy. Corresponding author: Giovanna A. 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