Original Article
Cytomorphology of Clear Cell Papillary Renal Cell Carcinoma Xiaoqi Lin, MD, PhD
BACKGROUND: Clear cell papillary renal cell carcinoma (CCPRCC) shares some morphologic and immunohistochemical markers with clear cell RCC and papillary RCC. To the author’s knowledge, its cytomorphology on fine-needle aspiration (FNA) or touch preparations (TPs) of core needle biopsy specimens has not been well delineated in the English language literature. METHODS: The FNA/TP cytomorphology of 7 retrieved cases was studied. RESULTS: The tumor cells were arranged in small nests (100%), 3-dimensional clusters (71%), papillary/tubular/acinar arrays (43%), and as single cells (57%). The tumor cells were columnar (100%) and polygonal (57%) in shape, with eccentric, small, round-to-oval nuclei. The nuclei contained evenly distributed, fine granular chromatin and demonstrated a smooth nuclear membrane (100%) (Fuhrman grade 1 to 2). The tumor cells had a moderate amount of delicate or clear cytoplasm containing small vacuoles (100%) and ill-defined cytoplasmic borders (100%). Scattered macrophages (57%) and necrosis (29%) were identified in the background. Vessels were noted within the papillary cores, transversing or surrounding nests of tumors. Immunochemical studies demonstrated expression of cytokeratin 7 (CK7) (100%), carbonic anhydrase IX (CA 9) (100% in a cup-shaped membranous pattern), a-methylacyl-CoA racemase (AMACR) (50%), and CD10 (43%). The tumor cells were negative for CD117. CONCLUSIONS: CCPRCC was found to demonstrate cytologic features that when taken together are helpful in diagnosing CCPRCC on FNA smears and TPs. If core needle biopsy specimens or cell blocks are available, an immunohistochemical panel including CK7, CA IX, CD10, and AMACR may help in excluding congeners. This subtype of RCC requires differentiation from clear cell RCC and papillary RCC due to its low-grade indolent behavior. Cancer Cytopathol C 2016 American Cancer Society. 2017;125:48-54. V
KEY WORDS: clear cell papillary renal cell carcinoma; cytomorphology; fine-needle aspiration; immunohistochemistry; core needle biopsy; touch preparation.
INTRODUCTION Clear cell papillary renal cell carcinoma (CCPRCC) as a distinct subtype of RCC was included in the recent World Health Organization tumor classification and the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.1,2 Histologically, CCPRCC is composed of cuboidal or columnar cells with clear cytoplasm, often arranged in tubular, papillary, tubulocystic, acinar, and compact nested patterns.3,4 However, the most characteristic morphological feature is the positioning of the small round nuclei within the cells away from the basement membrane,3,4 imparting an appearance reminiscent of secretory endometrium or papillary cystadenoma of the epididymis and broad ligament.5 These tumors originally were described within the setting of end-stage renal disease, but are now widely recognized to occur outside of this setting.4,6–10 It is the fourth most common histologic subtype of RCC,8 representing 1.3% to 4.3% of all RCC cases, and comprising 6.3% of pT1a, low-grade RCC.4,6–10 Patient ages range from 33 to 87 years,9 and the disease is distributed equally among both sexes. CCPRCC is morphologically, immunohistochemically, and molecularly distinct from both Corresponding author: Xiaoqi Lin, MD, PhD, Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Galter Pavilion 7-132F, 251 E. Huron St, Chicago, IL 60611; Fax: (312) 926-6037;
[email protected]. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois Received: July 8, 2016; Revised: August 23, 2016; Accepted: August 24, 2016 Published online September 16, 2016 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cncy.21779, wileyonlinelibrary.com
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Cancer Cytopathology
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Cytomorphology of CCPRCC/Lin
clear cell RCC (CCRCC) and papillary RCC (PRCC).3,4 At the molecular level, CCPRCC lacks the gain of chromosome 7 and loss of chromosome Y that are commonly noted in PRCC. CCPRCC also lacks the pathognomonic deletion of 3p observed in CCRCC.10 Rare cases harbor gains of chromosome 17, but to my knowledge the majority of studies to date have demonstrated little or no consistent copy number changes.10–13 CCPRCC is for the most part an indolent tumor, as evidenced by its low Fuhrman nuclear grade (grade 1 to 2); low pathologic T classification (pT1) at the time of presentation; and the presence of only rare documented examples demonstrating high-grade3 features, a high pathologic T classification (pT3), or metastatic spread (pT4).3,14 Fine-needle aspiration (FNA) and core needle biopsy (CNB) are less invasive than open biopsy, and are widely used diagnostic techniques with which to sample mass lesions of the kidney. With the advent of therapies targeting molecular pathways that are altered in specific RCC subtypes, an extra layer of complexity exists in the interpretation of biopsies of renal mass lesions. The onus is now on the pathologist to not only determine malignancy, but also to refine the diagnosis further by providing a specific subtype of renal carcinoma so that the clinician can administer the appropriate targeted therapy. Because to my knowledge the cytomorphology of FNA or touch preparations (TPs) of CNB specimens of CCPRCC has not been well studied and published to date, I examined the efficacy and accuracy of these modalities in providing a definitive diagnosis of CCPRCC.
MATERIALS AND METHODS Cases
The current study was approved by the Institutional Review Board of Northwestern University. Seven cases of CCPRCC with FNA and CNB specimens were retrieved from the database of the department of pathology at Northwestern Memorial Hospital. Patients included 4 men and 3 women ranging in age from 40 to 74 years (mean, 63.1 years; median, 66.0 years). The clinical follow-up interval for the patients ranged from 0.5 to 5 years. FNA and CNB
Percutaneous FNA and CNB biopsies were performed under ultrasound guidance or computed tomography Cancer Cytopathology
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imaging using a 22-gauge needle for FNA or a 20-gauge core biopsy device for CNB. One FNA pass was used for localization on one case, and FNA smears were stained with Diff-Quik and Papanicolaou stains. One to 4 CNB passes with TP (smears) were obtained for all cases. The FNA specimen and TP slides were air-dried and stained with modified Giemsa (Diff-Quik) stain for on-site evaluation for adequacy and immediate interpretation by 5 board-certified cytopathologists.
Cytomorphology of FNA/TP of CNB
The FNA specimens and TP slides were retrieved and retrospectively analyzed for: 1) tumor cellularity; 2) architectural patterns; 3) cell shape and cytoplasmic features; 4) nuclear features; 5) quality of stroma; and 6) background.
Histology and Immunohistochemistry
CNB specimens were fixed in formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H & E) for histomorphologic examination. Immunohistochemical staining on CNB specimens was performed on the sections of paraffin-embedded tissue with appropriate positive and negative controls (ie, positive controls expressed the immunoreagent and negative controls demonstrated no expression). Antibodies directed against cytokeratin 7 (CK7) (M7018; Dako Cytomation, Carpinteria, Calif), carbonic anhydrase IX (CA IX) (SC25599; Santa Cruz Biotechnology, Santa Cruz, Calif), CD10 (NCL-L-CD10-270; Novocastra, Milton Keynes, UK), a-methylacyl-CoA racemase (AMACR) (p504s) (M3616; DakoCytomation), CD117 (A4502; DakoCytomation), and high-molecular weight keratin (HMWCK) 34bE12 (M0630; DakoCytomation) were used. Immunohistochemical staining was graded in a semiquantitative manner and scored as either diffuse (>50% of tumor cells positive), focal (between 10% and 50% of tumor cells positive), or negative (
