Clear Cell Papillary Renal Cell Carcinoma

Clear cell papillary renal cell carcinoma (ccpRCC) is a recently recognized entity and represents the fourth most common variant of renal cell carcinoma (RCC). It has unique morphologic and immunohistochemical features and demonstrates an indolent clinical behavior. Microscopically, it may mimic other RCCs with clear cell features, such as clear cell RCC, translocation RCC, and papillary RCC with clear cell changes. A high index of suspicion is required to keep ccpRCC in the differential diagnosis of RCCs with features of clear cell and/or papillary architecture. In equivocal cases, immunohistochemistry is generally sufficient to substantiate the diagnosis of ccpRCC. In this review, we discuss the clinical, gross, and histopathologic features, immunohistochemical and genetic profiling, and prognosis of ccpRCC. (Arch Pathol Lab Med. 2019;143:1154–1158; doi: 10.5858/arpa.2018-0121-RS)

C lear cell papillary renal cell carcinoma (ccpRCC) was introduced as a new tumor entity by the 2016 World Health Organization (WHO) classification of renal neoplasia because of its unique morphologic, immunohistochemical, and genetic features, and its indolent clinical behavior. [1][2][3][4] It was initially described in 2006 in conjunction with end-stage renal disease. 5 However, sporadic cases of ccpRCC have been described in patients without kidney disease. 6 This tumor comprises 1% to 4% of all resected renal tumors, and it represents the fourth most common variant of renal cell carcinoma (RCC). 7 Microscopically, this tumor has both clear cell and papillary features, and the nuclei are often low grade, with characteristic linear arrangement away from the basal aspect of cells. 2 Because of its overlapping morphology, ccpRCC can be easily misdiagnosed with other subtypes of RCC, such as low-grade clear cell RCC (ccRCC), papillary RCC (PRCC) with clear cell changes, and translocation RCC. 8 It is important to note that this is an indolent tumor with good clinical outcomes that has not shown any recurrences, metastases, or lymph node involvement. 9 Therefore, it is crucial to correctly differentiate ccpRCC from other subtypes of RCC that have a much worse prognosis. In equivocal cases, a number of immunohistochemical stains will aid in arriving at the correct diagnosis, including cytokeratin 7 (CK7), a-methylacyl-CoA racemase (AMACR), carbonic anhydrase IX (CA IX), CD10, and transcription factor E3 (TFE3). 10

CLINICAL FEATURES
Clinically, patients with ccpRCC are asymptomatic, and the tumor is typically detected as an incidental finding in normally functioning kidneys or during the follow-up of patients with end-stage renal disease. The age at presentation varies from 18 to 88 years, with no sex predilection. 1 Radiology imaging will show tumors as solid or cystic heterogeneous lesions with smooth margins, growing within or beyond the renal cortex ( Figure 1). 11 Notably, ccpRCC has an indolent clinical behavior, and no recurrences or metastases have been reported to date.

GROSS PATHOLOGY
Grossly, these tumors are small, with an average size of 2.6 cm. They are usually encapsulated, with a well-defined, thin, fibrous capsule ( Figure 2). The cut surface is variable, frequently pink-tan with cystic change without areas of necrosis. Clear cell papillary RCC commonly presents as a small, solitary tumor, but patients can infrequently have multifocal and/or bilateral tumors, or it can coexist with other renal tumors. 12,13 The great majority of tumors are stage I at presentation.

HISTOPATHOLOGY
Microscopically, ccpRCC is usually well-circumscribed with a fibrous capsule. The overall architecture pattern can be tubular, papillary, solid, cystic, acinar, or a combination of these, but the most frequent architecture is the tubularpapillary pattern with characteristic branching tubules ( Figure 3). In some tumors, small acini or closely packed cells with scant cytoplasm give the impression of a solid tumor. The neoplastic cells have a cuboidal to columnar shape with clear cytoplasm. The nuclei are often small, round to oval in shape, with regular nuclear membranes and inconspicuous to small nucleoli, consistent with WHO/ International Society of Urological Pathology (ISUP) grade 1 or 2. Characteristically, the nuclei are typically localized in a linear fashion toward the luminal surface and away from the basement membrane, namely reverse polarity ( Figure 4). The tumor has variable amounts of fibrotic, collagenous, or smooth muscle stroma and scattered small blood vessels. Calcifications, hemosiderin deposition, and lymphoplasmacytic inflammatory infiltrate or nonnecrotizing granulomas have also been described in the stroma of ccpRCC. Some tumors may have a predominant smooth muscle component and were previously named as renal angiomyoadenomatous tumors (RATs). 14,15 Clear cell papillary RCC and RAT have been classified recently into the same spectrum of ccpRCC by the 2016 WHO guideline. 1 To date, no aggressive behavior, such as extrarenal invasion, lymphovascular invasion, high WHO/ISUP grade, necrosis, or sarcomatoid/rhabdoid changes, has been documented.
Genetically, ccpRCC has a molecular profile different from those of ccRCC and PRCC. ccpRCC usually lacks chromosome 3p deletion and VHL gene mutation, which are typical findings of ccRCC. 17,18 In contrast to PRCC, ccpRCC has no copy number abnormality of chromosomes 7, 17, and Y. 17,18 Some somatic mutations, such as MET, PTEN, ERBB4, and STK11, have been identified in ccpRCC by using nextgeneration sequencing. 19,20 Noncoding RNA profiling revealed overexpression of miR-200 family in ccpRCC. 20,21 A recent study showed that ccpRCC has a microRNA expression profile distinct from those of ccRCC or PRCC, supporting that ccpRCC is a unique entity distinct from ccRCC or PRCC. 21 The clinical significance of these findings is unclear, and further studies are needed to help in understanding the role of these changes in the pathogenesis and clinical behavior of ccpRCC.

DIFFERENTIAL DIAGNOSIS
Because ccpRCC is a clinically indolent tumor, a correct diagnosis will be crucially important for a patient's treatment plan and the impact on a patient's life. Three major relevant RCCs should be considered in the differential diagnosis, including ccRCC, PRCC, and Xp11 translocation RCC. All of them can have overlapping morphologic features with ccpRCC, such as prominent clear cell cytoplasm, and acinar, solid, papillary architecture ( Figure  7).
Clear cell RCC is the most common variant of RCC (70%). 1,10 Grossly, the cut surface typically looks yellow, often with cysts, hemorrhage, and necrosis. Tumor cells commonly have clear cytoplasm, and can have cystic, solid areas, like ccpRCC, but papillary areas are uncommon. The tumor usually has abundant small, thin-walled blood vessels. Nuclei commonly show random arrangement and may have high-grade features, such as prominent nucleoli or bizarre nuclei. Immunohistochemical staining of ccRCC usually shows a diffuse expression of CD10, CA IX (boxlike membranous pattern), AE1/AE3, CAM5.2, EMA, PAX8, PAX2, and vimentin, and a lack of CK7, AMACR, and 34bE12 expression. 1 Most ccRCCs have VHL gene mutation or chromosome 3p deletion, and it is the typical manifestation of von Hippel-Lindau (VHL) syndrome. It may also be associated with other familial renal cancer syndromes, such as Cowden syndrome, Birt-Hogg-Dubé syndrome, and tuberous sclerosis complex. 1,22 Uncommonly, ccpRCC can present as multifocal bilateral disease, raising the differential diagnosis of VHL syndrome-associated RCC. In addition, ccpRCC-like tumors have been described in patients with VHL syndrome; however, the characteristic immunophenotype and molecular features of ccRCC are preserved in these tumors, allowing for differentiation from ccpRCC. 4 Papillary RCC is the second most common variant of RCC (18%). 1,10 It often presents as a well-circumscribed tumor with a fibrous pseudocapsule, and a variable cut surface with areas of hemorrhage, necrosis, and cystic degeneration. Most PRCCs have papillary architecture with delicate fibrovascular cores, which often contain foamy macrophages, hemosiderin, and psammoma bodies. Some tumors may have extensive clear cell cytoplasm, raising the differential diagnosis with ccRCC and ccpRCC. Immunohistochemical stains will typically show positivity for CK7, CD10, AE1/ AE3, CAM5.2, EMA, vimentin, RCC antigen, AMACR, and 34bE12, and negativity for CA IX. 1 Genetically, PRCC is typically associated with gain of chromosome 7 or 17 and loss of chromosome Y.
Xp11 translocation RCC is the renal tumor characterized by chromosomal translocations with breakpoints involving the TFE3 gene, which maps to the Xp11.2 locus. This neoplasm is primarily seen in young patients (40% of pediatric RCCs) but may occur as an aggressive tumor in adults (1.6%-4% of adult RCCs). 1,23,24 The most common architectural pattern of this tumor is papillary or nested, with epithelioid clear cells and abundant psammomatous calcifications. The nuclei are usually high grade, and the cytoplasm can be granular or eosinophilic. Stromal hyaline nodules can also be seen. It can also present with unusual morphology mimicking other types of RCCs, including multilocular cystic RCC-like features and tubular growth reminiscent of collecting duct carcinoma. This tumor shows nuclear staining for TFE3, which is highly specific and sensitive. The antibody used is against the C-terminal portion of TFE3 and can detect chimeric (mutant) TFE3 protein. In addition, the tumor usually shows positive staining for cathepsin-K, PAX8, CD10, E-cadherin, AMACR, and RCC antigen, but weak or no expression of AE1/AE3, CAM5.2, CK7, and EMA. 24 Finally, 2 RCC entities have been recently described as showing some overlapping morphologic and immunohistochemical features of ccpRCC, including tuberous sclerosis complex-associated papillary RCC 25 and transcription elongation factor B subunit 1 (TCEB1)-mutated RCC. 26,27 Tuberous sclerosis complex-associated PRCC usually presents as tumor nodules circumscribed by thick, fibrous stroma with prominent large clear cells lining papillary structures, and the nuclei are oriented toward the basement membrane. These tumors are strongly and diffusely positive for CK7, CD10, CA IX (boxlike), AMACR, and vimentin, but negative for SDHB, TFE3, and RCC antigen. 25 Only a few TCEB1-mutated RCC cases have been reported, which show well-circumscribed tumors composed of clear cells with voluminous cytoplasm in variable architectural patterns   (including tubular-papillary), with intervening prominent, thick fibromuscular bands imparting a multinodular architecture to the tumor. These tumors can show focal ccpRCClike nuclear features. TCEB1-mutated RCCs typically express CK7 and CA IX (boxlike), variable CD10 expression, and are negative for 34E1b2. 26,27 PROGNOSIS AND TREATMENT Clear cell papillary RCC is a tumor with indolent clinical behavior and a favorable prognosis. [1][2][3][4]9 At presentation, this tumor is low stage, with a low WHO/ISUP grade. Based on follow-up studies of 362 ccpRCC patients in the literature (with a mean of 38 months), tumor recurrence, metastasis, or disease-related death has not been reported to date. 17 Partial or total nephrectomy is the primary treatment for a solitary ccpRCC. If the diagnosis can be made preoperatively by a core biopsy, a more conservative approach may be used to treat this indolent tumor, including minimal surgical procedures such as ablation, partial nephrectomy, or active surveillance with strict follow-up. 2,17