Fifteen years since the first recognition of clear cell papillary renal cell carcinoma, this distinct renal tumour type is now well accepted as a distinct entity in major classification schemes. It occurs both with and without end-stage renal disease and may be multifocal or bilateral in both scenarios. Recognisable morphological features include clear cells lining branching glands and variable papillary formations with nuclear alignment. Most tumours are small (pT1a) and nucleolar grade 1-2. Immunohistochemistry consistently shows positivity for carbonic anhydrase IX and cytokeratin 7, and often high molecular weight cytokeratin or GATA3, the latter suggesting distal nephron phenotype. Labeling for AMACR and CD10 is consistently negative or minimal. Despite a resemblance to clear cell renal cell carcinoma, molecular alterations of VHL and chromosome 3p are typically lacking, with debatable rare exceptions. Potential mimics include clear cell renal cell carcinoma (with branching architecture or nuclear alignment), papillary renal cell carcinoma with clear cytoplasm, or rarely MITF family translocation renal cell carcinoma. Clinical behaviour is highly favourable with rare, debatable reports of aggressive behaviour. Combined with striking similarity to several extrarenal benign neoplasms, it would be reasonable to reclassify this entity as a benign or low malignant potential neoplasm. Using the nomenclature of the extrarenal counterparts, clear cell papillary (cyst)adenoma is proposed.

Clear cell-papillary renal cell carcinoma (CC-Pap RCC) is a recently described renal tumor initially reported in the setting of end-stage renal disease (ESRD). It has unique morphologic and immunohistochemical features that differentiate it from the more common clear cell RCC and papillary RCC. Recently, these tumors have also been described in a sporadic setting. We studied 64 cases of CC-Pap RCC not associated with ESRD (57 CC-Pap RCCs and 7 cases with features of renal angiomyoadenomatous tumors [RAT] including 5 initially diagnosed as such). The morphologic features of all cases and the immunohistochemical profile of 59 cases were studied along with the clinical and molecular features of 30 and 12 cases, respectively. All the tumors were well circumscribed with a mean tumor size of 2.6 cm and showed a wide array of architectural patterns, usually mixed, including tubular (77%), papillary (62%), tubulocystic (52%), and compact nested (21%). Seventy-three percent of the cases showed areas in which the tumor nuclei had a distinct orientation away from the basement membrane. Ninety-two percent of the cases had a low Fuhrman nuclear grade (nuclear grade 2%-86%, and nuclear grade 1%-6%); however, 8% cases showed foci of Fuhrman nuclear grade 3. In 4 cases, epithelial tumor comprised <5% of the tumor; >95% of the tumor was cystic or hyalinized. The stroma varied from being minimal to occasionally prominent myxoid to hyalinized and rarely with organized amianthoid fibers or well-defined smooth muscle bundles. Pathologic stage was reliably assigned in 60 cases, of which 93.3% (56 cases) were pT1, 3.3% (2 cases) were pT2, and 3.3% (2 cases) were pT3a with extension into the perinephric fat. One case had coagulative necrosis; sarcomatoid change and vascular invasion was not identified. The tumors showed a fairly typical immunoprofile characterized by positivity for CK7 (100%), HMCK (96%), CAIX (94%), and vimentin (100%) with negativity for AMACR, RCC, and TFE3; CD10 was positive in 24%. None of the cases tested showed recurrent chromosomal imbalances by virtual karyotyping, fluorescence in situ hybridization, or 3p loss of heterozygosity analysis. VHL gene mutations were, however, noted in 3 cases (2 in exon 1 and 1 in exon 3). Clinical follow-up information was available in 47% of the patients, with a mean and median follow-up of 47 and 37 months, respectively (range, 18 to 108 mo). One case occurred in the setting of VHL syndrome and multiple benign cysts. None of the cases showed local recurrence, metastasis, or death due to disease. Morphology, immunophenotype, and molecular studies did not vary between typical cases, those with prominent smooth muscle (so-called RAT), and historically published data on cases occurring in ESRD. Our analysis confirms that CC-Pap RCC is a unique subtype of adult renal epithelial neoplasia in which tumors are frequently small, are of low nuclear grade and pathologic stage, and have extremely favorable short to intermediate range prognosis. Tumors occurring sporadically, with prominent smooth muscle stroma (so-called RAT), and occurring in ESRD are in the spectrum of the same category of tumors.

Rare renal epithelial neoplasms have been recognized to have an angioleiomyoma or leiomyoma-like proliferation of stromal smooth muscle; however, the nature of these tumors and their relationships to other renal cell carcinomas are poorly understood. We analyzed 23 such tumors for their clinicopathological, immunohistochemical, and cytogenetic features using fluorescence in situ hybridization. Twelve showed a homogeneous combination of features and were reclassified as renal cell carcinoma with angioleiomyoma-like stroma. These were composed of neoplastic glandular structures lined by cells with mixed clear, pale, and eosinophilic cytoplasm forming occasional papillary tufts. The stroma resembled smooth muscle and often extended away from the epithelial component, entrapping perinephric fat or non-neoplastic renal elements. Immunohistochemistry showed the epithelium to have reactivity for: carbonic anhydrase IX, CD10, vimentin, cytokeratin 7, cytokeratin 34βE12, and PAX8 but not α-methylacyl-coA-racemase. The stroma labeled for smooth muscle (smooth muscle actin 3+, desmin 1+, caldesmon 3+) but not epithelial antigens. Neither component showed substantial reactivity for HMB45, melan-A, cathepsin K, or TFE3 protein. An interrupted, conspicuous layer of CD34-positive endothelial cells rimmed the epithelium, imparting a two-cell layer pattern resembling myoepithelial or basal cells. Chromosome 3p deletion and trisomy 7 and 17 were uniformly absent. Follow-up was available for three patients, none of whom experienced malignant behavior. Eleven tumors were excluded from this category and considered to be clear cell renal cell carcinoma with a reactive proliferation of smooth muscle (n=4) or tangential sectioning of the pseudocapsule (n=2), renal cell carcinoma unclassified (n=4), or clear cell papillary renal cell carcinoma (n=1). In summary, renal cell carcinoma with angioleiomyoma-like stroma is a distinct neoplasm with characteristic morphological, immunohistochemical, and molecular features, unrelated to clear cell renal cell carcinoma. The immunoprofile overlaps partly with that of clear cell papillary renal cell carcinoma, though morphology and reactivity for CD10 are points of contrast.

This study was undertaken to determine the incidence and the clinicopathologic characteristics of those tumors that qualify as clear cell papillary renal cell carcinoma (CCPRCC) by the current definitions. From January 1, 2003 to April 30, 2013, a total of twenty-eight CCPRCC were identified (28/648, 4.3%). CCPRCC showed variable architectural patterns including cystic, papillary, tubular, and acinar. Irrespective of the architecture, the tumors were composed of cuboidal or columnar cells with clear cytoplasm, small vesicular, round or oval nuclei, and inconspicuous nucleoli. Variably thick bundles of smooth muscle actin-positive soft tissue encircled the whole tumors, forming a continuous pseudocapsule. CCPRCC strongly expressed PAX8, CA-IX, CK7, cytokeratin 34betaE12, and vimentin, and were negative for RCC, P504s/AMACR, and TFE3. On ultrastructural examination, CCPRCC showed short microvilli, cytoplasmic interdigitations, nuclear pseudoinclusions, and stromal myofibroblasts. To the best of our knowledge, this is first comprehensive ultrastructural study of CCPRCC in the literature. The major differential diagnostic considerations are clear cell renal cell carcinoma, multilocular cystic renal cell carcinoma, papillary renal cell carcinoma with clear cell changes, and Xp11.2 translocation renal cell carcinoma. CCPRCC seems to have a favorable prognosis. In the current series, none of the patients had local recurrence or metastatic disease.

Clear cell papillary renal cell carcinoma is a recently recognized renal neoplasm, composed of cells with clear cytoplasm lining cystic, tubular, and papillary structures. These tumors have immunohistochemical and genetic profiles distinct from clear cell renal cell carcinoma and papillary renal cell carcinoma. We studied morphologic and immunohistochemical features (cytokeratin 7 (CK7), carbonic anhydrase IX (CAIX), CD10, alpha-methylacyl-CoA racemase, smooth muscle actin, desmin, estrogen and progesterone receptors) in 55 tumors from 34 patients, 8 of whom had end-stage renal disease. These tumors comprised 3% of all adult renal cell carcinoma resections over a period of 3 years. The patients' ages ranged from 33 to 87 years (mean 61). Multiple tumors (2-8) were present in 9 patients. Other renal tumors were present concurrently in four patients and subsequently in two patients, including: oncocytoma, clear cell renal cell carcinoma, and multilocular cystic renal cell carcinoma. Sizes ranged from 0.2 to 7.5 (mean 2.0) cm; 87% were Fuhrman grade 2, and 96% were stage pT1a. Papillary architecture was usually limited to focal branching papillae (51% of 55 tumors) or small, blunt papillae (35%). Large areas of extensively branched papillae were present in only 14% of tumors. Almost all tumors (98%) included cysts, and 18 tumors were extensively (≥90%) cystic. Immunoprofile showed CK7+, AMACR-, CD10-, CAIX+ in the tubular and papillary components of all tumors; however, CD10 labeled the apical cell membrane of cyst epithelium in 59%. The stroma was focally actin positive (94%), with infrequent desmin expression (13%). Estrogen receptor and progesterone receptor were negative. During a median follow-up period of 56 months, no patient developed local recurrence, distant or lymph-node metastasis, or cancer death. Branched tubules, small papillae, and the immunohistochemical and molecular profiles aid in distinguishing these tumors from clear cell renal cell carcinoma and multilocular cystic renal cell carcinoma.