Papillary Renal Cell Carcinoma: Evolving Classification by Combined Morphologic and Molecular Means.

Papillary renal cell carcinoma classification has evolved as a result of attentive morphologic observations by pathologists coupled with specific immunohistochemical, molecular, and clinical data. Refinement of this relatively common diagnostic category of renal neoplasia has resulted in the parsing out of specific renal cell carcinoma subtypes that no longer belong in the papillary renal cell carcinoma category and can have distinct familial and prognostic implications (eg, fumarate hydratase (FH)-deficient renal cell carcinomas). In addition, evolving classification has enabled more accurate diagnosis by surgical pathologists (through the description of recognizable morphologic variants). In many cases, molecular findings have aided and confirmed morphologic categorization. The combination of morphologic and molecular findings continues to provide important prognostic information for patients and their clinicians.

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p = 0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Atypical intraductal proliferation detected in prostate needle biopsy is a marker of unsampled intraductal carcinoma and other adverse pathological features: a prospective clinicopathological study of 62 cases with emphasis on pathological outcomes.

AIMS: Intraductal proliferations of the prostate with more complexity and/or cytological atypia than high-grade prostate intra-epithelial neoplasia (HGPIN), but falling short of intraductal carcinoma (IDC-P), are described as 'atypical intraductal proliferation' (AIP). When present in needle biopsy (NBX) without IDC-P, the clinical significance is not known. METHODS AND RESULTS: Sixty-two NBX cases were diagnosed as AIP over 7 years with estimated incidence of 1%. AIP was characterised by loose cribriform architecture (90%) or non-cribriform architecture exhibiting significant nuclear atypia that fell short of IDC-P. Fifty patients had concomitant PCa (20% grade group (GG) 1, 48% GG2, 14% GG3, 8% GG4 and 10% GG 5), and 12 had AIP alone. Of 40 patients who were candidates for no therapy (AIP alone) or active surveillance (AIP with GG1 or GG2 PCa without cribriform pattern 4), 20 had subsequent follow-up pathology [seven NBXs and 13 radical prostatectomy (RP)]. Of the 12 AIP only patients, six had a subsequent biopsy diagnosis of: benign prostate (two), IDC-P with PCa (one) and PCa (three). One or more adverse pathological features at subsequent RP were present in 93% of patients with AIP and GG1 or GG2 PCa, defined as: GG ≥ 3 (15%), IDC-P (77%), cribriform Gleason pattern 4 (69%), pT3a (77%) or pT3b (8%). CONCLUSIONS: AIP in NBX may be a marker of unsampled IDC-P and/or other adverse pathological features in suspected low- to intermediate-risk PCa. AIP should be considered distinct from HGPIN for risk assessment and warrant consideration for further work-up to detect unsampled high-risk PCa.

Application of p16 Immunohistochemistry and RNA In Situ Hybridization in the Classification of Adenoid Basal Tumors of the Cervix.

Our understanding of adenoid basal tumors of the cervix has evolved over time. Most of the proliferations referred to as adenoid basal carcinoma have a clinically benign course--leading some to suggest the term "adenoid basal epithelioma." However, rarely, these may be associated with invasive carcinomas. These tumors have been etiologically linked with high-risk human papillomavirus (HR-HPV) infection. Here, we investigate the use of p16 immunohistochemistry and HR-HPV RNA in situ hybridization (ISH) in the classification of adenoid basal tumors of the cervix. Seventeen cases of adenoid basal tumors of the cervix were included. The patients' age ranged from 19 to 79 yr (average, 59 yr). p16 immunostain was performed on all cases and RNA ISH was performed in 4 cases with available formalin-fixed paraffin-embedded tissue. There were 11 low-grade tumors, 5 frankly invasive carcinomas, and 1 with histologic features that were intermediate between the former 2 categories. p16 immunostain was negative or showed patchy cytoplasmic staining in the low-grade tumors and was strongly and diffusely positive in the invasive carcinomas. HR-HPV RNA ISH was negative in the 3 low-grade tumors and was positive in 1 case of invasive carcinoma including the adenoid basal component. Distinct p16 immunostaining and HR-HPV RNA ISH patterns exist between low-grade adenoid basal tumors and invasive adenoid basal carcinomas. Our study indicates that p16 immunostaining and HR-HPV RNA ISH can be employed as useful ancillary tools in differentiating between noninvasive and invasive adenoid basal tumors along with careful histopathologic evaluation.

A genomic algorithm for the molecular classification of common renal cortical neoplasms: development and validation.

PURPOSE: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms. MATERIALS AND METHODS: Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization. RESULTS: The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved. CONCLUSIONS: In a clinical diagnostic setting the implementation of genome based molecular classification could serve as an ancillary assay to assist in the histological classification of common renal neoplasms.

Yolk sac tumor in postmenopausal patients: pure or associated with adenocarcinoma, a rare phenomenon.

Yolk sac tumors (YSTs) of the ovary usually present in young women and have been rarely reported in postmenopausal patients. Most of the cases in young patients are pure or associated with other germ cell components; however, in older patients there is an unusual association with Müllerian epithelial elements, for the most part malignant. We report two cases, both in older patients. One of the YSTs was associated with high-grade serous and endometrioid carcinoma, while the other case showed pure YST. The YST component showed positivity for SALL4, AFP and Glypican-3 and negative staining for PAX8 supporting a germ cell tumor differentiation; SALL4 and PAX8 markers have not been previously analyzed in this setting. Both tumors recurred within 7 months despite systemic chemotherapy.

Surgical Management and Oncologic Outcomes of Renal Cell Carcinoma and Inferior Vena Caval Thrombi With Aggressive Histologic Variants.

OBJECTIVE: To characterize the surgical management, perioperative, and cancer-specific outcomes, and the influence of aggressive histologic variants (AHV) on operative management among patients with renal cell carcinoma (RCC) and inferior vena cava (IVC) thrombus. RCC with rhabdoid and/or sarcomatoid differentiation, which we defined as AHV, portends a worse prognosis. AHV can be associated with a desmoplastic reaction which may complicate resection. METHODS: We reviewed patients undergoing radical nephrectomy and IVC thrombectomy between 1990 and 2020. Comparative statistics were employed as appropriate. Survival analysis was performed according to the Kaplan-Meier method, and intergroup analysis performed with log-rank statistics. Multivariable cox proportional hazards regression was used to assess the effect of AHV, age, thrombus level, vena cavectomy, metastases, and medical comorbidities on recurrence and overall survival (OS). RESULTS: Ninety-four of 403 (23.3%) patients had AHV, including 43 (46%) rhabdoid, 39 (41%) sarcomatoid, and 12 (13%) with both. AHV were more likely to present with advanced disease; however, increased perioperative complications or decreased OS were not observed. Median (IQR) survival was 16.7 (4.8-47) months without AHV and 12.6 (4-29) months with AHV (P = .157). Sarcomatoid differentiation was independently associated with worse OS (HR = 2.016, CI 1.38-2.95, P <.001), whereas rhabdoid alone or with sarcomatoid demonstrated similar OS (P = 0.063). CONCLUSION: RCC and IVC thrombus with AHV are more likely to present with metastatic disease, and sarcomatoid differentiation is associated with a worse OS. Resection of tumors with and without AHV have similar perioperative complications, suggesting that surgery can be safely accomplished in patients with RCC and IVC thrombus with AHV.

Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens.

Many hereditary tumor syndromes are associated with neoplasms of the kidney. It is becoming increasingly well recognized that a given familial tumor syndrome may be very heterogenous in clinical appearance and that unrecognized patients may present initially for the treatment of a renal mass. It is therefore important for surgical pathologists to be aware of the specific gross and microscopic findings in the kidney that suggest a possible syndromic association. In this review, we detail the histologic features of syndromic-associated renal neoplasms, describe the presence of characteristic changes in the background renal parenchyma, and provide an update on associated extrarenal manifestations for each of the following syndromes: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma (RCC), hereditary leiomyomatosis-RCC, Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, germline succinate dehydrogenase mutation, hereditary nonpolyposis colorectal cancer syndrome, hyperparathyroidism-jaw tumor syndrome, PTEN hamartoma syndrome, constitutional chromosome 3 translocation, and familial nonsyndromic clear cell RCC. We also include a synopsis of renal medullary carcinoma because of its association with hereditary hemoglobinopathies.

Myxoid Pseudotumor Involving the Renal Sinus: Clinicopathologic Study of 33 Cases Supporting a Distinct Benign Non-neoplastic Lesion.

We describe 33 cases of myxoid pseudotumor involving the renal sinus from 31 patients. Patients included 21 men and 10 women, ages 30 to 95 years. Twenty-seven cases (82%) had an associated malignancy, including urothelial carcinoma of the renal pelvis (22 cases), clear cell renal cell carcinoma (3 cases), urothelial carcinoma of the bladder (1 case), and poorly differentiated carcinoma of uncertain lineage (1 case). The remaining 6 (18%) had no associated malignancy and included 3 nephrectomies for ureteral stricture, 2 ureteropelvic junction repairs, and 1 resection of a "periureteral mass" (subsequently shown to be myxoid pseudotumor). Myxoid pseudotumor was identified by preoperative computed tomography imaging in 2 patients (6%) and identified by the gross dissector in 9 cases (27%). The mean size was 14 mm (range: 5 to 38 mm). All cases had an admixture of adipocytes, myxoid stromal matrix, variable collagenization, and a hypocellular population of bland spindled and stellate stromal cells. No multilobated atypical stromal cells were present. Clinical follow-up was available for 28 patients (90%), ranging from 1 to 132 months (mean: 24.6 mo). No patients had adverse events related to the myxoid pseudotumor. Myxoid pseudotumor of the renal sinus is often associated with a variety of adjacent neoplastic and non-neoplastic conditions and may present as a mass lesion detectable by imaging and/or gross inspection. Awareness of this benign process is important to avoid confusion with a neoplasm, especially liposarcoma.

Renal Neoplasia Occurring in Patients With PTEN Hamartoma Tumor Syndrome : Clinicopathologic Study of 12 Renal Cell Carcinomas From 9 Patients and Association With Intrarenal "Lipomas".

The aim of this study was to assess the histopathologic spectrum of renal tumors in patients with PTEN hamartoma tumor syndrome (PHTS), with a specific focus on potential features predictive of the underlying syndrome. A multi-institutional study was conducted to obtain clinical and pathologic data on renal tumors arising in patients with PHTS, either diagnosed by germline mutational analysis or clinical criteria for Cowden syndrome. Histologic sections of the renal tumors were re-reviewed for classification. Twelve renal epithelial tumors from 9 patients were identified (4 males and 5 females, with a mean age of 41.8 y), 7 of whom carried germline PTEN mutations. All 12 renal epithelial tumors were renal cell carcinomas (RCCs): 5 were chromophobe RCCs, 4 papillary RCCs, and 3 RCC not otherwise specified. Pathologic stage distribution was: 7 (59%) pT1a, 2 (17%) pT1b, 1 (8%) pT2a, 1 (8%) pT2b, and 1 (8%) pT3a. World Health Organization/International Society of Urological Pathology (WHO/ISUP) histologic grade was applicable in 7 (54%) nonchromophobe tumors: 4 (57%) G2, 2 (29%) G3, and 1 (14%) G4. An unexpected histologic finding was the presence of 2 patients with incidental microscopic collections of intrarenal adipocytes that had no features of angiomyolipoma (and were negative with 2 sensitive PEComa markers: cathepsin-K and GPNMB); both were classified as lipoma/"lipomatous hamartomas." The average follow-up interval was 67.8 months (13 to 172 mo): 5 patients had no evidence of disease, 2 were lost to follow-up, 1 died of other (non-PHTS) causes (ie, prostate cancer), and 1 was alive with metastatic RCC to the lung (RCC not otherwise specified with rhabdoid differentiation). All tumors showed loss of nuclear PTEN staining by immunohistochemistry. Fumarate hydratase was retained and 2SC was negative in all papillary RCCs. CK7 was moderate-strong/diffuse positive in 4 of 5 chromophobe RCCs and in 3 of 4 papillary RCCs. Renal epithelial tumors associated with PHTS represent a heterogeneous group of RCCs, but classic chromophobe and papillary RCC are most common. The majority have a favorable clinical behavior as would be predicted by subtype. In contrast to other hereditary renal neoplasia syndromes, morphologic features of the RCCs do not allow identification of PHTS-associated neoplasia with any degree of specificity in the absence of clinical setting and/or prior history, but the presence of microscopic "lipomas" within the kidney may provide a clue in rare cases. Therefore, clinical suspicion and genetic counseling with germline testing remain necessary for identifying PHTS-associated RCC.

Chromophobe renal cell carcinoma: Novel molecular insights and clinicopathologic updates.

Chromophobe renal cell carcinoma (ChRCC) is the third most common renal cell carcinoma (RCC) subtype, which predominantly occurs in sporadic setting. ChRCCs are considered to originate from the intercalated cell of distal tubules with two main morphological variants, classic and eosinophilic. Most ChRCCs carry a favorable clinical outcome. Histology alone is limited in predicting the behavior of ChRCCs that do not have overtly aggressive morphologic findings such as necrosis and sarcomatoid features. Along with positive CD117 expression, classic ChRCCs generally express diffuse and uniform CK7, while eosinophilic variant demonstrates more heterogeneous CK7 expression (rare or patchy). Multiple losses of chromosomes 1, 2, 6, 10, 13, 17, and 21 are considered to be the genetic hallmarks of classic and eosinophilic ChRCCs, while chromosomal gains are known to be associated with sarcomatoid ChRCCs. TP53 and PTEN are the two most frequently mutated genes in ChRCCs. The major challenge in the differential diagnosis of ChRCCs includes considerations around the eosinophilic variant (of ChRCCs), where it may share overlapping features with oncocytoma or other recent emergent oncocytic tumors. Most eosinophilic ChRCCs share expression of the recently described biomarkers, LINC01187 and FOXI1, with classic ChRCCs, however, a subset of eosinophilic-like ChRCCs with lower biomarker expression have been demonstrated to harbor MTOR gene mutations. Overall, the morphologic features of ChRCCs and genetic profile with combinations of chromosomal losses and gains suggest this tumor entity to represent a distinct, yet heterogeneous group of renal neoplasms.

Nodular Maturation of the Testis: A Non-neoplastic Lesion of Boys That May Present as a Mass on Clinical and Ultrasound Examination.

We have encountered a lesion of the pediatric testis, termed "nodular maturation," that clinically mimics a testicular neoplasm causing ultrasound abnormalities that may lead to surgical excision. To our knowledge, it has only been described anecdotally in textbooks without a series or description in the literature. We, therefore, report 8 cases in pediatric patients emphasizing the clinical presentation, ultrasound findings, histologic features, and clinical follow-up information. Patients ranged in age from 5 to 11 years (mean: 7.9 y). Precocious puberty was identified in 1 patient as isolated penile enlargement without other signs; another had a history of McCune-Albright syndrome, but did not have signs of precocious puberty; others had no clinical manifestations. All patients had testicular abnormalities on ultrasound; 6 had a discrete lesion and 2 showed diffuse testicular enlargement. In the 6 cases with available data, mean size of the lesion on ultrasound was 0.9 cm (range: 0.4 to 1.7 cm). In the 3 cases for which macroscopic descriptions were available, no gross abnormalities were noted in the testicular parenchyma, despite the ultrasound findings. Histologically, nodular maturation occurred as a zone of more mature testicular parenchyma having larger, lumen-bearing seminiferous tubules that contrasted with the smaller, immature cords of the remaining parenchyma. The mature tubules showed germ cell maturation (to the level of late spermatids/spermatozoa in 6 cases), mature Sertoli cells, and, in 4 cases, admixed nodules of mature Leydig cells. Of the 6 patients with available follow-up information, none developed a testicular neoplasm. Given its ability to cause a lesion on ultrasound leading to surgical intervention, pathologists, radiologists, and urologists should be aware of nodular maturation.

Papillary Renal Cell Carcinoma With Microcystic Architecture Is Strongly Associated With Extrarenal Invasion and Metastatic Disease.

Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavorable" architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.

Distal Tubular Hyperplasia: A Proposal for a Unique Form of Renal Tubular Proliferation Distinct From Papillary Adenoma.

We identified an unusual pattern of renal tubular proliferation associated with chronic renal disease, found in 23 patients, diffusely (n=12), or focally (n=11). Incidence was 5% of end-stage renal disease kidneys from one institution (8/177) and 7/23 patients with acquired cystic kidney disease-associated renal cell carcinoma from another. Most (19 patients) had 1 or more neoplasms including papillary (n=9), acquired cystic kidney disease (n=8), clear cell (n=4), or clear cell papillary (n=3) renal cell carcinoma. All (20 men, 3 women) had end-stage renal disease. The predominant pattern (n=18) was the indentation of chronic inflammation into renal tubules forming small polypoid structures; however, 5 had predominantly hyperplastic epithelium with less conspicuous inflammation. In 14 patients both patterns were appreciable, whereas the remainder had only the inflammatory pattern. Immunohistochemistry was positive for cytokeratin 7, high-molecular-weight cytokeratin, PAX8, and GATA3. Staining for alpha-methylacyl-CoA racemase was negative or weak, dramatically less intense than papillary neoplasms or proximal tubules. CD3 and CD20 showed a mixture of B and T lymphocytes in the inflammatory areas. Fluorescence in situ hybridization showed no trisomy 7 or 17 or loss of Y (n=9). We describe a previously uncharacterized form of renal tubular proliferation that differs from papillary adenoma (with weak or negative alpha-methylacyl-CoA racemase, lack of trisomy 7 or 17, and sometimes diffuse distribution). On the basis of consistent staining for high-molecular-weight cytokeratin and GATA3, we propose the name distal tubular hyperplasia for this process. Future studies will be helpful to assess preneoplastic potential and etiology.

Immunohistochemical staining patterns of Ki-67 and p53 in florid reactive urothelial atypia and urothelial carcinoma in situ demonstrate significant overlap.

Flat urothelial lesions with atypia may pose significant diagnostic challenges. Given frequent increased proliferation rates in florid reactive urothelial atypia and limited studies on the interpretation of p53 stains in the urothelium (following current standard guidelines for correlation with P53 mutation status), we sought to further study the discriminatory value of Ki-67 and p53 for florid reactive urothelial atypia versus urothelial carcinoma in situ (CIS). Bladder specimens diagnosed as reactive urothelial atypia (n = 40) and CIS (n = 40) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, CD44, and CK20. Immunoreactivity was scored based on percent cells positive for Ki-67 and pattern of reactivity with p53 (aberrant: diffuse strong positive or negative; normal: patchy/wild type). CD44 and CK20 reactivity patterns served as adjunctive internal validation controls for reactive urothelial atypia and CIS, as previously described. In reactive urothelial atypia, Ki-67 ranged from 0% to 90% (mean, 34% ± 26) with 30 cases (75%) having >10%. In CIS, Ki-67 ranged from 5% to 95% (mean, 50% ± 25) with 17 cases (43%) having >50%. In all 40 cases (100%) of reactive urothelial atypia, p53 expression had a wild-type pattern. In CIS, aberrant p53 expression was identified in 15 cases (37%): 3 cases (7%) were p53 negative (i.e. null phenotype) and 12 cases (30%) showed strong and diffuse nuclear reactivity (in >85% of cells). The remaining 25 cases (63%) of CIS had a p53 wild-type pattern of expression. Cytoplasmic CK20 immunoreactivity in umbrella cells was seen in 34 cases (85%) of reactive urothelial atypia, and 6 cases (15%) were negative. In addition, 35 cases (88%) of reactive urothelial atypia demonstrated full-thickness CD44 expression, while 5 cases (12%) had expression confined to the basal/parabasal layers of the urothelium. Strong and diffuse CK20 positivity was present in 39 cases (98%) of CIS, and patchy positivity was detected in 1 case (2%). None of the CIS cases overexpressed CD44: 16 cases (40%) showed focal expression in the nonneoplastic basal cell layer; 24 cases (60%) demonstrated no staining. In summary, Ki-67 has poor discriminatory value for reactive urothelial atypia versus CIS and adds little to the classic CK20/CD44 immunophenotype. While p53 sensitivity for CIS is relatively low (30%) and interpretation as either wild type or negative may be challenging in a small subset of cases, strong and diffuse nuclear reactivity was 100% specific in the distinction from florid reactive urothelial atypia in this cohort.

Cytology and curetting diagnosis of endocervical adenocarcinoma.

INTRODUCTION: Papanicolaou testing is effective in identifying squamous intraepithelial lesions of the cervix. Endocervical adenocarcinoma (EAC) and adenocarcinoma in situ (AIS) are far less commonly identified. Endocervical curettings (ECCs) are usually obtained after colposcopic biopsy, sample the endocervical canal, and aid in the detection of endocervical glandular lesions. Here, we examine the utility of Papanicolaou testing and endocervical curetting for detecting AIS and EAC. MATERIALS AND METHODS: Cases from 2007 to 2019 with a histologically confirmed diagnosis of AIS and EAC were identified and the clinical data and diagnostic material, including the cytology and surgical specimens, obtained. RESULTS: A total of 108 cases of AIS and EAC were identified, Papanicolaou tests were performed in 97 of these cases, and ECC in 87. AIS or EAC were detected in 46.4% of Papanicolaou tests; 41.4% of ECC showed AIS or EAC. A total of 92.7% of cases were positive for high-risk human papillomavirus (HPV) and concurrent squamous intraepithelial lesion was present in 53.3% of cases. AIS or EAC were more commonly identified in cases without concurrent squamous intraepithelial lesions. CONCLUSIONS: Papanicolaou testing and endocervical curettings have a low detection rate for AIS and EAC. The majority of AIS and EAC cases test positive for high-risk HPV. Papanicolaou test and ECC show different detection rates and are complementary tools in patients with AIS and EAC. In some settings, an ECC can increase the diagnostic sensitivity and specificity of the pathologic diagnosis.