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.

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.

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.

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.

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.

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.

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.

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).

Urothelial Carcinomas With Trophoblastic Differentiation, Including Choriocarcinoma: Clinicopathologic Series of 16 Cases.

Trophoblastic differentiation (including choriocarcinoma) arising in urothelial carcinoma has been described in numerous case reports, but never in a single series. We present a series of these tumors, describing the morphologic spectrum, applying traditional and novel immunohistochemical stains, and characterizing clinical follow-up. We identified 16 cases, arising predominantly in the bladder (N=14), but also the ureter (N=1) and prostatic urethra (N=1). Six of our cases (38%) contained invasive urothelial carcinoma with admixed syncytiotrophoblasts, 8 cases (50%) consisted of invasive urothelial carcinoma with choriocarcinoma, 1 case (6%) showed urothelial carcinoma in situ with associated choriocarcinoma, and 1 case (6%) consisted of pure choriocarcinoma. Other subtypes of variant morphology were seen in 5 of our cases (31%) and included squamous, glandular, lipoid, chordoid/myxoid, and sarcomatoid features. Given the limited specificity of human chorionic gonadotropin immunohistochemistry, we also studied the expression of a novel specific trophoblastic marker, hydroxyl-δ-5-steroid dehydrogenase, as well as Sal-like protein 4. Human chorionic gonadotropin expression was seen in nearly all cases (93%) but was often not limited to the trophoblastic component, staining the urothelial component also in 85% of the cases. Expression of hydroxyl-δ-5-steroid dehydrogenase was more sensitive and more specific, staining 100% of the cases and limited to trophoblasts in all but 1 case. Sal-like protein 4 expression was variable, staining trophoblast in only 50% of cases and staining the urothelial carcinoma component in 43% of those positive cases. Most of our tumors presented at a high stage and were associated with poor clinical outcomes, with at least muscle-invasive disease (pT2) in 10 of the 14 bladder tumors (71%), periureteric fat invasion in the ureter tumor (pT3), distant metastases in 7 of 16 cases (44%) and death of disease in 3 of the 15 patients with follow-up (20%). Our study describes a series of urothelial carcinomas with trophoblastic differentiation, demonstrating the morphologic spectrum of this entity, its frequent association with other subtypes of variant morphology, its characteristic immunoprofile, and its aggressive clinical behavior.

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.

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.

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.

Clinicopathologic features and outcomes of anterior-dominant prostate cancer: implications for diagnosis and treatment.

OBJECTIVE: This study aims to describe the pathological features and clinical outcomes in anterior-dominant prostate cancer (APCA) compared to posterior/posterolateral-dominant prostate cancer (PPCA) among men treated with radical prostatectomy for localized prostate cancer. METHODS: This is a single-institution, matched case-control analysis of short-term clinical outcomes stratified by pathologic tumor location at radical prostatectomy. Pathologic data extracted by expert genitourinary pathologists on tumor location was linked to clinical and oncologic outcomes data from a prospective institutional database for analysis. RESULTS: From 2005 to 2013, 1580 patients were identified for analysis with 150 (9.5%) having APCA. One-hundred and thirty two of these APCA men had complete clinical data and were matched to 353 men with PPCA (~1:3 ratio) by GrdGrp at surgery, margin status, and pathologic T stage. There were no racial/ethnic differences between APCA and PPCA (p = 0.13). Men with APCA demonstrated a higher median PSA at diagnosis (6.4 [4.6-9.1] ng/mL vs 5.6 [4.4-8.1] ng/mL; p = 0.04), a higher rate of GrdGrp 1 disease at diagnosis (57.7% vs. 40.0%, p = 0.003), and lower rates of abnormal digital rectal examination (DRE) (10.1% vs. 23.2%, p = 0.003) when compared to PPCA. The rate of surgical upgrading was higher among men with APCA vs. PPCA (55.3% vs 42.0%, p = 0.015). Freedom from biochemical failure (BF) at 5-years was 85.1% (95% CI 73.1-98.9) for APCA and 82.9% (95% CI 69.2-99.5) for men with PPCA (p = 0.70, log-rank test). CONCLUSIONS: The majority of anterior tumors were undetectable by DRE and were associated with higher PSA at diagnosis. Despite presenting mostly as low/intermediate grade cancers, more than half of the men with APCA had upgrading at surgery and slightly more than 40% had positive margins and/or extraprostatic disease. When matched to a cohort of posterior predominant tumors, no differences were seen in the rate of biochemical-failure after prostatectomy.

"Renal Cell Carcinoma With Leiomyomatous Stroma" Harbor Somatic Mutations of TSC1, TSC2, MTOR, and/or ELOC (TCEB1): Clinicopathologic and Molecular Characterization of 18 Sporadic Tumors Supports a Distinct Entity.

Renal cell carcinoma with (angio) leiomyomatous stroma (RCCLMS) is included as a provisional entity in the 2016 World Health Organization (WHO) classification of renal epithelial neoplasia; however, debate remains whether it represents a distinct entity or a heterogenous group of renal cell carcinomas (RCCs) with overlapping morphology. Also, its relationship to similar tumors occurring in the setting of tuberous sclerosis complex (TSC) is not fully addressed. We analyzed the clinicopathologic, immunohistochemical, and molecular characteristics of 23 sporadic RCCs associated with smooth muscle stroma and classified them into 2 groups, independent of molecular results: (1) RCCLMS (n=18) and (2) clear cell renal cell carcinoma (CCRCC) (n=5). The classification of a case as "RCCLMS" was based on morphologic comparison with 5 "index" RCCs from 3 patients with TSC showing similar features and the presence of diffuse CK7 expression. To investigate mutational and copy number alterations, a 170-gene solid tumor panel was utilized to sequence 14 RCCLMSs and control of 5 CCRCCs. Also, 4 RCCLMSs, suspicious for chromosome 8 monosomy, were further evaluated by a broader 479 gene sequencing panel that included ELOC (also referred to as TCEB1). Clinical information and follow-up data were obtained from electronic medical records. The mean age of patients with RCCLMS was 52 years (range, 33 to 69) with male:female ratio of 1:2. Macroscopically, all tumors were solitary and predominantly (82%) tan/red, circumscribed, and solid. The average tumor size was 2.3 cm (range, 1.1 to 4.5). Microscopically, the distinctive feature included tumor nodules of elongated and frequently branching tubules lined by cells with voluminous clear to mildly eosinophilic cytoplasm (100%), separated by focal to prominent smooth muscle stroma. Additional frequently identified features included: biphasic pattern of collapsed acini surrounding tubules with voluminous cytoplasm (50%), focal papillary architecture (39%), peritumoral lymphoid aggregates (39%), and hemosiderin-laden macrophages (33%). All 11 (100%) RCCLMSs with available staging information were pT1; 78% were WHO/International Society of Urologic Pathology (ISUP) grade 2 and 22% grade 3. Immunophenotypically, RCCLMSs were characterized by diffuse CK7, CAM5.2 and CD10 reactivity (100%). All patients with available follow-up (n=10) were alive and without disease progression after a mean and median follow-up of 25.2 (range: 1 to 58) and 25 months, respectively. The molecular results showed recurrent mutations in all RCCLMS: TSC1 (4), TSC2 (4), MTOR (6), and/or ELOC (2). Five control CCRCCs demonstrated primary alterations in VHL gene, while all 14 RCCLMS cases tested had intact VHL gene. Of 2 RCCLMSs with confirmed monosomy 8, 1 showed a hotspot ELOC mutation without TSC/MTOR mutations, and 1 showed a previously undescribed 3-bp in-frame ELOC deletion, along with a truncating TSC1 mutation. In conclusion, RCCLMS, as defined herein, harbors recurrent mutations of TSC1/TSC2, MTOR, and/or ELOC, consistent with hyperactive MTOR complex. Our findings argue that these tumors represent the sporadic counterpart to morphologically identical tumors occurring in TSC patients. Finally, the data support that RCCLMS is a novel subtype of RCC with unique morphologic, immunohistochemical, and molecular characteristics that is distinct from CCRCC and clear cell-papillary RCC.

Reporting Practices and Resource Utilization in the Era of Intraductal Carcinoma of the Prostate: A Survey of Genitourinary Subspecialists.

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.

A Novel Dual Immunostain to Characterize Sloughed Cells in Testicular Biopsies for Infertility.

Evaluation of testicular biopsies from azoospermic men requires recognition of phases of germ cell maturation as organized architecturally within the seminiferous tubule, as well as distinguishing the inability to generate mature spermatozoa (germ cell aplasia or maturation arrest) from normal spermatogenesis, which may be associated with a reversible obstruction. While traditional fixatives (eg, Bouin solution) provide exquisite nuclear detail and preserve the architectural integrity of the seminiferous tubule, formalin fixation yields biopsies with relatively poor nuclear detail and frequent luminal sloughing of cells, making it difficult to assess sperm maturation. One clone of the anti-DOG1 antibody was recently found to be expressed in late (postspermatogonial) germ cells. We developed a dual stain including DOG1 and SF-1 to mark late germ cells and Sertoli cells, respectively, in both sloughed and intact cells. Consecutive testicular biopsies (N=28) from men with azoospermia were classified by hematoxylin and eosin morphology and stained with a dual SF-1 (Perseus)/DOG1 (Cell Marque) immunohistochemical stain. Histologic patterns included normal spermatogenesis (5 cases), hypospermatogenesis (5 cases), late maturation arrest (2 cases), Sertoli cell only pattern (15 cases), and extensive tubular hyalinization (1 case). Architectural disruption of seminiferous tubules with sloughing of cells into the lumens was noted in all biopsies, at least focally. SF-1 (nuclear) was expressed in sloughed Sertoli cells; DOG1 (cytoplasmic) in sloughed postspermatogonial germ cells (spermatocytes and spermatids). This resulted in two distinct immunophenotypes: SF-1(+)/DOG1(-) sloughed cells in cases with the Sertoli cell only pattern and SF-1(+)/DOG1(+) sloughed cells in all other histologic patterns (normal spermatogenesis, hypospermatogenesis, and maturation arrest). Because the rate of sperm retrieval is lower in men with the Sertoli cell only pattern, this immunohistochemical stain may assist pathologists in the proper interpretation of testicular biopsies, allowing better-informed decision making by patients and clinicians regarding the subsequent use of assisted reproductive technologies.