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We evaluated the clinicopathologic and molecular characteristics of mostly incidentally detected, small, papillary renal neoplasms with reverse polarity (PRNRP). The cohort comprised 50 PRNRP from 46 patients, divided into 2 groups. The clinically undetected (5 mm) neoplasms (n = 34; 68%) had a median size of 1.1 mm (range 0.2-4.3 mm; mean 1.4 mm), and the clinically detected (≥5 mm) neoplasms (n = 16; 32%) which had a median size of 13 mm (range 9-30 mm; mean 16 mm). Neoplasms were positive for GATA3 (n = 47; 100%) and L1CAM (n = 34/38; 89%) and were negative for vimentin (n = 0/44; 0%) and, to a lesser extent, AMACR [(n = 12/46; 26%; weak = 9, weak/moderate = 3)]. KRAS mutations were found in 44% (n = 15/34) of the clinically undetected PRNRP and 88% of the clinically detected PRNRP (n = 14/16). The two clinically detected PRNRP with wild-type KRAS gene were markedly cystic and contained microscopic intracystic tumors. In the clinically undetected PRNRP, the detected KRAS mutations rate was higher in those measuring ≥1 mm vs1 mm [n = 14/19 (74%) vs n = 1/15 (7%)]. Overall, the KRAS mutations were present in exon 2-codon 12: c.35 G T (n = 21), c.34 G T (n = 3), c.35 G A (n = 2), c.34 G C (n = 2) resulting in p.Gly12Val, p. Gly12Asp, p.Gly12Cys and p.Gly12Arg, respectively. One PRNRP had a G12A/V/D complex mutation. Twenty-six PRNRP were concurrently present with other tumors of different histologic subtypes in the ipsilateral kidney; molecular testing of 8 of the latter showed wild-type KRAS gene despite the presence of KRAS mutations in 5 concurrent PRNRP. On follow up, no adverse pathologic events were seen (range 1-160 months; mean 44 months). In conclusion, the presence of KRAS mutations in small, clinically undetected PRNRP provides a unique finding to this entity and supports its being an early event in the development of these neoplasms.

We present a series of 18 (8 clinically benign, 8 clinically ambiguous [ie, lacking sufficient follow-up to determine behavior], and 2 clinically malignant) large cell calcifying Sertoli cell tumors (LCCSCT) of the testis. The median patient age and size were 15.5 years and 1.9 cm for the benign tumors; 19 years and 1.6 cm for the ambiguous tumors; and 28.5 years and 2.3 cm for the malignant tumors. The most common presentation was a mass (n=12/18, 67%). Two patients (11%) had the Carney complex, and 2 had neurofibromatosis type 1. All tumors showed nodular growth with frequent lymphoid aggregates at the periphery. Within the nodules, there were nests and trabeculae of pale to eosinophilic epithelioid tumor cells with frequent cytoplasmic vacuolization interspersed with hypocellular, often myxoid stroma with conspicuous neutrophils. Spindled tumor cells were a minor component (5%) in the clinically benign, ambiguous, and malignant tumors, except in 1 malignant tumor where they comprised 50% to 60% of the cellularity. Calcifications were noted in all but 2 benign tumors that were otherwise of typical appearance. Six tumors (3 in the clinically benign, 1 in the clinically ambiguous, and 2 in the malignant groups) were considered potentially malignant based on the presence of ≥1 adverse pathologic features previously recognized (see reference 1)-that is, size4 cm, extratesticular growth, necrosis, significant atypia, vascular invasion, and3 mitotic figures/10 HPFs. Of these, 3 tumors had ≥2 adverse features. One in a 7-year-old was clinically benign despite 5 "malignant" features; the remaining 2 in 27- and 30-year-olds, were clinically malignant, with both fulfilling previously suggested criteria for pathologically malignant tumors (age above 25 y and ≥2 adverse pathologic features). No clinically benign or ambiguous tumor met those same criteria. Of the adverse features, each of the 2 clinically malignant tumors showed tumor necrosis and lymphovascular invasion. All patients, except 1 with a clinically malignant tumor, were alive at a median follow-up of 33 months. In addition, in our literature review of 97 additional LCCSCTs, we identified 2 clinically malignant tumors in 42- and 45-year-old men that lacked any documented adverse pathologic criterion and 2 clinically malignant cases in patients with either the Carney complex or Peutz-Jeghers syndrome. In summary, our study and literature review support that all LCCSCTs in patients above 25 years old should be considered potentially malignant, and those in this age group with ≥2 adverse pathologic features warrant aggressive clinical management; furthermore, syndrome-associated cases are not uniformly benign. Tumor necrosis and lymphovascular invasion likely should receive greater adverse prognostic weight. LCCSCTs in young children may show benign outcomes despite several adverse pathologic features.

OBJECTIVES The Pediatric Eosinophilic Esophagitis (EoE) Symptom Score version 2 (PEESSv2.0) is an EoE-specific validated metric for disease monitoring, but its use has not been explored outside of EoE. Our aim was to determine if PEESSv2.0 scores differentiate between children with EoE and non-EoE esophageal dysfunction undergoing initial esophagogastroduodenoscopy (EGD). METHODS A prospective cohort study of pediatric subjects was conducted. Children ages 1-18 undergoing initial EGD for esophageal dysfunction were enrolled. Demographics, clinical history, and child self-report and parent-proxy report PEESSv2.0 symptom scores were collected at the time of EGD. Esophageal biopsies were reviewed, and EoE was defined as >15 eosinophils/high powered field (hpf) seen in any level of the esophagus. Non-EoE was defined as

Testicular Leydig cell tumor (LCT), the most common sex-cord stromal tumor in men, represents a small fraction of all testicular tumors (~1 to 3%). Although most testicular LCTs are indolent and cured by radical orchiectomy, 5-10% have aggressive biology and metastatic potential. In primary LCTs, large size, cytologic atypia, necrosis, increased mitotic activity, and vascular invasion have been associated with clinically aggressive tumors. From a molecular perspective, the characteristics of aggressive LCTs and the differences between aggressive and nonaggressive LCTs remain largely unexplored. This study compares the genomic landscape of aggressive and nonaggressive testicular LCTs. Twenty-six cases were analyzed using next-generation DNA sequencing (NGS) and immunohistochemistry. Cases were classified as aggressive LCT if they met published criteria for malignancy in primary (i.e., testicular) tumors or if they had pathology-proven metastatic disease; otherwise, cases were considered nonaggressive. This multi-institutional series included 18 aggressive LCTs (14 primary/testicular, 4 metastatic) and 8 nonaggressive LCTs. Two cases (2/26, 8%; both aggressive LCTs) failed sequencing and had negative (i.e., uninformative) FH immunohistochemistry results. One additional primary aggressive LCT failed sequencing but had informative FH immunohistochemistry results. Combined NGS and immunohistochemical analysis demonstrated FH inactivation in 5/26 cases (19%). In addition, NGS demonstrated CTNNB1 mutations or biallelic APC inactivation in 9/23 cases (39%), copy number changes without recurrent mutations in 6/23 (26%) cases, and no alterations in 4/23 cases (17%). CTNNB1 mutations were present in both aggressive and nonaggressive LCTs. In contrast, FH inactivation and multiple copy number changes were only identified in aggressive LCTs. In conclusion, three distinct subgroups of aggressive LCTs were characterized by FH inactivation, Wnt pathway activation, and copy number changes without recurrent mutations, respectively. Nuclear translocation of β-catenin and Wnt pathway activation appear to be early driver events that provide an environment conducive for progression to aggressive biology in a subset of LCTs.

Thyroid-like follicular renal cell carcinoma is an uncommon kidney tumor with no distinct molecular alteration described to date. This cohort of eight women with mean and median ages of 45 and 46 years, respectively (range 19-65 years), had unencapsulated, well-circumscribed tumors composed of tightly packed anastomosing follicle-like cysts filled with eosinophilic colloid-like material and lined by cuboidal cells with high nuclear to cytoplasmic ratios, oval to elongated nuclei with perpendicular arrangement toward the lumens, and prominent nuclear overlapping. The stroma between these was minimal with the exception of two tumors. Calcifications and necrosis were absent. Immunohistochemically, the tumors were positive for KRT19 (7/7), PAX8 (5/5), cyclin D1 (6/6), KRT7 (5/7), and AMACR (1/5; focal, weak), and were negative for WT1, TTF1 (transcription termination factor-1), and thyroglobulin. In three of three tumors tested molecularly, EWSR1-PATZ1 fusion was identified by RNA sequencing and confirmed by RT-PCR and Sanger sequencing. Over a follow-up period of 1-7 years, no evidence of recurrence or metastasis has been detected. The EWSR1-PATZ1 fusion has been recognized as a recurrent alteration in a subset of round to spindle cell sarcomas with EWSR1-non-ETS fusions (EWSR1-PATZ1 sarcoma) and in several central nervous system tumors. The finding of an EWSR1-PATZ1 fusion in all three of the thyroid-like follicular renal cell carcinomas for which sufficient tissue was available for genomic profiling provides the first distinct molecular abnormality in thyroid-like follicular renal cell carcinomas, supporting its designation as a distinct diagnostic entity.

Testicular tumors are the most common solid tumors in young men, the vast majority of which are of germ cell origin. The staging of human cancers is paramount to correct patient management. Staging systems have passed through several developments leading to the release of the most recent 8th edition of the American Joint Committee for Cancer (AJCC) staging manual, which is based on the current understanding of tumor behavior and spread. In this review, the authors summarize the current AJCC staging of the germ cell tumors, highlight essential concepts, and provide insight into the most important parameters of testicular tumors.

AimsLow-grade oncocytic tumour (LOT) has recently been introduced as a potential distinct entity.MethodsAt the Indiana University department of pathology, primary renal epithelial neoplasms between 2005 and 2020 were searched after appropriate institutional review board permissions.ResultsTwenty-three cases (male/female ratio 14/9) with a median age of 66 (23–84 years) were identified. The majority of patients underwent partial nephrectomy (15/23, 65%), with a median tumour size of 4.0 cm (2.2–10.5 cm). Only one case had infiltration beyond the kidney (perinephric fat). Solid/diffuse proliferation of tightly packed oncocytic tumour cells and occasional tubule formations, with an abrupt edematous change in the stroma with loosely connected small clusters of tumour cells. Along with diffuse CK7 expression with lack of CD117 in all cases, vimentin was positive in 8/23 cases (35%, 5 focal). CD10 was expressed in 6/13 (46%, 4 focal). Alpha-Methylacyl-CoA Racemase (AMACR) was positive in 5/8 (63%) cases. Focal but intense cytoplasmic colloidal iron stain was present in 3/20 (15%) cases. Luminal or cytoplasmic/perinuclear precipitation was observed in 8/20 (40%) cases. Succinate Dehydrogenase B (SDHB) was performed in 6 cases, with all retained expression.ConclusionsLOT is a clinically indolent and potentially benign entity with distinguishable morphology and immunohistochemical profile that can be performed and be easily interpreted in most of surgical pathology settings. Additional studies with larger cohorts, comprehensive molecular evaluation and longer follow-up are needed to definitively recognise these tumours as a separate entity and to further address the possibility of active surveillance options in eligible patients.

Cystoscopic visualization of bladder cancer is an essential method for initial bladder cancer detection and diagnosis, transurethral resection, and monitoring for recurrence. We sought to develop a new intravesical imaging agent that is more specific and sensitive using a polypeptide based NIR (near-infrared) probe designed to detect cells bearing epidermal growth factor receptors (EGFR) that are overexpressed in 80% of urothelial carcinoma (UC) cases. The NIR imaging agent consisted of an elastin like polypeptide (ELP) fused with epidermal growth factor (EGF) and conjugated to Cy5.5 to give Cy5.5-N24-EGF as a NIR contrast agent. In addition to evaluation in human cells and tissues, the agent was tested in canine cell lines and tissue samples with naturally occurring invasive UC. Flow cytometry and confocal microscopy were used to test cell-associated fluorescence of the probe in T24 human UC cells, and in K9TCC-SH (high EGFR expression) and K9TCC-Original (low EGF expression) canine cell lines. The probe specifically engages these cells through EGFR within 15 min of incubation and reached saturation within a clinically relevant 1 h timeframe. Furthermore

Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest "World Health Organization (WHO) classification of testicular tumors" was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non-GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.

ZusammenfassungDas zunehmende Verständnis molekularer Grundlagen von Tumoren sowie der Fortschritt in der Diversifizierung der onkologischen Therapien versprechen individualisierte Therapieoptionen, welche bislang jedoch nur ansatzweise in die Therapieplanung von urologischen Tumoren eingegangen sind. Daher hat die Internationale Gesellschaft für Urologische Pathologie (ISUP) im März 2019 eine Konsenskonferenz zur Erarbeitung evidenzbasierter Handlungsempfehlungen zur molekularpathologischen Diagnostik beim Urothelkarzinom, Nierenzellkarzinom, Prostatakarzinom, Peniskarzinom und testikulären Keimzelltumoren durchgeführt. Die auf dieser Konsenskonferenz erarbeiteten Empfehlungen sind kürzlich in 5 separaten Manuskripten veröffentlich worden und werden in der vorliegenden Arbeit zusammengefasst.Im Rahmen der Konferenzvorbereitung wurde eine umfassende Umfrage zur derzeitigen Praxis molekularer Testungen bei urogenitalen Tumoren unter den Mitgliedern der ISUP durchgeführt. Auf der Konferenz wurden die Ergebnisse und die entsprechenden Hintergrundinformationen durch 5 Arbeitsgruppen präsentiert und Handlungsempfehlungen für die Diagnostik erarbeitet. Eine Übereinstimmung von 66 % der Konferenzteilnehmer wurde als Konsens definiert.

Context.— Primitive neuroectodermal tumors (PNETs) may arise as a somatic-type malignancy in germ cell tumors. In this setting, most PNETs resemble those of the central nervous system and lack chromosome 22 translocations. However, description of the morphologic and differentiation spectrum of PNETs arising from germ cell tumors is lacking. Objective.— To investigate the morphologic and immunohistochemical features of these tumors, concentrating on neuronal and glial features. Design.— We selected cases based on a morphologically identifiable glial and/or differentiated neuronal component in association with the undifferentiated PNET. Immunohistochemistry for glial fibrillary acidic protein, S100 protein, synaptophysin, chromogranin A, and SOX11 was performed on tumors with available material, with the scoring of both staining intensity (0–3) and extent (0–3). Thirteen qualifying PNETs of testicular origin with available immunohistochemical stains or stainable material were identified. The complete stain panel was performed in 10 tumors. Results.— SOX11 demonstrated positive staining in the undifferentiated PNET component of all tumors (10 of 10) and was rarely positive in the differentiated (ie, neuronal/glial) component (1 of 10; focal and weak); synaptophysin was slightly less sensitive in the undifferentiated component (12 of 13; often focal and weak) and also showed positivity in the neuronal/glial component (5 of 13). Glial fibrillary acidic protein and S100 were more frequently positive in the differentiated areas (83% and 77%, respectively) compared with undifferentiated areas (25% and 17%, respectively). Conclusions.— SOX11 is a sensitive immunohistochemical marker for testicular PNET, particularly those lacking differentiation. Testicular PNETs often demonstrate glial and/or neuronal differentiation. Differentiation is marked by the acquisition of S100 and glial fibrillary acidic protein expression and SOX11 loss.

A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.

Adenocarcinomas of the rete testis (ACRT) are rare and aggressive testicular neoplasms that present predominantly in older men and have a tendency for early systemic spread. Their morphology spans a wide spectrum, including tumors with glandular, solid, papillary, micropapillary, glomeruloid, cribriform, and sarcomatoid growth patterns, or a combination thereof. The genomic alterations associated with these tumors have not been studied previously. We assessed eight ACRT published in prior clinicopathologic series using a solid tumor DNA sequencing panel. Pathogenic variants were identified in 6/8 cases. More specifically, four cases demonstrated inactivation of genes involved in cell cycle regulation, including CDKN2A, BAP1, TP53, and RB1. CDKN2A was the only recurrently affected gene, with pathogenic variants detected in 3/8 cases. One of these three cases had molecular evidence of concurrent homozygous (i.e. biallelic) NF2 inactivation by a frameshift variant and loss of the wildtype copy of the gene. One case had an internal tandem duplication in AKT, which has been previously described in juvenile granulosa cell tumor and sclerosing pneumocytoma and results in downstream activation of PI3K signaling. The remaining case with positive molecular findings harbored two concurrent truncating SETD2 variants. Multiple arm-level and chromosome-level copy number events were present in 3/8 cases, all of which harbored variants in genes involved in cell cycle regulation. In summary, ACRT are rare tumors with frequent inactivation of genes that play a major role cell cycle regulation, and a subset harbors variants that are potentially amenable to targeted therapy.

Rare hepatoid teratomas (HTs) in testicular germ cell tumor patients mimic hepatoid yolk sac tumor (HYST) and hepatocellular carcinoma (HCC). We compared the features of 2 metastatic HTs, 12 HYSTs, and 16 HCCs. The mean ages were 36, 40, and 62.5 years, respectively. The HTs formed sheets of hepatocyte-like cells with macrovesicular fat arranged in vague lobules with intervening fibrous bands containing biliary ductule-like structures and abortive portal triads. HTs lacked basement membrane deposits, with hepatoid cells staining for glypican-3, arginase, and HepPar-1 (2/2), whereas stains for CK19 (2/2) and CK7 (1/2) highlighted ductules and for villin hepatoid cells and ductules (1/2). SALL4 and CDX2 stains were negative (0/2). HYSTs formed nests, trabeculae, cords, and occasional gland-like structures, and most (10/12; 83%) produced intercellular basement membrane. No Mallory-Denk bodies were seen. Stains for SALL4 (100%), glypican-3 (100%), CK19 (88%), CDX2 (88%), and villin (75%) were positive, whereas those for HepPar-1 highlighted rare tumor cells (70%) and for arginase were mostly negative (26%). All HCCs lacked basement membrane deposits, with Mallory-Denk bodies occurring in 50%. Stains for HepPar-1 (100%) and arginase (94%) were positive, glypican-3 infrequent (19%), and SALL4, CK19, villin, and CDX2 negative. In summary, HTs are distinguished from HYST by the formation of ductules and abortive portal tracts, lack of basement membrane deposits, more consistent staining for arginase and HepPar-1, and negativity for SALL4 and CDX2. Contrasting features of HCCs with HYSTs include negativity for SALL4, CK19, and CDX2, frequent Mallory-Denk bodies, and absence of basement membrane deposits.

Summary The testicular hilum and paratestis contain several embryologically diverse anatomic structures, including the spermatic cord, tunica vaginalis, epididymis, rete testis, and several other embryonic remnants. Several benign and malignant lesions arise from these morphologically distinct structures, and owing to their proximity, it is challenging to classify and subsequently stage these tumors. Herein, we conducted a retrospective review of the paratesticular appendageal and rete testis tumors and tumor-like lesions diagnosed at our department from 1985 to 2016. Soft-tissue lesions/tumors were excluded. A total of 146 paratesticular appendageal and rete testis tumors and tumor-like lesions were identified. Most were benign (n = 107; 73%). Adenomatoid tumor (26%) was the most common benign tumor, followed by different types of cysts (19%), mesothelial hyperplasia (18%), serous cystadenoma (5.5%), and rete testis adenoma (4%). Malignant lesions comprised 23% of the cases, with mesothelioma the most common (15%), followed by adenocarcinoma of the rete testis (4%), serous cystadenocarcinoma (2%), and papillary and clear cell adenocarcinoma of the epididymis (2%). Finally, serous borderline tumors and melanotic neuroectodermal tumor (retinal anlage tumors) comprised the remaining 4% of cases. In conclusion, a wide range of benign and malignant lesions can arise from the paratesticular region. Awareness of these lesions and their histologic spectrum is crucial to avoid diagnostic pitfalls and to allow pathologists to establish a correct diagnosis and subsequent treatment plan.

We recently proposed that an epithelial renal tumor “papillary renal neoplasm with reverse polarity” represents a distinct entity. It constituted 4% of previously diagnosed papillary renal cell carcinoma at the participating institutions. Histologically, it is characterized by papillary or tubulopapillary architecture covered by a single layer of eosinophilic cells with finely granular cytoplasm and apically located nuclei. It is characteristically positive for GATA3 and L1CAM and lack vimentin and, to a lesser extent, α-methylacyl-CoA-racemase (AMACR/p504s) immunostaining. To investigate the molecular pathogenesis of these tumors, we performed targeted next-generation sequencing on ten previously reported papillary renal neoplasms with reverse polarity, followed by a targeted polymerase chain reaction analysis for KRAS mutations in a control series of 30 type 1 and 2 papillary renal cell carcinomas. KRAS missense mutations were identified in eight of ten papillary renal neoplasms with reverse polarity. These mutations were clustered in exon 2—codon 12: c.35 G > T (n = 6) or c.34 G > C (n = 2) resulting in p.Gly12Val and p.Gly12Arg alterations, respectively. One of the wild-type tumors had BRAF c.1798_1799delGTinsAG (p.Val600Arg) mutation. No KRAS mutations were identified in any of the 30 control tumors. In summary, this study supports our proposal that papillary renal neoplasm with reverse polarity is an entity distinct from papillary renal cell carcinoma and the only renal cell neoplasm to consistently harbor KRAS mutations.

In testicular germ cell tumors (TGCTs), components with nonspecific sarcomatous features that express keratins and glypican 3 are classified as sarcomatoid yolk sac tumor (SYST). SYST is most frequently seen in metastatic sites after chemotherapy. Like so-called "somatic-type" malignancies arising in TGCTs, SYST is markedly resistant to systemic therapy and has a more aggressive clinical course than conventional types of TGCT. However, the clinicopathologic and molecular features of SYST remain incompletely described. This study evaluated a multi-institutional series of 20 SYSTs using massively parallel sequencing and p53 immunohistochemistry. The histologic and clinical characteristics of the cases were also assessed, including analyses of disease-specific outcomes. DNA sequencing identified somatic mutations in 12/20 cases (60%), including recurrent TP53 and RIF1 mutations (present in 4/20 cases, 20% each). In 3 of the 4 SYST with TP53 mutations, there was molecular evidence of loss of heterozygosity. Immunohistochemistry demonstrated diffuse overexpression of p53 protein in 3/4 (75%) cases with TP53 mutations. The remaining TP53-mutant case demonstrated multifocal overexpression of p53, suggestive of subclonal inactivation of the gene. Overexpression of p53 protein was not seen in any of 15 TP53 wild-type cases evaluated by immunohistochemistry. A subset of 4 cases underwent RNA sequencing (fusion panel), which demonstrated the absence of oncogenic gene fusions. A 2-tiered grading system based on 3 histologic parameters (cellularity, number of mitoses, and necrosis) demonstrated that high-grade SYSTs have a higher risk of disease-specific death compared to low-grade tumors. The risk of disease-specific mortality was also higher in SYSTs with somatic mutations. In conclusion, this study demonstrated that 60% of SYSTs harbor somatic oncogenic mutations that are otherwise rare in TGCTs, and the presence of these mutations is associated with an aggressive clinical course. In addition, the results presented herein suggest that grading SYSTs may be clinically relevant.

AIMS Large cell calcifying Sertoli cell tumour (LCCSCT) is a rare testicular sex cord-stromal tumour that primarily affects young patients and is associated with Carney complex. We sought to characterize the clinicopathological features of a series of LCCSCT and evaluate the diagnostic utility of PRKAR1A immunohistochemistry (IHC). METHODS AND RESULTS The LCCSCT cohort (n=15) had a median age of 16 years (range: 2-30 years). Four patients were known to have Carney complex. PRKAR1A IHC was performed in each case. For comparison, PRKAR1A IHC was also assessed in other sex cord-stromal tumours, including Sertoli cell tumour, not otherwise specified (SCT, NOS; n=10), intratubular large cell hyalinizing Sertoli cell tumour (n=1), and Leydig cell tumour (n=23). Loss of cytoplasmic PRKAR1A expression was observed in all but one LCCSCT (14/15; 93%). PRKAR1A expression was retained in all SCTs, NOS (10/10; 100%), the majority of Leydig cell tumours (22/23; 96%), and an intratubular large cell hyalinizing Sertoli cell tumour (1/1; 100%). One Leydig cell tumour showed equivocal staining (multifocal weak expression). CONCLUSIONS Overall, PRKAR1A loss is both sensitive (93%) and highly specific (97%) for the diagnosis of LCCSCT. PRKAR1A loss may aid its diagnosis, particularly in sporadic cases and those that are the first presentation of Carney complex.

Summary Thoracic aortic aneurysm (TAA) predisposes to sudden, life-threatening aortic dissection. The factors that regulate interindividual variability in TAA severity are not well understood. Identifying a molecular basis for this variability has the potential to improve clinical risk stratification and advance mechanistic insight. We previously identified COQ8B, a gene important for biosynthesis of coenzyme Q, as a candidate genetic modifier of TAA severity. Here, we investigated the physiological role of COQ8B in human aortic smooth muscle cells (SMCs) and further tested its genetic association with TAA severity. We find COQ8B protein localizes to mitochondria in SMCs, and loss of mitochondrial COQ8B leads to increased oxidative stress, decreased mitochondrial respiration, and altered expression of SMC contractile genes. Oxidative stress and mitochondrial cristae defects were prevalent in the medial layer of human proximal aortic tissues in individuals with TAA, and COQ8B expression was decreased in TAA SMCs compared with controls. A common single nucleotide polymorphism (SNP) rs3865452 in COQ8B (c.521A>G [p.His174Arg]) was associated with decreased rate of aortic root dilation in young individuals with TAA. In addition, the SNP was less frequent in a second cohort of early-onset thoracic aortic dissection (TAD) cases compared with controls. COQ8B protein levels in aortic SMCs were increased in TAA individuals homozygous for rs3865452 compared with those homozygous for the reference allele. Thus, COQ8B is important for aortic SMC metabolism, which is dysregulated in TAA, and rs3865452 may decrease TAA severity by increasing the COQ8B level. Genotyping rs3865452 may be useful for clinical risk stratification and tailored aortopathy management., Mechanisms regulating thoracic aortic aneurysm (TAA) severity are unknown. Our study of human aortic tissues identifies mitochondrial and metabolic defects in TAA and delineates metabolic importance of COQ8B. A missense COQ8B polymorphism was associated with decreased TAA severity and increased endogenous COQ8B protein. Genotyping this polymorphism may improve clinical stratification.

Germ cell differentiation has been described in association with somatic tumors arising from several organ systems; rare cases arising from urothelium have been reported. Here we present a 62-year-old male with a remote history of lung cancer, a left adrenal gland mass, and a 5.6 cm left bladder wall mass; cystoscopy demonstrated a large papillary mass on the left anterior bladder wall. A transurethral resection specimen was sent for review in consultation and showed extensive papillary structures with thin fibrovascular cores lined by neoplastic cells with clear cytoplasm. These neoplastic cells were diffusely positive for pancytokeratin, CDX2 (caudal-type homebox 2), SALL4 (sal-like transcription factor 4), glypican-3, AFP (alpha-fetoprotein), while negative for PAX-8 (paired box gene 8), NKX3.1 (NK3 homeobox 1), PSA (prostate specific antigen), TTF-1 (thyroid transcription factor 1), Napsin A, inhibin, and OCT4 (octamer-binding transcription factor 4). Conventional urothelial conventional carcinoma and focal squamous differentiation were also identified as minor components. Urothelial carcinoma was focally positive for GATA3 (GATA-binding protein 3) and p63; SALL4 and glypican-3 were negative. Overall findings supported a yolk sac tumor with a smaller component of squamous cell carcinoma (

Sex cord-stromal tumors (SCSTs) account for the second most common category of testicular neoplasms and include several entities that may show overlapping morphologies and present diagnostic challenges. We analyzed a cohort of 120 testicular SCSTs and investigated the diagnostic utility of SRY-box transcription factor 9 (SOX9), forkhead box protein L2 (FOXL2), and steroidogenic factor 1 (SF-1) immunohistochemical stains. The results were compared with the more commonly used SCST markers, inhibin α, calretinin, and Wilms' tumor 1 (WT1). SF-1 was overall the most sensitive stain (91%), followed by inhibin α (70%), calretinin (52%), FOXL2 (50%), SOX9 (47%), and WT1 (37%), but sensitivities varied by tumor type. SOX9 and calretinin were more commonly positive in sex cord elements versus stromal elements (62% vs. 27% and 47% vs. 9%, respectively), whereas FOXL2 was more commonly positive in stromal elements versus sex cord elements (100% vs. 55%) when excluding Leydig cell tumors from the stromal category. Although no individual stain was diagnostically specific, some immunophenotypic patterns were noted that may help in the subclassification of SCSTs. We conclude that SOX9, FOXL2, and SF-1 are useful immunohistochemical stains for confirming sex cord-stromal differentiation in testicular tumors and provide increased sensitivity as well as additional diagnostic information, especially when combined with the more commonly used inhibin α, calretinin, and WT1 immunostains. Although morphology is paramount for subclassification of SCSTs, knowledge of certain immunohistochemical patterns may be helpful for diagnostically challenging cases.

"Sarcomas" in patients with testicular germ cell tumors (GCTs) are a common form of "somatic-type malignancy." There is support, based on morphology and immunohistochemistry, that many such sarcomatous tumors represent an unusual form of yolk sac tumor (YST). A virtually universal chromosomal anomaly in GCTs is increase in 12p copy number, often in the form of isochromosome 12p [i(12p)], but this aspect of sarcomatoid YSTs has not hitherto been studied. We performed interphase fluorescent in situ hybridization assay for detection of increased 12p copy number in sarcomatoid YSTs using a bacterial artificial chromosome-derived probe localized to 12p12.1 and a commercially available centromeric probe. Sixteen formalin-fixed, paraffin-embedded specimens from 11 patients, along with normal controls, were studied. Overrepresentation of 12p was expressed as a ratio between the number of signals for 12p and the number of signals for centromere 12. A ratio ≥1.3 was considered overrepresentation. All cases were postchemotherapy recurrences or metastases. Ages ranged 22 to 38 years (mean: 36). Most tumors (12/16) showed myxoid or fibromyxoid stroma and 15 of 16 were high grade. Thirteen of 16 specimens (81%) showed overrepresentation of 12p by the above criteria. Two cases exhibited loss of 12p and 1 case had gain of a whole chromosome 12 (trisomy 12). We conclude that, as in other GCTs, sarcomatous differentiation of YST demonstrates 12p alterations that can be identified by interphase fluorescent in situ hybridization. Apart from 12p overrepresentation, these tumors may exhibit loss of 12p or even gain of an entire chromosome 12 (trisomy 12). Increase in 12p copy number of a sarcomatous neoplasm provides support for sarcomatoid YST in clinically ambiguous settings.

We evaluated the clinicopathologic and chromosomal characteristics of a distinct subset of papillary renal tumors and compared them to a control series of papillary renal cell carcinoma types 1 and 2. Of the 18 patients, 9 were women and 9 were men, ranging in age from 46 to 80 years (mean, 64 y; median, 66 y). The tumors ranged in diameter from 0.6 to 3 cm (mean, 1.63 cm; median, 1.4 cm). Fourteen tumors were WHO/ISUP grade 2 and 4 were grade 1. All were stage category pT1. The tumors had branching papillae with thin fibrovascular cores, covered by cuboidal to columnar cells with granular eosinophilic cytoplasm, smooth luminal borders, and mostly regular and apically located nuclei with occasional nuclear clearing and inconspicuous nucleoli. Tubule formation and clear cytoplasmic vacuoles were observed in 5 and 9 tumors, respectively. Ten tumors had pseudocapsules. Psammoma bodies, necrosis, mitotic figures and intracellular hemosiderin are absent from all tumors. In contrast, papillary renal cell carcinoma type 1 consisted of delicate papillae covered by a single layer of cells with scanty pale cytoplasm with nuclei generally located in a single layer on the basement membrane of the papillary cores, while type 2 tumors had broad papillae covered by pseudostratified cells with eosinophilic cytoplasm and more randomly located nuclei. Both had occasional psammoma bodies, foamy macrophages and intracellular hemosiderin. Immunohistochemically, all were positive for pancytokeratin AE1/AE3, epithelial membrane antigen, MUC1, CD10, GATA3, and L1CAM. Cytokeratin 7 was positive in 16 tumors (1 had5% positivity). CD117 and vimentin were always negative. α-methylacyl-CoA-racemase (AMACR/p504s) showed variable staining (range, 10% to 80%) in 5 tumors. However, all tumors in the control group were negative for GATA3 and positive for AMACR/p504s and vimentin immunostains. Fluorescence in situ hybridization analysis of the study group demonstrated chromosome 7 trisomy in 5 tumors (33%), trisomy 17 in 5 tumors (33%), and trisomy 7 and 17 in 3 tumors (20%). Chromosome Y deletion was found in 1 of 7 male patients and chromosome 3p was present in all tumors. No tumor recurrence or metastasis occurred. In summary, we propose the term papillary renal neoplasm with reverse polarity for this entity.

Testicular biopsy may be a component of the work-up of male infertility. However, no reliable diagnostic tools are available for objective quantitative assessment of spermatogenic cells. It is well known that MAGE-A4 is selectively expressed in spermatogonia and our group has previously demonstrated that DOG1 differentially stains germ cells. Therefore, we performed DOG1 and a double stain cocktail (DOG1 and 57b murine monoclonal anti-MAGE-A4) immunohistochemical stains on 40 testicular infertility biopsies (10 each with active spermatogenesis, Sertoli cell-only, hypospermatogenesis, and maturation arrest), 25 benign seminiferous tubules from radical orchiectomies, and 5 spermatocytic tumors (ST). In biopsies/resections with active spermatogenesis, DOG1 stained spermatocytes and spermatids and was absent in spermatogonia, while MAGE-A4 stained spermatogonia and primary spermatocytes (weak). In hypospermatogenesis, DOG1 highlighted decreased spermatocytes/spermatids and MAGE-A4 highlighted decreased spermatogonia. DOG1 staining confirmed decreased to absent spermatocytes in maturation arrest and MAGE-A4 staining established the presence of preserved spermatogonia in all cases. All STs were negative for DOG1 and positive for MAGE-A4, while all Sertoli cell-only cases were negative for DOG1 and the double stain cocktail. In conclusion, we confirmed that DOG1 is expressed in spermatocytes and spermatids and MAGE-A4 highlights primarily spermatogonia. Usage of these stains facilitates confirmation of maturation arrest, assessment of the percentage of testis involvement in hypospermatogenesis and identification of mixed patterns. Finally, this study supports that the differentiation of STs is more closely related to spermatogonia than the more mature spermatocytes.

The incidence of bilateral testicular germ cell tumor (TGCT) is 1% to 5%. Despite the high rate of treatment success, resistance to chemotherapy has a detrimental effect. Some studies found MMR and BRAF gene mutations to be associated with chemotherapy resistance, which has not been found by others. However, the role of microsatellite instability (MSI) and BRAF mutations in bilateral disease has not been investigated. In this article, we studied the clinicopathologic characteristics and immunohistochemical expressions of MMR and BRAF in 13 patients with bilateral TGCT. Bilateral tumors were found in 4% of patients in our data. The mean ages at the first and subsequent diagnoses were 26.9 and 28.3 years, respectively. Eleven patients had metachronous disease; and the mean period between both tumors was 4.9 years. Six had mixed GCTs (MGCT) initially and later developed contralateral seminoma, 3 had bilateral MGCTs; 1 initially had pure embryonal carcinoma and subsequently MGCT and finally, 1 patient had initial seminoma and contralateral germ cell neoplasia in situ only. Of the patients with synchronous GCT, 1 had a MGCT and contralateral non-seminoma and 1 had seminoma and contralateral MGCT. In metachronous cases, 40% and 78% had an initial and subsequent stage of pT1, respectively. Hormonal and/or metastatic recurrence was observed in 30% of metachronous tumors. Six patients received chemotherapy, including patients with metastasis. No progression occurred after therapy. MLH1, PMS2, MSH2, and MSH6 staining was retained in all tumors. No BRAF staining was found. In conclusion, we found no association between bilateral TGCT and the MMR/MSI pathway and that subsequent metachronous tumors behaved much more indolently.

Overgrowth of neuroglial tissue is rare in testicular germ cell tumors and mostly reported as isolated cases. We retrospectively reviewed 13 cases of testicular germ cell tumors from 2 institutions from 1995 to 2018. Hematoxylin and eosin slides were collected and reviewed. Immunohistochemistry was performed in all cases with available material. The series included 4 primary tumors and 9 metastases, including 8 retroperitoneal and 1 axillary lymph node (LN). The average age was 34 (range: 19 to 54). Five of the LN dissections were postchemotherapy, with one a recurrence 5 years after the initial diagnosis. The average tumor size for primary tumors was 5.15 cm (range: 1.7 to 7.3) and for metastases was 6.4 cm (range: 0.6 to 15). The largest size of the neuroglial component was 4.5 cm in the primary tumors and 7.5 cm in metastatic sites. The neuroglial component in the primary site was associated with pure teratoma (n=2) and with a mixed germ cell tumor (teratoma, seminoma, and embryonal carcinoma) (n=2). Cases involving LNs were associated with teratoma (n=4), seminoma (n=2), rhabdomyosarcoma (n=2), primitive neuroectodermal tumors (n=1), and high-grade sarcoma (n=1) (some with1 other component). Two cases were pure glial tumor. Histologically, the neuroglial components included low-grade astrocytoma (n=3) (both with microcysts formation and pilocytic features), gemistocytic astrocytomas (n=3), anaplastic astrocytoma (n=2), ganglioglioma (n=1), glioblastoma (n=2), gliosarcoma (n=1), and developing central nervous system (CNS) (n=2). By immunohistochemistry, 13/13 (100%) cases were GFAP(+), 10/10 (100%) cases showed retained ATRX, 10/10 were IDH1 pR132H (-), 5/10 (50%) were p53 (+). A single case 1/10 (10%) was BRAF p.V600E (+), but a mutation was not identified by polymerase chain reaction. Follow-up was available in 6 patients; 4 were confirmed to have received chemotherapy with BEP; 1 had a local recurrence and the patient with gliosarcoma developed a lung metastasis morphologically similar to the gliosarcoma of the retroperitoneum. In conclusion, neuroglial differentiation and neoplasms are rare in testicular germ cell tumors and are most commonly associated with teratomas; they can be seen in primary and metastatic sites. They exhibit the full range of neuroglial differentiation including developing CNS to gliomas/glioneuronal tumors WHO grades I-IV. None of the cases showed results consistent with ATRX, IDH or BRAF alterations, suggesting they have different oncogenic mechanisms than their CNS counterparts.

We here describe the development of an evidence-based cancer dataset by an International Collaboration on Cancer Reporting expert panel for the reporting of primary testicular neoplasia, and present the 'required' and 'recommended' elements to be included in the pathology report, as well as a commentary. This dataset encompasses the updated 2016 World Health Organisation classification of urological tumours, the results of an International Society of Urological Pathology consultation, and also staging with our preferred method: the American Joint Committee on Cancer version 8. Implementation of this dataset will facilitate consistent and accurate data collection between different cohorts, facilitate research, and hopefully result in improved patient management.

The American Joint Committee for Cancer eighth edition staging manual incorporated several critical changes regarding staging of testis germ cell tumors, and these changes are summarized and discussed in this article. Further challenges, however, remain, and these are also highlighted.

Testicular Leydig cell tumor (LCT), the most common sex-cord stromal tumor in men, represents a small fraction of all testicular tumors (~1 to 3%). Although most testicular LCTs are indolent and cured by radical orchiectomy, 5-10% have aggressive biology and metastatic potential. In primary LCTs, large size, cytologic atypia, necrosis, increased mitotic activity, and vascular invasion have been associated with clinically aggressive tumors. From a molecular perspective, the characteristics of aggressive LCTs and the differences between aggressive and nonaggressive LCTs remain largely unexplored. This study compares the genomic landscape of aggressive and nonaggressive testicular LCTs. Twenty-six cases were analyzed using next-generation DNA sequencing (NGS) and immunohistochemistry. Cases were classified as aggressive LCT if they met published criteria for malignancy in primary (i.e., testicular) tumors or if they had pathology-proven metastatic disease; otherwise, cases were considered nonaggressive. This multi-institutional series included 18 aggressive LCTs (14 primary/testicular, 4 metastatic) and 8 nonaggressive LCTs. Two cases (2/26, 8%; both aggressive LCTs) failed sequencing and had negative (i.e., uninformative) FH immunohistochemistry results. One additional primary aggressive LCT failed sequencing but had informative FH immunohistochemistry results. Combined NGS and immunohistochemical analysis demonstrated FH inactivation in 5/26 cases (19%). In addition, NGS demonstrated CTNNB1 mutations or biallelic APC inactivation in 9/23 cases (39%), copy number changes without recurrent mutations in 6/23 (26%) cases, and no alterations in 4/23 cases (17%). CTNNB1 mutations were present in both aggressive and nonaggressive LCTs. In contrast, FH inactivation and multiple copy number changes were only identified in aggressive LCTs. In conclusion, three distinct subgroups of aggressive LCTs were characterized by FH inactivation, Wnt pathway activation, and copy number changes without recurrent mutations, respectively. Nuclear translocation of β-catenin and Wnt pathway activation appear to be early driver events that provide an environment conducive for progression to aggressive biology in a subset of LCTs.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

Thyroid-like follicular renal cell carcinoma is an uncommon kidney tumor with no distinct molecular alteration described to date. This cohort of eight women with mean and median ages of 45 and 46 years, respectively (range 19-65 years), had unencapsulated, well-circumscribed tumors composed of tightly packed anastomosing follicle-like cysts filled with eosinophilic colloid-like material and lined by cuboidal cells with high nuclear to cytoplasmic ratios, oval to elongated nuclei with perpendicular arrangement toward the lumens, and prominent nuclear overlapping. The stroma between these was minimal with the exception of two tumors. Calcifications and necrosis were absent. Immunohistochemically, the tumors were positive for KRT19 (7/7), PAX8 (5/5), cyclin D1 (6/6), KRT7 (5/7), and AMACR (1/5; focal, weak), and were negative for WT1, TTF1 (transcription termination factor-1), and thyroglobulin. In three of three tumors tested molecularly, EWSR1-PATZ1 fusion was identified by RNA sequencing and confirmed by RT-PCR and Sanger sequencing. Over a follow-up period of 1-7 years, no evidence of recurrence or metastasis has been detected. The EWSR1-PATZ1 fusion has been recognized as a recurrent alteration in a subset of round to spindle cell sarcomas with EWSR1-non-ETS fusions (EWSR1-PATZ1 sarcoma) and in several central nervous system tumors. The finding of an EWSR1-PATZ1 fusion in all three of the thyroid-like follicular renal cell carcinomas for which sufficient tissue was available for genomic profiling provides the first distinct molecular abnormality in thyroid-like follicular renal cell carcinomas, supporting its designation as a distinct diagnostic entity.

TFE3-fusion associated renal cell carcinoma (TFE3-RCC) accounts for up to 5% adults and 40% of childhood RCC. Their comprehensive immunohistochemical (IHC) profile in correlation to fluorescence in situ hybridization (FISH) testing and their role in the diagnostic approach are not well documented because of lacking published data. FISH confirmed TFE3-RCC between years 2010 and 2020 were identified from institutional electronic database and retrospectively reviewed. Eighty-five TFE3-RCC were identified. Seventy-six of 85 (89.4%) TFE3-RCC cases had positive TFE3 expression, with diffuse and strong/moderate TFE3 expression in 45 (54.2%). Three (3.5%) TFE3-RCC had negative TFE3 expression whereas 6 (7%) cases had equivocal TFE3 expression. On the other hand, positive TFE3-IHC expression was observed in 17/29 (58.6%) TFE3-FISH negative RCC cases, although only 8 (27.5%) had diffuse and moderate/strong TFE3 expression. Diffuse and strong TFE3-IHC expression was statistically significant in predicting TFE3-FISH positivity (P

Context. Primary renal mesenchymal neoplasms are rare but diverse. Several neoplasms of mesenchymal derivation can arise as a primary renal mass; however, incidental tumors are identified in nephrectomies performed for end-stage renal disease or other malignant epithelial renal neoplasms. In this article, we document their frequencies with demographic information in nephrectomy specimens. Design. We retrospectively searched our database for nephrectomy specimens from the year 2000 to 2016. Results. A total of 224 cases were identified with an incidence rate of 4.4% (224/5128). One hundred ninety (85%) neoplasms were benign, 27 (12%) were malignant, and 7 (3%) were of intermediate biologic behavior. The majority of cases occurred in adults (93%, 208/224), and 39% of cases represented an incidental finding. The most common neoplasms were angiomyolipoma (58%) and renomedullary interstitial cell tumor (17%). Malignant mesenchymal kidney tumors are rare (0.39% of nephrectomy specimens). The most common adults’ malignant tumors in our survey were synovial sarcoma and Ewing’s sarcoma. Conclusion. Primary renal mesenchymal tumors are rare and are mostly benign in nature with many incidentally identified lesions. They arise in different age groups with malignant lesions usually presenting at a younger mean age.

Supplemental Digital Content is available in the text., The International Society of Urological Pathology (ISUP) organized a Consultation Conference in March 2019 dealing with applications of molecular pathology in Urogenital Pathology, including testicular tumors (with a focus on germ cell tumors [GCTs]), preceded by a survey among its members to get insight into current practices in testicular germ cell tumor (TGCT) diagnostics and adoption of the ISUP immunohistochemical guidelines published in 2014. On the basis of the premeeting survey, the most commonly used immunomarker panel includes OCT3/4, placental alkaline phosphate, D2-40, SALL4, CD117, and CD30 for GCTs and the documentation of germ cell neoplasia in situ (GCNIS). Molecular testing, specifically 12p copy gain, is informative to distinguish non-GCNIS versus GCNIS related GCTs, and establishing germ cell origin of tumors both in the context of primary and metastatic lesions. Other molecular methodologies currently available but not widely utilized for TGCTs include genome-wide and targeted approaches for specific genetic anomalies, P53 mutations, genomic MDM2 amplification, and detection of the p53 inactivating miR-371a-3p. The latter also holds promise as a serum marker for malignant TGCTs. This manuscript provides an update on the classification of TGCTs, and describes the current and future role of molecular-genetic testing. The following recommendations are made: (1) Presence of GCNIS should be documented in all cases along with extent of spermatogenesis; (2) Immunohistochemical staining is optional in the following scenarios: identification of GCNIS, distinguishing embryonal carcinoma from seminoma, confirming presence of yolk sac tumor and/or choriocarcinoma, and differentiating spermatocytic tumor from potential mimics; (3) Detection of gain of the short arm of chromosome 12 is diagnostic to differentiate between non-GCNIS versus GCNIS related GCTs and supportive to the germ cell origin of both primary and metastatic tumors.

Summary Smooth muscle hyperplasia of the testicular adnexa (SMH-TA) is a rare mass-forming intrascrotal lesion. Although benign, it can be a diagnostic challenge, as we have seen in our consult practice. Herein, we discuss our experience with these lesions over 14 years. Twelve SMH-TA cases were identified in our institutional records between 2005 and 2019. The morphologic features were reviewed. Clinical information was obtained from physicians’ notes. The mean age was 51 years (range, 24–82 years). Six cases were on the left side, five on the right, and one was bilateral. The most common presentations were orchialgia (n = 10) and mass (n = 6). Two patients had a concurrent incarcerated inguinal hernia, and one had a recent groin trauma. Past medical history included 5 patients with previous surgeries in the inguinal region, 2 with a history of treated infections, and 1 with persistent chronic orchitis. Eight patients have undergone ultrasound imaging which showed lesions (n = 4), hematoma (n = 1), undescended testis (n = 1), or no abnormalities (n = 2). Grossly, the mean size was 1.7 cm (range, 1.0–3 cm). The lesions had ill-defined, focally cystic, pink-tan nodular surface. Microscopically, the lesions were comprised of an ill-defined smooth muscle proliferation arranged in fascicles or haphazard fashion, growing in a periductal, perivascular, interstitial, or most commonly in a mixed pattern. SMH-TA is a rare benign entity that can present clinically as orchialgia and/or a suspicious intrascrotal mass. As suggested in previous studies, we believe that this lesion represents a reactive process.

Background Utilization of fine-needle aspiration (FNA) biopsy for the evaluation of renal masses has been increasing at our institution. At times diagnostic material on direct smears is superior to that in the cell block/core biopsy, therefore assigning an accurate nuclear grade in the cytopathology report would provide useful prognostic information. Methods Search of the pathology database identified renal FNAs performed during an 11-year period (2006-2017). Corresponding core biopsies and resections were identified. Cases with a diagnosis of primary renal neoplasia on FNA, core biopsy, and/or resection were included. Two pathologists reviewed all cases and assigned a World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grade to each FNA, core biopsy, and resection case. Results A total of 162 kidney FNAs were identified. Primary renal neoplasia was diagnosed in 137 cases on core biopsy/resection. Among diagnostic FNAs of clear cell RCC and papillary RCC with core biopsy/resection specimens for re-review (n = 52), reviewers assigned a concordant WHO/ISUP grade to 83% (43/52) of cases. Among 9 cases with discrepant scores, all had a discrepancy of 1 grade and were undergraded on FNA. Using a two tier grading system (low vs. high grade), reviewers assigned a concordant grade to 88% (46/52) of cases. Among 6 cases with discrepant scores, all were classified as low grade (WHO/ISUP grade 2) on FNA versus high grade (WHO/ISUP grade 3) on resection. Conclusion The WHO/ISUP grade assigned on FNA shows good concordance with subsequent resection/core specimens (83%), with all discrepant cases being undergraded by one grade.

Endometriosis in men is extremely rare with only a few cases reported in the English literature. Different theories have been proposed as to its origin. In this article, we describe the clinicopathologic features of 2 cases of endometriosis occurring in male patients. The patients’ ages were 50 and 43 years, and sizes were 2 and 5.2 cm, respectively. No significant chemical or hormonal exposure was identified. Both patients presented with a testicular mass. Grossly, both lesions were cystic and contained hemorrhagic fluid. Microscopic examination revealed cysts and occasional glands lined by low columnar to cuboidal epithelium, surrounded by spindle cell stroma with abundant hemosiderin-laden macrophages reminiscent of endometrium. One case was predominantly intratesticular, with a minute focus of endometrial-type glands and spindled stroma within the tunica vaginalis. Focal chronic inflammation and epithelial denudation were present in both cases. The surrounding testicular and epididymal structures adjacent to the cystic mass were unremarkable. In summary, endometriosis is an extremely rare lesion in men. The presence of these lesions in both cases along the route of the Müllerian duct supports the theory that these lesions arise from embryonic remnants. Awareness of this entity is crucial for general pathologists to avoid wrong diagnosis and unnecessary management.

AIMS Testicular seminomas require accurate staging for effective management. Twenty per cent are metastatic at presentation, while 80% are clinical stage I, requiring only orchiectomy and surveillance. Tumour size, rete testis invasion, hilar soft tissue invasion and lymphovascular invasion have been shown to incur a higher risk of metastasis and recurrence in clinical stage I seminomas, with little congruence between studies. METHODS AND RESULTS We reviewed 211 cases of testicular seminomas and recorded patient age, tumour size, lymphovascular invasion and rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea and tunica vaginalis involvement. A univariate and multivariate analysis was performed comparing clinical stage I to advanced clinical stage patients (stages II and III) in reference to these factors. We found that tumour size (P = 0.02), vascular invasion (P = 0.02) and invasion of rete testis stroma (P = 0.01), epididymis (P = 0.02), spermatic cord (P = 0.047) and hilar soft tissue (P = 0.04) were predictors of higher clinical stage at the univariate level. However, multivariate analysis showed that only tumour size and vascular invasion remained significant (P = 0.008 and 0.032, respectively). A tumour size of 4 cm was the cut-off size found to be significant. CONCLUSIONS Tumour size and vascular invasion are the strongest predictors of higher clinical stage in testicular seminomas. Our univariate data suggest that rete testis and hilar soft tissue invasion relate to higher clinical stage. However, neither of these factors were found to be independent risk factors at multivariate analysis. Therefore, this study supports tumour upstaging based only upon size and vascular invasion.

The recent 8th edition of the American Joint Committee on Cancer (AJCC) staging manual had multiple changes concerning how pathologists should stage germ cell tumors (GCTs) of the testis. A significant one concerns the impact of different types of spermatic cord involvement, specifically direct tumor extension versus discontinuous involvement by invasion through lymphovascular spaces. We compared clinicopathologic findings and outcome data between 2 cohorts with these findings to evaluate the validity of the change in the AJCC 8th edition manual. GCTs (seminomatous and nonseminomatous) of the testis were identified that had previously been staged as pT3 due to involvement of the spermatic cord. Pathologic, radiographic, and clinical findings were reviewed. Tumors were restaged based on AJCC 8th edition criteria and the cohorts were split into direct extension by tumor into the spermatic cord (pT3), spermatic cord soft tissue invasion via spread from discontinuously involved lymphovascular spaces (pT2pM1), or a combination of both (pT3pM1). One hundred cases of primary GCTs of the testis, previously classified as pT3 by the AJCC 6th or 7th cancer staging manuals from 2007 to 2015, were selected. Mixed malignant GCTs were the predominant tumor type, comprising 66% of all cases. Pure tumor morphologies included embryonal carcinoma (n=17), seminoma (n=14), teratoma (n=2), and yolk sac tumor (n=1). The tumors either directly invaded into the spermatic cord (n=78), involved the cord discontinuously via spread from lymphovascular spaces (n=18), or had both findings (n=4). Overall, 93% of patients presented at advanced clinical stage (CS). Using the AJCC 8th parameters, 12% of all tumors were upstaged. Changes included CSI (n=1) and CSII (n=11) tumors being reclassified as prognostic stage group III. Clinical and/or pathologic recurrence was identified in 19% of all patients, including 12 pT3 and 7 pM1 patients (P=0.11). Overall mean time to recurrence was 24.6 months, with a mean of 28.0 months for pT3 tumors and 18.9 months for pM1 tumors. Five patients were dead at the time of this study, including 3 (4%) with pT3 tumors and 2 (9%) in the pM1 cohort. Our findings support that seminomatous and nonseminomatous GCTs with spermatic cord invasion have a high frequency of advanced CS at presentation, regardless of involvement by direct extension or discontinuous spread via invasion from lymphovascular spaces. By designating the latter as M1, a spurious upstaging to prognostic stage group III is required by the AJCC 8th edition. We were unable to identify statistically significant difference between the 2 groups as it pertained to CS at presentation and likelihood of recurrence. Conversely, statistical trends favor that pM1 patients have more likely recurrence and worse prognosis than pT3 patients.