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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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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 staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

Aims Accurate histological diagnosis and classification of germ cell tumours (GCTs) is key to informing successful therapeutic and surveillance strategy. The modern therapeutic approach for yolk sac tumour (YST) is highly curative. Because YST takes on a large morphological spectrum, it can be confused for other GCT subtypes as well as somatic carcinomas, particularly when YST presents in an extragonadal or a metastatic setting. Currently available immunohistochemical markers are limited by suboptimal sensitivity and specificity. We reported recently that ZBTB16 is a sensitive and specific marker for testicular YST. ZBTB16 is absent in other GCTs and in most common somatic carcinomas, including those of gastrointestinal, pancreatobillary, respiratory, genitourinary and gynaecological tracts. The purpose of this study is to investigate the diagnostic utility of ZBTB16 in the settings of metastatic and extragonadal YST. Methods and results We studied 32 archived metastatic and four extragonadal primary YSTs as well as 51 somatic malignancies for their immunohistochemical expression of ZBTB16. For comparison, α-fetoprotein (AFP) and glypican-3 were also studied in parallel. Our results demonstrated an overall sensitivity of 91.6% for ZBTB16 in detecting metastatic and extragonadal YSTs. The non-YST elements (teratoma and embryonal carcinoma) in 15 YST-containing metastatic mixed GCTs were non-reactive. With the exception of occasional myoepithelial cells of salivary gland carcinoma, all the 51 somatic malignancies were negative for ZBTB16. Conclusions ZBTB16 is a sensitive and specific marker for YST and is diagnostically superior to AFP and glypican-3 in metastatic and extragonadal settings.

Upper urinary tract urothelial carcinoma exhibiting variant morphology, especially in higher-grade tumors, is a recognized phenomenon but has not been comparatively studied in biopsy versus resection material. We studied the morphologic patterns and clinicopathological features, and provide a comparison between biopsy and resection specimens. Consultation cases were evaluated separately to investigate for possible consultation bias. A total of 383 in-house cases from 352 patients including 314 resection specimens and 69 biopsies from 2001 to 2014 were reviewed from a single institution. Histologic type, tumor grade, invasion, pathologic stage, nodal status, metastasis, and the presence and type of variant morphology for each case were evaluated. Variant morphology was identified in 5 biopsy specimens (7.2%) and 42 resection specimens (13.4%). The most common variant morphologic pattern was squamous differentiation (16 cases, 4.5%) followed by an inverted growth pattern (8 cases, 2.2%). The presence of variant morphology in resection specimens had a significant association with higher tumor grade, higher pT stage, and nonpapillary configuration. Of 69 patients with biopsies, 31 had a subsequent resection. In comparison, 181 consultation cases from 168 patients showed variant morphology in 6 biopsies (7.1%) and 27 resections (28.1%). In conclusion, the frequency of recognizing variant morphology in biopsies is about one-half of that in resections. The inclusion of consultation cases can inflate the incidence of variant morphology. As a result, the frequency of variant morphology in our in-house cases is lower than the percentage reported in the literature, most likely secondary to a consultation bias.

Cystic trophoblastic tumor (CTT) has been described in postchemotherapy retroperitoneal lymph node dissections of patients with testicular germ cell tumors. Prognostically, this lesion is similar to teratoma and no further treatment is required after surgery in the absence of other components. CTT has not, however, been reported in the testis. We identified 14 CTTs in the treated (4) and untreated (9; no information for 1 patient) testes of patients 15 to 43 years old (median, 25) with mixed germ cell tumors. The CTT was a minor component (

Context.— Testicular germ cell tumors with lymphovascular invasion (LVI) are staged pT2, and those with spermatic cord involvement are staged pT3. Objective.— To study the clinical significance of LVI within the spermatic cord without direct involvement of the cord soft tissues. Design.— A retrospective, multi-institutional review was performed on testicular GCTs with spermatic cord LVI in the absence of cord soft tissue invasion. Results.— Forty-four germ cell tumors had LVI in the spermatic cord without soft tissue invasion; 37 of 44 patients (84%) had nonseminomatous germ cell tumors (NSGCT), and 7 (16%) had pure seminomas. Patients with NSGCTs and spermatic cord LVI had worse clinical outcomes compared with patients with pure seminoma and spermatic cord LVI (P = .008). We then compared patients with NSGCTs and spermatic cord LVI (n = 37) to patients with NSGCTs and LVI limited to the testis (n = 32). A significantly greater percentage of patients with LVI in the spermatic cord presented with advanced clinical stage (76% versus 50%; P = .01). There was no statistically significant difference in disease recurrence/progression or death between patients with spermatic cord LVI and patients with LVI limited to the testis (P = .40; P = .50). There was no significant difference in the presence of embryonal dominant histology (P = .30) or rete testis invasion (P = .50) between the 2 groups. More hilar soft tissue invasion was seen in patients with LVI present in the spermatic cord (P = .004). Conclusions.— In patients with NSGCTs, LVI in the spermatic cord, without soft tissue invasion, is associated with worse clinical stage at presentation compared with patients with LVI confined to the testis.

Adenocarcinoma of the rete testis is rare and its etiological and pathologic characteristics are not well studied. We therefore investigated the clinical, morphologic, and immunohistochemical features of 6 cases diagnosed at our institution and conducted a detailed review of the literature. The mean age was 64 years. All patients presented with testicular masses; 4 were right-sided. On gross examination, all tumors were centered in the hilum and had solid and cystic cut surfaces. Microscopically, all had intrarete and invasive growth and showed multiple patterns, with a variable proportion of papillary, solid and glandular morphology, the latter varying from slit-like lumens to well-formed glands and tubules. Less common patterns included corded/trabecular (n=3), cribriform (n=3), glomeruloid (n=3), nested (n=2), and micropapillary (n=2). Discrete nests of eosinophilic and clear cells were a distinctive feature in 3 cases. Geographic necrosis occurred in 3 cases. All showed at least moderate nuclear pleomorphism with ovoid nuclei. Transition from benign to malignant rete epithelium was seen in all cases. The stroma was hyalinized to partially fibrotic. On immunohistochemical study, the tumor cells were positive for CK7 (5/5), AE1/AE3 cytokeratin (5/5), EMA (5/5), vimentin (5/5), EpCAM (detected by BerEP4 anitbody) (4/5), CK5/6 (4/5), nuclear Wilms Tumor-1 (4/5), epithelial specific antigen (detected by MOC31 antibody) (3/4), PAX8 (3/5), and calretinin (2/5). OCT3/4, SALL4, CD30, NKX3.1, PSA, α-inhibin, CK20, and S100 protein were negative. Ki-67 proliferative index ranged from 5% to 60% (mean: 40, median: 43). At presentation, 5 patients had retroperitoneal lymph node metastasis and one of these also had pulmonary metastases. The sixth patient developed pulmonary metastasis within 15 months of diagnosis. Three died within 4 years of diagnosis. In summary, adenocarcinoma of the rete testis is a rare malignant tumor with poor survival and a high propensity for retroperitoneal lymph node metastasis that must be distinguished from other testicular neoplasms and metastasis to the testis. Hilar localization, transition from benign to malignant rete epithelium, and supportive immunostains aid its accurate diagnosis.

Dr Robert E. Scully, who recognized and defined gonadoblastoma (GB), used the term "dissecting gonadoblastoma" (DGB) to describe variants with either an infiltrative type or diffuse pattern instead of the usual small nested arrangement. These patterns have not been emphasized in the literature. To investigate the features of DGB we examined 50 GBs microscopically and performed immunohistochemistry (IHC) in some. DGB was found in 38 (76%) GBs and was represented by 3 patterns. The most frequent was solid/expansile (n=26), consisting of large coalescent nests of germ cells, often (92%) interrupted by fibrovascular septa, with usually minor numbers of sex cord cells. Less frequent were small anastomosing nests (n=24) and cord-like arrangements (n=22) of germ cells irregularly distributed in a prominent stroma and with mostly inconspicuous sex cord cells. Most DGBs (24) showed >1 pattern and demonstrated the characteristic globular deposits of basement membrane, although these were often subtle. The germ cells in all patterns varied from spermatogonium-like to seminoma-like; OCT3/4 was positive only in the latter (7/7). The sex cord cells were small with dense, oval or angulated nuclei, inconspicuous nucleoli, and positivity for inhibin (9/9, strong), FOXL2 (9/9, strong), SF1 (8/9, strong), SOX9 (9/9, weak and focal), WT1 (5/7, variable), and calretinin (3/7, variable). Granulomas were present in 84% of germinoma foci, 13% of DGB foci, and 8% of classic GB foci. Twenty two of 38 DGBs had associated germinoma; 3 also had embryonal carcinoma, yolk sac tumor, and choriocarcinoma, respectively. Follow-up of 2 cases lacking an invasive tumor showed that both patients were disease free at 13 and 4.8 years after bilateral gonadectomy. We conclude that DGB is commonly seen with classic GB and displays identical IHC features, supporting it as a morphologic variant of GB. It appears likely that cord-like DGB is the earliest phase in a GB developmental continuum that may proceed successively into anastomosing, nested (classic GB), and solid/expansile patterns. DGB often mimics germinoma because of the large size of the nests, pseudoinfiltrative pattern of some cases, and inconspicuous sex cord cells. The presence of sex cord cells (identification aided by IHC for sex cord markers), the heterogenous morphology of the germ cells, and globules of basement membrane are useful differential features. The lack of a granulomatous reaction also favors DGB over germinoma. Mistaking DGB for GB with invasive germinoma may result in more aggressive therapy than warranted. The likely relationship of DGB to the relatively recently described concept of so-called "undifferentiated gonadal tissue" is discussed herein.

Introduction. Extramammary Paget disease (EMPD) of the vulva has been shown to express p16 by immunohistochemistry (IHC), however, p16 expression in the vulva and scrotum has not been extensively studied in relation to human papillomavirus (HPV) within EMPD of both the vulva and scrotum. Design. Twenty-two cases of EMPD (vulva, 16; scrotum, 6) were found in our laboratory information system. P16 and HPV IHC were performed. Any p16 reactivity less than 10% was considered negative. HPV in situ hybridization for both low- and high-risk HPV was also performed on all cases. Results. Of the 6 scrotal EMPD, 3 (50%) showed weak to moderate positive reactivity for p16 by IHC. Of the 16 vulvar EMPD, 13 (81%) were positive for p16, with at least moderate (2+) intensity with a mean expression of 33.3% (range = 10% to 80%) and 62% (range = 20% to 95%) in scrotal and vulvar EMPD, respectively. None of the scrotal or vulvar cases showed positive reactivity for HPV either by IHC or in situ hybridization. Conclusion. Both vulvar and scrotal EMPD can express p16 by IHC, more commonly vulvar than scrotal; however, no HPV was detected either by IHC or in situ hybridization. EMPD of vulva and scrotum does not appear to be related to HPV, and p16 expression may be regulated through a different mechanism.

Objectives Some of the scrotal masses are extratesticular neoplasias and develop from paratesticular tissues. Paratesticular region has a complex anatomy and contains epididymal and testicular appendages as spermatic cord, testicular tunicas, epididymis, and vestigial remnants. Therefore, neoplasms originating from this region comprise a heterogeneous group of tumors. Herein, we document paratesticular adipocytic neoplasms and the patient’s mean age and the mean size of tumor at presentation. Methods We retrospectively searched our database for paratesticular adipocytic neoplasms from the year 2001 to 2015. A total of 47 cases were identified and reports were reviewed. Results Of the total 47 cases, 28 (60%) spermatic cord lipomas, 9 (19%) well-differentiated liposarcomas, and 10 (21%) dedifferentiated liposarcomas were identified. The mean age for presentation for these diseases was of 41, 59, and 68 years, respectively. Conclusion The most common paratesticular adipocytic neoplasm in our institution is spermatic cord lipoma (60%), occurring in younger age group (mean age 40 years). However, up to 40% cases are malignant and include well-differentiated and dedifferentiated liposarcoma, occurring at a relatively older age population (59 and 68, respectively).

Tumors of trophoblastic derivation other than choriocarcinoma are very rare in the testis but have been reported on occasion in association with other germ cell tumors. Their morphologic spectrum is analogous to the trophoblastic tumors of the female genital tract including epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT). Herein we report our experience with 8 cases of trophoblastic tumors of testicular origin that lacked the features of choriocarcinoma; these included 4 ETTs, 1 PSTT, 1 unclassified trophoblastic tumor (UTT), 1 partially regressed choriocarcinoma with a monophasic morphology, and 1 hybrid tumor showing a mixture of adenocarcinoma and a UTT. All tumors occurred in young men 19 to 43 years old. Five arose de novo within the testis (2 ETTs, 1 UTT, 1 regressing choriocarcinoma, and the hybrid tumor) as a component of mixed germ cell tumors, and 3 (2 ETTs and 1 PSTT) were found in metastatic sites after chemotherapy. The trophoblastic component was minor (5% to 10%) in 6 tumors but was 95% of 1 metastatic tumor (ETT) and 50% of the hybrid tumor. Other germ cell tumor elements were identified in all cases, most commonly teratoma. The ETTs consisted of nodules and nests of squamoid trophoblast cells showing abundant eosinophilic cytoplasm, frequent apoptotic cells, extracellular fibrinoid material, and positivity for p63 and negativity for human placental lactogen (HPL). The PSTT showed sheets of discohesive, pleomorphic, mononucleated trophoblast cells that invaded blood vessels with fibrinoid change and were p63 negative and HPL positive. The UTT showed a spectrum of small and large trophoblast cells, some multinucleated but lacking distinct syncytiotrophoblasts, and was patchily positive for both p63 and HPL. The hybrid tumor had ETT-like and adenocarcinomatous areas that coexpressed inhibin and GATA3 but were negative for p63 and HPL, leading to classification of the trophoblastic component as UTT. Seven of the patients were alive and well on follow-up (8 to 96 mo; median, 39 mo), whereas the patient with the hybrid tumor died of liver metastases at 2 years. Our study verifies that trophoblastic neoplasms often having the features of nonchoriocarcinomatous gestational trophoblastic tumors may arise from the testis, occur either in the untreated primary tumor or in metastases after chemotherapy, and should be distinguished from choriocarcinoma given what appears to be a less aggressive clinical course.

Aims We examined gene rearrangement and the expression of anaplastic lymphoma kinase (ALK) in urinary bladder inflammatory myofibroblastic tumour (IMT) using fluorescence in-situ hybridization (FISH) and two immunohistochemical antibodies to ALK. We also investigated whether IMT represents an immunoglobulin (Ig)G4-related disease. Methods and results The performance of the Dako FLEX ALK monoclonal antibody (CD246) and the Cell Signaling Technology ALK (D5F3) XP monoclonal antibody were compared. Overall, 11 of 16 tumours showed ALK expression by immunohistochemistry (69%). Ten demonstrated ALK expression with both stains and one was positive with D5F3 but not CD246 (91% correlation). The D5F3 antibody yielded a stronger staining intensity and a higher sensitivity. Nine tumours demonstrated ALK rearrangements (56%) by FISH. Three were ALK+ by immunohistochemistry but negative for rearrangement by FISH, whereas one showed rearrangement by FISH but was negative by immunohistochemistry. In total, 12 tumours were positive for ALK abnormalities (75%). Using current criteria, no cases were classified as an IgG4-related disease. Conclusions The ALK D5F3 immunohistochemical stain showed superior staining characteristics compared with ALK CD246. Discrepancies in the results between FISH and immunohistochemistry for ALK abnormalities may have causes that are multifactorial. By current criteria, IMT does not represent an IgG4-related disease.

Aims Renal cell carcinoma, unclassified (RCCU) is a category that includes a morphologically and biologically heterogeneous group of tumours that are unable to be diagnosed as other well-defined entities. We aim to describe the morphological findings of tumours within this category and to determine the most frequent morphological features leading to classification difficulty. Methods and results One hundred and thirty-six cases of RCCU were examined. Patients ranged in age from 23 to 87 years. Seventy-seven patients were men and 59 were women. International Society of Urological Pathology (ISUP) grade was most commonly 3 (n = 66), followed by 2 (n = 42) and 4 (n = 28). Tumour size ranged from 0.6 to 24.9 cm. The American Joint Committee on Cancer (AJCC) pathological T categories included pT1a (n = 50), pT1b (n = 14), pT2a (n = 7), pT2b (n = 4), pT3a (n = 50) and pT4 (n = 9). Forty-four cases included lymph node(s), 41% of which (n = 18) had metastases. Tumours were assessed for a variety of histological features and assigned to the following morphological groups: predominantly oncocytoma/chromophobe RCC-like; clear cell RCC-like; papillary RCC-like; collecting duct-like; and pure sarcomatoid differentiation. The majority of the oncocytoma/chromophobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like and pure sarcomatoid phenotypes were mainly high stage (pT3 or pT4). Conclusions Renal cell carcinoma, unclassified is a term that encompasses tumours with a variety of morphological features and a wide biological spectrum. The most common source of diagnostic difficulty was tumours composed of predominantly eosinophilic cells.

The paratestis (PT) is defined by the testicular tunics, epididymis, spermatic cord, rete testis, and embryonic remnants. It gives rise to a large diversity of pathologies, including those of soft tissue, which may prompt orchiectomy. We performed a 17-year search of our database for orchiectomies for a PT soft-tissue mass. In a total of 4741 orchiectomy specimens, 138 orchiectomies were performed for primary neoplastic or nonneoplastic masses of the PT soft tissue or had an incidental PT soft-tissue mass. Of these, 65.9% were neoplastic. The mean age was 40.2 years (range

Objective: Central type primitive neuroectodermal tumors (PNET) are some of the most frequent somatic type tumors derived from germ cell tumors and can metastasize. We studied the cytomorphological features of metastatic central type PNET by fine-needle aspiration (FNA). Materials and Methods: A computerized search of our laboratory information system was performed for the 9-year period from 2005 through 2014 to identify all cytology cases in which a diagnosis of metastatic central type PNET had been rendered. A total of 5 FNA cases were collected and direct smears were reexamined. Results: All patients had a history of testicular or ovarian germ cell tumors. Direct smears displayed single and clusters of atypical round to oval cells with scant to moderate cytoplasm. Abundant naked nuclei were present in Diff-Quik-stained smears with mild to marked crushed artifacts and nuclear molding. Tumor cells showed fine granular chromatin, nuclear size variation (up to 1:3), and one or more small nucleoli. Pseudorosettes (Homer Wright-like rosette) were noticed in 1 case. Tumor cells were commonly positive for synaptophysin. Conclusion: Metastatic PNET can be reliably diagnosed by FNA. Differential diagnoses include Ewing sarcoma/peripheral PNET, alveolar rhabdomyosarcoma, neuroblastoma, etc. It is important to be familiar with this entity to avoid diagnostic pitfalls.

Understanding tumor genomic heterogeneity may offer vital information in an age of targeted therapy for renal cell carcinoma. We sought to investigate hallmark truncal chromosomal alterations between conventional, sarcomatoid, and matched metastatic tumor foci in clear cell and papillary renal cell carcinomas. A retrospective review identified 58 cases including clear cell (CCRCC) and papillary renal cell carcinomas (PRCC). All cases contained sarcomatoid transformation. Additionally, 10 of 58 patients had matched metastatic disease available for analysis. Three separate foci of conventional and sarcomatoid morphologies were analyzed in each tumor using dual color interphase fluorescence in situ hybridization. In the CCRCC cohort, hallmark chromosome 3p deletion was identified in 71% of cases (37/52). Complete concordance of chromosomal status between intratumoral foci in sarcomatoid and conventional foci was 89% and 86%, respectively. Overall chromosome 3p status between matched conventional and sarcomatoid morphologies was identified in 98% of cases (51/52). Hallmark 3p deletion was present in 91% of CCRCC metastatic samples (10/11) and was concordant with the matched primary CCRCC tumor in 91% (10/11). In the PRCC cohort, trisomy 7 and 17 was identified in all six cases (6/6). Complete concordance between intratumoral foci of trisomy 7 and 17 was 83% (5/6). Trisomy 7 and 17 were identified in all metastatic PRCC samples with 100% concordance with the matched primary tumor. These data show the relative preservation of truncal chromosomal abnormalities between conventional and sarcomatoid morphologic as well as matched metastatic settings.

Aims To investigate the immunohistochemical properties of the sex cord cells of gonadoblastoma and Sertoli cell nodule with intratubular germ cell neoplasia unclassified (IGCNU) as a means of objective distinction and to provide insight into the pathogenesis. Methods and results Immunohistochemical stains for SOX9, FoxL2 and SF-1 were performed on 10 gonadoblastomas (all phenotypical females) and 14 Sertoli cell nodules with IGCNU in normal phenotypical males with coexisting germ cell tumours. The sex cord cells of gonadoblastomas showed strong, diffuse FoxL2 and SF-1 positivity and focal weak to moderate SOX9 reactivity, whereas those of Sertoli cell nodules with IGCNU were uniformly, strongly positive for SOX9 and SF-1, while negative for FoxL2. Conclusions Coexpression of SOX9 and FoxL2 in the sex cord cells of gonadoblastomas provides evidence that these morphologically ambiguous sex cord cells are incompletely differentiated. The strong, diffuse SOX9 and SF-1 positivity and absence of FoxL2 reactivity in the Sertoli cell nodules with IGNCU support full Sertoli cell differentiation of the sex cord cells and distinguish them from gonadoblastomas. Deficient SOX9 expression in gonadoblastoma supports a current model of pathogenesis where immature germ cells, in the absence of well-formed Sertoli cells, retain a fetal phenotype and susceptibility to malignant transformation.

Sclerosing Sertoli cell tumor (SSCT) of the testis is rare, with only 22 previously reported cases. Most have been small, circumscribed masses, and none has had a malignant clinical course; however, follow-up is limited. We have examined 20 new SSCTs to better characterize their features and report long-term follow-up. At least focal tubule formation by sex cord cells in a dense, hypocellular fibrous stroma occupying at least 50% of the lesion was required. The patient age ranged from 23 to 52 years (mean, 37; median, 39). All SSCTs were unilateral with 11 left sided and 9 right sided. The average size was 1.7 cm (range, 0.5 to 6 cm). In most cases, the stroma represented 50% to 70% of the mass but was at least 80% in 2. The Sertoli cells formed cords, trabeculae, small nests, focal tubules (sometimes with a vague pseudovascular or retiform appearance), and rarely single cells. Most tumor cells had small, round, oval to polygonal nuclei with finely granular chromatin, small nucleoli, and modest amounts of pale, eosinophilic cytoplasm. No mitotic figures, significant atypia, or necrosis was seen. All tumors but 1 were circumscribed and lacked lymphovascular invasion. Follow-up in 15 patients (3 mo to 16 y; mean, 6.1 y) showed 9 alive and free of disease, 5 alive with unknown disease status, and 1 patient, who presented with bone metastases, dead of disease at 27 months. The only features in the malignant case that differed from all others in our study were lymphovascular invasion and lack of circumscription. Combining our cases with previously reported ones shows that SSCTs are unilateral, usually small (80%2 cm) tumors that occur in a wide age range (18 to 80 y old; mean, 35 y) and lack necrosis. Only 1 of 31 with follow-up (mean, 4.4 y) metastasized; this tumor was 3.8 cm and had lymphovascular invasion and invasive growth. We conclude that SSCTs2 cm with the typical features and lacking those associated with malignancy in Sertoli cell tumors, not otherwise specified, have a negligible risk of metastasis and are adequately managed by orchiectomy alone.

� Spindle cell neoplasms are rarely reported in liver allografts; most are benign and associated with Epstein– Barr virus infection. We present a case of a malignant spindle cell neoplasm arising in a liver allograft. The patient underwent orthotopic liver transplant for cirrhosis secondary to nonalcoholic steatohepatitis. After 2 years, he presented with vague abdominal complaints. Imaging studies revealed a 10-cm right hepatic lobe mass. The patient underwent right-sided hepatectomy. The tumor displayed areas of broad, relatively hypocellular fascicles, whorls, and perivascular clustering; spindle cells with mild to moderate nuclear pleomorphism; and relatively abundant eosinophilic cytoplasm. Mitotic activity ranged from 2 to 4 mitotic figures per 20 high-power fields. Immunostaining displayed positivity for epithelial membrane antigen, vimentin, CD99, BCL2, cytokeratin, and human herpesvirus 8. Interphase fluorescence in situ hybridization findings were negative for a translocation involving the SS18 gene (18q11). We believe the tumor represents the first reported case of a novel unclassified spindle cell malignant neoplasm in a liver allograft. (Arch Pathol Lab Med. 2014;138:274–277; doi: 10.5858/ arpa.2012-0480-CR)

We investigated the role of OCT4 immunohistochemical staining in detecting germ cell tumor lymph node metastases. Retroperitoneal lymph node dissection is important for staging and treatment of testicular germ cell tumors, and OCT4 is sensitive and specific for pluripotent testicular germ cell tumors; however, micrometastases, particularly from seminoma, can be difficult to detect. We examined 262 lymph nodes in 45 retroperitoneal lymph node dissection specimens from germ cell tumor patients. Specimens were categorized as postchemotherapy and untreated retroperitoneal lymph node dissection with or without clinical suspicion, based on lymphadenopathy or elevated serum germ cell tumor markers. Sections were stained with anti-OCT4 antibody. Twenty-one additional positive lymph nodes in 12 cases were detected to harbor scattered seminoma cells, singly and in small clusters, from 256 previously considered benign in: untreated retroperitoneal lymph node dissection with clinical suspicion (13% increase), postchemotherapy retroperitoneal lymph node dissection (7%), and untreated retroperitoneal lymph node dissection without suspicion (4%). However, no patient with an entirely negative dissection specimen was reclassified as positive. OCT4 immunohistochemistry detected scattered seminoma cells and small clusters of seminoma cells in lymph nodes previously considered to be benign for an overall increase of 8%, greatest in the setting of untreated retroperitoneal lymph node dissection with clinical suspicion. However, immunohistochemistry did not convert any entirely negative specimen to positive. Future studies will be useful to determine whether the small volume of disease detected by immunohistochemistry has the same impact as routinely detected lymph node metastases.

Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.

Urinary bladder squamous cell carcinoma and urothelial carcinoma with squamous differentiation are often high-grade and high-stage tumors that are thought to be associated with a poorer prognosis and response to therapy compared with urothelial carcinoma without divergent differentiation. Therefore, recognition of a squamous component is increasingly important in guiding prognosis and therapy. We investigated the expression of MAC387, desmoglein-3, and TRIM29 in pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation to determine whether they have utility as diagnostic biomarkers for squamous differentiation. Eighty-four cases were retrieved from participating institutions including 51 pure urinary bladder squamous cell carcinomas and 33 urothelial carcinomas with squamous differentiation. MAC387, desmoglein-3, and TRIM29 antibodies demonstrated positive staining in pure squamous cell carcinoma in 51 (100%), 46 (90%), and 48 (93%) cases, respectively. Urothelial carcinoma with squamous differentiation showed reactivity for MAC387, desmoglein-3, and TRIM29 in the squamous component for 32 (97%), 26 (79%), and 32 (97%) cases, respectively. MAC387 demonstrated a sensitivity of 99% and a specificity of 70% for squamous differentiation, whereas desmoglein-3 yielded a sensitivity of 86% and a specificity of 91%. No urothelial component showed greater than 10% labeling for desmoglein-3. TRIM29 labeling showed a sensitivity of 95%, but a poorer specificity of 33%. In summary, MAC387 and desmoglein-3 are reliable diagnostic markers for supporting the morphologic impression of squamous differentiation in urinary bladder carcinoma. Desmoglein-3 shows high specificity, whereas TRIM29 was most likely to demonstrate labeling in areas without light microscopically recognizable squamous differentiation.

Adrenocortical carcinosarcomas are rare aggressive neoplasms; only a few have been reported to date, all with dismal prognosis. These were reported as having varying morphology. We have encountered a case of adrenal carcinosarcoma with an undifferentiated component bearing similarities to primitive neuroectodermal tumors and other areas of oncocytic differentiation. The 48-year-old woman patient presented with abdominal pain and unintended, excessive weight loss. Computed tomographic imaging revealed a tumor located adjacent to the liver and kidney necessitating a partial nephrectomy and hepatectomy. Histologically, the tumor exhibited malignant features. Melan-A, inhibin, calretinin, cytokeratin AE1/AE3, synaptophysin, and neuron-specific enolase were positive immunohistochemically. The patient developed metastasis within 2 months of surgery and is currently alive with disease after chemotherapy. Adrenal carcinosarcoma is a rare highly aggressive malignancy with a wide morphologic spectrum. Recognition of variant morphology and applying correct immunohistochemical studies will aid in reaching an accurate diagnosis.

Inverted papilloma of the urinary bladder is rare, accounting for

Diverticula are saccular evaginations of urinary bladder mucosa that are encountered in all age groups with a prevalence of 1% to 10%. Intradiverticular neoplasms pose diagnostic and management challenges. The aim of this study was to document the common morphologic changes and neoplasms found in a large series of adult and pediatric vesical diverticula. A total of 174 diverticula from 133 patients were reviewed including 48 pediatric (mean age, 7.1 years) and 85 adult (mean age, 63.93 years); 92% were male. Of the 85 nonneoplastic cases, prominent morphologic findings included significant chronic inflammation (59), granulomatous inflammation including foreign body giant cell reaction (6), acute inflammation (7), squamous metaplasia (9), cystitis glandularis (10), and nephrogenic metaplasia (2). The pediatric cases showed no malignancy. Thirty-three of the 48 neoplastic cases had high-grade urothelial carcinoma, 4 had carcinoma in situ, 7 had low-grade papillary urothelial carcinoma, 2 had primary squamous cell carcinoma, 1 had primary melanoma, and 1 had urothelial dysplasia. Nine of the neoplastic cases had variant morphology. Diverticula from 31 cases were involved by primary tumors, of which 6 had coexisting intravesical neoplasia (3 had carcinoma in situ with invasion elsewhere). In 19 of 33 high-grade urothelial carcinomas, infiltration into adjacent fat was noted. Seven of these cases arose within diverticula. Diverticula may harbor neoplasms, most commonly urothelial carcinoma. Attenuation of the muscle layer associated with diverticulum formation may facilitate tumor invasion into peridiverticular soft tissues. It is emphasized that pT2 stage should be eliminated to avoid the confusion in staging these neoplasms.

Glandular neoplasms involving the urinary bladder carry a challenging differential diagnosis including primary and secondary processes. We investigated the potential diagnostic utility of cadherin-17 and GATA3 in 25 primary adenocarcinomas of the urinary bladder, as compared with other commonly used markers including β-catenin and p63. Urothelial carcinoma with glandular differentiation (11), colorectal adenocarcinoma secondarily involving the bladder (25), and primary colorectal adenocarcinoma (22) were also analyzed and the results were compared using a Fisher exact test. Cadherin-17 was expressed in 23/25 primary bladder adenocarcinomas (92%), 23/25 colorectal adenocarcinomas involving the bladder (92%), 21/22 primary colorectal adenocarcinomas (95%) and entirely negative (0/11) in both components of urothelial carcinoma with glandular differentiation (P

OCT4 immunostaining has become an essential resource in diagnosing germ cell neoplasia. OCT4 is a transcription factor with a characteristic nuclear staining pattern specific to germ cell neoplasms. Our institution has observed that paraganglionic tissue consistently displayed intense cytoplasmic staining by utilizing monoclonal OCT4 antibody, and we intended to determine whether OCT4 could provide additional diagnostic utility in adrenal tumors. We used monoclonal and polyclonal OCT4 antibodies for comparison of staining patterns and intensities. Thirty-eight pheochromocytomas (8 metastatic), 22 adrenal cortical carcinomas (2 metastatic), 15 metastatic tumors to the adrenal glands, and 10 normal adrenal glands containing cortical and medullary tissue were immunostained with OCT4. A 4-tier system (0 to 3), for recording intensity and extent of cytoplasmic staining, was used. All 30 primary pheochromocytomas displayed strong and diffuse (3+3) cytoplasmic immunoexpression. Six of 8 metastatic pheochromocytomas showed strong immunoexpression (3+3), whereas the remaining 2 showed moderate intensity (2+3). All 22 adrenal cortical carcinomas, including metastatic cases, were completely negative. Only 2 metastatic tumors to the adrenal gland showed weak, cytoplasmic positivity: a small cell carcinoma and a Merkel cell carcinoma. Controls stained in an appropriate nuclear manner. Immunoelectron microscopy demonstrated the antibody interacting with neurosecretory granules. To our knowledge, the cytoplasmic expression of OCT4 in adrenal medulla and pheochromocytoma has not been specifically studied. The goal of this study is to analyze the immunoreactivity of adrenal cortical carcinoma and pheochromocytoma to OCT4 and determine the sensitivity and specificity of this particular staining pattern and to compare monoclonal and polyclonal antibodies.

Similar to nephrogenic adenomas in adults, those in children are rare benign lesions that often occur in the setting of previous surgery or chronic irritation of the urinary tract. These lesions often present with hematuria and/or as polypoid or papillary lesions on cystoscopy, which may indicate malignancy. We sought to evaluate the various patterns of nephrogenic adenoma occurring in the pediatric population and better characterize the immunophenotype of these lesions. We reviewed 21 cases of nephrogenic adenomas from urinary bladder biopsies of 16 patients. Most patients had a history of urinary bladder augmentation with recurrent urinary stones and urinary tract infections. Many cases presented as a papillary or polypoid mass on cystoscopy. The most common morphologic patterns are papillary, tubulocystic, and a mixed pattern of papillary and tubulocystic, followed by cystic and tubular. On immunostaining, PAX-2, PAX-8, CK7, and MUC-1 provided the most diffuse and intense positive reactivity for nephrogenic adenoma, whereas CD10 and P504S were focal and lesser in intensity when positive. p63 and PAX-5 were consistently negative. We conclude that, although rare in children, nephrogenic adenoma should be included in the differential diagnosis of papillary/polypoid lesions in the urinary tract, especially in the context of previous surgery, chronic irritation from recurrent urinary tract infections, or stones. The immunohistochemistry profile of nephrogenic adenomas in our study also provides evidence that these are derived from distal renal tubular cells. In difficult cases, an immunohistochemical panel consisting of cytokeratin 7, PAX-2, PAX-8, and MUC-1 may be useful.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a recently described rare entity. The tumor histogenesis is proposed to be of primitive undifferentiated mesenchyme. The tumor has a predilection for the subcutaneous soft tissue especially of lower extremity, although other locations have been well documented. We report a case of PHAT arising in the hilum of the kidney, clinically mimicking an infiltrating malignant neoplasm of renal pelvis. The tumor was discovered during workup for unrelated gastrointestinal tract symptoms. Because of the location of the lesion, excision of mass and radical nephrectomy were performed. The tumor had strong immunohistochemical expression of vimentin, CD34, CD99, and vascular endothelial growth factor (VEGF). No additional lesions were documented during 3 years of follow-up. This is consistent with the current thinking that PHAT is a benign neoplasm with increased incidence of recurrence. We document the unique retroperitoneal location of this rare tumor and suggest that PHAT should be considered among the list of unusual lesions at this site.