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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.

It is estimated that 5-8% of renal tumours are hereditary in nature, with many inherited as autosomal-dominant. These tumours carry a unique spectrum of pathological and molecular alterations, the knowledge of which has expanded in recent years. Due to this knowledge, many advances in the treatment of these tumours have been achieved. In this review, we summarize the current understanding of the genetic renal neoplasia syndromes, clinical and pathological presentations, molecular pathogenesis, advances in therapeutic implications and targeted therapy.

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.

Renal oncocytoma is the most common benign epithelial renal neoplasm. Several adverse features that would typically increase the stage of renal cell carcinomas are not uncommon in renal oncocytoma, including perinephric, sinus fat, or renal vein invasion. Herein, we report the largest single institutional series of renal oncocytoma with adverse pathologic features. The cohort comprised 50 patients, 38 were men (76%) and 12 were women (24%), with a mean age of 68 years (range, 50-87 years). All cases were diagnosed on nephrectomy specimens. No laterality predilection was noted. The tumors ranged in size from 1.5-15.7 cm (mean, 5.3 cm). Adverse pathologic features included perinephric fat invasion (n = 25; 50%), renal sinus fat invasion (n = 9; 18%), and renal vein invasion (n = 5; 10%). More than one adverse feature was seen in 11 tumors (22%). All tumors showed diffuse reactions to KIT (n = 40; 100%) and cyclin D1 (n = 27; 100%). Keratin 7 highlighted rare (

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.

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.

Dysregulation of fibroblast growth factor receptors (FGFRs) has been implicated in several human malignancies, including urothelial carcinoma. In urothelial carcinoma, the oncogenic role of mutated FGFR is mediated by the RAS-mitogen-activated protein kinase pathway, resembling the effects observed with activated HRAS. Activating somatic mutations of FGFR3 are clustered in three hotspots in exons 7, 10 and 15, and are almost always missense mutations leading to amino acid substitution in the external, transmembrane or intracellular regions of the receptor. A fusion of FGFR3 to transforming acid coiled-coil containing protein 3, FGFR3 amplification and alternative splicing leading to aberrant FGFR3 activation are less common molecular alterations. In April 2020, the Food and Drug Administration (FDA) approved the first targeted FGFR therapy, erdafitinib, in patients with locally advanced or metastatic bladder cancer who have progressed on platinum-based chemotherapy. Herein, we reviewed the normal structure and function of FGFR. We also explored its role in the development of urothelial carcinoma and major developments in the FGFR-targeted therapy.

Adamantinoma-like Ewing sarcoma (ALES) is a newly described rare entity, which shows EWSR1::FLI1 rearrangement characteristic of Ewing sarcoma. This can be diagnostically challenging as it manifests histologically with epithelial differentiation and has diffuse keratin expression as well as p40 and p60 positivity. We hereby report a case of ALES in a 33-year-old woman with a past medical history of breast carcinoma who presented with a right-sided parotid mass. CT scan of the neck showed a heterogenous mass within the superficial lobe, measuring 17 mm in diameter for which the patient underwent superficial parotidectomy. Histopathology of the mass revealed a malignant neoplasm formed of solid nests, cords and sheets of cells with minimal cytoplasm and monomorphic nuclei with granular chromatin and indistinct nucleoli. Brisk mitotic activity and tumor necrosis were also present. The tumor showed strong and diffuse reactivity for pankeratin (clone AE1/AE3) and keratin 20, both in a dot-like pattern, raising the suspicion of metastatic Merkel cell carcinoma; however, molecular studies showed EWSR1::FLI1 rearrangement, supporting the diagnosis of ALES. In summary, it is prudent to have knowledge about this entity to avoid its misdiagnosis as other malignancies of the head and neck region which exhibit a different clinical course, prognosis and hence treatment modalities.

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.

Context.— Amyloidosis is caused by the deposition of misfolded proteins as insoluble eosinophilic material in the extracellular tissues of the body, leading to impairment of organ function. It can be systemic or localized. Localized genitourinary tract amyloidosis is rare and can be incidentally seen; however, in some cases, it can be the only presenting disease. Objective.— To review the clinical presentation and pathologic findings related to primary amyloidosis of the urogenital system and highlight some of the associated pathologic findings based on our personal experience. Data Sources.— Published peer-reviewed literature and personal experience of the senior author. Conclusions.— Primary localized amyloidosis within the urogenital tract can present as a neoplastic process and may be clinically and radiologically considered as a mass. Awareness of primary amyloidosis by pathologists and clinicians is required for accurate diagnosis and proper patient management.

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.

Williams syndrome (WS), also known as Williams-Beuren syndrome, is a rare genetic disorder characterized by infantile hypercalcemia, short stature, a varying degree of mental retardation, elfin-like facial features, and cardiovascular abnormalities, including systemic hypertension, aortic hypoplasia, coarctation of the aorta, and valvular heart disease (aortic and pulmonic stenosis, mitral valve prolapsed or bicuspid aortic valve). It is also characterized by friendly and outgoing personality. The majority of WS cases are sporadic, while few are familial. Both sporadic and familial cases are due to deletion of chromosome 7 (7q11.23). Herein, we present an autopsy case of a 16-day-old male infant born to a 25-year-old mother with a history of William syndrome. Prenatal echocardiogram showed supravalvular aortic stenosis and pulmonary stenosis. The postnatal course was complicated by feeding difficulties and desaturation. Gross autopsy findings included generalized edema, macrocephaly with short neck, and multiple facial anomalies (mandibular hypoplasia, depressed nasal bridge, long philtrum, ear malformation, and wide mouth). The heart was hypertrophied with obstructed ventricles and rudimentary, hypoplastic aortic root. An enlarged, dilated, and tortuous left ureter was a unique finding to this case, in addition to variation in the renal arteries' size and an small bowel outpouching located 33 cm from the ileocecal valve. Cytogenetic analysis revealed deletion of chromosome 7 (7q11.23). In conclusion, majority of WS cases are sporadic, and few are familial and are inherited as autosomal dominant.

Background The current risk stratification systems used to guide management of endometrial cancer are based on irreproducible post surgical pathological information, hence the need for more reliable classification systems. Using microarray and sequencing technologies, TCGA recently identified four prognostically significant endometrial carcinoma subtypes, which subsequently proved reproducible using clinically applicable surrogate tests. Using these tests, we sought to determine the level of concordance between endometrial biopsies and subsequent hysterectomy specimens in assessing the molecular classification of endometrial carcinoma. Materials and methods Fifty biopsies with corresponding hysterectomy specimens for endometrial carcinomas were collected. Additionally, 10 cases of biopsy proven atypical hyperplasia/EIN who were found to have endometrial carcinoma on resection were included. IHC for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) and P53 was performed. Microsatellite instability analysis was performed by PCR and Sanger sequencing was performed to detect mutations in exons 9 and 13 of the POLE gene. The level of concordance for tumor grade, histologic subtype, immunohistochemical and molecular profile in both specimens was determined using Cohen's kappa estimates. Results A high level of concordance was achieved for MMR-loss, MSI-high, P53-wild and abnormal types. In contrast, grade and histologic subtype showed only moderate levels of agreement. POLE gene mutation was detected in two patients. For both cases, mutations were detected only in resection specimens. When comparing atypical hyperplasia/EIN with subsequent hysterectomy tumor, the profile was identical to that of endometrial carcinoma. Conclusion In our cohort of endometrial carcinoma, a high level of concordance was achieved between biopsy and hysterectomy specimens for MMR-loss, MSI-high, P53-wild and abnormal types, superior to that of grade and histologic subtype, providing earlier and more reliable prognostic information to inform management. Similar concordance could not be achieved for POLE mutation, given the low frequency of this mutation in our study.

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.

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

Dysregulation of fibroblast growth factor receptors (

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 germ cell tumors (TGCT) are the most common solid malignant tumors in young men. Their incidence increases after puberty and peaks at the 3rd decade of life, following a bell-shaped age ...

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.

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.

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

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.

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.

Paratesticular liposarcomas are relatively common sarcomas in the paratesticular region, however, the myxoid variant; myxoid liposarcoma (MLS) is considered very rare. MLS peaks around the fourth-fifth decade. Herein, we describe a case of paratesticular MLS occurring in a 19-year-old African American male who underwent resection of a slowly growing testicular mass over a period of one and a half years that was considered initially by his primary care physician to be a benign lesion. The resection margins were positive for tumor and the patient developed local recurrence one year after the initial resection. An extremely unusual age of presentation along with the importance of margin status in tumor recurrence is highlighted.

Background Primary gastric actinomycosis is extremely rare, the appendix and ileocecal region being the most commonly involved sites in abdominopelvic actinomycosis. Herein, we report a case of primary gastric actinomycosis. The diagnosis was made on microscopic evaluation of gastroscopic biopsy specimens. To the best of our knowledge, this is the second case to be reported in the literature, in which the diagnosis was made in a gastroscopic biopsy rather than a resection specimen. Case presentation An 87-year-old Saudi male on medication for cardiomyopathy, premature ventricular contractions, renal impairment, hypertension, and dyslipidemia, presented to the emergency department with acute diffuse abdominal pain, abdominal distension, constipation and vomiting for two days, with no history of fever, abdominal surgery or trauma. The patient was admitted to the hospital with an impression of gastric outlet obstruction. Based on radiologic and gastroscopic findings, a non-infectious etiology was suspected, possibly adenocarcinoma or lymphoma. Gastroscopic biopsies showed an actively inflamed, focally ulcerated atrophic fundic mucosa along with fragments of a fibrinopurulent exudate containing brownish, iron negative pigment and abundant filamentous bacteria, morphologically consistent with Actinomyces. Conclusion Although extremely rare, primary gastric actinomycosis should be considered in the differential diagnosis of radiologic and gastroscopic diffuse gastric wall thickening and submucosal tumor-like or infiltrative lesions, particularly in patients with history of abdominal surgery or trauma or those receiving extensive medication. A high level of suspicion is required by the pathologist to achieve diagnosis in gastroscopic biopsies. Subtle changes such as the presence of a pigmented inflammatory exudate should alert the pathologist to perform appropriate special stains to reveal the causative organism.