Intratubular Germ Cell Neoplasia Research Articles

Primitive Embryonic-Type Neuroectodermal/Glandular Complexes in Testicular Germ Cell Tumors: A Mimic of Embryonic-Type Neuroectodermal Tumor.

Embryonic-type neuroectodermal elements are often intimately mixed with primitive endodermal-type glands, like those of yolk sac tumors, in germ cell neoplasia in situ (GCNIS)-derived germ cell tumors of the testis. Because the primitive glands mimic tubules or rosettes of embryonic-type neuroectodermal elements, these embryonic-type neuroectodermal/glandular complexes may be misinterpreted as pure lesions of embryonic-type neuroectodermal elements, which, if of sufficient size, may lead to a diagnosis of embryonic-type neuroectodermal tumor, despite that the criteria of the World Health Organization for a "somatic-type malignancy" are not met. A diagnosis of embryonic-type neuroectodermal tumor in the testis may lead to retroperitoneal lymphadenectomy even in clinical stage I patients, and in postchemotherapy resections indicates a poor prognosis. The distinction of the neuroectodermal and glandular elements is not always straightforward based on morphology alone. We, therefore, studied 34 testis-derived germ cell tumors with embryonic-type neuroectodermal/glandular complexes and 2 purely glandular yolk sac tumors to characterize the immunophenotypes and determine an efficient immunohistochemical panel to aid in this differential. We found that GFAP, synaptophysin, and paired-like homeobox 2B (PHOX2B) expression was specific to embryonic-type neuroectodermal elements, although PHOX2B had poor sensitivity. In contrast, positive reactions with antibodies directed against AFP, villin, and CDX2 were specific for the glandular elements, although CDX2 had poor sensitivity. Other markers, including AE1/AE3 cytokeratin, SALL4, glypican 3, SOX2, SOX11, CD56, INSM1, and neurofilament, proved less helpful because of their nonspecificity and/or poor sensitivity. We conclude that the optimal immunohistochemical panel for distinguishing the components of embryonic-type neuroectodermal/glandular complexes includes stains for synaptophysin, GFAP, villin, and AFP.

T cells in testicular germ cell tumors: new evidence of fundamental contributions by rare subsets.

Immune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown. Human testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes. Profound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. Despite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients' prognosis, and as putative targets for personalized immunotherapy.

The fate of germ cells in cryptorchid testis.

Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation.

Rudimentary and Incipient-Yolk Sac Tumour- Testis

Yolk sac tumour of testis configures as a germ cell neoplasm comprised of cellular articulations or structures simulating embryonic or foetal yolk sac, allantois and extra-embryonal mesenchyme. Testicular yolk sac tumour is pre-eminently comprised of prepubertal subtype which is non-concordant to germ cell neoplasia in situ, emerges as a ‘pure’ neoplasm and demonstrates multiple gains within chromosome 1q, 20q or 22 and losses within chromosomes 1p, 4 or 6q. Postpubertal subtype is concurrent to germ cell neoplasia in situ (GCNIS), preponderantly configures as a component of ‘mixed tumour’ and occurs due to testicular dysgenesis syndrome, subfertility or as single nucleotide polymorphism (SNP) variants within KITLG, SPRY4 or DMRT1 genes and expounds gain of isochromosome 12p. Upon microscopy, neoplasm may configure distinctive configurations as microcystic or reticular pattern, macrocystic pattern, myxomatous pattern, sarcomatoid or spindle shaped cellular pattern, solid pattern, glandular or alveolar pattern, endodermal sinus or perivascular pattern, hepatoid pattern, papillary pattern, parietal pattern or poly-vesicular vitelline pattern. Yolk sac tumour appears immune reactive to alpha fetoprotein (AFP), glypican 3, SALL4, pancytokeratin, villin or CK7. Neoplastic cells appear immune non-reactive to OCT3/4, CD30, CD117, placental alkaline phosphatase (PLAP), podoplanin (D2-40), inhibin, GATA3 or p63. Testicular yolk sac tumour requires segregation from neoplasms as teratoma, seminoma, embryonal carcinoma, rete testis with hyaline globules and microcystic leydig cell tumour. Tumefaction preponderantly depicts elevated levels of serum alpha fetoprotein (AFP). Testicular yolk sac tumour may be optimally subjected to surgical manoeuvers as orchiectomy.

Pre-germ cell neoplasia in-situ in a patient with complete androgen insensitivity syndrome

Abstract Introduction/Objective Complete androgen insensitivity syndrome is a disorder of sex development in 46, XY individuals with external female genitalia and undescended testes, often presenting with inguinal hernia in infancy and/or primary amenorrhea in adolescents. Given the increased risk for the development of germ cell neoplasms in the ectopic testis, early gonadectomy or orchidopexy may be indicated. Methods/Case Report We report a 21-year-old patient assigned female at birth (46, XY) with a history of bilateral inguinal hernia repairs (age 2) and later with lack of menarche (age 16). Additional work-up showed an elevated testosterone level (394 ng/mL) and normal luteinizing and follicle stimulating hormone values. On pelvic ultrasound, retained intraabdominal gonads were identified, but female sex organs were absent. During a gonadal relocation procedure, the gonads appeared irregular in shape with multiple cysts and small nodules, and bilateral gonadectomy was performed. Grossly, the gonads measured 4.9 and 4.3 cm with a smooth external surface and a lobulated cut surface with multiple cysts, up to 1.6 cm, containing clear, serous fluid. Histologic sections showed most seminiferous tubules were lined only by Sertoli cells with only occasional spermatogonia. Leydig cell hyperplasia and areas of ovarian-like stroma were seen. OCT4 immunostain highlighted the nuclei of individually disposed germ cells in the base of tubules (singly dispersed, non-linear pattern), raising concern for germ-cell neoplasia in-situ (GCNIS). However, the histology and staining pattern were better interpreted as diagnostic of germ cells with delayed maturation and pre-GCNIS. Additionally, OCT4 showed rare single cells within the stroma and considered to represent residual undifferentiated gonadal tissue. After gonadectomy, the patient was started on hormone replacement therapy. Results (if a Case Study enter NA) NA Conclusion This case highlights the potential pitfalls in the interpretation of OCT4 immunostain to avoid misdiagnosis of germ cell neoplasia.

The Safe Surgical Margin for the Testis Sparing Surgery in Testicular Cancer.

Testis sparing surgery (TSS) has an important role in preserving the functional capacity of testicular cancer (TC). Germ cell neoplasia in situ (GCNIS) lesions in the remaining testis have a significant risk for local recurrence. We aimed to evaluate the presence of satellite GCNIS lesions around the primary tumor and to measure the distance of the furthest GCNIS lesion to the primary tumor. The radical orchiectomy specimens of patients (n = 37) with a tumor size of ≤3 cm were reevaluated by the same pathologist. The satellite GCNIS lesions located around the primary tumor were detected, and the furthest GCNIS lesion distance to the primary tumor was measured under light microscopy. The mean tumor size was 1,9 ± 0,6 cm. The mean furthest GCNIS distance to the primary tumor was 5,08 ± 2,77 mm. A total of 19 (51,4%) patients had the furthest GCNIS lesions <5 mm, and 28 (75,6%) patients had the furthest GCNIS lesions <7 mm away from the primary lesion. Leaving a 5 mm safety margin during TSS would lead to excise the satellite GCNIS lesions in half of the patients. Increasing the safety margin to 7 mm would lead to excise the satellite GCNIS lesions at 75% of the patients.

Molecular Characterization of Patients with Cryptorchidism: Preliminary Search for an Expression Profile Related to That of Testicular Germ-Cell Tumors.

Cryptorchidism (CO) is a risk factor for the development of testicular germ-cell tumors (TGCT). This is supported by reports showing the persistence of gonocytes in CO patients. These cells are proposed to be related to the development of germ-cell neoplasia in situ (GCNIS), which is considered the precursor stage/lesion of TGCT. Therefore, it is proposed that some patients with CO could express some molecular markers related to TGCT. In this study, we analyzed testicular tissue samples from CO, TGCT, and controls. We determined the expression of POU5F1, PLAP, and KIT by immunohistochemistry and that of the hsa-miR-371-373 cluster, hsa-miR-367, and LATS2, PTEN, and IGFR1 genes by RT-qPCR. We then carried out a bioinformatic analysis to identify other possible candidate genes as tumor biomarkers. We found that 16.7% (2/12) of the CO patients presented increased expression of POU5F1, KIT, PLAP, hsa-miR-371-373, and hsa-miR-367 and decreased expression of LATS2 and IGF1R. Finally, the genes ARID4B, GALNT3, and KPNA6 were identified as other possible candidate tumor biomarkers. This is the first report describing the expression of the hsa-miR-371-373 cluster, hsa-miR-367, LATS2, and IGF1R in the testicular tissues of two CO patients with cells immune-positive to POU5F1, PLAP, and KIT, which is similar to what is observed in TGCT.

Male Infertility and the Risk of Developing Testicular Cancer: A Critical Contemporary Literature Review.

Background and Objectives: The relationship between male infertility (MI) and testicular cancer (TC) is bilateral. On one hand, it is well-established that patients diagnosed with TC have a high risk of pre- and post-treatment infertility. On the other hand, the risk of developing TC in male infertile patients is not clearly defined. The objective of this review is to analyze the histopathological, etiological, and epidemiological associations between MI and the risk of developing testicular cancer. This review aims to provide further insights and offer a guide for assessing the risk factors for TC in infertile men. Materials and Methods: A comprehensive literature search was conducted to identify relevant studies discussing the relationship between MI and the risk of developing TC. Results: The incidence rates of germ cell neoplasia in situ (GCNIS) appear to be high in infertile men, particularly in those with low sperm counts. Most epidemiological studies have found a statistically significant risk of developing TC among infertile men compared to the general or fertile male populations. The concept of Testicular Dysgenesis Syndrome provides an explanatory model for the common etiology of MI, TC, cryptorchidism, and hypospadias. Clinical findings such as a history of cryptorchidism could increase the risk of developing TC in infertile men. Scrotal ultrasound evaluation for testis lesions and microlithiasis is important in infertile men. Sperm analysis parameters can be useful in assessing the risk of TC among infertile men. In the future, sperm and serum microRNAs (miRNAs) may be utilized for the non-invasive early diagnosis of TC and GCNIS in infertile men. Conclusions: MI is indeed a risk factor for developing testicular cancer, as demonstrated by various studies. All infertile men should undergo a risk assessment using clinical examination, ultrasound, and semen parameters to evaluate their risk of TC.

Workflow for Management of Gonadal Neoplasm in 2 Patients with Differences of Sex Development Enrolled in an Experimental Gonadal Tissue Cryopreservation Protocol

To outline our experimental gonadal tissue cryopreservation (GTC) protocol that does not disrupt standard of care in medically-indicated gonadectomy for patients with differences of sex development (DSD), including highlighting the multidisciplinary collaborative protocol for when neoplasm is discovered in these cases. Two patients with complete gonadal dysgenesis (CGD) who were undergoing medically-indicated prophylactic bilateral gonadectomy elected to pursue GTC. Both were found to have germ cell neoplasia in situ (GCNIS) on initial pathologic analysis, requiring recall of the gonadal tissue, which had been cryopreserved. Cryopreserved gonadal tissue was successfully thawed and transferred to pathology for complete analysis. No germ cells were identified in either patient nor were found to have malignancy, so further treatment beyond gonadectomy was not indicated. Pathologic information was communicated to each family, including that long-term GTC was no longer possible. Organizational planning and coordination between the clinical care teams, GTC laboratory and pathology were key to handling these cases with neoplasia. Processes that anticipated the possibility of discovering neoplasia within tissue sent to pathology and the potential need to recall GTC tissue to complete staging included: (1) documenting the orientation and anatomical position of tissue processed for GTC, (2) defining parameters in which tissue will be recalled, (3) efficiently thawing and transferring GTC tissue to pathology, and (4) coordinating release of pathology results with verbal communication from the clinician to provide context. GTC is desired by many families and at the time of gonadectomy and is: (1) feasible for patients with DSD and (2) did not inhibit patient care in two patients with GCNIS.

Gonadal tumors in a contemporary cohort of patients with differences in sex development undergoing surgery – A multi-site study from the Pediatric Urologic Oncology Working Group of the societies for pediatric urology

Disturbances in gonadal development lead to increased risk of gonadal malignancy in some but not all patients with differences in sex development (DSD). However, the natural history of these tumors is poorly described, and the literature remains sparse. The objective of this study was to describe the incidence of germ cell neoplasia in situ (GCNIS) and germ cell tumor (GCT) in a contemporary cohort of patients with DSD undergoing surgery and to provide long-term oncologic outcomes for these patients. Patients with DSD who have undergone gonadectomy or gonadal biopsy were identified at four institutions. Clinical characteristics, pathology, and treatment details were obtained retrospectively. Patients were stratified into risk categories based on DSD diagnosis. Oncologic treatment and outcomes were recorded. Descriptive statistics are reported using parametric methods. 83 patients were identified. Distribution of diagnoses is summarized in the summary table. 14 (16.9%) patients underwent gonadal biopsy, and 71 (85.5%) patients underwent gonadectomy (50/71 gonadectomies were bilateral). 8/83 (9.6%) patients had GCNIS or GCT (7 GCNIS, 1 GCT). Median age at surgery was 2.95 years (y) (interquartile range [IQR] 0.6-12.2) and 14y (IQR 0.85-16.9) in patients without and with GCNIS/GCT, respectively. All 8 patients with GCNIS/GCT had high or intermediate risk DSD diagnoses (4 mixed gonadal dysgenesis, 3 Turner with Y, 1 partial gonadal dysgenesis). Of the patients with high-risk diagnoses, 8/54 (15%) had GCNIS/GCT. No patient received adjuvant therapy, no patient had a recurrence, and all patients were living with mean follow up 6.4y. The risk of gonadal malignancy is heterogeneous in the DSD population and can vary based on DSD diagnosis as well as maturation, testicularization, and location of the gonads. The most recent consensus recommendations on gonadal management emphasize risk stratification and consideration of gonadal surveillance based on gender of rearing, but supporting literature remains sparse. In this contemporary cohort of DSD patients who underwent gonadal surgery, most patients did not have evidence of adverse pathology, all patients with malignant or premalignant pathology had a high/intermediate risk DSD diagnosis, and all patients with GCNIS/GCT were treated with surgery alone without recurrence. The distribution of patients with premalignant and malignant gonadal pathology and DSD in this cohort aligns with prior literature, and oncologic outcomes were excellent. These data add valuable information to the current literature and highlight the necessity to develop appropriate screening regimens for retained gonads.

MP50-12 CLINICOPATHOLOGIC ANALYSIS AND DIGITAL EVALUATION OF ORCHIECTOMY SPECIMENS IN PATIENTS WITH GENDER DYSPHORIA

You have accessJournal of UrologyCME1 Apr 2023MP50-12 CLINICOPATHOLOGIC ANALYSIS AND DIGITAL EVALUATION OF ORCHIECTOMY SPECIMENS IN PATIENTS WITH GENDER DYSPHORIA Ivan De La Riva, Ruoji Zhou, Alcino Gama, Bonnie Choy, Bogdan Isaila, Diana Bowen, Robert Brannigan, and Ximing Yang Ivan De La RivaIvan De La Riva More articles by this author , Ruoji ZhouRuoji Zhou More articles by this author , Alcino GamaAlcino Gama More articles by this author , Bonnie ChoyBonnie Choy More articles by this author , Bogdan IsailaBogdan Isaila More articles by this author , Diana BowenDiana Bowen More articles by this author , Robert BranniganRobert Brannigan More articles by this author , and Ximing YangXiming Yang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003298.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Gender-affirmation therapy for transgender individuals is an area of increasing importance in genitourinary pathology. These patients undergo various forms of hormonal replacement therapy (HRT) followed by bilateral orchiectomy. To date, there are very limited studies on the histological and biochemical alterations in these testes. METHODS: We conducted a retrospective search of the database for gender-affirming orchiectomies performed at our institution from 2018 to 2022. Clinical features, including age, length and types of hormonal treatment, and pathologic features, were reviewed and summarized. 19 cases were subjected to whole slide imaging scanning for digital analysis using the Leica system. Immunohistochemistry for OCT4 and CD117 was performed on selected cases. RESULTS: Atrophic changes and decreased spermatogenesis were found in all the gender-affirming orchiectomy specimens examined, with decreased mean tubule diameter (102.9 μm, 202 tubules examined) compared to the tubular size of germ cell neoplasia in situ (GCNIS) and normal testis (139.3 μm and 143.7 μm, 326 and 185 tubules examined, respectively). All cases showed significant maturation arrest, with 55 testes showing aspermatogenesis and the remaining 14 testes showing hypospermatogenesis. Various degrees of basement membrane thickening were observed in all testes, and 55.1% of the testes were found to have focal tubule hyalinization/obliteration. The number of Leydig cells was reduced, with marked cytoplasmic vacuolization and degenerative changes. In a subset of specimens, scattered germ cells displayed prominent nucleomegaly. Using digital analysis, the average nuclear size of these abnormal germ cells was 14.4 μm in diameter (35 cells counted), approaching or exceeding the size of the neoplastic nucleus in GCNIS (mean diameter=12.1 μm, 33 cells counted). However, the enlarged nuclei of these germ cells demonstrated a smooth nuclear membrane, small nucleoli, and fine granular and smudged chromatin, significantly different from the nuclei in GCNIS. Furthermore, immunohistochemistry staining of the germ cells with nucleomegaly in tested cases demonstrated negative staining for both OCT4 and CD117, militating again the possibility of GCNIS. CONCLUSIONS: All the testes from gender-affirming orchiectomies in our study exhibit significantly reduced spermatogenesis, including maturation arrest and atrophic changes. In addition, the presence of scattered germ cells with nucleomegaly in these specimens can mimic GCNIS. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e689 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ivan De La Riva More articles by this author Ruoji Zhou More articles by this author Alcino Gama More articles by this author Bonnie Choy More articles by this author Bogdan Isaila More articles by this author Diana Bowen More articles by this author Robert Brannigan More articles by this author Ximing Yang More articles by this author Expand All Advertisement PDF downloadLoading ...

Undetectable anti-Mullerian hormone and inhibin B do not preclude the presence of germ cell tumours in 45,X/46,XY or 46,XY gonadal dysgenesis.

Individuals with 45,X/46,XYor 46,XYgonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone(AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999-2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. Thirteen males and 16 females were included, 20 with 46,XYand 9 with 45,X/46,XY DSD. Threefemales had dysgerminoma alongside gonadoblastoma; twogonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XYor 46,XYgonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

Characterization of Apelin/APJ Axis Expression in Normal Testicular Tissue, Germ Cell Neoplasia in Situ, and Testicular Seminoma

Aim: A testicular germ cell tumour is not observed widely, but its incidence and mortality rates have increased in recent years. One of the most common forms of this tumour is seminoma. Germ cell neoplasia in situ (GCNIS) is the precursor of seminoma. The apelin/APJ axis is increased in many cancers and is a pathway that plays an active role in angiogenesis, lymphangiogenesis, tumour growth, and migration. This study investigated the cellular distributions of apelin and APJ protein expressions in normal testicular tissue (TT), GCNIS, and seminoma.Material and Methods: Tissues from 18 patients who had undergone orchiectomy were used in this study. These tissues include areas of normal TT, GCNIS, and seminoma. Immunolocalisation of apelin and APJ were identified through the immunohistochemical method.Results: Apelin expression was significantly increased in seminoma and GCNIS compared to normal. Apelin expression were the same in GCNIS and seminoma. APJ expression was significantly increased in seminoma compared to normal and GCNIS. Normal and GCNIS APJ expressions were similar.Conclusion: Expressions of apelin and APJ proteins were significantly increased in seminoma in our study. Our findings were consistent with the results of relevant studies as increased expression of apelin/APJ has been observed in many different cancers. It can be predicted that the increase of this pathway in seminoma may support angiogenesis, lymphangiogenesis, migration, and metastasis. Therefore, the increase in mortality rates in seminoma patients may be related to apelin/APJ axis. Ultimately, the use of inhibitors of this pathway in these patients may reduce their mortality rate. New studies are needed before these inhibitors can be used clinically.

Germ cell neoplasms of the testis: Update for 2022.

Germ cell neoplasia in situ (GCNIS) is the precursor of both seminomatous and non-seminomatous germ cell tumors. It consists of distended tubules that may have either intratubular seminoma or intratubular embryonal carcinoma cells. Many invasive non-seminomatous tumors contain a mixture of tumor types, which are reviewed here. Morphology, aided by a panel of immunostains, can determine the presence and percent of embryonal carcinoma, yolk sac tumor, choriocarcinoma, or teratoma in such tumors. Use of immunostains, required for diagnosis in perhaps 25% of testicular neoplasms, is reviewed. Changes of classification in the AJCC (8th edition) in 2016 are discussed, including the partitioning of two tumor types: the central role of chromosome 12p amplification allows both teratoma and yolk sac tumor to be divided into prepubertal types (lacking amplification) and post-pubertal types. Occasionally, sex cord-stromal tumors, hematolymphoid tumors, or epididymal adenomatoid tumors enter the differential diagnosis of germ cell neoplasms.

Malignant germ cell tumors in men aged 50 years and over are associated with adverse pathologic features and higher stage at presentation

BackgroundGerm cell tumors (GCT) are the most common malignancy in men in the third and fourth decades of life. The occurrence of malignant GCT in men aged 50 years or over is rare, and their histopathologic characteristics and outcome is insufficiently characterized in the medical literature. Hence, we report the histopathologic features and clinical outcome of malignant GCTs in men aged ≥50 years at our institution. DesignWe performed a retrospective search of our database from 2005 to 2021 to identify men aged 50 years or older with malignant GCT. Cases of spermatocytic tumor were excluded. Clinical and histopathologic features of the tumors were reviewed. ResultsForty-seven cases were identified, showing a sharp decline in incidence over the age of 65. Thirty-nine (83 %) tumors were testicular while eight (17 %) were non-testicular in presentation. Cases included 26 (55 %) seminomas, 15 (32 %) non-seminoma/mixed malignant GCT, and 5 (11 %) regressed testicular germ cell tumors. The most common component in mixed malignant GCTs was embryonal carcinoma (77 %), followed by seminoma and yolk sac tumor (62 % each). Germ cell neoplasia in situ (GCNIS) accompanied 57 % of the cases. Aggressive pathologic features, including lymphovascular invasion, retroperitoneal/lymph node involvement and higher stage at presentation, were identified in a significant proportion of cases (36/47, 77 %). Clinical follow up showed six patients (14 %) died of disease-related causes. ConclusionOur findings expand and corroborate the previously reported data on malignant GCT in older men. Unique characteristics include tendency for higher stage at presentation with adverse pathologic features and more aggressive clinical course.

Synchronous Bilateral Testicular Tumors with Different Histology: Case Report and Review of Literature

Abstract Introduction/Objective Germ cell tumor (GCT) is the most common cancer among males in the 20–39 year-old age range, representing 21% of invasive cancer diagnoses. Majority of bilateral testicular tumors are metachronous. The synchronous tumors comprise approximately 0.5%-1% of all cases. Most of the synchronous tumors share the same histologic pattern, predominantly seminoma. The synchronous bilateral testicular GCTs (SBTGCTs) with discordant subtypes are extremely rare. Methods/Case Report A 26-year-old male presented with left testicular pain, the ultrasound revealed bilateral testicular masses with calcifications and microlithiasis in the right side. His serum markers showed elevated alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG). Lactate dehydrogenase (LDH) was normal. He underwent bilateral orchiectomy. The pathology report showed a non-seminomatous mixed germ cell tumor, 2.0 cm in greatest dimension, predominantly embryonal carcinoma (90%), with a minor yolk sac tumor component (10%), lymphovascular invasion, Germ-cell neoplasia in situ (GCNIS) and calcifications in the left testicle, and a seminoma, 0.3 cm in greatest dimension with GCNIS and calcifications in the right testicle. The pathologic staging was pT2pNX for the left testicle and pT1pNX for the right testicle. Computed tomography (CT) revealed two mildly enlarged left sided para-aortic retroperitoneal lymph nodes. Radical pelvic lymph node dissection was performed. The pathology report showed four para-aortic lymph nodes positive for metastatic carcinoma. Tumor was positive for CD30 in the embryonal component, positive for Glypican-3 in the yolk sac tumor component, and seminoma was positive for PLAP. The final staging was IIB for the left testicle and IA for the right testicle. He underwent 4 cycles of Etoposide and Cisplatin chemotherapy (EP). He is in complete remission after 10 months of his diagnosis. Results (if a Case Study enter NA) NA. Conclusion The SBTGCTs with discordant subtypes represent a rare entity with no standard therapy. Our patient was treated with 4 cycles of chemotherapy and achieved complete remission.

Expression of Intermediate Filaments in the Developing Testis and Testicular Germ Cell Cancer.

Cytokeratin and desmin expression have been associated with Sertoli cell maturity and the development of testicular germ cell cancer (TGCC). Thus, the present study aimed to characterize the expression of these intermediate filaments in normal testis development and TGCC. Cytokeratin and desmin were determined by immunohistochemistry and immunofluorescence in human fetal, and adult testis and tissue from patients with pre-invasive germ cell neoplasia in-situ (GCNIS) or invasive TGCC. Desmin was expressed in Sertoli cells of the human fetal testis, and the proportion of desmin expressing Sertoli cells was significantly reduced in the second trimester, compared with the first trimester (31.14% vs. 6.74%, p = 0.0016). Additionally, Desmin was expressed in the majority of Sertoli cells in the adult testis and TGCC samples. Cytokeratin was detected in Sertoli cells of human fetal testis but was not expressed in Sertoli cells of human adult testis. In patients with TGCC, cytokeratin was not expressed in Sertoli cells in tubules with active spermatogenesis but was detected in Sertoli cells in tubules containing GCNIS cells in patients with both pre-invasive and invasive TGCC. In conclusion, desmin was not associated with Sertoli cell maturation or progression to TGCC. However, cytokeratin appeared to be an indicator of impaired Sertoli cell maturation.

OR05-1 Testicular Magnetic Resonance Imaging (MRI) Findings and Predictive Factors of Gonadal Neoplasia in Complete Androgen Insensitivity Syndrome

Abstract Introduction Complete Androgen Insensitivity Syndrome (CAIS) is characterized by a complete external genitalia appearance and testicular development in 46,XY individuals carrying inactivating mutations in the AR gene. Prophylactic gonadectomy versus saving gonads has been debatable in CAIS management, mainly due to the absence of an accurate biomarker for testicular germ cell tumors (GCT). Objective to cross the preoperative pelvic MRI data with the histological gonadal findings from CAIS patients who underwent prophylactic gonadectomy to identify predictive factors of GCT development. Methods We evaluated 30 gonads from 15 CAIS patients with proven AR mutation. All performed pelvic MRI before gonadectomy through the same MRI machine and were included in the MRI data analysis. Three blinded radiologists specialized in urology performed image analysis. The immunohistochemical markers PLAP, c-KIT, OCT3/4, SALL4, ER, alpha-inhibin, CD99, and calretinin were performed. Results Nine (60%) performed gonadectomy after puberty (&amp;gt;16 years old). We identified one case of classical seminoma and one case of Sertoli cell neoplasia (at 18 and 19 years of age, respectively). Overall, the prevalence of neoplasia was 13.3%. No case of premalignant intratubular germ cell neoplasia was detected.Histological data revealed a high prevalence of benign lesions (n=12; 80%). Leydig Cell Hyperplasia (67%), stromal fibrosis (53%), Sertoli Cell nodules (47%), hamartomatoums nodules (40%) and paratesticular cysts (67%) which are more frequent after puberty (p&amp;lt;.01). MRI detected heterogeneity in all cases harboring hamartomatoums nodules, Sertoli cell nodules, and testicular neoplasia. Benign lesions were bilateral in all cases. Regarding the MRI data, the presence of testicular cystic mass (by tumoral necrosis) on MRI and tumor size (higher among malignancies) correlated with malignancy (p=.008 and p=.03, respectively), whereas gonadal location (inguinal/abdominal), presence of solid nodules, T2WI and postcontrast features, nodule diffusion restriction, and presence of perigonadal cysts did not. Chronological age &amp;gt;16 years was associated with malignancy with a 4.3 OR (1.6–11.69). Conclusion Pelvic MRI is sensitive to detect gonadal nodules in CAIS patients, regardless of the gonad position, but most nodules are benign. Testicular malignancy should be suspicious in the presence of testicular cystic mass and large testis size in CAIS patients &amp;gt;16 years old. Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.

The seminal plasma microbiome of men with testicular germ cell tumours described by small RNA sequencing.

It has been estimated that microorganisms are involved in the pathogenesis of approximately 20% of all cancers. Testicular germ cell tumours (TGCTs) are the most common type of malignancy in young men and arise from the precursor cell, germ cell neoplasia in situ (GCNIS). The microbiome of seminal plasma and testicular tissue has not been thoroughly investigated in regard to TGCTs. To investigate the differences in the seminal plasma microbiome between men with TGCT or GCNIS-only compared with controls. The study population consisted of patients with GCNIS-only (n=5), TGCT (n=18), and controls (n=25) with different levels of sperm counts in the ejaculate. RNA was isolated from the seminal plasma and sequenced. Reads not mapping to the human genome were aligned against a set of 2784 bacterial/archaeal and 4336 viral genomes using the Kraken pipeline. We identified reads from 2172 species and most counts were from Alteromonas mediterranea, Falconid herpesvirus 1, and Stigmatella aurantiaca. Six species (Acaryochloris marina, Halovirus HGTV-1, Thermaerobacter marianensis, Thioalkalivibrio sp. K90mix, Burkholderia sp. YI23, and Desulfurivibrio alkaliphilus) were found in significantly (q-value<0.05) higher levels in the seminal plasma of TGCT and GCNIS-only patients compared with controls. In contrast, Streptomyces phage VWB was found at significantly higher levels among controls compared with TGCT and GCNIS-only patients combined. Often the microbiome is analysed by shotgun or 16S ribosomal sequencing whereas our present data build on small RNA sequencing. This allowed us to identify more viruses and phages compared with previous studies but also makes the results difficult to directly compare. Our study is the first to report identification of the microbiome species in seminal plasma of men with TGCT and GCNIS-only, which potentially could be involved in the pathogenesis of TGCTs. Further studies are, however, needed to confirm our findings.

Cryptorchidism: The dog as a study model.

Cryptorchidism (CO) or undescended testicle is an abnormality of male gonadal development that can generate long-term repercussions in men, such as infertility and germ cell neoplasia in situ (GCNIS). The origin of these alterations in humans is not completely clear, due to the absence of an animal model with similar testicular development as in humans with CO. This work intends to describe the testicular histological development of dogs with congenital CO, and determine whether the species could adequately serve as a study model for this pathology in humans. The study was carried out with 36 dogs, equally distributed in two groups: healthy control (CTRL) and CO groups. The contralateral testis to the undescended one in CO group of the animals was considered and analyzed. Each group was subdivided in three stages of development: (1) peripubertal stage (6–8 months), (2) young adult (9–48 months) and (3) senile (49–130 months). Histological development, the presence of cells with gonocyte morphology, cell proliferation, testicular lipoperoxidation and hormonal concentrations of testosterone, estradiol, FSH and LH were evaluated and described. In the cryptorchid testes, the first histological alterations appeared from the first stage of development and were maintained until the senile stage. A pronounced testicular lipoperoxidation occurred only in the second stage of development. The histological alterations due to CO were markedly evident in the young adult stage. Testosterone concentrations witnessed a decrease starting from in the second stage and kept on until the last stage. The contralateral testes of the CO animals showed alterations that positioned them between the control and CO testes. Testicular development of dogs with CO is similar to that of humans. The results of the study suggest that this species could serve as a suitable model for the study of CO in humans.