On the origin of germ cell neoplasia in situ: Dedifferentiation of human adult Sertoli cells in cross talk with seminoma cells in vitro.

Germ cell neoplasia in situ (GCNIS) is the noninvasive precursor of testicular germ cell tumors type II, the most common cancer in young men, which originates from embryonic germ cells blocked in their maturation. GCNIS is associated with impaired Sertoli cells (SCs) that express fetal keratin 18 (KRT18) and the pluripotency factor SRY-Box transcription factor 2 (SOX2). According to the current theory concerning the origin of GCNIS, these SCs are prepubertal cells arrested in their maturation due to (epi)genetic anomalies and/or environmental antiandrogens. Thus, they are unable to support the development of germ cells, which leads to their maturational block and further progresses into GCNIS. Alternatively, these SCs are hypothesized to be adult cells dedifferentiating secondarily under the influence of GCNIS. To examine whether tumor cells can dedifferentiate SCs, we established a coculture model of adult human SCs (FS1) and a seminoma cell line similar to GCNIS (TCam-2). After 2 wk of coculture, FS1 cells showed progressive expression of KRT18 and SOX2, mimicking the in vivo changes. TCam-2 cells showed SOX2 expression and upregulation of further pluripotency- and reprogramming-associated genes, suggesting a seminoma to embryonal carcinoma transition. Thus, our FS1/TCam-2 coculture model is a valuable tool for investigating interactions between SCs and seminoma cells. Our immunohistochemical and ultrastructural studies of human testicular biopsies with varying degrees of GCNIS compared to biopsies from fetuses, patients with androgen insensitivity syndrome, and patients showing normal spermatogenesis further suggest that GCNIS-associated SCs represent adult cells undergoing progressive dedifferentiation.

Diagnostic value of multislice spiral computed tomography (CT) combined with CT angiography for intra-abdominal undescended testis secondary seminomas.

OBJECTIVE: To discuss the diagnostic value of multislice spiral tomography (CT) combined with CT angiography (CTA) technology in intra-abdominal undescended testis secondary seminoma cases. METHODS: We retrospectively analyzed the CT and CTA imaging features of CT and CTA findings of nine patients with an intra-abdominal undescended testis secondary seminoma. RESULTS: The tumors in all nine patients were mainly solid, and the average CT value was 38.4 ± 3.4 HU. Low-density areas of various sizes were visible in the tumors, and calcifications were detected in two patients. The tumors in eight patients had a complete capsule, which pressed on the surrounding structures. In one patient, the tumor had an incomplete capsule, which invaded the surrounding structures. Some of the solid tumors showed progressive and slight enhancement on the CT-enhanced scans. The values in the arterial phase, venous phase, and delayed phase were 46.3 ± 5.1 (40-55 HU), 57.3 ± 7.3HU (48-68 HU), and 65.1 ± 7.2HU (56-77 HU), respectively, with an average increase rate of 27.0 ± 7.2 HU. No enhancement was found in low-density areas on the CTA scans, and the supply arteries of the tumors in the nine patients all originated from the abdominal aortic wall 2-3 cm below the renal ostia. These arteries became thickened and tortuous when near the tumors, and there were no branching vessels. In eight patients, the supply arteries of the tumors originated from the posterior tumor and ended inside the tumor, and they originated from anterior of the tumor in one patient. Testicular venous drainage was detected in three patients, and lymph node metastasis in the abdominal aorta detected in two cases. CONCLUSION: An intra-abdominal undescended testis secondary seminoma exhibits a characteristic appearance on CT. CTA shows a three-dimensional testicular vascular pedicle sign of a seminoma. A combination of CT and CTA can improve the diagnostic accuracy of an intra-abdominal undescended testis secondary seminoma.

[A woman with a pure seminoma and a contralateral intratubular germinal neoplasm. A case report]. / Mujer con seminoma puro y neoplasia intratubular germinal contralateral. Informe de un caso.

BACKGROUND: Androgen insensitivity syndrome is an X-linked disorder, and is characterised by a female phenotype in a chromosomally male individual. It usually occurs in puberty with primary amenorrhoea or as an inguinal tumour in a female infant. In recent years, it is often also diagnosed in fertility clinics in adulthood. OBJECTIVE: The case is presented of a pure seminoma in a woman with the reference diagnosis of inguinal hernia. CLINICAL CASE: A 53 year old woman, who was operated on in 2014 due to a nodule in left groin. Androgen insensitivity syndrome was corroborated, and histopathology reported it as a right testicular seminoma. DISCUSSION: The importance of early diagnosis is discussed, highlighting the consequences of misdiagnosis, and question whether these patients have been adequately treated in the past. The risk of malignant transformation of an undescended testicle increases with age, thus gonadectomy should be performed after puberty, and in some cases hormone replacement therapy.

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma.

Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM-a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting self-renewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382-95. ©2016 AACR.

Intraoperative injection of (99mm)Tc- nanocolloid for localization of nonpalpable intratesticular tumours in organ-sparing surgery.

OBJECTIVE: Radical orchidectomy is the standard treatment for malignant testis tumours. Radical orchidectomy results in androgen deprivation, infertility and impaired psychological well-being, especially in synchronous bilateral tumours, metachronous contralateral tumours or tumour in a solitary testis. According to the European Association of Urology Guidelines, if pre-operative testosterone level is normal and the tumour volume is less than 30% of the testicular volume, organ preserving surgery can be performed. For nonpalpable tumours, organ-sparing surgery needs a precise intraoperative localization with high-frequency ultrasound, especially for nonpalpable tumours. MATHERIAL AND METHODS: We report two cases of nonpalpable intratesticular tumours successfully localised using (99mm)Tc nanocolloid injected with intraoperative US and detected with a γ-ray detection probe. CONCLUSIONS: This method is easily reproducible and safe for the patient. This technique could guarantee complete excision of the tumour, especially if the mass is poorly delimited.

[Testicular tumor with opposite inguinal lymph node metastasis in a patient with prior orchiopexy for undescended testis].

The patient was a 54-year-old man. At age 6 years, he had undergone orchiopexy for left undescended testis. Six months prior to the current presentation, he visited our hospital with a chief complaint of painless enlargement of the left testis. Left high orchiectomy was performed under a diagnosis of left testicular tumor. Histopathological examination determined the tumor to be a seminoma (pT2). Postoperatively, the patient was placed on surveillance without preventive radiation treatment. He visited our hospital six months after surgery due to a painless mass in the right inguinal region. All tumor markers (AFP, HCG-ß, and LDH) were within normal ranges. However, based on ultrasound and CT scan findings, lymph node metastasis was suspected and a right inguinal lymph node excision was thus performed. Histopathological examination led to the diagnosis of seminoma.

Obscure etiology, unusual disparity: the epidemiology of testicular cancer in New Zealand.

PURPOSE: Testicular cancer (TC) remains perplexing, both in terms of what causes the disease and why certain populations are at greater risk of developing it. In New Zealand, an unusual ethnic disparity exists, whereby the indigenous Maori population suffer the highest rates of disease. In this study, we further describe the epidemiology of TC in the New Zealand context. METHODS: Eligible patients diagnosed with TC between 2000 and 2011 (n = 1,800) were determined from the NZ Cancer Registry and linked to mortality data. Census data were used to estimate population incidence of TC and tumor sub-type by ethnic group. Kaplan-Meier and Cox regression analyses were used to compare survival between ethnic groups. RESULTS: Maori males aged 15-44 were 80% more likely to be diagnosed with TC compared to European/Other males [age-standardized relative risk (RR) 1.80, 95% CI 1.58-2.05]. By contrast, disease burden was comparatively low among Pacific and Asian populations. Maori had a greater incidence of both seminoma (RR 1.88, 95% CI 1.52-2.22) and non-seminoma (RR 1.67, 95% CI 1.35-2.07) germ cell tumors than the European/Other population, reducing the likelihood that our observed disparity is driven by differential propensity to one given sub-type among Maori. Maori had poorer survival outcomes [cancer-specific adjusted hazard ratio (HR) 2.29, 95% CI 1.14-4.59] than the European/Other population. CONCLUSIONS: Understanding the drivers of New Zealand's unusual incidence disparities--particularly between Maori and Pacific--could further our understanding of the key exposures involved in TC etiology.

Supernumerary nipple and seminoma: case report and review of polythelia and genitourinary cancers.

The presence of supernumerary nipples, known as polythelia, is the most common presentation of accessory breast tissue. It is usually considered to be a benign congenital anomaly. However, polythelia may warrant attention for more than mere cosmetic concern because supernumerary nipples have been shown to be associated with an increased risk of genitourinary malignancies. We describe a 53-year-old man with an accessory nipple on the left chest who presented with stage IIA testicular seminoma at the age of 47. Published reports of patients with polythelia and genitourinary malignancies, as well as other neoplasms, are reviewed. Because patients with accessory nipples have a predisposition to develop visceral cancers, polythelia should be considered as a genodermatosis with malignant potential.

Lack of evidence for an association between seminoma and human papillomavirus infection using GP5+/GP6+ consensus primers.

Testicular germ cell tumors account for about 1% of all cancers. The incidence of these tumors is increasing and they represent the most common solid malignancies of young men aged 15-40 years with seminoma being one of the most common histotype. Pathogenesis of testicular germ cell tumors remains unknown and, although cryptorchidism is considered the main risk factor, there is evidence of an association with environmental and genetic risk factors. Human papillomaviruses (HPV) are a family of DNA viruses and represent a major risk factor for cervical cancer. In addition, they have been associated with other human non-malignant and malignant diseases, including breast and head and neck cancer. HPV sequences have been detected throughout the male lower genitourinary tract as well as in seminal fluid and an increased testicular tumorigenesis has been reported in HPV transgenic mice. Aim of this study was to evaluate the potential involvement of HPV in human testicular tumorigenesis. Real-time PCR employing GP5+/GP6+ consensus HPV primers was used to examine the presence of HPV sequences in a subset of human seminoma (n = 61) and normal testicles (n = 23). None of the specimens tested displayed the presence of HPV DNA. These findings do not support an association between HPV and human seminoma and warrant further studies to assess definitively the role of these viruses in human testicular tumorigenesis.

Ionizing radiation in patients with Crohn´s disease. Estimation and associated factors.

INTRODUCTION: exposure to ionizing radiation is associated with an increased risk of developing tumors. Patients with Crohn's disease (CD) usually require multiple imaging tests using this type of radiation. OBJECTIVES: the objectives of this study were to estimate the total dose of ionizing radiation received by patients with Crohn's disease during their course and to identify the factors associated with higher radiation doses. METHODS: two hundred thirty-five CD patients diagnosed between 1972 and 2010 were included. The effective dose (ED) received by each patient was calculated retrospectively based on the number of gastrointestinal transit studies and computed tomography scans performed. Considering recent epidemiological studies, an ED greater than or equal to 50 mSv was used as the cut-off point for increased risk of developing cancer. RESULTS: the mean ED received per patient was 33.4 mSv (95% CI 29.3-37.5). A total of 49 (20.8%) patients received an ED ≥ 50 mSv. The following factors were identified as independent predictors associated with an ED ≥ 50 mSv: Age older than 40 years, need for surgery, age under 16 years at diagnosis and disease duration over 8 years. CONCLUSIONS: a substantial proportion of patients with Crohn's disease receive high doses of potentially carcinogenic ionizing radiation. Identification of the most susceptible patients to receive high doses of radiation, monitoring of effective doses received and the use of imaging techniques that do not require ionizing radiation (MR enterography, abdominal ultrasound) could contribute in reducing patients' exposure to potentially carcinogenic ionizing radiation.

Significant calendar period deviations in testicular germ cell tumors indicate that postnatal exposures are etiologically relevant.

PURPOSE: The current working model of type II testicular germ cell tumor (TGCT) pathogenesis states that carcinoma in situ arises during embryogenesis, is a necessary precursor, and always progresses to cancer. An implicit condition of this model is that only in utero exposures affect the development of TGCT in later life. In an age-period-cohort analysis, this working model contends an absence of calendar period deviations. We tested this contention using data from the SEER registries of the United States. METHODS: We assessed age-period-cohort models of TGCTs, seminomas, and nonseminomas for the period 1973-2008. Analyses were restricted to whites diagnosed at ages 15-74 years. We tested whether calendar period deviations were significant in TGCT incidence trends adjusted for age deviations and cohort effects. RESULTS: This analysis included 32,250 TGCTs (18,475 seminomas and 13,775 nonseminomas). Seminoma incidence trends have increased with an average annual percentage change in log-linear rates (net drift) of 1.25 %, relative to just 0.14 % for nonseminoma. In more recent time periods, TGCT incidence trends have plateaued and then undergone a slight decrease. Calendar period deviations were highly statistically significant in models of TGCT (p = 1.24(-9)) and seminoma (p = 3.99(-14)), after adjustment for age deviations and cohort effects; results for nonseminoma (p = 0.02) indicated that the effects of calendar period were much more muted. CONCLUSION: Calendar period deviations play a significant role in incidence trends of TGCT, which indicates that postnatal exposures are etiologically relevant.

Rare cases of disorders of sex development (DSD) in adolescents with female phenotype.

BACKGROUND: Disorders of sex development (DSD) belong to uncommon pathologies; in addition, there are especially rare forms, such are ovotesticular disorders (OT), Turner syndrome and early malignisation of intraabdominal located gonads in the cases of androgen insensitivity syndrome. OBJECTIVE: In this article we present four rare cases of DSD in female phenotype adolescents: two cases of ovotesticular DSD with 46,XX and 46,XY karyotypes; one familial case of androgen insensitivity syndrome (AIS) with early malignancy (19-year-old) of intra-abdominally-located testicle in older siblings, and a case of spontaneous menstruation in a patient with Turner syndrome and mosaic karyotype 45,X/47,XXX. Rare cases of DSD are connected with diagnostic and management difficulties and so description of each such case and collection of data in this field is very important from a scientific, as well as a practical, point of view. Determination of prognosis and adequate management of each individual patient are also essential. Study of this issue is especially sensitive in the case of adolescent patients in order to avoid physiological stress, to reduce health risks and to improve quality of life.

Mediastinal seminoma occurring in Down syndrome.

The increased incidence of testicular tumor occurrence, especially seminoma, in Down syndrome has been well documented. However, primary mediastinal seminoma occurring in Down syndrome has not been reported. Incidental discovery of an anterior mediastinal tumor was made in a 28-year-old Japanese man with Down syndrome, who had been scheduled for bone marrow transplantation to treat aplastic anemia. Histopathological findings of the resected tumor were typical of seminoma. This case indicates that seminoma can occur in the mediastinum in addition to testis in Down syndrome.

Spermatocytic seminoma: toward further understanding of pathogenesis.

Human germ cell tumours comprise a heterogeneous group of neoplasms which, based on pathobiological, genetic and clinical characteristics, can be subdivided into different entities. One of these subgroups relates to the so-called spermatocytic seminomas, benign tumours only found in the testis, preferentially in elderly men. Various developmental models for this type of germ cell tumour have been proposed and it is clear that spermatocytic seminoma has a pathogenesis independent from that of seminoma. A recent study examining expression of spermatogonial markers shows that spermatocytic seminomas are a heterogeneous group of tumours, with a supposed difference in origin, ie the majority from A(pale) or B spermatogonia, and a minority from A(dark) spermatogonia. However, this does not exclude an earlier cell of origin, possibly explaining the unique properties of this type of human germ cell tumour, with various counterparts in animals.

Etiologic differences between seminoma and nonseminoma of the testis: a systematic review of epidemiologic studies.

Descriptive epidemiologic features of testicular cancer suggest that the etiologies of seminoma and nonseminoma of the testis differ. To address this, the authors conducted a systematic review of 150 case-control and cohort studies of the etiology of testicular cancer including 1,148 relative risk estimates, stratified by histologic subgroup, reflecting 631 exposures. Their results do not support the hypothesis that seminoma and nonseminoma have different etiologies among adolescents and young men. To date, only descriptive epidemiologic features, including incidence age patterns and incidence time trends of seminoma and nonseminoma, provide evidence suggesting different etiologies, especially among newborns, infants, and elderly men.

Gonadal dysgenesis and gynecologic cancer.

BACKGROUND: Gonadal dysgenesis encompasses a variety of sexual differentiation disorders. Within this population of patients, there is an increased risk of gonadal tumor formation. CASES: In this case series of three patients, two with Swyer's syndrome (complete gonadal dysgenesis) and one with mosaic Turner's syndrome, three separate histologic subtypes of tumors were identified: dysgerminoma, seminoma, and gonadoblastoma. The patients with dysgerminoma and seminoma had regular menses and were without recurrent disease. We recommend that the patient with gonadoblastoma start on hormone therapy. CONCLUSION: Once the diagnosis of gonadal dysgenesis is made, prophylactic gonadectomy should be performed owing to the probability of malignant transformation. These patients illustrate the potential different presentations with gonadal dysgenesis and the importance of complete evaluation of patients with primary amenorrhea.