CXCL12 expression is an adverse predictor for disease recurrence in patients with metastatic non-seminomatous testicular germ cell tumors.

BACKGROUND: To validate the utility of the chemokine ligand 12 (CXCL12) as prognostic marker in patients with localized and metastatic germ cell tumors (GCT). METHODS: CXCL12 expression was analyzed on a tissue microarray consisting of 750 tissue cores of different histological tumor components, Germ cell neoplasia in situ (GCNIS) and adjacent normal tissue of 263 testicular cancer patients using a semi-quantitative score. The association between CXCL12 expression and recurrence-free survival (RFS) as well as overall survival (OS) was assessed using Kaplan-Meier curves with log-rank tests. RESULTS: CXCL12 expression was absent in all seminomas but was found in 52 of 99 (52.5%) non-seminomas. Follow-up was available for 260 patients of which 36 (13.8%) recurred. In patients with stage 1 non-seminoma GCT, CXCL12 expression was not associated with higher risk of disease recurrence (p = 0.270). In contrast, post chemotherapy RFS of patients with metastatic non-seminoma and positive CXCL12 expression was significantly shorter compared to CXCL12 negative patients (p = 0.003). OS differences were not statistically different between patients with CXCL12 positive or negative tumors for either localized or metastatic disease. CONCLUSIONS: CXCL12 is almost exclusively expressed in non-seminoma. Pure seminoma, GCNIS and adjacent normal testicular tissue are CXCL12 negative. Our analysis suggests that patients with metastatic disease and a CXCL12-positive non-seminoma are at higher risk for disease recurrence after first-line chemotherapy and might thus be candidates for more intensive treatment and/or closer follow-up.

What Is the Significance of Rete Testis Invasion by Malign Germ Cell Tumor and Does Hilum Predict Metastasis?

BACKGROUND: The significance of hilar soft tissue invasion of rete testis in malign germ cell tumors is still controversial on current guidelines. OBJECTIVES: We aimed to investigate the importance of hilar soft tissue involvement in germ cell tumors and evaluated the possibility of a risk factor such as rete testis. METHOD: Totally, 59 radical orchiectomy specimens operated between 2007 and 2015 at our clinics. All records were retrospectively researched. Patients' age, level of tumor markers, tumor size, histological subtype, clinical stage, presence or absence of carcinoma in situ, vascular/lymphatic and/or hilar soft tissue invasion, tumoral necrosis, number, site and diameter of metastasis, type of further treatment (radiotherapy or chemotheraphy) and follow-up period were recorded and evaluated for all patients. RESULTS: Twenty-six of totally 59 malign germ cell tumors were seminomatous and 33 were nonseminomatous (NS). Mean patients age was 38.54 years (range 17-89 years). Mean follow-up duration was 39.84 months (range 3-96). Serum tumor marker levels were found associated with rete testis invasion (p = 0.035). Hilar soft tissue invasion was significantly associated with vascular invasion (p = 0.001). As it was expected, vascular invasion was significantly associated with metastasis (p = 0.024). CONCLUSIONS: We concluded that there is a strong association between hilar soft tissue invasion and vascular invasion. Especially in NS germ cell tumors, hilar soft tissue involvement a risk factor for prognosis and to determine the need for additional treatment. According to our study, hilar soft tissue status should be reported on routine pathology report.

Bilateral Testicular Germ Cell Tumors in the Era of Multimodal Therapy.

OBJECTIVE: To characterize the incidence, presentation, management, and relapse of a large population of bilateral testicular germ cell tumors (TGCT) from a single institution. PATIENTS AND METHODS: We identified bilateral TGCT diagnosed between January 1989 and February 2014. We categorized synchronous and metachronous TGCT, noting time between first and second TGCT, histology (seminoma vs nonseminoma [NSGCT]), stage, and treatments. Kaplan-Meier survival estimates characterized relapse. RESULTS: Of 5132 patients with TGCT, 128 (2.5%) had bilateral TGCT. Bilateral TGCT increased over time-1.7% in 1989-1994 up to 3.8% in 2010 to February 2014. The 35 (27%) synchronous cases of TGCT had 20 (57%) concordant seminoma, 5 (14%) concordant NSGCT, and 10 (29%) discordant NSGCT. The 93 (73%) metachronous cases had median time interval to second TGCT of 73 months (range: 5 months-28.6 years). Compared with first TGCT, 39 (42%) had discordant histology, 29 (31%) had concordant seminoma, and 25 (27%) had concordant NSGCT. Stage at first tumor was statistically similar to second TGCT (second stage I, II, II in 69%, 22%, 10%). Increasing duration between first and second TGCT was not associated with higher stage (II or III) at second TGCT (P = .09). Treatment at first tumor was not associated with stage at second tumor. Relapse following bilateral diagnosis was 16.8% (95% confidence interval 10.5%-26.2%) at 5 years. CONCLUSION: Incidence of bilateral TGCT increased with >25% of metachronous TGCT presenting ≥10 years after first TGCT; possible causes include increased survivorship and referral bias. Stage was statistically similar at first and second tumor; stage at second tumor was not associated with time interval between tumors or prior treatment modality at first tumor.

Management of Low-Stage Testicular Seminoma.

Management of testicular seminoma has benefited from numerous advances in imaging, radiotherapy, and chemotherapy over the last 50 years leading to nearly 100% disease-specific survival for low-stage seminoma. This article examines the evaluation and management of low-stage testicular seminoma, which includes clinical stage I and IIA disease. Excellent outcomes for stage I seminoma are achieved with active surveillance, adjuvant radiotherapy, and adjuvant single-agent carboplatin. Current areas of research focus on optimizing surveillance regimens and minimizing the morbidity and long-term complications of adjuvant treatment. Radiotherapy continues to be the primary treatment option for patients with clinical stage IIa disease.

Caval Seminoma Thrombus on FDG PET/CT / Trombo tumoral en cava detectado con FDG PET/TAC en un caso de seminoma

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Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.

BACKGROUND: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. METHODS: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. RESULTS: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. CONCLUSIONS: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.

Testicular seminoma in a 75-year-old patient.

Testicular cancer is an uncommon cancer and of the estimated 7,920 new cases diagnosed in 2013, 370 will result in death. It is most common in young or middle-aged males and rarely occurs in older males. Ninety-five percent of these cancers originate in sperm-producing germ cells. There are two different subclasses of testicular cancer, namely nonseminoma and seminoma. Nonseminoma testicular cancers, such as embryonal carcinomas, yolk sac carcinomas, choriocarcinomas, and teratomas usually affect younger-aged males, whereas seminoma testicular cancers often occur in older males. It is unclear why testicular cancer is rare in older men, but because it is so unusual in older men, the diagnosis is frequently overlooked when presenting with signs suggestive of testicular carcinoma. A 75-year-old male recently presented with signs and symptoms classically descriptive of testicular cancer. The patient was treated with an orchiectomy. The pathologic evaluation of the excised testicle confirmed the diagnosis of a seminoma. This report is an account of the case from initial visit to treatment and a discussion of its relevance.

Seminoma tímico mediastínico caracterizado mediante resonancia magnética cardiaca / Characterization of a mediastinal thymic seminoma using cardiac magnetic resonance

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Mediastinal extragonadal seminoma presenting as severe back pain in a young male.

Back pain is a common complaint in the outpatient setting. The etiology is most often benign but it can be a serious, even life-threatening problem. This report describes a 33-year-old Caucasian male who presented with severe upper back pain for three weeks that did not respond to symptomatic outpatient treatment. Imaging studies revealed a mediastinal mass and lymphadenopathy with superior vena cava and tracheal compression. Pathology showed a poorly-differentiated malignant neoplasm consistent with seminoma. No evidence of primary testicular tumor was found. His atypical presentation of back pain was thus consistent with an extragonadal seminoma in the mediastinum.

Changes of stage, predictive factors and adjuvant treatment modalities in seminomatous testicular cancer from 1987 to 2007 and their impact on the status of metastasis, recurrence-free and overall survival: a single-center analysis.

INTRODUCTION: To observe the changing presentation of seminomatous testicular cancer (STC), placing particular emphasis on predictive factors with a view to evaluating their impact on the status of metastasis, recurrence-free survival (RFS) and overall survival (OAS). MATERIALS AND METHODS: 180 patients with STC were evaluated retrospectively. Four study periods were generated and compared for changes. The data were analyzed for predictive factors for metastasis. Mean follow-up was 83 months (range 10-246, patients alive = 146). RESULTS: The number of STC patients increased constantly throughout 2007. From 1992 onwards, significantly more patients were diagnosed as being in CS1 (p = 0.001). The odds ratio (OR) of metastasis was significantly higher for pT3 than pT2 STC (OR 12.4 vs. 1.7; p = 0.003); pT1 tumors showed a lower risk factor. The 10- and 15-year RFS were 91 and 85%, respectively. Patients in clinical stages higher than CS1 (CS>1) had significantly reduced RFS (p < 0.001). The 5- and 10-year OAS were 97 and 96%, respectively. Patients in CS>1 had significantly reduced OAS rates (p = 0.013). CONCLUSIONS: The number of STC cases is increasing, particularly in the case of patients in CS1. This emphasizes the need for surveillance regimens and makes the evaluation of predictive factors for metastasis, recurrence and survival essential.

Pure seminoma in the setting of androgen insensitivity syndrome treated with surgical resection and para-aortic radiation: a case report and review of literature.

Complete androgen insensitivity is a rare X-linked disorder characterized by a female phenotype in a chromosomally male individual. Malignant transformation of the un-descended testis is a rare phenomena compared to other inter-sex syndromes. This is a case of a 32-year-old female who was diagnosed with androgen insensitivity and presented to the emergency room with pelvic pain. Later the pelvic pain was found to be due to testicular masses, one of which was pure seminoma. We reviewed the literature emphasizing the biochemical and endocrinologic abnormalities leading to the syndrome, as well as the potential for malignant changes of the un-descended testes, diagnosis, and therapeutic management. We discuss the importance of early diagnosis and the consequence associated with misdiagnosis.

Individual and seminal characteristics of patients with testicular germ cell tumors.

OBJECTIVE: To analyze the characteristics of patients with testicular germ cell cancer and compare patients' sperm quality according to histologic type (seminomatous and nonseminomatous tumors). DESIGN: Prospective study. SETTING: Sperm bank at a university. PATIENT(S): One hundred consecutive patients with testicular tumor who had been referred to our infertility center for cryopreservation, between 2004 and 2006. INTERVENTION(S): A questionnaire, through personal interview, was given to all patients and collection of seminal data before cryopreservation was performed. MAIN OUTCOME MEASURE(S): Patient characteristics, including age, time between diagnosis and orchiectomy, history of cryptorchidism, histologic type, and seminal analysis were taken into consideration. RESULT(S): The mean age of the patients at the time of diagnosis was 26.9 years. The mean time between cancer suspicion and the diagnosis of neoplasm was 58.9 days, and 19.4 more days were necessary until orchiectomy was performed. Eleven patients had a history of cryptorchidism. Thirty-seven patients had seminomatous tumors. Men with a seminoma present a higher number of motile and morphologically normal sperm in the ejaculate than men with a nonseminoma, although individual semen variables are not different. CONCLUSION(S): The majority of the patients with testicular cancer, referred to our infertility center, are very young, single, do not have children, and are unaware of their fertility potential status by the time diagnosis is made. Men with a nonseminoma present semen of lower quality.

Seminoma in a southern black rhinoceros (Diceros bicornis minor): diagnosis, surgical management and effect on fertility.

A testicular mass was identified by ultrasonography performed during a routine reproductive evaluation of an adult male southern black rhinoceros (Diceros bicornis minor). Histological examination of a testicular biopsy supported a presumptive diagnosis of testicular neoplasia. Hemi-castration was performed to excise the affected testis and a pathological diagnosis of a seminoma was made. Assessment of semen suggested reduced fertility as a consequence of the neoplastic process, but hemi-castration prevented further growth and metastasis of the tumour and ensured the animal's breeding potential. This is the second documented case of a seminoma in a rhinoceros species and the first case in a black rhinoceros.

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas.

Activin is a pleiotropic growth factor belonging to the transforming growth factor-beta (TGFB) superfamily of signaling molecules. Regulated activin signaling is known to influence several steps in rodent male gamete differentiation. TGFB ligand isoforms, TGFB1-B3, also influence germ cell survival in the rodent testis at the onset of spermatogenesis and around the time of puberty. Given the importance of regulated activin and TGFB signaling in testis development and function, we sought to investigate the cellular production sites of activin/TGFB-signaling modulators in normal and dysfunctional adult human testes samples. Signaling transducers phosphorylated SMAD2/3, and signaling modulators SMAD6, MAN-1, inhibin alpha (INHA), and beta-glycan were detected in Bouins fixed, paraffin-embedded adult human testis sections using immunohistochemistry. Additional samples examined were from testicular cancer patients and from normal men subjected to gonadotropin suppression with androgen-based contraceptives. Our findings identify distinct differences between normal and gonadotropin-deprived human testis in the expression and cellular localization of activin/TGFB-signaling modulators. The presence of a nuclear phosphorylated SMAD2/3 signal in all analyzed seminoma specimens indicated active activin/TGFB signaling. Moreover, a subset of seminoma specimens exhibited selective enhanced expression of beta-glycan (4 out of 28 seminoma tumors), INHA (6 out of 28), and MAN-1 (6 out of 28), highlighting potential functional differences between individual tumors in their capacity to regulate activin/TGFB signaling. Within the heterogenous nonseminomas, expression of signaling modulators was variable and reflected the degree of somatic differentiation. Thus, synthesis of activin and TGFB-signaling modulators may be affected by spermatogenic disruption and altered hormone levels in the testis.

Tumor development in three patients with Noonan syndrome.

The diagnosis of Noonan syndrome is essentially clinical, based upon the distinct phenotype and the involvement of the cardiovascular system. Tumor development is a rare manifestation of Noonan syndrome but can be explained by the molecular pathophysiology involved in the disorder. We present three Noonan patients who developed solid tumors. The first patient, a 4-year-old girl, developed granular cell tumors as did her mother in childhood. The second patient, a 1-year-old boy, had a low grade pilocytic astrocytoma, the clinical expression of which was persistent headache. MRI showed a pituitary mass in the posterior lobe. It was surgically removed. The third patient, a 7-year-old boy was found to have Sertoli tumors in his right cryptorchid testis. All three patients fulfilled the clinical criteria for Noonan syndrome. However, genetic testing was negative in patients 1 and 3. The diagnosis of Noonan syndrome was made based on distinct phenotypic findings in three patients who had different types of tumors.

TCam-2 but not JKT-1 cells resemble seminoma in cell culture.

Of all malignancies diagnosed in men between 17 and 45 years of age, 60% are germ cell tumors (GCT). GCT arise from carcinoma in situ cells, which are thought to originate from a transformed fetal germ cell, the gonocyte. Seminoma together with embryonal carcinoma represent the most frequent subtypes of GCT. However, the nature of the molecular pathways involved in seminoma formation remains elusive. Therefore, analysis of appropriate cell culture systems is an important prerequisite for further understanding of the etiology of this tumor entity. Although several cell lines for embryonal carcinoma have been established and analyzed, so far only two cell lines from seminoma patients have been reported. In the present study, we have analyzed these seminoma cell lines (TCam-2 and JKT-1) and compared the gene-expression profiles with those of normal tissue and of seminoma and embryonal carcinoma by using DNA Array technology. We have found that TCam-2 clusters with the group of classical seminoma, whereas JKT-1 clusters with the group of embryonal carcinoma. Using reverse transcription/polymerase chain reaction, Western blot, and immunohistochemistry, we have confirmed the seminoma-like nature of TCam-2, whereas JKT-1 lacks expression for most of the genes detectable in GCTs, thus making doubtful the germ cell nature of this cell line. The data represent the first genome-wide expression analysis of the two cell lines and comparison/clustering with subgroups of germ cell tumors. Only TCam-2 seems to represent a suitable in vitro model for seminoma.

[Fertility and testicular function in a patient with germ cell extragonadal tumor. A report of a case]. / Fertilidad y función testicular en un paciente con tumor extragonadal de células germinales. Comunicación de un caso.

Males are affected from primary extragonadal germ cell tumors with a frequency of 2 to 5%. There is a high incidence of infertility of more than 60% and most of the cases have azoospermia due to testicular damage. The hormonal profile of these patients shows normal luteinizing hormone, normal follicle stimulating hormone and normal testosterone and estradiol. We communicate the case of a male who had a primary retroperitoneal germ cell tumor with a low title of chorionic gonadotropin, elevated estradiol and normal testosterone, prolactin and seminogram. Before beginning treatment with chemotherapy, his wife became pregnant delivering twins, both males. The patient was treated with chemo and radiotherapy after which he became azoospermic with an increase in both luteinizing hormone and follicle stimulating, decreased levels of estradiol and without alteration in prolactin and testosterone. The pituitary testicle axis was affected by the tumor, but the microenvironment of the testicles did not seem to be damaged only after initiating treatment.

Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies.

Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron or the distal axon was primarily affected, we have carried out serial clinical and electrophysiological studies in 16 males with testicular cancer before or early and late during and after treatment with cisplatin, etoposide and bleomycin at limited (<400 mg/m2 cisplatin), conventional (approximately 400 mg/m2 cisplatin) or high (>400 mg/m2 cisplatin) doses. At cumulative doses of cisplatin higher than 300 mg/m2 the patients lost distal tendon and H-reflexes and displayed reduced vibration sense in the feet and the fingers. The amplitudes of sensory nerve action potentials (SNAP) from the fingers innervated by the median nerve and the dorsolateral side of the foot innervated by the sural nerve were 50-60% reduced, whereas no definite changes occurred at lower doses. The SNAP conduction velocities were reduced by 10-15% at cumulative doses of 400-700 mg/m2 consistent with loss of large myelinated fibres. SNAPs from primarily Pacinian corpuscles in digit 3 and the dorsolateral side of the foot evoked by a tactile probe showed similar changes to those observed in SNAPs evoked by electrical stimulation. At these doses, somatosensory evoked potentials (SEPs) from the tibial nerve had increased latencies of peripheral, spinal and central responses suggesting loss of central processes of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal axonal degeneration even at the lowest toxic doses of cisplatin.

Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors.

Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray ( approximately 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core "stemness" genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas.

Testicular germ-cell tumours in a broader perspective.

The germ-cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating germ cell. Recent progress begins to explain the apparent unpredictable development of germ-cell tumours and offers a basis for understanding their exquisite sensitivity to therapy.