Positive Oct -3/4 and D2–40 Immunohistochemical Expression in Germ Cells and Suspected Histology Pattern of Intratubular Germ Cell Neoplasia in Boys with Cryptorchidism Vanish after the Age of 2 Years

2016 ◽  
Vol 27 (04) ◽  
pp. 313-318 ◽  
Author(s):  
Erik Clasen-Linde ◽  
Dina Cortes ◽  
Jorgen Thorup
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Cell Cancer ◽  
Germ Cell Cancer ◽  
Repeat Biopsy ◽  
Seminiferous Tubules ◽  
Histological Pattern ◽  
Immunohistochemical Markers ◽  
Increased Risk ◽  
Intratubular Germ Cell Neoplasia

Introduction Intratubular germ cell neoplasia (ITGCN) is a precursor to testicular germ cell cancer. Adult germ cell cancer immunohistochemical markers may fail to detect ITGCN in prepubertal boys with congenital cryptorchidism, because positive immunohistochemistry is commonly seen in boys younger than the age of 2 years, where most orchiopexies are performed. The aim of the study was to evaluate the diagnostic challenge to differentiate between a histological pattern of ITGCN and a histological pattern with some atypical germ cells and all positive cancer immunohistochemical markers, but no increased risk of malignancy. Materials and Methods Histology sections from 373 testicular biopsies from 289 boys aged 1 month to 2 years operated for cryptorchidism were incubated with primary antibodies including anti-placental-like-alkaline phosphatase, antiOct-3/4, anti-C-kit, anti-D2–40, and in case of repeat biopsy with anti-stem cell factor (SCF) receptor. Results The prevalence of Oct-3/4 and D2–40-positive staining of germ cells in testicular biopsies were in age groups less than 6 months, 100% and 50%; 6–12 months, 60% and 17%; and 1–2 years, 12% and 4%. A 1 year, 1-month-old boy with Prader–Willi syndrome treated with growth hormone had ITGCN in both cryptorchid testes. In another three bilateral nonsyndromic cases, 8 months, 8 months and 1-year-old, a histological pattern in accordance with ITGCN was found. These three boys had a repeat biopsy from both testes performed at the age of 3 years, 4 months, 3.5 years, and 3 years, 10months, respectively. In all cases, the Oct-3/4 and D2–40 positive germ cells turned negative and the histological pattern normalized completely. The primary biopsies had SCF negative germ cells. Conclusion This study is valuable in identifying the age-related change in Oct-3/4 or D2–40 immunopositive germ cells in seminiferous tubules. An ITGCN-like histological pattern in nonsyndromic cryptorchidism will vanish after the age of 3 years. Even when immunohistochemistry is applied, prepubertal ITGCN is so rarely demonstrated in cryptorchid testes, that it is not plausible that ITGCN generally originates during fetal development in cryptorchidism.

scholarly journals Ectopic FGF23 production induces mineral changes, osteogenic transdifferentiation, and cancer associated microcalcifications

2020 ◽  
Author(s):  
Ida Marie Boisen ◽  
John Erik Nielsen ◽  
Ireen Kooij ◽  
Jovana Kaludjerovic ◽  
Peter J. O’Shaughnessy ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Germ Cell ◽  
Phosphatase Activity ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Alkaline Phosphatase Activity ◽  
Cell Cancer ◽  
Seminiferous Tubules ◽  
Testicular Germ Cell ◽  
Increased Risk

AbstractTesticular microcalcifications consist of hydroxyapatite and their demonstration by ultrasound has been associated with increased risk of testicular germ cell cancer (TGCT). Here, we show that fibroblast growth factor 23 (FGF23), a bone-specific regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and thus rapidly cleaved into a C-terminal fragment that serves as a competitive antagonist for full-length FGF23. High levels of C-terminal FGF23 occupy the receptor formed by Klotho and FGF receptor 1 (FGFR1) in the germ cells facilitating a shift in the expression of phosphate transport proteins from SLC34A2 to SLC34A1 in seminiferous tubules adjacent to GCNIS. Fgf23 knockout mice have a marked epididymal deposition of hydroxyapatite, while the testicular phenotype is milder with spermatogenic arrest and focal germ-cell-specific expression of the bone-like markers runt-related transcription factor 2 (RUNX2) and bone gamma-carboxyglutamic acid-containing protein (BGLAP). In accordance, mice with no functional androgen receptor and lack of circulating gonadotropins develop microcalcifications in 94% of cases and have lower Slc34a2, and higher Slc34a1 and Bglap expression. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2, and focally germ cells express SLC34A1, BGLAP, and RUNX2. Importantly, calcium or phosphate induced osteogenic transdifferentiation of a spermatogonial cell line in vitro demonstrated by induction of alkaline phosphatase activity and deposition of hydroxyapatite, which could be fully rescued by pyrophosphate (PPi). Severe microcalcifications were also found in a mouse model with Sertoli-cell ablation particularly when Sertoli-ablation was conducted prepubertally where the germ cells retain stem cell potential. In conclusion, cancer-related microcalcifications may arise secondary to gonadal mineral alterations, which in combination with impaired Sertoli cell function and reduced PPi due to high alkaline phosphatase activity in GCNIS and TGCTs, facilitates osteogenic transdifferentiation of testicular germ cells and deposition of hydroxyapatite.

scholarly journals Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology

2019 ◽  
Vol 20 (20) ◽  
pp. 5017 ◽  
Author(s):  
Leendert H. J. Looijenga ◽  
Chia-Sui Kao ◽  
Muhammad T. Idrees
Keyword(s):  
Germ Cell ◽  
Y Chromosome ◽  
Association Studies ◽  
Cell Cancer ◽  
Disorders Of Sex Development ◽  
Germ Cell Cancer ◽  
Genome Wide Association Studies ◽  
Sex Development ◽  
Stage Of Development ◽  
Increased Risk

The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients.

scholarly journals Low RBM3 Protein Expression Correlates with Clinical Stage, Prognostic Classification and Increased Risk of Treatment Failure in Testicular Non-Seminomatous Germ Cell Cancer

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0121300 ◽  
Author(s):  
Sven-Erik Olofsson ◽  
Björn Nodin ◽  
Alexander Gaber ◽  
Jakob Eberhard ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Protein Expression ◽  
Treatment Failure ◽  
Germ Cell ◽  
Clinical Stage ◽  
Cell Cancer ◽  
Germ Cell Cancer ◽  
Increased Risk ◽  
Risk Of Treatment

Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer.

1988 ◽  
Vol 6 (11) ◽  
pp. 1728-1731 ◽  
Author(s):  
S W Hansen ◽  
S Groth ◽  
G Daugaard ◽  
N Rossing ◽  
M Rørth
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Germ Cell ◽  
Cell Cancer ◽  
Germ Cell Cancer ◽  
Long Term Effects ◽  
Increased Risk ◽  
The Mean

Long-term effects of cisplatin on renal function were investigated in 34 patients with germ cell cancer observed for a median of 65 months (range, 43 to 97 months). All patients achieved a complete remission after treatment with cisplatin (median dose 583 mg/m2), vinblastine, and bleomycin. None of the patients relapsed during follow-up. During treatment the glomerular filtration rate (GFR) decreased by 18% (P less than .05). During follow-up kidney function recovered in ten patients and partly improved in eight patients. Changes in plasma creatinine did not consistently correspond to alterations in GFR. The mean increase in systolic blood pressure during follow-up did not differ from the increase seen in a group of age-matched healthy men. The mean increase in diastolic pressure, however, was significant (P less than .05), but was entirely due to hypertension observed in six patients. Renography of these patients was normal. We conclude that the decrease in GFR observed during treatment with cisplatin is partly reversible. Cisplatin-treated patients have an increased risk of developing hypertension years after treatment.

Risk factors for thromboembolic events in testicular cancer patients receiving chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16109-e16109
Author(s):  
K. Shim ◽  
K. R. Potvin ◽  
K. Mills ◽  
F. Whiston ◽  
L. Stitt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Germ Cell ◽  
Cancer Patients ◽  
Cell Cancer ◽  
Germ Cell Tumors ◽  
Retrospective Chart Review ◽  
Germ Cell Cancer ◽  
Thromboembolic Events ◽  
Increased Risk ◽  
Risk Of Hemorrhage

e16109 Background: Cancer patients are at increased risk for thromboembolic events (TTEs), and those receiving chemotherapy are at even greater risk. Clinical experience and the literature have suggested that men receiving cisplatin-based chemotherapy for metastatic germ cell tumors are at particularly high risk. As TTEs can be fatal and treatment is curative, the stakes are high. Despite this, prophylactic anticoagulation (PA) is not routinely used. Methods: All men treated with cisplatin-based chemotherapy for metastatic germ cell cancer at the London Regional Cancer Program from January 1978 to December 2007 were identified from electronic databases. Data including type and timing of TTEs were extracted by retrospective chart review. Multivariable analyses were used to identify predictors of TTEs. Results: 196 eligible patients were identified with median age 31 years (range, 15–75). No patients received PA. Thirty-two TTEs were identified in 29 patients for an overall incidence of 14.8% (95% CI, 9.8–19.8%). The majority of events were deep venous thromboses, and five patients died due to TTE or its complications. Sixteen of the patients with TTE (55.2%) were diagnosed while on treatment (defined as TTE within 6 months of chemotherapy initiation); 8 (27.6%) had their TTE prior to, and 5 (17.2%) after this time period. Age greater than 30 years (OR = 3.02; 95% CI, 1.10–8.33; p = 0.033) and elevated LDH (OR = 1.93; 95% CI, 1.07–3.48; p = 0.029) were independently associated with an increased risk of TTE. If both adverse risk factors were present, the risk of TTE on treatment was 21.7% (95% CI, 9.8–33.7%). If neither were present, the negative predictive value was 97% (95% CI, 92–100%). Conclusions: The overall TTE incidence rate of 14.8% is consistent with prior reports (8.4–19%). The risk of TTE appears greatest during chemotherapy and shortly thereafter, and nearly one in 10 patients in this group had a TTE. These data support the concept of PA for selected patients starting chemotherapy for metastatic germ cell cancer. However, the efficacy of PA and risk of hemorrhage in this group is unknown. In this cohort, patients under 30 with normal LDH were at very low risk for TTE. Confirmation of these findings to help guide the study and optimal use of PA should be pursued. No significant financial relationships to disclose.

Germ Cell Cancer and Multiple Relapses: Toxicity and Survival

2015 ◽  
Vol 33 (28) ◽  
pp. 3116-3123 ◽  
Author(s):  
Jakob Lauritsen ◽  
Maria G.G. Kier ◽  
Mette S. Mortensen ◽  
Mikkel Bandak ◽  
Ramneek Gupta ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Germ Cell ◽  
Cell Cancer ◽  
Late Toxicity ◽  
Germ Cell Cancer ◽  
Line Treatment ◽  
Disease Information ◽  
Number Of Patients ◽  
Increased Risk ◽  
Disseminated Disease

Purpose A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment for disseminated disease. Methods From the Danish Testicular Cancer database, we identified all patients who received more than one line of treatment for disseminated disease. Information about late toxicity and mortality was obtained by means of linkage to national registers. Prognostic factors for relapse and death were identified and compared with the International Prognostic Factors Study Group (IPFSG) classification. Results In total, 268 patients received more than one line of treatment for disseminated GCC. Approximately half of patients (n = 136) died as a result of GCC. The 132 remaining patients, compared with patients treated with only orchiectomy, had an increased risk for a second cancer (hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.5), major cardiovascular disease (HR, 1.9; 95% CI, 1.0 to 3.3), pulmonary disease (HR, 2.0; 95% CI, 1.0 to 3.8), GI disease (HR, 7.3; 95% CI, 3.6 to 14.8), renal impairment (HR, 8.3; 95% CI, 3.0 to 23.2), neurologic disorders (HR, 6.3; 95% CI, 3.1 to 12.6), and death as a result of other causes (HR, 2.6; 95% CI, 1.6 to 4.2). In large part, the IPFSG classification was confirmed in our population; however, we could not confirm the primary site and the level of human chorionic gonadotropin as independent factors. We identified increasing age as a possible new prognostic factor for treatment failure after second-line treatment (HR, 1.2 per 10 years; 95% CI, 1.2 to 15). Conclusion Patients with GCC who survive after more than one line of treatment for disseminated disease have a highly increased risk of late toxicity and death as a result of causes other than GCC. Therefore, they should be candidates for life-long follow-up. The IPFSG classification was confirmed in this unselected population.

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