Testicular Nonseminoma Research Articles

Testicular seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up H.-J. Schmoll, K. Jordan, R. Huddart, M. P. Laguna, A. Horwich, K. Fizazi & V. Kataja On behalf of the ESMO Guidelines Working Group* Department of Oncology/Haematology/Haemostaseology, University Hospital Halle, Halle, Germany; Department of Academic Radiotherapy, Institute of Cancer Research, Royal Marsden Hospital, Sutton Hospital, UK; Department of Urology, AMC University Hospital, Amsterdam, The Netherlands; Department of Medicine, Institute Gustave Roussy, Villejuif, France; Department of Oncology, Kuopio University Hospital, Kuopio and Vaasa Central Hospital, Vaasa, Finland

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Testicular seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Testicular non-seminoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up H.-J. Schmoll, K. Jordan, R. Huddart, M. P. Laguna, A. Horwich, K. Fizazi & V. Kataja On behalf of the ESMO Guidelines Working Group* Department of Oncology/Haematology/Haemostaseology, University Hospital Halle, Halle, Germany; Department of Academic Radiotherapy, Institute of Cancer Research, Royal Marsden Hospital, Sutton Hospital, UK; Department of Urology, AMC University Hospital, Amsterdam, The Netherlands; Department of Medicine, Institute Gustave Roussy, Villejuif, France; Department of Oncology, Kuopio University Hospital, Kuopio and Vaasa Central Hospital, Vaasa, Finland

Cervical mature teratoma 17 years after initial treatment of testicular teratocarcinoma: report of a late relapse

BackgroundLate relapses of testicular germ cell tumor are uncommon. We report a case of cervical mature teratoma appeared 17 years after treatment of testicular teratocarcinoma.Case presentationA 20- year- old patient underwent left sided orchiectomy followed by systemic therapy and retroperitoneal residual mass resection in 1989. He remained in complete remission for 200 months. In 2005 a huge left supraclavicular neck mass with extension to anterior mediastinum appeared. Radical surgical resection of the mass was performed and pathologic examination revealed mature teratoma.ConclusionThis is one of the longest long-term reported intervals of a mature teratoma after treatment of a testicular nonseminoma germ cell tumor. This case emphasizes the necessity for follow up of testicular cancer throughout the patient's life.

IGF2/H19 imprinting analysis of human germ cell tumors (GCTs) using the methylation‐sensitive single‐nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development

Previous studies have demonstrated biallelic expression of the imprinted genes H19 and IGF2 and loss of DNA methylation of the SNRPN gene, indicating a common precursor cell of human germ cell tumors (GCTs), namely, the primordial germ cell (PGC). In this study, we applied the methylation-sensitive single-nucleotide primer extension (MS-SNuPE) technique to the analysis of the IGF2/H19 imprinting control region (ICR) in 55 GCTs from representative clinical and histologic subgroups. Most GCTs showed low methylation at the IGF2/H19 ICR. All 8 ovarian GCTs, 9 of 10 testicular seminomas, 7 of 10 testicular nonseminomas (all in adolescents/adults), 6 of 9 testicular yolk sac tumors (YSTs), and 12 of 14 nongonadal GCTs (all in infants/children) were hypomethylated. The highest methylation was observed in three childhood YSTs (boys) and 2 of 4 spermatocytic seminomas. The latter are derived from more advanced stages of germ-cell development. The predominantly low methylation of most of the other GCTs correlates with studies that demonstrated erasure of the methylation imprint of the IGF2/H19 ICR during embryonal PGC migration and development. These findings suggest that the IGF2/H19 methylation status in GCTs might reflect preservation of the physiologic imprinting erasure in PGCs rather than a loss of imprinting in a sense that is accepted for somatic tumors. Furthermore, this study indicates that imprinting control mechanisms other than the proposed CTCF (CCCTC binding factor) boundary model regulate IGF2 expression during this stage of PGC development as well as in GCTs derived from PGC. (c) 2005 Wiley-Liss, Inc.

New markers for testicular non-seminoma and seminoma: HA and HAS-1

New markers for testicular non-seminoma and seminoma: HA and HAS-1

Pathology and pathomorphologic diagnosis of germ cell tumors of the testis

Testicular germ cell tumors are rare and comprise about 90% of all testis tumors. Genetic factors may play a role in the pathogenesis as can be deduced by a higher family-linked incidence and the p53 gene seems to be important in the development of these tumors which derive from a malignant transformed germ cell. Testicular intraepithelial neoplasia (TIN) may differentiate in two directions, namely into seminomas which comprise nearly 50% of all testicular germ cell tumors and non-seminomas. Since the term "differentiated teratoma" may be misleading, we propose the use of the term "teratoma" only. A preoperative diagnosis by biopsy is not indicated. An exact postoperative diagnosis including all necessary classifications, particularly the WHO and the TNM classifications, requires a very careful preparation of the resected specimen. The histological diagnosis should list all the different types of the WHO classification and the percentage of the tumor should be indicated, at least for embryonal carcinomas. For T categorisation in the TNM classification, the presence of invasion of veins or lymph vessels is important. Documentation, preferably in the form of a standard checklist, is strongly recommended.

A Truncated Form of Teratocarcinoma-Derived Growth Factor-1 (Cripto-1) mRNA Expressed in Human Colon Carcinoma Cell Lines and Tumors

The human teratocarcinoma-derived growth factor (TDGF)-1 gene encodes a 188-amino acid protein, cripto-1. The TDGF-1 gene is overexpressed in the majority of human primary colorectal carcinomas and hepatic metastases, in breast carcinomas and in testicular nonseminoma germ cell embryonal carcinomas. In the human embryonal carcinoma cell line NTERA-2 clone D1, a 2-kb TDGF-1 mRNA transcript is expressed. The present study shows that a 1.7-kb mRNA transcript lacking the first two exons of the TDGF-1 gene is expressed in the human colon carcinoma cell line GEO. This shorter mRNA is the only TDGF-1 transcript that is present in the majority of primary human colorectal carcinomas and hepatic metastases and in adult human tissues such as the pancreas, heart, stomach, mammary gland, skeletal muscle, liver and placenta. In contrast, in the kidney, brain, testis, ovary and spleen, the longer 2-kb TDGF-1 mRNA transcript is expressed. The putative shorter protein starts at a CUG codon 129 nucleotides downstream of the starting AUG codon of the longer protein. These data indicate the potential for differential transcriptional regulation of the TDGF-1 gene in different normal and tumor tissues.

Cytogenetic Analysis of a Mature Teratoma and a Yolk Sac Tumor Component of a Late Relapse of a Disseminated Testicular Nonseminoma

We report on the cytogenetics of a primary testicular nonseminoma, a residual mature teratoma after remission-induction chemotherapy, and a late relapse after 9 years of follow-up, in one patient. The late relapse was composed of a mature teratoma and a yolk sac tumor component. Cytogenetic comparison of the different tumors shows that progression of primary testicular nonseminoma to residual mature teratoma and to a late-relapse lesion is accompanied by net loss of chromosomes. In addition, our findings may suggest that transformation to viable cancer in a late-relapse lesion is accompanied by further chromosomal losses.

Frequent p161NK4 (MTS1) Gene Inactivation in Testicular Germ Cell Tumors

The molecular mechanisms responsible for the development of testicular germ cell tumors (GCTs) have not as yet been elucidated. The aim of the present study was to determine whether genetic alterations of p161NK4 (MTS1) and/or cyclin-dependent kinase 4 (CDK4) occur in the genesis of these tumors. We have analyzed these two genes in 29 testicular GCTs, seminomas, and nonseminomas. None of the tumors showed either p161NK4 or CDK4 mutations. Only 1 of the 29 GCTs displayed loss of heterozygosity of the p161NK4 gene. No homozygous deletions of p161NK4 were detected. Evidence of hypermethylation of p161NK4 exon 1, however, was demonstrated in 13 of the 26 (50%) GCTs analyzed. Tumor samples having exon 1 of p161NK4 methylated expressed significantly lower levels of p16INK4 mRNA, as analyzed by reverse transcriptase polymerase chain reaction. These results suggest that p161NK4 inactivation plays a role in the genesis of GCTs.

Comparison of the chromosomal pattern of primary testicular nonseminomas and residual mature teratomas after chemotherapy

About 70 to 75% of patients with nonseminomatous testicular germ cell tumors (NSs) present with metastases. When these metastases are treated with chemotherapy, often residual mature teratoma (RMT) is left. RMT is composed of fully differentiated somatic tissue. Untreated metastases of NSs rarely consist exclusively of mature somatic tissue. Apparently, after chemotherapy treatment there is a shift towards higher degrees of differentiation. Investigating tumor progression and the mechanism(s) involved in therapy-related differentiation, we compared the cytogenetically abnormal karyotypes of a series of 70 NSs with those of 31 RMTs. In NSs and RMTs, the modal total chromosome number does not differ and is in the triploid range. Both the frequency and the average copy number of i(12p) are the same, and the pattern of chromosomal over- and underrepresentation and distribution of breakpoints do not differ significantly in these series. So, we found the chromosomal pattern of RMTs as abnormal as those of primary NSs. Based on cytogenetics, we found no indication that specific chromosomal alterations parallel metastasis and therapy-related differentiation of the metastases. The cytogenetic data suggest that both induction of differentiation of (selected) cells or selection of cells with capacity to differentiate are possible mechanisms for the therapy-related differentiation of RMTs.

Current concepts about testicular cancer

In the past 20 years, testicular cancer, which occurs in the young, has become a curable malignancy; 90% of the patients treated will achieve long-term survival. However, there is a significant morbidity associated with the management of the disease process. The literature was reviewed concerning the current treatment strategies and prognosis, as well as the long-term sequelae of the various diagnostic and therapeutic procedures. Surveillance has become a key element in the management of patients with a primary (stage I) testicular non-seminoma. Although approximately 25% of these patients will relapse, 100% survival can be achieved with cisplatin in combination with etoposide and bleomycin (BEP). Patients with a disseminated non-seminoma are usually treated with 4 courses of BEP; an 80% survival rate can be achieved. The long-term effects of chemotherapy include Raynaud's phenomenon, acral paraesthesia, hyperlipidaemia, nephrotoxicity, infertility and hormonal disturbances. Retroperitoneal lymph node dissection or resection of residual disease following chemotherapy are associated with a low mortality and morbidity rate, ejaculatory dysfunction excepted. However, with specific modifications in technique (e.g. nerve-sparing) antegrade ejaculation can be preserved in the majority of patients. Radiotherapy is used in stage I and II seminoma. With the conventional dose of 25-30 Gy to the retroperitoneal and ipsilateral iliac lymph nodes, temporary dysfunction of the germ and Leydig cells of the remaining testis may occur by scatter radiation. Patients with advanced seminoma are treated with cisplatin-based chemotherapy. To date, testicular cancer patients can receive appropriate curative treatment with acceptable acute toxicity, depending on the therapy given. The detrimental effects of late toxicities require careful study and follow-up. However, little attention is paid currently to quality of life aspects, in particular the impact of the disease and its treatment on general well-being, including sexual function.

Cytogenetics of primary testicular nonseminoma, residual mature teratoma, and growing teratoma lesion in individual patients

Residual mature teratoma (RMT) is often left behind when metastases of primary nonseminomatous germ cell tumors (NSs) are treated with chemotherapy. RMT is composed of fully differentiated somatic tissue. A growing teratoma (GTE) lesion may occur after (incomplete) resection of RMT. To shed light on tumor progression or the mechanism(s) of therapy related differentiation we investigated the chromosomal pattern of the primary NSs and RMTs in twelve patients, of the primary NS, RMT, and GTE lesion in one patient, and of the RMT and GTE lesion in two patients. Although several chromosomal differences are observed between the RMT and NSs and between the GTE and RMTs in the same patient, we obtained no evidence that specific chromosomal alteration(s) play a role in metastasis or differentiation.

ARTICLES: Testicular Nonseminoma and Seminoma in Relation to Perinatal Characteristics

Testicular cancer incidence peaks during the third decade of life, and an increasing trend in the occurrence of this disease has been seen in many countries. Few risk factors have been established for testicular cancer, but evidence suggests that causal factors operate early in life, perhaps even in utero. We performed a case-control study to evaluate specific perinatal characteristics as risk factors for the two main histopathologic types of testicular cancer: seminomas and nonseminomas. Two hundred thirty-two case patients with invasive testicular cancer and 904 individually matched control subjects (all singleton births), nested in a cohort of men born at 10 hospitals in Sweden from 1920 through 1978, were included in the study. Perinatal information about the study subjects and their parents was obtained from birth records. For the mothers, information was recorded concerning age at menarche, marital status, parity, age at delivery, maternal weight at delivery and at first visit to a maternal-care center, education and/or profession, and any medical problems encountered during pregnancy or after delivery. For the fathers, information was obtained concerning age at delivery and education and/or profession. For the study subjects, information was recorded about the following: gestational age, birth length and weight, placental weight, method of delivery (normal, cesarean section, or with forceps or vacuum extractor), medical problems during hospital stay, presence of jaundice, method of feeding at discharge, and duration of hospital stay after birth. Individuals diagnosed with testicular cancer were identified through the Swedish National Cancer Registry and the Uppsala Regional Cancer Registry. The data were analyzed by use of conditional logistic regression modeling. When testicular cancer was modeled as a single entity, significantly elevated risks were associated with neonatal jaundice (adjusted odds ratio [OR] = 2.30; 95% confidence interval [CI] = 1.07-4.94) and with either low (< 2500 g) or high (> or = 4000 g) birth weight (OR = 2.59; 95% CI = 1.05-6.38 and OR = 1.58; 95% CI = 1.10-2.29, respectively). When seminomas and nonseminomas were analyzed separately, high maternal socioeconomic status (OR = 2.54; 95% CI = 1.05-6.12), neonatal jaundice (OR = 3.96; 95% CI = 1.47-10.69), and low birth weight (OR = 7.62; 95% CI = 1.59-36.60) were associated with nonseminomas, whereas high placental weight (OR = 3.50; 95% CI = 0.97-12.62) suggested increased risk for seminomas. Perinatal exposures appear to influence the risk of testicular cancer, and seminomas and nonseminomas may have somewhat different risk profiles. Future epidemiologic studies should consider the possibility of etiologic heterogeneity in the development of seminomas and nonseminomas.

Results of treatment in testicular nonseminoma.

Seventy-one testicular nonseminomatous germ cell tumours were treated in the Helsinki University Central Hospital between 1980 and 1990. Thirty-five (49%) were stage I, 16 (23%) stage II and 20 (28%) stage III tumours. The 5-year survival rates were 91%, 94% and 70%, respectively. Five of the eight patients relapsing in stage I had adverse histopathological risk factors in their tumours. In the retrospective evaluation two stage I patients had actually a higher stage. The good results in stage II were achieved with a routine combination of chemotherapy and retroperitoneal lymph node dissection. All five patients lost for stage III nonseminoma had risk factors for unfavourable prognosis: liver metastases or very high serum markers at diagnosis. The results presented here are considerably better than in the 1970s in this country and well comparable to results from countries where this malignancy is more common. Still some patients were lost. Co-operation in different fields of medicine is essential to find and treat optimally those with more aggressive disease and those who are cured with less strenuous treatment modalities.

Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma; a randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group

We have investigated whether an alternating induction chemotherapy regimen of PVB/BEP is superior to BEP in patients with poor-prognosis testicular non-seminoma. A total of 234 eligible patients were randomised to receive an alternating schedule of PVB/BEP for a total of four cycles or four cycles of BEP. Poor prognosis was defined as any of the following: lymph node metastases larger than 5 cm, lung metastases more than four in number or larger than 2 cm, haematogenic spread outside the lungs, such as in liver and bone, human chorionic gonadotrophin > 10,000 IU l-1 or alphafetoprotein > 1000 IU l-1. The complete response (CR) rates to PVB/BEP and BEP were similar, 76% and 72% respectively (P = 0.58). In addition, there was no significant difference in relapse rate, disease-free and overall survival at an average follow-up of 6 years. The 5-year progression-free and survival rates in both treatment groups were approximately 80%. The PVB/BEP regime was more toxic with regard to bone marrow function; the frequencies of leucocytes below 1000 microliters-1, leucocytopenic fever and platelets below 25,000 microliters-1, throughout four cycles were 28% vs 5% (P < 0.001), 16% vs 5% (P = 0.006), and 10% vs 1% (P = 0.001) respectively. Neuropathy also occurred more often in the PVB/BEP arm: 47% vs 25% (P = 0.001). This study shows that an alternating regimen of PVB/BEP is not superior to BEP and that it is more myelo- and neurotoxic.

Original Articles: Testis Cancer: A Review of Scrotal Violation in Testicular Cancer: Is Adjuvant Local Therapy Necessary?

ABSTRACTHigh inguinal orchiectomy is the standard initial treatment for suspected testicular carcinoma. Nonstandard surgical approaches (scrotal violations), including scrotal orchiectomy, open testicular biopsy and fine needle aspiration, have historically been condemned as significantly compromising patient prognosis. Patients with scrotal violation are often subjected to potentially morbid or disfiguring local therapies. In addition, patients with scrotal violations are usually disqualified from surveillance protocols.A review was conducted of all published series of testicular cancer patients in whom scrotal violation occurred. A meta-analysis was then performed to choose a subset for critical analysis on the effect of scrotal violation on patient prognosis. Of 1,182 cases included in the final analysis scrotal violation occurred in 206. The rates for local recurrence, distant recurrence and survival were analyzed separately for all patients, patients with stage I disease and patients with pure semino...

Retroperitoneal imaging with third and fourth generation computed axial tomography in clinical stage I nonseminomatous germ cell tumors

Objectives. To examine the accuracy rate of abdominal staging using thirdand fourth generation computed tomography (CT) scanning in clinical Stage I testicular nonseminoma patients. Methods. Between January 1985 and August 1993, 57 patients presented to ourcenter with clinical Stage I testicular nonseminoma. Retroperitoneal computed tomographic staging studies were interpreted to be normal preoperatively in the entire group. In addition, tumor marker values were normal or returned to normal postorchiectomy within the appropriate half-life intervals. All patients were subjected to radical or modified retroperitoneal lymph node dissection (19% and 72%, respectively). Original abdominal CT scans (preretroperitoneal lymph node dissection) were available for blinded retrospective re-review in 16 cases (7 pathologic Stage II, 9 pathologic Stage I). Results. Nineteen of 57 (33%) patients were upstaged at surgery including 6 patients (11%) who demonstrated II B volume disease. Third and fourth generation CT scanning of the retroperitoneum yielded a 66% accuracy rate in this population. Six out of 7 pathologic Stage II pre-lymph node dissection abdominal CT scans that were available for blinded re-review revealed nonpathologic nodes by size criteria in the primary landing zone for the corresponding original tumor. Conclusions. Our data suggests that for clinical Stage I nonseminoma in the 1985 to1993 era, undue reliance was placed on a less than ideal staging test. The 33% false-negative rate reported showed no improvement over earlier reports and reaffirms concern for relying solely on third or fourth generation CT imaging of the retroperitoneum in the staging of clinical Stage I nonseminomatous germ cell tumor (NSGCT) patients. The presence of any number of lymph nodes in the expected primary landing zone, regardless of size, should raise serious suspicion for occult nodal disease.

Prognosis of testicular teratoma differentiated.

To determine whether the clinical course of patients with testicular teratoma differentiated (TD) and those with testicular teratoma undifferentiated justify a different follow-up protocol. Between 1979 and 1989, 16 adult patients with testicular TD were treated at the Royal Marsden Hospital. These represented 2.7% of the 592 testicular teratoma patients seen during this period. With the exception of a propensity to involve the right testis (76%), there were no differences in clinical presentation between TD and non-TD histological subtypes. The mean follow-up was 55 months (range 7-137). Seven of the 16 patients had Stage I disease and were entered into surveillance programmes; one relapsed at 7 months. Ten men were treated with cisplatin or carboplatin-based chemotherapy for metastases, of whom three had had prior chemotherapy at other hospitals and were referred after relapse. In the seven previously-untreated chemotherapy group two patients failed. In the concurrent era, 375 patients with other subtypes of metastatic testicular non-seminoma were treated with chemotherapy and 47 (12.5%) failed (Progress Free Survival chi square (chi 2) = 2.73, P = 0.01). Although no difference in progression-free survival was demonstrated between TD and non-TD patients, the former had a worse overall survival probability (chi 2 = 9.02, P = 0.003); this may be an artefact due to the small number of events. Despite the apparently more benign histology, it is recommended that the management of adult TD should not deviate from the general principles established for other histological subtypes of testicular teratoma.

Primary Chemotherapy for Stage II Nonseminomatous Germ Cell Tumors of the Testis

Between 1979 and 1989, 122 patients with clinical stage II testicular nonseminoma were treated with primary platinum-based combination chemotherapy following orchiectomy. Of the patients 58 had Royal Marsden Hospital stage IIA (nodes less than 2cm. in diameter) and the other 64 had stage IIB (nodes 2 to 5cm. diameter) disease. With a median followup after chemotherapy of 5.5 years, 118 patients (97%) were disease-free. Two patients died of progressive germ cell tumors, 1 of bleomycin toxicity and 1 of coincidental disease. The 5-year actuarial survival probability was 95% (95% confidence intervals 91 to 99%) and the 5-year failure-free survival probability was 92% (95% confidence intervals 88 to 97%). Tumor substage was not predictive of relapse but did indicate the probability of lymphadenectomy for a post-chemotherapy residual mass since this was performed in 17% of the patients with stage IIA disease and 39% with stage IIB disease (p <0.05). Resected specimens contained mature teratoma (29), necrosis alone (5) or embryonal carcinoma (1). We conclude that for these clinical stages primary chemotherapy was as effective as primary lymph node dissection and a major operation was avoided in 68% of the cases.