Advances in the Biosciences, Volume 91: Germ Cell Tumours III documents the proceedings of the Third Germ Cell Tumor Conference held in Leeds, UK on September 8-10, 1993. This book focuses on germ cell tumors, which can be cancerous or non-cancerous tumors that normally occur inside the gonads. The topics discussed include the embryological mechanisms of maldescent and tumorigenesis; epidemiology of cryptorchidism; simultaneous bilateral testicular tumors; and mediastinal germ cell tumors. The classification of germ cell tumors; role of positron emission tomography in the assessment of germ cell tumors; chemotherapy of seminoma; and prognostic factors in disseminated non-seminomatous testicular cancer are also elaborated in this text. This publication is intended for medical students and individuals interested in germ cell tumors.

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Yes, you can access Germ Cell Tumours III by W.G. Jones,P. Harnden,I. Appleyard in PDF and/or ePUB format, as well as other popular books in Medicine & Diseases & Allergies. We have over one million books available in our catalogue for you to explore.

Information

Publisher

Pergamon

Year

2013

ISBN

9781483278384

Topic

Medicine

Subtopic

Diseases & Allergies

Embryological Mechanisms of Maldescent and Tumourigenesis

John M. Hutson, Marilyn L. Baker, Masaru Terada, Baiyun Zhou and Georgia Paxton, Surgical Research Unit, Royal Children’s Hospital, Research Foundation, Melbourne, Victoria, Australia, 3052

ABSTRACT

Testicular descent occurs in two stages with separate morphology and hormonal control. The key structure in mediating descent is the gubernaculum, which enlarges in the first phase to anchor the testes near the inguinal regions as the embryo enlarges. In the second phase, the gubernaculum migrates from the inguinal region to the scrotum. Non-androgenic hormones control the first phase, with conflicting evidence about whether Müllerian inhibiting substance (MIS) is the active agent. Testosterone controls the second phase, apparently indirectly via the nervous system. Calcitonin gene-related peptide (CGRP) has been identified recently within the gentofemoral nerve and has been postulated to act as a final common pathway for androgenic control of descent. Animal models of undescended testes, including the androgen resistant mouse, the TS rat, and the flutamide-treated rat all have an absence or deficiency of gubernacular migration and abnormality of CGRP.

These studies suggest that undescended testes may be caused by physiological or anatomical abnormalities of the gentofemoral nerve. The commonest cause of maldescent would appear to be failure of gubernacular migration, leaving the testes in the groin or so- called “superficial inguinal pouch”.

The abnormally high temperature of the undescended testes leads to deficiencies in postnatal secretion of testosterone and MIS. In addition, germ cell maturation from fetal gonocyte to type A spermatogonium is significantly inhibited. Gonocytes which fail to undergo this transformation either die off leading to infertility, or develop signs of dysplasia, eg. carcinoma-in-situ.

At present, it is not proven in humans that early surgery can prevent these hormonal and anatomical changes. However, animal experiments strongly support the view that early surgery, prior to these changes occurring, can prevent their development.

Introduction

The gubernaculum, or genitoinguinal ligament, enlarges in the male fetus between 10 and 15 weeks. The enlarged gubernaculum holds the testis near the future inguinal canal as the embryo enlarges. By contrast, failure of the homologous structure in the female to enlarge allows the ovary to ascend with the kidney, as seen in rodents, or to remain near the enlarging uterus, as seen in humans. The difference between the ovarian position in rodents and humans is probably related to the greater fusion of the Müllerian ducts in humans to form a solid uterus, thereby preventing further ovarian ascent. In either mammalian species, the long attenuated female gubernaculum is unable to anchor the ovary near the inguinal region and is preserved postnatally as two separate parts known as the ligament of the ovary and the round ligament.

The second phase, or inguinoscrotal descent, begins at 26–28 weeks of gestation, when the gubernaculum begins to migrate from the future inguinal canal towards the scrotum. A peritoneal diverticulum known as the processus vaginalis develops within the gubernaculum, allowing the testes to descend intra-peritoneally. By 35 weeks of gestation the gubernaculum has reached the scrotum and the testis arrives shortly after. Standard anatomical textbooks describe a gubernaculum attached to the bottom of the scrotum, but this is not the case until after descent is complete. Migration from the groin to the scrotum is a precarious journey of 3-5 cms for a gubernaculum which is only 1 cm in diameter. The gubernaculum after enlargement becomes gelatinous and mucoid at its distal end, and its proximal end is hollowed out by the processus vaginalis. The mucoid caudal end of the gubernaculum remains palpable until descent is complete, and then reabsorption of the extracellular matrix molecules causes it to regress. The postnatal gubernaculum is usually made up of fibrous attachments of the caudal epididyMIS and testis to the bottom of the processus vaginalis and adjacent scrotal subcutaneous tissue.

Hormonal Control

At one time it was believed that testicular descent was controlled by androgens from the fetal testis under maternal or chorionic gonadotrophin stimulation. In 1932, Engle (1) showed that the testis of immature Macaque monkeys were stimulated to descend with extracts from the anterior pituitary gland and with pregnancy urine. Since that time, cryptorchidism has been treated in many parts of the world with hCG and/or LHRH (2, 3). Although there are numerous clinical descriptions of abnormalities of the hypothalamic-pituitary-testicular axis which cause cryptorchidism, the role of androgens in controlling testicular descent has been controversial. This is because many natural mutants and experimental studies showed that the effect of androgen was absent or only partial. In particular, the second or inguinoscrotal phase of descent is absent in androgen resistant mice and humans (4). Furthermore, inguinoscrotal descent is absent in the hypogonadal mouse (5). Prenatal treatment with flutamide, which is an antiandrogen, also blocks the inguinoscrotal phase of descent (6, 7). Although the postnatal or inguinoscrotal phase of descent is blocked in the rat by flutamide, the flutamide only works when given prenatally. By contrast, no androgenic effects on descent of the testis could be observed in the fetus (8, 9). Also, androgens failed to produce the swelling reaction in the gubernaculum (8), and pituitary disconnection also failed to stop gubernacular swelling (10).

The apparent contradictions in the results of studies of androgens have been reconciled by the hypothesis that testicular descent occurs in two separate steps under independent hormonal control (11).

The first phase of testicular descent in mice can be inhibited by administering exogenous oestrogens to the pregnant dams, and this treatment also causes retention of the Müllerian ducts (5, 12). In addition, in the persistent Müllerian duct syndrome where there is a genetic defect in the synthesis of MIS or its receptor, the swelling reaction of the gubernaculum is absent in association with high intraabdominal testis and retained Müllerian ducts (13, 14). Both the oestrogen-injected mouse and the human with a mutation in the MIS gene provide evidence for an important role for this testicular hormone. However, there is some experimental evidence against a role for MIS, including the fact that immunisation of pregnant rabbits against purified MIS failed to stop testicular descent (15). Also, purified MIS did not stimulate fetal pig gubernacular fibroblasts in vitro (16).

The mechanism by which androgens control the second or inguinoscrotal phase of descent has remained obscure (17). The mechanism whereby the gubernaculum migrates from the inguinal region to the scrotum is also not understood. Although the gubernaculum was thought to be the primary target for androgens, measurement of significant numbers of androgen receptors has been controversial (18–20). A clue to an alternative site for androgen action was revealed by a study done by Lewis (21), where the gentofemoral nerve was transected in neonatal rats. This caused undescended testes which Lewis interpreted as evidence for a role by the cremaster muscle. Recently, we repeated this study and found a similar result (22). We went on to investigate the possibility that the primary action of androgen may be indirect on the gubernaculum via the central nervous system and the gentofemoral nerve. Careful study of gubernacular migration in the rodent postnatally showed that nerve transection inhibited migration (23). Looking at children with spina bifida in the high lumbar region where the gentofemoral nerve arises, we found 36% cryptorchidism (24). More importantly, when we did retrograde labelling of the gentofemoral nerve motor neurons, we found that the motor nucleus in the anterior horn is sexually dimorphic. Also, we found that the neonatal male gentofemoral nerve contains a much higher content of calcitonin gene-related peptide (CGRP) than the female equivalent (25).

In recent years we have investigated the possible role of CGRP in mediating gubernacular migration and testicular descent. CGRP receptors were identified within the cremaster muscle within the gubernaculum, (26). Also, in organ culture CGRP was found to induce rapid rhythmic contraction of ...

Cover image
Title page
Table of Contents
ADVANCES IN THE BIOSCIENCES
Copyright
Germ Cell Tumour Conference: Bodington Hall of Residence, Leeds 8-10 September 1993
Dedication
Preface
Acknowledgements
Chapter 1: Embryological Mechanisms of Maldescent and Tumourigenesis
Chapter 2: The Epidemiological Association between Undescended Testis, Inguinal Hernia and Testicular Cancer: Results from the U.K. National Case-Control Study of Testicular Cancer
Chapter 3: The Epidemiology of Cryptorchidism: Results from the John Radcliffe Hospital Cryptorchidism Study
Chapter 4: Maldescent and Cryptorchidism: A Rational Approach to Management
Chapter 5: Recent Progress in Research on CIS in Adults. Biological Aspects and Screening
Chapter 6: Simultaneous Bilateral Testicular Tumours
Chapter 7: Are Paediatric Germ Cell Tumours Germ Cell Tumours?
Chapter 8: Pathology and Cytogonetics of Germ Cell Tumours in Children
Chapter 9: UKCCSG Studies of Paediatric Germ Cell Tumours
Chapter 10: Changing Pattern of Incidence and Survival in Children with Germ Cell Tumours (GCTs)
Chapter 11: Testicular Non-Seminomatous Germ Cell Tumour (TGMnS) French Society of Pediatric Oncology Experience (SFOP), 1985–1989
Chapter 12: Chemotherapy Associated Toxicity in Patients with Malignant Non Testicular Germ Cell Tumours (MNGCTs). Comparison of MAKEI 83/86 and MAKEI 89
Chapter 13: Germ Cell Tumours in Children: A Report of 84 Cases
Chapter 14: Paediatric Germ Cell Tumours in the West Midlands Health Authority Region (WMHAR): Increasing Incidence and Pattern of Geographical Distribution
Chapter 15: Gonadotrophin and Sex Hormone Levels in Testis Cancer Patients with and without Carcinoma In Situ of the Contralateral Testis
Chapter 16: Contralateral Biopsies in Patients with Testicular Germ Cell Tumour —The German Experience
Chapter 17: Seminal Fluid Analysis and Carcinoma-In-Situ of the Testis
Chapter 18: Abdominal CT Scans in Patients with Retroperitoneal Germ Cell Tumours with or without Carcinoma In Situ
Chapter 19: The Value of Testicular Biopsy as a Screening Procedure for Future Malignant Germ Cell Tumours in Infertile Men
Chapter 20: Interphase Cytogenetics of Testicular Germ Cell Tumours: Clonal Origin of Seminoma and Nonseminoma Components in Combined Tumours
Chapter 21: Growth of Human Seminoma Cells on STO Feeder Depends on Phenotype, Presence of Fetal Calf Serum and Added Growth Factors
Chapter 22: Molecular Genetics in Germ Cell Tumours
Chapter 23: Mediastinal Germ Cell Tumours
Chapter 24: The Origin of Non-Germ Cell Tumour Elements within Germ Cell Tumours and Midline Tumours of Uncertain Histogenesis
Chapter 25: Unusual Neoplasms Detected in Testis Cancer Patients Undergoing Post Chemotherapy Retroperitoneal Lymphadenectomy
Chapter 26: Outcome Analysis for Patients with Persistent Non-Seminomatous Germ Cell Tumour in Post-Chemotherapy Retroperitoneal Lymph Node Dissections
Chapter 27: The Wilms’ Tumour 1 Gene in Testicular Cancer Patients
Chapter 28: Image Analysis Quantitation of p53 Gene Product and Ki-67 in Testicular Germ Cell Tumours — A Quantitative Immunohistochemical Study
Chapter 29: Is Apoptosis an Important Mode of Death in Embryonal Carcinoma?
Chapter 30: Growth Inhibition and Differentiation of a Human Embryonal Carcinoma (EC) Cell Line by Osteogenic Protein-1 (OP-1)
Chapter 31: Revised International Histological Classification of Testicular Tumours
Chapter 32: New Classification of Germ Cell Tumours
Chapter 33: Discussion on the Classification of Germ Cell Tumours
Chapter 34: Grading Germ Cell Tumours as a Means to Resolve the Last Twenty Five Years Transatlantic Conflict over Testis Tumour Classification
Chapter 35: The Clinical Value of Imaging Germ Cell Tumours with Radiolabelled Antibodies
Chapter 36: The Role of Positron Emission Tomography in the Assessment of Germ Cell Tumours
Chapter 37: The Princess Margaret Hospital Experience in the Management of Stage I and II Seminoma — 1981 to 1991
Chapter 38: Chemotherapy of Seminoma
Chapter 39: Late Relapse in Patients on Surveillance for Stage I Testicular Seminoma
Chapter 40: Surveillance of Stage 1 Non-Seminomatous Testicular Cancer — A Preliminary Report of the EORTC GU-Cooperative Group Surveillance Study
Chapter 41: Short Course Adjuvant Chemotherapy in High Risk Stage I Non-Seminomatous Germ Cell Tumours of the Testis (NSGCTT): An MRC Study Report
Chapter 42: One Course Adjuvant Treatment for Stage 1 Germ Cell Tumours
Chapter 43: NSGCT Stage I — Adjuvant Chemotherapy for Patients with Vascular Invasion and Surveillance for Patients without Vascular Invasion: Update of a Prospective Trial after 8 Years
Chapter 44: Testicular Cancer in Russia
Chapter 45: Good Risk Chemotherapy Trials for Patients with Advanced Germ Cell Tumours: The MSKCC Experience
Chapter 46: Carboplatin-Based Chemotherapy in Good Prognosis Metastatic Non-Seminoma of the Testis (NSGCT): An Interim Report of an MRC/EORTC Randomised Trial
Chapter 47: Insurance Status as a Prognostic Factor for Stage and Survival of Testicular Cancer Patients in Illinois
Chapter 48: Prognostic Factors in Metastatic Seminoma and Non-Seminomatous Germ Cell Tumours
Chapter 49: Prognostic Factors in Disseminated Non-Seminomatous Testicular Cancer
Chapter 50: Predictors of Residual Mass Histology Following Chemotherapy for Metastatic Nonseminomatous GCT: Univariate and Multivariate Meta-Analysis
Chapter 51: Resection of Small Masses of Residual NSGCT and Subsequent Therapy: Dilemmas in Clinical Decision Making
Chapter 52: Needs, Findings and Outcome of Post-Chemotherapy Surgery of Residual Masses (RM) in Patients with Non-Seminomatous Germ Cell Testis Tumours (NSGCTT) at a Single Institution
Treatment of Brain Metastases Round Table
Salvage Chemotherapy and ABMT Round Table
Abstracts of Poster Presentations
Index