CHAPTER X CHAPTER 4 - Cancer et environnement

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wartime birth cohorts illustrate that the propensity to develop testicular cancer is established early in life. Testicular germ cell tumours are associated with intratubular germ cell neoplasia, unclassified (IGCNU). The association is very strong and very specific {1766}. The prevalence of carcinoma in situ in a population of men corresponds almost exactly to the lifetime risk of testicular cancer in these men, ranging from less than 1% in normal men in Denmark {891} to about 2-3% in men with a history of cryptorchidism {887} and 5% in the contralateral testicle in men who have already had one testicular germ cell tumour {614}. Intratubular germ cell neoplasia, unclassified is practically always present in the tissue surrounding a testicular germ cell tumour and the condition has never been observed to disappear spontaneously. From these observations it may be inferred that the rate limiting step in testicular germ cell tumour is the abnormal differentiation of primordial germ cells leading to the persisting unclassified intratubular germ cell neoplasia which then almost inevitably progresses to invasive cancer. The area under the age incidence curve may reflect the rate of occurrence of IGCNU. The decline in the age specific incidence rates after about forty years of age may be due to the depletion of the pool of susceptible individuals with ITCGNU as these progress to invasive cancer {1766}. Etiology The research for the causes of testicular germ cell tumours has been guided by the hypothesis that the disease process starts in fetal life and consists of the abnormal differentiation of the fetal population of primordial germ cells. There are several strong indications that testicular germ cell tumour is associated with abnormal conditions in fetal life. Associations with congenital malformations of the male genitalia Cryptorchidism (undescended testis) is consistently associated with an increased risk of testicular germ cell tumour. The incidence is about 3-5 fold increased in men with a history of cryptorchidism {3}. In those with unilateral cryptorchidism, both the undescended testicle and the normal, contralateral testicle have increased risk of testicular cancer {1768}. The incidence of testicular cancer is possibly increased in men with hypospadias and in men with inguinal hernia, but the evidence is less strong than for cryptorchidism {2105}. Atrophy adds to the risk of germ cell tumours in maldescent {613,1020} and the normal, contralateral testicle has an increased risk of testicular cancer {1768}. The presence of atrophy in maldescended testes is a major factor in germ cell neoplasia. Prenatal risk factors Case control studies have shown consistent associations of testicular cancer with low birth weight and with being born small for gestational age, indicating a possible role of intrauterine growth retardation {43,1769}. A similar association is evident for cryptorchidism and hypospadias {2797}. Other, less consistent associations with testicular cancer include low birth order, high maternal age, neonatal jaundice and retained placenta {2186,2270,2775}. Exposures in adulthood There are no strong and consistent risk factors for testicular cancer in adulthood. Possible etiological clues, however, include a low level of physical activity and high socioeconomic class {4}. There is no consistent evidence linking testicular cancer to particular occupations or occupational exposures. Immunosuppression, both in renal transplant patients and in AIDS patients seem to be associated with an increased incidence {245,900}. Male infertility Subfertile and infertile men are at increased risk of developing testicular cancer {1203,1770}. It has been hypothesized that common causal factors may exist which operate prenatally and lead to both infertility and testicular neoplasia. Specific exposures For more than twenty years, research in testicular cancer etiology has been influenced by the work of Brian Henderson and his colleagues who hypothesized an adverse role of endogenous maternal estrogens on the development of the male embryo {1070}. More recently, the emphasis has changed away from endogenous estrogens to environmental exposures to estrogenic and anti androgenic substances {2378}. The empirical evidence, however, for these hypotheses remains rather weak and circumstantial. Follow-up of a cohort of men who were exposed in utero to the synthetic estrogen diethylstilboestrol have shown an excess occurrence of cryptorchidism and a possible, but not statistically significant, increase in the incidence of testicular cancer (about two fold) {2520}. From the studies, which have attempted to analyse the etiology of seminoma and non-seminoma separately, no consistent differences have emerged. It is most likely that the etiological factors in the two clinical subtypes of testicular germ cell tumour are the same {1769,2186}. Epidemiology and etiology of other testicular germ cell tumours Apart from testicular germ cell tumours in adult men, several other types of gonadal tumours should be mentioned briefly. A distinct peak in incidence of testicular tumours occurs in infants. These are generally yolk sac tumour or teratoma. These tumours do not seem to be associated with carcinoma in situ and their epidemiology and etiology are not well known. Spermatocytic seminoma occurs in old men. These tumours are not associated with ITCGNU and are not likely to be of prenatal origin. This may be a tumour derived from the differentiated spermatogonia. Their etiology is unknown. Finally, it may be of interest to note that there is a female counterpart to testicular germ cell tumours. Ovarian germ cell tumours such as dysgerminoma (the female equivalent of seminoma) and teratomas may share important etiological factors with their male counterparts, but their incidence level is much lower than in males {1767}. Familial predisposition and genetic susceptibility are important factors in the development of testis tumours, which will be discussed in the genetic section. Clinical features Signs and symptoms The usual presentation is a nodule or painless swelling of one testicle. Approximately one third of patients complain of a dull ache or heaviness in the scrotum or lower abdomen. Not infrequently, a diagnosis of epididymitis is made. In this situation, ultrasound may reduce the delay. In approximately 10% of patients evidence of metastasis may be the pre- 222 Tumours of the testis and paratesticular tissue
senting symptom: back or abdominal pain, gastrointestinal problems, cough or dyspnoea. Gynecomastia may also be seen in about 5% of cases. Occasionally, extensive work ups have resulted without an adequate examination of the genitalia. Imaging Ultrasound (US) is the primary imaging modality for evaluating scrotal pathology. It is easily performed and has been shown to be nearly 100% sensitive for identifying scrotal masses. Intratesticular versus extratesticular pathology can be differentiated with 98-100% sensitivity {211,378,2194}. The normal testis has a homogeneous, medium level, granular echo texture. The epididymis is isoechoic to slightly hyperechoic compared to the testis. The head of the epididymis is approximately 10-12 mm in diameter and is best seen in the longitudinal plane, appearing as a slightly rounded or triangular structure on the superior pole of the testis. Visualization of the epididymis is often easier when a hydrocele is present. When evaluating a palpable mass by ultrasound, the primary goal is localization of the mass (intratesticular versus extratesticular) and further characterization of the lesion (cystic or solid). With rare exception, solid intratesticular masses should be considered malignant. While most extratesticular masses are benign, a thorough evaluation must be performed. If an extratesticular mass has any features suspicious of malignancy it must be removed. The sonographic appearance of testicular tumours reflects their gross morphology and underlying histology. Most tumours are hypoechoic compared to the surrounding parenchyma. Other tumours can be heterogeneous with areas of increased echogenecity, calcifications, and cyst formation {211,378,927,1007, 2194,2347}. Although larger tumours tend to be more vascular than smaller tumours, colour Doppler is not of particular use in tumour characterization but does confirm the mass is solid {1126}. Epididymal masses are more commonly benign. It can, however, be difficult to differentiate an epididymal mass from one originating in the spermatic cord or other paratesticular tissues. This is especially true in the region of the epididymal body and tail where normal structures can be difficult to visualize. Since ultrasound is easily performed, inexpensive, and highly accurate, magnetic resonance (MR) imaging is seldom needed for diagnostic purposes. MR imaging can, however, be a useful problem solving tool and is particularly helpful in better characterizing extratesticular solid masses {507,2362}. Computed tomography (CT) is not generally useful for differentiating scrotal pathology but is Table 4.02 Overview of the three different subgroups of testicular germ cell tumours, characterized by age at clinical presentation, histology of the tumour, clinical behaviour and genetic changes. Age of the patient at clinical presentation (years) Adolescents and young adults (i.p. 15-45) Elderly (i.p. over 50) Histology of the tumour 0-5 Teratoma and/or yolk sac tumour Seminoma Non-seminoma (embryonal carcinoma, teratoma, yolk sac tumour, choriocarcinoma) Spermatocytic Seminoma * found in all invasive TGCTs, regardless of histology. Clinical behaviour Benign Malignant Malignant Malignant Benign, although can be associated with sarcoma Chromosomal imbalances Not found Loss: 6q Gain: 1q , 20q, 22 Aneuploid, and Loss: 11, 13, 18, Y Gain: 12p*, 7, 8, X Gain: 9 the primary imaging modality used for tumour staging. Tumour markers There are two principal serum tumour markers, alpha fetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (ßhCG). The former is seen in patients with yolk sac tumours and teratomas, while the latter may be seen in any patients whose tumours include syncytiotrophoblastic cells. AFP is normally synthesized by fetal yolk sac and also the liver and intestine. It is elevated in 50-70% of testicular germ cell tumours and has a serum half life of 4.5 days {305,1333}. hCG is secreted by placental trophoblastic cells. There are two subunits, alpha and beta, but it is the beta subunit with a half life of 24-36 hours that is elevated in 50% of patients with germ cell tumours. Patients with seminoma may have an elevation of this tumour marker in 10-25% of cases, and all those with choriocarcinoma have elevated ßhCG {1333}. If postorchiectomy levels do not decline as predicted by their half lives to appropriate levels residual disease should be suspected. Also a normal level of each marker does not necessarily imply the absence of disease. Lactate dehydrogenase (LDH) may also be elevated, and there is a direct relationship between LDH and tumour burden. However, this test is nonspecific although its degree of elevation correlates with bulk of disease. Tumour spread and staging The lymphatic vessels from the right testis drain into lymph nodes lateral, anterior, and medial to the vena cava. The left testis drains into lymph nodes distal, lateral and anterior to the aorta, above the level of the inferior mesenteric artery. These retroperitoneal nodes drain from the thoracic duct into the left supraclavicular lymph nodes and the subclavian vein. Somatic genetics Epidemiology, clinical behaviour, histology, and chromosomal constitution define three entities of germ cell tumours (GCTs) in the testis {1540,1541,1965}: teratomas and yolk sac tumours of neonates and infants, seminomas and non-seminomas of adolescents and young adults, the so called TGCTs, and the spermatocytic seminomas of elderly. Germ cell tumours 223
Page 1 and 2: CHAPTER 4X Tumours of the of the Te
Page 3 and 4: TNM classification of germ cell tum
Page 5: Germ cell tumours P.J. Woodward A.
Page 9 and 10: A B Fig. 4.03 Germ cell tumours gen
Page 11 and 12: process at all {1524}. In addition,
Page 13 and 14: A B Fig. 4.12 Comparison of morphol
Page 15 and 16: small tumour insufficient to produc
Page 17 and 18: A B C Fig. 4.22 Seminoma. A Pseudog
Page 19 and 20: A B Fig. 4.27 Spermatocytic seminom
Page 21 and 22: Differential diagnoses Differential
Page 23 and 24: Histologic patterns Microcystic or
Page 25 and 26: A Fig. 4.40 Yolk sac tumour. A Pleo
Page 27 and 28: Teratoma Teratomas are generally we
Page 29 and 30: A B C Fig. 4.49 Teratoma. A Teratom
Page 31 and 32: A B Fig. 4.52 Teratoma with somatic
Page 33 and 34: A B Fig. 4.59 Mixed germ cell tumou
Page 35 and 36: A B C Fig. 4.64 Leydig cell tumour.
Page 37 and 38: A Fig. 4.69 Androgen insensitivity
Page 39 and 40: tinguished from Sertoli cell nodule
Page 41 and 42: ound and have spherical, regularly
Page 43 and 44: Tumours containing both germ cell a
Page 45 and 46: Miscellaneous tumours of the testis
Page 47 and 48: Lymphoma and plasmacytoma of the te
Page 49 and 50: Tumours of collecting ducts and ret
Page 51 and 52: Tumours of paratesticular structure
Page 53 and 54: Epidemiology Nodular mesothelial hy
Page 55 and 56: A B Fig. 4.104 Papillary cystadenom
Page 57 and 58:
Fig. 4.109 Desmoplastic small round
Page 59 and 60:
Fig. 4.115 Leiomyosarcoma. Coronal,
Page 61 and 62:
Secondary tumours C.J. Davis Defini
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CHAPTER X CHAPTER 4 - Cancer et environnement

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