University Departments of 1Growth and Reproduction and 2 Oncology, Rigshospitalet, Copenhagen, Denmark
* Correspondence to: Dr C. E. Hoei-Hansen, University Department of Growth and Reproduction (GR5064), Rigshospitalet Blegdamsvej 9, DK2100 Copenhagen, Denmark. Tel: +45-35-45-50-64; Fax: +45-35-45-60-54; Email: chh{at}dadlnet.dk
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Abstract |
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Key words: intratubular germ cell neoplasia, unclassified type, testicular cancer, testicular dysgenesis syndrome, testicular intraepithelial neoplasia
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Introduction |
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Virtually all TGCTs are believed to originate from a common precursor, the carcinoma in situ (CIS) cell [3], with the exception of the rare spermatocytic seminoma occurring in elderly men and infantile tumours (yolk sac tumours and mature teratomas). Varying terms for the precursor are used, including intratubular germ cell neoplasia [4
] and testicular intraepithelial neoplasia [5
]. At present, very few patients are diagnosed with CIS, although CIS almost invariably progresses to overt testicular cancer. The circumstances in which CIS should be suspected are well defined, and the opportunity to intervene is available before an invasive tumour has developed.
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Histopathology and biological aspects of CIS |
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Risk factors and prevalence of CIS in various patient populations |
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Information about the prevalence of CIS in the general population of young adults is not available, but has been estimated to be slightly below 1% in Denmark, i.e. the same as the lifetime risk of testicular cancer in the Danish male population [22]. In retrospective studies of infertile men, CIS was found in
0.51% [23
, 24
] and infertility has been stated as a risk factor for testicular cancer [25
]. In infertile patients, the highest risk of CIS is in males with atrophic testes and extremely low sperm counts (<3 x 106/ml). Patients with a one-sided testicular tumour have an increased risk of developing a second tumour, and the prevalence of contralateral CIS seems to be around 58%, corresponding to the cumulative incidence of bilateral testicular tumours [8
, 26
, 27
]. In adult men with a history of cryptorchidism, CIS prevalence is 24% [28
], which corresponds well to the known incidence of TGCTs in this group. There is an increased risk of CIS in patients with cryptorchidism irrespective of the age of surgical orchidopexy. Children with ambiguous genitalia and testicular tissue harbour CIS in >6% of cases [29
]. Finally, in a recent study of 46 intersexual patients, CIS (in addition to gonadoblastoma) was detected in more than half of cases with mixed or partial gonadal dysgenesis and in 16.7% of cases with true haermaphroditism [30
].
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Current views on CIS pathogenesis |
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A possible causal role of lifestyle or environmental factors in the aetiology is implicated by the significant rise in incidence of TGCT and other symptoms of the TDS in recent decades [1, 33
36
], and the fact that epidemiologically the occurrence of one disorder is a risk factor for the occurrence of another. We assume that all components of TDS share common aetiological factors, which include environmental factors acting during development in individuals with genetic predisposition [37
]. This may be due to an intrauterine or perinatal hormonal imbalance that delays differentiation of germ cells and may render them more susceptible to transformation [38
]. The following malignant progression can, in early infancy or around puberty, be triggered by endocrine stimulation [31
, 39
]. This may explain the extremely rare occurrence of testicular tumours in individuals with hypogonadotropic hypogonadism, despite the fact that the testes are usually underdeveloped. The hormonal links have drawn attention to endocrine disrupters, chemicals widely present in the environment that interfere with hormonal pathways. The candidate chemical agents include natural and synthetic oestrogens and anti-androgens, e.g. those often found in plastics and cosmetics or components of pesticides. The two groups of hormones are known to adversely affect testicular development in animal models [34
]. However, the causal link between endocrine disrupters and human reproductive disorders is much more difficult to prove, and remains a plausible hypothesis.
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Clinical diagnosis and management of CIS |
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Performing a contralateral testicular biopsy at the time of orchidectomy remains a contentious issue, where some groups prefer a close follow-up with emphasis on patient education and self-examination. However, despite excellent treatment results for testicular cancer in the cisplatin era, a second testicular cancer is not without risk, and some of the patients that develop a second testicular cancer will die of their disease. The 5-year survival rate for patients with stage I testicular cancer is 99%, but for patients with disseminated disease the 5-year survival rate is 90% and 80% for patients with good and intermediate prognosis, respectively [36
]. In patients who have had a negative contralateral biopsy performed, the follow-up period may be limited to 5 years, whereas in patients in whom a contralateral biopsy has not been performed, the follow-up period should be extended to perhaps 25 years or more; this is an unnecessary psychological burden to the patients, as well as having economical implications.
An auxiliary method to select patients at-risk for CIS is ultrasonography, as testes harbouring CIS may have an irregular echo pattern with so-called microliths detected by ultrasound (Figure 1F). Despite that microlithiasis may also be observed in testes without CIS, the presence of these changes, especially in patients with smaller testes, indicates an increased risk of CIS [24, 42
]. The pathophysiological background for the irregular echo pattern is not known, but may be associated with either CIS, intratubular microcalcifications or histological testicular dysgenesis with hyalinised or atrophic testicular tubules [43
].
In general, we recommend that screening for CIS should be performed in the patient groups listed in Table 1. Management of CIS prevents progression to an overt TGCT and possible metastasis, and may either be orchidectomy, radiotherapy or, in seldom cases, surveillance. The treatment modality depends mainly on the age of the patient and whether the neoplasia is unilateral or bilateral. If CIS-like cells are detected in the testis of a prepubertal boy, therapy must be individualised, as prepubertal CIS may be difficult to acknowledge histologically [44] and the natural history of prepubertal CIS has not been fully elucidated [9
, 45
]. This could be the case in a cryptorchid testis, where the biopsy may be delayed until after puberty, and the further management then planned if an adult CIS pattern is confirmed. Treatment may be delayed, with careful surveillance, in patients with CIS who wish to father a child, as there usually is a relatively long time-span between the diagnosis of CIS and the development of an overt TGCT. Whatever the reason for the delay, the patient should be offered semen cryopreservation when CIS has been diagnosed.
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A staging procedure including X-ray of the chest, computed tomography scan of the abdomen and measurement of serum tumour markers (alpha-fetoprotein and ß-human chorionic gonadotrophin) should be performed in patients with CIS, even without an overt tumour. This maps the extent of the pathology and is imperative, because testicular CIS may accompany up to one-third of cases with an extragonadal GCT, especially those with a retroperitoneal tumour [50]. In patients with CIS, pretreatment fertility is usually poor [51
], and cryopreservation of semen should always be considered prior to initiation of treatment, as CIS and testicular cancer often strikes young men who have not yet started or completed a family. Follow-up after the treatment of CIS should include determination of serum testosterone levels, and replacement therapy be offered in patients with subnormal levels.
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Concluding remarks |
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In light of the recent marked increase in incidence of testicular cancer, further research is warranted to identify causal factors that would explain this rise and perhaps lead to a change in the trends. Furthermore, it would be valuable to obtain a method of non-invasive detection of CIS, thus rendering obsolete the continuous discussion on the usefulness of the surgical biopsy. Whether or not such a method becomes available soon, and in spite of the high cure rate of testicular cancer, efforts should be made to establish diagnosis at the preinvasive stage, as the diagnosis of CIS is not of mere academic interest, but makes it possible to offer the patient optimal, evidence-based treatment.
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Acknowledgements |
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Received for publication October 6, 2004. Revision received December 20, 2004. Accepted for publication December 21, 2004.
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References |
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