Eble JN, Sauter G., Epstein JI, Sesterhenn IA - iarc

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