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[1650]. The risk of low libido and ED is also increased in TGCT patients [1676]. Patients treated for TGCT are
also at increased risk of CVD [1672]. Therefore, patients may require a multi-disciplinary therapy approach and,
in this context, survivorship programmes incorporating a holistic view of patients considering psychological,
medical and social needs could be beneficial. In patients who place a high value on fertility potential, the
use of testosterone therapy in men with symptoms suggestive for TDS needs to be balanced with worsening
spermatogenesis. In these patients consideration can be given to the use of selective oestrogen receptor
modulators (SERMs; e.g., clomiphene) or gonadotrophin analogues (e.g., hCG), although these are off-label
treatments in this particular clinical setting.

10.4.2.2 Testicular microcalcification (TM)
Microcalcification inside the testicular parenchyma can be found in 0.6-9% of men referred for testicular US
[1677, 1678]. Although the true incidence of TM in the general population is unknown, it is most probably rare.
Ultrasound findings of TM have been seen in men with TGCT, cryptorchidism, infertility, testicular torsion and
atrophy, Klinefelter syndrome, hypogonadism, male pseudohermaphroditism and varicocele [1625]. The incidence
reported seems to be higher with high-frequency US machines [1679]. The relationship between TM and infertility
is unclear, but may relate to testicular dysgenesis, with degenerate cells being sloughed inside an obstructed
seminiferous tubule and failure of the Sertoli cells to phagocytose the debris. Subsequently, calcification with
hydroxyapatite occurs. Testicular microcalcification is found in testes at risk of malignant development, with a
reported incidence of TM in men with TGCT of 6-46% [1680-1682]. A recent systematic review and meta-analysis
of case-control studies indicated that the presence of TM is associated with a ~18-fold higher odds ratio for
testicular cancer in infertile men (pooled OR: 18.11, 95% CI: 8.09, 40.55; P < 0.0001) [1607].

Testicular microcalcification should therefore be considered pre-malignant in this setting and patients
counselled accordingly. Testicular biopsies from men with TM have found a higher prevalence of GCNIS,
especially in those with bilateral microcalcifications [1683]. However, TM can also occur in benign testicular
conditions and the microcalcification itself is not malignant. Therefore, the association of TM and TGCT is
controversial and the challenge is to identify those men at risk of harbouring GCNIS and future risk of TGCT.
Further investigation of the association between TM and GCNIS requires testicular biopsies in large series
of men without signs of TGCT with or without risk factors for TGCT. However, clinicians and patients should
be reassured that testicular cancer does not develop in most men with asymptomatic TM [1660]. Available
data indicate that only men in whom TM is found by US, and who have an increased risk of TGCT, should be
offered testicular biopsy to exclude GCNIS. Men potentially at high-risk of harbouring or developing GCNIS
include those with infertility, atrophic testes, undescended testes, history of TGCT, and contralateral TM and
it has been suggested that men with these risk factors could be offered testicular biopsy [1654, 1659]. The
normal mean testicular volume is estimated to be 12-30 mL and < 12 mL is considered small [1677]. Patients
with a history of TGCT and TM in the contralateral testis and sub-fertile patients have been demonstrated to
have an increased risk of GCNIS [1660], while there are only a few studies showing a further increase in GCNIS
with TM in the context of cryptorchidism [1654, 1678, 1684]. A useful algorithm has been proposed [1654] to
stratifying those patients at increased risk of GCNIS who may benefit from testicular biopsy. However, when
undertaking a biopsy in this setting, the full risks and complications of adopting this strategy must be explained
to the patient. With the lack of availability of large cohort studies, these recommendations must be treated with
caution given the risk of overtreatment (i.e., biopsy) in these patients.

Decastro et al. [1685] suggested that testicular cancer would not develop in most men with TM (98.4%)
during a 5-year follow-up. As such, an extensive screening programme would only benefit men at significant
risk. In this context it would be prudent to advise patients with TM and risk factors for testicular cancer to at
least undergo regular testicular examination. It has been suggested that these patients could also be offered
annual physical examination by a urologist and US follow-up, although follow-up protocols may be difficult
to implement in this invariably young cohort of patients [1625]. As testicular atrophy and infertility have an
association with testicular cancer, some authors recommend biopsy or follow-up US if TM is seen [1654].
However, most patients who are azoospermic will be undergoing therapeutic biopsy (i.e., with the specific
purpose of sperm retrieval) and therefore a definitive diagnosis can be made and there is a lack of evidence
demonstrating a higher prevalence of testicular cancer in patients with both TM and testicular atrophy. In
patients with incidental TM, the risk of GCNIS is low and a logical approach is to instruct patients to perform
regular testicular self-examination.

142 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021