Niels J. van Casteren

Effect of childhood cancer treatment on fertility markers in adult male long-term survivors

Although it is accepted that pediatric cancer treatment harbors a risk of gonadal damage, large cohort studies using up‐to‐date fertility markers are lacking.

Gonadal dysfunction in male cancer patients before cytotoxic treatment

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.

Testicular biopsy: clinical practice and interpretation.

Testicular biopsy was considered the cornerstone of male infertility diagnosis for many years in men with unexplained infertility and azoospermia. Recent guidelines for male infertility have limited the indications for a diagnostic testicular biopsy to the confirmation of obstructive azoospermia in men with normal size testes and normal reproductive hormones. Nowadays, testicular biopsies are mainly performed for sperm harvesting in men with non-obstructive azoospermia, to be used for intracytoplasmic sperm injection. Testicular biopsy is also performed in men with risk factors for testicular malignancy. In a subgroup of infertile men, there is an increased risk for carcinoma in situ of the testis, especially in men with a history of cryptorchidism and testicular malignancy and in men with testicular atrophy. Ultrasonographic abnormalities, such as testicular microlithiasis, inhomogeneous parenchyma and lesions of the testes, further increase the risk of carcinoma in situ (CIS) in these men. For an accurate histological classification, proper tissue handling, fixation, preparation of the specimen and evaluation are needed. A standardized approach to testicular biopsy is recommended. In addition, approaches to the detection of CIS of the testis testicular immunohistochemistry are mandatory. In this mini-review, we describe the current indications for testicular biopsies in the diagnosis and management of male infertility.

Heterogeneous Distribution of ITGCNU in an Adult Testis: Consequences for Biopsy-Based Diagnosis

Carcinoma in situ (CIS) of the testis, also referred to as intratubular germ cell neoplasia unclassified (ITGCNU), is currently accepted as the common precursor for all malignant germ cell tumors of adolescents and adults— that is, the seminomatous and nonseminoma cancers. These preinvasive cells have specific cellular characteristics, which can be used for the early diagnosis—routinely done by morphological analysis, sometimes supported by immunohistochemistry—of tissue obtained by an open surgical biopsy. False-negative biopsy results can occur mostly because of the nonrandom distribution of ITGCNU within the testis, misdiagnosis, or suboptimal tissue treatment and analysis. In this article, we demonstrate the potential pitfalls in the diagnosis of ITGCNU. The results support the use of the highly specific and sensitive immunohistochemical marker OCT3/4 for the diagnosis of ITGCNU and provide evidence for the nonrandom distribution of ITGCNU, which is a significant limitation in the diagnosis of this preinvasive lesion.

Role of Hormonal Treatment in Prostate Cancer Patients with Nonmetastatic Disease Recurrence After Local Curative Treatment: A Systematic Review

CONTEXT The relative benefits and harms of hormonal treatment (HT) versus no or deferred HT in patients with nonmetastatic prostate cancer (PCa) relapse after primary curative therapy are controversial. OBJECTIVE To assess the effectiveness of HT for nonmetastatic PCa relapse, prognostic factors for treatment outcome, timing of treatment, and the most effective treatment strategy to provide guidance for clinical practice. EVIDENCE ACQUISITION A systematic literature search was undertaken incorporating Medline, Embase, and the Cochrane Library (search ended March 2015). Studies were critically appraised for risk of bias. The outcomes included overall and cancer-specific survival, metastasis-free survival, symptom-free survival, progression to castrate resistance, adverse events, and quality of life. EVIDENCE SYNTHESIS Of 9687 articles identified, 27 studies were eligible for inclusion (2 RCTs, 8 nonrandomised comparative studies, and 17 case series). The results suggest that only a subgroup of patients, especially those with high-risk disease, may benefit from early HT. The main predictors for unfavourable outcomes were shorter PSA doubling time (<6-12 mo) and higher Gleason score (>7). Early HT may be warranted for patients with high-risk disease. An intermittent HT strategy appears feasible. Most studies had a moderate to high risks of bias. CONCLUSIONS HT for PCa relapse after primary therapy with curative intent should be reserved for patients at highest risk of progression and with a long life expectancy. The potential benefits of starting HT should be judiciously balanced against the associated harms. PATIENT SUMMARY This article summarises the evidence on the benefits and harms of hormonal treatment in prostate cancer (PCa) patients in whom the disease has recurred following earlier curative treatment. We found that only a select group of patients with aggressive PCa and a fast rising prostate-specific antigen may benefit from early hormonal treatment (HT), whereas in others HT may be more harmful than beneficial.

Testicular microlithiasis is worrisome in a selected patient population.

Correspondence to Leendert H.J. Looijenga, Professor in Translational Patho-oncology, Department of Pathology, Erasmus MC-University Medical Center Rotterdam, (Daniel den Hoed Cancer Center), Josephine Nefkens Institute, Building Be, room 430b, PO Box 2040, 3000 CA Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands Tel: +31 10 7044329; fax 31 10 7044365; e-mail: l.looijenga@erasmusmc.nl