Testicular biopsies in men with testicular microlithiasis and additional risk factors for cancer: A case series.

BACKGROUND: Testicular microlithiasis is the presence of small calcifications in the testicular parenchyma. The association between testicular microlithiasis and germ cell neoplasia in situ, a precursor to testicular cancer, is still unclear. OBJECTIVES: To determine the incidence of germ cell neoplasia in situ in men with testicular microlithiasis and evaluate the indication for testicular biopsy according to risk factors in the form of male infertility/reduced semen quality, testicular atrophy, and history of cryptorchidism. MATERIALS AND METHODS: This retrospective case series included all patients diagnosed with testicular microlithiasis who underwent testicular biopsies at three hospitals in Denmark between 2007 and 2021. The medical records of 167 patients were reviewed, and data on patient demographics, testicular microlithiasis characteristics, risk factors, histological findings, and treatments were collected. The main outcome measure was the incidence of germ cell neoplasia in situ in relation to each risk factor. The data were analyzed using descriptive statistics. Logistic regression was used to examine the odds ratio of germ cell neoplasia in situ in patients with testicular microlithiasis and testicular atrophy. RESULTS: Germ cell neoplasia in situ was found in 13 out of 167 patients (7.8% [95% confidence interval: 4.3, 13.2]). Eleven of these had testicular atrophy resulting in a significantly higher incidence in this group than other risk factors (odds ratio 9.36 [95% confidence interval: 2.41, 61.88]; p = 0.004). DISCUSSION: The study comprises the largest cohort to date of men who have undergone testicular biopsies because of testicular microlithiasis and additional risk factors. Limitations include its retrospective design, and relatively low absolute numbers of patients with germ cell neoplasia in situ on biopsies. CONCLUSION: This study found that men with testicular microlithiasis and testicular atrophy are at an increased risk of germ cell neoplasia in situ. Additionally, our results indicate that biopsies should be considered in men with a combination of subfertility and bilateral testicular microlithiasis. Our findings do not support testicular biopsies for men with testicular microlithiasis and other risk factors.

The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients.

INTRODUCTION: In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. MATERIAL AND METHODS: A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. RESULTS: Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). CONCLUSIONS: Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.

Is a CIS phenotype apparent in children with Disorders of Sex Development? Milder testicular dysgenesis is associated with a higher risk of malignancy.

All malignant testicular germ cell tumors (TGCT) of adult men are preceded by an in situ stage (CIS) of protracted evolution. The adult CIS is well characterized, but there is debate on the phenotype of infantile CIS, its distinction from delayed maturation of germ cells and prognostic potential. A large series of 43 patients with Disorders of Sex Development (DSD) and dysgenetic testes (90% ranging from neonates to 12 years, mean age 4.7 years), was studied by quantifying dysgenetic features, degree of germ cell abnormalities/atypia (GCA), expression of OCT 3/4 (a pluripotency-undifferentiation marker), germ cell ploidy and evolution to CIS and invasive TGCT. Findings were compared with those of normal testes. The type of gonads present defined three groups of patients: bilateral testes (BT-DSD, n = 21), one testis and one streak gonad (CT-DSD, C for combined, n = 13), and ovarian-testicular combinations (OT-DSD, n = 9). There were 5 boys with infantile CIS, bilateral in 3 (total of 8 infantile CIS) and two patients with adult CIS, bilateral in one (total of 3 adult CIS). Two patients had bilateral seminomas one at 12-17 and the other at 23 years. Histological dysgenesis was significantly higher in CT-DSD (p < 0.05), that had only 1 CIS. The highest frequency of GCA was in BT-DSD (p < 0.05), which coincided with a total of 11CIS + Seminomas. In all patients, aneuploidy was significantly higher (63%) than diploidy (p < 0.02), and GCA were more frequent in aneuploid than in diploid samples (p < 0.02). All CIS and TGCT were OCT 3/4 positive. Finally, there was a significant association between the triad Aneuploidy + GCA + OCT 3/4 positivity and the incidence of CIS (Fisher Exact test p < 0.002, relative risk 7.0). The degree of testicular dysgenesis (derived from abnormal organization of Sertoli cells in fetal testicular cords) is inversely related to the incidence of CIS. Our data demonstrate that the combined use of OCT 3/4 expression, quantification of germ cell abnormalities-atypia and ploidy in dysgenetic testes can satisfactorily identify infantile CIS with high risk of malignant evolution and set it aside from delayed germ cell maturation with lower or nil neoplastic potential.

Partial orchiectomy and testis intratubular germ cell neoplasia: World literature review.

Approximately 5% of all patients diagnosed with testicular cancer may have contralateral intratubular germ cell neoplasia (ITGCN) and may develop contralateral germ cell tumor. Here, we present a historical review and current literature regarding ITGCN and partial orchiectomy. The PubMed world literature search was performed for articles written in the English language. Search terms used were: Partial orchiectomy and ITGCN, with a return of 322 articles. Articles obtained were from the United States, Germany, Denmark and the Netherlands as well as a few case reports from Australia, France, Turkey and Spain. A critical review of the literature was performed. Partial orchiectomy is an option for the management of testicular malignancy in a select group of patients in whom radical orchiectomy is not desirable, including those with a solitary testicle, bilateral concurrent malignancies and a desire for paternity or being independent from androgen supplementation. Reports have demonstrated the feasibility of partial orchiectomy, but there are strict surgical criteria; tumor less than 2 cm in size, maintenance of cold ischemia, meticulous dissection to maintain testicular blood supply and biopsying of adjacent testicular parenchyma to ensure negative margins and absence of concurrent ITGCN. Partial orchiectomy is followed by testicular irradiation of 18-20 Gy; this radiation dose reduces fertility but maintains leydig cell function with androgen independence. Patients with a history of testicular carcinoma have a 5% chance of developing a metachronous contralateral tumor. Partial orchiectomy is a technically challenging procedure that requires close follow-up, but may represent a reasonable management option in selected patients.