Testicular involvement of acute lymphoblastic leukemia in children and adolescents: Diagnosis, biology, and management

Abstract

Acute lymphoblastic leukemia (ALL) in children and adolescents can involve the testes at diagnosis or upon relapse. The testes were long considered pharmacologic sanctuary sites, presumably because of the blood-testis barrier, which prevents the entry of large-molecular-weight compounds into the seminiferous tubule. Patients with testicular involvement were historically treated with testicular irradiation or orchiectomy. With the advent of contemporary intensive chemotherapy, including high-dose methotrexate, vincristine/glucocorticoid pulses, and cyclophosphamide, testicular leukemia present at diagnosis can be eradicated, with the risk of testicular relapse being 2% or lower. However, the management of testicular leukemia is not well described in the recent literature and remains relevant in low- and middle-income countries where testicular relapse is still experienced. Chemotherapy can effectively treat late, isolated testicular B-cell ALL relapses without the need for irradiation or orchiectomy in patients with an early response and thereby preserve testicular function. For refractory or early-relapse testicular leukemia, newer treatment approaches such as chimeric antigen receptor-modified T (CAR-T) cell therapy are under investigation. The control of testicular relapse with CAR-T cells and their penetration of the blood-testis barrier have been reported. The outcome of pediatric ALL has been improved remarkably by controlling the disease in the bone marrow, central nervous system, and testes, and such success should be extended globally. LAY SUMMARY: Acute lymphoblastic leukemia (ALL) in children and adolescents can involve the testes at diagnosis or upon relapse. Modern intensive chemotherapy has largely eradicated testicular relapse in high-income countries. Consequently, most current clinicians are not familiar with how to manage it if it does occur, and testicular relapse continues to be a significant problem in low- and middle-income countries that have not had access to modern intensive chemotherapy. The authors review the historical progress made in eradicating testicular ALL and use the lessons learned to make recommendations for treatment.

Keywords: acute lymphoblastic leukemia; adolescents; biology; children; diagnosis; management; testicular leukemia.

Figure 1.. Ultrasound imaging of testicular leukemia

(A) Asymmetric testes (left > right). (B) Doppler sagittal imaging of the right testis shows normal vascularity at the epididymis. (C) Doppler sagittal imaging of the left testis shows hypervascularity.

Figure 2.. Decreasing incidences of isolated testicular relapses

The percentages of isolated testicular relapse are shown according to the decade in which the treatment protocols were initiated. As the testicular relapses were rarely presented as survival curves, the percentages of relapses represent proportions (total isolated testicular relapses/total male enrollments) during the median follow-up period of each treatment protocol. The numbers in parentheses show the total male enrollments in the study. References for the treatment studies are provided in the supplemental information. Abbreviations: CALGB, Cancer and Leukemia Group B; CCG, Children’s Cancer Group; UKALL, United Kingdom Acute Lymphoblastic Leukemia; AIEOP, Associazione Italiana di Ematologia e Oncologia Pediatrica; BFM, Berlin–Frankfurt–Münster; DCOG, Dutch Childhood Oncology Group; DFCI, Dana-Farber Cancer Institute; POG, Pediatric Oncology Group; NOPHO, Nordic Society of Pediatric Hematology and Oncology; COG, Children’s Oncology Group

Figure 3.. Possible mechanisms of chemotherapy resistance in the testes

Testicular leukemia relapse is considered to occur as a result of insufficient exposure to chemotherapy. (1) Leukemia relapse in the testes can develop from a clone that is independent of the one seen in the bone marrow relapse; in a patient with relapsed ALL, the testicular leukemia cells were found to have an NT5C2-D407V mutation, whereas the bone marrow cells had an NT5C2-R367Q mutation. (2) The chemotherapy concentration can be reduced in the interstitium; for example, methotrexate levels in the interstitium are lower than those in the serum by a factor of two to four. (3) Tight junctions between the myoid cells and Sertoli cells prevent the entry of large molecules into the seminiferous tubule. Methotrexate levels in seminiferous tubule are lower than those in the serum by a factor of 18 to 50. (4) The testes are 2.5°C colder than the body temperature, which could decrease the efficacy of chemotherapy. (5) P-glycoprotein can export chemotherapy agents (e.g., doxorubicin) from the testes into capillaries. (6) Prostaglandin E2, anti-inflammatory cytokines, and complement inhibitors in the testes help to make the testes an immune-privileged site.