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.

Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience

“…[20][21][22] HDMTX, typically dose >500mg/m 2 , is effective in penetrating the blood-brain and blood-testes barrier, exerting cytocidal effect in the interstitial tissue of the testes. 19 This has translated to decreased use of radiotherapy, even in the setting of testicular relapse. Our institution has been incorporating HDMTX since the 1990s, which is likely contributing to the low testicular relapse rates even among the non-boost subsets.…”

“…Our institution has been incorporating HDMTX since the 1990s, which is likely contributing to the low testicular relapse rates even among the non-boost subsets. 17,19 Even among patients treated with testicular boost, relapses in the testes have been observed. Li et al also described an isolated testicular relapse in a boy with Ph+ ALL who received 4 Gy testicular boost in addition to 12 Gy TBI as part of the conditioning regimen.…”

“…12,13 Moreover, recent series have reported the rarity and decreasing incidence of testicular relapse with the use of modern systemic therapy regimens that typically include high dose methotrexate (HDMTX). [14][15][16][17][18][19][20][21][22] As a result, incorporation of a testicular radiation boost in addition to TBI has not been universally adopted, with many institutions using it, and some institutions reserving it only for persistent or recurrent leukemic disease in the testes after completion of induction systemic therapy. [14][15][16][17] Thus, the current role of testicular radiation boost as part of TBI in children with leukemia remains unclear, with a lack of clarity and paucity of data regarding the effects of testicular boost on disease control and toxicity outcomes available to guide practice 1 .…”

Shear-wave elastography for the assessment of testicular involvement of hematologic malignancies in children and young adults: a feasibility study

“…The most common pediatric hematologic malignancy is acute lymphoblastic leukemia. Overt testicular involvement is more common in pediatric patients than in adults at diagnosis despite the rarity of this entity, and it has the risk of testicular relapse due to the blood-testis barrier, even if systemic chemotherapy is administered [ 16 ]. Testicular involvement often presents as leukemic cell infiltrations in the testis with a bone marrow abnormality in pediatric patients, whereas adult patients older than 60 years present with primary lymphoma such as diffuse large B-cell lymphoma in the testis [ 17 ].…”

Adjuvant Scrotal Radiation Therapy As Bridging Therapy to Chimeric Antigen Receptor T-Cell Following Extramedullary Relapse in B-Cell Acute Lymphoblastic Leukemia

“…In this patient, there was concern that systemic therapies would have decreased availability in the uninvolved testicle due to the blood-testis barrier, although this impact is a matter of controversy and the impact it could have on CAR T function is not well-defined [ 18 ]. Regardless, in the setting of unilateral testicular relapse, prophylactic radiation following orchiectomy is recommended, irrespective of whether CAR T is planned, given limited data for CAR T when patients have testicular relapse [ 19 ]. Data on contralateral testicle failure is limited, but in one small case report of patients with isolated testicular relapse, three of seven patients treated with orchiectomy without adjuvant radiation subsequently relapsed in the testicle [ 20 ].…”