Journal of Reproductive Immunology, 18 (1990) 117-- 121

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Elsevier Scientific Publishers Ireland Ltd.

JRI 00667

Testicular relapse of acute lymphoblastic leukemia (ALL) E. M a r t i n Ritz6n Pediatric Endocrinology Unit, Department of Pediatrics, Karolinska Hospital, S-104 O1 Stockholm

(Sweden)

Summary Several aspects of acute lymphoblastic leukemia (ALL) converge towards the testis: (1) the overall prognosis is worse for boys than for girls; (2) the testis is a more frequent site of relapse of ALL than other organs; (3) age over 10 years (coinciding with the start of pubertal activation) is a recognized "high risk" background factor; (4) occult testicular relapse of ALL seems to be common. The underlying mechanisms behind these observations are discussed. If immunological defence mechanisms are important for the rejection of ALL cells from the body, the immunological tolerance of the testicular microenvironment might favour growth of ALL cells. Alternatively, the presence of specific growth promoting factors in the testis might enhance tumour cell proliferation. In this context, the newly discovered presence of a lymphocyte growth factor (interleukin-l-like, IL-1) at high concentrations in the testis of several mammals, including man, is of great interest. As this factor seems to be under hormonal control, in future it may offer opportunities to influence the tendency to testicular involvement, and thus prognosis, in ALL. Key words: testis; acute lymphoblastic leukemia; growth factors; suppressor

factors.

Introduction Survival after childhood A L L has improved remarkably during the last decades. In a recent review o f all children diagnosed in the Nordic countries from 1981 to 1985, 4-year survival has increased to an average of about 60o70 from a previous value close to 0o70. In the most favourable subgroup (females between 2 and 10 years o f age having a white blood cell count less than 0165-0378/90/$03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd. Published and Pr~,ated in Ireland

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20 X 109/1), 4-year survival was better than 70°70 (Gustafsson et al., 1987). However, in all follow-up studies of ALL, boys are found to be worse off than girls. In the study cited above, the male/female difference was most marked in the high risk group; out of a total of 165 children in this group, 70% of the girls had an event-free survival for more than 50 months, compared to only 37% of the boys. This was corroborated by observations by the same authors for children with A L L diagnosed between 1973 and 1980, followed for up to 8 years after diagnosis; in the whole group of 483 children, 50% of the girls but only 30% of the boys were still in complete clinical remission 8 years after diagnosis. In a Scandinavian group of 367 children with ALL, the peak incidence was between 2 and 3 years of age, with a second smaller peak at 13 years (Gustafsson et al., 1981). During the age periods 2--4 and 9--13 years, there was a significantly higher incidence among boys than among girls. Also, an age at diagnosis of less than 1 and more than 10 years has been recognized to constitute a factor that increases the risk for fatal outcome of ALL (Robison et al., 1980). The second peak at 13 years and the worsened prognosis below 1 and above 10 years coincide with periods of increased gonadal activity, compared to the period of relatively good prognosis between 2 and 10 years of age. A m o n g the children surviving for the first 3 years, testicular relapse accounts for a major fraction of the worsened prognosis of boys versus girls. However, bone marrow relapse is also more c o m m o n in boys than in girls (Sather et al., 1981). The reason for this apparent sex difference in survival after ALL is not clear. Endocrine factors are of obvious interest; either gonadal secretions or the intragonadal milieu itself might influence the persistence of ALL cells. The latter aspect has been studied extensively. Incidence of testicular leukemia

In postmortem studies, the reported incidence of testicular involvement ranges from 28°70 to 92°7o/~(Hustu and Aur, 1978), while the ovary is infiltrated in 11--24070 of the cases. The testes were more frequently affected than any other organ. The frequency of testicular involvement during the course of the disease is more difficult to assess; even after three years of continuous complete remission, 5 out of 59 boys that underwent testicular biopsy proved to have occult testicular leukemia (Askin et al., 1981). On top of that, the incidence of overt testicular leukemia has been reported to be between 8°7o and 16°70 (Stoffel et al., 1975; Kuo et al., 1976; Steinfeld, 1976; Schaison et al., 1977). Thus, it can be concluded that the testis is especially prone to be a site of relapse of ALL. - - T e s t i c u l a r leukemia is not restricted to the periods of testicular activation. In a series of 169 boys with leukemia in remission, reported by Hustu and

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Aur (1978), 25 boys developed overt clinical signs of testicular relapse. Their median age at diagnosis of leukemia was 4 years (range 2--12), at the time of testicular involvement 9 years (range 3--13). This is compatible with an increased tendency to develop testicular infiltrates when puberty is approaching, but there are no studies that report the pubertal stage either at first diagnosis of ALL or at the time of relapse. In another group of 361 boys with ALL who achieved a first remission, 20 later developed testicular relapse as the first sign of recurrency, or concurrent with bone marrow relapse. Only one of these boys was more than 10 years old (Nesbit et al., 1980). Local factors possibly involved in testicular ALL

In looking for factors responsible for the tendency of ALL cells to thrive in the testis, several factors have to be considered: the vascular endothelial barrier; the interstitial cells (including Leydig cells, macrophages, leukocytes, fibroblast-like cells and others); secretions by the above cells and by Sertoli cells; and the so-called blood-testis barrier (here defined as the tight inter-Sertoli cell junctions). As the leukemic infiltrates are localized to the interstitium, it is unlikely that the intratubular milieu is important for the occurrence of testicular leukemia. The normal testis undergoes dramatic changes from childhood to full sexual maturity. The Leydig cells gradually increase their secretion of steroids, notably testosterone, under the influence of pituitary LH; the Sertoli cells change their secretory pattern of several products, mostly due to the increasing stimulation by FSH and testosterone; and the vascular endothelium changes its permeability to both cells and macromolecules. The testis is now known to be a site of intense cell-to-cell communication through soluble factors. This milieu creates conditions for the most active cell proliferation of the adult human body, that is, spermatogenesis. The vascular endothelium of the testis lacks fenestrations between endothelial cells (see Setchell et al., this issue). This may slow down but not inhibit passage of cytotoxic drugs used in treatment of ALL. It is unlikely that this barrier would create a real concentration gradient between blood and the interstitial space, but this should be studied for the drugs used. Several of the above clinical observations of impaired prognosis in boys and testicular relapse of ALL would be understood if the Leydig cell produced factors that promote lymphoblast proliferation. Testosterone itself does not seem to promote lymphocyte proliferation (yon Euler et al., unpublished), but methionine enkephalin and substance P, both of which may be synthesized by Leydig cells, stimulate lymphocyte proliferation in vitro (see P611~nen et al., this issue). However, direct ceil-to-cell contact between Ley-

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dig cells and lymphocytes seems to inhibit rather than to stimulate lymphocyte growth in vitro (see P611~inen et al., this issue). It is not known to what extent the immune system participates in the defence against overt disease or relapse of ALL. However, the identification of a lymphocyte growth inhibiting factor (see P611~nen et al., this issue) in the testicular interstitium is of obvious interest. This factor may contribute to the marked immunosuppression that occurs naturally in the testis (see Maddocks and Setchell, this issue). If there are tumour-specific antigens on ALL cells, the immunosuppression in the testis may completely inhibit an immune response against the leukemic cells in this site. The testicular immunosuppressive activity could also be involved in the high relapse rate of acute lymphoblastic leukemia in the testis, if it affected the malignant lymphocytes and decreased their proliferative activity, because drugs used in the chemotherapy of acute lymphoblastic leukemia, such as vincristine, which inhibits formation of the nuclear spindles, and mercaptopurine, which inhibits DNA and RNA synthesis, affect non-dividing cells poorly. Sertoli cells produce a multitude of regulatory peptides, which are partly secreted into the interstitial space (see Maddocks et al., this issue). Many of these peptides are identified as growth factors, either unique to the testis or c o m m o n to several organ systems. It is not surprising to find growth factors in the testis, considering the rapid rate of germ cell proliferation. In the context of testicular relapse of ALL, it is of special interest that the seminiferous tubules (Sertoli cells and possibly other cells) produce large amounts of an interleukin-l~-like peptide that can be recovered from homogenates of whole testis, from seminiferous tubules, and from spent media from tubule incubations, with and without lining peritubular cells (S6der et al., 1988). It is present in several species, including man. In the rat it has been demonstrated in the interstitial fluid and it has been proven to be dependent on the age of the rat and the state of gonadotropin stimulation. This interleukin-lotlike peptide that is described in more detail by O. S6der elsewhere in this issue (see P611~nen et al.), is of obvious interest in the search for the cause of testicular ALL. In conclusion, the testis has been shown to be a c o m m o n site of recurrency of ALL, and boys have a worse prognosis than girls. An age above 10 years (coinciding with the start of puberty) is an additional risk factor. This points to the testis as the site of production of factors that promote ALL cell growth or survival from treatment with cytotoxic drugs. Both specific growth factors (especially cytokines) and the marked immunosuppression in the testis may relate to the tendency for testicular relapse of ALL. Once this has been worked out, we may have the therapeutic tools to improve further survival after ALL.

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References Askin, F.B., Land, V.J., Sullivan, M.P., Ragab, A.H., Steuber, C.P., Dyment, P.G., Talbert, J. and Moore, T. (1981) Occult testicular leukemia: Testicular biopsy at three years continuous complete remission of childhood leukemia: A southwest oncology group study. Cancer 47,470--475. Gustafsson, G., Kreuger, A. and Dohlwitz, A. (1981) Acute lymphoblastic leukemia in Swedish children 1973--1978. Acta Pediatr. Scand. 70, 609--614. Gustafsson, G., Garwicz, S., Hertz, H., Johanesson, G., Jonmundsson, G., Moe, P.J., Salmi, T., Seip, M., Siimes, M.A., Yssing, M. and Ahstr6m, L. (1987) A population-based study of childhood acute lymphoblastic leukemia diagnosed from July 1981 through June 1985 in the five Nordic countries. Acta Paediatr. Scand. 76, 781--788. Hustu, H.O. and Aur, R.J.A. (1978)ExtrameduUary leukaemia. Clin. Haematol. 7,313--337. Kuo, T.-T., Tschang, T.-P. and Chu, J.-Y. (1976) Testicular relapse in childhood acute leukemia during bone marrow remission. Cancer 38, 2604--2612. Nesbit, M.E., Robison, L.L., Ortega, J.A., Sather, H.N., Donaldson, M. and Hammond, D. (1980) Teso ticular relapse in childhood acute lymphoblastic leukemia: association with pretreatment patient characteristics and treatment. A report for Childrens Cancer Study Group. Cancer 45, 2009--2016. Robison, L.L., Nesbit, M.E., Sather, H.N., Hammond, G.D. and Coccia, P.F. (1980) Assessment of the interrelationship of prognostic factors in childhood acute lymphoblastic leukemia. Am. J. Pediatr. Hematol./Oncol. 2, 5--13. Sather, H., Coccia, P., Nesbit, M., Level, C. and Hammond, D. (1981) Disappearance of the predictive value of prognostic variables in childhood acute lymphoblastic leukemia. Cancer 48,370--376. Schaison, G., Jacquillat, C., Weil, M., Auclerc, M.F., Desprez Cutely, J.-P., Bernard, J. (1977) Rechute ~tlocalization gonadique au cours des leuc6mies aigt~6s. 113 cas. Nouv. Presse Med. 6, 1029--1032. SOder, O., Syed, V., P611~inen, P., Gustafsson, K., Granholm, K., Khan, S., Arver, S., Holst, M., yon Euler, M. and Ritzen, E.M. (1988) Testicular interleukin-l-like factor. In: The Molecular and Cellular Endocrinology of the Testis (Cooke, B.A. and Sharpe, R.M., eds.), Serono Symposia Publication, Volume 50, pp. 325--332. Raven Press, New York. Steinfeld, A.D. (1976) Radiation therapy in the treatment of leukemic infiltrate of the testes. Radiology 120, 681--682. Stoffel, T.J., Nesbit, M.E. and Levitt, S.H. (1975) Extramedullary involvement of the testes in childhood leukemia. Cancer 25, 1203-- 1211.

Testicular relapse of acute lymphoblastic leukemia (ALL).

Several aspects of acute lymphoblastic leukemia (ALL) converge towards the testis: (1) the overall prognosis is worse for boys than for girls; (2) the...
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