Original article 352
Elective Testicular Biopsy at the End of Maintenance Treatment for Acute Lymphoblastic Leukemia. A Prospective Study A. N. Bikdssy, C. ""1. Kullendorff, E. Arnbjörnsson Departments of Pediatrics and Pediatric Surgery. L'nh'ersity Hospital. Lund, Sweden
Open te ticular wedge biopsy has electi\'ely been performed prior to completion of maintenance therapy far acute lymphoblastic leukemia. 25 boys during 6 years \\'ere included in this prospecti\'e study. Three boys c1e\'eloped testicular enlargement while on maintenance therapy and biopsies confirmecl testicular leukemia. The remaining 22 boys \\we biopsied at termination of maintenance therapy. Occult testicular relapse \\'as re\'ealed on histologie examination in only one boy \\'ith normal testicuJar size. During the follo\\'-up periocl, one boy de\'eloped O\'ert testicular relapse two months after negati\-e biopsy. These results will notjustify electi\'ely performed routine biopsy prior to termination of chemotherapy. Instead, careful and minute clinical examination of the testicles, estimating their size and consistence, should be performed regularly at short inter\·als.
Kcy wo_r_ds_ _ Acute Iymphoblastic leukemia - Children Extramedullary leukemia - Routine procedure - Testicular wedge biopsy
Resume Des biopsies testiculaire chirurgieales furent effectuees electivement, a la fin du traitement de consolidation de leucemies lymphoIdes aigue . 25 enfants furent introduits dans cette etude prospective de 6 ans. Trois enfants ctevelopperent une masse tumorale testiculaire pendant leur traitement de consolidation. Les biopsies confirmerent la presence d'une leucemie dans le testicule. Les 22 autre enfants eurent une biopsie a la fin du traitement de consolidation. Un seul d'entre eux avec un testicule de taille normale a presente une infiltration leucemique. Durant la periode d'ob-
Introduction Significant ad\'ances in treatment of childhood acute lymphoblastic leukemia (ALL) ha\'e resulted in prolonged hematological remis ion for many children. Recognition of Kecel\'ed February
~.
HlV2
Eur.J Pediatr Surg 2 (1992) 352-35-1 © Ilippokrate \'erlag Stullgart \\asson Editeur Pari
sen'ation, un enfant a developpe une recidi\'e testiculaire deux mois apres une biopsie negati\'e. Ces resultats ne justifient pas des biopsies de routine electi\'es a\'antla fin du traitement par chimiotherapie. Cependanl. ils demontrent la necessite d'un examen clinique precis et meticuleux prenant en consideralion la taille, la consistance testiculaire et ceci il de courts inten'alles reguliers.
\\ots-cles Leucemie Iymphobla tique aigue - Enfants - Leucemie extramedullaire - Procedure de routine - Biopsie te ticuJaire
Zusammenfassung Offene Hodenbiopsien wurden zur \'en'ollständigung der Therapie einer akuten Iymphoblastischen Leukämie angewandt. Innerhalb von 6 Jahren wurden 25 Knaben im Rahmen einer prospekti\'en Studie untersucht. Drei Knaben entwickelten \\'ährend der Therapie einen Hodentumor. Die Biopsien bestätigten den Verdacht auf Hodenleukämie. Die übrigen 22 Jungen wurden nach Beendigung der Therapie biopsiert. 1 ur bei einem Knaben mit normaler Hodengröße fanden sich Zeichen für eine leukämische Infiltration. Auf der anderen Seite wurde im , achuntersuchungszeitraum bei einem weiteren Kind 2 Monate nach negativer Hodenbiopsie klinisch ein Rezidiv diagnostiziert. Diese Ergebnisse rechtfertigen keine Routinebiopsie vor Beendigung der Chemotherapie, weisen jedoch auf die otwendigkeit einer sorgfältigen langfristigen klinischen Kontrolle der Hodengröße und Konsistenz in kurzen Abständen hin.
SchI üssel wörter Lymphatische Leukämie - Hodenbiopsie
leukemia in the central ner\"Ous system (CNS) led to improvement in the survival foJlowing prophylactic treatment of Cl S (140). Testicular infiltration may be the fir t e\'ent of ALL recurrence following an extended disease-free period, but it i most frequent 2 to 3 years after diagnosis (6). Im'oh'ement of the testis during chemotherapy, occurring as isolated relapse, indicates that bone marro\\' relapse is likely \\'ithin a few months (9), Routine testicular biopsy has been incorporated into the management of ALL in male patients; ho\\'e\'er, the
Downloaded by: Universite Laval. Copyrighted material.
Summary
diagnostic accuracy of this procedure and its influence on outcome have been widely discussed (8,10,12,13,16). We report on the results of a prospective study evaluating testicular involvement by performing routine testicular wedge biopsy prior to termination of chemotherapy.
Material and methods Twenty-five boys, who were diagnosed as having ALL and aehieved eomplete remission during the period 1983-1988 at the Department of Pediatrics in Lund, entered this study. They were treated aeeording to the eriteria of the Swedish ALL protocol for standard risk (SR) ~ = 19, intermediate risk (IR) ~ = 5 and high-risk (HR) ~ = I patients (4). Their age varied from 2 8112 years to 17 2/ 12 years (mean 6 2/ 12 years) at presentation and no signs of testieular im'ol\'ement oeeurred at diagnosis. Three boys de\'eloped testieular enlargeme nt while on maintenanee therapy. Maintenanee therapy was electively stopped in the remaining 22 boys after two years eomplete eontinuous remission (CCR) in IRIHR group and after 3 years CCR in SR group. An elliptieal orehidometer introdueed by Prader and made of Swedish birehwood was used for determination of testieular \'olume (11). By selecting the wooden model \\'hieh is dosest in volume, the testieular size was determined by pal pation. All 22 boys in CCR underwent bilateral testieular biopsy as a routine proeedure prior to eompletion of therapy. An open wedge biopsy was always performed. The ineision for the testieular biopsy was inguinal in 20 boys and serotal in two boys.
In eaeh case fresh bilateral testieular biopsies were sent to the Department of Histopathology, University Hospital Lund. Following imprint, the speeimens were proeessed aeeording to routine fixing and staining proeedures for eonventional histologie examination. Leukemie relapses were all easiIy deteetable on eonventional histopathologie examination, showing massive infiltrates with Iyrnphoblasts. Additional immunostaining of the sarnples with preseleeted monoclonal antibodies were performed when available using APAAP-teehnique.
Results All 25 boys were followed up in ovember 1990, 3.0-21.6 (mean 13.9) mont.hs after eessation of therapy. Three boys developed testieular enlargement during maintenanee treatment and histology of the wedge biopsy speeimens revealed infiltration off Iyrnphoblasts. Out of 22 eleetive biopsies at the termination of maintenanee therapy, one showed oeeuJt leukemie involvement in both testides. Other pathologieal ehanges included testieular atrophy or fibrosis in 4 boys, thiek adventitia in 2 and easily bleeding testis in 5 boys. Age related, normal testieuJar size was found in 10 boys without malignaney. There were no eomplications related to the surgicaJ proeedure. During the follow-up period, one boy developed overt testicular relapse two months after negative biopsy and 20 boys v.'ith negative biopsies are still in CCR.
Discussion Leukemic infiltration of the testis is the initial presenlation of recurrent extramedullar disease. It may be the only evidence of wide-spread subclinical recurrence (13).
EurJ Pediatr Surg 2 (1992)
Testicular relapse is often followed by bone marrow or another extramedullary relapse at the median of 5 weeks and by death at a median of 9 months after the discovery of testicular involvement (15). This poor outcome may be due to the partially protected environment of the testis, regarded as a sanctuary site similar to the CNS. In the testis the baITier is near the seminiferous tubules, between the contractile myoid cells and the Serioli cells. This barrier is not complete as cylotoxic drugs can enter to some extent. Drugs may inhibit but not eliminate Iymphoblastic cells lying in the adluminal area during therapy. When treatment is stopped blast cells would spill out of the adluminal area into the interstitialtissue reseeding the marro\\'. When a clinically obvious relapse occurs, even many months after treatment is finished, it may be thatleukemic cells by then have become drug resislant (6). Early detection and intensified treatment of the relapse may contribute to an increased survival rate in ALL (1). Isolated relapse may occur from 2 months to 7 years after the diagnosis of ALL. The most common clinical presenlation is enlargement of the testis (8, 9, 10, 12, 13, 16), documented in four boys in our study, butleukemic infiltration may occur even without enlargement as verified in one boy in our material. Open testicular wedge biopsy was easy to perform and carried virtually no eomplications. The value of a routine biopsy procedure would be to reveal recurrence before symptoms have developed (13). The prognosis for patienls wi.th leukemic infiltration of the testis mainly depends on when the relapse occurs (10). Early relapse in patienls d uri.ng treatment generally carries a worse prognosis (8), while relapse after discontinuation of therapy still enables rescue of the patients (1,8, 12,15,16). Occult testicular leukemic infiltration in clinically normal testis has been found in 21 % of boys atthe time of diagnosis and in 8-12 % of biopsies while boys were in CCR (5). The involvement was bilateral in 50 % (2). The risk of subsequent bone marrow relapse and death is estimated to be 2-4 times higher for patienls with a positive testicular biopsy at the time when treatment is discontinued (1) compared to patients with a negative biopsy, suggesting that the testis will not be the first site of disease relapse. The outcome is the same for patienls with unilateral versus bilateral testicular involvement as weIl as focal versus diffuse involvement (8). Difficulties in identifying the malignant cells and the often focal distribution may explain the false negative result of around 10 % of patienls (10, 16) as occurred in one of our patients developing overt testicular relapse two months after the previously negative biopsy. Early local irradiation of the gonads has been used to prevent testicular leukemia (9). This treatment virtually eliminated the risk of isolated testicular involvement; however, it did not reduce bone marrow relapse. Radiotherapy of the gonads in the recommended doses gives rise to testicular atrophy. Hormonal studies have revealed severe tubular damage and significant hormonal impairment (3). Prophylactic irradiation of the testicles should therefore be avoided. In a population-based study of 656 children with ALL in five Nordic countries, eight boys developed isolated testicular leukemia out of 96 relapsing boys (4). There was no consensus of performing testicular biopsy atthe end of maintenance treatment. Leukemic infiltration in the testis occurred in this material in 5 (20 %) of 25 boys. Clinically overt testicular enlargement urged biopsy in 4 boys. ConsequenUy only 1 (5 %) patient was detected by the routine procedure. That biopsy,
353
Downloaded by: Universite Laval. Copyrighted material.
Elective Testicular Biopsy at the End ofMaintenance Treatmentfor Acute Lymphoblastic Leukemia
Eur J Pediatr Surg 2 (1992)
routinely performed in order to identify a subclinieal testieular ALL involvement prior to termination of ehemotherapy would, aecording to our experienee, not be justified. Introdueing new therapeutie strategies, the ineidenee of testieular relap e may deerease making this proeedure even more unneeessary (2). However, early identification of the patients running high risk for developing testieular leukemia may still be important to plan appropriate treatment with the hope of improving the survival of these patients (7). In our study, the diseovery of only 1 patient (5 %) clinieally not suspeeted of having a leukemie teslieular in-
filtrate does not justify the poliey of routine biopsy prior lo lermination of maintenanee lherapy. We lherefore suggest lhal careful clinieal examination including palpation of the lesticles and estimation of their size and eonsistenee routinely should regulari)' be performed and with short intervals during lherap)', allhe end and during the years of follow-up when off lherapy. An)' suspieion of leslieular enlargemenl should resull in a lestieular biopsy. Thi proeedure should be performed on both leslicles as the invoh'ement is bilateral in 50 % (2). The dala of this study subslanliate lhe findings presenled in earlier sludies and we report on it to support our eurrenl polie)'.
References ----Askin FB, Land \], Sul/ivan ,HP, Ragab AH, Sieuber CP, oymenl PG, Talbert}, Moore T: Oeeult testieuJar leukemia: Testieular biopsy at three years eontinuous eomplete remission of ehildhood leukemia: A Southwest Oneology group study. Cancer 47 (1981) 470-475 2 Bowman IVP, Aur RjA, Huslu HO, Rivera G: Isolated testieular relapse in aeute Iymphoeytie leukemia of ehildhood: Categories and innuenee on sUf\ival. J Clin Oneol 2 (1984) 924-929 3 Carrascosa A, Andi L, Ortega }}, }avier G, Toran N: Hypothalamohypophysent testieular funetion in prepubertaJ leukemie boys after ehemotherapy and testieular radiotherapy. Acta Paediatr Scand 73 (1984) 364-371 4 Gustavsson G, Garwicz 5, Hertz H, ]onmundsson G, Moe PI, Salmi TT, Seip M, Siimes MA, Yssing M, Ahslröm L: A population based study of ehildhood aeute Iymphoblastie leukemia diagnosed from July 1981 I
A _N. Biklissy et al through June 1985 in the five Nordie countries. Acta Paediatr Seand 76 (1987) 781-788 5 Heaney]A, Klauber GT, Conely GR: Acute leukemia diagnosis and man· agement of testieular involvement. Urology 21 (1983) 573 6 Kay H, Rankin A: Significanee of testieuJar involvement in ALL. Cancer topics 130 (1981) 130 7 Kim TH, Hargreaves HK, Chan WC, Brynes RK, Alvarado C, Woodard }, Ragab AH: Sequential testieular biopsies in ehildhood aeute Iymphocytie leukemia. Cancer 57 (1986) 1038-104 I 8 Nachman}, Palmer NF, Salher HN, Bleyer \VA, Coccia PF, Lukens] , Siegel SE, Hammond GO: Open wedge testieular biopsy in ehildhood aeute Iymphoblastie leukemia after two years of maintenanee therapy: Di· agnostie aeeuraey and innuenee on ouleome. Areport from ehildren's cancer study group. Blood 75 (1990) 1051-1055 9 .\'esbil ,\JE, Robinso/l LL, Ortega}A. Salher H.\', oO/laldsson M, f1am/lwnd O. Testieular relapse in ehildhood Iyrnphoeytie leukaemia: As· sociation with pre-treatment patient eharacteristics and lreatment. Cancer45 (1980) 2009-2016 10 Ortega}},}avier G, Toran S: Testicular infiltrates in children with acule lymphoblastie leukemia: A prospective study..\Ied Ped Oncol 12 (1984) 386-393 II Prader A: Testicular size: Assessment and clinieal importanee. Triangle 7 (1966) 240-243 12 Pui CH. Dahl G\-, Bowma/l \\P, Rao B.\', Abromowilch ,\/, Ochs}, Ri"era G: Elecli\-e testicular biopsy during chemotherapy for childhood leukaemia is of no c1inical value. Lancet Aug 24 (1985) 4 10-·112 I:l Rlmo A, Schi/iro G The enigma of testicular leukemia: A critical re\iew. tvled Ped Oneol 14 (1986) 300-305 II Simo/lej. A/lr RjA, f1ust/l HO, PinkeiD' "Total therapy" studies of acute Iymphoeytie leukemia in ehildren, Current re ults and prospects for eure. Cancer 30 (1912) 1-188-149..J 15 Sioffel T}, .\'esbil ,\J E, Levilt SH: Extramedullary in\'oh-ement of the tesles in childhood leukemia. Cancer 25 (1975) 1203-1211 16 lVong KY, Bal/ard ET, Strayer FH, I(isker T, Lampkin BC Clinieal and oecult testieular leukemia in long-term sun'ivors of aeute Iymphoblastie leukemia. J Pediatr 96 (1980) 569-57..J
Albert N. Beklissy, M. 0., M. S. Hemalology-Oneology Seetion University ChiJdren's Hospital S-22185 Lund, Sweden
Downloaded by: Universite Laval. Copyrighted material.
354
Elective Testicular Biopsy at the End of Maintenance Treatment for Acute Lymphoblastic Leukemia. A Prospective Study A. N. Bikdssy, C. ""1. Kullendorff, E. Arnbjörnsson Departments of Pediatrics and Pediatric Surgery. L'nh'ersity Hospital. Lund, Sweden
Open te ticular wedge biopsy has electi\'ely been performed prior to completion of maintenance therapy far acute lymphoblastic leukemia. 25 boys during 6 years \\'ere included in this prospecti\'e study. Three boys c1e\'eloped testicular enlargement while on maintenance therapy and biopsies confirmecl testicular leukemia. The remaining 22 boys \\we biopsied at termination of maintenance therapy. Occult testicular relapse \\'as re\'ealed on histologie examination in only one boy \\'ith normal testicuJar size. During the follo\\'-up periocl, one boy de\'eloped O\'ert testicular relapse two months after negati\-e biopsy. These results will notjustify electi\'ely performed routine biopsy prior to termination of chemotherapy. Instead, careful and minute clinical examination of the testicles, estimating their size and consistence, should be performed regularly at short inter\·als.
Kcy wo_r_ds_ _ Acute Iymphoblastic leukemia - Children Extramedullary leukemia - Routine procedure - Testicular wedge biopsy
Resume Des biopsies testiculaire chirurgieales furent effectuees electivement, a la fin du traitement de consolidation de leucemies lymphoIdes aigue . 25 enfants furent introduits dans cette etude prospective de 6 ans. Trois enfants ctevelopperent une masse tumorale testiculaire pendant leur traitement de consolidation. Les biopsies confirmerent la presence d'une leucemie dans le testicule. Les 22 autre enfants eurent une biopsie a la fin du traitement de consolidation. Un seul d'entre eux avec un testicule de taille normale a presente une infiltration leucemique. Durant la periode d'ob-
Introduction Significant ad\'ances in treatment of childhood acute lymphoblastic leukemia (ALL) ha\'e resulted in prolonged hematological remis ion for many children. Recognition of Kecel\'ed February
~.
HlV2
Eur.J Pediatr Surg 2 (1992) 352-35-1 © Ilippokrate \'erlag Stullgart \\asson Editeur Pari
sen'ation, un enfant a developpe une recidi\'e testiculaire deux mois apres une biopsie negati\'e. Ces resultats ne justifient pas des biopsies de routine electi\'es a\'antla fin du traitement par chimiotherapie. Cependanl. ils demontrent la necessite d'un examen clinique precis et meticuleux prenant en consideralion la taille, la consistance testiculaire et ceci il de courts inten'alles reguliers.
\\ots-cles Leucemie Iymphobla tique aigue - Enfants - Leucemie extramedullaire - Procedure de routine - Biopsie te ticuJaire
Zusammenfassung Offene Hodenbiopsien wurden zur \'en'ollständigung der Therapie einer akuten Iymphoblastischen Leukämie angewandt. Innerhalb von 6 Jahren wurden 25 Knaben im Rahmen einer prospekti\'en Studie untersucht. Drei Knaben entwickelten \\'ährend der Therapie einen Hodentumor. Die Biopsien bestätigten den Verdacht auf Hodenleukämie. Die übrigen 22 Jungen wurden nach Beendigung der Therapie biopsiert. 1 ur bei einem Knaben mit normaler Hodengröße fanden sich Zeichen für eine leukämische Infiltration. Auf der anderen Seite wurde im , achuntersuchungszeitraum bei einem weiteren Kind 2 Monate nach negativer Hodenbiopsie klinisch ein Rezidiv diagnostiziert. Diese Ergebnisse rechtfertigen keine Routinebiopsie vor Beendigung der Chemotherapie, weisen jedoch auf die otwendigkeit einer sorgfältigen langfristigen klinischen Kontrolle der Hodengröße und Konsistenz in kurzen Abständen hin.
SchI üssel wörter Lymphatische Leukämie - Hodenbiopsie
leukemia in the central ner\"Ous system (CNS) led to improvement in the survival foJlowing prophylactic treatment of Cl S (140). Testicular infiltration may be the fir t e\'ent of ALL recurrence following an extended disease-free period, but it i most frequent 2 to 3 years after diagnosis (6). Im'oh'ement of the testis during chemotherapy, occurring as isolated relapse, indicates that bone marro\\' relapse is likely \\'ithin a few months (9), Routine testicular biopsy has been incorporated into the management of ALL in male patients; ho\\'e\'er, the
Downloaded by: Universite Laval. Copyrighted material.
Summary
diagnostic accuracy of this procedure and its influence on outcome have been widely discussed (8,10,12,13,16). We report on the results of a prospective study evaluating testicular involvement by performing routine testicular wedge biopsy prior to termination of chemotherapy.
Material and methods Twenty-five boys, who were diagnosed as having ALL and aehieved eomplete remission during the period 1983-1988 at the Department of Pediatrics in Lund, entered this study. They were treated aeeording to the eriteria of the Swedish ALL protocol for standard risk (SR) ~ = 19, intermediate risk (IR) ~ = 5 and high-risk (HR) ~ = I patients (4). Their age varied from 2 8112 years to 17 2/ 12 years (mean 6 2/ 12 years) at presentation and no signs of testieular im'ol\'ement oeeurred at diagnosis. Three boys de\'eloped testieular enlargeme nt while on maintenanee therapy. Maintenanee therapy was electively stopped in the remaining 22 boys after two years eomplete eontinuous remission (CCR) in IRIHR group and after 3 years CCR in SR group. An elliptieal orehidometer introdueed by Prader and made of Swedish birehwood was used for determination of testieular \'olume (11). By selecting the wooden model \\'hieh is dosest in volume, the testieular size was determined by pal pation. All 22 boys in CCR underwent bilateral testieular biopsy as a routine proeedure prior to eompletion of therapy. An open wedge biopsy was always performed. The ineision for the testieular biopsy was inguinal in 20 boys and serotal in two boys.
In eaeh case fresh bilateral testieular biopsies were sent to the Department of Histopathology, University Hospital Lund. Following imprint, the speeimens were proeessed aeeording to routine fixing and staining proeedures for eonventional histologie examination. Leukemie relapses were all easiIy deteetable on eonventional histopathologie examination, showing massive infiltrates with Iyrnphoblasts. Additional immunostaining of the sarnples with preseleeted monoclonal antibodies were performed when available using APAAP-teehnique.
Results All 25 boys were followed up in ovember 1990, 3.0-21.6 (mean 13.9) mont.hs after eessation of therapy. Three boys developed testieular enlargement during maintenanee treatment and histology of the wedge biopsy speeimens revealed infiltration off Iyrnphoblasts. Out of 22 eleetive biopsies at the termination of maintenanee therapy, one showed oeeuJt leukemie involvement in both testides. Other pathologieal ehanges included testieular atrophy or fibrosis in 4 boys, thiek adventitia in 2 and easily bleeding testis in 5 boys. Age related, normal testieuJar size was found in 10 boys without malignaney. There were no eomplications related to the surgicaJ proeedure. During the follow-up period, one boy developed overt testicular relapse two months after negative biopsy and 20 boys v.'ith negative biopsies are still in CCR.
Discussion Leukemic infiltration of the testis is the initial presenlation of recurrent extramedullar disease. It may be the only evidence of wide-spread subclinical recurrence (13).
EurJ Pediatr Surg 2 (1992)
Testicular relapse is often followed by bone marrow or another extramedullary relapse at the median of 5 weeks and by death at a median of 9 months after the discovery of testicular involvement (15). This poor outcome may be due to the partially protected environment of the testis, regarded as a sanctuary site similar to the CNS. In the testis the baITier is near the seminiferous tubules, between the contractile myoid cells and the Serioli cells. This barrier is not complete as cylotoxic drugs can enter to some extent. Drugs may inhibit but not eliminate Iymphoblastic cells lying in the adluminal area during therapy. When treatment is stopped blast cells would spill out of the adluminal area into the interstitialtissue reseeding the marro\\'. When a clinically obvious relapse occurs, even many months after treatment is finished, it may be thatleukemic cells by then have become drug resislant (6). Early detection and intensified treatment of the relapse may contribute to an increased survival rate in ALL (1). Isolated relapse may occur from 2 months to 7 years after the diagnosis of ALL. The most common clinical presenlation is enlargement of the testis (8, 9, 10, 12, 13, 16), documented in four boys in our study, butleukemic infiltration may occur even without enlargement as verified in one boy in our material. Open testicular wedge biopsy was easy to perform and carried virtually no eomplications. The value of a routine biopsy procedure would be to reveal recurrence before symptoms have developed (13). The prognosis for patienls wi.th leukemic infiltration of the testis mainly depends on when the relapse occurs (10). Early relapse in patienls d uri.ng treatment generally carries a worse prognosis (8), while relapse after discontinuation of therapy still enables rescue of the patients (1,8, 12,15,16). Occult testicular leukemic infiltration in clinically normal testis has been found in 21 % of boys atthe time of diagnosis and in 8-12 % of biopsies while boys were in CCR (5). The involvement was bilateral in 50 % (2). The risk of subsequent bone marrow relapse and death is estimated to be 2-4 times higher for patienls with a positive testicular biopsy at the time when treatment is discontinued (1) compared to patients with a negative biopsy, suggesting that the testis will not be the first site of disease relapse. The outcome is the same for patienls with unilateral versus bilateral testicular involvement as weIl as focal versus diffuse involvement (8). Difficulties in identifying the malignant cells and the often focal distribution may explain the false negative result of around 10 % of patienls (10, 16) as occurred in one of our patients developing overt testicular relapse two months after the previously negative biopsy. Early local irradiation of the gonads has been used to prevent testicular leukemia (9). This treatment virtually eliminated the risk of isolated testicular involvement; however, it did not reduce bone marrow relapse. Radiotherapy of the gonads in the recommended doses gives rise to testicular atrophy. Hormonal studies have revealed severe tubular damage and significant hormonal impairment (3). Prophylactic irradiation of the testicles should therefore be avoided. In a population-based study of 656 children with ALL in five Nordic countries, eight boys developed isolated testicular leukemia out of 96 relapsing boys (4). There was no consensus of performing testicular biopsy atthe end of maintenance treatment. Leukemic infiltration in the testis occurred in this material in 5 (20 %) of 25 boys. Clinically overt testicular enlargement urged biopsy in 4 boys. ConsequenUy only 1 (5 %) patient was detected by the routine procedure. That biopsy,
353
Downloaded by: Universite Laval. Copyrighted material.
Elective Testicular Biopsy at the End ofMaintenance Treatmentfor Acute Lymphoblastic Leukemia
Eur J Pediatr Surg 2 (1992)
routinely performed in order to identify a subclinieal testieular ALL involvement prior to termination of ehemotherapy would, aecording to our experienee, not be justified. Introdueing new therapeutie strategies, the ineidenee of testieular relap e may deerease making this proeedure even more unneeessary (2). However, early identification of the patients running high risk for developing testieular leukemia may still be important to plan appropriate treatment with the hope of improving the survival of these patients (7). In our study, the diseovery of only 1 patient (5 %) clinieally not suspeeted of having a leukemie teslieular in-
filtrate does not justify the poliey of routine biopsy prior lo lermination of maintenanee lherapy. We lherefore suggest lhal careful clinieal examination including palpation of the lesticles and estimation of their size and eonsistenee routinely should regulari)' be performed and with short intervals during lherap)', allhe end and during the years of follow-up when off lherapy. An)' suspieion of leslieular enlargemenl should resull in a lestieular biopsy. Thi proeedure should be performed on both leslicles as the invoh'ement is bilateral in 50 % (2). The dala of this study subslanliate lhe findings presenled in earlier sludies and we report on it to support our eurrenl polie)'.
References ----Askin FB, Land \], Sul/ivan ,HP, Ragab AH, Sieuber CP, oymenl PG, Talbert}, Moore T: Oeeult testieuJar leukemia: Testieular biopsy at three years eontinuous eomplete remission of ehildhood leukemia: A Southwest Oneology group study. Cancer 47 (1981) 470-475 2 Bowman IVP, Aur RjA, Huslu HO, Rivera G: Isolated testieular relapse in aeute Iymphoeytie leukemia of ehildhood: Categories and innuenee on sUf\ival. J Clin Oneol 2 (1984) 924-929 3 Carrascosa A, Andi L, Ortega }}, }avier G, Toran N: Hypothalamohypophysent testieular funetion in prepubertaJ leukemie boys after ehemotherapy and testieular radiotherapy. Acta Paediatr Scand 73 (1984) 364-371 4 Gustavsson G, Garwicz 5, Hertz H, ]onmundsson G, Moe PI, Salmi TT, Seip M, Siimes MA, Yssing M, Ahslröm L: A population based study of ehildhood aeute Iymphoblastie leukemia diagnosed from July 1981 I
A _N. Biklissy et al through June 1985 in the five Nordie countries. Acta Paediatr Seand 76 (1987) 781-788 5 Heaney]A, Klauber GT, Conely GR: Acute leukemia diagnosis and man· agement of testieular involvement. Urology 21 (1983) 573 6 Kay H, Rankin A: Significanee of testieuJar involvement in ALL. Cancer topics 130 (1981) 130 7 Kim TH, Hargreaves HK, Chan WC, Brynes RK, Alvarado C, Woodard }, Ragab AH: Sequential testieular biopsies in ehildhood aeute Iymphocytie leukemia. Cancer 57 (1986) 1038-104 I 8 Nachman}, Palmer NF, Salher HN, Bleyer \VA, Coccia PF, Lukens] , Siegel SE, Hammond GO: Open wedge testieular biopsy in ehildhood aeute Iymphoblastie leukemia after two years of maintenanee therapy: Di· agnostie aeeuraey and innuenee on ouleome. Areport from ehildren's cancer study group. Blood 75 (1990) 1051-1055 9 .\'esbil ,\JE, Robinso/l LL, Ortega}A. Salher H.\', oO/laldsson M, f1am/lwnd O. Testieular relapse in ehildhood Iyrnphoeytie leukaemia: As· sociation with pre-treatment patient eharacteristics and lreatment. Cancer45 (1980) 2009-2016 10 Ortega}},}avier G, Toran S: Testicular infiltrates in children with acule lymphoblastie leukemia: A prospective study..\Ied Ped Oncol 12 (1984) 386-393 II Prader A: Testicular size: Assessment and clinieal importanee. Triangle 7 (1966) 240-243 12 Pui CH. Dahl G\-, Bowma/l \\P, Rao B.\', Abromowilch ,\/, Ochs}, Ri"era G: Elecli\-e testicular biopsy during chemotherapy for childhood leukaemia is of no c1inical value. Lancet Aug 24 (1985) 4 10-·112 I:l Rlmo A, Schi/iro G The enigma of testicular leukemia: A critical re\iew. tvled Ped Oneol 14 (1986) 300-305 II Simo/lej. A/lr RjA, f1ust/l HO, PinkeiD' "Total therapy" studies of acute Iymphoeytie leukemia in ehildren, Current re ults and prospects for eure. Cancer 30 (1912) 1-188-149..J 15 Sioffel T}, .\'esbil ,\J E, Levilt SH: Extramedullary in\'oh-ement of the tesles in childhood leukemia. Cancer 25 (1975) 1203-1211 16 lVong KY, Bal/ard ET, Strayer FH, I(isker T, Lampkin BC Clinieal and oecult testieular leukemia in long-term sun'ivors of aeute Iymphoblastie leukemia. J Pediatr 96 (1980) 569-57..J
Albert N. Beklissy, M. 0., M. S. Hemalology-Oneology Seetion University ChiJdren's Hospital S-22185 Lund, Sweden
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