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Year : 2010  |  Volume : 47  |  Issue : 2  |  Page : 93-94

Relapsed testicular leukemia: Local insights in to a vanishing disease

Pediatric Oncology Division, Tata Memorial Hospital, Mumbai, India

Date of Web Publication5-May-2010

Correspondence Address:
P A Kurkure
Pediatric Oncology Division, Tata Memorial Hospital, Mumbai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.62992

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How to cite this article:
Arora B, Kurkure P A. Relapsed testicular leukemia: Local insights in to a vanishing disease. Indian J Cancer 2010;47:93-4

How to cite this URL:
Arora B, Kurkure P A. Relapsed testicular leukemia: Local insights in to a vanishing disease. Indian J Cancer [serial online] 2010 [cited 2021 Jan 26];47:93-4. Available from:

Childhood acute lymphoblastic leukemia (ALL) is the single most common childhood malignancy. It comprises almost one-fourth of cancers in children ages 0-15 years. At least 25-30% of patients have relapse with current therapies, making relapsed ALL the fourth most common malignancy in children after newly diagnosed ALL, astrocytoma and neuroblastoma. Indeed, relapsed ALL is the second most common leukemia in children and is more common than newly diagnosed non-Hodgkin's lymphoma, Wilms' tumor, Hodgkin's disease and primitive neuroectodermal tumors. [1]

Results of treatment with chemotherapy in children after an ALL relapse remain unsatisfactory worldwide, especially in early relapses and heavily pretreated patients. Based on the available robust prognostic factors, ALL relapses are classified as very early, early or late according to time from diagnosis to relapse (< 18; > 18 and < 30; > 30 months, respectively). It is evident from the literature that about two-thirds of children with late extramedullary relapse and about one-third of those with early extramedullary relapses or late non-T marrow relapses or early combined non-T relapses can be rescued by chemotherapy; conversely, bone marrow relapses occurring early or with T-immunophenotype can be rescued only by bone marrow transplantation (BMT). [2]

Extramedullary relapses in ALL draw a lot of attention, because of good outcome with salvage therapies and fascinating biology. Extramedullary relapses used to constitute approximately 40% of all relapses of which 20-25% used to be in central nervous system (CNS) and 10-15% used to be in testis. However, with the improved frontline treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. Currently, the incidence of isolated CNS relapse is less than 5% and testicular relapse is less than one to two per cent. [3],[4],[5]

Testis is considered a barometer of extramedullary involvement in ALL. In majority of the children with isolated testicular relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques. [6] Before 1960, relapsed testicular leukemia was rare because of early death due to marrow disease in children with ALL. With the significant improvement of survival in 1980s, an increase in the testicular recurrence rate occurred; the reported frequency of overt testicular recurrence in children with ALL ranged between 2-8.8%. Currently, with the modern era methotrexate-based chemotherapy regimens, testicular relapses have virtually been eliminated and range from 0-1%. [3],[4],[5]

In this issue of Indian Journal of Cancer, Kulkarni et al. share the pattern and outcome of testicular relapses at their center in the last two decades. The incidence in their series is a whopping 9.5% (27% of all relapses in boys), which is much like the middle era of ALL therapy and is higher than most current series. [7],[8] This seems to be obviously because of usage of 3 drug induction and non-methotrexate-based consolidation in all newcomers irrespective of risk-group. Biologic differences from the West are unlikely since in a recent Indian series, the incidence of testicular relapse was 4.4%. [9] Due to the absence of temporal trends over two decades, it is difficult to assess the impact of improving diagnostics and treatment quality over time. Interestingly, 80% patients in this series relapsed very early/early (within six months of therapy completion). In the seminal COG series, only 10% of isolated testes relapses occurred in the initial 12 months after diagnosis, and 59% occurred late after 36 months. [3] This might again reflect the low early treatment intensity used in this study permitting early relapses.

Several factors such as high white blood cell (WBC) count (>20,000 per cmm), T-cell disease, bulky lymphadenopathy, splenomegaly, significant thrombocytopenia (<30,000/cmm), high-risk cytogenetics (Bcr-Abl and MLL rearrangement) and poor early response have been shown to be risk factors for testicular relapses. [1],[3],[8],[10] This study attempts to analyze the risk factors for testicular relapses but could only confirm high WBC as the risk-factor. It seems most likely due to small patient population and non-availability of data on cytogenetics, immunophenotype or early response. However, the impact of differences in the protocol or biology of disease cannot be ruled out.

Relapsed testicular ALL is highly curable. The results of treatment of isolated testicular relapse depend on the timing of the relapse. The three-year event-free survival (EFS) of boys with early testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse. [1],[2],[3],[8],[10] In a recent Indian series, 67% patients were long-term survivors. [11] However, the outcome data in this series is disturbing. Of 30 relapsers, only seven (20%) are on treatment and less than 10% of all patients are expected to be survivors with the current non-methotrexate based salvage regimen used in this study. This, unfortunately, is largely due to treatment abandonment due to a slew of socioeconomic factors in resource-challenged environments and perceived dismal outcome of relapse after a long mentally, physically as well as economically crippling therapy. Authors plan to introduce intermediate or high - dose methotrexate in their current therapy to prevent testicular relapses. While it is an important component of current/relapse therapy, equally important is to dispense with testicular radiotherapy using aggressive therapy incorporating high-dose methotrexate which has been shown to be feasible and prevents long-term endocrine and gonadal complications. [12],[13]

Where do we go from here? The dictum of 'the first chance is the best chance' is most relevant in resource-constrained settings since it is probably the last and only chance to motivate and support the family to take and comply with treatment. While it is imperative to provide socioeconomic support by leveraging the wide range of sources in India, it is equally important to focus on providing optimally intensive risk-stratified frontline therapy of ALL rather than trying to salvage after relapse. It is hoped that use of conventional risk factors, cytogenetics, early response assessment and minimal residual disease based risk-stratification coupled with optimal upfront chemotherapy would bring the outcome of Indian patients on par with the west in the near future.

  References Top

1.Gaynon PS. Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol 2005;131:579-87.  Back to cited text no. 1      
2.Einsiedel HG, von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G, et al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: Results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Mόnster Group 87. J Clin Oncol 2005;23:7942-50.  Back to cited text no. 2      
3.Gaynon PS, Qu RP, Chappell RJ, Willoughby ML, Tubergen DG, Steinherz PG, et al. Survival after relapse in childhood acute lymphoblastic leukemia: Impact of site and time to first relapse--the Children's Cancer Group Experience. Cancer 1998;82:1387-95.  Back to cited text no. 3      
4.Brecher ML, Weinberg V, Boyett JM, Sinks LF, Jones B, Glicksman A, et al. Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse. Cancer 1986;58:1024-8.  Back to cited text no. 4      
5.Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC, et al. Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 2010;24:371-82.   Back to cited text no. 5      
6.Hagedorn N, Acquaviva C, Fronkova E, von Stackelberg A, Barth A, zur Stadt U, et al. Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: A more precise definition of "isolated" and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group. Blood 2007;110:4022-9.  Back to cited text no. 6      
7.Kulkarni KP, Marwaha RK, Trehan A, Bansal D. Testicular relapse in childhood acute lymphoblastic leukemia: The challenges and lessons. Indian J Cancer 2010;47:134-8.  Back to cited text no. 7  [PUBMED]  Medknow Journal  
8.Wofford MM, Smith SD, Shuster JJ, Johnson W, Buchanan GR, Wharam MD, et al. Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 1992;10:624-30.   Back to cited text no. 8      
9.Advani SH, Banavali S, Pai SK, Bhagwat R, Lokeshwar N, Kolhatkar B, et al. Pattern of relapses in children and young adults with acute lymphoblastic leukemia: Who are the late relapsers? Med Pediatr Oncol 2001;37:167.  Back to cited text no. 9      
10.Finklestein JZ, Miller DR, Feusner J, Stram DO, Baum E, Shina DC, et al. Treatment of overt isolated testicular relapse in children on therapy for acute lymphoblastic leukemia. A report from the Children's Cancer Group. Cancer 1994;73:219-23.  Back to cited text no. 10      
11.Shama G, Bhagwat R, Pai SK, Kurkure PA, Nair CN, Parikh PM, et al. Isolated testicular relapse in acute lymphoblastic leukemia - effective treatment with the modified CCG-112 protocol. Indian J Cancer 2005;42:65-9.  Back to cited text no. 11  [PUBMED]  Medknow Journal  
12.van den Berg H, Langeveld NE, Veenhof CH, Behrendt H. Treatment of isolated testicular recurrence of acute lymphoblastic leukemia without radiotherapy Report from the Dutch Late Effects Study Group. Cancer 1997;79:2257-62.  Back to cited text no. 12      
13.Grundy RG, Leiper AD, Stanhope R, Chessells JM. Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukemia. Arch Dis Child 1997;76:190-6.  Back to cited text no. 13      


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