when he developed hemoptysis. Bronchoscopy was perfor- med and later right upper lobectomy for presumed Asper-. Keywords: testicular relapse; acute ...
Bone Marrow Transplantation, (1997) 20, 689–690 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Testicular relapse of acute promyelocytic leukemia after allogeneic BMT DL Forrest1, BI Dalal2, SC Naiman2, DE Horsman3, BR Berry4, MI Parslow4, CP Singh4, WB Benny1 and MJ Barnett1 Leukemia/Bone Marrow Transplantation Program of British Columbia: Divisions of 1Hematology, 2Hematopathology and 3 Laboratory Medicine, British Columbia Cancer Agency, Vancouver Hospital and Health Sciences Centre and the University of British Columbia, Vancouver; and 4 Greater Victoria Hospital Society, Victoria, British Columbia, Canada
Summary: After treatment of acute leukemia (typically ALL and the monocytic variants of AML), relapse may occur at sites other than the marrow. Isolated extramedullary relapse of acute promyelocytic leukemia (APL) however, is rare. We describe such an event in a man who underwent allogeneic BMT for APL in second relapse and 4 years later presented with testicular relapse. The marrow was morphologically and cytogenetically normal, but RT-PCR analysis revealed the specific PML/RAR chimeric RNA transcript. Keywords: testicular relapse; acute promyelocytic leukemia; allogeneic BMT
Acute promyelocytic leukemia (APL) is a distinct subtype of AML characterized by a consumptive coagulopathy, a specific chromosomal rearrangement, a defined molecular abnormality in a retinoid receptor, and a relatively good prognosis. The (15;17) chromosomal translocation fuses the PML gene on chromosome 15 with the RAR gene on chromosome 17, resulting in a hybrid gene PML/RAR which encodes a fusion protein, undoubtedly involved in leukemogenesis.1 Both combination chemotherapy2 and all-trans retinoic acid (ATRA)3 are effective treatments. We describe an unusual case in which isolated testicular relapse of APL occurred after allogeneic BMT.
analysis of the marrow revealed trisomy 8 and t(15;17) (Table 1). He was treated with Ara-C and amsacrine and a second remission was achieved after two courses. Followup marrow cytogenetic analysis was normal. This hospitalization was complicated by Aspergillus flavus pneumonia requiring ICU admission and treatment with 3000 mg of amphotericin B. He was eventually discharged home on cisretinoic acid in October 1985. Because of concern about Aspergillus reactivation, an allogeneic BMT was considered inappropriate at this time. He remained well on cis-retinoic acid until December 1987 when he developed hemoptysis. Bronchoscopy was performed and later right upper lobectomy for presumed Aspergillus infection. The pathology of the resected lung, however, revealed necrotizing granulomas consistent with active pulmonary tuberculosis. He was therefore treated with an 8-month course of anti-tuberculous medication. Treatment with cis-retinoic acid continued. Second relapse occurred in September 1990. Cytogenetic analysis of the marrow revealed tetrasomy 8 and t(15;17) (Table 1). He was treated with Ara-C and DNR but a follow-up marrow revealed persistent disease. In October 1990, he underwent an HLA-matched sibling donor BMT using BU, CY conditioning and CsA with methylprednisolone as GVHD prophylaxis. His hospital course was rela-
Table 1 Karyotype of marrow cells at various time points from 1984–1994 Marrow karyotype
Case report A 34-year-old East Indian man presented in March 1984 with APL. Remission was achieved with high-dose Ara-C and DNR, and consolidated with the same drugs. First relapse occurred in August 1985. Cytogenetic Correspondence: Dr MJ Barnett, Leukemia/Bone Marrow Transplantation Program of British Columbia, Vancouver Hospital and Health Sciences Centre, 910 West 10th Avenue, Vancouver, British Columbia, Canada, V5Z 4E3 Received 25 April 1995; accepted 8 May 1997
Diagnosis (March 1984) First relapse (August 1985) Second remission (September 1985) Second relapse (September 1990) Post-BMT, day +27 (November 1990) Third relapsea (December 1994) a
Failed analysis 47, XY, +8, t(15;17) [10] 46, XY [25] 48, XY, +8, +8, t(15;17) [12] 46, XY [49] 46, XY [25] b,c
Occurred in the testicle (see text). FISH analysis with an 8c probe was negative. c RT-PCR analysis revealed the specific PML/RAR chimeric RNA transcript. b
Testicular relapse of APL after allogeneic BMT DL Forrest et al
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Figure 1 Photomicrograph of right testicle showing infiltration with hypergranular promyelocytes containing numerous Auer rods.
tively uncomplicated and the day +27 marrow showed a normal karyotype (Table 1). However, later he developed acute GVHD of the gut which responded to treatment with corticosteroids. CsA and prednisone were discontinued in August 1991 without recurrence of GVHD. In October 1994, he complained of painless swelling of the right testicle. The testicle was removed and found to be infiltrated by APL (Figure 1). Cytogenetic analysis of the testicular tissue revealed inv(6), tetrasomy 8, t(15;17). The peripheral blood and marrow were morphologically normal. Cytogenetic analysis of the marrow was also normal; however, RT-PCR analysis revealed the specific PML/RAR chimeric RNA transcript (Table 1). He was treated with radiotherapy to the left testicle. Over the next 2 years, he developed relapse of APL at three other extramedullary sites – retroperitoneal nodes, psoas muscle and skin – without morphological evidence of leukemia in the marrow. He was treated effectively with ATRA as well as Ara-C and DNR, but died of progressive disease in December 1996. Discussion Extramedullary myeloid leukemia has been the subject of several recent review articles,4–6 which seem relevant to this case of isolated testicular relapse of APL after allogeneic BMT. The predisposing factors for extramedullary disease in AML include the FAB M4 and M5 morphological subtypes, t(8;21) and inv(16) chromosomal abnormalities as well as T cell (CD2, CD4 and CD7) and CD56 cell surface markers.4 Testicular relapse of AML is distinctly unusual and most reported cases describe monocytic morphology.7 Extramedullary relapse of APL is particularly uncommon. Recently, two cases of extramedullary relapse of APL originally treated with ATRA were reported; both involved the skin and occurred in association with marrow relapse.8 This
and a similar report9 prompted a review of extramedullary APL which raised the possibility that the problem may be more common after ATRA than other therapy.5 It was also suggested that certain ethnic groups may be at higher risk for this manifestation of APL.5 After allogeneic BMT for AML, the vast majority of relapses are medullary, while extramedullary relapses, if they occur, usually do so in association with a marrow relapse.10 Testicular relapses of AML after BMT are rare, occurring in approximately 2% of patients with a marrow relapse.10 In a recent survey by the European Group for Blood and Marrow Transplantation (EBMT), isolated extramedullary relapse occurred in 20 of 3071 patients allografted for AML.6 Disease was documented at most sites of the body including the testicle in one case reported as FAB M3.6 In summary, we have presented what is presumably a very rare event – a case of isolated testicular relapse of APL after allogeneic BMT. In light of recent observations, it is of interest to speculate on the influence of prior treatment with cis-retinoic acid on this outcome. Whether or not the extramedullary manifestations of leukemia could have been avoided by the use of either a TBI (rather than a BU) containing conditioning regimen or prophylactic testicular irradiation is a matter of debate. References 1 Grignani F, Fagioli M, Alcalay M et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994; 83: 10–25. 2 Tezcan H, Barnett MJ, Bredeson CN et al. Treatment of acute promyelocytic leukemia in patients presenting at Vancouver General Hospital from 1983 to 1992. Leuk Lymphoma 1995; 16: 439–444. 3 Meng-er H, Yu-chen Y, Shu-rong C et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–572. 4 Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995; 13: 1800–1816. 5 Wiernik PH, De Bellis R, Muxi P et al. Extramedullary acute promyelocytic leukemia. Cancer 1996; 78: 2510–2514. 6 Bekassy AN, Hermans J, Gorin NC et al. Granulocytic sarcoma after allogeneic bone marrow transplantation: a retrospective European multicenter survey. Bone Marrow Transplant 1996; 17: 801–808. 7 Shaffer DW, Burris HA, O’Rourke TJ. Testicular relapse in adult acute myelogenous leukemia. Cancer 1992; 70: 1541– 1544. 8 Weiss MA, Warrell RP Jr. Two cases of extramedullary acute promyelocytic leukemia. Cancer 1994; 74: 1882–1886. 9 Giralt S, O’Brien S, Weeks E et al. Leukemia cutis in acute promyelocytic leukemia: report of three cases after treatment with all-trans retinoic acid. Leuk Lymphoma 1994; 14: 453– 456. 10 Mortimer J, Blinder MA, Schulman S et al. Relapse of acute leukemia after marrow transplantation: natural history and results of subsequent therapy. J Clin Oncol 1989; 7: 50–57.
