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Isolated extramedullary ocular relapse of acute lymphoblastic leukemia after peripheral blood stem cell transplantation GUO Qing, HUANG Hou-bin, PI Yu-li and LIU Tian-xing. Department of Ophthalmology, First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China(Guo Q and Pi YL) Department of Ophthalmology, Chinese PLA General Hospital, Beijing 100853, China(Huang HB) Correspondence to: Dr. LIU Tian-xing, Department of Radiation Oncology, First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048,China (Tel:86-10-66848130.Fax: 86-10-66848134.Email:[email protected]) Keywords: acute lymphoblastic leukemia; peripheral blood stem cell transplantation; extramedullary relapse; retinal detachment Isolated extramedullary ocular relapse of acute lymphoblastic leukemia (ALL) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT) without concomitant involvement of the bone marrow is very rare. While the common sites of extramedullary relapse are central nervous system, skin, bone, and breasts.1 This is the report of isolated ocular relapse without any extra-ocular involvement of ALL after allo-PBSCT confirmed by histopathology. A 30-year-old man with ALL in complete remission was admitted to our hospital due to blurred vision of the right eye. Six months ago, he underwent an allo-PBSCT from his HLA-identical brother. His best-corrected visual acuity in the right eye was 20/200 and 20/20 in the left. Fundus examination revealed a bullous exudative retinal detachment(ERD)in the inferior portion in the right eye (Figure 1A). Systemic examination, the peripheral blood, and bone marrow showed no evidence of the relapse of ALL. Lumbar puncture and magnetic resonance imaging scanning showed no involvement of central nervous system. The patient was treated with methylprednisolone (1000mg daily for 3 days) and prednisone (60mg daily for 5 days; the dose tapered 5mg for every 5 days) for presumed noninfectious panuveitis. ERD completely resolved 7 days after corticosteroids treatment, and the visual acuity of the right eye recovered to 20/20. However, ERD recurred 2 months after corticosteroids treatment. Laboratory examinations showed cytomegalovirus IgM (-), toxoplasma IgM antibodies (-), and herpes simplex virus IgM antibodies (-). A computed tomography scan of the orbit showed normal. B-mode ultrasonography of the right eye showed retinal detachment with choroid thickening (Figure 1B). Prednisone was re-instituted immediately (70mg daily for 10 days; the dose tapered 5mg for every 10 days) and then ERD re-resolved 6 days after treatment. Fourteen days later, following his second relapse of ERD, choroid detachment occurred and then significantly exacerbated. Repeated systemic evaluation still showed no relapsing evidence of ALL. Corticosteroids and scleral fenestration were used to treat choroid detachment without any significant change. He went on to develop neovascular glaucoma with loss of light perception in the right eye and underwent evisceration of the right eye and implantation of synthetic hydroxyapatite in another hospital. After 3 months of implantation, he was admitted to our hospital due to severe conjunctival chemosis and orbital pressure increase. The surgery to remove the hydroxyapatite sphere was performed. A biopsy from the removed hydroxyapatite sphere and the surrounding tissues specimen showed diffuse lymphoblastic cells with high nuclear to cytoplasmic ratios and dense chromatin. Mitotic figures were also observed (Figure 1C). Systemic examination, the peripheral blood, and lumbar puncture were still normal. His bone marrow cells were 100% of donor origin. The patient was finally diagnosed with isolated extramedullary ocular relapse of ALL after allo-PBSCT. Chemotherapy consisting of vincristine, daunomycin, L-asparaginase and dexamethasone was administered. Intensity modulated radiation therapy was then performed for the involvement of the eye and the orbit. Ocular involvement was covered with a 90% isodose gradient, and a 28-Gy dose was delivered to the tumor margin; the maximum dose was 30 Gy. His condition improved following treatment. Later on, his general condition got worse with severe pulmonary infection and died 17 months after allo-PBSCT. Leukemia relapses could occur in extramedullary sites only, bone marrow only or in both extramedullary and bone marrow sites. The lesions of the other sites with normal bone marrow can easily lead to misdiagnosis. In this case, considering ERD with an initial favorable response to corticosteroids without leukemia involvement of the bone marrow, a possible diagnosis of noninfectious panuveitis was suspected. As frequently ERD recurred after allo-PBSCT, we then suspected that ERD may be a rare sign of ocular graft-versus-host disease(GVHD). But the patient had no any chronic GVHD lesions of skin and other affected sites. Other ocular GVHD symptoms including ocular sicca, conjunctivitis, and keratitis were no found. No ocular infiltrative mass occurred and his systemic laboratory work-up showed no evidence of relapse. Although the detection of unusual repeated ERD should raise suspicion of ocular relapse, the diagnosis of the ocular relapse required a pathological finding. In the present case, isolated extramedullary ocular relapse presenting as a recurrent ERD after allo-PBSCT was confirmed by histopathological examination. Golan et al 2 reported the causes of ERD could be attributed to direct invasion of lymphoblasts to the choroidal vasculature causing ischemia of the retinal pigment epithelial and disruption of their pumping ability. The definitively mechanisms of extramedullary relapse have not been identified as yet. Extramedullary relapse usually occur in the sanctuary sites not only for the conditioning chemo-radiotherapy, but also for the graft-versus-leukemia effector cells. One possible mechanism of isolated extramedullary ocular relapse is the continued effect of graft versus leukemia effect in the bone marrow, but not at the ocular site where chemotherapy or antileukemic effector cells are unable to function due to the presence of a blood retinal barrier. Peng et al reported 2 cases of bullous ERD after allo-PBSCT died shortly after eye symptoms. One case showed ERD with concomitant involvement of the bone marrow. The other showed ERD simultaneously with acute GVHD. No pathological examination to be done in this two cases. Peng considered ERD may be a poor prognostic factor after PBSCT.3 Harris4 reported Extramedullary relapse is a major contributor to mortality after allogeneic transplantation. Our patient tolerated chemo-radiotherapy procedure well and the ocular involvement was sensitive to intensity modulated radiation therapy. But the patient died of severe pulmonary infection 17 months after allo-PBSCT. Effective treatment strategies for patients with extramedullary ocular relapse are not yet defined. The blood retinal barrier may prevent chemotherapeutic agents to penetrate the eye and intraocular infiltration does not seem to respond to intrathecal chemotherapy. Moreover, it is still not ascertained chemotherapy or radiation is used first to treat ocular involvements. Some physicians have claimed systemic chemotherapy should be performed first. If systemic chemotherapy fails, ocular radiation is also recommended. Fadilah5 reported chemotherapy combined with radiation and donor lymphocyte infusion may be a better option to improve outcomes after transplantation. In conclusion, this case suggested the appearance of recurrent ERD in ALL after PBSCT, although the systemic examination showed no evidence of the relapse, should alert the ophthalmologist for an isolated extramedullary ocular relapse. The timely choroidal or retinal biopsy should be used to confirm the diagnosis. Earlier detection and the relapse treatment may be able to improve the patient’s prognosis. 1. 2. 3. 4. 5. REFERENCES Shi JM, Meng XJ, Luo Y, Tan YM, Zhu XL, Zheng GF, et al. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. Leuk Res 2013;37:372-377. PMID:23347901 Golan S, Goldstein M. Acute lymphocytic leukemia relapsing as bilateral serous retinal detachment: a case report. Eye 2011;25:1375-1378. PMID:21720411 Peng KL, Chen SJ, Lin PY, Hsu WM, Yang MH, Tzeng CH, et al. Exudative bullous retinal detachment after peripheral blood stem cell transplantation. Eye 2005;19:603-606. PMID:15332110 Harris AC, Kitko CL, Couriel DR, Braun TM, Choi SW, Magenau J, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica 2013;98:179-184. PMID:23065502 Fadilah SAW, Goh KY. Breast and ovarian recurrence of acute lymphoblastic leukaemia after allogeneic peripheral blood haematopoietic stem cell transplantation. Singapore Med J 2009; 50 :e407-e409. PMID:20087541 Figure 1. A: Fundus photograph showed the exudative retinal detachment in the right eye. B: Ultrasonogram of the right eye shows shallow retinal detachment with the diffuse choroid thickening. C: Light micrograph of the biopsy specimen showed diffuse lymphoblastic cells with high nuclear to cytoplasmic ratios and dense chromatin (hematoxylin-eosin staining; original magnification ×100).