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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.
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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
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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).