ORIGINAL ARTICLE

Unusual Sites of Relapse in Pre-B Acute Lymphoblastic Leukemia Richa Jain, MD,* Amita Trehan, MD,* Ramandeep Singh, MS,w Radhika Srinivasan, MD, PhD,z Mangat Dogra, MS,w Deepak Bansal, MD, MNAMS,* and Ram K. Marwaha, MD, MNAMS*

Summary: Relapses of acute lymphoblastic leukemia (ALL) in unusual sites can be challenging to diagnose. We present unusual relapses occurring in children with ALL treated in a single institution over a 22-year period. Of 172 relapses, 9 (5.2%) were at unusual sites (nonmarrow, testes, central nervous system). The most common site of relapse was ocular (66%). The median symptom-to-diagnosis interval was 20 days. Two of 9 children attained second remission. A possibility of relapse should be considered when evaluating unusual symptoms in a child with underlying ALL. Key Words: acute lymphoblastic leukemia, extramedullary relapse, ocular relapse

(J Pediatr Hematol Oncol 2014;36:e506–e508)

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ith current treatment strategies, less than 10% to 15% children with acute lymphoblastic leukemia (ALL) suffer from relapse.1,2 Relapse occurs predominantly in the marrow (up to 65%) and 16% are combined relapses of the marrow and central nervous system (CNS).3 Testicular relapse is less frequent, with current trials reporting the figure to be 2% to 5%.2,4 Relapses are treated with chemotherapy ± radiation or with allogenic stem cell transplant in second remission, depending on the nature and the timing of relapse. Occasionally, relapses occur at unusual sites, making them a challenge to diagnose and causing diagnostic delays.5 We present 9 children with pre-B ALL who relapsed at unusual sites in the last 2 decades in our pediatric hematology oncology clinic. We treated patients on the UKALL X, XI and 2003 protocols.

CASE REPORTS

Case 2 A 9-year-old girl with high-risk ALL in CR1 presented at week 84 of therapy with conjunctival congestion along with pain in the right eye. Patient had white reflex on presentation. Ocular examination revealed neovascular glaucoma, with retinal detachment and leukemic infiltrates in the right eye. The left eye was normal. Vitreous tap was positive for blasts. Computed tomography brain was normal, CSF was negative, and BM was in remission. With a diagnosis of isolated ocular relapse, she was given chemotherapy along with ocular radiation 40 Gy units. Her eye improved but the family opted to discontinue therapy after 3 months of reinduction.

Case 3 A 7-year-old boy with standard-risk ALL in CR1 presented at week 18 of maintenance therapy with headache and swelling of the left eye. Ocular examination revealed severe visual impairment with leukemic infiltrates involving optic disc and peripapillary retina in both the eyes. Vitreous tap revealed blasts. A diagnosis of isolated ocular relapse was made with the BM and CSF being negative. He was started on ocular and CNS RT and palliative chemotherapy. He progressed to a CNS relapse within 4 months.

Case 4 A 9-year-old boy with standard-risk ALL in CR1 presented during maintenance week 76 with sudden-onset painless visual loss in the right eye. Ocular examination showed severe visual loss with frosted branch angiitis with preretinal bleed. Left eye was normal. Vitreous tap revealed blasts. CSF was negative and BM was normal. Uniocular relapse was diagnosed. He received ocular RT and is currently in the maintenance phase of salvage chemotherapy.

Case 5

Case 1 A 2-year-old girl with National Cancer Institute high-risk ALL in first complete remission (CR1) presented at maintenance week 78 with bilateral painless diminution of vision. Ocular examination showed bilateral hypopyon in the anterior segment. Posterior segment examination was normal in both the eyes. Aqueous tap was performed which revealed lymphoblasts. Received for publication November 27, 2013; accepted July 23, 2014. From the *Pediatric Hematology Oncology Unit, Department of Pediatrics, Advanced Pediatric Centre; Departments of wOphthalmology; and zCytology & Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. The authors declare no conflict of interest. Reprints: Amita Trehan, MD, Pediatric Hematology Oncology Unit, Advanced Pediatric Centre, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India (e-mails: [email protected]; [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins

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Simultaneous cerebrospinal fluid (CSF) and bone marrow (BM) examination did not show leukemic involvement. A diagnosis of isolated biocular relapse was made, and the child was started on orbital radiotherapy (RT). However, she experienced a BM relapse within 4 months and went onto palliative care.

A 7-year-old boy with high-risk ALL in CR1 presented at week 45 of therapy with painless diminution in vision bilaterally. Ocular examination revealed leukemic infiltrates involving the optic disc in the right eye and posterior pole infiltration in both eyes. A biopsy was not possible. He was given biocular RT (30 Gy), and continued on chemotherapy. This child presented again at week 125 with normal blood counts and a 2 2 cm painless mass in the right iliac fossa that persisted for 17 days. Prebiopsy peripheral blood counts demonstrated blasts in peripheral smear and confirmed BM relapse.

Case 6 A 5-year-old boy, with standard-risk ALL completed therapy uneventfully. On follow-up at 9 years of age, 6 months after therapy completion he complained of headache. He had no ocular symptoms. Ocular examination of the right eye revealed leukemic infiltration of the optic disc and peripapillary retina. Examination of the left eye was normal. CSF examination was

J Pediatr Hematol Oncol



Volume 36, Number 8, November 2014

J Pediatr Hematol Oncol



Volume 36, Number 8, November 2014

normal. Contrast-enhanced magnetic resonance imaging of bilateral orbits showed heterogeneous enhancing sheet-like tissue along the right retinochoroidal region associated with optic nerve thickening. BM was infiltrated at this time. Because repeat CSF also showed infiltration, palliative care was initiated.

Case 7 An 8-year-old girl with standard-risk ALL in CR1 presented with fever at 76 weeks of therapy. Examination revealed a firm mass in the lower abdomen. Ultrasonography suggested a solid left adnexal mass which was confirmed on computed tomography, and fine-needle aspiration cytology from the mass revealed lymphoblasts. BM and CNS were not involved. Reinduction therapy was started. However, 2 weeks after initiation of therapy, she developed frank hematological relapse and was put on palliative care.

Case 8 A 9-year-old boy with high-risk ALL in CR1 developed chronic diarrhea after 80 weeks on treatment. Repeated stool evaluation was negative for any infectious etiology (ova, cyst, atypical organisms, Clostridium difficile, and culture for Salmonella or Shigella). Cytomegalovirus, tuberculosis, and human immunodeficiency virus infections were ruled out. The serology for celiac disease was negative (antiendomysium antibody and tissue transglutaminase antibody). An upper gastrointestinal endoscopy and colonoscopy with duodenal and colonic biopsy found leukemic blasts in the lamina propria, throughout the intestine. Simultaneous BM and CSF examinations were normal. A diagnosis of isolated gut relapse was made. He was lost to follow-up.

Case 9 A 5-year-old boy with standard-risk ALL in CR1 presented in maintenance at week 127 with a soft-tissue swelling over his left shoulder. A tissue biopsy revealed lymphoblasts. Simultaneous BM and CSF examination were normal. Isolated extramedullary relapse was diagnosed and the child was started on a relapse protocol. He completed relapse therapy and remains in remission for the last 24 months.

Symptom-to-Diagnosis Interval The symptom-to-diagnosis interval was calculated taking the day the patients initially experienced the symptom at home, as determined by history (Table 1). The median symptom-to-diagnosis interval for the diagnosis of a relapse at an unusual site was 20 days. Most of the relapses (6/9) occurred beyond 18 months and before 36 months from diagnosis. Two children (cases 3 and 5) had very early relapse at 18 and 45 weeks of therapy, respectively, and 1 had a late relapse after 6 months of therapy completion (case 6) in the posterior chamber of the eye. All the children with ocular relapse had an initial normal ocular examination by direct fundoscopy after dilation done by the oncology registrar. Four of 9 children (cases 2, 4, 7, and 9) were offered salvage therapy. Four were given palliative care. One child was lost to follow-up. One of 4 on salvage therapy had progressive disease and

Unusual Relapses in ALL

another opted out midway (case 2). The other 2 children (cases 4 and 9) are in CR2, 1 having completed chemotherapy.

DISCUSSION Relapses in leukemia occur most commonly in the BM, CNS, and the testes. Other sites have been reported which include breast, bone, skin and subcutaneous tissue, head and neck, uterus and adnexa, gut, kidney, eye, and lung.5 Most atypical sites of relapse are identified subsequent to a hematological relapse; frequently as an autopsy finding, and are not often clinically evident.5,6 Here, we have presented a series of primary unusual sites of relapse seen, over a period of 22 years. Overall, 172 relapses were seen; the marrow being the site of relapse in 98 patients and CNS in 63 patients. Testicular relapse occurred in 27 patients. Thirty-one (18%) patients had combined relapse (a combination of any of these: BM, CNS, testes). A few (n = 9; 5.2% of all relapses) had isolated unusual site relapse, the details of which are presented herein. These children had unusual signs and symptoms at relapse. In atypical presentations, the diagnosis of relapse may get delayed. The mean time from symptom to diagnosis was 31 days (5 to 150 d) with median of 20 days in the 9 cases reported. Ocular relapse was the most frequent site, seen in 6 patients (3.5% of all relapses). Posterior chamber ocular relapse was present in 5 and 1 child had isolated anterior chamber relapse. Four of 6 children had vision loss as a presenting symptom of relapse. Two children had features of inflammation in the eye (cases 1 and 2). Laterality does not appear to be a helpful distinguishing point between infections and relapse. Three children each had uniocular or biocular relapse. Five ocular relapses occurred within 2 years of diagnosis, whereas 1 child had a late relapse after completion of therapy. In the previous series, the most frequent time of ocular relapse was noted to be the initial few months after the cessation of chemotherapy (9/12 patients). Anterior chamber was involved in all 12 cases in the 2 series.7,8 These observations are in contrast to our series where children relapsed predominantly during maintenance chemotherapy with posterior chamber involvement in the majority. We cannot comment on outcome as most of our patients received palliative therapy. Four of 6 children in our series had progression of disease. Ocular relapse may affect virtually any orbital structure. Extraocular muscles, retina, optic nerve, and anterior chamber have all been reported as sites of relapse.7–11 Secondary glaucoma and corneal swelling may occur. The eye has also been considered as a sanctuary site in leukemias. Anterior

TABLE 1. Characteristics of Patients With Unusual Sites of Relapse

Cases 1 2 3 4 5 6 7 8 9

Age (y)/Sex

Site of Relapse

Time to Relapse (wk)

SDI (d)

Therapy

Outcomes

2/F 9/F 7/M 9/M 7/M 9/M 8/F 9/M 5/M

Ocular: AC Ocular: AC and PC Ocular: PC Ocular: PC Ocular: PC Ocular: PC Adnexa Gut Soft-tissue mass (shoulder)

78 84 18 76 45 182 76 80 127

10 10 5 28 20 10 150 26 21

RT, palliative CTx Salvage CTx RT, Palliative CTx Salvage CTx RT, Palliative CTx Palliative CTx Salvage CTx No therapy Salvage CTx

Disease progression Opted out of therapy Disease progression On therapy (in CR2) Disease progression Disease progression Disease progression LFU CR2 (44 mo)

AC indicates anterior chamber; CR, complete remission; CTx, chemotherapy; LFU, lost to follow-up; PC, posterior chamber; RT, radiotherapy; SDI, symptom-to-diagnosis interval.

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2014 Lippincott Williams & Wilkins

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J Pediatr Hematol Oncol

Jain et al

chamber relapses account for

Unusual sites of relapse in pre-B acute lymphoblastic leukemia.

Relapses of acute lymphoblastic leukemia (ALL) in unusual sites can be challenging to diagnose. We present unusual relapses occurring in children with...
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