Pediatrics International (2010) 52, e171–e174
Patient Report
ped_3113
doi: 10.1111/j.1442-200X.2010.03113.x
171..174
Gastrointestinal presentation of late acute lymphoblastic leukemia relapse Vassilios Papadakis,1 Eleftheria Roma,2 Kalliopi Stefanaki,3 Ioanna Panagiotou,2 Sofia Papargyri,1 George Paterakis4 and Sofia Polychronopoulou1 Departments of 1Pediatric Hematology-Oncology and 3Pathology, Agia Sofia Children’s Hospital, 2First Department of Pediatrics, University of Athens and 4Department of Immunology, G. Gennimatas General Hospital, Athens, Greece Key words
Acute lymphoblastic leukemia, child, gastrointestinal relapse, late relapse.
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. With current treatment protocols, event-free survival >80% has been achieved. Despite these major improvements, some patients will relapse (15–18%) and most of them will present with isolated bone marrow (BM) relapse or combined BM and central nervous system (CNS) and/or testicular relapse.1,2 Acute lymphoblastic leukemia infiltration of the gastrointestinal (GI) tract is an extremely rare event, either at diagnosis or at the time of ALL relapse.3–6 We report a young patient with a history of ALL, presenting with bulky GI tract ALL infiltration (ALL relapse), 10 years after the initial diagnosis. To our knowledge and after thorough review of the English-language literature, late ALL relapse with GI presentation confirmed on endoscopy and biopsies is a very rare event and not reported so far.
Case report The patient, aged 31/2 years, was initially admitted in June 1998, complaining of diarrheas. Complete blood count on diagnosis was as follows: white blood cells, 9.3 k/mL (10% blasts); hemoglobin, 11.3 g/dL; hematocrit, 33.4%; platelets, 89 k/mL. With concomitant hepatosplenomegaly and thrombocytopenia, ALL was diagnosed on BM aspiration. CNS, mediastinum and testes were unaffected. No further GI tract evaluation was performed. Bone marrow ALL blast flow cytometry was positive (>75%) for human leukocyte antigen (HLA)-DR, CD34, CD10, CD19, and CD10/CD34. The patient was treated according to the ALLBFM-95 Protocol (median-risk arm), with prompt response and improvement. Treatment was completed 3 years later, including intensified maintenance treatment.2,7 Since February 2008, due to intermittent abdominal pain, fever, occasionally hemorrhagic diarrheas, migrating selfresolving arthralgias and skin rash arthralgias, extensive work-up
Correspondence: Vassilios Papadakis, MD, PhD, Department of Pediatric Hematology-Oncology, Goudi, Athens 11527, Greece. Email:
[email protected] Received 23 April 2009; revised 5 August 2009; accepted 14 October 2009.
© 2010 Japan Pediatric Society
for infections and autoimmune diseases was non-conclusive. In April 2008 a BM aspirate evaluation was unremarkable. The patient then underwent upper and lower GI endoscopy, to exclude atypical ALL/non-Hodgkin lymphoma or inflammatory bowel disease. On upper endoscopy a large ulcerative lesion was found between the antrum and corpus, towards the great curvature, and multiple small whitish polypoid lesions of diameter 3–7 mm at the second and third part of the duodenum (Fig. 1). On colonoscopy an isolated ulcerative lesion in the middle of the ascending colon was seen. Multiple biopsies of the upper and lower GI tract indicated infiltration by blasts (Fig. 2). Immunohistochemistry showed expression of nuclear terminal deoxynucleotidyl transferase (Tdt) and paired box gene 5/ B-cell lineage specific activator protein (PAX-5/BSAP), cytoplasmic CD79a, CD22 and bcl-2, membranous CD10, CD34 and HLA-DR. There was no expression of CD20/L-26, CD3[PS1], CD5, CD13, CD15, or CD68/PG-M1. Ki-67 was >60% and p53 protein was positive in 30% of the cells. These findings were compatible with a B-precursor lymphoblastic lymphoma/leukemia (World Health Organization [WHO] classification). They are characteristic of B-ALL and identical to the initial ALL-blast immunophenotype. Moreover, the immunophenotype excluded the possibility of a primary/secondary GI lymphoma of any kind. A concurrent BM biopsy indicated 30% BM infiltration by blasts, with immunophenotype identical to the initial ALL and the current GI blast infiltration (Fig. 3). Karyotype of the BM aspirate was 46XY. Clinically, CNS, testes and mediastinum were unaffected. Fludeoxyglucose positron emission tomography–computed tomography (18FDG PET-CT), however, showed increased tracer uptake over most bones (spine/scapula/ ribs/femoral bones etc), both testes and the stomach (Fig. 1). On the diagnosis of combined GI-BM ALL relapse, the patient started treatment (Berlin-Frankfurt-Munster ALLRelapse 2002 Protocol) with prompt symptomatic relief. BM indicated no blasts within 2 weeks and thereafter. Repeated upper and lower GI endoscopy 1 and 5 months on treatment showed remission. The 18FDG-PET-CT scan also normalized. Following completion of the intensive part of the protocol, in March 2009 the patient was given 12 Gy prophylactic CNS irradiation. Two weeks later the patient developed left testicular
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Fig. 1 (a) Endoscopy of the duodenal lesions; (b) Fludeoxyglucose 18FDG-positron emission tomography–computed tomography, showing avid heterogeneous tracer uptake over the stomach, as well as the ribs, vertebral bodies and the iliac bones.
enlargement with sonographic appearance of relapse. Bilateral testicular biopsies confirmed left testicular relapse. Cerebrospinal fluid was unaffected, but BM evaluation indicated a 10–15% blast infiltration. Blast immunophenotype of the testicular relapse (second relapse) showed positivity for Tdt, PAX-5/BSAP (nuclear), CD79a, CD22, CD10, CD34, Ki-67/MIB-1(>60%; Fig. 3). Although the immunophenotype was identical to the initial presentation 10 years earlier and the first ALL relapse (GI and BM) 1 year earlier, the blasts showed increased size and nuclear atypia. Following orchiectomy, the patient is receiving treatment in preparation for stem cell transplantation, with guarded prognosis.
Discussion More than 15% of pediatric ALL patients relapse.1,2,7 A “late relapse” could also represent a novel malignancy.8 In the present case the GI tract symptoms were prominent, but initial BM aspirate was unaffected. Two other reported cases of GI ALL occurred much earlier in a 15- and a 45-year-old patient, respectively, 3 and 6 months after BM transplantation and without BM involvement on BM aspirate.5,6 Both patients initially responded © 2010 Japan Pediatric Society
to treatment and had recurrence soon thereafter of extramedullary-only ALL. In the present patient GI endoscopy and biopsies established the diagnosis of ALL relapse. Initially, BM aspirate did not indicate ALL, although a few weeks later BM biopsy confirmed the presence of ALL blasts. GI blast phenotype was identical to the ALL-diagnosis phenotype, a decade earlier. Although the possibility of a lymphoblastic lymphoma was taken into consideration, the definite 30% blastic infiltration of the BM in the trephine BM biopsy at first relapse favored the diagnosis of ALL according to WHO classification.9 Furthermore, the immunophenotype of the blasts on the paraffin sections of the GI biopsies, the involved testis during the second relapse and the BM is identical to the one at initial presentation. Despite the low percentage of blasts on flow cytometry at second relapse, the BM showed again a 10–15% infiltration on trephine biopsy. It has been reported that childhood ALL can present with GI symptoms, such as diarrhea, but these are rarely documented and linked to ALL-blast infiltration.10 Even in cases of extensive leukemia infiltrates of liver/spleen/lungs, GI bleeding cannot be attributed to leukemia infiltrates but to the presence of
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Fig. 2 (a,b) Upper and (c,d) lower gastrointestinal immunostaining (Bond Polymer Refine kit, Leica Microsystems, Wetzlar, Germany). (a) Terminal deoxynucleotidyl transferase (Tdt) immunohistochemical expression in the blastic cells infiltrating the duodenal mucosa; (b) Ki67/MIB-1 expression in >70% of the nuclei of the blasts infiltrating the gastric mucosa; (c) CD79a expression and (d) Tdt expression in the blasts infiltrating the colonic mucosa.
Fig. 3 (a–c) Bone marrow and (d–f) testicular immunostaining (Bond Polymer Refine kit, Leica Microsystems, Wetzlar, Germany). (a) CD34 expression in the blastic population infiltrating 30% of the bone marrow; (b) higher magnification of CD34 expression in the blastic population infiltrating the bone marrow; (c) CD79a expression in the blastic population infiltrating the bone marrow; (d) Terminal deoxynucleotidyl transferase (Tdt) expression, (e) CD34 expression and (f) CD79a expression in the blastic population infiltrating the left testis. © 2010 Japan Pediatric Society
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non-specific duodenal ulcers.11 Adult chronic lymphocytic leukemia patients can have normal colonoscopy, but positive histology in ileum/colon.12 Postmortem studies in adults, however, indicate gross leukemic infiltration in 13–25% and microscopic alterations in an additional 28% of patients.13,14 Adult patient with acute myelogenous leukemia (AML) have presented with appendicitis. Children with AML can present with granulocytic sarcoma of the colon, but sarcomatous masses in AML are not rare. In the present patient diarrhea, low-grade fever, and arthralgias could have indicated the onset of inflammatory bowel disease. In contrast, late ALL relapse 10 years later was proven. Unfortunately, ALL relapse was further confirmed by subsequent testicular relapse while on treatment. When there is a suspicion of GI tract leukemia infiltration, endoscopy and full evaluation are indicated. After reviewing the available English-language literature, a similar pediatric case of GI presentation of late ALL relapse, confirmed on endoscopy and biopsies was not found.
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© 2010 Japan Pediatric Society
4 de Ridder L, Bosman DK, Benninga MA et al. Endoscopic diagnosis of leukemia in a child with acute abdominal pain. Endoscopy 2004; 36: 933–4. 5 Weisdorf D, Arthur D, Rank J et al. Gastric recurrence of acute lymphoblastic leukaemia mimicking graft-versus-host disease. Br. J. Haematol. 1989; 71: 559–61. 6 Kletzel M, Meitar D, El-Youssef M et al. Gastrointestinal relapse of leukemia, mimicking acute graft vs. host disease, following a stem cell transplant. Med. Pediatr. Oncol. 2000; 34: 287–9. 7 Papadakis V, Panagiotou JP, Polychronopoulou-Androulakaki S et al. Results of childhood acute lymphoblastic leukaemia treatment in Greek patients using a BFM-based protocol. Haema 2003; 6: 208–16. 8 Pui CH, Cheng C, Leung W et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N. Engl. J. Med. 2003; 349: 640–49. 9 Borowitz MJ, Chan JK. B lymphoblastic leukemia/lymphoma not otherwise specified. In: Swerlow SH, Campo E, Harris NL et al. (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon, 2008; 168–70. 10 Robazzi TC, Silva LR, Mendonca N et al. Gastrointestinal manifestations as initial presentation of acute leukemias in children and adolescents. Acta Gastroenterol. Latinoam. 2008; 38: 126–32. 11 Horny HP, Krokowski M, Feller AC et al. [Aleukemic mast cell leukemia (formerly: “malignant mastocytosis”): An extremely rare form of leukemia. A case report and simultaneously a contribution to revised classification of mastocytosis]. Wien. Klin. Wochenschr. 2002; 114: 222–8. 12 Arkkila PE, Nuutinen H, Ebeling F et al. Colonic involvement in a patient with chronic lymphocytic leukaemia. Gastroenterol. Res. Pract. 2008. doi: 10.1155/2008/742146 13 Sherman NJ, Woolley MM. The ileocecal syndrome in acute childhood leukemia. Arch. Surg. 1973; 107: 39–42. 14 Steinberg J, Brandt LJ, Brenner S et al. Acute lymphoblastic leukemia with infiltration of the colon. Am. J. Gastroenterol. 1988; 83: 1002–4.
