Correspondence
Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: Case report and review of literature ABSTRACT Acute promyelocytic leukemia (APL) is an uncommon malignancy in the pediatric population, accounting for only 5‑10% of pediatric acute myeloid leukemias, and for this disease to present with bone lesions at diagnosis is extremely unusual. We wish to convey that very rarely, in a pediatric cancer patient presenting with multiple extensive lytic bone lesions, the diagnosis can be APL. The treatment protocol and prognostic implications are vastly different. Histopathology is the gold standard in arriving at a correct diagnosis and delivering proper treatment in such cases. This patient had excellent response to chemotherapy. KEY WORDS: Acute promyelocytic leukemia, lytic bone lesions, pediatric
INTRODUCTION Lytic bone lesions are well‑known to occur in disseminated bone tumors like Ewing’s sarcoma and osteosarcoma, metastatic neuroblastoma, and Langerhans cell histiocytosis. They are uncommon in leukemia and lymphomas. We report the case of a child with acute promyelocytic leukemia (APL) who presented with multiple bone tumors at the onset. The patient also had marrow disease, was treated with All Trans Retinoic Acid (ATRA)‑containing chemotherapy regimen, and his bone lesions responded completely. CASE REPORT A 7‑year‑old boy was referred to us with a history of pain in the left hip associated with intermittent fever of 6 months’ duration. He had received symptomatic treatment initially, with temporary relief. One month back, he had developed swelling of the left hip, followed 2 weeks later by appearance of multiple swellings over the skull. CT (computed tomography) scan revealed multiple bone tumors, hence the patient was referred to us for further evaluation. On examination, the patient was afebrile, and had no pallor or bleeding. There was no generalized lymphadenopathy or hepatosplenomegaly. He had visible swelling of the left hip, and multiple swellings over the skull. His blood investigations results
were-Hb 10.1 gm%, white blood corpuscles (WBC) 5300/mm3, and platelet count 53,000/mm3. His biochemistry values, X‑ray chest, and coagulation profile were normal. Peripheral smear showed few atypical WBCs and thrombocytopenia. His skeletal survey showed destructive lesions over both iliac bones with periosteal reaction, and multiple lytic lesions on the skull [Figure 1]. CT scan of pelvis and brain showed irregular areas of bone destruction with soft tissue component on right and left iliac bones [Figure 2] and temporal region [Figure 3]. There was no intracranial lesion. Bone scan revealed increased uptake over skull, right maxilla, frontal, and left sacro‑iliac joint region. Fine needle aspiration cytology from iliac bone yielded small round cell neoplasm. So, our initial diagnosis was disseminated bone tumor, possibly Ewing’s sarcoma. However, a bone biopsy showed intensely peroxidase‑positive myeloblasts, some of them showing Auer rods and more classically, faggots, suggesting the diagnosis of APL. So bone marrow aspiration with flow cytometry was done, and showed that the blast cells were positive for Leucocyte Common Antigen (LCA), Cluster of Differentiation CD13, CD33, CD64, and CD 117 markers, and negative for CD34 and HLA DR (Human Leucocyte Antigen). Cytogenetics revealed the classical t (15:17) translocation, and molecular testing by Fluorescent In Situ Hybridization (FISH) revealed presence of Promyelocytic Locus-Retinoic Acid Receptor Alpha (PML‑RARA) translocation in blasts, confirming the diagnosis of APL [Figure 4].
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
Manjusha Nair, P. Kusumakumary, P. Sindhu Nair1 Departments of Pediatric Oncology and 1Pathology, Regional Cancer Centre, Trivandrum, Kerala, India For correspondence: Dr. Manjusha Nair, PRA‑19, Prasanth, Pathirappally Road, Poojappura, Trivandrum ‑ 695 012, Kerala, India. E‑mail: drmanjushanair@ gmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.136664 PMID: *** Quick Response Code:
381
Nair, et al.: Pediatric acute promyelocytic leukemia presenting as lytic bone lesions
Figure 1: X-ray pelvis showing destructive lesions
Figure 2: Computed tomography pelvis showing iliac bone lesion with soft tissue component
Figure 3: Computed tomography head showing destructive lesion temporal bone
Figure 4: FISH showing t:(15;17)
The patient received chemotherapy as per PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatía Maligna). Protocol with ATRA at a dose of 25 mg/m2 and anthracycline induction followed by high dose consolidation chemotherapy. One month after initial induction, skull swellings had disappeared completely and hip swelling was reducing in size. CT scan of pelvis showed no demonstrable lytic or sclerotic bone lesions, and skeletal survey was normal. Bone marrow examination showed disease in remission. Chemotherapy was continued, and at the end of treatment, there was complete regression of bone lesions and attainment of bone marrow remission. At present, the patient is on follow‑up, and doing well. DISCUSSION APL is rare in children, accounting for only around 5‑10% of pediatric acute myeloid leukemia.[1] Though lytic bone lesions are well documented in acute lymphatic leukemia and lymphomas, they are extremely rare in nonlymphoid malignancies.[2,3] Extramedullary involvement by acute leukemia is a relatively 382
rare but clinically significant phenomenon that often poses diagnostic and therapeutic dilemmas. [4] Extramedullary disease (EMD) in APL is particularly rare, and nowhere in literature multiple extensive osteolytic lesions at initial presentation have been described. Hence, we are reporting probably the first such case of its kind. EMD in acute leukemia may precede or may co‑exist with marrow disease.[4] Localized promyelocytic sarcoma occurring in the bone can mimic bone tumor, or other conditions like osteomyelitis or rheumatoid disease, and patients often receive orthopedic treatment for these conditions.[5] Cases have been reported where the bone lesions showed radiologic, pathologic, and immunohistochemistry features of Ewing’s sarcoma including blue round cell morphology and strong CD 99 positivity, and later revision of diagnosis had to be made when other evidence of myeloid sarcoma was found.,[6,7] As a proportion of patients never develop systemic disease,[8] correct and timely diagnosis of APL, which is essential for optimal outcome of the patient, can be missed. In our patient, bone lesions and marrow disease were co‑existing.
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
Nair, et al.: Pediatric acute promyelocytic leukemia presenting as lytic bone lesions
Worch et al. have described a patient with hematological APL who had lytic lesions of humerus, tibia, and femur at disease onset.[8] Prakash et al and Haresh et al.[6,7] have reported promyelocytic sarcoma of the ulna., Literature is also available for one case of hip lesion in adult, one vertebral lesion, and one sternal lesion which turned out to be promyelocytic sarcoma., [5,10,11] A few case reports of extramedullary promyelocytic sarcomas occurring occasionally at sites like central nervous system (CNS), lymph nodes, skin, thoracic vertebra, testes, sites of vascular access, external ear, and auditory canal, lung, pleura, heart, mediastinum, thymus, spine, breast, pelvis, mandible, gingival, and bowel have been previously described.[4,9] but most of these are of patients at relapse. Extramedullary relapse of APL occurring as bone lesions are reported, but these are only few and anecdotal, and mostly in the adult population.,[5,10,11] The optimal management and outcome of APL patients with EMD has not been critically assessed, since the disease and such presentations are so rare.[4] Localized promyelocytic sarcoma has been treated with surgery, local radiotherapy and intensive systemic chemotherapy regimens with ATRA and anthracyclines.[11] In our patient, the bone lesions disappeared completely after chemotherapy with ATRA‑containing regimen. Because of the rarity of the disease, the prognosis of patients with EMD in APL is still unclear.[4] EMD by itself is not an adverse prognostic factor in promyelocytic leukemia, but it is reported that it is associated with higher initial WBC count, CNS infiltration, and chance of later relapse, these being factors associated with poor prognosis.[8] In our patient, these adverse factors were not associated, and he has been relapse‑free for 2 years after the completion of treatment.
bone destruction in acute megakaryocytic leukemia: A rare presentation. Pediatr Radiol 1997;27:20‑2. 2. Sirelkhatim A, Kaiserova E, Kolenova A, Puskacova J, Subova Z, Petrzalkova D, et al. Systemic malignancies presenting as primary osteolytic lesion. Bratisl Lek Listy 2009;110:630‑5. 3. Shimonodan H, Nagayama J, Nagatoshi Y, Hatanaka M, Takada A, Iguchi H, et al. Acute lymphocytic leukemia in adolescence with multiple osteolytic lesions and hypercalcemia mediated by lymphoblast‑producing parathyroid hormone‑related peptide: A case report and review of the literature. Pediatr Blood Cancer 2005;45:333‑9. 4. Albano F, Specchia G. Extramedullary disease in acute promyelocytic leukemia: Two‑in‑one disease. Mediterr J Hematol Infect Dis 2011;3:e2011066. 5. Thomas X, Chelghoum Y. Promyelocytic sarcoma of the sternum: A case report and review of the literature. Korean J Hematol 2011;46:52‑6. 6. Prakash G, Ganesan P, Ahuja A, Bakhshi S. MIC‑2 positive granulocytic sarcoma of ulna mimicking Ewing sarcoma. Pediatr Blood Cancer 2008;51:836‑7. 7. Haresh KP, Joshi N, Gupta C, Prabhakar R, Sharma DN, Julka PK, et al. Granulocytic sarcoma masquerading as Ewing’s sarcoma: A diagnostic dilemma. J Cancer Res Ther 2008;4:137‑9. 8. Worch J, Ritter J, Frühwald MC. Presentation of acute promyelocytic leukemia as granulocytic sarcoma. Pediatr Blood Cancer 2008;50:657‑60. 9. Tirado CA, Chen W, Valdez F, Karandikar N, Arbini A, Acevedo I, et al. Unusual presentation of myeloid sarcoma in a case of acute promyelocytic leukemia with a cryptic PML‑RARA rearrangement involving multiple sites including the atrium. Cancer Genet Cytogenet 2010;200:47‑53. 10. Agarwal N, Tepe EM, Mishra A, Ward JH. Relapse of acute promyelocytic leukemia presenting as granulocytic sarcoma in the hip. Ann Hematol 2006;85:741‑2. 11. Stankova J, Mitchell D, Bernard C, Farmer JP, Faingold R, Jabado N. Atypical presentation of acute promyelocytic leukaemia. Br J Haematol 2006;132:379‑80.
REFERENCES
Cite this article as: Nair M, Kusumakumary P, Nair PS. Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: Case report and review of literature. J Can Res Ther 2014;10:381-3.
1. Fisher D, Ruchlemer R, Hiller N, Blinder G, Abrahamov A. Aggressive
Source of Support: Nil, Conflict of Interest: No.
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
383
Copyright of Journal of Cancer Research & Therapeutics is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: Case report and review of literature ABSTRACT Acute promyelocytic leukemia (APL) is an uncommon malignancy in the pediatric population, accounting for only 5‑10% of pediatric acute myeloid leukemias, and for this disease to present with bone lesions at diagnosis is extremely unusual. We wish to convey that very rarely, in a pediatric cancer patient presenting with multiple extensive lytic bone lesions, the diagnosis can be APL. The treatment protocol and prognostic implications are vastly different. Histopathology is the gold standard in arriving at a correct diagnosis and delivering proper treatment in such cases. This patient had excellent response to chemotherapy. KEY WORDS: Acute promyelocytic leukemia, lytic bone lesions, pediatric
INTRODUCTION Lytic bone lesions are well‑known to occur in disseminated bone tumors like Ewing’s sarcoma and osteosarcoma, metastatic neuroblastoma, and Langerhans cell histiocytosis. They are uncommon in leukemia and lymphomas. We report the case of a child with acute promyelocytic leukemia (APL) who presented with multiple bone tumors at the onset. The patient also had marrow disease, was treated with All Trans Retinoic Acid (ATRA)‑containing chemotherapy regimen, and his bone lesions responded completely. CASE REPORT A 7‑year‑old boy was referred to us with a history of pain in the left hip associated with intermittent fever of 6 months’ duration. He had received symptomatic treatment initially, with temporary relief. One month back, he had developed swelling of the left hip, followed 2 weeks later by appearance of multiple swellings over the skull. CT (computed tomography) scan revealed multiple bone tumors, hence the patient was referred to us for further evaluation. On examination, the patient was afebrile, and had no pallor or bleeding. There was no generalized lymphadenopathy or hepatosplenomegaly. He had visible swelling of the left hip, and multiple swellings over the skull. His blood investigations results
were-Hb 10.1 gm%, white blood corpuscles (WBC) 5300/mm3, and platelet count 53,000/mm3. His biochemistry values, X‑ray chest, and coagulation profile were normal. Peripheral smear showed few atypical WBCs and thrombocytopenia. His skeletal survey showed destructive lesions over both iliac bones with periosteal reaction, and multiple lytic lesions on the skull [Figure 1]. CT scan of pelvis and brain showed irregular areas of bone destruction with soft tissue component on right and left iliac bones [Figure 2] and temporal region [Figure 3]. There was no intracranial lesion. Bone scan revealed increased uptake over skull, right maxilla, frontal, and left sacro‑iliac joint region. Fine needle aspiration cytology from iliac bone yielded small round cell neoplasm. So, our initial diagnosis was disseminated bone tumor, possibly Ewing’s sarcoma. However, a bone biopsy showed intensely peroxidase‑positive myeloblasts, some of them showing Auer rods and more classically, faggots, suggesting the diagnosis of APL. So bone marrow aspiration with flow cytometry was done, and showed that the blast cells were positive for Leucocyte Common Antigen (LCA), Cluster of Differentiation CD13, CD33, CD64, and CD 117 markers, and negative for CD34 and HLA DR (Human Leucocyte Antigen). Cytogenetics revealed the classical t (15:17) translocation, and molecular testing by Fluorescent In Situ Hybridization (FISH) revealed presence of Promyelocytic Locus-Retinoic Acid Receptor Alpha (PML‑RARA) translocation in blasts, confirming the diagnosis of APL [Figure 4].
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
Manjusha Nair, P. Kusumakumary, P. Sindhu Nair1 Departments of Pediatric Oncology and 1Pathology, Regional Cancer Centre, Trivandrum, Kerala, India For correspondence: Dr. Manjusha Nair, PRA‑19, Prasanth, Pathirappally Road, Poojappura, Trivandrum ‑ 695 012, Kerala, India. E‑mail: drmanjushanair@ gmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.136664 PMID: *** Quick Response Code:
381
Nair, et al.: Pediatric acute promyelocytic leukemia presenting as lytic bone lesions
Figure 1: X-ray pelvis showing destructive lesions
Figure 2: Computed tomography pelvis showing iliac bone lesion with soft tissue component
Figure 3: Computed tomography head showing destructive lesion temporal bone
Figure 4: FISH showing t:(15;17)
The patient received chemotherapy as per PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatía Maligna). Protocol with ATRA at a dose of 25 mg/m2 and anthracycline induction followed by high dose consolidation chemotherapy. One month after initial induction, skull swellings had disappeared completely and hip swelling was reducing in size. CT scan of pelvis showed no demonstrable lytic or sclerotic bone lesions, and skeletal survey was normal. Bone marrow examination showed disease in remission. Chemotherapy was continued, and at the end of treatment, there was complete regression of bone lesions and attainment of bone marrow remission. At present, the patient is on follow‑up, and doing well. DISCUSSION APL is rare in children, accounting for only around 5‑10% of pediatric acute myeloid leukemia.[1] Though lytic bone lesions are well documented in acute lymphatic leukemia and lymphomas, they are extremely rare in nonlymphoid malignancies.[2,3] Extramedullary involvement by acute leukemia is a relatively 382
rare but clinically significant phenomenon that often poses diagnostic and therapeutic dilemmas. [4] Extramedullary disease (EMD) in APL is particularly rare, and nowhere in literature multiple extensive osteolytic lesions at initial presentation have been described. Hence, we are reporting probably the first such case of its kind. EMD in acute leukemia may precede or may co‑exist with marrow disease.[4] Localized promyelocytic sarcoma occurring in the bone can mimic bone tumor, or other conditions like osteomyelitis or rheumatoid disease, and patients often receive orthopedic treatment for these conditions.[5] Cases have been reported where the bone lesions showed radiologic, pathologic, and immunohistochemistry features of Ewing’s sarcoma including blue round cell morphology and strong CD 99 positivity, and later revision of diagnosis had to be made when other evidence of myeloid sarcoma was found.,[6,7] As a proportion of patients never develop systemic disease,[8] correct and timely diagnosis of APL, which is essential for optimal outcome of the patient, can be missed. In our patient, bone lesions and marrow disease were co‑existing.
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
Nair, et al.: Pediatric acute promyelocytic leukemia presenting as lytic bone lesions
Worch et al. have described a patient with hematological APL who had lytic lesions of humerus, tibia, and femur at disease onset.[8] Prakash et al and Haresh et al.[6,7] have reported promyelocytic sarcoma of the ulna., Literature is also available for one case of hip lesion in adult, one vertebral lesion, and one sternal lesion which turned out to be promyelocytic sarcoma., [5,10,11] A few case reports of extramedullary promyelocytic sarcomas occurring occasionally at sites like central nervous system (CNS), lymph nodes, skin, thoracic vertebra, testes, sites of vascular access, external ear, and auditory canal, lung, pleura, heart, mediastinum, thymus, spine, breast, pelvis, mandible, gingival, and bowel have been previously described.[4,9] but most of these are of patients at relapse. Extramedullary relapse of APL occurring as bone lesions are reported, but these are only few and anecdotal, and mostly in the adult population.,[5,10,11] The optimal management and outcome of APL patients with EMD has not been critically assessed, since the disease and such presentations are so rare.[4] Localized promyelocytic sarcoma has been treated with surgery, local radiotherapy and intensive systemic chemotherapy regimens with ATRA and anthracyclines.[11] In our patient, the bone lesions disappeared completely after chemotherapy with ATRA‑containing regimen. Because of the rarity of the disease, the prognosis of patients with EMD in APL is still unclear.[4] EMD by itself is not an adverse prognostic factor in promyelocytic leukemia, but it is reported that it is associated with higher initial WBC count, CNS infiltration, and chance of later relapse, these being factors associated with poor prognosis.[8] In our patient, these adverse factors were not associated, and he has been relapse‑free for 2 years after the completion of treatment.
bone destruction in acute megakaryocytic leukemia: A rare presentation. Pediatr Radiol 1997;27:20‑2. 2. Sirelkhatim A, Kaiserova E, Kolenova A, Puskacova J, Subova Z, Petrzalkova D, et al. Systemic malignancies presenting as primary osteolytic lesion. Bratisl Lek Listy 2009;110:630‑5. 3. Shimonodan H, Nagayama J, Nagatoshi Y, Hatanaka M, Takada A, Iguchi H, et al. Acute lymphocytic leukemia in adolescence with multiple osteolytic lesions and hypercalcemia mediated by lymphoblast‑producing parathyroid hormone‑related peptide: A case report and review of the literature. Pediatr Blood Cancer 2005;45:333‑9. 4. Albano F, Specchia G. Extramedullary disease in acute promyelocytic leukemia: Two‑in‑one disease. Mediterr J Hematol Infect Dis 2011;3:e2011066. 5. Thomas X, Chelghoum Y. Promyelocytic sarcoma of the sternum: A case report and review of the literature. Korean J Hematol 2011;46:52‑6. 6. Prakash G, Ganesan P, Ahuja A, Bakhshi S. MIC‑2 positive granulocytic sarcoma of ulna mimicking Ewing sarcoma. Pediatr Blood Cancer 2008;51:836‑7. 7. Haresh KP, Joshi N, Gupta C, Prabhakar R, Sharma DN, Julka PK, et al. Granulocytic sarcoma masquerading as Ewing’s sarcoma: A diagnostic dilemma. J Cancer Res Ther 2008;4:137‑9. 8. Worch J, Ritter J, Frühwald MC. Presentation of acute promyelocytic leukemia as granulocytic sarcoma. Pediatr Blood Cancer 2008;50:657‑60. 9. Tirado CA, Chen W, Valdez F, Karandikar N, Arbini A, Acevedo I, et al. Unusual presentation of myeloid sarcoma in a case of acute promyelocytic leukemia with a cryptic PML‑RARA rearrangement involving multiple sites including the atrium. Cancer Genet Cytogenet 2010;200:47‑53. 10. Agarwal N, Tepe EM, Mishra A, Ward JH. Relapse of acute promyelocytic leukemia presenting as granulocytic sarcoma in the hip. Ann Hematol 2006;85:741‑2. 11. Stankova J, Mitchell D, Bernard C, Farmer JP, Faingold R, Jabado N. Atypical presentation of acute promyelocytic leukaemia. Br J Haematol 2006;132:379‑80.
REFERENCES
Cite this article as: Nair M, Kusumakumary P, Nair PS. Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: Case report and review of literature. J Can Res Ther 2014;10:381-3.
1. Fisher D, Ruchlemer R, Hiller N, Blinder G, Abrahamov A. Aggressive
Source of Support: Nil, Conflict of Interest: No.
Journal of Cancer Research and Therapeutics - April-June 2014 - Volume 10 - Issue 2
383
Copyright of Journal of Cancer Research & Therapeutics is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
