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• W2414707960 abstract "Case ReportsGranular Acute Lymphoblastic Leukemia: Report of Two Cases and Review of the Literature Layla A. Al-Gwaiz, MD, FCAP Abdallah A. Al-Nasser, MD, FAAP Salem Khalil, FRCP(A) Mohammed S. Harakati, and MD, FRCP(C), FACP Hassan El-SolhMD, FRCP(C), FAAP Layla A. Al-Gwaiz Address reprint requests and correspondence to Dr. Al-Gwaiz, Hematology Section, Department of Pathology (32), College of Medicine and King Khalid University Hospital, P.O. Box 2925, Riyadh 11461, Saudi Arabia. From the Department of Pathology (Hematology Section), King Khalid University Hospital and College of Medicine, King Saud University, Riyadh Search for more papers by this author , Abdallah A. Al-Nasser From the Department of Oncology (Pediatric Hematology-Oncology Section), King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , Salem Khalil From the Department of Pathology (Hematology Section), King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , Mohammed S. Harakati From the Department of Medicine (Hematology-Oncology Section), King Khalid University Hospital and College of Medicine, King Saud University, Riyadh Search for more papers by this author , and Hassan El-Solh From the Department of Oncology (Pediatric Hematology-Oncology Section), King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author Published Online::1 Sep 1996https://doi.org/10.5144/0256-4947.1996.573SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionThe classification of acute leukemias into lymphoid leukemia (ALL) and nonlymphoid leukemia (ANLL) is of critical therapeutic importance. The differentiation of ALL from ANLL is usually achieved through morphologic, cytochemical and immunophenotypic analysis of leukemic blasts. One of the main morphologic criteria in the differentiation between the two types is the presence of granules in the cytoplasm of ANLL blasts. There have been scattered reports of patients with ALL who have lymphoblasts with azurophilic cytoplasmic granules. We describe two cases of granular ALL with review of the literature.CASE REPORTCase 1A 22-year-old Saudi male was referred to King Khalid University Hospital (KKUH) in April 1995 with a diagnosis of ALL. He presented with malaise and shortness of breath for one month prior to admission. On examination, he was pale with no jaundice or cyanosis. He had generalized lymphadenopathy and hepatosplenomegaly. Chest and central nervous system (CNS) examinations were unremarkable. The diagnosis of ALL was confirmed (see below) and chemotherapy was started using hydroxyurea 2 g, p.o., q.i.d., for three days, followed by mitoxantrone 12 mg/m2 intravenously (IV) daily for three days, vincristine 1.4 mg/m2 IV weekly for seven weeks, and methylprednisolone 60 mg/m2 IV daily for 21 days. Because of CNS involvement, he was started on intrathecal (IT) methotrexate (MTX) 10 mg, cytosine arabinoside (Ara-C) 50 mg and hydrocortisone 50 mg three times a week for a total of 10 doses. Induction was complicated by fever and neutropenia and he was managed with broad spectrum antibiotics and amphotericin-B. He did not achieve complete remission. Reinduction was started, but the patient died of neutropenia and septic shock.Hematological EvaluationOn admission, complete blood count (CBC) revealed a white blood count (WBC) of 23.8x109/L, hemoglobin (Hb) of 107 g/L, and platelet count of 59x109/L. The WBC differential count showed 8% neutrophils, 70% lymphocytes and 20% blasts. Bone marrow (BM) aspirate revealed hypercellular marrow with 55% blasts. The blasts were variable in size with some showing high nuclear cytoplasmic (N/C) ratio, while others were larger with low N/C ratio and prominent nucleoli. The morphology was that of L2 by the French American British (FAB) classification of ALL.1 Fifteen percent of the blasts contained cytoplasmic granules that were variable in size and stained purple by May-Giemsa stain. The number of granules was also variable, but most of the blasts contained more than three granules. Occasional hand mirror cells were also present. Auer rods were absent.The blasts were negative for Sudan black (SBB) and chloroacetate esterase (CAE) and positive for periodic acid Schiff (PAS), nonspecific esterase (NSE) without inhibition by sodium fluoride (NaFl), and weakly positive for acid phosphatase (AP). Flow cytometry was performed on the bone marrow aspirate and showed the blasts to be positive for CD10 (CALLA), CD19, CD20, CD22 and HLADR and negative for CD7, CD3, CD13 and CD33. The diagnosis of L2, CALLA positive, pre-B ALL was made. At the time of presentation, cerebrospinal fluid (CSF) smear examination revealed involvement by leukemia with blasts containing granules similar to those seen in the peripheral blood and bone marrow blasts.Case 2A six-year-old Saudi male was referred to King Faisal Specialist Hospital and Research Centre (KFSH&RC) in August 1995 with a diagnosis of ALL. He presented with fatigability and fever for one week. On admission, he had generalized lymphadenopathy and hepatosplenomegaly. CNS examination was unremarkable. The diagnosis of ALL was confirmed. Chemotherapy was started as per Children's Cancer Group (CCG) 1882 protocol for high-risk patients, which consists of oral prednisolone 60 mg/m2/day for 28 days, vincristine 1.5 mg/m2/dose IV weekly for four weeks, daunomycin 25 mg/m2/dose IV weekly for four weeks, and L-asparaginase 6000 U/m2/dose, three doses/week for nine doses. For CNS disease, he received IT MTX 10 mg weekly for four doses. However, the patient did not achieve remission in four weeks, with persistent blasts in the peripheral blood, CSF and the bone marrow. Induction phase was extended using teniposide 150 mg/m2/dose, Ara-C 300 mg/m2/dose twice weekly for three weeks and since his CSF was still positive for blasts, his IT therapy was changed to weekly triple IT therapy with MTX, Ara-C and hydrocortisone. Subsequently, he achieved complete remission of his BM and CNS.Hematological EvaluationOn admission, the patient had a WBC of 5.6x109/L, with a differential of 1% neutrophils, 46% lymphocytes and 53% blast cells, Hb was 85 g/L and platelet count was 29x10 g/L. BM examination revealed 80% blasts. The blasts were of L1, FAB morphology subtype. Ten percent of the blasts contained granules. No Auer rods were seen (Figure 1A). The blasts were negative for SBB and CAE and positive for PAS and NSE without NaFl inhibition. By immunophenotyping of the bone marrow aspirate, the blasts were positive for CD10, CD19, CD34 and HLADR and negative for CD3, CD33 and CD13. A diagnosis of L1, CALLA positive pre-B ALL was made. Using PCR technique, the blasts were found to be positive for the immunoglobulin heavy chain gene (Jh) rearrangement (Figure 2). On presentation, the CSF was positive for blasts containing similar granules (Figure 1B).Figure 1A. Bone marrow aspirate showing lymphoblasts with cytoplasmic granules (May-Giemsa stain 1125x).Download FigureFigure 1B. Cerebrospinal fluid smear showing lymphoblasts with cytoplasmic granules (May-Giemsa stain 1125x).Download FigureFigure 2. Ethidium bromide-stained 6% polyacrylamide gel of PCR products amplified with the IGH primers VH and JH. Lanes (1) 100 base pair ladder; (2) pretherapy bone marrow; (3) post-therapy bone marrow; (4) mycosis fungoides; (5) common ALL, positive control; (6) normal DNA, negative control; (7) water control. Lanes 2, 3 and 5 demonstrate a single prominent band indicating a monoclonal B-cell population.Download FigureDISCUSSIONThe presence of granules in acute leukemias is usually associated with myeloblasts. Lymphoblasts are usually devoid of granules. ALL with granules or granular ALL mimicking acute myeloid leukemia (AML) has been previously reported in both children and adults. We describe two cases of ALL in which the blasts contained granules, to emphasize this uncommon variant of ALL which could be misdiagnosed as AML.Other than the presence of cytoplasmic granules in the blasts, there was no evidence of myeloid differentiation in our cases. There were no Auer rods and the blasts were negative for SBB and CAE. They lacked myeloid antigens CD33 and CD13 and exhibited a CALLA immunologic phenotype, and one case showed immunoglobulin heavy chain gene rearrangement. One case was of L2 morphology, while the other was L1 subtype. The clinical findings at diagnosis were similar to most cases of ALL. However, both patients had CNS involvement at presentation and did not achieve remission four weeks after induction. Reinduction was started in both cases. However, the first patient died seven weeks following admission. The second patient is still in remission and is considered for BM transplantation.The first report of cytoplasmic inclusions in lymphoid cells was by Zucker-Franklin2 in 1963, who described “virus-like particles” in the lymphocytes of a case of chronic lymphocytic leukemia. Andy et al.,3 in 1973, described a case of lymphosarcoma cell leukemia with round cytoplasmic inclusions with ribosomal nature. However, the first report of ALL with granules was by Brunning et al.4 in 1974, who described a group of four children with Down syndrome and acute leukemia in whom the blasts contained cytoplasmic granules. The blasts were SBB negative, myeloperioxidase (MPOX) negative and PAS positive.The first adult with granular ALL was described in 1976 by Komiyama et al.5 The blasts had L2 FAB subtype and were AP positive, PAS negative and MPOX negative. By electron microscopy, the granules appeared lysosomal in nature. Since then, several cases of granular ALL were reported in both adults and children.6–14 Most of these cases had CALLA phenotype, but the blasts were of both L1 and L2 FAB subtypes and were positive for PAS and negative for SBB and MPOX. The granules or intracytoplasmic inclusions described were variable in size, color and shape. In most cases, they were described as 2 μ to 5 μ in size. However, some granules were large and had some resemblance to the giant lysosomal granules described in the lymphocyte, monocyte and granulocyte of hereditary Chediac-Hegashi syndrome. The number of the granules was also variable in different cases, from a few granules to large multiple granules resembling those of mast cells.8 The number of blasts containing granules ranged from 3% to 35% of all blasts. Ultrastructural examination of these inclusions revealed membrane-bound organelles which could be degenerating mitochondria,7 while others were described to have a lysosomal nature.4,9,11 The acid phosphatase activity in the granules described by some authors suggest that they may be analogous to lysosomal granules found in stimulated normal lymphocytes.The largest group of granular ALL cases was reported by Cerezo et al.,15 who described 56 cases of granular ALL in a review of 1252 children with ALL. Cases were classified as granular ALL if they met the FAB morphologic criteria for ALL and were characterized by the presence of more than 5% marrow blasts, with at least three clearly defined azurophilic cytoplasmic granules. Their cases did not show any correlation with a specific immunophenotype. Within the early pre-B/pre-B group, granular ALL was equally distributed between good- and poor-risk clinical groups but was more frequent among FABL2 than FABL1 cases. This may be because L2 blasts have more cytoplasm than L1. They showed a significantly poorer outcome for granular early pre-B and pre-B cases compared to nongranular ALL, with complete remission (CR) rates lower for those with granular ALL than nongranular, regardless of the risk group, immunophenotype or FAB type. The CR in granular cases based on granular blasts alone was 81% versus 97% in nongranular cases. The presence of granules had a greater effect on CR than L2 morphologic subtype, with CR for L2 of 91% compared to 98% for L1. Also, granules had a greater effect than L2 on event-free survival. Involvement of CNS at diagnosis was not reported by Cerezo et al.15 Both of our patients had CNS disease at diagnosis. It will be interesting to see in larger studies if there is an association between granular ALL and CNS involvement at diagnosis. Analyses of granular ALL in large series of adults have not been performed.The presence of granules, although usually associated with AML, is not exclusive for AML and morphologic, cytochemical and immunophenotypic features have to be evaluated to avoid misdiagnosis of this morphologic subtype of ALL as AML. Granular ALL, at least in children, appears to be associated with L2 morphology and poor outcome. However, additional studies are required to evaluate larger groups, especially in adults, for the incidence of such a variant and its prognostic significance.ARTICLE REFERENCES:1. Bennett JM, Catovsky D, Daniel MT, et al. The French-American-British (FAB) Cooperative Group. Proposals for the classification of acute lymphoblastic leukemia: concordance among observers and clinical correlations . Br J Haematol. 1981; 47: 553. Google Scholar2. Zucker-Franklin D. Virus-like particles in the lymphocytes of a patient with CLL . Blood. 1963; 21: 509. Google Scholar3. Andy G, Goodman J, Tishkoff G, et al. An unusual cytoplasmic ribosomal structure in pathological lymphocytes . Blood. 1973; 41: 439–47. Google Scholar4. Brunning RD, Parkin J, Dick F, et al. Unusual inclusions occurring in the blasts of four patients with acute leukemia and Down syndrome . Blood. 1974; 44: 735–41. Google Scholar5. Komiyama A, Ogawa M, Eurenius K, et al. Unusual cytoplasmic inclusions in blast cells in acute leukemia . Arch Pathol Lab Med. 1976; 100: 590–4. Google Scholar6. Rosen NR, Difino S, Douglas A, et al. Acute leukemia with unusual cytoplasmic inclusions: a cytochemical and ultrastructural study . Cancer. 1979; 43: 2405–9. Google Scholar7. Yanagihara E, Naeim F, Gale R, et al. Acute lymphoblastic leukemia with giant intracytoplasmic inclusions . Am J Clin Pathol. 1980; 74: 345–9. Google Scholar8. Le Bien TW, Parkin J, Brunning R, et al. Immunologic and ultrastructural heterogenicity of acute lymphoblastic leukemia-associated antigen-positive human leukemias . J Nat Cancer Inst. 1980; 65: 1231–6. Google Scholar9. Grogen T, Insalaco S, Savage R, et al. Acute lymphoblastic leukemia with prominent azurophilic granulation and punctate nonspecific esterase and phosphatase activity . Am J Clin Pathol. 1989; 75: 716–22. Google Scholar10. Stein P, Peiper S, Butler D, et al. Granular acute lymphoblastic leukemia . Am J Clin Pathol. 1983; 7: 426–30. Google Scholar11. Fradera J, Valez-Garcia E, White J, et al. Acute lymphoblastic leukemia with unusual cytoplasmic granulation, a morphologic cytochemical and ultrastructural study . Blood. 1986; 68: 406–11. Google Scholar12. De Salvo C, Weir M, Gomez S, et al. Granular CALLA positive acute lymphoblastic leukemia . Invest Clin. 1990; 31: 153–61. Google Scholar13. Tauchi T, Ohyashiki K, Saito M, et al. Acute lymphoblastic leukemia with azurophilic granules that contain ultrastructural myeloperioxidase activity . Am J Hematol. 1991; 36: 288–90. Google Scholar14. Schuarzinger I, Fodinger M, Scherrer R, et al. Hypergranular acute lymphoblastic leukemia (ALL). Report of a case and review of the literature . Ann Hematol. 1993; 67: 301–3. Google Scholar15. Cerezo L, Shuster J, Pullen J, et al. Laboratory correlates of prognostic significance of granular acute lymphoblastic leukemia in children . Am J Clin Pathol. 1991; 95: 526–31. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 16, Issue 5September 1996 Metrics History Received18 December 1995Accepted30 April 1996Published online1 September 1996 InformationCopyright © 1996, Annals of Saudi MedicinePDF download" @default.
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