Contributed by Lin Liu, MD, PhD and Sara Monaghan, MDFINAL DIAGNOSIS
PART 1: PERIPHERAL BLOOD
PANCYTOPENIA WITH OCCASIONAL BLASTS.
PART 2 AND 3: BONE MARROW, BIOPSY, TOUCH IMPRINTS AND ASPIRATE
ACUTE MYELOID LEUKEMIA WITH MONOCYTIC DIFFERENTIATION AND LARGE AREAS OF NECROSIS (see comment).
DIAGNOSTIC COMMENT
Morphologic evaluation reveals 5% blasts in the peripheral blood and 82% blasts in the bone marrow. Flow cytometry studies, cytochemical studies and immunohistochemistry confirm these cells are myeloblasts with monocytic differentiation. The large areas of necrosis likely contributed to the difficulty in obtaining a more cellular sample for flow cytometry and cytogenetic studies.
DISCUSSION
Diagnosis of acute myeloid leukemia is facilitated by ancillary studies including flow cytometry, cytochemical stains and immunohistochemistry studies. By flow cytometry, leukemic blasts with monocytic differentiation variably express myeloid antigens CD13, CD33 (often very bight), CD15 and CD65. There is generally expression of at least two markers characteristic of monocytic differentiation such as CD14, CD4, CD11b, CD11c, CD64, CD68, CD36 and lysozyme. CD34 is positive only in 30% of cases, while CD117 may be more often expressed. Almost all cases are positive for HLA-DR. In the presented case, flow cytometric studies demonstrate leukemic blasts with many features consistent with monocytic differentiation (i.e. positive for CD33 (bright), CD15, CD11b, CD64, CD36, and HLA-DR). Due to extensive bone marrow necrosis, flow cytometry studies for lymphoid markers were very limited; however immunohistochemical studies on the biopsy negative for CD79a, PAX5, and CD3 help to exclude B- and T-lineage differentiation. Cytochemical studies demonstrate the blasts in the presented case are predominantly negative for enzymes associated with neutrophilic differentiation (peroxidase, chloroacetate esterase, and Sudan black) while they are positive for the non-specific esterases (alpha-naphthyl butyrate esterase and alpha-naphthyl acetate esterase), which offers strong support for monocytic differentiation. The non-specific esterases are positive in monocytes and megakaryocytes, but enzyme activity in monocytes is inhibited by fluoride.
AML with monocytic differentiation has been found frequently associated with deletion and translocations involving 11q23, inv(16) and t(9,11), and may also harbor t(6,9), inv(3), NPM1 or FLT3-ITD mutations. The cytogenetic studies in this case revealed hyperdiploidy, which is rare in AML and is not one of the recurrent genetic abnormalities that defines a specific subtype according to the World Health Organization Classification (2008). Although the bone marrow specimen yielded only 5 metaphases for evaluation, classical cytogenetic studies performed on a concurrent peripheral blood specimen revealed the same hyperdiploid clone in all 20 metaphase cells evaluated. PCR performed on the peripheral blood specimen was negative for the NPM1 mutation. Based on the constellation of findings, the final classification of this leukemia is "acute myeloid leukemia, not otherwise specified (acute monocytic leukemia)."
Massive hyperdiploidy, variably defined as > 50 chromosomes or ? 52 chromosomes, is rare in myeloid malignancies. In contrast, hyperdiploidy with more than 50 chromosomes accounts for about 25% of cases of B lymphoblastic leukemia (B-ALL). The extra chromosomes commonly observed in B-ALL (e.g. 21, X, 14, 4) were not observed in the current case. Priess BS, et al, reported massive hyperdiploidy in 3% of 337 adult patients with de novo AML. Patients with hyperdiploidy in that study had a median age 69 years (range: 18-90 years). The finding was most frequent in cases classified as AML-M5 (i.e. acute monocytic or monoblastic leukemia), according to FAB, but the association did not reach statistical significance. Because of the rarity of the finding, the prognostic significance is unclear. Nevertheless, Iyer RV, et al, attempted to evaluate the prognostic impact of massive hyperdiploidy and tetraploidy in 11 AML patients and 2 MDS patients (median age: 70 years; range: 44-84 years). Ten of AML patients had de novo disease and 1 had evolved from a prior MDS. Among their cases, the most frequently gained chromosomes were 8, 19, 13, 15, 21, 1 and 9. Unlike the patient presented here, 69% of their patients had additional clonal cytogenetic abnormalities without massive hyperdiploidy or tetraploidy and evidence for clonal evolution was seen in 38%. Of the 10 AML patients who received induction chemotherapy, only 40% achieved complete remission. They noted that 7 patients had some cells with normal metaphases, which is a finding also detected on the bone marrow study in the patient presented here. The patients with some normal metaphases seemed to have a longer median survival compared to the other patients (9 months vs. 5.3 months). Based on their data, this group suggested that massive hyperdiploidy and tetraploidy were prognostically unfavorable, associated with a low remission rate and short survival. However, this study is not sufficient for generalization or to use for predicting the prognosis for the present patient.
The extensive bone marrow necrosis seen in this bone marrow is the other unusual feature seen in this case. This finding is rare and probably more commonly seen at autopsy. It is characterized by necrosis of the medullary stroma and myeloid tissue in large areas of hematopoietic bone marrow, leaving an amorphous eosinophilic background, poorly defined necrotic cells, and preserved cortical bone. It has been associated with fever, bone pain, and elevated serum lactate dehydrogenase. TNF-? has been considered for a possible role in the etiology of bone marrow necrosis. Bone marrow necrosis has been reported most frequently in patients with malignancy involving bone marrow, either of hematopoietic origin or due to metastatic carcinoma. Childhood acute lymphoblastic leukemia is the most common malignancy associated with bone marrow necrosis and, in this setting, does not appear to have prognostic significance. Bone marrow necrosis may also have an association with some drug therapies (e.g. imatinib mesylate, interferon alpha, G-CSF, ATRA and fludarabine). Non-malignant causes for bone marrow necrosis include sickle cell disease, infections (e.g. tuberculosis), and sepsis. More rare causes that have been reported include anorexia nervosa, hemolytic uremic syndrome, antiphospholipid syndrome, DIC and hyperparathyroidism. It is very rare in AML; very limited data and case reports suggest that it may be associated with a poor prognosis, but the available information is not conclusive. Fortunately, despite the prominent necrosis in this case, there was sufficiently intact tissue obtained for morphologic, immunophenotypic and cytogenetic studies and the diagnosis was promptly established.
In the patient presented here, the bone marrow evaluations on days 14 and 21, status post induction chemotherapy, showed persistence of leukemia with extensive bone marrow necrosis. The patient received re-induction chemotherapy and the most recent bone marrow evaluation, day 29, status post re-induction, revealed a variably cellular marrow with large zones of stromal injury/repair, but no evidence for persistent AML. An HLA sibling matched donor marrow transplantation is planned.
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Iyer RV, Sait SN, Matsui S, Block AW, Barcos M, Slack JL, Wetzler M, Baer MR. Massive hyperdiploidy and tetraploidy in acute myelocytic leukemia and myelodysplastic syndrome. Cancer Genet Cytogenet. 2004 Jan 1;148(1):29-34.
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Preiss BS, Kerndrup GB, Schmidt KG, Sørensen AG, Clausen NA, Gadeberg OV, Mourits-Andersen T, Pedersen NT; AML Study Group Region of Southern Denmark. Cytogenetic findings in adult de novo acute myeloid leukaemia. A population-based study of 303/337 patients. Br J Haematol. 2003 Oct;123(2):219-34.
Contributed by Lin Liu, MD, PhD and Sara Monaghan, MD
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