A case of fatal overwhelming microgranular variant (M3v) of acute promyelocytic leukemia with extensive extramedullary involvement.

A 38-year-old man presented on January 2007 with dyspnea on exertion, cough, hepatosplenomegaly, and fever. WHO performance status was 2. White blood cells at admission were 38 9 10/L (neutrophils 35.6 9 10/L). Lactate dehydrogenase was 1513 U/L (ULN 500 U/L); aspartate transaminase and alanine aminotransferase 308 and 360 U/L, respectively (ULN 45 and 55 U/L). Grade 2 (no bleeding, according to CTCAEv3) disseminated intravascular coagulation (DIC) was recorded. Chest X-ray was normal, no ascites was found, and oxygen saturation was 95%. A blast population representing 99% of bone marrow nucleated hematopoietic cells and 90% of the peripheral blood cells was identified. The blasts had typically bilobed or reniform nuclei with inconspicuous cytoplasmic granules and rare Auer rods (Fig. 1). Cytochemistry showed intense reactivity with myeloperoxidase while a nonspecific esterase stain was negative. Immunophenotyping performed on peripheral blood cells showed positivity for CD2 (51%), CD34 (86%), CD38 (80%), CD64 (85%), CD13 (94%), CD45 (99%), HLA DR (35.4%), CD33 (96%), and CD117 (93.5%); CD 56 was not evaluated. CD64 expression displayed a light scatter pattern indistinguishable from that of AML with monocytic differentiation; however, coexpression of CD14 was not detected. Standard cytogenetics analysis showed a t(15;17), confirmed by FISH. At diagnosis, RT-PCR analysis for bcr3 PML/RARa was positive only in the bone marrow specimen (we assumed this was due to poor RNA stability in peripheral blood or a failure in performing the technique). An induction regimen was started immediately, according to the current guidelines [1]: retinoic acid (ATRA) 45 mg/ m/day for 30 days plus four doses of idarubicin 12 mg/m. However, only one idarubicin dose was administered because the patient was deteriorating quickly; moreover, the patient could take only 40 mg of retinoic acid during the third day. In fact, on day ?3, a rapid clinical worsening with fever, abdominal pain, and serious dyspnoea was recorded. A computerized tomography scan revealed massive hepatosplenomegaly, peritoneal, and pleural effusion, and thoracic adenomegaly. The white blood cell count increased to 93 9 10/L; worsening DIC and hepatic and renal failure (LDH 9650 U/L, transaminases 1452 and 1388 U/L and creatinine 2.3 mg/dl) were demonstrated. The patient died due to multi-organ failure on day ?4. Post-mortem examination revealed massive leukemic involvement of the lungs, heart, kidneys, gut, bone marrow, spleen, liver, and brain (Fig. 2). Positivity for bcr3 transcript was confirmed in the bone marrow post-mortem specimen. The microgranular variant (M3v) of acute promyelocytic leukemia (APL) accounts for approximately 20% of all cases [2] and the immunophenotype form is more heterogeneous than classic, with variable expression of CD2, CD34, and HLA DR [3]. It could be a differentiation syndrome developed before treatment, as the CD64 expression might suggest [4], even if the involvement of the heart appears somewhat unusual. However, our interpretation is rather different. We believe that this M3v APL was characterized by some adverse prognostic factors (CD2, bcr3) [4, 5] and an unusual immunophenotype with CD38, CD34, and CD64 expression. A monocytic AML-like course could be hypothesized because of the light scatter pattern of CD64 expression and the aggressive and diffuse extramedullary C. Romani (&) R. Murru M. Pettinau A. A. Di Tucci F. Culurgioni D. Pulisci E. Angelucci Hematology and Transplant Centre, ‘‘Armando Businco’’ Cancer Centre, Cagliari, Italy e-mail: claromani@tiscali.it