March 2013

A 23 year old female with heavy menses for one week

Nariman A. Nawar, M.D., Jeffrey A. Vos, M.D., Sharon L. Wenger, Ph.D.

Overview

A 23 year old female presented to the emergency department with a chief complaint of heavy menses and abdominal cramps for one week. Physical examination revealed pale conjunctivae and generalized skin petechial hemorrhages.

Laboratory Results

Gross Description

Figure 1. Peripheral blood smear showing characteristic white blood cells (representative field).
Figure 2. Bone marrow biopsy showing hypercellular interstitium with cellular features which reflect the diagnosis.
Figure 3. Flow cytometry on peripheral blood.
a) Initial CD45 vs side scatter (SSC) characteristics of population of interest (blue events)
b) CD33 positivity with lack of HLA-DR expression
c) Bright CD33 and variable CD13 co-expression
d) Population virtually negative for CD34
Figure 4. Karyotype in bone marrow aspirate with diagnostic translocation.

Diagnosis

Based on the information provided, what is the best diagnosis ?

Answer

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Discussion

Acute promyelocytic leukemia (APL) represents 5-8% of acute myeloid leukemia (AML). It falls under the category of AML with recurrent genetic abnormalities according to the World Health Organization (WHO) classification (2008). APL is diagnosed based on blast morphologic and immunophenotypic features, and most importantly, the chromosomal analysis. While the diagnosis of AML typically relies on a blast count of at least 20% in the peripheral blood or bone marrow, detecting the characteristic genetic abnormality [i.e., t(15;17)] is sufficient to make the diagnosis of APL, regardless of the blast count.
Blast cells in APL are described morphologically as hypergranular and hypogranular. The hypergranular type is rich with azurophilic granules and Auers rods, while the hypogranular type has few granules and folded, bilobed nuclei. Both types are positive for myeloperoxidase and myeloid antigens such as CD13 and CD33. The blasts are typically negative for HLA-DR and negative or only weakly positive for CD34. Cytochemical stains may also aid in the differential diagnosis, especially in the hypogranular variant which may resemble acute monocytic or myelomonocytic leukemia. In this situation, positivity for specific esterase and negativity for nonspecific esterase is characteristic of APL, while the reverse staining pattern is consistent with a monocytic process.

Multiple cytogenetic variants for APL have been identified. All result in inactivation of the retinoic acid receptor alpha gene (RARA) on chromosome 17 resulting in blast maturation arrest. Variants of RARA translocation include:

t(15;17)(q24;q12): PML-RARA, shown in the fluorescence in situ hybridization (FISH) image using a PML-RARA dual fusion probe.

t(11;17)(q23;q12): ZBTB16-RARA, ZBTB16 (or PLZF) Promyelocytic leukemia zinc finger protein translocated to RARA.
t(11;17)(q13;q12): NuMA1-RARA, nuclear matrix associated gene (NuMA1) translocated to RARA.
t(5;17)(q35;q12): nucleophosmin gene translocated to RARA.

Clinically, APL manifests as a coagulopathy in the form of disseminated intravascular coagulation (DIC). For this reason, APL was originally considered to be leukemia with high fatality before the introduction of all-trans retinoic acid (ATRA) to its therapeutic regimen in 1988. Different mechanisms contributing to the development of DIC in APL have been identified.

Figure 5. FISH using PML/RARA probes demonstrating the translocation in interphase cells by the formation of two gene-fusion (red-green) signals

One of the main mechanisms is the up regulation of tissue factor by the cytokines released from promyelocytes, such as tumor necrosis factor alpha and IL-1B, and by cancer procoagulants expressed by leukemic cells. In addition to thrombosis, bleeding tendency develops in APL by the release of chymotrypsin, elastasis and urokinase type plasminogen activator from the blast cell granules. Furthermore, excessive fibrinolysis in APL is induced by the expression of annexin-II by blast cells.
Prognosis of APL is favorable in cases where treatment with ATRA is given early in the course of the disease. ATRA induces apoptosis and maturation of blast cells preventing the development of DIC. With moderation therapies to include ATRA with an anthracycline, or arsenic trioxide in refractory cases, APL is considered one of the most treatable forms of AML with an overall survival rate of over 70%.

References

  1. Disseminated Intravascular Coagulationin Hematologic Malignancies,Massimo Franchini, M.D.,1 Matteo Nicola Dario Di Minno, M.D.,2and Antonio Coppola, M.D.
  2. Hematopathology. 2nd Edition. Eric D. His, M.D.
  3. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T, Lengfelder E, Büchner T, Döhner H, Burnett AK, Lo-Coco F. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood. 2009 Feb 26;113(9):1875-91. Epub 2008 Sep 23. Review. PubMed PMID: 18812465.
  4. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th Edition. International Agency for Research on Cancer. Lyon, 2008.