The initial presentation of this case was active pulmonary tuberculosis with a high total leukocyte count and immature cells in peripheral blood. A leukemoid blood picture simulating acute myeloblastic leukemia has been previously described in association with disseminated tuberculosis [
6], and in this case, BM and cytogenetic study confirmed the diagnosis of APL with t(11;17)(q23;q21). Retrospectively, the patient probably had an impaired immune response that caused reactivation of a latent focus of tuberculosis. Possible relationships between tuberculosis and blood dyscrasias can include: (i) Activation and dissemination of latent tuberculosis focus due to loss of immune mechanism, particularly, cell-mediated immunity in BM failure and leukemia; (ii) Blood dyscrasias might be an unusual immunological response to tubercle bacilli [
7].
APL is a distinct subtype of AML. Morphologically, it is identified as AML-M3 by the French-American-British classification. Cytogenetically, APL is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion of the promyelocytic leukemia (
PML) gene and the retinoic acid receptor α (
RARα). Variant chromosomal translocations (e.g., t(11;17), t(5;17)) can be detected in less than 2% of APL patients [
8]. The present case exhibited morphological features similar to AML, which was confirmed to be an APL variant t(11;17)
ZBTB16/RARA by cytochemical stains and cytogenetics. Of interest, APL cases with the variant t(11;17)
ZBTB16/RARA show some morphological differences compared to APL with t(15;17) (q22;q12) (
PML/RARα). This variant subgroup of APL has a predominance of cells that lack the characteristic bi-lobed or folded nuclei with many granules, the occasional Auer rods, and strong MPO reactivity. These cases have also demonstrated an increased number of pseudo-Pelger-Huet cells with strong MPO reactivity. Several cases of APL have been described in detail in the literature and are discussed below.
Kang et al. [
9] reported 2 cases of acute myeloid leukemia with t(11;17) associated with varying morphology and immunophenotype. Their first case had a prominent monocytic component based on flow cytometric analysis and nonspecific esterase staining of BM core biopsy touch preparations. Cytogenetic analysis of BM aspirate revealed 2 normal cells and 18 cells with an apparently balanced t(11;17)(q23; q21). The second case was more consistent with APL morphologically and immunophenotypically. The leukemic cells had a moderate amount of eosinophilic cytoplasm with numerous granules and Auer rods, and irregular nuclear contours with morphology similar to promyelocytes. These leukemic cells displayed strong positivity with MPO, SBB, and chloroacetate esterase stains. α-Naphthyl acetate esterase and α-naphthyl butyrate esterase stains revealed positive staining in less than 20% of the total BM cells. These morphological findings were similar to our case.
In APL with the variant t(11;17), the
RARα gene on chromosome 17 fuses with the promyelocytic leukemia zinc finger gene
ZBTB16 (
PLZF) on chromosome 11 [
9]. In another study conducted by Grimwade et al., 60 cases of APL were reviewed along with FISH analysis, reverse transcription/polymerase chain reaction (RT-PCR), and immunofluorescence. In 11 patients, APL was associated with
ZBTB16/RARA rearrangement as determined by RT-PCR. The epidemiological survey revealed that
ZBTB16/RARA accounted for approximately 0.8% of cases. Identification of this group is extremely important because of their poor response to retinoids as single-agent therapy and possible resistance to As
2O
3. However, it is clear from this study that complete response (CR) is attainable in this group with combination chemotherapy, indicating that cases of
ZBTB16/RARA-positive APL are not necessarily associated with an adverse prognosis, as previously suggested [
2].
In addition, Sainty et al. reviewed 67 cases of APL. The majority of cases (49) were due to insertion events with documented formation of PML/RARA. Of the 18 cases lacking a
PML/RARA gene rearrangement, 11 cases possessed
ZBTB16/RARA rearrangements [t(11;17)(q23;q21)]. There were 2 cases with t(5;17): a new case with t(5;17)(q34;q21), expressing
NPM/RARA, and a case with an unbalanced der(5)t(5;17). Morphological analysis of the
ZBTB16/RARA group showed that the majority of blasts had a regular nucleus and abundant cytoplasm with either coarse granules, or less frequently, fine or no granules. Only 2 cases exhibited faggots a rare finding [
3]. Licht et al. reviewed the clinical and molecular features of 6 patients with t(11;17)-associated APL. The clinical course of 3 patients was characterized by early death, and 3 experienced disseminated intravascular coagulation. All 6 patients had
ZBTB16/RARA gene fusion as detected by RT-PCR, Southern blotting, or pulsed-field gel electrophoresis [
10]. After a thorough literature search, no case of
ZBTB16/RARA APML along with tuberculosis was found.
In conclusion, this case illustrates a rare presentation of ZBTB16/RARA along with tuberculosis, and the importance of correlating unusual features of promyelocytes, i.e., rounded eccentric nuclei, few granules, and occasional Auer rods with pseudo-Pelger-Huet cells, while evaluating a case of APL. These features may indicate an underlying ZBTB16/RARA rearrangement. Additionally, leukemoid reactions closely simulating blastic leukemia, and in some cases, impossible to differentiate from true leukemia, have been reported in patients suffering from disseminated tuberculosis. Such a mode of presentation, though distinctly rare, is important to recognize as the treatment of these 2 diseases is entirely different, since this variant of APL is resistant to As2O3 and ATRA as a single-agent therapy.
1 and Sanjay D. Cruz2
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