4. Sites of involvement and symptoms

myelodysplastic disorders (MPD) [3, 4]. At present, MS represents a major subgroup of mye-

MS can manifest under different clinical scenarios including, (1) MS with concurrent AML, (2) as an isolated tumor and may precede the blood and bone marrow involvement or without any history of myeloid neoplasia and, (3) extramedullary relapse of AML [1, 3, 6–9]. However, with a limited number of prospective studies, the exact frequency and the extent of MS are not well described. Based on the retrospective and the autopsy studies, the occurrence of MS in AML patients is reported to be 10% across genders and all age groups [3, 10, 11]. In depth analysis however revealed that MS primarily affects pediatric patients (>50% of all MS patients) with slight male biasness [7, 12, 13]. In 15–35% of cases, MS can appear concomitantly with AML, whereas, in 50% of cases MS appears following the diagnosis of AML. In rare instances (<1%), MS has also been diagnosed after allogenic stem cell transplantation (allo-SCT), which manifests as an isolated tumor with or without accompanying blood and bone

The precise mechanism underlying the development of MS is unclear. However, extramedullary infiltration by acute leukemia strongly implicates the presence of an alternative homing signal that enables the blast cells to re-localize to these secondary sites. In this context, strong evidence was provided by the studies demonstrating the presence of different chemokine receptors on blast cells in MS and concurrent AML involving blood and bone marrow [16]. Taken together, these observations led to the proposal that unusual manifestations of adhesion molecules dictate the migration of AML subclones to surrounding tissues. Stefanidakis et al. provided further insights into the migratory capacity of blast cells. In their study, the authors reported that a major factor for the migration of AML cells into non-myeloid regions is the interactions between matrix metalloproteinase (MMP) – 9 and leukocyte β2 integrin along with some unidentified proteins [2]. Stefanidakis et al. termed the complex, 'invadosome' [2]. The observations that highly invasive AML cell lines express high level of MMP-2 and tissue inhibitor of metalloproteinase 2 (TIMP2) further support the conclusion of Stefanidakis and colleagues [17]. In a recent study, Zhu et al. has reported a correlation between high expression of enhancer of Zeste 2 (EZH2), the catalytic subunit of polycomb repressor complex 2 (PRC2), and extramedullary infiltration of AML [18]. The authors have indicated that increased expression of EZH2 attenuates the expression of TIMPs, which result in the upregulation of MMPs. The uninhibited MMPs ultimately degrades the extracellular matrix (ECM) and thus aid in the escape of the blast cells in the extramedullary space [18].

loid neoplasms and acute leukemia in WHO classification [5].

2. Epidemiology

116 Hematology - Latest Research and Clinical Advances

marrow relapse [14, 15].

3. Mechanisms

MS can manifest in different anatomical sites. However, there is a lack of study to establish a correlation between AML and predilection for sites by MS. The most commonly involved sites of MS are skin, bone and lymph nodes [3, 10, 11]. In addition, other sites associated with MS include central nervous system (CNS), oral and nasal mucosa, breasts, genitourinary tract, chest wall, testis etc. Skin is the primary sites for the development of MS in pediatric patients (54%), followed by ocular region [3, 10, 11].

In majority of instances, MS is asymptomatic. Even so, depending on the size and location of the tumor, the most common signs and symptoms associated with MS are compression accompanied by pains, bleeding, fever and fatigues [1].
