5. Diagnosis and disease pathology

At present, there is no specific diagnosis for MS. Given the fact that MS in majority of cases is asymptomatic and does not elicit any specific symptoms, it often poses serious diagnostic challenge for a clinician. Consequently, MS is often misdiagnosed as large cell lymphoma, malignant melanoma, extramedullary hematopoiesis or inflammation. However, diagnosis of MS in association with existing leukemia is comparatively easier than isolated MS. Detection and identification of MS requires the coordinated intervention of different medical procedure. Computed tomography (CT) and magnetic resonance imagery (MRI) are generally used for the detection of the tumors [19]. Following the detection of tumors biopsies are conducted to confirm the malignancy of the mass.

However, accurate diagnosis of MS requires histological examination and immunophenotypic analysis. Histological analysis of MS generally elicits myeloid cells at different stages of maturation. The infiltrating leukemic cells generally elicit irregular large nuclei and large cytoplasm-to-nuclear ratio. Depending on the predominant cell types in the tumors, MS are classified into granulocytic, monoblastic and myelomonocytic. In addition, depending on the maturity of the cells, MS are further subdivided into immature, mature and blastic types [11]. In addition to morphology, cytochemical stainings on imprints may allow for confirming the myeloid affiliation and differentiating granulocytic-lineage and monoblastic forms. According to the WHO 2016 classification, cytochemical stains may include myeloperoxidase and naphthol AS-D chloroacetate esterase (positive in granulocytic MS), as well as non-specific esterase (positive in monoblastic MS) [5]. The diagnosis is further validated by immunophenotyping. Flow cytometric analysis on cell suspensions can be performed; however, immunohistochemistry on paraffin-embedded tissue sections is more commonly used for the detection of lineage affiliation and evaluation of maturation. MS are usually positive for myeloid and monocytic markers, i.e. CD33, CD68, lysozyme, the more immature markers such as CD117 and CD34, CD61, glycophorin, CD4, etc. CD99 and TdT may also be positive. CD56 can be detected in


mutant positive MS is also associated with the loss of CD34 expression and normal karyotype. Studies conducted by Ansari-Lari et al. have reported the presence of FLT3-ITD mutation in 33% (three of nine) of MS patients with concurrent AML [27]. However, the implications of NPM-1 and FLT3-ITD mutations on prognosis of MS are still not clear and data are too scarce for definite conclusions. In their retrospective study, Vega-Ruiz et al. showed that 3% of patients with acute promyelocytic leukemia (APL) manifest MS, predominantly in CNS [28]. Studies conducted by several groups have also attributed the development of MS to the use of

Myeloid Sarcoma: The Other Side of Acute Leukemia http://dx.doi.org/10.5772/intechopen.74931 119

Timely identification of MS has a significant impact on the treatment outcomes and achieving remission in case of AML. As often, these extramedullary tumors serve as sanctuary sites for future relapse. However, detection and simultaneous identification of MS is challenging. The standard AML diagnosis does not include MS, nor there are any specific diagnostic regimens for MS. Consequently, in majority of cases diagnosis of MS is either significantly delayed or remain undetected. In this context, multimodal imaging procedure can be beneficial for early detection of tumors [30]. This generally involves employment of traditional imaging techniques such as, positron emission tomography (PET), CT and MRI [25]. Particularly, in the last decades, PET/CT is becoming an essential tool for disease detection [25]. In this context, 18Ffluorodeoxygenase (18F-FDG)PET/CT has been recognized as a very potent instrument for the identification of not only leukemia but also extramedullary invasion of blast cells [8, 31, 32]. In a prospective study, Stölzel et al. have successfully employed whole-body 18F-FDG PET/CT in 94 AML patients, consisting of both newly diagnosed and relapsed cases of AML for detection of MS [33]. In a different study, Aschoff et al. have demonstrated the sensitivity of 18F-FDG PET/CT by reducing the number of false-positive associated with traditional PET imaging [34]. In addition, 18F-FDG PET/CT has also been able identify new sites of MS, which is not

Although, encouraging, 18F-FDG PET/CT does have some restrictions. Several reports have shown that 18F-FDG PET/CT is not sensitive enough to pick up extramedullary infiltration in the soft tissues such as skin meninges and mucus membranes. In addition, 18F-FDG is not a tumor specific marker but rather depends on the glucose uptake by the cells [8]. As such, there is an increase chance of false-positive signals associated with 18F-FDG PET/CT specifically, in brain and kidney that have high basal glucose metabolism [9]. As an alternative, various groups have used 18F-fluorodeoxythymidine (FLT), a thymidine analogue and proliferating marker, as a tracer for PET/CT in place of 18F-FDG [8]. Unlike 18F-FDG, 18F-FLT has generally low uptake in different organs, such as brain and kidney and therefore elicits comparatively less background [35]. Although, as of now there has been no prospective/retrospective study with 18F-FLT PET/CT for MS detection, but the sensitivity and accuracy of 18F-FLT PET/CT has been demonstrated in different cancers including, non-small cell lung cancer (NSCLC) and

all-trans retinoic acid (ATRA) or with conventional chemotherapy [29].

7. Imaging as a diagnostic tool

identified by traditional imaging techniques [8].

NPM-ALK-Positive lymphoma [8, 36].

Table 1. Common immunophenotypes.

around 20% of MS cases [1, 12]. NPM1 cytoplasmic and nuclear staining indicates NPM1 gene mutations. To exclude the possibility of lymphoma the tumors should be interrogated for different T and B lineage markers such as, CD3, CD20, and CD79a. Aberrant expression of B/T-cell markers is possible, however, if criteria for a mixed-lineage leukemia are fulfilled the case is not classified as MS according to WHO 2016. Particular antigenic constellations may more precisely define subtypes shown in Table 1.

MS is also associated with several cytogenetic and chromosomal abnormalities (please see next section for detailed report). Consequently, fluorescence in situ hybridization (FISH) should be employed as a part diagnostic work up for patient stratification [20].
