Educational Case: Myeloid Sarcoma: A Subtype of Acute Myeloid Leukemia

What Is the Differential Diagnosis of the Clinical Findings in This Patient?

Given patient’s history of underlying malignancy status post-chemotherapy, the differential diagnosis to consider is malignancy (a newly developed malignancy versus recurrent AML) versus an infectious process. The infections to consider in an immunocompromised host will be opportunistic infections, viral, fungal, and mycobacterial infections.

What Does the CBC Show?

The CBC showed normocytic anemia (Mean corpuscular volume (MCV): 87.2 and hemoglobin: 7.9 g/dL) with marked leukopenia and thrombocytopenia (white blood cell count: 0.9 K/mm³ and platelet: 24 K/mm³). Based on the CBC results, a peripheral blood smear (Figure 1) was prepared and subsequently.

OPEN IN VIEWER

Figure 1.

High power (Cellavision software image of peripheral blood smear equivalent to 100×) view of peripheral blood smear showing peripheral blasts. The cells are large in size with open chromatin, irregular nuclear membrane, high Nuclear-Cytoplasmic ratio, and occasional prominent nucleoli.

Describe the Cells in the Peripheral Blood Smear

The cells in the peripheral blood smear (Figure 1) are large with large nuclei, high N:C ratio, lacy chromatin, some with prominent nucleoli and some with small cytoplasmic granules, which are characteristic of immature cells.

What Are the Histologic Findings on the Gluteal Mass Biopsy in this Case?

Histologic evaluation by hematoxylin and eosin stain shows skin with underlying soft tissue diffusely infiltrated by immature neoplastic cells with complete distortion of the papillary and reticular dermis (Figure 2). The cells are immature with scant cytoplasm, high nuclear to cytoplasmic ratio, round to oval nuclei with finely dispersed chromatin, and prominent nucleoli (Figure 3). Numerous immature cells are noted (Figure 4).

OPEN IN VIEWER

Figure 2.

Low power (2×) view of hematoxylin and eosin (H&E) stained slide showing an expanded epidermis (acanthosis) overlying an expanded dermis infiltrated diffusely by an atypical cellular infiltrate. The cells in the infiltrate are immature cells involving the papillary and reticular dermis.

OPEN IN VIEWER

Figure 3.

A high-power view (40×) of the tumor cells from the skin lesion. The cells are immature with scant cytoplasm, high nuclear to cytoplasmic ratio, round to oval nuclei with finely dispersed chromatin, and prominent nucleoli. There are occasional small mature lymphocytes in the background. Increased number of mitotic figures are noted. There is no necrosis and acute inflammation.

OPEN IN VIEWER

Figure 4.

Oil emersion field (100×) view of numerous immature cells (see black arrows). The cells are large in size, have high nuclear to cytoplasmic ratio, round to oval nuclei with irregular nuclear membrane, finely dispersed chromatin, and prominent nucleoli.

Describe the Findings of the Bone Marrow Biopsy

Bone marrow biopsy shows a hypercellular marrow with diffuse proliferation of large atypical cells with high N:C ratio, lacy chromatic, and prominent nucleoli comprising 40% of the marrow. Occasional eosinophilic granules are noted in the neoplastic cells.

What Is Your Diagnosis Based on the Immunohistochemical Findings?

CD34 is expressed on the immature cells along with CD117 which also indicated a myeloid origin of the cells. Myeloperoxidase is expressed on myeloid lineage cells. CD68 is a histiocytic marker and can be expressed in myeloid cells. The neoplastic cells staining for these markers show them being immature and of myeloid lineage. TdT is a lymphoblastic marker, AE1/AE3 highlights epithelial cells, and Melan-A is expressed in melanoma cells. The lack of expression of these markers help exclude epithelial neoplasm, melanoma, and lymphoblastic origin of these cells. Based on the immunoprofile of the neoplastic cells expressing CD34, CD117, and MPO in the bone marrow and MPO and CD68 in the biopsy section along with immature morphologic features on the cells findings are consistent with an immature myeloid process.

What Explains the Difference in Immunomarkers Expressed in the Bone Marrow and Gluteal Mass Neoplastic Cells?

There can be different staining of the blasts in the marrow and the tissue, depending on the maturation pattern of the blasts present in each tissue examined. Tumors with more immature myeloid profile express CD33, CD34, CD117, CD68, and staining for MPO is sometimes inconsistent. However, in promyelocytic cases of myeloid sarcoma (MS), generally the blasts express MPO and are negative for CD34.

How Would You Interpret the Immunophenotypic Findings of the Neoplastic Cells in the Biopsy?

The neoplastic cells express myeloid markers such as MPO and CD68 without expression of cytokeratin and melanin markers. The morphologic and immunophenotypic findings are consistent with an MS. The proliferation index (Ki67) is generally high with 50% to 95% cells being positive. ^2,3

What Is Myeloid Sarcoma?

According to World Health Organization (WHO) 2017, MS is a mass lesion consisting of blasts of myeloid lineage, which may or may not have maturation, and characteristically present at an anatomical site outside of the bone marrow. ⁴ However, presence of myeloid blasts infiltrating any organ of the body cannot be considered as MS unless there is complete effacement of the tissue architecture. ⁵ Myeloid sarcoma has been described in the earlier literature as a green colored tumor due to the greenish hue on fresh specimens as result of MPO production and has its alternate name as “chloroma.” Later, it was named as “granulocytic sarcoma” by Rappaport followed by “MS” by WHO in 2002, due to the higher expression of MPO staining.

What Is the Epidemiology of Myeloid Sarcoma?

Generally older males (male-to-female ratio is 1.2:1) with a median age of 56 years are affected, although case reports have described MS occurring in 1 month olds to 89 year olds. ^6,7

What Is the Clinical Presentation of Myeloid Sarcoma?

Myeloid sarcoma has no predilection toward any specific anatomical site, but literature describes skin, lymph nodes, gastrointestinal tract, bone, soft tissue, and testes to be the most favorable sites of involvement.^3-7 Rarely (<10%), MS presents at multiple sites of the body. ^6,7 Clinical presentation of MS depends on its location and generally caused by the mass effect of the tumor or due to its infiltration of the organ system. Most importantly, it is to be kept in mind that, in 25% of cases, MS can occur in absence of an underlying AML or any other myeloid neoplasm. Diagnosis of MS is equivalent to diagnosis of AML even in the absence of bone marrow infiltration of blasts. Sometimes the development of MS can herald the onset or overlap with the development of AML. It can also represent a blast transformation of myelodysplastic syndromes or myeloproliferative neoplasms. ^6,7

What Is the Differential Diagnosis and Immunophenotype of Myeloid Sarcoma?

The main differential diagnosis to consider is that of B or T lymphoblastic lymphomas. However, these diagnoses can be easily discerned using cytochemical and immunohistochemical stains as well as with flow cytometry. The main cytochemical stains to consider for MS are Chloroacetate esterase, MPO, and nonspecific esterase. Immunohistochemically, the paraffin embedded sections of MS can be stained with CD68, CD43, MPO, CD117, lysozyme, and CD34. To eliminate other differential diagnoses, B- and T-cell markers, especially CD20, Pax-5, and CD3, should be tested. ⁸ Using flow cytometry, CD13, CD33, CD117, and MPO can help to identify blasts with myeloid differentiation. Immunohistochemistry shows CD68 as the most commonly expressed marker, ⁹ followed by MPO, CD117, CD99, lysozyme, CD34, terminal deoxynucleotidyl transferase, CD56, CD61, CD30, glycophorin A, and CD4. ^10,11 This panel helps in the differentiation of MS from lymphoblastic lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma, blastic plasmacytoid dendritic neoplasm, neuroblastoma, rhabdomyosarcoma, primitive neuroectodermal tumor, and medulloblastoma. ⁹ The proliferation index (KI-67/MIB-I) is frequently high (50%-95%). ^3,8

What Are the Treatment Options and Prognosis of Myeloid Sarcoma?

Radiation, chemotherapy, targeted molecular therapy, and surgery with debulking with or without bone marrow transplantation have been considered as current modalities for MS treatment. ⁸ Tumor behavior and response to treatment does not depend on age, sex, anatomical site of involvement, or type of presentation. ⁷ Bone marrow transplantation may or may not be helpful in MS; however, people do consider it to be a therapy after induction chemotherapy in patients with remission. ⁸ Isolated MS patients have comparable disease-free survival rates with patients with AML without MS when managed with AML-based induction regimens. ^12,13

Studies show that overall survival of patients receiving systemic chemotherapy at diagnosis was significantly longer. ^14,15 Published reports also mention that systemic chemotherapy along with radiotherapy, although there is no improvement in overall survival in isolated MS, radiotherapy may prolong failure-free survival. ¹⁶ In the era of molecular medicine, targeted therapies with tyrosine kinase inhibitors have found a role in the treatment of AML cases with complex cytogenetic abnormalities. ¹⁷ The emerging data on the molecular profile of different AML and their targeted treatment options might shine light on different treatment options with prognostic implications in subgroups of MS patients.

What Are the Different Subtypes of AML as per WHO 2017?

WHO classifies AML into 6 main categories with multiple subcategories ¹⁸ :

Acute myeloid leukemia with recurrent genetic abnormalities: This classification of AML is based on the genetic findings noted with chromosome analysis or other molecular techniques. A few subtypes of this category include AML t(8;21), AML inv 16, or t(16;16) and APL t (15;17) which generally are considered to have a good prognosis.