FINAL DIAGNOSIS: MYELOID SARCOMA
Myeloid sarcoma, also known as extramedullary myeloid tumour, is a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site or in bone (1).
Myeloid sarcomas were first described in the early 19th century. They were initially termed "chloroma"(green tumor) owing to their green gross appearance. This appearance is a result of the presence of myeloperoxidase enzymes in the immature myeloid cells. The favored name later changed to granulocytic sarcoma, following descriptions of cases that were not green and had the gross features of a sarcoma. Because we now know that not all myeloid leukemias are derived from granulocytes the preferred term is myeloid sarcoma.
The clinical presentation of myeloid sarcomas varies and is dependent on the site of involvement. Commonly involved sites of occurrence include subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae and pelvis; lymph nodes and skin are also common sites (1). Rare sites reported in the literature include the pancreas, heart, brain, mouth, breast, gastrointestinal and biliary tract, prostate, urinary bladder and gynecologic tract and more (2). A single tumor or sometimes multiple nodular masses of various sizes may occur. Myeloid sarcomas may be found in one of four settings:
Grossly the neoplastic tissue usually appears firm with a fish-flesh appearance. Not all lesions will have the peculiar green color and if present it commonly disappears with exposure to air or with fixation in formalin. Larger tumors may contain necrotic and hemorrhagic areas (3). Microscopically there is a diffuse monotonous infiltrate that may or may not destroy underlying normal structures. Although myeloid sarcomas are cytologically variable, most often they are composed of medium-sized to large blastic cells with ovoid vesicular nuclei with medium-sized or large centrally located nucleoli and dispersed chromatin. Their cytoplasm is scant to moderate. The mitotic count can be high. There may be apoptotic bodies phagocytosed by histiocytes (tingible body macrophages) that impart a starry sky appearance. The WHO Classification of Tumours; Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues (1) recognizes three major variants defined according to the predominant cell type and their degree of maturation. These variants are:
Less common variants recognized by the WHO include monoblastic sarcoma that is composed of monoblasts and associated with acute monoblastic leukemia and also tumors with bilineage or trilineage hematopoiesis, predominant erythroid precursors or predominant megakaryocytes that may occur in conjunction with transformation of a CMPD (1). Other variants reported in the literature include a monocytic variant, a myelomonocytic variant and a variant with intracytoplasmic Auer bodies, most often associated with acute transformation of MDS (3)
Giemsa or Wright/Giemsa stains on imprints are the best way to see the morphology of the blasts. Cytochemical stains such as a positive sudan black or myeloperoxidase stain are helpful if touch imprints are available to identify the myeloid lineage. Nonspecific esterase stains can be performed to assess monocytic differentiation if imprints are available and CAE to identify granulocytic differentiation. If only paraffin embedded tissue sections are available, a Naphthol-ASD-chloracetate-esterase (Leder) stain can be performed. Myeloid sarcomas with granulocytic differentiation will often be positive.
The definitive diagnosis today is usually based on immunohistochemistry (1, 7). The best immunohistochemical stains used for this include MPO and lysozyme. MPO immunostain is positive in most myeloblastic variants (as well as in some cells myelomonocytic variants) while lysozyme is frequently expressed in monoblastic variants. CD 15 is seen in tumors with mainly mature granulocytic cells, while CD68/PGM1 is more specific for the monocytic series. Megakaryoblastic cells are characterized by the expression of factor VIII, CD 61, and CD 31(8) while Glycophorin C and/or blood group proteins occur in the rare erythroblastic variant. A variable percentage of non-differentiated blasts may be positive for CD13, CD33, CD 34, CD117 (c-Kit), or CD99 (8). TdT is rarely positive and only in the most blastic variants. CD 45 expression demonstrates the leukocytic origin of the neoplastic cells; however this stain is often also not expressed. Sometimes expression of aberrant markers such as B-cell-, T-cell-, or NK-associated antigens including CD30 may be seen (10). Reactivity of tumor cells with CD43, a T-cell marker, without coexpression of CD3 should always prompt consideration of a myeloid tumor and not be misinterpreted as a neoplasm of T-cell origin. The use of only four antibodies (MPO, CD68, Lysozyme and CD34) has been proposed to distinguish the more common variants of myeloid sarcomas (7) A study of 30 cases showed CD117 reactivity in 87%, MPO, 97%; lysozyme, 93%; CD34, 47%; CD45, 84%; CD43, 97%; TdT, 37%; CD79a, 20%; CD20, 10%; CD3, 10%; and CD10, 1% (11).
The most frequent chromosomal abnormality associated with certain myeloid sarcomas has been observed to be t(8;21)(q22;q22), an abnormality that it shares with some AMLs (12).
The correct diagnosis of myeloid sarcoma is important so appropriate therapy can be instituted. While the diagnosis is often thought of in patients with an established history of AML, MDS or a CMPD, in other patients the diagnosis is often missed. The differential diagnosis is lengthy and includes non-Hodgkin lymphoma (including precursor B- or T-cell, Burkitt, some peripheral NK/T-cell and diffuse large B-cell lymphomas), small round cell tumors (including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, peripheral neuroectodermal tumor and medulloblastoma), undifferentiated carcinoma or melanoma, malignant histiocytosis and malignant mastocytosis with atypical mast cells. Extramedullary localizations of chronic myeloproliferative diseases without blast crisis should also be differentiated from myeloid sarcoma. Immunohistochemistry may aid distinguish myeloid sarcoma from malignant lymphoma, however the coexpression of some T-cell markers and staining with TdT and CD 34 can cause difficulties in interpretation.
Treatment is similar to that for AML, even in cases of isolated tumors with no blood or bone marrow involvement (13). Radiotherapy has been proposed in association with chemotherapy for patients with massive tumors or for patients with spinal cord compression.
In patients with AML the progression of myeloid sarcoma has the same prognosis as the underlying leukemia. Patients with an AML associated with a t(8;21) and presenting myeloid sarcoma have a low rate of complete remission, and overall survival is poor(14). This appears to be in contrast to the better prognosis generally senn in AML with t(8; 21). In patients with CMPD and MDS myeloid sarcoma defines a blastic transformation often associated with a short survival.
Contributed by Kudakwashe Chikwava, MB, ChB. and Steven Swerdlow, MD.