(aka Myeloid Sarcoma, Granulocytic Sarcoma, Extramedullary Myeloid Tumor)
The condition now known as chloroma was first described by the British physician A. Burns in 1811, although the term chloroma did not appear until 1853. This name is derived from the Greek word chloros (green), as these tumors often have a green tint due to the presence of myeloperoxidase. The link between chloroma and acute leukemia was first recognized in 1902 by Dock and Warthin. However, because up to 30% of these tumors can be white, gray, or brown rather than green, the more correct term granulocytic sarcoma was proposed by Rappaport in 1967 and has since become virtually synonymous with the term chloroma.
Currently, any extramedullary manifestation of acute myeloid leukemia can be termed a granulocytic sarcoma or chloroma. Specific terms which overlap with granulocytic sarcoma include:
Leukemia cutis, describing infiltration of the dermis (skin) by leukemic cells, which is also referred to as cutaneous granulocytic sarcoma.
Meningeal leukemia, or invasion of the subarachnoid space by leukemic cells, is usually considered distinct from chloroma, although very rarely occurring solid central nervous system tumors composed of leukemic cells can be termed chloromas.
In recent years, the term “myeloid sarcoma” has been favored.
In acute leukemia
Chloromas are rare; exact estimates of their incidence are lacking, but they are uncommonly seen even by physicians specializing in the treatment of leukemia. Chloromas may be somewhat more common in patients with the following disease features:
French-American-British (FAB) classification class M4 or M5
those with specific cytogenetic abnormalities (e.g. t(8;21) or inv(16))
those whose myeloblasts express T-cell surface markers, CD13, or CD14
those with high peripheral white blood cell counts
However, even in patients with the above risk factors, chloroma remains an uncommon complication of acute myeloid leukemia.
Rarely, a chloroma can develop as the sole manifestation of relapse after apparently successful treatment of acute myeloid leukemia. In keeping with the general behavior of chloromas, such an event must be regarded as an early herald of a systemic relapse, rather than as a localized process. In one review of 24 patients who developed isolated chloromas after treatment for acute myeloid leukemia, the mean interval until bone marrow relapse was 7 months (range, 1 to 19 months).
In myeloproliferative or myelodysplastic syndromes
Chloromas may occur in patients with a diagnosis of myelodysplastic syndrome (MDS) or myeloproliferative syndromes (MPS) (e.g. chronic myelogenous leukemia (CML), polycythemia vera, essential thrombocytosis, or myelofibrosis). The detection of a chloroma is considered de facto evidence that these pre-malignant conditions have transformed into an acute leukemia requiring appropriate treatment. For example, presence of a chloroma is sufficient to indicate that chronic myelogenous leukemia has entered its blast crisis phase.
Very rarely, chloroma can occur without a known pre-existing or concomitant diagnosis of acute leukemia, acute promyleocytic leukemia or MDS/MPS; this is known as primary chloroma. Diagnosis is particularly challenging in this situation (see below). In almost all reported cases of primary chloroma, acute leukemia has developed shortly afterward (median time to development of acute leukemia 7 months, range 1-25 months). Therefore, primary chloroma could be considered an initial manifestation of acute leukemia, rather than a localized process, and could be treated as such. Where disease development or markers indicate progresses to acute promyleocytic leukemia (AML3) treatment should be tailored to this form of disease.
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
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.
-solid collection of leukemic cells occurring outside of the bone marrow.
Chloromas may occur in virtually any organ or tissue. The most common areas of involvement are the skin (also known as leukemia cutis) and the gums. Skin involvement typically appears as violaceous, raised, nontender plaques or nodules, which on biopsy are found to be infiltrated with myeloblasts. Note that leukemia cutis differs from Sweet’s syndrome, in which the skin is infiltrated by mature neutrophils in a paraneoplastic process. Gum involvement (gingival hypertrophy) leads to swollen, sometimes painful gums which bleed easily with tooth brushing and other minor trauma.
Other tissues which can be involved include lymph nodes, the small intestine, the mediastinum, epidural sites, the uterus, and the ovaries. Symptoms of chloroma at these sites are related to their anatomic location; chloromas may also be asymptomatic and be discovered incidentally in the course of evaluation of a person with acute myeloid leukemia.
Central nervous system involvement, as described above, most often takes the form of meningeal leukemia, or invasion of the subarachnoid space by leukemic cells. This condition is usually considered separately from chloroma, as it requires different treatment modalities. True chloromas (i.e. solid leukemic tumors) of the central nervous system are exceedingly rare, but has been described.
Definitive diagnosis of a chloroma usually requires a biopsy of the lesion in question. Historically, even with a tissue biopsy, pathologic misdiagnosis was an important problem, particularly in patients without a clear pre-existing diagnosis of acute myeloid leukemia to guide the pathologist. In one published series on chloroma, the authors stated that 47% of the patients were initially misdiagnosed, most often as having a malignant lymphoma.
However, with advances in diagnostic techniques, the diagnosis of chloromas can be made more reliable. Traweek et al. described the use of a commercially available panel of monoclonal antibodies, against myeloperoxidase, CD68, CD43, and CD20, to accurately diagnose chloroma via immunohistochemistry and differentiate it from lymphoma. Nowadays, immunohistochemical staining using monoclonal antibodies against CD34 and CD117 would be the mainstay of diagnosis. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions.
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:
1) In patients with known acute myeloid leukemia (AML) in the active phase of the disease.
2) In patients with a chronic myeloproliferative disorder (CMPD) or a myelodysplastic syndrome (MDS), in whom myeloid sarcoma may be the first manifestation of blastic transformation.
3) As the first manifestation of relapse in patients previously treated for primary or secondary acute leukemia
4) De novo in healthy subjects, in whom a typical form of AML may occur after an interval of weeks, months or even years.(1,3) Rarely no leukemia develops.
No age group is immune; however, some reports suggest that two thirds of the cases occur before the age of 15 (4) while some others shows a wider age range (5,6).
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:
1) A blastic variant with predominance of myeloblasts,
2) An immature variant with a mix of myeloblasts and promyelocytes,
3) A differentiated variant with promyelocytes and more mature granulocytes
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.
As described above, chloromas should always be considered manifestations of systemic disease, rather than isolated local phenomena, and treated as such. In the patient with newly diagnosed leukemia and an associated chloroma, systemic chemotherapy against the leukemia is typically utilized as the first-line treatment, unless there is an emergent indication for local treatment of the chloroma (e.g. compromise of the spinal cord). Chloromas are typically quite sensitive to standard anti-leukemic chemotherapy.
If the chloroma is persistent after completion of induction chemotherapy, local treatment such as surgery or radiation therapy is often considered.
Patients presenting with a primary chloroma typically receive systemic chemotherapy, as development of acute leukemia is nearly universal in the short term after detection of the chloroma.
Patients treated for acute leukemia who relapse with an isolated chloroma are typically treated with systemic therapy for relapsed leukemia. However, as with any relapsed leukemia, outcomes are unfortunately poor.
Patients with “pre-leukemic” conditions such as myelodysplastic syndromes or myeloproliferative syndromes who develop a chloroma are often treated as if they have transformed to acute leukemia.
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.
- There is conflicting evidence on the prognostic significance of chloromas in patients with acute myeloid leukemia. In general, they are felt to augur a poorer prognosis, with a poorer response to treatment and worse survival; however, others have reported that chloromas associate, as a biologic marker, with other poor prognostic factors, and therefore do not have independent prognostic significance.
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