Granulocytic sarcoma

A chloroma, or granulocytic sarcoma, or most appropriately, extramedullary myeloid tumor, is a solid tumor composed of immature malignant white blood cells called myeloblasts. A chloroma is an extramedullary manifestion of acute myeloid leukemia; in other words, it is a solid collection of leukemic cells occurring outside of the bone marrow.

History

 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 manifestion 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.

 Frequency and patterns of presentation

 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:

     * FAB 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.

 Primary chloroma

 Very rarely, chloroma can occur without a known pre-existing or concomitant diagnosis of acute 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 should probably be considered an initial manifestation of acute leukemia, rather than a localized process, and treated as such.

   Location and symptoms

 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.

  Diagnosis

 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. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions.

  Prognostic significance

 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