Orbital myeloid sarcoma / chloroma
Introduction and epidemiology
Myeloid sarcoma is also known as chloroma, an extramedullary solid tumor that is caused by an abnormal proliferation of immature precursors of white blood cells (1). In 1811, a British physician Alan Burns observed the first case of chloroma .later in 1853 king coined the term chloroma due to its greenish hue secondary to the presence of intracellular myeloperoxidase enzyme(2). In 1966 chloroma was renamed as granulocytic sarcoma by Rappaport. Granulocytic sarcoma had many synonyms including myeloblastoma, myelocytoma, chloroleukaemia, and the World Health Organisation currently favors the name myeloid sarcoma(3).
Ocular structures can be involved in AML via two distinct mechanisms. Direct infiltration of leukemic cells may occur as anterior segment uveal infiltration, orbital infiltration, or central nervous system (CNS) involvement with neuro-ophthalmic signs which is known as primary involvement . Hematologic abnormalities seen in leukemia leads to secondary involvement. Anemia and thrombocytopenia can produce tissue ischemia and hemorrhage, while leukostasis and immunosuppression may predispose to occlusion injury and infection, respectively. Orbital involvement is uncommon and primary orbital presentation without any evidence of systemic involvement is rare. Chloroma may develop at any age even though nearly 60 % of cases are seen in children under 15 years of age with a median age of 7 years old (4) . Myeloid sarcoma-associated AML is more frequently seen in boys than girls(5).In the pediatric population, acute leukemias account for about 30 % of the malignancies in which acute leukemia accounts for about 15 % (6). Myeloid sarcoma is indeed a rare disease that is often related to other underlying myeloproliferative disorders. In patients with acute myeloid leukemia, myeloid sarcoma is a rare manifestation that may occur in around 2.5-9.1 % of patients (7). Less frequently it may be associated with chronic myeloid leukemia with impending blast crisis or other myelodysplastic disorders like myeloid metaplasia, polycythemia vera, hypereosinophilic syndrome, or essential thrombocytosis (8)(9). orbit is one of the most common sites of occurrences in the pediatric population. Rarely it may occur in lymphoid leukemia also. These are thought to originate in the bone marrow, the cells being spread through the haversian canals to penetrate the sub periosteum to form soft tissue masses which explains the typical location near bone structures(6).it occurs in orbit in 9.3% of cases due to active hematopoiesis which leads to proptosis in one or both eyes(10).
Audoin et al have described the following patterns (11):
a. Concurrent with AML: being the commonest manifestation that may be present at the time of initial presentation or any time during the active phase of AML. b. Relapse: which may present after AML remission, especially in bone marrow transplant recipients. This is considered a systemic disease despite normal blood counts and marrow findings. c. The precursor of blast phase transformation: In non-leukemic myeloproliferative conditions which heralds the blast crisis and subsequent AML transformation. d. Primary chloroma: which is a rare nonleukemic form, occurring in otherwise healthy individuals in the absence of any marrow abnormality. Primary chloroma may precede any hematological abnormality in nearly 35 % of cases.it may undergo a leukemic transformation in an average interval of 10 months.
Certain types of AML predispose the individual to develop chloroma which includes AML M4 /M5 (French American-British classification). other risk factors include high peripheral total leukocyte counts, chromosomal abnormalities t (8,21) or inv (16), myeloblasts expressing T cell markers like CD 13, CD 14.
Clinical features and differential diagnosis:
Correct diagnosis of orbital myeloid sarcoma is quite difficult sometimes owing to its uncommon presentation and mimickers during clinical and radiological examination perse.
When myeloid sarcoma presents as an isolated finding which is very rare, this may mimic inflammatory/infective or lymphoproliferative diseases(12,13) . Even though it can be asymptomatic, proptosis is the most common presenting feature (14–16). Zimmerman et all noted that 88% of their patients presented with proptosis (5). It commonly presents as unilateral exophthalmos (5). proptosis is usually due to leukemic infiltrates, retrobulbar hemorrhage, orbital muscle infiltration, or venous blockage. In such cases, acute leukemia may develop shortly afterward with a median time ranging from 1-25 months (17). therefore when they are presented alone it should be treated as the initial manifestation of acute leukemia as such rather than a localized lesion. Shields et al have reported that about 88 % of cases with proptosis that are seen by ophthalmologist does not have a history of leukemia at the time of presentation and an estimate of 60% of orbital sarcoma being bilateral(18). other clinical differential diagnosis includes vascular lesion, lymphoma, metastatic neuroblastoma, and rhabdomyosarcoma. a further radiological examination may pave the way for the right diagnosis. Most childhood tumors are unilateral. It may present as bilateral exophthalmos also may or may not be rarely accompanied by bitemporal swelling(19). the differential diagnosis of a bilateral orbital mass in children are idiopathic non granulomatous orbital inflammation which is initially unilateral, to begin with, metastatic neuroblastoma which accounts for 3-4% of patient and is bilateral in 50%, and myeloid sarcoma even though it's relatively uncommon. The diagnosis of orbital MS becomes easy when the patient is already a known case of hematological malignancy or when there are associated symptoms like epistaxis and other systemic features suggestive of malignancies. Other causes of acute bilateral proptosis in children include bilateral optic nerve glioma, an orbital extension of retinoblastoma, cavernous sinus thrombosis. They can also be presented as painful lacrimal swelling, conjunctival mass lesion, lacrimal gland swelling, retinal hemorrhages, ptosis, iris and uveal alterations, dystopia (20,21). Decreased visual acuity and ocular movement restriction have been reported in the majority.
1.Peripheral smear: it is an invaluable tool in diagnosing the systemic disease which may show immature blast cells with a high total leukocyte count and relative neutropenia.
2. Bone marrow biopsy: sometimes myeloid sarcoma may not be associated with peripheral smear abnormality; hence bone marrow aspirate and biopsy can be done to confirm AML based on finding greater than 30 % myeloid blast cells.
3.radiological imaging: Since myeloid sarcoma is a soft tissue tumor that may be circumscribed or diffusely infiltrating, CT findings may be variable. Lesions in orbit are frequently hypodense with mild enhancement. But sometimes it can present as heterogeneous enhancing with non-enhancing areas which represent necrosis and sign of rapid growth (22). on MRI, its isointense or hypointense on T1 W and mildly hyperintense on T2 weighted images.it can also be used in follow-up imaging because the radiation concerns are little. Nuclear imaging like FDG-PET/CT and gallium 67 shows avid uptake by chloroma, which can be used to decipher the multiplicity as well as a response after chemotherapy. FDG-PET is imperative in radiotherapy planning. But despite all these imaging, it can be confused with lymphoma, a much commoner malignancy.
Confirmation of myeloid sarcoma is established on immunohistochemistry after the demonstration of monoclonal antibodies against specific antigens. The most widely used are CD43, CD68, and lysozyme. Specific cytochemical stains for diagnostic purposes as per WHO classification (2008) are chloroacetate esterase, myeloperoxidase, and nonspecific esterase. Other markers are CD33, CD34, CD4, CD56, or CD 117 depending on maturation and lineage of myeloid cells. MPO, lysozyme, and CD68 are the most sensitive markers for myeloid differentiation(23,24).
No consensus on the best therapeutic options or a unified protocol has been identified owing to the rarity of the tumor. Orbital myeloid sarcoma has been generally thought to be an antecedent event to the evolution of AML, treatment options are tailormade to prevent the emergence of AML. There are surgery, radiotherapy, and chemotherapy available as the therapeutic options in which chemotherapy is the mainstay of management. Isolated orbital MS in AML remission and primary isolated myeloid sarcoma is considered as systemic disease and is treated on the lines of AML even when the peripheral blood smear is within normal limits. Chloroma associated with other myelodysplastic syndromes also warrants systemic chemotherapy because it suggests leukemic transformation Lee et al had studied patients with isolated MS who had undergone only local treatment and found out that 22.2% of them did not progress to AML and complete remission duration of 1.8 months who were treated with surgery alone and 83.9 months for those who received radiotherapy. In contrast, 44.4% who received systemic chemotherapy had evolved to AML within a median time of 13.4 months(7). A review of 20 cases of nonleukemic MS reported that combined treatment with chemotherapy and radiotherapy had better survival than chemotherapy alone(25).hence surgery or radiotherapy may play an important role in controlling the primary disease without much toxicity and evolution into the systemic disease. But combining the systemic and local treatment for isolated orbital myeloid sarcoma will be a more promising therapeutic strategy to achieve complete remission of the systemic disease as well than a treatment modality alone. If the chloroma persists after completion of induction therapy local treatment such as surgery and radiotherapy may be considered. Chemotherapy includes both intensive and consolidated phase. Doxorubicin and cytosine arabinoside is used for the intensive phase. bone marrow suppression is strictly monitored with allogenic hematopoietic cell transplantation is another therapeutic option for systemic disease.
The detection of a chloroma is considered as a piece of evidence that the premalignant conditions have transformed into an acute phase. As such presence of chloroma may be sufficient to indicate that chronic myelogenous leukemia has entered its blast crisis. When it occurs during relapse after successful treatment of disease, it can be regarded as the early sign of systemic relapse. A review in which 24 patients who developed isolated chloromas after treatment for AML has reported that the mean interval until bone marrow relapse to be 7 months (26).On average, the median survival after diagnosis is 7.5 months for myeloid sarcoma. age, gender, or underlying systemic disease does not affect the prognosis of the disease. Since the emergence of new treatment options for leukemia like allogenic bone marrow transplantation, repeated donor lymphocyte infusion the longevity of patients has increased thus increasing the incidence of chloroma. Even after aggressive involvement due to their high responsiveness to induction chemotherapy timely diagnosis is warranted.
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