Granulocytic sarcoma
Encyclopedia
A myeloid sarcoma is a solid tumor
composed of immature white blood cell
s called myeloblast
s. A chloroma is an extramedullary
manifestation of acute myeloid leukemia
; in other words, it is a solid collection of leukemic cells occurring outside of the bone marrow
.
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:
In recent years, the term "myeloid sarcoma" has been favored.
. Chloromas may be somewhat more common in patients with the following disease features:
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).
(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.
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 node
s, the small intestine
, the mediastinum
, the lung
, epidural
sites, the uterus
, the ovaries
, and the orbit of the eye
. 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.
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.
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.
). 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
may be considered, although neither has an effect on survival.
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 syndrome
s or myeloproliferative syndromes who develop a chloroma are often treated as if they have transformed to acute leukemia.
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
composed of immature white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s called myeloblast
Myeloblast
The myeloblast is a unipotent stem cell, which will differentiate into one of the actors of the Granulocyte series.- Origin :These cells descend from the primitive reticulum cells, which are found in the stroma of the marrow. There is also an intermediate phase between the myeloblast and these...
s. A chloroma is an extramedullary
Extramedullary
Extramedullary is something located within a living organism, but outside the spinal cord and bone marrow....
manifestation of acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
; in other words, it is a solid collection of leukemic cells occurring outside of the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
.
History
The condition now known as chloroma was first described by the BritishBritish people
The British are citizens of the United Kingdom, of the Isle of Man, any of the Channel Islands, or of any of the British overseas territories, and their descendants...
physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
A. Burns in 1811, although the term chloroma did not appear until 1853. This name is derived from the Greek
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...
word chloros (green), as these tumors often have a green tint due to the presence of myeloperoxidase
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...
. The link between chloroma and acute leukemia
Acute leukemia
Acute leukemia or acute leukaemia is a generic term used to describe a family of serious medical conditions relating to an original diagnosis of 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 dermisDermisThe dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...
(skin) by leukemic cells, which is also referred to as cutaneous granulocytic sarcoma. - Meningeal leukemia, or invasion of the subarachnoid spaceSubarachnoid spaceIn the central nervous system, the subarachnoid cavity is the interval between the arachnoid membrane and pia mater....
by leukemic cells, is usually considered distinct from chloroma, although very rarely occurring solid central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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 prevalence are lacking, but they are uncommonly seen even by physicians specializing in the treatment of leukemiaLeukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. Chloromas may be somewhat more common in patients with the following disease features:
- French-American-British (FAB) classificationFrench-American-British classificationThe French-American-British classification systems refers to a series of classifications of hematologic diseases.It was first produced in 1976.Types include:* FAB classification of acute lymphoblastic leukemias...
class M4 or M5 - those with specific cytogeneticCytogeneticsCytogenetics is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-Banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ...
abnormalities (e.g. t(8;21) or inv(16)) - those whose myeloblastMyeloblastThe myeloblast is a unipotent stem cell, which will differentiate into one of the actors of the Granulocyte series.- Origin :These cells descend from the primitive reticulum cells, which are found in the stroma of the marrow. There is also an intermediate phase between the myeloblast and these...
s express T-cell surface markers, CD13, or CD14CD14Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form... - those with high peripheral white blood cellWhite blood cellWhite blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
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 syndromeMyelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
(MDS) or myeloproliferative syndromes (MPS) (e.g. chronic myelogenous leukemia
Chronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML), polycythemia vera
Polycythemia vera
Polycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
, essential thrombocytosis
Essential thrombocytosis
Essential thrombocythemia is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis...
, or myelofibrosis
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
). 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, 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.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 biopsyBiopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
are found to be infiltrated with myeloblasts. Note that leukemia cutis differs from Sweet's syndrome
Sweet syndrome
Sweet's syndrome , or acute febrile neutrophilic dermatosis is a skin disease characterized by the sudden onset of fever, leukocytosis, and tender, erythematous, well-demarcated papules and plaques which show dense infiltrates by neutrophil granulocytes on histologic examination.The syndrome was...
, 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 node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s, the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
, the mediastinum
Mediastinum
The mediastinum is a non-delineated group of structures in the thorax, surrounded by loose connective tissue. It is the central compartment of the thoracic cavity...
, the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, epidural
Epidural
The term epidural is often short for epidural analgesia, a form of regional analgesia involving injection of drugs through a catheter placed into the epidural space...
sites, the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, the ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, and the orbit of the eye
Eye
Eyes are organs that detect light and convert it into electro-chemical impulses in neurons. The simplest photoreceptors in conscious vision connect light to movement...
. Symptoms of chloroma at these sites are related to their anatomic location; chloromas may also be asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
and be discovered incidentally in the course of evaluation of a person with acute myeloid leukemia.
Central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
involvement, as described above, most often takes the form of meningeal leukemia, or invasion of the subarachnoid space
Subarachnoid space
In the central nervous system, the subarachnoid cavity is the interval between the arachnoid membrane and pia mater....
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 biopsyBiopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
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
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
.
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
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...
, CD68
CD68
CD68 is a glycoprotein which binds to low density lipoprotein.It is expressed on monocytes/macrophages.The mouse equivalent is called "macrosialin".-Use in pathology:...
, CD43
CD43
Leukosialin also known as sialophorin or CD43 is a transmembrane cell surface protein that in humans is encoded by the SPN gene.- Function :...
, and CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
, to accurately diagnose chloroma via immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
and differentiate it from lymphoma. Nowadays, immunohistochemical staining using monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
against CD34
CD34
CD34 molecule is a cluster of differentiation molecule present on certain cells within the human body. It is a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells...
and CD117
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
would be the mainstay of diagnosis. The increasingly refined use of flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
has also facilitated more accurate diagnosis of these lesions.
Prognostic significance
There is conflicting evidence on the prognosticPrognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
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.
Treatment
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 cordSpinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
). Chloromas are typically quite sensitive to standard anti-leukemic chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
If the chloroma is persistent after completion of induction chemotherapy, local treatment such as surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
or radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
may be considered, although neither has an effect on survival.
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 syndrome
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
s or myeloproliferative syndromes who develop a chloroma are often treated as if they have transformed to acute leukemia.