Granulocytic sarcoma

# Overview
Granulocytic sarcoma (GS, also known as chloroma) was first discovered by Allen Burns, a British physician, in 1811. The term chloroma was first used by King to address the greenish appearance of the tumor due to myeloperoxidase. The association of the GS with acute myeloid leukemia (AML) was first recognized by Dock in 1902. GS can be classified into two categories based on its co-occurence with other malignancies. Infiltration of the tumor with myeloblasts is the main characteristic of the tumor on H&E stain. GS rises from primitive precursors of granulocytes. The disease is an extramedullary manifestation of myeloid diseases, however, it can occur as a primary disease. Aggregation of myeloblasts, promyelocytes and myelocytes outside of the bone marrow presents itself as these solid tumors. Tumors can occur at any site and can appear as green, gray, white or brown masses.  GS must be differentiated from other diseases that can present as extramedullary solid tumors. All patients with GS must be evaluated for concurrent or future malignancies as GS can occur in the course of or prior to other malignancies. The prevalence of GS is approximately 2 per 1,000,000 individuals worldwide. The most important risk factor for development of GS is genetic mutations and susceptibility.  Symptoms of GS may include the following: Symptoms due to mass effect such as deafness, ptosis, altered vision, intestinal obstruction, headache, neck pain, abdominal pain, and constitutional symptoms. Chemotherapy is the main stain of treatment in patients with GS. Even patients with isolated GS must receive systemic treatment to better the prognosis.

# Historical Perspective
- Plain radiograph of femur in a patient with GS. Courtesy of image: pathology outlines ()Granulocytic sarcoma (GS, also known as chloroma) was first discovered by Allen Burns, a British physician, in 1811 .
- The term chloroma was first used by King to address the greenish appearance of the tumor due to myeloperoxidase.
- The association of the GS with acute myeloid leukemia (AML) was first recognized by Dock in 1902 .
- The term "granulocytic sarcoma" was suggested by Rappaport in 1967 to grant generalisability to it .

# Classification
- GS can be classified into two categories based on its co-occurence with other malignancies:
GS associated with other myeloid diseases:
Acute leukemias (especially AML)
Myelodysplastic syndromes
Other myeloproliferative diseases
Isolated GS
- GS associated with other myeloid diseases:
Acute leukemias (especially AML)
Myelodysplastic syndromes
Other myeloproliferative diseases
- Acute leukemias (especially AML)
- Myelodysplastic syndromes
- Other myeloproliferative diseases
- Isolated GS

# Pathophysiology
- Infiltration of the tumor with myeloblasts is the main characteristic of the tumor on H&E stain.
- GS rises from primitive precursors of granulocytes.
- The disease is an extramedullary manifestation of myeloid diseases, however, it can occur as a primary disease.
- Aggregation of myeloblasts, promyelocytes and myelocytes outside of the bone marrow presents itself as these solid tumors.
- Tumors can occur at any site and can appear as green, gray, white or brown masses.

# Differentiating GS from other Diseases
GS must be differentiated from other diseases that can present as extramedullary solid tumors, such as:
- Large cell lymphoma
- Non-Hodgkin lymphoma
- Thymoma
- Myeloma
- Esosinophilic sarcoma
- Ewing sarcoma
- Extramedullary sites of hematopoiesis
- Burkitt lymphoma
- Hypereosinophilic syndrome
- Polycythemia vera
All patients with GS must be evaluated for concurrent or future malignancies as GS can occur in the course of or prior to other malignancies.

# Epidemiology and Demographics
- The prevalence of GS is approximately 2 per 1,000,000 individuals worldwide.
- Most of the cases of GS are case reports and the disease is extremely rare.

## Age
- Patients of all age groups may develop GS.
- GS associated with AML occurs more commonly in children.

## Gender
- GS affects both men and women.
- Due to the rarity of the disease it is not clear whether there is a gender predilection for it.

## Race
- There is no racial predilection for GS.

# Risk Factors
- Risk factors for GS are usually chromosomal aberrations and include:
Trisomy 8
Monosomy 7
MLL gene rearrangement
NPM1 mutations
FLT3 mutations
- Trisomy 8
- Monosomy 7
- MLL gene rearrangement
- NPM1 mutations
- FLT3 mutations

# Natural History, Complications and Prognosis
- GS evolve over time, that depends on the co-occurence of the disease with other malignancies.
- GS may present before evidences of other malignancies manifest or after these malignancies are evident.
- Symptoms of the isolated GS depends on the location and the site of the tumor.
- Majority of cases are associated with AML or other myeloproliferative/myelodysplastic syndromes.
- Majority of GS tumors are found in the soft tissues such as the peritoneum, lymph nodes, CNS and skin. They are also found in bone and periosteum.
- Early clinical features include weight loss, fatigue. Other manifestations of the tumor depend on its size and location.
- Prognosis of GS depends on its association with other malignacies. In cases of isolated GS the prognosis is good. However, GS associated with myeloproliferative disorders has poor prognosis.
- Prognosis of isolated GS with chromosome 8 abnormalities is worse than other cases of isolated GS.

# Diagnosis

## Diagnostic Criteria
- There are no predefined criteria for diagnosis of granulocytic sarcoma.
- Granulocytic sarcoma must be suspected in patients with AML or myelodysplastic syndromes. Diagnosis must be confirmed with histopathologic study of the specimen.

## Symptoms
Symptoms of GS may include the following:
- Symptoms due to mass effect such as deafness, ptosis, altered vision, intestinal obstruction, etc.
- Headache, neck pain, abdominal pain,etc. based on the site of the tumor
- Constitutional symptoms such as fever, fatigue, etc.

## Physical Examination
Patients with GS can present with varying presentations.
Physical examination may be remarkable for:
- Lymphadenopathy (in cases associated with AML and other myeloproliferative syndromes)
- Skin lesions (of varying colors such as green, grey, brown, etc.)
- Organ enlargement such as hepatosplenomegaly
- Petechiae in patients with thrombocytopenia
- Hearing loss
- Heart murmurs in cases with heart chamber masses
- Crackles on lung auscultation
- Abdominal distention/tenderness in cases with intestinal obstruction
- Limb swelling due to different pathologies such as deep vein thrombosis (DVT)

## Laboratory Findings
- In cases associated with AML/CML, anemia, thrombocytopenia with normal, low or high white blood cells can be present.
- In cases associated with polycythemia vera, thrombocytosis and high levels of hemoglobin is present in complete blood count (CBC).
- High eosinophil levels can be present in CBC.

## Imaging Findings
- In cases of CNS involvement, magnetic resonance imaging (MRI) or CT scan of the CNS can reveal extra-axial masses.
- In cases with soft tissue involvement, sonogram of the tissue can reveal the mass.
GS appears as:
- Hyperdense/isodence to brain/muscle in CT scan without enhancement
- Isointense/hyperintense on T2-weighted MRI
- Isointemse/hypointense on T1-weighted MRI
Abdominal plain radiogram can reveal obstruction, intussusception, etc.
Echocardiogram may reveal mobile masses in any heart chamber in cases of heart involvement.
Chest radiographs can show lymph node enlargement and consolidation.

## Other Diagnostic Studies
- Peripheral blood smear can reveal circulating blasts.
- Flow cytometry can help differentiate AML from acute lymphoblastic leukemia (ALL).
- Histopathologic analysis of biopsy specimen retrieved by excision or fine needle aspiration shows abundant myeloblasts.
- Histopathologic analysis of GS lesions reveals high infiltration with myeloblasts.

# Treatment

## Medical Therapy
- Chemotherapy is the main stain of treatment in patients with GS. Even patients with isolated GS must receive systemic treatment to better the prognosis.
- Patients receiving cytarabine have better prognosis.
- Patients with chemotherpeutic regimens accepted for AML had longer period of progression to AML.
Treatment includes different regimens:
- Idarubicine and cytarabine
- Fludarabine and cytarabine
- Idarubicine and G-CSF
- Cyclophosphamide, cytarabine, topotecan and G-CSF
All of these therapeutic agents act through DNA damage and interferes with DNA synthesis.

## Bone marrow transplantation
- Hematopoietic stem cell transplantation can be considered as a treatment option following induction chemotherapy in patients with AML.

## Radiation
- Radiation can be considered as an adjunctive therapy.
- Combination of chemotherapy and radiotherapy can be considered in patients with CNS involvement or when rapid regression of symptoms is required.

## Surgery
- Surgery alone is not a good treatment strategy for GS.
- Surgery can be considered prior to chemotherapy in patients where debulking can better the prognosis and help with symptom relief.
- Surgery can also have a diagnostic role in cases where excision of the mass provides specimen for histopatjologic diagnosis.

## Prevention
- There are no primary preventive measures available for GS.