|Year : 2016 | Volume
| Issue : 2 | Page : 70-75
Aleukemic granulocytic sarcoma and leukemia cutis: A report of two rare cases and review of literature
Rahul S Kulkarni1, Asha S Anand1, Apurva A Patel1, Sandip A Shah1, Harsha P Panchal1, Sonia K Parikh1, Hemangini H Vora2, Biren P Parikh3, Avinash Talele1
1 Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
2 Department of Immunohistochemistry and Flow Cytometry, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
3 Department of Pathology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
|Date of Web Publication||14-Jul-2016|
Asha S Anand
Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
Granulocytic sarcoma (GS), also called myeloid sarcoma is an extramedullary tumor of the immature granulocytic cells. It is a rare entity and mostly accompanied by acute myeloid leukemia (AML). Very rarely, it is detected before clinical signs of leukemia or other diseases. When the bone marrow biopsy reveals no other hematologic malignancies, the GS is described as aleukemic, primary or isolated. Here, we report two rare cases, one of which presented as aleukemic GS of lymph nodes with aleukemic leukemia cutis, and the other with aleukemic GS of lung. Both cases posed diagnostic dilemma in view of their atypical presentations and site of involvement. Final diagnosis was made by immunohistochemistry (IHC). Both patients were treated with standard induction chemotherapy for AML. One patient had relapsed on treatment and was further treated with only 6-thioguanine leading to complete remission. Our cases emphasize the importance of early suspicion and use of IHC in diagnosis of aleukemic GS and also potential role of oral thioguanine alone in relapsed cases not eligible for hematopoietic stem cell transplant.
Keywords: 6-thioguanine, aleukemic granulocytic sarcoma, aleukemic leukemia cutis, chemotherapy, lung
|How to cite this article:|
Kulkarni RS, Anand AS, Patel AA, Shah SA, Panchal HP, Parikh SK, Vora HH, Parikh BP, Talele A. Aleukemic granulocytic sarcoma and leukemia cutis: A report of two rare cases and review of literature. J Appl Hematol 2016;7:70-5
|How to cite this URL:|
Kulkarni RS, Anand AS, Patel AA, Shah SA, Panchal HP, Parikh SK, Vora HH, Parikh BP, Talele A. Aleukemic granulocytic sarcoma and leukemia cutis: A report of two rare cases and review of literature. J Appl Hematol [serial online] 2016 [cited 2021 Jan 17];7:70-5. Available from: https://www.jahjournal.org/text.asp?2016/7/2/70/186327
| Introduction|| |
Extramedullary (EM) involvement by acute leukemia is a relatively rare but clinically significant phenomenon that often poses therapeutic and diagnostic dilemmas for both oncologists and pathologists.  Granulocytic sarcoma (GS) and leukemia cutis (LC) are two well-known EM manifestations of acute leukemia.  GS and LC occurring before bone marrow involvement of leukemia are very rare. We, hereby, present two cases of aleukemic GS involving the skin and lung. The purpose of this study is to highlight the uncommon presentations of this rare disease and review of literature and treatment options.
| Case reports|| |
A 45-year-old male farmer presented with erythematous lesions all over body and face, associated with itching for 2 months, followed by the development of swellings on both sides of neck and axilla for 15 days. There was no history of drug allergy, joint pains, chronic cough, fever, weight loss, hemoptysis, hematuria, photosensitivity, or any major medical or surgical illness in the past. Family and personal history were not significant.
General examination showed multiple scaly erythematous confluent papules and patches involving face, neck, trunk, and upper and lower limbs sparing the body folds (deck chair sign). Bilateral firm, fixed, nontender cervical, axillary and inguinal lymphadenopathy was present [Figure 1]a, c, e, and i. Rest general and systemic examination was within normal limits.
|Figure 1: (a, c, e, and i) Diffuse erythematous patches and plaques involving face, trunk and bilateral axillary, and cervical lymphadenopathy. (g) Relapse of cutaneous granulocytic sarcoma after first high-dose cytarabine. (h) Complete resolution of relapsed cutaneous lesions after starting of 6-thioguanine. (b, d, f, and j) Complete resolution of cutaneous lesions and lymphadenopathy after chemotherapy and while on 6-thioguanine (till 11 months follow-up)|
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Routine laboratory investigations showed hemoglobin - 13.4 g/dL, white blood cell - 11.6 × 10 9 /L, and platelet count - 380 × 10 9 /L. Differential count showed absolute eosinophil count - 4.6 × 10 9 /L (normal 0-0.54 × 10 9 /L). Serum IgE levels were more than 2000 IU/ml (normal level 1-87 IU/ml). Hence, he was being treated with steroids and antihistamines considering the differential diagnosis of papuloerythroderma of Ofuji or systemic mastocytosis but with no significant improvement. Computed tomography (CT) scan of neck showed multiple bilateral cervical lymphadenopathy [Figure 2]a. Cervical lymph node biopsy was suggestive of infiltration with atypical large cells possibly large cell lymphoma [Figure 2]b. Hence, he was referred to our institute for further management. Liver and renal function tests and chest radiograph were within normal limits [Table 1]. The possibility of cutaneous T-cell lymphoma was considered at this stage. However, immunohistochemistry (IHC) revealed atypical cells, positive for myeloperoxidase (MPO), CD43, and CD68KP1 and negative for CD20, CD2, and CD5, which was suggestive of GS [Figure 2]e-h. Skin biopsy showed eosinophils and occasional premature granulocytic infiltration around the vessels suggestive of leukemic infiltration [Figure 2]d. Bone marrow biopsy revealed normocellular marrow with increased eosinophils [Figure 2]c. Cytogenetic testing was within normal limits. Thus, the final diagnosis was aleukemic GS with LC. He was started on induction chemotherapy with daunorubicin and cytarabine (7 + 3 induction regimen). On postinduction chemotherapy, he had complete resolution of lymphadenopathy and skin lesions and peripheral eosinophilia. Hence, consolidation with three cycles of high-dose cytarabine (HiDAC) was planned. After the first cycle of HiDAC, the patient again developed erythematous nodular skin lesions over the trunk and extremities [Figure 1]g. Fine-needle aspiration cytology from the skin lesions was consistent with leukemic infiltration. Bone marrow was still uninvolved by leukemia. The patient was not willing for reinduction and hematopoietic stem cell transplant (HSCT). The patient was started on oral 6-thioguanine (6TG) as the best supportive care. Surprisingly, 1 month after starting of 6TG, the patient had complete resolution of recurrent skin lesions. In view of good response, 6TG was continued. The patient is currently completely asymptomatic, with no skin lesions and lymphadenopathy, and is only on 6TG for the last 11 months and close follow-up [Figure 1]b, d, f, h, and j.
|Figure 2: (a) Computed tomography neck showing bilateral lymphadenopathy. (b) Cervical lymph node biopsy suggestive of infiltration with atypical large cells. (c) Normal bone marrow (×40). (d) Skin biopsy showing granulocytic infiltration. (e) Immunohistochemistry showing cells positive for myeloperoxidase. (f) CD43 positive. (g) CD20 negative. (h) CD2 negative|
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An 18-year-old male presented with gradually progressive cough and breathlessness for 1 month, associated with occasional hemoptysis. There was no history of fever with chills, weight loss, joint pains, hematuria, abdominal pain, or any other major medical or surgical illness in the past. Family history and personal history were not significant. He was treated outside with antibiotics but with no relief. Chest radiograph was suggestive of soft-tissue opacity in right paracardiac and lower lobe [Figure 3]a. CT scan of thorax was carried out, which showed soft-tissue opacity in right hilar region and right lower lobe of lung [Figure 3]d suggestive of malignancy and was referred to our institute for further management.
|Figure 3: (a) Chest X-ray showing soft tissue opacity involving right paracardiac and lower lobe. (b) Chest X-ray showing partial resolution of lung mass after induction chemotherapy. (c) Lung biopsy showing infiltration by atypical large cells. (d) Computed tomography scan thorax showing soft tissue opacity involving right lower lobe. (e) Immunohistochemistry showing myeloperoxidase positive cells. (f) Placental alkaline phosphatase negative. (g) CD20 negative. (h) CD2 negative|
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General examination was within normal limits. Cardiovascular, abdominal, and central nervous system examinations were within normal limits. Respiratory system examination showed decreased air entry in right lower and middle zone. In view of young age, the differential diagnoses of lymphoma, germ cell tumor, and small cell carcinoma of lung were considered. Routine blood investigations, tumor markers, along with ultrasonography of abdomen and scrotum, were within normal limits [Table 1]. Bronchoscopy-guided biopsy was performed, and histopathological examination showed atypical lymphoid cell infiltration suggestive of large cell lymphoma [Figure 3]c. IHC showed atypical cells positive for MPO, CD117 and negative for CD20, CD2, CD3, and placental alkaline phosphatase suggestive of GS [Figure 3]e-h. Bone marrow examination showed normocellular marrow. Conventional cytogenetics was within normal limits. Thus, the final diagnosis was aleukemic GS of lung. The patient received standard induction chemotherapy with daunorubicin and cytarabine (7 + 3 regimen). Postinduction chest radiography showed partial resolution of lung mass [Figure 3]b. Hence, three cycles of HiDAC followed by local radiotherapy as consolidation was planned. However, after first HiDAC, the patient developed febrile neutropenia and fungal pneumonitis and succumbed to death.
|Table 1: Routine laboratory investigations and cytogenetics in Case 1 and Case 2|
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| Discussion|| |
GS (also known as myeloid sarcoma, chloroma, or myeloblastoma) is a rare EM tumor of immature myeloid cells.  It was first described in 1811  and later named "chloroma" by King  in 1853 because of its green color caused by the presence of MPO.  LC is the infiltration of the epidermis, dermis, or subcutis by leukemia cells and commonly presents as subcutaneous nodules and is sometimes referred as cutaneous GS.  LC occurs in 3% of patients with acute myeloid leukemia (AML)  and less frequently in the accelerated phase of chronic myeloid leukemia, myelodysplastic syndrome and rarely in acute lymphocytic leukemias. 
GS is reported in 2.5-9.1% of patients with AML and occurs concomitantly, following or rarely before the onset of systemic bone marrow leukemia.  When GS occurs in the absence of leukemia, it is termed as isolated or aleukemic GS and has been described in only limited case reports.  In most of the cases, it is often misdiagnosed as lymphoma.  Certain cytogenetic abnormalities such as t (8;21) have been associated with a higher incidence of GS.  Patients with GS have a poor prognosis and the majority of the patients without bone marrow infiltration at presentation die of leukemia within an average of 16.5 months after diagnosis.  GS can also develop at relapse, with or without marrow involvement. The incidence of GS after allogeneic HSCT has been reported to be 0.2-1.3% with poor overall survival. 
The mechanisms for GS and LC are not fully understood. Blast cell CD56 (neural cell adhesion molecule) expression has been associated with both GS and LC. Homing of blast cells into the skin may be mediated through interactions between lymphocyte function associated with antigen-1 and intercellular adhesion molecule-1 and/or cutaneous leukocyte antigen and E-selectin. 
GS commonly involves the bone, periosteum, soft tissue, lymph nodes, and skin.  The involvement of other organs is rare and is reported in anecdotal case reports only. Involvement of the gastrointestinal tract, head and neck region, central nervous system, pericardium, kidney, bladder, testicles, ovaries, uterus, and mediastinum has been reported.  Very rarely, it can involve the lung or pleura with only a few cases reported in the literature so far. Guimarγes et al.  and Sathyanarayanan et al.  have reported intrathoracic GS in patients with AML. Kim et al.  have reported isolated pulmonary GS 4 years after treatment of AML whereas aleukemic GS with mediastinal and cardiac infiltration has been reported by Lima et al.  However, as per our extensive literature search, pulmonary involvement with mediastinal extension without bone marrow involvement as initial presentation has not been reported so far.
Skin involvement in AML may present as nonspecific lesions such as macules, papules, vesicles, pyoderma gangrenosum, vasculitis, neutrophilic dermatitis (Sweet syndrome), and erythema multiforme. LC is mostly associated with monocytic or myelomonocytic subtypes and usually presents either concomitantly or after the diagnosis of systemic leukemia.  Skin involvement preceding marrow involvement as in our case (Case 1) is very rare.  Aleukemic LC (ALC) defines a rare form of leukemia in which the invasion of leukemic blasts into the skin occurs at least 1 month before the appearance of disease in peripheral blood or bone marrow.  ALC clinically presents with multiple papules, nodules, and plaques with a red-brown or plum-colored surface. The most common sites of EM involvement other than the skin have been found to be lymph nodes, followed by the spleen. 
Diagnosis of GS with known AML is relatively easy, but the differential diagnosis of primary GS is relatively difficult. The rate of misdiagnosis is approximately 75%, and the most frequent misdiagnosis is large cell lymphoma.  Other differential diagnoses include histiocytic lymphoma, thymoma, myeloma, eosinophilic sarcoma, Ewing sarcoma, and carcinoma.  Tissue biopsy is the preferred method of diagnosis which shows tissue infiltration by myeloblasts on hematoxylin and eosin staining. However, confirmation by IHC is required in cases with no evidence of leukemia.  CD68-KP1 is the most commonly expressed marker followed by MPO. 
In view of rarity, data about the treatment options of aleukemic GS come from case reports and small case series. The treatment depends on the localization of the disease, whether it is an initial diagnosis or at relapse, the performance status, and the age of the patient. One study showed that 25% patients with aleukemic GS did not develop acute leukemia during the follow-up period of 3.5-16 years, but no prognostic factors about progressing to acute leukemia have been identified.  Chemotherapy regimens similar to that used in AML induction treatment are recommended. Retrospective studies have shown that patients treated with cytarabine and anthracycline, which is the standard treatment of AML, have significantly longer period of progression to acute leukemia than with other chemotherapies.  Since there is a high propensity for progression to acute leukemia, especially in patients who are treated with localized methods, systemic treatment is recommended to all patients with isolated GS. 
Combination chemoradiotherapy has revealed superior failure-free interval in some studies.  Local radiotherapy could be used as a consolidation therapy after systemic chemotherapy or primarily in patients who need a rapid relief of symptoms or in patients with central nervous system involvement. Similarly, the incidence of AML or EM relapse is significantly higher in patients treated with surgery alone. Thus, surgery or radiotherapy should be considered before the systemic treatment only in acute situations where rapid debulking and symptomatic relief are needed. 
Other modalities such as the use of high-dose methylprednisolone, alpha-interferon, methotrexate, allogeneic bone marrow transplant, and autologous stem cell transplantation have been used with variable success.  There is no targeted therapy for patients with GS but new agents such as FLT3 inhibitors, farnesyltransferase inhibitors and, histone deacetylase inhibitors studied in patients with AML could be considered as an option for GS patients. 
At present, there are very limited data about relapsed GS. In these patients, reinduction chemotherapies such as Fludarabine, high dose cytarabine and granulocyte colony stimulating factor (FLAG) regimen have been used concomitantly with HSCT. Narvαez-Moreno et al.  have reported treating cutaneous relapses with oral idarubicin, etoposide, and thioguanine. However, to the best of our knowledge, complete resolution of relapsed ALC with thioguanine alone as in our case (Case 1) has not been reported previously.
| Conclusion|| |
Aleukemic GS and LC are very rare and can have varied presentation. Early suspicion and advanced IHC can help in accurate diagnosis and early institution of chemotherapy, which can improve treatment outcomes. Although reinduction and HSCT are currently advocated in the treatment of relapsed GS and LC, oral 6TG alone can serve as an effective option in patients not eligible for such intensive treatment modalities.
Declaration of Patient Consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of Interest
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[Figure 1], [Figure 2], [Figure 3]