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Acute promyelocytic leukemia

Acute promyelocytic leukemia (APL; AML with t(15;17)(q22;q12) PML/RARα and variants; FAB subtype M3) is a subtype of acute myelogenous leukemia (AML), a cancer of the blood and bone marrow. more...

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In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARα) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid (ATRA) therapy.

Signs and symptoms

Signs and symptoms of acute promyelocytic leukemia are similar to other forms of AML. The accumultation of promyelocytes in the bone marrow results in a reduction in the production of normal red blood cells and platelets resulting in anemia and thrombocytopenia. Either leukopenia or leukocytosis may be observed in the peripheral blood.

Symptoms include:

  • Fatigue, weakness, shortness of breath (from anemia)
  • Easy bruising and bleeding (from thrombocytopenia and coagulopathy)
  • Fever and infection (from lack of normal white blood cells)

In addition, acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulopathy.


Acute promyelocytic leukemia represents 5-8% of AML in adults. The median age is approximately 40 years, which is considerably younger than the other subtypes of AML (70 years). The incidence is increased in Latin American countries.


Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17. In 95% of cases of APL, retinoic acid receptor-alpha (RARα) gene on chromosome 17 to the promyelocytic leukemia gene (PML) on chromosome 15.

Four other gene rearrangements have been described in APL fusing RAR to promyelocytic leukemia zinc finger (PLZF), nucleophosmin (NPM), nuclear matrix associated (NuMA), or signal transducer and activator of transcription (STAT) 5b genes.

These fusion proteins disrupt the function of RARα which blocks the normal maturation of granulocytes. Although the chromosomal translocation involving RARa is believed to be the initiating event, additional mutations are required for the development of leukemia.


Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow biopsy or aspirate. Definitive diagnosis requires testing for the RARα fusion protein and may be obtained by polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or conventional cytogenetics of peripheral blood or bone marrow.


APL is unique among the leukemias distinguished by its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA causes differentiation of the immature leukemic promyelocytes into mature granulocytes. ATRA is typically combined with anthracycline based chemotherapy resulting in a clinical remission in approximately 90% of patients.


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Head and neck granulocytic sarcoma with acute myeloid leukemia: Three rare cases
From Ear, Nose & Throat Journal, 4/1/01 by Hakan Cankaya


We conducted a retrospective review of pathology files and hospital records and identified three unusual presentations of granulocytic sarcoma associated with acute myeloid leukemia (AML) of the head and neck. At least one mass was observed on the skin of all three patients. A 17-year-old boy had masses in each temporal region that were accompanied by bilateral facial paralysis. He was administered chemotherapy and radiotherapy, but he died of infection secondary to a second relapse 29 months after the initial diagnosis. A 17-year-old girl had a tumor in the right parotid area. She received chemotherapy, but she died of infection and bleeding 2 months after the initial diagnosis. A 33-year-old man had numerous tumors widely disseminated over his skin. He received chemotherapy and was in remission 12 months after the initial diagnosis, but he eventually relapsed and died. Granulocytic sarcoma can be localized in unexpected regions, including the head and neck. This tumor is very often misdiagnosed as a maligna nt lymphoma, which leads to delayed treatment and a poor outcome. Therefore, clinical and histopathologic findings should be evaluated before any diagnosis of malignant lymphoma is pronounced. Immunohistochemical stains should also be performed on patients with suspected granulocytic sarcoma, and aggressive chemotherapy or immunotherapy should be administered. We believe that high-dose chemotherapy can improve survival rates in granulocytic sarcoma associated with AML.


A granulocytic sarcoma is a rare, extramedullary, solid aggregate of malignant myeloid precursor cells. The term granulocytic sarcoma was first used by Rappaport in 1966. [1] This malignancy is also known as a chloroma.

In this article, we describe three unusual presentations of granulocytic sarcoma that were associated with acute myeloid leukemia (AML). One patient had bilateral facial paralysis caused by temporal bone involvement of bilateral granulocytic sarcoma; we believe that this is the first such reported case in the literature. Another patient exhibited parotid gland involvement; we determined that this is only the second such reported case. The third patient had 12 tumors widely disseminated over his skin; to our knowledge this is the first reported case in the literature. In addition to these case reports, we also discuss the clinical behavior, histopathology, treatment, and prognosis of granulocytic sarcoma associated with AML of the head and neck region.

Case reports

Patient 1. In January 1996, a white 17-year-old boy was admitted to our hospital with a 2-week history of weakness and fever. On admission, the patient's general condition was poor. Physical examination revealed pallor, diffuse petechia and purpura, and hepatosplenomegaly. Morphologic, cytochemical, and immunocytochemical studies confirmed the diagnosis of AML (M4-FAB). He was administered the standard chemotherapeutic regimen for remission induction of AML.

After 21 months of therapy, the patient was readmitted because of a sudden onset of bilateral facial paralysis, a sudden hearing loss, vision disturbance, and the appearance of a firm, painful, rapidly growing mass in each of his postauricular areas. The masses were 7 and 5 cm in diameter on the right and left, respectively; the skin covering the two masses was normal. On computed tomography (CT), the masses could be seen in both temporal regions (figure 1).

The patient's white blood cell count (WBC) was 150 x [10.sup.9]/L. An incisional biopsy of the mass in the right postauricular area was obtained, and the histopathologic examination revealed a highly cellular tumor. The patient was given a histopathologic diagnosis of granulocytic sarcoma (his first relapse). At this time, leukemic cells were observed in bone marrow. He was placed on a chemotherapeutic regimen of daunorubicin and cytosine arabinoside (ARA-C) for remission induction of AML.

Following chemotherapy, a CT examination found no evidence of tumor in either postauricular area, and the patient's facial paralysis had subsided. The patient was then administered a 10-day regimen of radiotherapy (240 cGy/day) delivered to both temporal regions.

Two months later, the patient experienced a second relapse and his condition deteriorated. Leukemic cells were observed in the peripheral smear and in bone marrow. Further induction chemotherapy was planned, but the patient died of infection before it could be initiated. His death came 2 years and 5 months after the initial diagnosis. An autopsy was not performed.

Patient 2. In June 1998, a white 17-year-old girl was admitted to our hospital with a 3-month history of abdominal pain, right preauricular swelling, weight loss, and weakness. On admission, her general condition was poor, and her physical examination showed pallor and an ill-defined soft mass measuring 5 cm in diameter in the right preauricular area; the skin covering the mass was erythematous. In addition, bilateral cervical and submandibular lymphadenopathy and hepatosplenomegaly were observed.

The patient's WBC, platelet, and hemoglobin levels were 3.5 x [10.sup.9]/L, 17 x [10.sup.9]/L, and 8 g/dl, respectively. Morphologic, cytochemical, and immunocytochemical studies, including peripheral smear and bone marrow aspiration analyses, confirmed the diagnosis of AML (M4-FAB). Ultrasonographic examination showed that the right parotid gland and its covering skin had been infiltrated by tumor (figure 2). Fine-needle aspiration biopsy of the mass revealed that the tumor cells were immature blast forms. The cytopathologic diagnosis was granulocytic sarcoma. The patient was administered the standard chemotherapeutic regimen for remission induction of AML.

Evaluation on day 28 following the cessation of chemotherapy showed no remission, and the marrow aspiration and biopsy showed more than 5% blasts. However, no evidence of tumor was noted in the right preauricular area on ultrasonographic examination, and no blast was detected in the peripheral smear. Taken together these findings were considered to represent a partial remission. and a course of reinduction chemotherapy was planned. However, the patient refused a second round of therapy.

One month later, she was readmitted to the hospital in poor condition. Her peripheral smear showed 80% blasts. Ten days later, she died of infection and bleeding. An autopsy was not performed.

Patient 3. In December 1997, a white 33-year-old man was admitted to the hospital with a 4-month history of multiple masses on his skin. A previous skin biopsy had been misdiagnosed by the pathologist as a malignant lymphoma, and the patient had undergone three courses of chemotherapy. When his general condition had not improved and his masses had not disappeared, he returned to seek further treatment. On admission, the patient's general condition was poor. Physical examination showed fever, bilateral cervical and axillary lymphadenopathy, and splenomegaly. The skin was marked by 12 soft, tender, nonulcerated, and violaceous nodules, which varied in diameter from 4 to 12 cm (figure 3).

The patient's WBC, platelet, and hemoglobin levels were 150 x [10.sup.9]/L, 60 x [10.sup.9]/L, and 6 g/dl, respectively. Bone marrow aspiration detected 85% monoblasts. Morphologic, cytochemical, and immunocytochemical studies confirmed the diagnosis of AML (M5A-FAB). An incisional biopsy of the tumor showed that the tissue was made up of large immature mononuclear cells, which featured high nuclear-cytoplasmic ratios and immature nuclear chromatine patterns (figure 3). The nuclei were round to oval and had one or two prominent nucleoli. The histopathologic diagnosis was granulocytic sarcoma. The patient was placed on the standard chemotherapeutic regimen for remission induction of AML.

Evaluation on day 26 following the cessation of remission-induction therapy showed no remission. The patient's lesions were smaller, but they had not disappeared. He was therefore administered reinduction chemotherapy, which consisted of daunorubicin, etoposide, and ARA-C.

Evaluation on day 28 following reinduction therapy showed that the patient's masses had disappeared and that he was in remission. Two identical courses of reinduction chemotherapy were then given for consolidation.

By August 1998, the patient was still in remission and an allogenic peripheral stem cell transplant was suggested. However, the patient could not afford this treatment, so postconsolidation immunotherapy with interleukin-2 was initiated instead. However, 3 months later he relapsed and died.


Granulocytic sarcoma usually involves the bone, soft tissue, lymph nodes, and skin. [2] It rarely involves the parotid area. [3] Although leukemic infiltration of the temporal bone is seen occasionally, symptomatic facial nerve involvement is extremely rare, even in patients with granulocytic sarcoma. [4] Through January 2001, only three cases of unilateral facial paralysis secondary to temporal bone involvement of unilateral granulocytic sarcoma associated with AML have been reported in the English-language literature. [5-7] To our knowledge, our case represents the first report of bilateral paralysis. Involvement of the parotid gland is extremely rare in granulocytic sarcoma associated with AML; as far as we know, only one other case has been reported in the English-language literature. [3]

Granulocytic sarcoma usually develops before or during the course of myeloid leukemia. [2] One of our cases (patient 1) was diagnosed as granulocytic sarcoma 2 years after the AML diagnosis. The other two patients were diagnosed with granulocytic sarcoma after they had been admitted to the hospital.

There are three types of skin involvement in AML: nonspecific lesions, [8] leukemia cutis, [9] and granulocytic sarcoma. [10] The most common initial symptoms in patients with temporal bone involvement are postauricular aching and swelling, hearing loss, otalgia, and tinnitus. [6,11] Facial and acoustic nerve paralysis can subsequently develop as a result of a perineural and/or meningeal leukemic infiltration associated with hemorrhage, edema, or an adverse reaction to drug therapy. [12] One of our patients (patient 1) had bilateral temporal bone involvement, bilateral facial paralysis, hearing loss, and vision disturbance.

Histochemical and immunohistochemical techniques allow for a conclusive diagnosis of granulocytic sarcoma, even with routinely processed paraffin-embedded material. [13] Histopathologically, this diagnosis is often difficult to make in patients who do not have acute leukemia. As many as 75% of these tumors are initially misdiagnosed, most as malignant lymphoma. [14,15] This is precisely what had happened in one of our three cases (patient 3).

Patients with granulocytic sarcoma associated with AML have a poor prognosis. [16] Patients are routinely treated with chemotherapy, with or without radiotherapy, but as many as 85% relapse within 1 year. 17] Therefore, the definitive treatment should be chemotherapy followed by hematopoietic stem cell transplantation. When transplantation is not possible, we believe that chemotherapy might still improve survival rates if it is administered in higher doses than usual.


(1.) Rappaport H. Tumors of the Hematopoictic System. Washington. D.C.: Armed Forces Institute of Pathology, 1966:241-3.

(2.) Saleh HA, Khatib G. Fatal gastrointestinal bleeding as the primary manifestation of granulocytic sarcoma in a patient with myclodysblastic syndrome. J Fla Mcd Assoc 1997;84: 11-4.

(3.) Dufour C, Garaventa A, Brisigotti M, et al. Massively diffuse multifocal granulocytic sarcoma in a child with acute myeloid leukemia. Tumori 1995;81:222-4.

(4.) Zappia JJ, Bunge FA, Koopmnann CF, McClatchcy KD. Facial nerve paresis as the presenting symptom of leukemia. Int J Pediatr Otorhinolaryngol 1990; 19:259-64.

(5.) Almadori G, Del Ninno M, Cadoni G, et al. Facial nerve paralysis in acute otomastoiditis as presenting symptom of FAB M2, T8;2 I leukemnic relapse. Case report and review of the literature. Int J Pediatr Otorhinolaryngol 1996:36:45-2.

(6.) Todd NW, Bowman CA. Acute myclogenous leukemia presenting as atypical mastoiditis with facial paralysis. Int J Pediatr Otorhinolaryngol l984;7: 173-7.

(7.) Wuillemin WA, Vischer MW, Tobler A, Fey MF. Relapse of acute myeloblastic leukaemia presenting as temporal bone chloroma with facial nerve paralysis. Ann Oncol l993:4:339-40.

(8.) Braverman IM. Leukemia and allied disorders. In: Braverman IM, ed. Skin Signs of Systemic Disease. Philadelphia: W.B. Saunders, 1981:179.

(9.) Shaikh BS. Frantz E, Lookingbill DP. Histologically proven leukemia cutis carries a poor prognosis in acute nonlymphocytic leukemia. Cutis 1987;39:57-60.

(10.) Sun NC, Ellis R. Granulocytic sarcoma of the skin. Arch Dermatol 1980:116:800-2,

(11.) Chapman P. Johnson SA. Mastoid chloroma as relapse in acute myeloid leukaetnia. J Laryngol Otol 1980:94:1423-7.

(12.) Rontal E, Sigel ME. Bilateral facial paralysis. Laryngoscope 1972;82:607-16.

(13.) Roth MJ, Medeiros U, Elenitoba-Johnson K, et al. Extramedullary mycloid cell tumors. An immunohistochemical study of 29 cases using routinely fixed and processed paraffin-embedded tissue sections. Arch Pathol Lab Med 1995;l 19:790-8.

(14.) Frohna BJ. Quint DJ. Granulocytic sarcoma (chloroma) causing spinal cord compression. Neuroradiology l993;35:509-11.

(15.) Colle I, Lacor P. Peeters P, et al. Granulocytic sarcoma (chloroma): A report of two cases. Acta Clin Belg 1996:51:106-10.

(16.) Neiman RS, Barcos M, Berard C, et al. Granulocytic sarcorna: A clinicopathologic study of 61 biopsied cases. Cancer 1981; 48:1426-37.

(17.) Lichtman MA. Acute myelogenous leukemia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. New York: McGraw-Hill, 1995:272-88.

COPYRIGHT 2001 Medquest Communications, Inc.
COPYRIGHT 2001 Gale Group

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