Acute promyelocytic leukemia presenting as a pelvic mass
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Medical and Pediatric Oncology 4:289-295 (1978)
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Acute Promyelocytic Leukemia Presenting as a Pelvic Mass Jean Bello Belasco, MD, J. Hugh Bryan, MD, and Campbell W. McMillan, MD Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of North Carolina, Chapel Hill
The case history of a child with acute promyelocytic leukemia (APL) is reported to illustrate both an unusual presentation of APL as a pelvic mass and to review the pathophysiology and treatment of the disease. Therapy of APL consists of chemotherapy, namely adriamycin/daunomycin for remission induction, and of control of disseminated intravascular coagulation. A chloroma, if present, may require local irradiation in addition t o chemotherapy. With aggressive management, the number of prolonged remissions may be greater for APL than for any other form of acute myelogenous leukemia (AML), with significant numbers of patients achieving five-year survival. Key words: acute promyelocytic leukemia, chloroma, disseminated intravascular coagulation
The differential diagnosis of a pelvic mass occurring in childhood generally includes sarcoma (rhabdomyosarcoma, Ewing sarcoma), neuroblastoma, dysgerminoma, lymphoma, and teratoma. Acute promyelocytic leukemia (APL) is uncommon in childhood and rarely presents with extramedullary disease. This report describes a child with APL who presents with a pelvic mass and extensive bony lesions. Presented as well is the initial management of both the malignancy and the associated coagulopathy. CASE HISTORY
Propositus is a white male, aged 4 years, 9 months, referred to North Carolina Memorial Hospital on November 18, 1976 for evaluation of a pelvic mass. The patient was in good health until six to eight months prior to admission, at which time he developed vague pain of the right hip and an occasional limp. Repeat physical examinations were negative. On November 1,1976, x-ray films of the hips were made and then revealed diffuse lytic lesions of the right ileum (Fig 1). An open biopsy of the right iliac wing was Address reprint requests to Jean Bello Belasco, MD, Dept of Pediatric Hematology and Oncology, Univ of North Carolina Memorial Hospital, Chapel Hill, NC 27514.
0098-lS32/78/0404-0289$01.70 0 1978 Alan R. Liss, Inc.
Belasco, Bryan, and McMillan
Fig 1. Residual defects of right ileum, December, 1976, during epidosde of pneumatosis intestinalis.
performed at an outside hospital. Grossly, the specimen consisted of tan-gray fragments of bone with focal areas of tan-green discoloration. Microscopically, there was evidence of cortical erosion by proliferating myelocytic cells (Fig 2). The impression was of “granulocytic leukemia.” Physical examination on referral t o North Carolina Memorial Hospital revealed weight 18.6 kg, height 105.4 cm, temperature 37.8”C, pulse 120/min, respiration 20/min. Ibs liver was not palpably enlarged. His spleen was palpated 2 cm below the left costal margin in the midclavicular line. A mass was felt in the right lower quadrant extending from the ileum to the pelvic brim. There was no significant lymphadenopathy. Musculoskeletal examination showed slightly decreased abduction of the right hip and a limp favoring the right leg. Physical examination was otherwise noncontributory. Admission CBC revealed the following: hemoglobin 9.9 gm%, hematocrit 28%; WBC 14,9OO/cu mm with 13%promyelocytes, 5% myelocytes, 8%bands, 29% polys, 1% basophils, 34% lymphocytes, 5% atypical lymphocytes, 5% monocytes), platelets 325,100. Bone marrow aspiration yielded a hypercellular specimen with 59% promyelocytes, 13% myelocytes, 8%metamyelocytes, 6% bands, 7%lymphocytes. Only one megakaryoche was observed (Fig 3). His BUN was 11 mg/dl, creatinine 0.8 mg/dl, SCOT 84 SF units, SGPT 43 SF units, alkaline phosphatase 5.8 NP units, uric acid 3.9 mg/dl, lactic dehydrogenase (LDH) 1,531 units/ml, calcium 9.5 mg/dl. Coagulation studies showed a PT of 12.8 sec (control 11.7), PTT 55.7 sec (control 48.0), TCT 1 1 .O sec (control 11.7), fibrinogen 356 mg% (normal 200400), factor V 124%, factor VIII 132%, and negative fibrin split products.
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Fig 2. Biopsy of right ileum X 70. Proliferation of immature myelocytic cells. Courtesy of Charlotte Orthopedic Hospital.
Fig 3. Bone aspirate X 85. Hypercellular. Malignant promyelocytes with intense granulation apparent.
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Computerized axial tomography of the pelvis revealed increased density of the right ileum with a soft tissue mass extending from the bone t o displace the right ureter anteriorly and medially (Fig 4). The diagnosis of APL with concomitant chloroma (granulocytic sarcoma) was made. On November 11,1976, the patient began antileukemic induction therapy consisting ofvincristine 2 mg/mZ/day intravenously on days 1 , 8 , and 15, prednisone 60 mg/ m2/day orally, and adriamycin 30 mg/mZ intravenously on days 1,2, and 3. Concomitantly he was started on heparin 50 units/kg intravenously every six hours. On November 15 his fibrinogen level had dropped t o 238 mg% and to 144 mg% on November 18. Fibrin split products became positive as well at 1 :64.On November 18 heparin was increased to 7 5 unitslkg intravenously every four hours. The fibrinogen returned to normal and no difficulties with clinical bleeding were encountered. On December 21, 1976, physical examination revealed that the tumor mass had decreased. At this time a bone marrow aspiration was performed that revealed a hypocellular specimen with 36%promyelocytes. The patient received a second induction course of vincristine, adriamycin, and prednisone, as well as 1,500 rads of irradiation to the pelvic mass. Heparin was not given during the second induction course because of decreased tumor mass with concomitantly normal coagulation parameters. The patient achieved complete bone marrow remission after a stormy course marked by severe myelosuppression, sepsis, pneumocystis carinii, and pneumatosis intestinalis. He initially continued on a maintenance program consisting of adriamycin, thioguanine, prednisone, and vincristine pulses. However, because of moderately severe toxicity on this regimen, he was placed on oral 6-MP 50 mg/mz/day and methotrexate 20 mg/mZ/wk. He tolerated this maintenance program well and remains symptom-free in complete remission 14 months after initial diagnosis.
APL was first described in 1949 by Croizat and Favre-Gilly [ l ] . In 1957 Hillestad  first classified APL as a distinct entity and as a specific subtype of acute myelogenous leukemia. The works of Didisheim et a1 , Rosenthal , and especially Bernard and
Fig 4. Computerized axial tomography. Note increased density of right ileum with soft tissue mass estending medially.
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co-workers [5-81 and Gralnick and co-workers [9-121 among others [ 13-16] have helped to elucidate its pathophysiology. Until recently, APL has been fulminant and fatal, causing death in less than four months. An associated coagulopathy contributes substantially to the aggressiveness of the disease process. Bernard et a1  has reported a 25% mortality in the first five days of therapy from hemorrhage secondary to uncontrolled disseminated intravascular coagulation. Infection remains the other major cause of death during induction. In Bernard's series, infectious complications occurred later in the induction period, generally in the second and third weeks of therapy. In 1973, Bernard reported an approximately 50% remission induction rate with daunomycin as a single agent. At present, daunomycin and adriamycin [17, 181 remain the most efficacious induction agents available. Once remission is attained, hemostasis normalizes as well. Weil et a1  now project a greater than 30%eight-year disease-free survival for patients who achieved a complete remission. This prolonged remission rate significantly surpasses that of other subtypes of acute myelogenous leukemia. APL accounts for approximately 5% of all reported leukemias. Typically, the patient presents with a history of clinical bleeding. Often, this bleeding iliathesis precedes the diagnosis by several weeks. This was not the case with our patient. Extramedullary infiltration in APLis rare. Again, our patient was an exception, presenting with a pelvic chloroma. The diagnosis depends on significant numbers of abnormal promyelocytes in bone marrow and peripheral blood. The criteria for diagnosis established by Bernard are: 1) at least 50%typical malignant promyelocytes in the bone marrow and 2) some promyelocytes evident on peripheral smear. The malignant promyelocyte is 15-20 p in diameter. The nucleus is eccentric, irregular, immature, and obscured by increased numbers of cytoplasmic azurophilic granules. These granules are larger and more spindle-shaped than normal. The cytoplasmic granules are thought to be derived from the Golgi apparatus and contain lysosomal enzymes. There is evidence that Auer rods may arise from these azurophilic granules and that these granules and Auer rods may actually represent different evolutionary stages [lo, 151 . Disseminated intravascular coagulation classically is distinguished by prolonged prothrombin and partial thromboplastin times, by a decrease in factors 11, V, VIII, and fibrinogen, and by thrombocytopenia. In malignancy, especially hematologic malignancy, the laboratory manifestations are less consistent. Thrombocytopenia may be present secondary to a malignant state involving the marrow and/or secondary to chemotherapy. Often in the malignant state, fibrinogen and factor VIII are elevated possibly as a compensatory response to chronic low-grade disseminated intravascular coagulation, where synthesis of these proteins outstrips their degradation. The coagulation parameters in APL are usually suggestive of disseminated intravascular coagulation and generally are associated with clinical bleeding. The most consistent finding in APL is a low fibrinogen level. At diagnosis, the fibrinogen level may be normal but will fall with therapy or with progression of the disease. In fully expressed cases, there is prolongation of the prothrombin time, partial thromboplastin time, and thrombin time; decreased activity of factqrs 11, V, and VIII; and increased fibrin split products. The half-time of administered labeled fibrinogen is markedly reduced [ 121 . Gralnick, by a two-stage assay of tissue factor, compared tissue factor activity of polymorphonuclear leukocytes, myeloblasts, and malignant promyelocytes. Acute promyelocytic leukemia cells demonstrated greatly increased tissue factor activity compared to either normal or acute myelogenous leukemia cells. By subcellular fractionation, tissue
Belasco, Bryan, and McMillan
factor activity appears to be most marked in the granular fraction of the promyelocyte, although some activity resides in its nuclear and membrane fractions as well. Liberation of the granular thromboplastic activity by cellular breakdown, whether secondary to metabolic turnover or to accelerated destruction by chemotherapy, may then trigger intravascular coagulation. APL cell lysates also may demonstrate fibrinolytic activity; however, the increase in tissue factor always exceeds its fibrinolytic activity. Because of this induced coagulation state secondary to membrane breakdown and release of thromboplastic activity, heparin would appear to be logical therapy. This has been challenged by Valdivieso , who argues that chemotherapy is the single means of control of both the leukemia and coagulopathy. In Gralnick’s experience [9-121, however, low doses of heparin, in the order of 50 units/kg IV every four to six hours, generally stopped or prevented clinical bleeding. In his series, control of the bleeding diathesis was much more effective if heparin was instituted concomitantly with chemotherapy rather than later in the course, when bleeding tended to be more severe. As in all the acute leukemias undergoing induction therapy, severe thrombocytopenia may necessitate frequent platelet transfusions as well . Granulocytic sarcoma [20-251 is a well-described but rare accompaniment of the myeloid leukemias, especially APL. Granulocytic sarcomas are extramedullary tumors which in general, are nodular, firm, and green or green-brown in appearance. The frequency of this green coloration accounts for the designation chloroma. In a series by Muss and Moloney  green coloration of this tumor is much more frequently found in AML than in chronic myelogenous leukemia (CML). Histologically, the tumor is composed of sheets of immature myeloid cells. The green color is presumably related to myeloperoxidase activity. Schultz and Rosenthal  have postulated that the myeloperoxidase is derived from a porphyrin-protein complex and catalyzes the oxidation of amino acids. The tumor behaves malignantly, invading local structures as well as metastasizing distantly. Chloroma classically presents as an orbital lesion with resultant proptosis in children. Acute leukemia may always be considered in the differential diagnosis of a child who presents with proptosis. These sarcomas typically cause symptoms of pain or of mass or pressure. Most of these tumors arise from the skull and the subperiosteal regions of bone, possibly as tumor extension from the bone marrow. These sarcomas uncommonly involve the viscera. In adults, chloromas are usually periosteal, perineural, and not infrequently ovarian. In adults as well, myeloblastic tumors occur more commonly with CML than with AML,and in CML they may herald rapid clinical deterioration [I 71 . Usually, the chloroma presents concomitantly with the leukemia; however, it rarely may precede +hediagnosis by months. Effective therapy for the sarcoma consists of local irradiation and chemotherapy. The long-term prognosis of acute myelogenous leukemia patients with and without such sarcomas is identical. In conclusion, we have reported APL both as an uncommon form of leukemia and as an unusual cause of pelvic masses of the pediatric age group. Effective therapy for such leukemia involves control of both malignancy and coagulopathy. Even if coagulation studies are normal at diagnosis, cellular breakdown secondary to chemotherapy often will trigger disseminated intravascular coagulation. Hence, attempts to induce remission in APL have to focus on two areas: 1) control of the malignant state with chemotherapy and 2 ) control and/or prevention of disseminated intravascular coagulation with low-dose heparin.
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