Granulocytic Sarcoma Presenting as Pulmonary Nodules and Lymphadenopathy

MARK CALLAHAN, MD.' SHERRY WALL, MD,t FRED ASKIN, MD.t DAVID DELANEY MD,+ CHARLES KOLLER, MD.5 AND EUGENE P. ORRINGER. MD'

A patient presented with anterior and posterior cervical lymphadenopathy as well as widespread intra- pulmonary nodules. Histologic sections of both lymph node and lung revealed dense infiltration by sheets of cells which were cytochemically positive for chloroacetate esterase and myeloperoxidase, thus suggesting a diagnosis of granulocytic sarcoma. The patient was initially treated with daily hydroxyurea. After 6 weeks, when progression of the disease was apparent, hydroxyurea was discontinued and the patient was placed on mithramycin, an agent reported to induce differentiation of myeloid precursor cells both in vitro and in v i v a On this latter agent, a dramatic response has been noted with a decrease in the pulmonary symptoms, and a marked reduction in the size of the lymph nodes and lung nodules. The authors report this case because it represents a rare presentation of an uncommon disease and because of the striking improvement that followed the initiation of a novel therapeutic modality.

Cuncer 60:1902-1904, 1987.

RANULOCYTIC SARCOMA (or chloroma) has at- G tracted considerable attention because of its close association with the various myeloproliferative dis- orders,' most often acute or chronic leukemia. Upon occasion, granulocytic sarcoma can actually appear as the initial manifestation of a myeloproliferative state. The typical presentation of these tumors is a localized mass of granulocytic precursor cells in bone, lymph nodes, or skin.' In addition to these more commonly affected areas, granulocytic sarcoma also has been de- scribed in a wide variety of other body sites. Although several case reports allude to pleural and/or chest wall disease,'-5 pulmonary parenchymal involvement is dis- tinctly unusuaL6 This report describes a case of granulo- cytic sarcoma with lymph node and extensive, symp- tomatic pulmonary parenchymal involvement. This case is made even more interesting because after failing a trial of hydroxyurea, she had a striking response to mithramycin, an agent which has recently been shown to be effective in treating the myeloid blast phase of chronic granulocytic leukemia. This case is described

-- From the Departments of *Medicine, tPathology, and $Radiology,

School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, and the $Department of Medicine, Uni- versity of Texas System Cancer Center. M. D. Anderson Hospital, Houston. 'Texas.

Address for reprints: Eugene P. Oninger, MD, Division of Hematol- ogy, Department of Medicine, School of Medicine. University of North Carolina at Chapel Hill, 340 MacNider Building (202H). Chapel I f i l l . NC 27514.

Accepted for publication April 22. 1987.

because of the unusual degree of pulmonary parenchy- mal involvement and because it appears to be the first instance in which granulocytic sarcoma has been effec- tively treated with mithramycin.

Case Report

A previously healthy 74-year-old woman presented with a 2-month history of malaise, weakness. low-grade fevers, weight loss. and a chronic, nonproductive cough. Physical examina- tion revealed multiple, 2-cm lymph nodes in the cervical chains bilaterally and coarse rhonchi throughout both lung fields. A chest roentgenogram demonstrated numerous pul- monary nodules. A computerized axial tomography (CAT) scan of the abdomen and chest revealed, in addition to the pulmonary parenchymal tumors, both retroperitoneal and para-aortic lymph node enlargement.

Laboratory studies disclosed the following values: hemoglo- bin, 13.9 g/dl; hematocrit. 4370; leukocyte count 18,200/pl, with 72% segmented neutrophils, 18% lymphocytes, 4% monocytes, 370 eosinophils, and 3% atypical lymphocytes; platelet count, 766,0OO/pl. A few metamyelocytes and a rare myelocyte also was noted on the peripheral blood film. Liver and kidney function tests and serum electrolytes all were within normal limits.

Biopsy of a right cervical lymph node revealed disruption of the normal nodal architecture and a dense cellular infiltrate. The initial impression was that the tumor represented a diffuse large cell lymphoma. The positive reaction with chloracetate esterase (Leder) stain, however, suggested instead the diagnosis of granulocytic sarcoma.

A bone marrow aspirate and trephine core biopsy yielded a very cellular sample. There was orderly maturation of both

1902

No. 8 CHLOROMA INVOLVING THE LUNG AND LYMPH NODES * Callahan et a/. I903

myeloid and erythroid precursors, and megakaryocytes were plentiful. The high marrow cellularity, coupled with the my- eloid to erythroid ratio of 10: I , was thought to be most consis- tent with either chronic granulocytic leukemia (CGL) or a leukemoid reaction. The diagnosis of CGL was considered unlikely because the leukocyte alkaline phosphatase score was 175, and because cytogenetics failed to disclose a Philadelphia chromosome. However, an extra C group chromosome was noted in four of 20 nietaphase spreads.

The patient subsequently underwent a transbronchial biopsy, with fluorosclopic guidance, of one of the large pulmo- nary parenchymal nodules in the left midlung field. The pathologic appearance of this specimen was identical to that seen in the lymph node biopsy. Cultures of both lung tissue and bone marrow for bacteria, fungi, and mycobacteria were all negative, as were special stains for these organisms that were performed on the paraffin-embedded tissue.

Further confirmation of the diagnosis of granulocytic sar- coma was provided by immunocytochemical staining. The cells in both the lymph node and transbronchial biopsy speci- mens produced diffuse staining with anti-leu-M I , an anti- serum that recognizes cells of the myeloid series. In addition, T-cell lymphoma was excluded by the presence of cytoplasmic granules in the primitive malignant cells and by the lack of reactivity of these same cells with other, more specific T-cell markers.

Because of progres:sive enlargement of the pulmonary nod- ules and because of the patient's worsening symptomatology including paroxysms of cough, dyspnea, and weight loss, she was begun on hydroxyurea at a dose of 1.5 g d. Over the initial 6 weeks of this therapy, she became anemic and leukopenic, her pulmonary symptoms worsened, and the lung nodules in- creased in size. The dosage of hydroxyurea was initially re- duced, then the drug 'was discontinued altogether, yet the clin- ical course continued to progress. The patient was next placed on mithramycin at a dose of 20 &kg body weight. This drug was diluted in 500 ml of 5% dextrose in water and given as a 3-hour intravenous infusion in the outpatient clinic on Mon- days, Wednesdays, and Fridays. Over the initial 3 months of this treatment, the patient experienced a dramatic improve- ment in her energy, strength, and overall sense of well-being. She has tolerated the mithramycin extremely well, with no subjective complaints. no hypocalcemia, and minimal abnor- malities of liver function tests. In addition, there has been a dramatic decrease in the size of both the cervical adenopathy and the pulmonary parenchymal mass lesions.

Discussion

Granulocytic sarcoma can present in a wide variety of locations; however, lytic bone lesions, lymph nodes, and skin are the most common sites of involvement.1-6 This tumor, often but not always,' heralds the onset of, or develops during the course of, various myeloprolifera- tive disorders, including CGL, acute myeloid leukemia, polycythemia Vera, and primary myelofibrosis with my- eloid metaplasia. ' Only 34 cases of isolated granulocytic sarcoma, in whom no evidence of leukemia was identi-

fied within 1 month of diagnosis, have been collected and reported in the English literature.8 Even in these rare instances in which granulocytic sarcoma has appar- ently occurred as an isolated finding, it appears to be an ominous development, and some authors have actually suggested that an aggressive approach should be taken, advocating antineoplastic regimens similar to those used for acute nonlymphocytic le~kemia. ' .~

Our patient presented with marked cervical lymphad- enopathy. The preliminary impression of diffuse large cell lymphoma, which was based primarily upon the size and morphologic appearance of the abnormal cells, is a common misdiagnosis in cases of granulocytic sar- coma. lo After cytochemical and irnmunocytological studies were available, however, the correct diagnosis became readily apparent. This patient also had large intrapulmonary lesions which could have been either infection or tumor. Since granulocytic sarcoma of the lung is distinctly unusual, we believed that it was neces- sary to have a definitive tissue diagnosis of the lung nodules before initiating therapy. Fluoroscopically guided transbronchial biopsy confirmed the presence of pulmonary granulocytic sarcoma.

Although the diagnosis of granulocytic sarcoma was secure, the age of the patient and her poor clinical status seemed to preclude a trial of aggressive chemotherapy as might be employed for acute nonlymphocytic leukemia. Instead, hydroxyurea, an agent often used to control the chronic phase of chronic granulocytic leukemia, was se- lected. When disease progression continued despite this drug, the hydroxyurea was stopped and the patient was begun on mithramycin. Although we have reported some success in the management of the myeloid blast phase of chronic granulocytic leukemia with mithramy- cin,11912 this case represents the first instance in which mithramycin has been used to treat a patient with gran- ulocytic sarcoma.

The response of this patient to lower dose, alternate- day mithramycin has been gratifying. There has been a rapid improvement in the pulmonary symptoms and a striking decrease in the size of the lung lesions, all of which has been accomplished with very little, if any, subjective toxicity. This improved mithramycin toler- ance is in marked contrast to the original mithramycin regimens in which the agent was given on a daily basis at high dosage and was associated with considerable toxic- ity that often masked its beneficial effects. I3By selecting a dose of mithramycin that does not cause abnormalities in hepatic, renal, or hematologic parameters, the lower- dose, alternate-day regimen can be safely administered over a prolonged interval.",l2

The mechanism by which mithramycin exerts its beneficial effect is unknown at this time. It may be through selective toxicity to malignant cells, by induc-

1904 CANCER October 15 1987 Vol. 60

tion of cellular differentiation, or through some other mechanism which remains to be established.' '

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