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Chronic granulocytic leukemia
Chronic Granulocytic Leukemia Prolonged Survival, Muscle Infiltration and Sea-Blue Histiocytosis
MARTIN BERNARD Jackson.
H. STEINBERG.
M.D.
J. DREILING.
M.D.
Mississippi
Most patients with chronic granulocytic leukemia (CGL) survive from three to four years after diagnosis. We describe a patient with CGL who remained well for almost 13 years after the initiation of treatment. Shortly before death, when he was hematologically stable, the skin, subcutaneous tissue and muscle became infiltrated with leukemic cells. Many sea-blue histiocytes were found in his bone marrow. During the terminal phase of his disease, fever, basophilia, blast transformation, elevated leukocyte alkaline phosphatase activity and myelofibrosis were all present. The, average duration of life in chronic granulocytic leukemia (CGL) is reported to be three to four years after the initiation of therapy [l]. An accurate estimation of survival in individual cases is difficult to make early in the course of the disease, but as the disease progresses from an indolent, treatable stage to an aggressive accelerated phase, signs appear which allow an accurate prognosis to be made. These have been recently reviewed by Theologides [2] and include fever, cutaneous lesions, basophilia, elevated leukocyte alkaline phosphatase activity and myelofibrosis. We describe a patient with CGL and an unusually long survival who preterminally manifested almost all the known unfavorable prognostic signs. In addition he had extensive muscle infiltration, a previously unreported complication of CGL, and sea-blue histiocytosis of the bone marrow. At the time these abnormalities occurred, there was no evidence in either the blood or marrow of transformation of the disease to a more aggressive stage. CASE
From the Jackson Veterans Administration Center and the University of Mississippi School of Medicine, Jackson, Mississippi. Requests for reprints should be addressed to Dr. Martin H. Steinberg, Hematology Research, Jackson Veterans Administration Center, Jackson, Mississippi 39216. Manuscript accepted February 5. 1973.
REPORT
A 35 year old black man (R.C.L.), initially sought medical attention in April 1959 because of a two month history of weakness, fever, night sweats and weight loss. Physical examination revealed mild hepatomegaly and moderate splenomegaly. The leukocyte count was 120,000/mm3, with polymorphonuclear cells predominating but all cells of the myeloid series present. A bone marrow aspirate showed myeloid hyperplasia with orderly maturation. The patient was given a four week course of 6-mercaptopurine (6-MP) therapy, 200 mg
July 1973
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Volume 55
93
CHRONIC
GRANULOCYTIC
LEUKEMIA-STEINBERG.
DREILING
daily: the leukocyte count fell to 12,000/mm3 and all symptoms remitted. He was discharged from the hospital on no therapy. He was first seen at the Jackson VA Hospital in June 1959 with a three day history of chest pain, hemoptysis and dyspnea. Hepatosplenomegaly was again noted. Laboratory and x-ray studies were consistent with a diagnosis of pulmonary infarction. His leukocyte count was 132,000/mm3, platelet count 1.2 million/ mm3, hemoglobin concentration 10 g/l00 ml. His symptoms abated with supportive therapy, and another four week course of 6-MP therapy was instituted. The leukocyte count fell to 9,000/mm3, but there was little change in hemoglobin concentration and platelet count. In September 1959 he was admitted for elective removal of a fibroma of the tongue, a procedure which was complicated by development of an oral-antral fistula which responded to appropriate antibiotic therapy and ultimately closed. Because of a persistently elevated leukocyte count, busulfan therapy was started, 6 mg daily. When discharged in November 1959, the leukocytes numbered 12,000/mm3 with a normal differential count, the hemoglobin concentration was 13 g/l00 ml, and the platelet count was 800,000/mm3. The spleen and liver were no longer palpable. The patient was then followed in the outpatient clinic at frequent intervals for the ensuing 12 years, remaining normal hematologically on doses of busulfan varying from 2 to 6 mg daily. The spleen and liver remained normal in size and he was symptom-free. He was hospitalized in March 1971 for evaluation of persistent epigastric pain. The findings on physical examination were normal. An x-ray series of the upper gastrointestinal tract and gastroscopy showed mild gastritis. The leukocyte count was 3,500/mm3, hemoglobin concentration 14.4 g/l00 ml and platelet count 300,000/mm3. A bone marrow aspirate revealed marked myeloid hyperplasia and rare “blue” histiocytes. The leukocyte alkaline phosphatase score was 3 (normal 15 to 100). A Ph’ chromosome was present in 6 of 9 marrow metaphases. The dose of busulfan was reduced, and the patient was discharged with a leukocyte count of 9,000/mm3. In December 1971 he was hospitalized for control of symptomatic diabetes mellitus. which responded satisfactorily to diet and oral hypoglycemic agents. Hematologic values on this admission were normal, and busulfan therapy was continued. In February 1972 he was readmitted for evaluation of a painless, rapidly enlarging mass located at the inferior aspect of the left sternocleidomastoid muscle. This measured 6 by 6 cm, was stoney hard and nontender. In addition, there was diffuse brawny induration of the skin and subcutaneous tissues of the left upper thoracic wall. The spleen and liver were not palpable. The leukocyte count was 1 2,000/mm3
with
but occasional
predominantly
metamyelocytes,
mature
granulocytes,
myelocytes
and
pro-
The hemoglobin concentration was 12 g/100 ml and the platelet count 230,000/mm3. Of particular note was a significant change in red blood cell morphology which showed myelocytes
94
were
July 1973
present.
The American Journal of Medicine
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marked anisocytosis and poikilocytosis. 15 to 20 nucleated red cells/100 white cells. basophilic stippling and many teardrop cells. A bone marrow aspirate showed marked granulocytic hyperplasia, and many histiocytes which stained a sea-blue color with WrightGiemsa preparation were observed. On further study these cells were negative for hemosiderin, had a negative Feulgen reaction, stained positively with periodic acid-Schiff and Sudan 6 black and showed autofluorescence. Biopsy of the neck mass revealed leukemic infiltration of muscle and subcutaneous tissues. Because of increasing dyspnea, thought to be a result of tracheal compression and chest wall fixation due to the leukemic infiltrate, a tumor dose of 2,000 R was delivered to the affected sites using a linear accelerator. There was a decrease in the size of the mass and chest wall infiltrate and the symptoms subsided. The patient was discharged on a regimen of busulfan with little change in his blood counts from those on admission. He remained well for a short period of time but then experienced increasing tightness and nodularity of the anterior chest wall. He was readmitted in May 1972 for radiotherapy to additional areas of infiltration which involved almost the entire upper anterior chest wall and both shoulders. He again received a tumor dose of 2,000 R this time using a 110 KV machine. Upon completion of his treatment the hemoglobin concentration was 10 g/l00 ml and the leukocyte count was 2,900/ mm3. Busulfan therapy was withheld. The tissue infiltration again regressed and he did well until June 1972 when he was hospitalized with fever, night sweats. anorexia and chest wall pain. On examination his temperature was 104”F, the anterior thorax was hard, indurated and for the first time, tender; the spleen and liver were not palpable. The hemoglobin concentration was 10 g/100 ml; the leukocyte count was 12,000/mm3 with 24 per cent myeloblasts, 23 per cent basophils and 6 per cent eosinophils; platelets numbered 320,000/mm3, and 20 nucleated red blood cells/l00 leukocytes were seen. The leukocyte alkaline phosphatase score was 160. The blood glucose was 370 mg/lOO ml, blood urea nitrogen 20 mg/lOO ml, uric acid 4.9 mg/lOO ml, total protein 5.9 g/100 ml, albumin 2.0 g/l00 ml, calcium 7.6 mg/lOO ml, serum glutamic oxaloacetic transaminase 72 units, lactic dehydrogenase 425 units and bilirubin 0.9 mg/lOO ml. Marrow aspiration at three different sites in the sternum and iliac crest was unproductive of spicules, and a needle biopsy specimen showed the marrow to be replaced by dense fibrous tissue. A chest roentgenogram was normal, and cultures of the urine and pharynx were negative, however Herellea vaginacolor was grown from several blood cultures. Gentamicin therapy was instituted and the patient’s temperature fell to normal and his symptoms diminished. Blast crisis was suspected and treatment was begun with vincristine, 4 mg weekly, and prednicount fell to sone, 100 mg daily. The leukocyte with 2 per cent myeloblasts and 2 per 2,100/mm3 cent basophils, and there was a coincident decrease in the nodularity and infiltration of the chest wall. The
CHRONIC
last weeks of the patient’s life were characterized by recurrent fevers for which no infectious cause could be documented despite repeated bacterial and fungal cultures of his sputum, blood and urine; progressive anemia and thrombocytopenia, requiring red cell and platelet transfusions; increasing lethargy and an ill defined pulmonary infiltrate. Treatment with a variety of antimicrobial agents was ineffective. He continued to receive vincristine and only occasional blast cells were noted in his blood. He died in August 1972. At autopsy the skin over the anterior chest and shoulders showed atrophy, hyperpigmentation and nodularity. There was myeloblastic infiltration of skin and muscle as well as hyalinized fibrous tissue and proliferative endarteritis. The lungs contained areas of edema and pneumonitis. The esophagus had many mucosal erosions which contained mycelial fragments consistent with Candida. Areas of hemorrhage, necrosis and ulceration were scattered throughout the length of the gastrointestinal tract, and a severe pseudomembranous colitis was present. The liver weighed 1,800 g and was normal. The spleen weighed 160 g. There were areas of myeloblastic infiltration but only minimal evidence of extramedullary hematopoiesis. Several lymph nodes showed extensive destruction by infiltrating myeloblasts, however, this was not found in all nodes examined. Bone marrow from the sternum, ribs, spine, pelvis, humerus, femur and tibia was examined. The striking feature of the “central” marrow was the marked variation in morphology from site to site. There were areas in which the marrow was replaced by myeloblasts, others in which there was dense myelofibrosis as well as scattered foci of normal appearing hematopoiesis. Marrow of the long bones showed foci of hematopoiesis, myeloblastic in-
GRANULOCYTIC
LEUKEMIA-STEINBERG,
DREILING
accelerated phase. There were no additional areas of extramedullary extension and the spleen did not become enlarged. The response of the lesions to radiotherapy was good, with marked regression and alleviation of symptoms; however, recurrence soon occured both within and outside the treatment ports. Additional radiation as well as vincristine therapy resulted in further regression, but lesions continued to recur in areas previously treated and new infiltrates developed in untreated sites. Careful examination of the radiated fields and surrounding areas at autopsy showed persistent infiltration with myeloblasts as well as the changes of prior radiotherapy. The bone marrow contained many sea-blue staining histiocytes (Figure 3) at the time the soft tissue infiltrates appeared. These cells were not present in skin, subcutaneous tissue or muscle. Sea-blue histiocytes and cells identical to those seen in Gaucher’s disease have been found both together and separately in the marrow of patients with CGL [4]. Unlike hereditary Gaucher’s disease, the activity of glucocerbrosidase in the leu-
filtration and fibrosis. COMMENTS Following 13 years of benign CGL, a three month period saw the development of extramedullary spread of disease, sea-blue histiocytosis of the marrow, basophilia, elevated leukocyte alkaline phosphatase score, myelofibrosis and blast transformation, which culminated in the death of the patient. The infiltrative process in the skin, subcutaneous tissues and muscle of the neck and anterior chest wall (Figure 1) developed at a time the blood and bone marrow appeared to be free of blast transformation. A biopsy specimen of the involved tissue revealed a diffuse leukemic infiltrate, especially marked in muscle, which showed wide separation of fibers by infiltrating cells (Figure 2). Although skin lesions have been reported in CGL [3], we have been unable to find previous reports of muscle infiltration in this disease. Cutaneous involvement in CGL is generally nodular in nature and associated with a very short survival after its appearance [3]. Of note in our patient is the onset of this diffuse soft tissue infiltration prior to overt evidence of the disease entering an
Figure
1.
Appearance of skin at the time infiltrates thickening, loss noticed. There is induration. mobility and an early peau d’orange texture. The biopsy site (arrow) is well healed. were first of normal
July 1973
The American Journal of Medicine
Volume 55
95
CHRONIC
GRANULOCYTIC
LEUKEMIA-STEINBERG.
DREILING
.
“.
I
Figure
I
*
kocytes
of patients
with
CGL and Gaucher
cells
is
increased [5]. It has been postulated that Gaucher cells form in CGL as a result of excessive glucocerebroside production due to increased granulocyte turnover. Despite the induction of greater than normal amounts of enzyme activity, an inability to metabolize the excessive glucocerebroside produced results, and typical Gaucher storage cells are formed [5]. Gaucher cells were not seen in our patient, however, histiocytes with a granular, sea-blue staining cytoplasm were present in the marrow. Silverstein and co-workers [6] introduced the designation “syndrome of the sea-blue histiocyte” for a disease characterized by splenomegaly, mild thrombocytopenic purpura
.
2
2. Muscle biopsy specimen from left neck area showing separation of muscle fibers by a cellular infiltrate which is composed of cells of the granulocytic series (arrows). Hematoxylin and eosin stain: original magnification X 200, reduced by 34 per cent.
and histiocytes in the spleen and bone marrow which contained bright blue granules when stained with Romanowsky dyes. Although they, and others, believe this syndrome is a nosologic entity, the presence of very similar cells in the marrow have been reported in a variety of diseases [7]. The lipid material in these histiocytes is believed to be ceroid, a pigment formed upon the liberation of lipid during cell death [8]. Following the phagocytosis of effete cells by macrophages, lipid is oxidized and polymerized yielding ceroid pigment. Increased leukocyte turnover in CGL has been calculated to result in the formation of excessive amounts of lipid. If the essential enzyme systems for degradation of specific lipids are unable to
Figure 3. A large sea-blue histiocyte occupies the center of this field and is surrounded by cells of the myeloid and erythroid series. The cytoplasm of this cell stains a vivid blue and contains scattered dark blue granules (arrow) Wright-Giemsa stain: original magnification X 1.000. reduced by 34 per cent.
96
July 1973
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CHRONIC
GRANULOCYTIC
LEUKEMIA-STEINBERG,
DREILING
Figure 4. Needle biopsy specimen of the posterior iliac crest marrow showing a marked increase in agyrophilic reticulum fibers, Wilder’s reticulum stain; original magnification X 200, reduced by 34 per cent. Hematoxylin and eosin stain of this section revealed dense myelofibrosis.
meet the demand of increased substrate concentration, the accumulation of phagocytized lipid or necrotic granulocytes could lead to the development of the “sea-blue” histiocyte, in a fashion analogous to the formation of Gaucher cells in CGL. This possibility has been suggested by Katflove et al. [9]. The available evidence favors an idiopathic or familial sea-blue histiocyte syndrome, the defect being primarily one of a lack of appropriate enzyme activity with subsequent inability to metabolize normal amounts of lipid formed [7], as well as an acquired type seen in association with a variety of diseases and characterized by excessive lipid production [7]. During the latter phase of the disease in our patient, nucleated red blood cells and teardrop poikilocytes became common in the peripheral blood, a finding said to be unusual when myelofibrosis complicates CGL [lo]. Over the course of three months the marrow architecture changed from the intensely cellular organ typical of CGL to the fibrotic structure characterizing myelofibrosis (Figure 4). Variable degrees of fibrosis of the bone marrow are found in CGL, frequently at a very early stage of the disease [lo]. Dense myelofibrosis, however, is an event which heralds the terminal stages of this disorder [2,10]. Of interest in this respect is the possible relationship of prolonged treatment with busulfan, a drug known to produce lung fibrosis, and the development of myelofibrosis. We were unable to aspirate marrow from the sternum, anterior or posterior iliac crests and a single needle biopsy specimen showed dense fibrosis. Postmortem examination of the marrow of the sternum, ribs, spine and pelvis
infiltration as well as myeloshowed myeloblastic fibrosis. Sections of the humerus, femur and tibia fatty marrow with foci of showed a predominantly in addition to myeloid and erythroid development nests of myeloblasts and areas of fibrosis. Minimal evidence of myeloid metaplasia was present in the liver. The successful treatment of blast crisis in CGL is unusual. The presence of myelofibrosis would seem to raise even further complications in treatment, although as seen in this instance, the fibrotic process may be focal and areas of viable, hemopoietic marrow remain. Treatment with vincristine and prednisone rapidly decreased the number of blasts in the peripheral blood of our patient although, despite this seemingly favorable response, remission did not occur. Survival in CGL averages three to four years from the time of diagnosis [l]. Our patient lived over 13 years following the inception of therapy and for most of that time had a virtually complete remission. Following his initial treatment, he never again demonstrated splenomegaly or thrombocytosis, and leukocyte counts and hemoglobin levels remained normal while he was receiving small doses of busulfan. Hepatosplenomegaly, leukocytosis with immature cells in the blood, thrombocytosis, marrow hyperplasia, the presence of a Philadelphia chromosome and a low leukocyte alkaline phosphatase score leave no doubt that he had CGL. The treatment he received was in no way unusual except for the initial use of 6-mercaptopurine which failed to induce a remission. At no time during his observation did he have peripheral cytopenias or marrow hypocellularity suggestive
July 1973
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CHRONIC GRANULOCYTIC LEUKEMIA-STEINBERG,
DREILING
of drug-induced aplasia. Remission in CGL has been reported following busulfan-induced marrow aplasia [ 111. Viral infection has been associated with prolonged disease-free intervals in patients with lymphoma [12] and monoclonal gammop,athies [13]. Unfortunately, it was impossible to document any such incident in our patient. Unidentified factors in host response to neoplasia
must play an important role in the prolonged viva1 of patients with CGL.
sur-
ACKNOWLEDGMENT
Thanks are due Arthur Starr, M.D. and George Smith, M.D. for their interpretation of the biopsy material and autopsy findings.
REFERENCES 1.
2.
3. 4.
5.
6.
7.
98
Medical Research Council’s Working Party for Therapeutic Trials in Leukaemia: Chronic granulocytic leukaemia: comparison of radiotherapy and busulfan therapy. Brit Med J 1: 201, 1968. Theologides A: Unfavorable signs in patients with chronic myelocytic leukemia. Ann Intern Med 76: 95, 1972. Scott RB: Leukaemia. Lancet 1: 1099, 1957. Dosik H, Rosner F, Sawitsky A: Acquired lipidosis: Gaucher-like cells and “blue cells” in chronic granulocytic leukemia. Seminars Hemat 9: 309, 1972. Kattlove HE, Williams JC, Gaynor E, Spivack M, Bradley RM. Brady RO: Gaucher cells in chronic myeloid leukemia: an acquired abnormality. Blood 33: 379, 1969. Silverstein MN, Ellefson RD. Ahearn EJ: The syndrome of the sea-blue histiocyte. New Eng J Med 282: 1, 1970. Silverstein MN, Ellefson RD: The syndrome of the sea-
July 1973
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8.
9. 10. 11.
12. 13.
blue histiocyte. Seminars Hemat 9: 299, 1972. Rywlin AM, Hernandez JA. Chastain DE, Pardo V: Ceroid histiocytosis of spleen and bone marrow in idiopathic thrombocytopenic purpura (ITP): a contribution to the understanding of the sea-blue histiocyte. Blood 37: 587, 1971. Kattlove HE, Gaynor E, Spivack M, Gottfried EL: Seablue indigestion. New Eng J Med 282: 630, 1970. Gralnick HR. Harbor J. Vogel C: Myelofibrosis in chronic granulocytic leukemia. Blood 37: 152. 1971. Finney R, McDonald GA, Baikie AG, Douglas AS: Chronic granulocytic leukaemia with Phl negative cells in bone marrow and a 10 year remission after busulphan hypoplasia. Brit J Haemat 23: 283, 1972. Weintraub LR: Lymphosarcoma: remission associated with viral hepatitis. JAMA 410: 5091, 1969. Wolf RE, Riedel LO, Levin WC, Ritzmann SE: Remission of macroglobulinemia coincident with hepatitis. Arch Intern Med (Chicago) 130: 392, 1972.
MARTIN BERNARD Jackson.
H. STEINBERG.
M.D.
J. DREILING.
M.D.
Mississippi
Most patients with chronic granulocytic leukemia (CGL) survive from three to four years after diagnosis. We describe a patient with CGL who remained well for almost 13 years after the initiation of treatment. Shortly before death, when he was hematologically stable, the skin, subcutaneous tissue and muscle became infiltrated with leukemic cells. Many sea-blue histiocytes were found in his bone marrow. During the terminal phase of his disease, fever, basophilia, blast transformation, elevated leukocyte alkaline phosphatase activity and myelofibrosis were all present. The, average duration of life in chronic granulocytic leukemia (CGL) is reported to be three to four years after the initiation of therapy [l]. An accurate estimation of survival in individual cases is difficult to make early in the course of the disease, but as the disease progresses from an indolent, treatable stage to an aggressive accelerated phase, signs appear which allow an accurate prognosis to be made. These have been recently reviewed by Theologides [2] and include fever, cutaneous lesions, basophilia, elevated leukocyte alkaline phosphatase activity and myelofibrosis. We describe a patient with CGL and an unusually long survival who preterminally manifested almost all the known unfavorable prognostic signs. In addition he had extensive muscle infiltration, a previously unreported complication of CGL, and sea-blue histiocytosis of the bone marrow. At the time these abnormalities occurred, there was no evidence in either the blood or marrow of transformation of the disease to a more aggressive stage. CASE
From the Jackson Veterans Administration Center and the University of Mississippi School of Medicine, Jackson, Mississippi. Requests for reprints should be addressed to Dr. Martin H. Steinberg, Hematology Research, Jackson Veterans Administration Center, Jackson, Mississippi 39216. Manuscript accepted February 5. 1973.
REPORT
A 35 year old black man (R.C.L.), initially sought medical attention in April 1959 because of a two month history of weakness, fever, night sweats and weight loss. Physical examination revealed mild hepatomegaly and moderate splenomegaly. The leukocyte count was 120,000/mm3, with polymorphonuclear cells predominating but all cells of the myeloid series present. A bone marrow aspirate showed myeloid hyperplasia with orderly maturation. The patient was given a four week course of 6-mercaptopurine (6-MP) therapy, 200 mg
July 1973
The American Journal of Medicine
Volume 55
93
CHRONIC
GRANULOCYTIC
LEUKEMIA-STEINBERG.
DREILING
daily: the leukocyte count fell to 12,000/mm3 and all symptoms remitted. He was discharged from the hospital on no therapy. He was first seen at the Jackson VA Hospital in June 1959 with a three day history of chest pain, hemoptysis and dyspnea. Hepatosplenomegaly was again noted. Laboratory and x-ray studies were consistent with a diagnosis of pulmonary infarction. His leukocyte count was 132,000/mm3, platelet count 1.2 million/ mm3, hemoglobin concentration 10 g/l00 ml. His symptoms abated with supportive therapy, and another four week course of 6-MP therapy was instituted. The leukocyte count fell to 9,000/mm3, but there was little change in hemoglobin concentration and platelet count. In September 1959 he was admitted for elective removal of a fibroma of the tongue, a procedure which was complicated by development of an oral-antral fistula which responded to appropriate antibiotic therapy and ultimately closed. Because of a persistently elevated leukocyte count, busulfan therapy was started, 6 mg daily. When discharged in November 1959, the leukocytes numbered 12,000/mm3 with a normal differential count, the hemoglobin concentration was 13 g/l00 ml, and the platelet count was 800,000/mm3. The spleen and liver were no longer palpable. The patient was then followed in the outpatient clinic at frequent intervals for the ensuing 12 years, remaining normal hematologically on doses of busulfan varying from 2 to 6 mg daily. The spleen and liver remained normal in size and he was symptom-free. He was hospitalized in March 1971 for evaluation of persistent epigastric pain. The findings on physical examination were normal. An x-ray series of the upper gastrointestinal tract and gastroscopy showed mild gastritis. The leukocyte count was 3,500/mm3, hemoglobin concentration 14.4 g/l00 ml and platelet count 300,000/mm3. A bone marrow aspirate revealed marked myeloid hyperplasia and rare “blue” histiocytes. The leukocyte alkaline phosphatase score was 3 (normal 15 to 100). A Ph’ chromosome was present in 6 of 9 marrow metaphases. The dose of busulfan was reduced, and the patient was discharged with a leukocyte count of 9,000/mm3. In December 1971 he was hospitalized for control of symptomatic diabetes mellitus. which responded satisfactorily to diet and oral hypoglycemic agents. Hematologic values on this admission were normal, and busulfan therapy was continued. In February 1972 he was readmitted for evaluation of a painless, rapidly enlarging mass located at the inferior aspect of the left sternocleidomastoid muscle. This measured 6 by 6 cm, was stoney hard and nontender. In addition, there was diffuse brawny induration of the skin and subcutaneous tissues of the left upper thoracic wall. The spleen and liver were not palpable. The leukocyte count was 1 2,000/mm3
with
but occasional
predominantly
metamyelocytes,
mature
granulocytes,
myelocytes
and
pro-
The hemoglobin concentration was 12 g/100 ml and the platelet count 230,000/mm3. Of particular note was a significant change in red blood cell morphology which showed myelocytes
94
were
July 1973
present.
The American Journal of Medicine
Volume 55
marked anisocytosis and poikilocytosis. 15 to 20 nucleated red cells/100 white cells. basophilic stippling and many teardrop cells. A bone marrow aspirate showed marked granulocytic hyperplasia, and many histiocytes which stained a sea-blue color with WrightGiemsa preparation were observed. On further study these cells were negative for hemosiderin, had a negative Feulgen reaction, stained positively with periodic acid-Schiff and Sudan 6 black and showed autofluorescence. Biopsy of the neck mass revealed leukemic infiltration of muscle and subcutaneous tissues. Because of increasing dyspnea, thought to be a result of tracheal compression and chest wall fixation due to the leukemic infiltrate, a tumor dose of 2,000 R was delivered to the affected sites using a linear accelerator. There was a decrease in the size of the mass and chest wall infiltrate and the symptoms subsided. The patient was discharged on a regimen of busulfan with little change in his blood counts from those on admission. He remained well for a short period of time but then experienced increasing tightness and nodularity of the anterior chest wall. He was readmitted in May 1972 for radiotherapy to additional areas of infiltration which involved almost the entire upper anterior chest wall and both shoulders. He again received a tumor dose of 2,000 R this time using a 110 KV machine. Upon completion of his treatment the hemoglobin concentration was 10 g/l00 ml and the leukocyte count was 2,900/ mm3. Busulfan therapy was withheld. The tissue infiltration again regressed and he did well until June 1972 when he was hospitalized with fever, night sweats. anorexia and chest wall pain. On examination his temperature was 104”F, the anterior thorax was hard, indurated and for the first time, tender; the spleen and liver were not palpable. The hemoglobin concentration was 10 g/100 ml; the leukocyte count was 12,000/mm3 with 24 per cent myeloblasts, 23 per cent basophils and 6 per cent eosinophils; platelets numbered 320,000/mm3, and 20 nucleated red blood cells/l00 leukocytes were seen. The leukocyte alkaline phosphatase score was 160. The blood glucose was 370 mg/lOO ml, blood urea nitrogen 20 mg/lOO ml, uric acid 4.9 mg/lOO ml, total protein 5.9 g/100 ml, albumin 2.0 g/l00 ml, calcium 7.6 mg/lOO ml, serum glutamic oxaloacetic transaminase 72 units, lactic dehydrogenase 425 units and bilirubin 0.9 mg/lOO ml. Marrow aspiration at three different sites in the sternum and iliac crest was unproductive of spicules, and a needle biopsy specimen showed the marrow to be replaced by dense fibrous tissue. A chest roentgenogram was normal, and cultures of the urine and pharynx were negative, however Herellea vaginacolor was grown from several blood cultures. Gentamicin therapy was instituted and the patient’s temperature fell to normal and his symptoms diminished. Blast crisis was suspected and treatment was begun with vincristine, 4 mg weekly, and prednicount fell to sone, 100 mg daily. The leukocyte with 2 per cent myeloblasts and 2 per 2,100/mm3 cent basophils, and there was a coincident decrease in the nodularity and infiltration of the chest wall. The
CHRONIC
last weeks of the patient’s life were characterized by recurrent fevers for which no infectious cause could be documented despite repeated bacterial and fungal cultures of his sputum, blood and urine; progressive anemia and thrombocytopenia, requiring red cell and platelet transfusions; increasing lethargy and an ill defined pulmonary infiltrate. Treatment with a variety of antimicrobial agents was ineffective. He continued to receive vincristine and only occasional blast cells were noted in his blood. He died in August 1972. At autopsy the skin over the anterior chest and shoulders showed atrophy, hyperpigmentation and nodularity. There was myeloblastic infiltration of skin and muscle as well as hyalinized fibrous tissue and proliferative endarteritis. The lungs contained areas of edema and pneumonitis. The esophagus had many mucosal erosions which contained mycelial fragments consistent with Candida. Areas of hemorrhage, necrosis and ulceration were scattered throughout the length of the gastrointestinal tract, and a severe pseudomembranous colitis was present. The liver weighed 1,800 g and was normal. The spleen weighed 160 g. There were areas of myeloblastic infiltration but only minimal evidence of extramedullary hematopoiesis. Several lymph nodes showed extensive destruction by infiltrating myeloblasts, however, this was not found in all nodes examined. Bone marrow from the sternum, ribs, spine, pelvis, humerus, femur and tibia was examined. The striking feature of the “central” marrow was the marked variation in morphology from site to site. There were areas in which the marrow was replaced by myeloblasts, others in which there was dense myelofibrosis as well as scattered foci of normal appearing hematopoiesis. Marrow of the long bones showed foci of hematopoiesis, myeloblastic in-
GRANULOCYTIC
LEUKEMIA-STEINBERG,
DREILING
accelerated phase. There were no additional areas of extramedullary extension and the spleen did not become enlarged. The response of the lesions to radiotherapy was good, with marked regression and alleviation of symptoms; however, recurrence soon occured both within and outside the treatment ports. Additional radiation as well as vincristine therapy resulted in further regression, but lesions continued to recur in areas previously treated and new infiltrates developed in untreated sites. Careful examination of the radiated fields and surrounding areas at autopsy showed persistent infiltration with myeloblasts as well as the changes of prior radiotherapy. The bone marrow contained many sea-blue staining histiocytes (Figure 3) at the time the soft tissue infiltrates appeared. These cells were not present in skin, subcutaneous tissue or muscle. Sea-blue histiocytes and cells identical to those seen in Gaucher’s disease have been found both together and separately in the marrow of patients with CGL [4]. Unlike hereditary Gaucher’s disease, the activity of glucocerbrosidase in the leu-
filtration and fibrosis. COMMENTS Following 13 years of benign CGL, a three month period saw the development of extramedullary spread of disease, sea-blue histiocytosis of the marrow, basophilia, elevated leukocyte alkaline phosphatase score, myelofibrosis and blast transformation, which culminated in the death of the patient. The infiltrative process in the skin, subcutaneous tissues and muscle of the neck and anterior chest wall (Figure 1) developed at a time the blood and bone marrow appeared to be free of blast transformation. A biopsy specimen of the involved tissue revealed a diffuse leukemic infiltrate, especially marked in muscle, which showed wide separation of fibers by infiltrating cells (Figure 2). Although skin lesions have been reported in CGL [3], we have been unable to find previous reports of muscle infiltration in this disease. Cutaneous involvement in CGL is generally nodular in nature and associated with a very short survival after its appearance [3]. Of note in our patient is the onset of this diffuse soft tissue infiltration prior to overt evidence of the disease entering an
Figure
1.
Appearance of skin at the time infiltrates thickening, loss noticed. There is induration. mobility and an early peau d’orange texture. The biopsy site (arrow) is well healed. were first of normal
July 1973
The American Journal of Medicine
Volume 55
95
CHRONIC
GRANULOCYTIC
LEUKEMIA-STEINBERG.
DREILING
.
“.
I
Figure
I
*
kocytes
of patients
with
CGL and Gaucher
cells
is
increased [5]. It has been postulated that Gaucher cells form in CGL as a result of excessive glucocerebroside production due to increased granulocyte turnover. Despite the induction of greater than normal amounts of enzyme activity, an inability to metabolize the excessive glucocerebroside produced results, and typical Gaucher storage cells are formed [5]. Gaucher cells were not seen in our patient, however, histiocytes with a granular, sea-blue staining cytoplasm were present in the marrow. Silverstein and co-workers [6] introduced the designation “syndrome of the sea-blue histiocyte” for a disease characterized by splenomegaly, mild thrombocytopenic purpura
.
2
2. Muscle biopsy specimen from left neck area showing separation of muscle fibers by a cellular infiltrate which is composed of cells of the granulocytic series (arrows). Hematoxylin and eosin stain: original magnification X 200, reduced by 34 per cent.
and histiocytes in the spleen and bone marrow which contained bright blue granules when stained with Romanowsky dyes. Although they, and others, believe this syndrome is a nosologic entity, the presence of very similar cells in the marrow have been reported in a variety of diseases [7]. The lipid material in these histiocytes is believed to be ceroid, a pigment formed upon the liberation of lipid during cell death [8]. Following the phagocytosis of effete cells by macrophages, lipid is oxidized and polymerized yielding ceroid pigment. Increased leukocyte turnover in CGL has been calculated to result in the formation of excessive amounts of lipid. If the essential enzyme systems for degradation of specific lipids are unable to
Figure 3. A large sea-blue histiocyte occupies the center of this field and is surrounded by cells of the myeloid and erythroid series. The cytoplasm of this cell stains a vivid blue and contains scattered dark blue granules (arrow) Wright-Giemsa stain: original magnification X 1.000. reduced by 34 per cent.
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Figure 4. Needle biopsy specimen of the posterior iliac crest marrow showing a marked increase in agyrophilic reticulum fibers, Wilder’s reticulum stain; original magnification X 200, reduced by 34 per cent. Hematoxylin and eosin stain of this section revealed dense myelofibrosis.
meet the demand of increased substrate concentration, the accumulation of phagocytized lipid or necrotic granulocytes could lead to the development of the “sea-blue” histiocyte, in a fashion analogous to the formation of Gaucher cells in CGL. This possibility has been suggested by Katflove et al. [9]. The available evidence favors an idiopathic or familial sea-blue histiocyte syndrome, the defect being primarily one of a lack of appropriate enzyme activity with subsequent inability to metabolize normal amounts of lipid formed [7], as well as an acquired type seen in association with a variety of diseases and characterized by excessive lipid production [7]. During the latter phase of the disease in our patient, nucleated red blood cells and teardrop poikilocytes became common in the peripheral blood, a finding said to be unusual when myelofibrosis complicates CGL [lo]. Over the course of three months the marrow architecture changed from the intensely cellular organ typical of CGL to the fibrotic structure characterizing myelofibrosis (Figure 4). Variable degrees of fibrosis of the bone marrow are found in CGL, frequently at a very early stage of the disease [lo]. Dense myelofibrosis, however, is an event which heralds the terminal stages of this disorder [2,10]. Of interest in this respect is the possible relationship of prolonged treatment with busulfan, a drug known to produce lung fibrosis, and the development of myelofibrosis. We were unable to aspirate marrow from the sternum, anterior or posterior iliac crests and a single needle biopsy specimen showed dense fibrosis. Postmortem examination of the marrow of the sternum, ribs, spine and pelvis
infiltration as well as myeloshowed myeloblastic fibrosis. Sections of the humerus, femur and tibia fatty marrow with foci of showed a predominantly in addition to myeloid and erythroid development nests of myeloblasts and areas of fibrosis. Minimal evidence of myeloid metaplasia was present in the liver. The successful treatment of blast crisis in CGL is unusual. The presence of myelofibrosis would seem to raise even further complications in treatment, although as seen in this instance, the fibrotic process may be focal and areas of viable, hemopoietic marrow remain. Treatment with vincristine and prednisone rapidly decreased the number of blasts in the peripheral blood of our patient although, despite this seemingly favorable response, remission did not occur. Survival in CGL averages three to four years from the time of diagnosis [l]. Our patient lived over 13 years following the inception of therapy and for most of that time had a virtually complete remission. Following his initial treatment, he never again demonstrated splenomegaly or thrombocytosis, and leukocyte counts and hemoglobin levels remained normal while he was receiving small doses of busulfan. Hepatosplenomegaly, leukocytosis with immature cells in the blood, thrombocytosis, marrow hyperplasia, the presence of a Philadelphia chromosome and a low leukocyte alkaline phosphatase score leave no doubt that he had CGL. The treatment he received was in no way unusual except for the initial use of 6-mercaptopurine which failed to induce a remission. At no time during his observation did he have peripheral cytopenias or marrow hypocellularity suggestive
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of drug-induced aplasia. Remission in CGL has been reported following busulfan-induced marrow aplasia [ 111. Viral infection has been associated with prolonged disease-free intervals in patients with lymphoma [12] and monoclonal gammop,athies [13]. Unfortunately, it was impossible to document any such incident in our patient. Unidentified factors in host response to neoplasia
must play an important role in the prolonged viva1 of patients with CGL.
sur-
ACKNOWLEDGMENT
Thanks are due Arthur Starr, M.D. and George Smith, M.D. for their interpretation of the biopsy material and autopsy findings.
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Medical Research Council’s Working Party for Therapeutic Trials in Leukaemia: Chronic granulocytic leukaemia: comparison of radiotherapy and busulfan therapy. Brit Med J 1: 201, 1968. Theologides A: Unfavorable signs in patients with chronic myelocytic leukemia. Ann Intern Med 76: 95, 1972. Scott RB: Leukaemia. Lancet 1: 1099, 1957. Dosik H, Rosner F, Sawitsky A: Acquired lipidosis: Gaucher-like cells and “blue cells” in chronic granulocytic leukemia. Seminars Hemat 9: 309, 1972. Kattlove HE, Williams JC, Gaynor E, Spivack M, Bradley RM. Brady RO: Gaucher cells in chronic myeloid leukemia: an acquired abnormality. Blood 33: 379, 1969. Silverstein MN, Ellefson RD. Ahearn EJ: The syndrome of the sea-blue histiocyte. New Eng J Med 282: 1, 1970. Silverstein MN, Ellefson RD: The syndrome of the sea-
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blue histiocyte. Seminars Hemat 9: 299, 1972. Rywlin AM, Hernandez JA. Chastain DE, Pardo V: Ceroid histiocytosis of spleen and bone marrow in idiopathic thrombocytopenic purpura (ITP): a contribution to the understanding of the sea-blue histiocyte. Blood 37: 587, 1971. Kattlove HE, Gaynor E, Spivack M, Gottfried EL: Seablue indigestion. New Eng J Med 282: 630, 1970. Gralnick HR. Harbor J. Vogel C: Myelofibrosis in chronic granulocytic leukemia. Blood 37: 152. 1971. Finney R, McDonald GA, Baikie AG, Douglas AS: Chronic granulocytic leukaemia with Phl negative cells in bone marrow and a 10 year remission after busulphan hypoplasia. Brit J Haemat 23: 283, 1972. Weintraub LR: Lymphosarcoma: remission associated with viral hepatitis. JAMA 410: 5091, 1969. Wolf RE, Riedel LO, Levin WC, Ritzmann SE: Remission of macroglobulinemia coincident with hepatitis. Arch Intern Med (Chicago) 130: 392, 1972.