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Granulocytic Sarcoma With an Indolent Course and Destructive Skeletal Disease Tumor Characterization With Immunologic Markers, Electron Microscopy, Cytochemistry, and Cytogenetic Studies PAMELA WELCH, MD, CARL0 GROSSI, MD, PHD, ANDREW CARROLL, PHD, WILLIAM DUNHAM, MD, STUART ROYAL, MD, EDWARD WILSON, MD, PHD, AND WILLIAM CRIST, MD A 6-year-old girl with a granulocytic sarcoma (GS) of the left maxillary sinus that followed a uniquely indolent clinical course (3.5 years) and was associated with highly destructive skeletal disease is described. The tumor cells demonstrated an unusual hematogenous “homing” preference for bone and soft tissue sites. Tumor cell characterization with immunologic markers, electron microscopy, cytochemistry, and cytogenetic studies revealed that the tumor cells expressed OKMl and MMA (Leu-Ml), but not HLA- DR, B-, or T-cell markers. The cells were nonspecific esterase- and myeloperoxidase-positive, had ultra- structural features of promyelocytes, and were clonal. The laboratory characterization of the tumor cells in this clinically unusual case of GS illustrates the utility of monoclonal antibodies, applied in conjunction with cytochemistry and ultrastructural analysis, in establishing the specific diagnosis, cell lineage, and maturational stage of this tumor. Cancer 57:lOOS-1010, 1986. RANULOCYTIC SARCOMA (GS), or chloroma, is a rare G tumor composed of early myeloid precursor cells. It was first described by Burns in 18 1 1 ,’ and was subse- quently termed “chloroma” because of the green color sometimes imparted by cellular myeloperoxidase. Dock was the first to note the association of GS with acute leu- kemia,’ and this tumor is now regarded as an ominous harbinger of acute myelocytic leukemia (AML), or the onset of blast crisis in chronic myelogenous leu- kemia (CML). The lack of differentiation of the tumor cells in GS has often resulted in problems with diagnosis, since identifi- cation by routine histologic methods is dependent on some degree of cellular differentiation. Histochemical tech- niques and electron microscopy (EM) have been helpful in selected cases, but erroneous diagnoses have occurred frequently. Recently, monoclonal antibodies directed against normal myeloid surface antigens that are sequen- From the Departments of Pediatrics, Pathology, and Surgery, the Comprehensive Cancer Center of The University of Alabama in Bir- mingham, and The Children’s Hospital of Alabama, Birmingham, Al- abama. Supported in part by the following DHEW grants from the National Cancer Institute, DHEW. CA 25408 and CA 13148. Address for reprints: Pamela Welch, MD, The Children’s Hospital of Alabama, 1600 7th Avenue South, Birmingham, AL 35233. Accepted for publication June 21, 1985. tially expressed during maturation have provided a new diagnostic tool that provides increased diagnostic speci- ficity through improved definition of the lineage and stage of maturation of the malignant cells comprising GS. We recently studied a child with an unusually indolent case of GS. The 3-year course was characterized by wide- spread progression of highly destructive skeletal lesions and soft tissue involvement, without the development of acute leukemia. Histopathology, cytochemistry, cytoge- netic studies, electron microscopy, and studies using monoclonal antibodies to myeloid cell surface antigens were applied to determine tumor cell lineage, maturational stage, and extent of tumor spread. These studies dem- onstrated that the tumor cells were promyelocytes that exhibited a unique “homing” pattern to soft tissue and bone. Case Report A black girl, aged 3 years and 2 months, presented in January 198 1 with a nontender left maxillary mass. She was asymptom- atic, and results of the physical examination were otherwise un- remarkable. Computerized axial tomography (CAT) of the si- nuses and plain radiographs revealed a soft tissue mass in the left maxillary sinus, with destruction of the anterior wall and contiguous spread to the base of the skull (Fig. 1A). Skeletal radiographs, chest x-ray and abdominal and pelvic ultrasonog- raphy all showed normal results. Laboratory studies included a 1005

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Granulocytic Sarcoma With an Indolent Course and Destructive Skeletal Disease

Tumor Characterization With Immunologic Markers, Electron Microscopy, Cytochemistry, and Cytogenetic Studies

PAMELA WELCH, MD, CARL0 GROSSI, MD, PHD, ANDREW CARROLL, PHD, WILLIAM DUNHAM, MD, STUART ROYAL, MD, EDWARD WILSON, MD, PHD, AND WILLIAM CRIST, MD

A 6-year-old girl with a granulocytic sarcoma (GS) of the left maxillary sinus that followed a uniquely indolent clinical course (3.5 years) and was associated with highly destructive skeletal disease is described. The tumor cells demonstrated an unusual hematogenous “homing” preference for bone and soft tissue sites. Tumor cell characterization with immunologic markers, electron microscopy, cytochemistry, and cytogenetic studies revealed that the tumor cells expressed OKMl and MMA (Leu-Ml), but not HLA- DR, B-, or T-cell markers. The cells were nonspecific esterase- and myeloperoxidase-positive, had ultra- structural features of promyelocytes, and were clonal. The laboratory characterization of the tumor cells in this clinically unusual case of GS illustrates the utility of monoclonal antibodies, applied in conjunction with cytochemistry and ultrastructural analysis, in establishing the specific diagnosis, cell lineage, and maturational stage of this tumor.

Cancer 57:lOOS-1010, 1986.

RANULOCYTIC SARCOMA (GS), or chloroma, is a rare G tumor composed of early myeloid precursor cells. It was first described by Burns in 18 1 1 ,’ and was subse- quently termed “chloroma” because of the green color sometimes imparted by cellular myeloperoxidase. Dock was the first to note the association of GS with acute leu- kemia,’ and this tumor is now regarded as an ominous harbinger of acute myelocytic leukemia (AML), or the onset of blast crisis in chronic myelogenous leu- kemia (CML).

The lack of differentiation of the tumor cells in GS has often resulted in problems with diagnosis, since identifi- cation by routine histologic methods is dependent on some degree of cellular differentiation. Histochemical tech- niques and electron microscopy (EM) have been helpful in selected cases, but erroneous diagnoses have occurred frequently. Recently, monoclonal antibodies directed against normal myeloid surface antigens that are sequen-

From the Departments of Pediatrics, Pathology, and Surgery, the Comprehensive Cancer Center of The University of Alabama in Bir- mingham, and The Children’s Hospital of Alabama, Birmingham, Al- abama.

Supported in part by the following DHEW grants from the National Cancer Institute, DHEW. CA 25408 and CA 13148.

Address for reprints: Pamela Welch, MD, The Children’s Hospital of Alabama, 1600 7th Avenue South, Birmingham, AL 35233.

Accepted for publication June 21, 1985.

tially expressed during maturation have provided a new diagnostic tool that provides increased diagnostic speci- ficity through improved definition of the lineage and stage of maturation of the malignant cells comprising GS.

We recently studied a child with an unusually indolent case of GS. The 3-year course was characterized by wide- spread progression of highly destructive skeletal lesions and soft tissue involvement, without the development of acute leukemia. Histopathology, cytochemistry, cytoge- netic studies, electron microscopy, and studies using monoclonal antibodies to myeloid cell surface antigens were applied to determine tumor cell lineage, maturational stage, and extent of tumor spread. These studies dem- onstrated that the tumor cells were promyelocytes that exhibited a unique “homing” pattern to soft tissue and bone.

Case Report

A black girl, aged 3 years and 2 months, presented in January 198 1 with a nontender left maxillary mass. She was asymptom- atic, and results of the physical examination were otherwise un- remarkable. Computerized axial tomography (CAT) of the si- nuses and plain radiographs revealed a soft tissue mass in the left maxillary sinus, with destruction of the anterior wall and contiguous spread to the base of the skull (Fig. 1A). Skeletal radiographs, chest x-ray and abdominal and pelvic ultrasonog- raphy all showed normal results. Laboratory studies included a

1005

1006 CANCER March 1 1986 VOl. 57

FIGS. 1 A AND I B. (A. left) Axial CT scan of the mandible reveals a lytic expansile lesion in the left maxillary sinus. (B, right) Anteropos- tenor radiograph of the right humerus reveals a lytic proximal diaphyseal lesion with unusual periosteal reaction extending into a soft tissue mass medially.

hemoglobin level of 1 1.5 g/dl, a mean cell volume (MCV) of 66 fl, a leukocyte count of 15,300/mm3 (52% eosinophils, 35% lym- phocytes, 6% polymorphonuclear leukocytes [polys], 6% mono- cytes), and a platelet count of 166,000/mm3. Examinations for ova, cysts, and parasites in the stools were negative, and Toxocuru cunzs titers were not elevated. Bone marrow aspirate was ab- normal in that 40% of the marrow nucleated cells were eosin- ophils. The spinal fluid was normal. Cytogenetic studies on bone marrow aspirates were performed (see Results section). A biopsy of the maxillary mass, complicated for interpretation by crush artifact, demonstrated a malignant neoplasm interpreted by var- ious consultants as poorly differentiated sarcoma, rhabdomyo- sarcoma, or lymphoma. The mother refused treatment for the child, and the child was seen intermittently by her local physician, apparently without complaint.

Routine re-evaluation in June 1983 disclosed a 1.5-cm right mandibular mass and mild hepatosplenomegaly. CAT scan showed bilateral maxillary sinus and mandibular involvement, with extension into contiguous soft tissue. Skeletal radiographs revealed multiple foci of bony expansion and coarsened trabec- ular pattern, involving both femurs, radii, and ulnae bilaterally, ribs bilaterally, left ileum, and the right proximal humerus (Fig. 1 €3). Abdominal ultrasound findings were unremarkable. Ex- amination of the peripheral blood smear showed persistence of mature eosinophilia. A biopsy specimen of the right humerus in July 1983 was interpreted as GS.

TABLE 1. Cytogenetic Studies

Date

Tissue 1/81 8/83 10/83 2/84 3/84

Blood Not done 47,XX,+C 47,XX,+8 Normal Not done Bone Normal Normal Normal Normal 47,XX,+8

Marrow

In August 1983, the patient returned with difficulty in walking, markedly decreased mobility of the right shoulder, and a vague history of intermittent constipation and urinary incontinence. A 6 X 7 X 18-cm circumferential anterior right humeral mass, a 7 X 8-cm sacral mass, and mild hepatosplenomegaly were noted. She had generalized weakness, but no evidence of spinal cord compression. Progressive, marked skeletal destruction was noted.

Laboratory studies included a hemoglobin level of 1 1.4 g/dl, a leukocyte count of 28,000/mm3 (34% eosinophils, 30% gran- ulocytes, 20% lymphocytes, 8% monocytes, 2% atypical lym- phocytes), a platelet count of 325,000/mm3, serum BI2 level of 6306 pg/ml, and a leukocyte alkaline phosphatase (LAP) level of 43. A bone marrow aspirate revealed myeloid hyperplasia with a M:E ratio of 16:l (30% eosinophils, 34% polymorpho- nuclear leukocytes, 9% metamyelocytes, 6% myelocytes, I 'Yo

promyelocytes, 13% lymphocytes, 4% monocytes, and 3% ery- throid cells). The cerebrospinal fluid findings were normal. The methods and results of the morphologic, cytochemical, ultra- structural, and cytogenetic methods used to study the tumor cells obtained from a biopsy specimen of the sacral mass are summarized in the Materials and Methods and Results sections that follow.

In August 1983, the patient was treated with combination chemotherapy, including daunomycin, cytosine arabinoside, 6- thioguanine, and 5-azacytidine. The humeral and sacral masses diminished within 5 days from the onset of chemotherapy, but recurred before each monthly therapy course. Skeletal re-eval- uation in October 1983 demonstrated healing and reparative changes, with no new areas of destruction. Bone marrow had normal cellularity, with a M:E ratio of 4.4: 1, with 6% eosinophils. Cytogenetic studies were performed on peripheral blood and marrow cells (Table 1). Radiation therapy (2700 rad) was given to the right shoulder because of incomplete response to che- motherapy.

On re-evaluation in February 1984, she was asymptomatic, with minimal swelling of the right humerus and partial alopecia. Skeletal radiograph results demonstrated healing of the majority of skeletal lesions, but new lesions in the right proximal tibia and skull. The patient's disease continued to progress despite chemotherapy, and she died in July 1984.

Materials and Methods Zmmunologic Marker Studies

A cell suspension was prepared for immunologic marker studies from the sacral biopsy specimen in August 1983. Pre-B- and B-cells were identified by immunoflu- orescence staining for surface and cytoplasmic immu- noglobulin components on the same cell. Monoclonal antibodies with specificities, as noted, were used to define the myeloid lineage of the tumor cells. OKM 1 is directed against an antigenic determinant on monocytes, granu- locytes, and AML c e k 3 MMA (Leu-M1) recognizes a differentiation antigen on monocytes, granulocytes, ma- ture and precursor myelomonocytic cells, and mitogen- activated T-cells! Anti-Ia detects antigenic determinants of the HLA-DR system, which are found on precursor

No. 5 CHARACTERIZATION OF GRANULOCYTIC SARCOMA - We/ch et a/.

FIG. 2. Photomicrograph of tissue from the sacral mass showing marked pleomorphism and mitotic figure (arrow) (H & E, X400).

cells of the myelomonocytic, B-lymphoid, erythroid, and megakaryocytic lineage. These Ia-like antigens disappear during differentiation, becoming undetectable during transition to the promyelocyte, plasma cell, mature eryth- rocyte, and platelet, re~pectively.~ T1 1, a monoclonal an- tibody with pan-T-cell reactivity (sheep erythrocyte re- ceptors),6 and anti-B 1, which recognizes a B-cell surface differentiation antigen,' were used to identify T- and B- cells, respectively.

Morphologic Studies

Bone marrow aspirates were taken after informed con- sent was obtained, and were stained with Wright's Giemsa stain, periodic acid-Schiff s reagent (PAS), Sudan black, and peroxidase by standard techniques.

Tissues from the masses involving the humerus and sacrum were fixed in 10% buffered formalin or 1.25% glu- taraldehyde, and embedded in paraffin. Sections were stained with hematoxylin and eosin (HE), PAS, and a Leder stain for nonspecific esterase.

Tissue from the humeral biopsy specimen and sacral mass were fixed in 1.25% glutaraldehyde and prepared for ultrastructural study by routine methods. The tissue

1007

was gently homogenized to obtain a cell suspension, which was fixed with 1% glutaraldehyde in cacodylate buffer. After they were rinsed in cacodylate buffer, cells were in- cubated for 45 minutes at 37°C in a substrate containing 2.2' diamino benzidine hydrochloride (Sigma, St. Louis, MO) in 0.05 M tris-maleate buffer, pH 7.6, and H202, for the demonstration of endogenous myeloperoxidase activity.' After incubation, cells were washed with caco- dylate buffer and processed for ultrastructural study.

Cytogenetic Studies

Bone marrow aspirates were cultured in RPMI-1640 supplemented with 10% fetal calf serum for 24 hours at 34"C, then exposed to Colcemid (colchicine) (0.06 g/ml) for 3.5 hours at 4°C. Routine methods were employed for culture harvest, slide preparation, and GTG-banding. In addition, direct chromosome preparations were ex- amined.

Results

immunologic Marker Studies

Immunologic cell marker studies revealed expression of myelomonocytic antigens (OKM 1, MMA) by 70% and

1008 CANCER March 1 1986 Vol. 51

FIG. 3. Electron micrograph of myeloid tumor cells from the sacral mass. Notice the disparity between the nuclear and cytoplasmic maturation. Inset: Eosinophils with prominent nucleoli (X4500).

84%, respectively, of the cells obtained from the sacral mass. Absence of HLA-DR reactivity was noted in 90% of the cells from the tumor mass. Direct immunofluores- cent stains for IgM, IgG, IgA, kappa and lambda light chains, and C1, C3, and C4 components of complement were all negative. Four percent of the cells from the tumor mass were stained with T 1 1 and 6% with Bl .

Morphologic Studies

Bone marrow aspirates revealed a predominance of peroxidase-positive myeloid cells at all stages of matura- tion, with normal erythroid precursors and megakaryo- cytes.

Light microscopic study of tumor tissue from the hu- merus and sacrum revealed pleomorphic cells whose nu- clei varied from round to markedly irregular, with nu- merous infoldings. Many cells had large prominent nu- cleoli. Mitotic figures were numerous. Scattered immature and mature eosinophils were noted (Fig. 2). Cytochemical stains for nonspecific esterase and myeloperoxidase were positive.

Ultrastructural examination of the tumor revealed that most cells were of the myeloid series, with occasional macrophages and lymphoid cells present. Some neutro-

phils displayed nuclear blebs. There was a nuclear-cyto- plasmic disparity within polymorphonuclear leukocytes, characterized by nuclear segmentation in cells containing very few cytoplasmic granules (Fig. 3). Eosinophils with characteristic large granules and Charcot-Leyden crystals were present. Studies of cell suspensions showed that more than 95% of the cells contained peroxidase-positive gran- ules, and that the majority of them were promyelocytes (Fig. 4).

Cytogenetic Studies

Cytogenetic studies of unstimulated cultures of periph- eral blood and bone marrow cells were performed on sev- eral occasions. The results are summarized in Table 1. Insufficient cells were available for chromosomal analysis of cells taken directly from the tumor mass.

Discussion

These studies illustrate the utility of monoclonal anti- bodies directed against myeloid cell surface antigens in determining the histogenesis and stage of maturation of GS. These reagents, in conjunction with cytochemistry and electron microscopic studies, demonstrate that this

No. 5 CHARACTERIZATION OF GRANULOCYTIC SARCOMA Welch et al. 1009

FIG. 4. Electron micrograph of cell suspension from the sacral mass. The majority of the cells display peroxidase- positive granules (X3500).

patient's tumor was composed of promyelocytes. The im- munologic phenotype of the tumor cells (OKM 1+, MMA+, Ia-, peroxidase+) is comparable to that reported for most cases of acute promyelocytic leukemia (APL), French-American-British FAB type M3 in both children and adult^.^^^,'^ HLA-DR negativity, as noted in our pa- tient, is considered characteristic of AML FAB type 3 (APL), since loss of this antigen occurs during differen- tiation of myeloblasts to promyel~cytes.~ The EM studies confirm the APL phenotype. The FAB M3 phenotype is the most unusual one encountered within the myeloid leukemias, at any age. Correlation of surface marker pro- files with classic FAB morphologic features has been demonstrated in the majority of cases of AML, with sim- ilar findings in children and adults? but has not been examined in GS. Cytogenetic studies confirm the clonality of the malignant cells, but do not demonstrate the com- mon translocation ( 15: 17) seen in the majority of cases of APL. l o

Both cytochemistry and electron microscopy proved useful in establishing the diagnosis in our patient. The immaturity of the myeloid precursors in GS has resulted in frequent diagnostic errors. In one series, the initial di- agnosis was correctly made in only 44% of the cases, with lymphoma being the most frequent misdiagnosis." Other series have noted confusion with undifferentiated sarcoma or neoplasm, l 2 Ewing's sarcoma, l 3 eosinophilic granu-

l ~ m a , ' ~ or multiple mye10ma.I~ Cytochemical stains, in- cluding Sudan black B, peroxidase, naphthol AS-D chlo- roacetate esterase, and antilysozyme immunoperoxidase, are often positive, and therefore helpful in establishing the diagnosis of GS. Electron microscopy has confirmed these histochemical findings in some cases with the pres- ence of peroxidase-positive phi bodies and rods, the pre- sumed parent organelles of Auer rods, typical of immature myeloid cells.16

In the majority of patients with GS, AML develops within a year of tumor re~ognition."-'~,~' This patient's 3-year progression of extensive, destructive skeletal lesions without overt marrow involvement is unique. GS most frequently demonstrates periosteal involvement of the skull, paranasal sinuses, orbit, ribs, vertebrae, and ex- tremities; the lesions are typically localized and nonin- vasive."," There are few reports of destructive skeletal disease associated with myeloproliferative disorders, in- cluding AML, CML, and myelofibrosis with myeloid metaplasia. I L*18-20 The few previously reported cases of extensive skeletal disease involved unusual sarcomas comprised of both atypical megakaryocytes and myeloid cells.21'22

It is unclear whether the eosinophilia noted in our pa- tient, and in some others with myeloproliferative diseases, is reactive or intrinsically malignant. GS has been reported in association with the hypereosinophilic syndrome, eo-

1010 CANCER March I 1986 VOl. 57

sinophilic leukemia, or reactive eosinophilia in various reports.”,*2s23 Although Keating has noted an increased duration of remission in adult patients with AML and marrow eosinophilia at diagnosis,24 the prognostic impli- cations of this finding in GS are unknown.

Trisomy 8 is one of the most common findings in de HOVO AML, CML in blast crisis, or eosinophilic leuke- mia,25-27 and defines the clonality of the malignant cell population in this patient. The development of trisomy 8 in the peripheral blood, with normal marrow cytoge- netics, coincided with widespread bone and soft tissue tumor extension. This finding, coupled with the normal bone marrow cytogenetic studies, provided evidence of hematogeneous spread with preferential homing to bone and soft tissues. Only later in the clinical course did the bone marrow become involved (Table 1). The explanation for this unusual tumor cell homing is unknown, but it may reflect unique biologic characteristics specific to the phenotype of this child‘s GS.

The clinical management of patients with GS is gen- erally dictated by the type of underlying malignancy, and thus is often treated as AML. Our patient’s tumor re- sponded partially to such therapy. Her indolent course is in marked contrast to the rapid progression to death ob- served in most patients with GS.

REFERENCES

1. Burns A. Observations on the Surgical Anatomy of the Head and Neck. Edinburgh: Thomas Royce and Co., 181 1.

2. Dock G. Chloroma and its relation to leukemia. Am J Med Sci 1893; 106:152-157.

3. Breard J , Reinherz EL, Kung PC, Goldstein G, Schlossman SF. A monoclonal antibody reactive with human peripheral blood monocytes. J lmmunol 1980; 124:1943-1948.

4. Hanjan SNS, Kearney JF, Cooper MD. A monoclonal antibody (MMA) that identifies a differentiation antigen on human myelomono- cytic cells. Clin Immunol immunopath 1982; 23: 172-188.

5 . Winchester RJ, Ross GD, Jarowski CI, Wang CY, Halper J, Brox- meyer HE. Expression of Ia-like antigen molecules on human granulo- cytes during early phases of differentiation. Proc Nail Acad Sci 1977; 74:

6. Verbi W, Greaves MF, Schneider C ef al. Monoclonal antibodies OKT 1 1 and OKT 1 1 A have pan-T reactivity and block sheep erythrocyte “receptors.” Eur JImmunol 1982; 12:81-86.

7. Nadler LM, Ritz J, Hardy R, Pesando JM, Schlossman SF. A unique cell surface antigen identifying lymphoid malignancies of B cell origin. J Clin Invesf 1981; 67:134-40.

4012-40 16.

8. Graham RC, Karnovsky MJ. The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: Ultrastructural cytochemistry by a new technique. J Histuchem Cyfochem

9. Herrmann F, Komischke B, Odenwald E, Ludwig WD. Use of monoclonal antibodies as a diagnostic tool in human leukemia: Acute myeloid leukemia and acute phase of chronic myeloid leukemia. Blut

10. van der Reijden HJ, van Rhenen DJ, Lansdorp PM ef al. A com- parison of surface marker analysis and FAB classification in acute myeloid leukemia. Blood 1983; 61:443-448.

1 1. Neiman RS, Barcos M, Berard C et al. Granulocytic sarcoma: A clinicopathologic study of 6 1 biopsied cases. Cancer 198 1; 48: 1426- 1437.

12. Comings DE, Fayen AW, Carter P. Myeloblastoma preceding blood and marrow evidence of acute leukemia. Cancer 1965;

13. Miller LP, Steinherz PG, Miller DR. Granulocytic sarcoma of

14. Wiernik PH, Serpick AA. Granulocytic sarcoma (chloroma). Blood

15. Carmichael GP, Lee YT. Granulocytic sarcoma simulating “nonsecretory” multiple myeloma. Hum Pafhol 1977; 8:697-700.

16. McCarty KS, Wortman J, Daly J, Rundles RW, Hanker JS. Chlo- roma (granulocytic sarcoma) without evidence of leukemia: Facilitated light microscopic diagnosis. Blood 1980; 56: 104- 108.

17. Lusher JM. Chloroma as a presenting feature of acute leukemia: A report of two cases in children. Am J Dis Child 1964; 108:62-66.

18. Chabner BA, Haskell CM, Canellos GP. Destructive bone lesions in chronic granulocytic leukemia. Medicine 1969; 48:401-4 10.

19. Rudders RA, Kilcoyne RF. Myeloproliferative disorder with lytic osseous lesions and chromosomal anomalies. Am J Clin Pathol 1974;

20. Longo DL, Whang-Peng J, Jaffe E, Triche TJ, Young RC. My- eloproliferative syndromes: A unique presentation of chronic myeloge- nous leukemia (CML) as a primary tumor of bone. Blood 1978;

2 1. Fayemi AO, Gerber MA, Cohen I, Davis S, Rubin AD. Myeloid sarcoma: Review of the literature and report of a case. Cancer 1973; 32:

22. Raia TJ, Hentz EC, Theros EG. An exercise in radiologic-patho- logic correlation. Radiology 1967; 89:94 1-946.

23. Benvenisti DS, Ultmann JE. Eosinophilic leukemia: Report of five cases and review of literature. Ann Intern Med 1969; 71:73 1-745.

24. Keating MJ. Early identification of potentially cured patients with acute myelogenous leukemia: A recent challenge. In: Bloomfield C1, ed. Adult Leukemias I. The Hague: Martinus Nijhoff, 1982.

25. Rowley JD, Alimena G, Garson OM, Hagemeijer A, Mitelman F, Prigogina EL. Karyotype related to age and type of ANLL. Blood 1981; (Suppl 1) 58513.

26. Rowley JD. Nonrandom chromosomal abnormalities in hema- tologic disorders of man. Proc Natl Acad Sci 1975; 72:152-156.

27. Huang CS, Gomez GA, Kohno Sl, Sokal JE, Sandberg AA. Chro- mosomes and causation of human cancer and leukemia: XXXIV. A case of “Hypereosinophilic Syndrome” with unusual cytogenetic findings in a chloroma, terminating in blastic transformation and CNS leukemia. Cancer 1979; 44: 1284-1289.

1966; 14:29 1-302.

1983; 47:157-163.

18:253-258.

the clavicle. Am JPediatr Hematol Oncol 1982; 4:425-427.

1970; 351361-369.

6 1 :673-679.

52:793-80 I.

253-258.