acute. In these instances, a misdiagnosis of histiocytic lymphoma may occur.17 This report describes an unusual case of granulocytic sarcoma that presented.
GRANULOCYTIC SARCOMA PRECEDING ACUTE LEUKEMIA A Report of Six Cases JOHN
R. KRAUSE,MD
An unusual case of granulocytic sarcoma presenting in a pericardial effusion following trauma and preceding acute myelogenous leukemia (AML) by 8 months is presented. Five additional cases of granulocytic sarcoma preceding leukemia collected by the author are also tabulated. Granulocytic sarcoma in a nonautopsy population of myelogenous leukemic patients was found to be 2.9%. When presenting in an extramedullary site, especially preceding peripheral blood and bone marrow manifestations of leukemia, a misdiagnosis of histiocytic lymphoma may result. In questionable cases, other techniques including the naphthol-ASD-chloroacetate stain, touch imprints, immunoperoxidase stain for lysozyme, and electron microscopy should be utilized. Although only a small series, the most recent cases have shown inductionhemission and survival characteristics of AML patients without granulocytic sarcoma. Cancer 44: 1017- 1021,1979.
G
breath after being struck in the sternum by a softball. He was seen in the emergency room, where a chest x-ray revealed enlargement of the cardiac silhouette. Heart sounds were described as faint over the precordium. He was admitted and an echocardiogram confirmed the diagnosis of pericardial effusion. Laboratory data revealed a hemoglobin 14.8 g/dl, hematocrit 44.5%, WBC 8.7 X 10g/literwith 65% polys, 3% bands, 21% lymphocytes, 8% monocytes, and 1% eosinophils. Platelet count was 290 x 10g/liter. Urinalysis and serum chemistries were within normal limits. Because of the fear of tamponade, a pericardiocentesis was performed, yielding about 200 cc of a slightly red-tinged fluid. The specific gravity of the fluid was 1.011 and the hematocrit 6%. A cell count was 6.2 x 10g/liter and a smear and differential count revealed 63% immature cells, 30% polymorphonuclear cells, and 7% lymphocytes. The immature cells had a moderate nudeadcytoplasmic ratio with blue cytoplasm occasionally containing fine granules. Some of the nuclei were slightly cleaved and nucleoli were faintly visable. Auer rods were seen in some of CASEREPORT the cells (Fig. 1A). These cells stained positively A previously healthy 16-year-old boy com- with the cytochemical stains, Sudan black and plained of pain in the chest and shortness of naphthol-ASD-chloroacetate, and negative with the PAS stain. Four bone marrow aspirations and needle biopsy specimens were examined From the Division of Hernatopathology, Depart- from different sites including the sternum and ment of Pathology, University of Pittsburgh School iliac crests. All showed a normocellular marrow of Medicine, Pittsburgh, Pennsylvania. Address for reprints: John R. Krause, MD, Di- with a normal myeloid erythroid ratio and abrector, Central Hematology, Presbyterian-University sence of immaturity. Repeat blood counts, platelet counts, and white cell differentials were Hospital, Pittsburgh, PA 15213. Accepted for publication August 18, 1978. normal.
(chloroma) is a tumor composed of granulocytic precursors occurring in an extramedullary site." These tumors often develop during the course of, or as a presenting sign of, myelogenous leukemia. On rare occasions, however, the tumor may precede peripheral blood or bone marrow manifestations of acute I n these instances, a misdiagnosis of histiocytic lymphoma may occur.17 This report describes an unusual case of granulocytic sarcoma that presented in a pericardial effusion examined following trauma and which preceded systemic acute myelogenous leukemia by 8 months. In addition, the files at Presbyterian-University Hospital were reviewed and examined and 5 additional cases of granulocytic sarcoma preceding blood and bone marrow involvement of leukemia were found. These cases are tabulated along with the present case. RANULOCYTIC SARCOMA
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FIG. 1 . A. Immature cells in pericardial fluid. One cell contains numerous Auer rods (Wright-Giemsa, X1000). B. Immature myelomonocytic cells in bone marrow aspirate (Wright-Giemsa, x 1000).
Following pericardiocentesis, the patient felt fine except for soreness at the sternal site where he was struck by the softball. The effusion did not recur. Chest and abdominal x-ray films were normal. An EKG showed a slight reduction in amplitude of the QRS complex. It was considered that an extramedullary site of leukemia (granulocytic sarcoma) might be arising in the pericardium and/or heart that was fortuitously made manifest by the traumatic blow. The patient was given 600 rads to the mediastinum. He was followed very closely over the next months with repeat blood counts, differential and marrow examinations, and chest x-rays, all of which remained normal. In the eighth month of follow-up, his hemoglobin was found to be 11.5 g/dl and platelet count 120 x 10g/liter.The white cell count was 9 x 10g/liter with a normal differential, but a marrow examination revealed 25% myelomonoblasts (Fig. 1B). He was started on therapy for acute myelogenous leukemia (doxorubicin hydrochloride [Adriamycin] and cytosine arabinoside [Cytosar]). He obtained a complete remission and did well for a year when relapse occurred. Over the next 2 months following relapse, the blast count in the marrow rose to 80% with peripheral pancytopenia. He subsequently developed a Cundidu sepsis and died of overwhelming pneumonia and gastrointestinal bleeding. Autopsy permission was denied. The duration of survival from diagnosis of leukemia to death was 14 months.
associated with, o r terminating in, acute myelogenous leukemia. All suspected cases were thoroughly reviewed and histologic sections recut and stained when questionable. In addition, at least one naphthol-ASDchloroacetate-stained section* was examined in each case. T h e charts on suspected cases were reviewed and follow-up information obtained from these files or from the patient's physician files. Only those cases of granulocytic sarcoma or misdiagnosed histiocytic lymphoma clearly preceding acute myelogenous leukemia were included in this study. RESULTS During the past 20 years, 28 cases of granulocytic sarcoma were found within the Hematology and/or Surgical Pathology files. Approximately 950 new cases of acute myelogenous o r acute myelomonocytic leukemia were seen during this time period. Six of these cases, including the present case, preceded peripheral blood or bone marrow manifestations of acute myelogenous leukemia. These results are summarized in Table 1 .
DISCUSSION MATERIALS A N D METHODS The hematology and surgical files of PresGranulocytic sarcoma has been reported in byterian-University Hospital were examined 3-8% of autopsy series of patients with for coded cases of granulocytic sarcoma or acute myelogenous leukemia (AML).9,14This histiocytic lymphoma (reticulum cell sarcoma) series only considered surgical material in
GRANULOCYTIC SARCOMA PRECEDING AML
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*
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Krause
TABLE 1. Granulocytic Sarcoma Preceding Leukemia
Location
Treatment
Time from Dx to onset of leukemia
Evidence for leukemia
Response to leukemic chemotherapy
Survival after Dx of leukemia
Case
Agehex
1
23 F
Breast
Biopsy 2500 RAD
3% months
PB--27,000 with 30% blasts BM-50% blasts
NR
2 months
2*
27 M
Tonsil
Biopsy 2300 RAD
7 months
PB--13,000 with 45% blasts BM-60% blasts
NR
3% months
3
51 M
Eye
Biopsy 3000 RAD
6 months
PB-8,000 with 40% blasts BM-70% blasts
PR
4 months
4
41 F
Small intestine
Surgical excision 1500 RAD
9 months
PB-40,000 with 20% blasts Auer Rods BM-35% blasts
CR
1 year
5
50 M
Stomach
Surgical excision 2500 RAD
1 % months
PB-5,000 with 20% blasts BM-50% blasts
PR
6 months
6
16 M
Pericardiud heart
600 RAD
8 months
PB-normal BM-25% blasts; later 80%
CR
14 months
* Originally diagnosed as histiocytic lymphoma. PB-Peripheral
blood leukocyte count; BM-Bone
which case the tumor was likely to be clinically significant. T h e overall incidence of granulocytic sarcoma in this institution is 2.9% (28/950). Six of these cases preceded development of acute leukemia (0.6%).The overall figures may be low since they were accumulated from a nonautopsy population whereas clinically silent granulocytic sarcomas are often found in leukemic patients at autopsy. The unusual presentation of granulocytic sarcoma in the case presented prompted a review of granulocytic sarcoma, particularly preceding leukemic manifestations, since unique problems in diagnosis may arise when this entity presents in this manner. The case described in depth was uncommon in that leukemic cells were first found in a body fluid (pericardial) without disseminated leukemia being present when discovered. Although a discrete tumor mass was never observed firsthand, there was little doubt that the immature cells represented myeloblasts with Auer rods. The multiple negative biopsies with normal hematologic parameters presumed an origin of granulocytic sarcoma arising in the heart and/or pericardium. Diagnostic problems may arise however, with the most common misdiagnosis being histiocytic lymphoma (re-
marrow; NR-No response; PR-Partial remission: CRComplete remission.
ticulum cell ~ a r c o m a ) . ~ * One ~ * ' *of~the ~ , ~cases ~ in this series (Case 2) was initially considered to be a histiocytic lymphoma arising in a lingual tonsil with the occurrence of leukemia '7 months later. Review of the original histology (Fig. 2) and the staining of recuts with naphthol-ASD-chloroacetate prompted a rediagnosis of granulocytic sarcoma. Although histiocytic lymphoma is reported to terminate in AML,'l the diagnosis of histiocytic lymphoma in the presence of AML must be viewed with suspicion and strong evidence presented to show that the immature tumor cells are not myeloid elements. The histology of the surgical specimens revealed sheets of immature cells (Fig. 2) occasionally with foci of necrosis. On careful examination, usually eosinophilic-appearing myelocytes were present as well as evidence of granulocytic differentiation (metamyelocytes, bands). It is important to examine viable areas of the tumor since polymorphonuclear cells and bands may be present in areas of necrosis associated with any type of neoplasm. T h e diagnosis of granulocytic sarcoma depends upon the demonstration of granulocytic differentiation in the tumor. On oc-
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FIG. 2. Section of lymph node illustrating typical appearance of granulocytic sarcoma. Diagnosis confirmed with naphthol-ASDchloroacetate stain ( H & E, X400).
casion, the diagnosis can be made from routinely stained paraffin sections. T h e presence of eosinophilic myelocytes is highly suggestive of granulocytic sarcoma. T h e naphthol-ASD-chloroacetate stain is frequently helpful in demonstrating neutrophilic and eosinophilic precursors and this stain may be performed on formalin-fixed paraffin tissue sections.' Although mast cells may also stain strongly, clinical history and/or presentation should help in eliminating this possibility. Tissue imprints are also important, for by utilizing the Giemsa stain, granulocytic precursors (myeloblasts, promyelocytes, myelocytes) may be readily apparent when present. This technique is helpful when granulocytic differentiation within the tumor is minimal. Electron microscopy may also help by demonstrating electron-dense specific granules in the cells of granulocytic sarcoma.l9 Another technique that is beginning to be utilized is the immunoperoxidase stain for intracellular 1ys0zyrne.l~ Lysozyme is found in primary granules and thus will first appear at the promyelocyte stage. This procedure may be done on formalin-fixed or Zenker-fixed tissue, the latter of which will inactivate the naphthol-ASD-chloroacetate enzyme. It should be pointed out that
monocytes/histiocytes also contain lysozyme. However, since the vast majority of the histiocytic lymphomas are really transformed lymphocytes,5.l0 this technique would differentiate the granulocytic sarcoma, for lymphocytes do not contain lysozyme. A "true" histiocytic lymphoma might also be expected to contain lysozyme; in which case, the other techniques described above should be employed as well as utilizing a specific cytochemical stain for monocyteslhistiocytes (a-napht h yl-acetate-esterase)." The survival of patients with granulocytic sarcoma is reported to be similar to that of patients with acute myelocytic leukemia without tumor f0rmati0n.l~The first 3 cases in this series occurred before adequate chemotherapeutic agents became available and survival was only a few months after leukemia developed. Cases 4, 5 , and 6 were treated with the more recent chemotherapeutic agents following diagnosis of AML and had an initial complete or partial remission with survival periods of 1 year, 6 months, and 8% months, respectively. Although this represents only a very small series, the most recent cases have shown induction/remission and survival characteristics of AML patients without granulocytic ~ a r c o m a . ~ * ~ ~ , ~ '
REFERENCES I . Brugo, E. A., Larkin, E., Molina-Escobar, J., and Constanzi, J.: Primary granulocytic sarcoma of the small bowel. Cancer 35: 1333-1340, 1975. 2. Brugo, E. A., Marshall, R. B., Riberi, A. M., and Pautasso, 0. E.: Pre-leukemic granulocytic sarcomas of
the gastrointestinal tract: Report of two cases. Am. J . Clzn. Pathol. 68:616-62 1 , 1977. 3. Clarkson, B. D., Dowling, M. D., Gee, T. S., Cunningham, I. B., and Burchenal, J. H.: Treatment of acute leukemia in adults. Cancer 36:775-795, 1975.
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12. Mason, T. E., Damaree, R. S., and Margolis, C. I.: 4 . Comings, D. E., Fayen, A. W., and Carter, P.: Myeloblastoma preceding blood and marrow evidence Granulocytic sarcoma (chloroma), two years preceding myelogenous leukemia. Cancer 3 1:423-432, 1973. of acute leukemia. Cancer 18:253-258, 1965. 13. McCredie, K. B.: Current concepts in acute 5. Dorfman, R. F.: The non-Hodgkin’s lymphomas. In The Reticuloendothelial System, IAP Monograph leukemia. Postgrad. Med. 61:221-224, 1977. 14. Muss, H. G., and Maloney, W. C.: Chloroma No. 16, J. W. Rebuck, C. W. Berard, and M. R. Abell, Eds. Baltimore, Williams & Wilkins, 1975; pp. and other myeloblastic tumors. Blood 42:72 1-727, 1973. 15. Pinkus, G. S., and Said, J. W.: Profile of intra262-28 1. 6. Hurwitz, B. S., Sutherland, J. C., and Walker, cytoplasmic lysozyme in normal tissues, myeloproliferaM. D.: Central nervous system chloromas preceding tive disorders, hairy cell leukemia, and other pathologic acute leukemia by one year. Neurology 20:771-775, 1970. processes: An immunoperoxidase study of paraffin 7. Laszlo, J., and Grode, H. E.: Granulocytic leu- sections and smears. Am. J. Pathol. 89:351-366, 1977. 16. Ragins, A. B. and Tinsley, M.: Chloroma: kemia and reticulum cell sarcoma. Cancer 20:545-551, Report of a case. J. Neuroputhol. Exp. Neurol. 9:1861967. 8 . Leder, L. D.: Uber die selektive ferment cyto- 192, 1950. 17. Rappaport, H.: Atlas of Tumor Pathology, section chemische Dartsellung von neutrophiler myelosschem zellen und gewebsmastzellen in parafinschnitt. Klin. 3, fascicle 8. Washington, D.C., Armed Forces Institute of Pathology, 1966; pp. 241-243. Wochemchr. 42:553, 1964. 18. Ross, R. R.: Chloroma and chloroleukemia. Am. J . 9. Liu, P. I., Jshimaru, T., McGregor, D. H., Okada, H., and Steer, A.: Autopsy study of granulocytic Med. 18:671-676, 1955. 19. Scott, R. E., and Horn, R. G.: Ultrastructural sarcoma (chloroma) in patients with myelogenous leukemia: Hiroshima-Nagasaki 1949-1965. Cancer 3 1: aspects of neutrophil granulocyte development in humans. Lab. Invest. 23:202-215, 1970. 948-955, 1973. 20. Weil, M., Jacquillat, C. I., Gemon-Auclera, M. F., 10. Lukes, R. J., and Collins, R. D.: A functional classification of malignant lymphomas. In The Reticulo- Chastang, C. L., Izrael, V., Boiron, M., and Bernard, endothelial System, IAP Monograph No. 16, J. W. Re- J.: Acute granulocytic leukemia. Arch. Intern. Med. buck, C. W. Berard, and M. W. Abell, Eds. Balti- 136:1389-1395, 1976. 21. Wiernick, P. H., and Serpick, A. A.: Granulomore, Williams & Wilkins, 1975; pp. 213-242. 1 1 . Marin-Padilla, M., Fahimi, H. D., and Maloney, cytic sarcoma (chloroma). Blood 35:361-369, 1970. 22. Yam, L. T., Li, C. Y., and Crosby, W. H.: W. C.: Leukemic reticulum cell sarcoma (reticulum cell sarcoma terminating in acute leukemia). Am. J. Cytochemical identification of monocytes and granulocytes. Am. J. Clin. Pathol. 55:283-290, 1971. Clin. Pathol. 41:402-410, 1964.
