1346
GRANULOCYTIC
sclerotic features have been reported.‘**” As in both cases presented here, many authors have reported symptomatic metastases of the mandible or TMJ in which no radiographic abnormalities were initially evident.3”‘8,“,16,17
14.
1. Liotta LA, Stetler-Stevenson WG: Principles of molecular cell biology of cancer: Cancer metastasis, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology, vol 1 (ed 3). Philadelphia, PA, Lippincott, 1989, p 98 2. Kyriakos ML: Tumors and tumor-like conditions of soft tissues, in Kissane JM (ed): Anderson’s Pathology, ~012 (ed 9). St Louis, MO, Mosby, 1990, p 1838 3. Castigliano SG, Rominger CJ: Metastatic malignancy of the jaws. Am J Surg 87:496, 1954 4. Cash CD, Royer RQ, Dahlin DC: Metastatic tumors of the jaws. Oral Surg 14:897, 1961 5. Clausen F, Paulsen H: Metastatic carcinoma to the jaws. Acta Path Micro Scan 57:361, 1963 6. Meyer I, Shklar G: Malignant tumors metastatic to mouth and jaws. Oral Surg 20:350, 1965 7. McDaniel RK, Luna MA, Stimson PG: Metastatic tumors in the jaws. Oral Surg 31:380, 1971 8. Schwartz ML, Baredes S, Mignogna FV: Metastatic disease to the mandible. Laryngoscope 98:270, 1988 9. Keller EE, Gunderson LL: Bone disease metastatic to the jaws. J Am Dent Assoc 115:697, 1987 10. Horton J, Means ED, Cunningham TJ, et al: The numb chin
49:1346-1350,
12.
13.
References
J Oral Maxillofac
11.
15. 16.
17.
18.
19.
20.
21.
SARCOMA OF THE GINGIVA
in breast cancer. J Neurol Neurosurg Psychiatry 36:211, 1973 Massey EW, Moore J, Schold SC: Mental neuropathy from systemic cancer. Neurology 31:1277, 1981 DeBoom GW, Jensen JL, Siegel W, et al: Metastatic tumors of the mandibular condyle. Review of the literature and report of a case. Oral Surg 60:512, 1985 Owen DG, Stelling CB: Condylar metastasis with initial presentation as TMJ syndrome. J Oral Med 40: 198, 1985 Rubin MM, Jui V, Cozzi GM: Metastatic carcinoma of the mandibular condyle presenting as temporomandibular joint syndrome. J Oral Maxillofac Surg 47:507, 1989 Wolujewicz MA: Condylar metastasis from a carcinoma of the prostate gland. Br J Oral Surg 18: 175, 1980 Blaschke DP: The temporomandibular joint, in Bergeron RT, Osbom AG, Som PM (eds): Head and Neck Imaging. St Louis, MO, Mosbv. 1984. D 251 Catrambone RJ, Pfeffer-RC: Significant postoperative hemorrhage following biopsy of a prostate tumor metastatic to the mandibular condyle: Report of a case. J Oral Maxillofac Surg 48:858, 1990 Gates GF: Radionuclide diagnosis, in Laskin DM (eds): Oral and Maxillofacial Surgery, vol 1. St Louis, MO, Mosby, 1980, p 463 Garcia DA, Tow DE, Sullivan TM, et al: The appearances of common dental diseases on radionuclide bone images of the jaws. J Dent Res 58:1040, 1979 Matteson SR, Staab EV, Fine JT: Bone-scan appearance of benign oral pathologic conditions. J Oral Surg 38:759, 1980 Wahner HW, Brown ML: Role of bone scanning, in Sim FH (ed): Diagnosis and Management of Metastatic Bone Disease. A Multidisciplinary Approach. New York, NY, Raven Press, 1988, p 51
Surg
1991
Granulocytic
Sarcoma (Chloroma) the Gingiva: Report
of
of a Case
ELLEN EISENBERG, DMD,* EDWARD S. PETERS, DMD,t AND DAVID J. KRUTCHKOFF, DDS, MS+ Granulocytic sarcoma is an unusual malignancy composed of relatively immature, neoplastic granulocytes (myelocytes). It may arise in association * Associate Professor, Division of Oral Pathology, Department of Oral Diagnosis, University of Connecticut, Farmington. t Formerly, General Practice Resident, The Brigham and Women’s Hospital, Boston; currently, Fellow in Hospital Dentistry, The Brigham and Women’s Hospital, Brigham Dental Group, and Fellow in Dental Medicine, Dana-Farber Cancer Center, Boston. $ Professor, Division of Oral Pathology, Department of Oral Diagnosis, University of Connecticut, Farmington. Address correspondence and reprint requests to Dr Eisenberg: Division of Oral Pathology, Department of Oral Diagnosis, University of Connecticut, Farmington, CT 06030. 0 1991 American
Association
geons 0276-2391/91/4912-0016$3.00/O
of Oral and Maxillofacial
Sur-
with acute myelogenous leukemia (AML) or, less frequently, in patients with chronic myelogenous leukemia (CML).’ Expression of AML as a softtissue mass was first described by Burns in 1811.* This mode of presentation was referred to as “chloroma” by King in 1853, because of the striking green color acquired by the tumor tissue on exposure to air.3 Although granulocytic sarcomas commonly arise during a leukemic blast crisis, in some instances the chloroma may precede the peripheral blood or bone marrow expression of the disease. In such cases, diagnosis is difficult due to the absence of typical signs and symptoms of leukemia. In fact, it is not uncommon that the isolated granulocytic sarcoma may be mistakenly diagnosed histologically as his-
EISENBERG.
1347
PETERS, AND KRUTCHKOFF
tiocytic or lymphocytic lymphoma.‘*4,5 When granulocytic sarcoma arises without attendant hematologic or myelopoietic evidence of frank leukemia, it must be regarded as an extramedullary precursor of emerging leukemia, and the patient should be treated accordingly by aggressive means.6,7 This report describes an unusual case of granulocytic sarcoma that presented initially as a gingival enlargement with regional lymphadenopathy in an otherwise healthy young man. Report of a Case In January 1990, a 33-year-old man was referred to an oral and maxillofacial surgeon by his periodontist for evaluation and biopsy of several painless gingival nodules and a swollen submandibular lymph node, both present since November 1989. The gingival lesions had been refractory to repeated attempts at conventional periodontal therapy. The patient had been seen by his physician for the lymphadenopathy 2 weeks prior to the visit to the oral and maxillofacial surgeon. At that time he was treated with penicillin V for 2 weeks without improvement. In other respects, the patient appeared to be healthy and had no other complaints. The past medical history was unremarkable. Physical examination revealed multiple, raised, granular-appearing, erythematous nodules localized to the free and attached gingiva in the right maxillary and mandibular molar areas, plus an enlarged, nontender right submandibular lymph node (Figs 1, 2). The remainder of the examination was unremarkable. Representative gingival biopsies were taken and submitted for histologic examination. Two weeks later, a biopsy was performed on the enlarged right submandibular lymph node.
FIGURE 1. Nodular, exophytic lesions of right maxillary and mandibular posterior gingivae (arrows).
FIGURE 2.
Painless swelling, right submandibular
GINGIVAL
area.
BIOPSY
The initial gingival specimens consisted of mucosal wedges covered by thin squamous epithelium with a normal maturation pattern. The submucosa exhibited sheets of large, uniform, immature-appearing lymphoid cells (Fig 3A) containing large vesicular nuclei with many mitotic figures (Fig 3B). The preliminary diagnostic impression was large-cell malignant lymphoma, most likely of the B-cell type.
LYMPH NODE
The cortical and paracortical lymph node regions were expanded and effaced by a uniform population of large cells with round to cleaved nuclei surrounded by a thin rim of amphophilic cytoplasm (Fig 4). Cells were noted to infiltrate the perinodal adipose tissue. A touch preparation of the node (Romanofsky stain) showed intracellular granules consistent with those seen in myeloblasts. Cytochemical analysis of other touch preparations showed a population of blastic cells, 5% of which were positive for Sudan black B and myeloperoxidase (characteristics of granulocytic precursors), and approximately 50% of which were positive for a-naphthyl butyrate esterase (characteristic of monocytes and their precursors).’ On review of the prior gingival biopsy, the cytomorphologic features of the gingival lesions were similar, if not identical, to those within the excised lymph node tissue. Thus, both gingival and lymph node findings were interpreted as consistent with foci of acute nonlymphocytic leukemia (ANLL), specifically, granulocytic sarcoma of the acute myelomonocytic type (AMML; FAB M,). In view of the amended diagnosis, a complete blood count and differential blood cell count were ordered, and bilateral bone marrow aspirations were subsequently performed. The findings of both the hematologic profile and the bone marrow analysis were normal, with no demonstrable evidence of leukemia. Thus, the diagnosis of AMML was confirmed. The patient was subsequently admitted on February 26 for a course of standard induction chemotherapy’ with daunorubicin 45 mg/m* (90 mg) for 3 days and ara-C 100 mg/m’ (200 mg) for 7 days. The gingival lesions persisted
1348
GRANULOCYTIC
SARCOMA OF THE GINGIVA
and completed on April 9. Although the gingival lesions diminished with respect to swelling and erythema, a repeated biopsy performed on April 25 showed persistent granulocytic sarcoma. Findings of a second right cervical lymph node biopsy performed at this time were similar. The patient again underwent 5 days of chemotherapy beginning June 4, with mitoxantrone 12 mg/m’ (24 mg)/VP16/etoposide 100 mg/m2 (200 mg). Following this treatment, both the right cervical lymphadenopathy and gingival lesions resolved completely. A follow-up gingival biopsy on July 17 showed no evidence of leukemic cells. The peripheral blood and bone marrow remained consistently negative for both monocytic blast cells and other indications of leukemia. Nonetheless, in view of the generally poor prognosis of granulocytic sarcoma, additional aggressive therapy was advised. Accordingly, in September 1990, radiation therapy was administered to the right neck and gingivae and autologous bone marrow was obtained for transplantation (BMT), which was performed in November 1990. He recovered from the BMT and has remained free of systemic leukemia to date. There has been no recurrence of the granulocytic sarcoma either in gingival tissues or in the cervical lymph nodes.
Discussion Granulocytic extramedullary cytic/monocytic
FIGURE 3. A, Granulocytic sarcoma, right mandibular gingiva. Dense atypical lymphoid infiltrate tills submucosa (hematoxylin-eosin stain, original magnification x40). B, High-power view of gingival biopsy. Large atypical lymphoid cells with vesicular nuclei. Note numerous mitotic figures (hematoxylin-eosin stain, original magnification x240).
following completion of this therapeutic cycle, and a repeated gingival biopsy on March 22 showed many residual leukemic cells. A second course of induction chemotherapy with the same doses of daunorubicin and ara-C was initiated on an outpatient basis beginning March 30
FIGURE 4. Granulocytic sarcoma, right submandibular lymph node. Architecture effaced by monotonous infiltrate of large, immature lymphoid cells. Mitoses are evident (hematoxylineosin stain, original magnification X 120).
sarcomas (chloromas) are localized masses of neoplastic granulocells that can occur in virtually any
organ. They are characteristically myeloperoxidase (verdoperoxidase)-positive and represent true leukemic tumors capable of local tissue destruction and invasion. In some instances, granulocytic sarcoma presents as an asymptomatic incidental finding on physical examination, or is discovered at autopsy. Its occurrence in the head and neck is usually limited to periosteum and soft tissues of the orbit, nasal cavity, and paranasal sinuses.8710-‘2 The occurrence of chloroma in the oral cavity is rare, particularly when the lesion appears on the gingiva, as it did in this case. The lesions may arise de novo in the absence of detectable leukemic marrow involvement, and predate the onset of frank leukemia In other instances, granby as much as a year. 7,1’Y13 ulocytic sarcomas present in conjunction with a recognized myeloproliferative disturbance such as polycythemia Vera, myeloid metaplasia, or myelogenous leukemia. In cases of AML, chloromas may represent the initial presentation of the disease (as was the case in this patient) or arise during reof granulocytic sarcoma lapse. 11,14 Occurrence bears no direct relationship to the peripheral blood count. lo Diagnosis of solitary granulocytic sarcoma may be extremely difftcult to establish in the absence of leukemic peripheral blood or bone marrow, particularly in the absence of a history of leukemia.15 The variable cytomorphology of the tumor cells may broaden the microscopic differential diagnosis to include, among other possibilities, poorly differenti-
EISENBERG,
PETERS, AND KRUTCHKOFF
ated lymphomas. When presenting as an isolated finding, granulocytic sarcoma may be particularly difficult to distinguish from malignant lymphoma (as it was in this case) with conventional histologic examination alone.‘*8~‘1*‘6 On either tissue or smear preparations stained with Wright-Giemsa, myeloblasts exhibit a delicate nuclear chromatin pattern with several nucleoli and fine cytoplasmic granules. Auer bodies (crystalline, rodlike azurophilic intracytoplasmic structures representing clumped primary lysosomal granules of myeloid cell precursors) are considered a consistent marker of myeloid cells. ‘,“*” They are, however, observed in less than 10% of cases of AML.18 Diagnostic confirmation of granulocytic sarcoma is established through cytochemical stains.‘.8*‘0*1” 15.17,~ Myeloperoxidase, which imparts the green color (thus the designation “chloromas”) to these tumors on exposure to air, can be identified within cytoplasmic granules by Sudan black B or through peroxidase or diaminobenzidine reactions. Positive staining serves to distinguish AML from ALL (acute lymphocytic leukemia), in which blast cells are negative for myeloperoxidase. Naphthol ASDchloroacetate esterase and ol-naphthyl acetate esterase disclose the presence of a specific granulocytic esterase associated with neutrophilic granules of promyelocytes and late-stage myeloblasts. Also of use is the immunoperoxidase reaction to lysozyme. which is present in granulocytes and monocytic precursors. 1~4~8~10~12~15~‘8 The acute myeloblastic leukemias are seen predominantly in young adults, but chloromas develop more frequently in association with childhood leukemia.‘0~““4 They arise through neoplastic transformation of a single pluripotent hematopoietic stem cell and are classified according to the FrenchAmerican-British (FAB) Cooperative group system. The FAB nosologic classification reflects both the degree of evident cellular maturation as well as the apparent line of leukemic stem cell differentiation. Thus, AMLs may be subclassified into four separate types (acute myelogenous, acute myelomonocytic, acute monocytic, and acute erythroleukemic), according to the predominant cytomorphology observed in Romanofsky-stained preparations of bone marrow and peripheral blood smears. Within the FAB system, six variants of AML are recognized. Subtypes M, and M, (in which chloromas occur most commonly”) and M, are of granulocytic origin; types M, and M, derive from monocytic precursors, and subtype M, originates in an erythroblastic line.8 This patient’s disease designation, FAB M,, describes AMML, a heterogeneous group, comprised of varying proportions of granulocytic and mono-
1349 cytic neoplastic blast cells.” This type of leukemia represents 20% to 30% of adult AML. The monocytic cell component is identified by cytochemical staining with an esterase, such as a-naphthyl butyrate esterase. It also stains positive for lysoan enzyme found in significantly zyme, ‘~4*5~‘o~1’~17~18 elevated amounts in serum of individuals with AMML involving marrow.8 Complete remission in newly diagnosed, previously untreated AML adult patients under age 60 can be achieved through combined induction chemotherapy (usually with daunorubicin, an anthracycline, as the primary agent) and other agents, such as (ara-C) cytarabine, followed by postremission treatment. The latter may consist of a “consolidation” regimen, in which the original chemotherapy is repeated, or a “maintenance” type regimen, in which less myelosuppressive therapy than that used in induction is used. Alternatively, “intensification” schemes may be used, where myelosuppressive doses of agents other than those used for induction chemotherapy, or higher doses of the latter, are used.9*‘8-21 Recently, carboplatin (CBDCA) has also been found to be an effective antileukemic agent in ANLL (acute nonlymphocytic leukemia).22 Chemotherapeutic intensification regimens also are given in conjunction with allogeneic or autologous bone marrow transplantation. In first remissions, allogeneic bone marrow transplantation plus intensive chemotherapy have achieved cures.’ Following chemotherapeutic purge in AML, long-term bone marrow cultures have been successfully used as a source of cells for autologous bone marrow transplantation.23 There is no uniform or consistent approach to management of isolated granulocytic sarcoma in remission. Given the poor prognostic profile of granulocytic sarcoma,4~677~‘o~‘1~‘4 additional aggressive therapy is considered advisable to prevent hematopoietic leukemic relapse. This patient, with exclusively extramedullary AMML, failed to respond to two identical courses of daunorubicin/ara-C. However, these lesions eventually resolved following combined chemotherapy with other agents. Despite the fact that blood and bone marrow findings continued to remain normal (thus suggesting remission), bone marrow transplantation was nevertheless recommended as an attempt to cure. It was acknowledged that this recommendation was purely empirical since, unlike for frank AML (for which there are published cases of cures with allogeneic bone marrow transplantation and intensive chemotherapy following first remission9,24,25), there is virtually no documentation to support the efficacy of such treatment for cases presenting with isolated granulocytic sarcoma.
1350 Nonetheless, there was concern that failure to initiate prompt aggressive treatment would place the patient at risk of resurgent disease with involvement of bone marrow and peripheral blood. Thus, the patient’s sister was tissue-typed to determine HLA compatibility for possible allogeneic bone marrow transplantation. At the same time, the patient underwent an autologous marrow procurement, which was subsequently purged with 4-HCYVP-16 in an attempt to eradicate possible occult leukemic cells. The patient was ultimately transplanted with his purged autologous marrow. He has remained in remission for 11 months (as of this date) and is expected to continue to do well. He will be considered cured if he is free of disease 1 year posttransplant. Should this prediction hold true, the prompt diagnosis and appropriate management in this case will have effectively intercepted and prevented emergence of systemic leukemia in a patient whose sole manifestation of hematologic malignancy consisted of granulocytic sarcoma of oral mucosa and regional lymph nodes.
GRANULOCYTIC
9.
10.
11.
12. 13.
14. 15.
16.
17.
18.
Acknowledgment The authors wish to acknowledge the assistance of Drs Kay Heidecke and Roger Lowlicht in providing follow-up information on the progress of this patient.
19.
References
20.
1. McCarty KS, Wortman J, Daly J, et al: Chloroma (granulocytic sarcoma) without evidence of leukemia: Facilitated light microscopic diagnosis. Blood 56: 104, 1980 2. Bums A: Observations on Surgical Anatomy, Head and Neck. Edinburgh, Thomas Royce, 1811, p 364 3. Kina A: A case of chloroma. Monthlv J Med 17:97, 1853 4. Krause JR: Granulocytic sarcoma preceding acute leukemia: Report of 6 cases. Cancer 44:1017, 1979 5. Juneja SK, Pilkington GR, Ding JC, et al: Diagnosis of granulocytic sarcoma facilitated by monoclonal antibodies. Pathology 18:469, 1986 6. Neiman RS, Barcos M, Berard C, et al: Granulocytic sarcoma: A clinicopathologic study of 61 biopsied cases. Cancer 48:1426, 1981 7. Eshghabadi M, Shojania AM, Carr I: Isolated granulocytic sarcoma: Report of a case and review of the literature. J Clin Oncol4:912, 1986 8. Bennett JM: The classification of acute leukemias: Cytochemical and morphological considerations, in Wiemik
21.
22. 23.
24.
25.
SARCOMA OF THE GINGIVA
PH, Canellos GP, Kyle RA, et al (eds): Neoplastic Diseases of the Blood, vol 1. New York, NY, Churchill Livingstone, 1985, pp 201-217 Mayer RJ: Intensive chemotherapy versus allogeneic bone marrow transplantation in first-remission acute myeloid leukemia. Bone Marrow Transpl 6:48, 1990 (suppl) Dreizen S, McCredie KB, Keating MJ: Mucocutaneous granulocytic sarcomas of the head and neck. J Oral Path01 16:57, 1987 Rappoport H: Tumors of the hematopoietic system, in Rappbport H (ed): Atlas of Tumor Pathology, section III, fascicle 8. Washington. DC, Armed Forces Institute of Pathology, 1966, p-p 239-263 Muss HB, Moloney WC: Chloroma and other myeloblastic tumors. Blood 42:721, 1973 Hajdu SI: Miscellaneous soft tissue tumors: Granulocytic sarcoma, in Hajdu SI (ed): Pathology of Soft Tissue Tumors. Philadelphia, PA, Lea & Febiger, 1979, pp 519-525 Barker GR, Sloan P: Maxillary chloroma: A myeloid leukaemic deposit. Br J Oral Maxillofac Surg 26: 124, 1988 Reichart PA, Roemeling RV, Krech R: Mandibular myelosarcoma (chloroma): Primary oral manifestation of promyelocytic leukemia. Oral Surg 58:424, 1984 Timmis DP, Schwartz JG, Nishioka G, et al: Granulocytic sarcoma of the mandible. J Oral Maxillofac Surg 44:814, 1986 Cotran RS, Kumar V, Robbins SL: Acute myeloblastic leukemia (AML), in Cotran RS, Kumar V, Robbins SL (eds): Robbins Pathologic Basis of Disease (ed 4). Philadelphia, PA, Saunders, 1989, pp 724-728 Zighelboim J, Gale RP: Acute leukemia, in Haskell CM (ed): Cancer Treatment. Philadelphia, PA, Saunders, 1980, pp 820-829 (chap 12) Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia, in Wiemik PH, Canellos GP, Kyle RA, et al (eds): Neoplastic Diseases of the Blood. New York, NY, Churchill Livingstone, 1985, pp 335-355 Mayer RJ: Current chemotherapeutic treatment approaches to the management of previously untreated adults with de nova acute myelogenous leukemia. Semin Oncol 14:384, 1987 Cassileth PA, Harrington DP, Hines JD, et al: Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol 6:583, 1988 Martinez JA, Martin G, Sanz GF, et al: A phase II clinical trial of carboplatin infusion in high-risk acute nonlymphoblastic leukemia. J Clin Oncol 9:39, 1991 Schiro R, Coutinho LH, Will A, et al: Growth of normal versus leukemic bone marrow cells in long term culture from acute lymphoblastic and myeloblastic leukemias. Blut 61:267, 1990 Zander AR, Keating M, Dicke K, et al: A comparison of marrow transplantation with chemotherapy for adults with acute leukemia of poor prognosis in the first complete remission. J Clin Oncol 6: 1548, 1988 Ash RC, Carper JT, Chitanbar CR, et al: Successful ahogeneic transplantation of T-cell-depleted bone marrow from closely HLA-matched unrelated donors. N Engl J Med 322:485, 19%
GRANULOCYTIC
sclerotic features have been reported.‘**” As in both cases presented here, many authors have reported symptomatic metastases of the mandible or TMJ in which no radiographic abnormalities were initially evident.3”‘8,“,16,17
14.
1. Liotta LA, Stetler-Stevenson WG: Principles of molecular cell biology of cancer: Cancer metastasis, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology, vol 1 (ed 3). Philadelphia, PA, Lippincott, 1989, p 98 2. Kyriakos ML: Tumors and tumor-like conditions of soft tissues, in Kissane JM (ed): Anderson’s Pathology, ~012 (ed 9). St Louis, MO, Mosby, 1990, p 1838 3. Castigliano SG, Rominger CJ: Metastatic malignancy of the jaws. Am J Surg 87:496, 1954 4. Cash CD, Royer RQ, Dahlin DC: Metastatic tumors of the jaws. Oral Surg 14:897, 1961 5. Clausen F, Paulsen H: Metastatic carcinoma to the jaws. Acta Path Micro Scan 57:361, 1963 6. Meyer I, Shklar G: Malignant tumors metastatic to mouth and jaws. Oral Surg 20:350, 1965 7. McDaniel RK, Luna MA, Stimson PG: Metastatic tumors in the jaws. Oral Surg 31:380, 1971 8. Schwartz ML, Baredes S, Mignogna FV: Metastatic disease to the mandible. Laryngoscope 98:270, 1988 9. Keller EE, Gunderson LL: Bone disease metastatic to the jaws. J Am Dent Assoc 115:697, 1987 10. Horton J, Means ED, Cunningham TJ, et al: The numb chin
49:1346-1350,
12.
13.
References
J Oral Maxillofac
11.
15. 16.
17.
18.
19.
20.
21.
SARCOMA OF THE GINGIVA
in breast cancer. J Neurol Neurosurg Psychiatry 36:211, 1973 Massey EW, Moore J, Schold SC: Mental neuropathy from systemic cancer. Neurology 31:1277, 1981 DeBoom GW, Jensen JL, Siegel W, et al: Metastatic tumors of the mandibular condyle. Review of the literature and report of a case. Oral Surg 60:512, 1985 Owen DG, Stelling CB: Condylar metastasis with initial presentation as TMJ syndrome. J Oral Med 40: 198, 1985 Rubin MM, Jui V, Cozzi GM: Metastatic carcinoma of the mandibular condyle presenting as temporomandibular joint syndrome. J Oral Maxillofac Surg 47:507, 1989 Wolujewicz MA: Condylar metastasis from a carcinoma of the prostate gland. Br J Oral Surg 18: 175, 1980 Blaschke DP: The temporomandibular joint, in Bergeron RT, Osbom AG, Som PM (eds): Head and Neck Imaging. St Louis, MO, Mosbv. 1984. D 251 Catrambone RJ, Pfeffer-RC: Significant postoperative hemorrhage following biopsy of a prostate tumor metastatic to the mandibular condyle: Report of a case. J Oral Maxillofac Surg 48:858, 1990 Gates GF: Radionuclide diagnosis, in Laskin DM (eds): Oral and Maxillofacial Surgery, vol 1. St Louis, MO, Mosby, 1980, p 463 Garcia DA, Tow DE, Sullivan TM, et al: The appearances of common dental diseases on radionuclide bone images of the jaws. J Dent Res 58:1040, 1979 Matteson SR, Staab EV, Fine JT: Bone-scan appearance of benign oral pathologic conditions. J Oral Surg 38:759, 1980 Wahner HW, Brown ML: Role of bone scanning, in Sim FH (ed): Diagnosis and Management of Metastatic Bone Disease. A Multidisciplinary Approach. New York, NY, Raven Press, 1988, p 51
Surg
1991
Granulocytic
Sarcoma (Chloroma) the Gingiva: Report
of
of a Case
ELLEN EISENBERG, DMD,* EDWARD S. PETERS, DMD,t AND DAVID J. KRUTCHKOFF, DDS, MS+ Granulocytic sarcoma is an unusual malignancy composed of relatively immature, neoplastic granulocytes (myelocytes). It may arise in association * Associate Professor, Division of Oral Pathology, Department of Oral Diagnosis, University of Connecticut, Farmington. t Formerly, General Practice Resident, The Brigham and Women’s Hospital, Boston; currently, Fellow in Hospital Dentistry, The Brigham and Women’s Hospital, Brigham Dental Group, and Fellow in Dental Medicine, Dana-Farber Cancer Center, Boston. $ Professor, Division of Oral Pathology, Department of Oral Diagnosis, University of Connecticut, Farmington. Address correspondence and reprint requests to Dr Eisenberg: Division of Oral Pathology, Department of Oral Diagnosis, University of Connecticut, Farmington, CT 06030. 0 1991 American
Association
geons 0276-2391/91/4912-0016$3.00/O
of Oral and Maxillofacial
Sur-
with acute myelogenous leukemia (AML) or, less frequently, in patients with chronic myelogenous leukemia (CML).’ Expression of AML as a softtissue mass was first described by Burns in 1811.* This mode of presentation was referred to as “chloroma” by King in 1853, because of the striking green color acquired by the tumor tissue on exposure to air.3 Although granulocytic sarcomas commonly arise during a leukemic blast crisis, in some instances the chloroma may precede the peripheral blood or bone marrow expression of the disease. In such cases, diagnosis is difficult due to the absence of typical signs and symptoms of leukemia. In fact, it is not uncommon that the isolated granulocytic sarcoma may be mistakenly diagnosed histologically as his-
EISENBERG.
1347
PETERS, AND KRUTCHKOFF
tiocytic or lymphocytic lymphoma.‘*4,5 When granulocytic sarcoma arises without attendant hematologic or myelopoietic evidence of frank leukemia, it must be regarded as an extramedullary precursor of emerging leukemia, and the patient should be treated accordingly by aggressive means.6,7 This report describes an unusual case of granulocytic sarcoma that presented initially as a gingival enlargement with regional lymphadenopathy in an otherwise healthy young man. Report of a Case In January 1990, a 33-year-old man was referred to an oral and maxillofacial surgeon by his periodontist for evaluation and biopsy of several painless gingival nodules and a swollen submandibular lymph node, both present since November 1989. The gingival lesions had been refractory to repeated attempts at conventional periodontal therapy. The patient had been seen by his physician for the lymphadenopathy 2 weeks prior to the visit to the oral and maxillofacial surgeon. At that time he was treated with penicillin V for 2 weeks without improvement. In other respects, the patient appeared to be healthy and had no other complaints. The past medical history was unremarkable. Physical examination revealed multiple, raised, granular-appearing, erythematous nodules localized to the free and attached gingiva in the right maxillary and mandibular molar areas, plus an enlarged, nontender right submandibular lymph node (Figs 1, 2). The remainder of the examination was unremarkable. Representative gingival biopsies were taken and submitted for histologic examination. Two weeks later, a biopsy was performed on the enlarged right submandibular lymph node.
FIGURE 1. Nodular, exophytic lesions of right maxillary and mandibular posterior gingivae (arrows).
FIGURE 2.
Painless swelling, right submandibular
GINGIVAL
area.
BIOPSY
The initial gingival specimens consisted of mucosal wedges covered by thin squamous epithelium with a normal maturation pattern. The submucosa exhibited sheets of large, uniform, immature-appearing lymphoid cells (Fig 3A) containing large vesicular nuclei with many mitotic figures (Fig 3B). The preliminary diagnostic impression was large-cell malignant lymphoma, most likely of the B-cell type.
LYMPH NODE
The cortical and paracortical lymph node regions were expanded and effaced by a uniform population of large cells with round to cleaved nuclei surrounded by a thin rim of amphophilic cytoplasm (Fig 4). Cells were noted to infiltrate the perinodal adipose tissue. A touch preparation of the node (Romanofsky stain) showed intracellular granules consistent with those seen in myeloblasts. Cytochemical analysis of other touch preparations showed a population of blastic cells, 5% of which were positive for Sudan black B and myeloperoxidase (characteristics of granulocytic precursors), and approximately 50% of which were positive for a-naphthyl butyrate esterase (characteristic of monocytes and their precursors).’ On review of the prior gingival biopsy, the cytomorphologic features of the gingival lesions were similar, if not identical, to those within the excised lymph node tissue. Thus, both gingival and lymph node findings were interpreted as consistent with foci of acute nonlymphocytic leukemia (ANLL), specifically, granulocytic sarcoma of the acute myelomonocytic type (AMML; FAB M,). In view of the amended diagnosis, a complete blood count and differential blood cell count were ordered, and bilateral bone marrow aspirations were subsequently performed. The findings of both the hematologic profile and the bone marrow analysis were normal, with no demonstrable evidence of leukemia. Thus, the diagnosis of AMML was confirmed. The patient was subsequently admitted on February 26 for a course of standard induction chemotherapy’ with daunorubicin 45 mg/m* (90 mg) for 3 days and ara-C 100 mg/m’ (200 mg) for 7 days. The gingival lesions persisted
1348
GRANULOCYTIC
SARCOMA OF THE GINGIVA
and completed on April 9. Although the gingival lesions diminished with respect to swelling and erythema, a repeated biopsy performed on April 25 showed persistent granulocytic sarcoma. Findings of a second right cervical lymph node biopsy performed at this time were similar. The patient again underwent 5 days of chemotherapy beginning June 4, with mitoxantrone 12 mg/m’ (24 mg)/VP16/etoposide 100 mg/m2 (200 mg). Following this treatment, both the right cervical lymphadenopathy and gingival lesions resolved completely. A follow-up gingival biopsy on July 17 showed no evidence of leukemic cells. The peripheral blood and bone marrow remained consistently negative for both monocytic blast cells and other indications of leukemia. Nonetheless, in view of the generally poor prognosis of granulocytic sarcoma, additional aggressive therapy was advised. Accordingly, in September 1990, radiation therapy was administered to the right neck and gingivae and autologous bone marrow was obtained for transplantation (BMT), which was performed in November 1990. He recovered from the BMT and has remained free of systemic leukemia to date. There has been no recurrence of the granulocytic sarcoma either in gingival tissues or in the cervical lymph nodes.
Discussion Granulocytic extramedullary cytic/monocytic
FIGURE 3. A, Granulocytic sarcoma, right mandibular gingiva. Dense atypical lymphoid infiltrate tills submucosa (hematoxylin-eosin stain, original magnification x40). B, High-power view of gingival biopsy. Large atypical lymphoid cells with vesicular nuclei. Note numerous mitotic figures (hematoxylin-eosin stain, original magnification x240).
following completion of this therapeutic cycle, and a repeated gingival biopsy on March 22 showed many residual leukemic cells. A second course of induction chemotherapy with the same doses of daunorubicin and ara-C was initiated on an outpatient basis beginning March 30
FIGURE 4. Granulocytic sarcoma, right submandibular lymph node. Architecture effaced by monotonous infiltrate of large, immature lymphoid cells. Mitoses are evident (hematoxylineosin stain, original magnification X 120).
sarcomas (chloromas) are localized masses of neoplastic granulocells that can occur in virtually any
organ. They are characteristically myeloperoxidase (verdoperoxidase)-positive and represent true leukemic tumors capable of local tissue destruction and invasion. In some instances, granulocytic sarcoma presents as an asymptomatic incidental finding on physical examination, or is discovered at autopsy. Its occurrence in the head and neck is usually limited to periosteum and soft tissues of the orbit, nasal cavity, and paranasal sinuses.8710-‘2 The occurrence of chloroma in the oral cavity is rare, particularly when the lesion appears on the gingiva, as it did in this case. The lesions may arise de novo in the absence of detectable leukemic marrow involvement, and predate the onset of frank leukemia In other instances, granby as much as a year. 7,1’Y13 ulocytic sarcomas present in conjunction with a recognized myeloproliferative disturbance such as polycythemia Vera, myeloid metaplasia, or myelogenous leukemia. In cases of AML, chloromas may represent the initial presentation of the disease (as was the case in this patient) or arise during reof granulocytic sarcoma lapse. 11,14 Occurrence bears no direct relationship to the peripheral blood count. lo Diagnosis of solitary granulocytic sarcoma may be extremely difftcult to establish in the absence of leukemic peripheral blood or bone marrow, particularly in the absence of a history of leukemia.15 The variable cytomorphology of the tumor cells may broaden the microscopic differential diagnosis to include, among other possibilities, poorly differenti-
EISENBERG,
PETERS, AND KRUTCHKOFF
ated lymphomas. When presenting as an isolated finding, granulocytic sarcoma may be particularly difficult to distinguish from malignant lymphoma (as it was in this case) with conventional histologic examination alone.‘*8~‘1*‘6 On either tissue or smear preparations stained with Wright-Giemsa, myeloblasts exhibit a delicate nuclear chromatin pattern with several nucleoli and fine cytoplasmic granules. Auer bodies (crystalline, rodlike azurophilic intracytoplasmic structures representing clumped primary lysosomal granules of myeloid cell precursors) are considered a consistent marker of myeloid cells. ‘,“*” They are, however, observed in less than 10% of cases of AML.18 Diagnostic confirmation of granulocytic sarcoma is established through cytochemical stains.‘.8*‘0*1” 15.17,~ Myeloperoxidase, which imparts the green color (thus the designation “chloromas”) to these tumors on exposure to air, can be identified within cytoplasmic granules by Sudan black B or through peroxidase or diaminobenzidine reactions. Positive staining serves to distinguish AML from ALL (acute lymphocytic leukemia), in which blast cells are negative for myeloperoxidase. Naphthol ASDchloroacetate esterase and ol-naphthyl acetate esterase disclose the presence of a specific granulocytic esterase associated with neutrophilic granules of promyelocytes and late-stage myeloblasts. Also of use is the immunoperoxidase reaction to lysozyme. which is present in granulocytes and monocytic precursors. 1~4~8~10~12~15~‘8 The acute myeloblastic leukemias are seen predominantly in young adults, but chloromas develop more frequently in association with childhood leukemia.‘0~““4 They arise through neoplastic transformation of a single pluripotent hematopoietic stem cell and are classified according to the FrenchAmerican-British (FAB) Cooperative group system. The FAB nosologic classification reflects both the degree of evident cellular maturation as well as the apparent line of leukemic stem cell differentiation. Thus, AMLs may be subclassified into four separate types (acute myelogenous, acute myelomonocytic, acute monocytic, and acute erythroleukemic), according to the predominant cytomorphology observed in Romanofsky-stained preparations of bone marrow and peripheral blood smears. Within the FAB system, six variants of AML are recognized. Subtypes M, and M, (in which chloromas occur most commonly”) and M, are of granulocytic origin; types M, and M, derive from monocytic precursors, and subtype M, originates in an erythroblastic line.8 This patient’s disease designation, FAB M,, describes AMML, a heterogeneous group, comprised of varying proportions of granulocytic and mono-
1349 cytic neoplastic blast cells.” This type of leukemia represents 20% to 30% of adult AML. The monocytic cell component is identified by cytochemical staining with an esterase, such as a-naphthyl butyrate esterase. It also stains positive for lysoan enzyme found in significantly zyme, ‘~4*5~‘o~1’~17~18 elevated amounts in serum of individuals with AMML involving marrow.8 Complete remission in newly diagnosed, previously untreated AML adult patients under age 60 can be achieved through combined induction chemotherapy (usually with daunorubicin, an anthracycline, as the primary agent) and other agents, such as (ara-C) cytarabine, followed by postremission treatment. The latter may consist of a “consolidation” regimen, in which the original chemotherapy is repeated, or a “maintenance” type regimen, in which less myelosuppressive therapy than that used in induction is used. Alternatively, “intensification” schemes may be used, where myelosuppressive doses of agents other than those used for induction chemotherapy, or higher doses of the latter, are used.9*‘8-21 Recently, carboplatin (CBDCA) has also been found to be an effective antileukemic agent in ANLL (acute nonlymphocytic leukemia).22 Chemotherapeutic intensification regimens also are given in conjunction with allogeneic or autologous bone marrow transplantation. In first remissions, allogeneic bone marrow transplantation plus intensive chemotherapy have achieved cures.’ Following chemotherapeutic purge in AML, long-term bone marrow cultures have been successfully used as a source of cells for autologous bone marrow transplantation.23 There is no uniform or consistent approach to management of isolated granulocytic sarcoma in remission. Given the poor prognostic profile of granulocytic sarcoma,4~677~‘o~‘1~‘4 additional aggressive therapy is considered advisable to prevent hematopoietic leukemic relapse. This patient, with exclusively extramedullary AMML, failed to respond to two identical courses of daunorubicin/ara-C. However, these lesions eventually resolved following combined chemotherapy with other agents. Despite the fact that blood and bone marrow findings continued to remain normal (thus suggesting remission), bone marrow transplantation was nevertheless recommended as an attempt to cure. It was acknowledged that this recommendation was purely empirical since, unlike for frank AML (for which there are published cases of cures with allogeneic bone marrow transplantation and intensive chemotherapy following first remission9,24,25), there is virtually no documentation to support the efficacy of such treatment for cases presenting with isolated granulocytic sarcoma.
1350 Nonetheless, there was concern that failure to initiate prompt aggressive treatment would place the patient at risk of resurgent disease with involvement of bone marrow and peripheral blood. Thus, the patient’s sister was tissue-typed to determine HLA compatibility for possible allogeneic bone marrow transplantation. At the same time, the patient underwent an autologous marrow procurement, which was subsequently purged with 4-HCYVP-16 in an attempt to eradicate possible occult leukemic cells. The patient was ultimately transplanted with his purged autologous marrow. He has remained in remission for 11 months (as of this date) and is expected to continue to do well. He will be considered cured if he is free of disease 1 year posttransplant. Should this prediction hold true, the prompt diagnosis and appropriate management in this case will have effectively intercepted and prevented emergence of systemic leukemia in a patient whose sole manifestation of hematologic malignancy consisted of granulocytic sarcoma of oral mucosa and regional lymph nodes.
GRANULOCYTIC
9.
10.
11.
12. 13.
14. 15.
16.
17.
18.
Acknowledgment The authors wish to acknowledge the assistance of Drs Kay Heidecke and Roger Lowlicht in providing follow-up information on the progress of this patient.
19.
References
20.
1. McCarty KS, Wortman J, Daly J, et al: Chloroma (granulocytic sarcoma) without evidence of leukemia: Facilitated light microscopic diagnosis. Blood 56: 104, 1980 2. Bums A: Observations on Surgical Anatomy, Head and Neck. Edinburgh, Thomas Royce, 1811, p 364 3. Kina A: A case of chloroma. Monthlv J Med 17:97, 1853 4. Krause JR: Granulocytic sarcoma preceding acute leukemia: Report of 6 cases. Cancer 44:1017, 1979 5. Juneja SK, Pilkington GR, Ding JC, et al: Diagnosis of granulocytic sarcoma facilitated by monoclonal antibodies. Pathology 18:469, 1986 6. Neiman RS, Barcos M, Berard C, et al: Granulocytic sarcoma: A clinicopathologic study of 61 biopsied cases. Cancer 48:1426, 1981 7. Eshghabadi M, Shojania AM, Carr I: Isolated granulocytic sarcoma: Report of a case and review of the literature. J Clin Oncol4:912, 1986 8. Bennett JM: The classification of acute leukemias: Cytochemical and morphological considerations, in Wiemik
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