Intraoral granulocytic sarcoma presenting as multiple maxillary and mandibular masses: A case report and literature review

Intraoral granulocytic sarcoma presenting as multiple maxillary and mandibular masses: A case report and literature review

Intraoral granulocytic sarcoma presenting as multiple maxillary and mandibular masses: A case report and literature review Zhijian Xie, DDS, PhD,a Fen...

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Intraoral granulocytic sarcoma presenting as multiple maxillary and mandibular masses: A case report and literature review Zhijian Xie, DDS, PhD,a Feng Zhang, DDS,b En Song, DDS,b Weili Ge, DDS,b Fudong Zhu, DDS, PhD,b and Ji’an Hu, DDS, MS,a Hangzhou, China ZHEJIANG UNIVERSITY SCHOOL OF MEDICINE

Granulocytic sarcoma (GS) is an unusual localized tumor composed of immature granulocytic precursor cells that occurs in extramedullary sites. However, GS involving the oral cavity is rare. We report a case of intraoral GS with an unusual clinical presentation, including a history of chronic myelogenous leukemia in remission, multiple maxillary and mandibular gingival masses mimicking acute inflammation that developed over a short period, complete remission after 1 week of treatment with imatinib mesylate (Gleevec), and no bone marrow or peripheral blood involvement over a 6-month follow-up period. To our knowledge, this is the first report of treatment of intraoral GS with Gleevec resulting in a complete remission. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103: e44-e48)

Granulocytic sarcoma (GS), also known as chloroma, extramedullary myeloid tumor, and myeloid sarcoma, is defined as a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site or bone according to the new World Health Organization classification for lymphoid and hematopoitic neoplasm.1 Granulocytic sarcoma most often occurs in the subperiosteal bone structure and soft tissue2 but can be found in any location throughout the body, including the skin, lymph nodes, bone, soft tissue, orbit and eye, bronchi, pericardium, peritoneum, gastrointestinal tract, kidney, reproductive organs, breast, and bladder.2-5 Intraoral GS is rare. A search of the Englishlanguage literature in the PubMed online database found only 30 reported cases of intraoral GS.6-15 In the majority of the reported cases, only 1 site was involved with a single GS mass, and the cases predominantly associated with acute myeloid leukemia (AML).6-15 Furthermore, GS involving multiple regions and associated with chronic myelogenous leukemia (CML) in remission is extremely rare. We present an case of intraoral GS interesting because of its unusual clinical presentation and significant response to treatment.

Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Zhejiang University School of Medicine. a Professor. b Resident. Received for publication Aug 20, 2006; returned for revision Nov 12, 2006; accepted for publication Dec 21, 2006. 1079-2104/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.12.028

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CASE REPORT This patient was a 32-year-old woman with a history of chronic myelogenous leukemia (CML). She received her diagnosis of CML in January 2004 and underwent treatment with hydroxyzine, resulting in a complete remission by the April of 2004. In February 2006, the patient saw her dentist for pain in the upper right third molar, which the dentist diagnosed as pericoronitis. The dentist extracted the affected tooth in response to the patient’s persistent request. Two days after the extraction, the patient experienced severe restriction of mouth opening. She was found to have a palpable mass on the buccal vestibule of her lower right mandible. Her dentist determined that it was inflammation and she took antibiotics for 1 week, which did not result in improvement. On the contrary, the mass gradually grew, and several additional masses developed. She was then referred to our institution for further evaluation. Physical examination of the patient revealed 2 firm unmovable nontender masses in the buccal vestibule of her lower left mandible measuring 3.0 cm and 1.0 cm in diameter (Fig. 1). In addition, she had several unequivocal masses in bilateral submandibular regions that were attached to the mandible. Also, there was obvious swelling in the buccal and palatal of the right maxilla in the molar area that was firm and slightly painful with palpation. There were no odontogenic sources or other associated intraoral lesions. The patient’s mouth-open width was only 2 cm. Computerized tomographic scanning of the patient’s head and neck demonstrated several soft tissue masses in the nasopharyngeal, maxillary, and mandibular regions (Fig. 2). Some of these masses involved the periosteum of the mandible. It also showed bilateral multiple neck lymphadenopathies. Serum biochemistry tests, a complete blood count, and a peripheral blood smear were normal. Bone marrow aspiration showed normal cellularity without any blasts. The patient underwent needle biopsy of the right mandib-

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Fig. 1. Clinical appearance of intraoral granulocytic sarcoma, presenting as multiple sessile masses in the buccal vestibule and gingiva.

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Fig. 3. Histology of granulocytic sarcoma, showing infiltrated immature-looking tumor cells. They are intermediate size with high nuclear-to-cytoplasmic ratio and scant cytoplasm in a sclerotic fibrous collagen background (hematoxylin and eosin staining, ⫻100).

Fig. 4. Myeloperoxidase (MPO) stain, showing the tumor cells have strongly positive reaction to MPO (⫻200). Fig. 2. Computerized tomography, demonstrating soft tissue masses in the nasopharyngeal and maxillary regions.

ular mass under local anesthesia. Histologic examination of the biopsy specimen showed a diffuse infiltrate with a monomorphous population of immature blast-like cells. The cells were intermediate in size and round to oval in shape with mild to moderate basophilic cytoplasm without granules. Also the cells had an increased nuclear-to-cytoplasmic ratio. The nuclei were round with fine chromatin and conspicuous nucleoli. In addition, mitotic figures and rare eosinophilic myelocytes were readily identified. Some areas demonstrated sclerotic proliferation of small to intermediate size cells with pyknotic chromatin (Fig. 3). Special stains and immunohistochemical

stains were performed on the paraffin-embedded sections of the biopsy. The tumor cells demonstrated positive reaction to myeloperoxidase (Fig. 4), CD43, and CD33 antibodies and negative reation to CD20 and CD2 monoclonal antibodies. Taking these results together with the patient’s medical history, clinical presentation, and morphologic findings, a diagnosis of GS was rendered. The patient received imatinib mesylate (Gleevec) to treat her GS. Her GS masses regressed significantly after 1 week of treatment. All of her masses, including the maxillary, mandibular, and nasopharyngeal masses, were completely resolved as shown on follow-up computerized tomography scans. The patient’s follow-up period was 6 months. She is now alive and symptom free with no tumor masses or evidence of bone marrow or peripheral blood involvement.

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Table I. Summary of reported cases of intraoral granulocytic sarcoma Authors

Patient Year age/gender

Type of malignancy

Tumor location

Wiernik et al. Brooks et al. Neiman et al. Hansen et al. Conran et al. Takagi et al. Reichart et al. Castella et al. Timmis et al. Welch et al. Ficarra et al. Saleh et al. Barker et al. Rodriguez et al. Cho et al. Eisenberg et al.

1970 1974 1981 1982 1982 1983 1984 1984 1986 1986 1987 1987 1988 1990 1990 1991

35/F 8/M NR 83/F 23/F 25/F 35/F 89/F 52/M 3/F 67/F 62/F 4/F 56/M 3/M 33/M

AML AML NR AML NR AML Promyelocytic NR Not developed Not developed AML MDS MML AML APML AMML

70/M NR 76/F 60/F 43/F 62/F 58/M 12/F 50/M 32/M 62/F 84/F 44/F 63/M 32/F

CML MDS AML CML Not developed MML AML AML AML AML Not developed Not developed Not developed Not developed CML

Cheek Maxilla Soft palate Maxilla Mandible Mandible Mandible Hard palate Mandible Maxilla Maxilla Mandible Maxilla Mandible Mandible Maxilla and mandible Mandible Mandible Maxilla Mandible Maxilla Mandible Hard palate Maxilla Palate Mandible Maxilla Hard palate Maxilla Maxilla Maxilla and mandible

Stack et al. Tuset et al. Tong et al. Tomas et al. Lee et al. Jordan et al. Amin et al. Antmen et al. Stoopler et al. Dikbas et al. Colella et al. Goteri et al. Yinjun et al. Yoon et al. Present case

1994 1995 2000 2000 2001 2002 2002 2003 2004 2004 2005 2006 2006 2006 2006

AML, acute myeloid leukemia; APML, acute promyelocytic leukemia; CML, chronic myeloid leukemia; F, female; M, male; MDS, myelodysplastic syndrome; MML, myelomonocytic leukemia; NR, not recorded.

DISCUSSION Although intraoral GS is rare, it can occur in the palate, the gingiva, extraction sockets, and the cheek. Jordan et al.6 in 2002 briefly summarized 20 reported cases of intraoral GS without a detailed discussion. To better understand this rare entity, we reviewed all of the case reports in the English-language literature in the PubMed online database from 1970 to June 2006, which revealed 30 cases of intraoral GS (Table I).6-15 There were 10 male and 18 female patients (in 2 cases, the patient’s gender was unspecified.). Their median age at diagnosis was 45.7 years (range 3-89 years). Most of the cases involved just 1 site and presented as a mass or mucosal ulceration. The maxillary (11 cases) and mandibular (12 cases) gingivae were the most common sites involved, followed by the palate (5

cases) and cheek (1 case). The occurrence of intraoral GS as multiple masses involving multiple sites is extremely rare. There was only 1 reported case in which the tumor involved both the maxilla and the mandibular gingivae.16 Thus, the present case is only the second reported with multiple masses involving multiple sites. There are 3 possible clinical courses of GS: in association with AML, in association with chronic myeloproliferative disorders, and as a predecessor to AML.2,6 Granulocytic sarcoma usually occurs concomitantly with or subsequent to the development of leukemia. Rarely, it precedes the appearance of AML. The vast majority of GS have occurred in patients with known leukemia or in whom leukemias eventually developed, although GS has reportedly occurred in nonleukemic patients.4 Generally speaking, GS is more commonly associated with CML than with AML. Neiman et al.2 reviewed 61 cases of GS and found that 26 were associated with a known myeloproliferative disorder (the most common of which was CML), 22 were associated with no known disease, and 13 were associated with proven AML. However, intraoral GS is generally associated with AML; it is most often seen in patients with the subtype AML-M1 (myeloblastic leukemia without maturation) or AML-M2 (myeloblastic leukemia with maturation).17 The incidence of intraoral GS is much lower in association with CML. In reviewing the 30 reported cases of intraoral GS, we found only 2 cases associated with CML, compared with 16 associated with AML, 7 associated with no discernible hematologic abnormality, 2 associated with myelodysplastic disease, and 3 without such information.17,18 The 2 cases of intraoral GS associated with CML developed concurrently with blastic crisis. The present case had an unusual presentation. The patient had a history of CML for 2 years, but her disease was in complete remission when intraoral GS developed. Neiman et al.2 indicated that whether the underlying disease was CML or another myeloproliferative disorder, GS was either the initial manifestation of blast transformation or a harbinger of AML within 4 months. We followed the present case for 6 months and did not observe any bone marrow or peripheral blood involvement. Although GS may occur during the evolution of CML in which the disease appears to be stable in all other clinical and hematologic respects, GS strongly suggests that blast crisis is imminent.2 Therefore, close clinical follow-up is critical. Diagnosis of GS may be difficult when it occurs in the oral cavity, especially when it presents as an isolated finding and with no history of hematological disorders or peripheral blood or bone marrow in-

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volvement of myeloproliferative disorders. Clinically, most intraoral GS present with a mass and mucosa ulceration. They may resemble periodicities, periodic abscesses, pyogenic granuloma, carcinoma, or lymphomas.7,8,12-14 For example, the present case was also initially considered as pericoronitis. Histologically, although GS usually has sheets of relatively monomorphic intermediate to large size polyhedral cells with irregular nuclear contours, vesicular chromatin, variably prominent nucleaoli, and frequent mitotic figures,1-3 diagnosis of it is complicated by the diversity and inconsistency of its morphologic features.3 For example, it may be misdiagnosed as malignant lymphoma, Ewing’s sarcoma, acute lymphoblastic leukemia, or other small blue cell tumors.1,3,6 In such cases, use of histochemical staining, immunophenotyping with flow cytometry, or immunohistochemical studies may help in reaching a definitive diagnosis.1 Myeloid cells contain distinctive primary granules that are not seen in lymphomas or other small blue cell tumors. Histochemical analyses to detect myeloperoxidase (MPO) and chloroacetate esterase markers is diagnostic for myeloid leukemia.1,3 Immunohistochemically, in addition to being reactive to antibodies against MPO, lysozyme, and chloroacetate esterase, GS myeloblasts usually express myeloid-associated antigens such as CD43, CD13, CD33, and CD117 but are not reactive with lymphoid antigens such as CD3 and CD20.1 Traweek et al.3 found that the single most useful antibody for GS was an anti-MPO antibody. They concluded that the use of an immunohistochemical panel including CD20, CD43, CD68, and MPO can successfully identify the vast majority (90%) of GS. It is always true that increased awareness of this entity combined with the patient’s medical history may minimize misinterpretation of clinical and pathologic findings and help reach the definitive diagnosis. In the present case, the patient’s medical history of CML made us directly consider a related hematologic disease, and we reminded the pathologist to consider the feasibility of GS. This made the diagnosis much simpler. Treatment of and prognosis for intraoral GS depend on the patient’s medical history and the clinical presentation.1,2,6 In the present case, we treated intraoral GS with history of CML with Gleevec, which resulted in a complete remission. Gleevec, a selective BCR/ABL tyrosine kinase inhibitor, is the first therapeutic agent designed to target a known molecular defect in human malignancies. It has demonstrated remarkable effectiveness and safety in the treatment of CML and is currently the first-line treatment for CML.19 However,

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there have been no reports of treatment of GS with Gleevec. With respect to the prognosis for GS in patients with known AML, treatment apparently does not affect the prognosis and is that of the underlying leukemia even if the patients is in complete remission; however, in a patient with CML, the prognosis is poor and it is equivalent to blast transformation.1,17 The 2 reported patients with a history of CML who had intraoral GS died at 1 month and 3 months after diagnosis.17,18 In comparison, our patient was alive and free of disease after 6 months. This is the first reported case of intraoral GS treated with Gleevec and resulted in a complete remission. It may indicate that Gleevec is the therapeutic agent of choice for GS in patients with a history of CML even if they are free of CML. In summary, intraoral GS is an unusual tumor with characteristic but not specific clinical and pathologic features. Awareness of this disease, knowledge of its clinical history and presentation, and appropriate differential diagnosis considerations are critical in making a presumptive diagnosis. Confirmation of the diagnosis of GS relies on pathologic examination and judicious use of ancillary studies, including histochemical, immunohistochemical, and flow cytometry studies. The treatment of and prognosis for intraoral GS depend on the patient’s medical history and clinical presentation. In patients with a history of CML, GS may be treated with Gleevec. REFERENCES 1. Brunning RD, Matutes E, Head D, Flandrin G, Harris NL, Vardiman J. Acute myeloid leukemia not otherwise categorised. In: Jaffe ES, Stein H, Vardiman JW, editors. Tumors of hematopoietic and lymphoid tissues, Lyon: IARC Press; 2001. p. 104-5. 2. Neiman RS, Barcos M, Berard C, Bonner H, Mann R, Rydell RE, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer 1981;48:1426-37. 3. Traweek ST, Arber DA, Rappaport H, Brynes RK. Extramedullary myeloid cell tumors. An immunohistochemical and morphologic study of 28 cases. Am J Surg Pathol 1993;17:1011-9. 4. Meis JM, Butler JJ, Osborne BM, Manning JT. Granulocytic sarcoma in nonleukemic patients. Cancer 1986;58:2697-709. 5. Yamauchi K, Yasuda M. Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 2002;94:1739-46. 6. Jordan RC, Glenn L, Treseler PA, Regezi JA. Granulocytic sarcoma: case report with an unusual presentation and review of the literature. J Oral Maxillofac Surg 2002;60:1206-11. 7. Yinjun L, Jie J, Zhimei C. Granulocytic sarcoma of the gingiva with trisomy 21. Am J Hematol 2006;81:79-80. 8. Colella G, Tirelli A, Capone R, Rubini C, Guastafierro S. Myeloid sarcoma occurring in the maxillary gingiva: a case without leukemic manifestations. Int J Hematol 2005;81:138-41. 9. Dikbas O, Isik M, Purnak T, Karadag O, Uner A, Altundag K. Isolated granulocytic sarcoma of the head and neck preceding acute myeloid leukemia. Am J Hematol 2004;76:95-6. 10. Stoopler ET, Pinto A, Alawi F, Raghavendra S, Boyce R Jr,

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Porter D, et al. Granulocytic sarcoma: an atypical presentation in the oral cavity. Spec Care Dent 2004;24:65-9. Antmen B, Haytac MC, Sasmaz I, Dogan MC, Ergin M, Tanyeli A. Granulocytic sarcoma of gingiva: an unusual case with aleukemic presentation. J Periodontol 2003;74:1514-9. Amin KS, Ehsan A, McGuff HS, Albright SC. Minimally differentiated acute myelogenous leukemia (AML-M0) granulocytic sarcoma presenting in the oral cavity. Oral Oncol 2002;38:516-9. Lee SS, Kim HK, Choi SC, Lee JI. Granulocytic sarcoma occurring in the maxillary gingiva demonstrated by magnetic resonance imaging. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:689-93. Goteri G, Ascani G, Messi M, Filosa A, Segura-Egea JJ, Rubini C, et al. Myeloid sarcoma of the maxillary bone. J Oral Pathol Med 2006;35:254-6. Yoon AJ, Pulse C, Cohen LD, Lew TA, Zegarelli DJ. Myeloid sarcoma occurring concurrently with drug-induced gingival enlargement. J Periodontol 2006;77:119-22. Eisenberg E, Peters ES, Krutchkoff DJ. Granulocytic sarcoma

(chloroma) of the gingiva: report of a case. J Oral Maxillofac Surg 1991;49:1346-50. 17. Tomas Carmona I, Cameselle Teijeiro J, Diz Dios P, Fernandez Feijoo J, Limeres Posse J. Intra-alveolar granulocytic sarcoma developing after tooth extraction. Oral Oncol 2000;36:491-4. 18. Stack BC Jr, Ridley MB. Granulocytic sarcoma of the mandible. Otolaryngol Head Neck Surg 1994;110:591-4. 19. Ren R, Roepke TJ. Identification of chronic myelogenous leukemia. Tech sample. Am Soc Clin Pathol 2005;H-2:9-15. Reprint requests: Dr. Zhijian Xie Department of Oral and Maxillofacial Surgery Affiliated Stomatological Hospital Zhejiang University 395 Yan’an Road Hangzhou, Zhejiang 310006 China [email protected]