ORIGINAL CONTRIBUTIONS
DIAGNOSTIC CHALLENGE
Intraoral mass in the posterior maxillary vestibule Francisco Samuel Rodrigues Carvalho, DDS; Fábio Wildson Gurgel Costa, DDS, PhD; Filipe Nobre Chaves, DDS; Ana Paula Negreiros Nunes Alves, DDS, PhD; Fabrício Bitu Sousa, DDS, PhD; Régia Maria do Socorro Vidal do Patrocínio, MD, MSc; Karuza Maria Alves Pereira, DDS, PhD
544 JADA 146(7) http://jada.ada.org
THE CHALLENGE
A
42-year-old woman came to our clinic for consultation regarding a painful swelling inside her mouth that had developed over approximately 1 month. During this time, the patient had no recurrent fever, generalized malaise, or weight loss. The patient reported that her most recent dental visit had been 15 days ago, and since that time, her oral discomfort had worsened. The patient’s primary care professional previously had prescribed amoxicillin (500 milligrams); however, after completing the 7-day drug regimen, the patient continued to have symptoms. An oral health care professional at our clinic observed a smooth, painful, soft, sessile nodular mass with well-defined margins in the posterior maxillary vestibule sulcus (Figure 1). The clinician also observed heavily decayed teeth and clinical signs of periodontal disease. The patient had a history of untreated myelodysplastic syndrome (MDS) and nonspecific heart murmur, and she was taking folic acid to treat severe anemia. In addition, the patient had no history of cancer, alcohol consumption, smoking, or hospitalizations. An overview of the patient’s panoramic radiograph revealed multiple lost teeth, root residues, heavily decayed teeth with periapical radiolucent lesions, horizontal bone resorption in the jaws, and bone sclerosis in the periapical area of tooth no. 34 (Figure 2). The clinician did not observe any radiographic changes in the area corresponding to the nodular lesion. The patient’s preoperative blood screening showed the following results (Table): low values for red blood cell count, hemoglobin, and hematocrit; increased mean corpuscular volume; low values for white blood cell and platelet counts; and increased clotting time. The clinician performed an oral incisional biopsy and submitted the specimen for histopathologic evaluation. The histopathologic analysis revealed diffuse sheets of large cells with ovoid and sometimes hyperchromatic nuclei, scarce cytoplasm, mild mitotic activity, and necrotic foci, resulting in a preliminary diagnosis of lymphoproliferative disorder (Figure 3). The clinician performed an immunohistochemical analysis using the antibodies PAX-5, terminal deoxynucleotidyl transferase (TdT), CD3, CD79a, CD34, CD117, and myeloperoxidase (MPO). The results were positive in 90% of cells for MPO (Figure 4), diffuse positive for CD117, focal positive in rare cells for CD3 and TdT, positive in plasmocytes for CD79a and in vessels for CD34, and negative for PAX-5. The results of a cytogenetic study showed deletion in the long arm of chromosome 11 in 4 metaphases (that is, del[11][q32]).
July 2015
ORIGINAL CONTRIBUTIONS
Figure 1. Intraoral aspect: a soft mass with well-defined margins in the posterior maxillary vestibule sulcus.
Figure 2. Panoramic radiograph showing lost teeth, root residues, heavily decayed teeth, periapical radiolucent lesions, generalized horizontal bone resorption, and tooth no. 34 with periapical bone sclerosis.
Figure 3. Diffuse sheets of large cells with ovoid and sometimes hyperchromatic nuclei in scarce cytoplasm, mild mitotic activity, and necrotic area (hematoxylin and eosin stain, original magnification 200).
Figure 4. Myeloperoxidase stain showing a strongly positive and diffuse cellular reaction (immunohistochemical staining, original magnification 400). mm, micrometer.
TABLE
Preoperative laboratory values. HEMATOLOGIC PARAMETERS
PATIENT VALUES
LABORATORY REFERENCE VALUES
2.39 million cells/mm3*
4.0-5.5 million cells/mm3
Hemoglobin
7.8 g/dL†
11.5-15.5 g/dL
Hematocrit
25.6%
36%-45%
Red Blood Cell
Mean Corpuscular Volume Leukocyte Segmented Lymphocyte Platelet
107.1 fL‡
80-96 fL
2,300 cells/mm3
3,600-11,000 cells/mm3
220 cells/mm3 125,000 units/mm
1,500-7,000 cells/mm3 3
150,000-400,000 units/mm3
7 min, 33 s
1-3 min
Prothrombin Time
16 s
11-14.6 s
Prothrombin Activity
76%
70%-100%
International Normalized Ratio
1.26
1.20
Serum Creatinine
0.6 mg/dL§
0.5-1.0 mg/dL
Fasting Blood Glucose
96 mg/dL
66-99 mg/dL
Clotting Time
* † ‡ §
cells/mm3: Cells per cubic millimeter. g/dL: Grams per deciliter. fL: Femtoliters. mg/dL: Milligrams per deciliter.
CAN YOU MAKE THE DIAGNOSIS? A. epulis fissuratum (inflammatory fibrous hyperplasia) B. chronic apical periodontitis with vestibular mucosa extension
C. extranodal non-Hodgkin lymphoma D. myeloid leukemia, extramedullary type
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ORIGINAL CONTRIBUTIONS
THE DIAGNOSIS D. Myeloid leukemia, extramedullary type Myeloid leukemia, extramedullary type (MLET), is characterized by immature granulocytes (that is, immature neutrophils with a neutrophilic, acidophilic, or basophilic pattern), and it has been associated with myeloid leukemia, MDS, and other myeloproliferative disorders.1,2 Previously, this disease has been known as chloroma, granulocytic sarcoma,1 and extramedullary myeloid sarcoma3; however, it is more accurately called MLET.4 When we searched the PubMed database for intraoral MLET, we found a total of 81 cases reported from March 1970 through January 2015. In addition, investigators have described a small number of intraoral MLET cases occurring after the development of an acute myeloid leukemia (AML) process in patients with a previous diagnosis of MDS.5 MLET can affect people of any age, especially women,5,6 and intraoral lesions typically present as diffuse gingival enlargement most often in the mandible, followed by the maxilla, palate, gingiva, postextraction sites, and buccal region.7-9 The clinical findings for the patient described in this article allied with that of a woman with a history of MDS who had an intraoral mass that was suspected to have a possible diagnosis of MLET. In this article, we presented the case of a patient with an important oral lesion that is associated with systemic disease in the field of the hematopathology and that can be mistaken for a variety of benign or malignant processes. Clinically, MLET is an aggressive lesion that may be symptomatic9 or asymptomatic.8 Rapid growth with local bone destruction and invasion of adjacent tissues is a common finding.7 The most typical clinical sign is the presence of an enlargement in the oral mucosa. Other characteristics include color in a spectrum covering black, brown, red, and light gray, and the absence of ulcerations.1 Tumors can promote bone and radicular tooth resorption, whereas pressure on nerve structures may cause pain, facial nerve paralysis, deafness, and blindness.7 Our patient was symptomatic and had a soft-tissue lesion. MYELOID LEUKEMIA, EXTRAMEDULLARY TYPE
Investigators have observed MLET in association with myeloid leukemia and other myeloproliferative disorders such as polycythemia vera, hypereosinophilia, and myeloid metaplasia.9,10 Although clinicians have observed MLET most commonly in patients with myeloid leukemia, only 3.0% to 9.1% of patients diagnosed with chronic myeloid leukemia or AML have MLET.10 Intraoral MLET usually is associated with AML.9 According to Pau and colleagues,11 only 4 cases of MLET in patients with MDS have been reported, 3 of
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July 2015
whom developed AML; these findings support the diagnosis of the patient described in this article. Although oral manifestations of AML are common and patients with AML often have gingival and mucosal tissue enlargement, this finding is rare in patients with MLET.6 Our patient’s differential diagnosis list included an inflammatory oral mucosal disease; however, she did not have factors causing local trauma, such as dental prosthesis or parafunctional habits.12,13 Although periapical diseases of nonendodontic origin may resemble malignant neoplasms,14 our review of the patient’s case revealed a lack of the following important signs of chronic apical periodontitis: clinical radiographic evidence of bone involvement or vestibular cortical expansion, and negative pulp vitality testing.14-16 Extranodal non-Hodgkin lymphoma may occur in the jaws and is associated with nonspecific clinical signals or symptoms such as local discomfort, related cervical lymphadenopathy, swelling, pain, ulcer, and tooth mobility.14 Thus, clinicians should perform histopathologic analysis and immunohistochemistry to establish a definitive diagnosis of MLET.6 Investigators have described 4 histologic variants of MLET: a blastic variant (mainly with myeloblasts), an immature variant (with myeloblasts and promyelocytes), a differentiated variant (with myeloblasts, promyelocytes, and more mature granulocytes), and a variant with intracytoplasmic Auer bodies.4 For our patient, we confirmed the hematologic origin by noting positivity for CD117, which is associated with AML. We identified the myeloid lineage by noting a strong positivity for MPO, which indicates a granulocytic myeloperoxidase subtype.4 The presence of MLET suggests a poor prognosis: it may be an early manifestation of myeloid leukemia (as in the case described in this article) or a worsening of the clinical condition of a patient with leukemia.7 Our patient had MDS and, according to Kim and colleagues,7 the presence of MLET indicates the transformation of myeloproliferative disease into acute leukemia. Historically, AML was classified as follows: M0 (AML with minimal evidence of myeloid differentiation), M1 (acute myeloblastic leukemia without maturation), M2 (acute myeloblastic leukemia with maturation), M3 (acute promyelocytic leukemia), M4 (acute myelomonocytic leukemia), M5 (acute monocytic, monoblastic leukemia, or both), M6 (acute erythroleukemia), and M7 (acute megakaryoblastic leukemia).17,18 In 2008, a revision of the World Health Organization (WHO) classification for tumors of hematopoietic and lymphoid tissues included a new group called “AML with myelodysplasia-related
ORIGINAL CONTRIBUTIONS
changes.”18 Thus, in agreement with the WHO revision, our patient may be assigned to a group called “AML arising from previous myelodysplastic syndrome (MDS) or an MDS or myeloproliferative neoplasm.”18 Once MLET is diagnosed, aggressive therapy is warranted owing to the poor prognosis.10 After receiving the diagnosis of AML, our patient began chemotherapy (daunorubicin [87 mg], Ara-C [195 mg]) and prophylaxis (vancomycin, meropenem, piperacillin and tazobactam, and fluconazole); however, her condition rapidly evolved toward severe neutropenia, which was followed by septicemia and death (4 months after the diagnosis). DIFFERENTIAL DIAGNOSIS
Epulis fissuratum (inflammatory fibrous hyperplasia). Epulis fissuratum (that is, inflammatory fibrous hyperplasia) is an oral mucosal disease caused by low-intensity chronic trauma (for example, wearing ill-fitting dentures) or parafunctional habits.12 Lesions typically appear as a single or multiple hyperplastic tissue covered with stratified squamous ephithelium in the maxillary alveolar vestibule.12 The lesion size varies from a few millimeters to several centimeters, and the surface may be smooth or ulcerated (the latter often is associated with pain).12,13 According to Naderi and colleagues,13 these lesions have been reported to occur in patients aged 3 to 72 years (average, 34.7 years), and the lesions occur predominantly in males. In a Brazilian cross-sectional study of 1,290 soft-tissue reactive lesions, the prevalence of epulis fissuratum in the oral cavity was 15%, and the most commonly affected site was the buccal mucosa, followed by the lower lip and tongue.19 De Santana Santos and colleagues19 reported local trauma in 90.7% of the cases they studied. In our patient’s case, the clinical findings (for example, age, oral site, and soft-tissue aspect) we observed in the patient resembled an inflammatory fibrous hyperplasia. Chronic apical periodontitis with vestibular mucosa extension. Chronic apical periodontitis is a clinical form of apical periodontitis, which is characterized by an inflammatory disorder of periradicular tissues caused by microorganisms in the root canal system of an affected tooth, coupled with a local immune response.20 This inflammatory process involves bone resorption that is revealed as radiolucency on radiographic examinations.15,16 Clinically, chronic apical periodontitis is generally asymptomatic; however, a soft-tissue mass (that is, vestibular mucosa extension) can arise if the patient has symptoms similar to periodontitis, such as gingival inflammation and bleeding.14 Investigators have reported several lesions that suggest the diagnosis of apical periodontitis, such as benign odontogenic (for example, cysts and tumors) and nonodontogenic (for example, pseudocysts, infections, central giant cell lesions, fibro-osseous lesions, soft-tissue neoplasms) processes and malignant neoplasms.21 Our patient had a vestibular mucosal lesion
associated with signs of generalized periodontal disease that reinforced a possible diagnosis of chronic apical periodontitis with vestibular mucosa extension. Extranodal non-Hodgkin lymphoma. Lymphomas represent a distinct group of clonal malignant proliferative diseases that originate from a somatic mutation in a lymphocyte progenitor (B-, T-, or natural killer-cells phenotype) situated in lymph nodes or any organ.21 Lymphomas are categorized as Hodgkin and nonHodgkin diseases.22 Approximately 40% of non-Hodgkin lymphomas present as extranodal disease.23 The most common extranodal site is the gastrointestinal tract, but the oral cavity (mainly maxillary involvement) is a rare site of primary occurrence of disease.22 Clinically, nonHodgkin lymphoma may be characterized as a mass with or without superficial ulceration. Although it is uncommon, patients may have painful symptoms, fever, or weight loss.23 In the case described in this article, our patient’s maxillary involvement and clinical aspects could have represented possible signs of a malignant lesion, such as the extranodal non-Hodgkin lymphoma. CONCLUSIONS
Although the occurrence of MLET in the oral cavity is rare, it is important for clinicians to understand the oralsystemic connection of the condition. Knowing a patient’s medical history of MDS can alert the clinician to suspect MLET, because an oral lesion may be a manifestation of that pre-existing blood disorder. The laboratory finding of severe pancytopenia in a patient with a history of MDS should serve as a warning to the clinician that the concurrent presence of an ulcerated oral mucosal lesion for more than 1 month in duration can be a sign of a life-threatening medical condition. n http://dx.doi.org/10.1016/j.adaj.2015.02.009 Copyright ª 2015 American Dental Association. All rights reserved.
Dr. Carvalho is a postgraduate student and a resident in Oral and Maxillofacial Surgery, Walter Cantídio University Hospital, Fortaleza, Brazil. Dr. Costa is an adjunct professor, Division of Oral Radiology, Federal University of Ceará, Fortaleza, Brazil. Address correspondence to Dr. Costa at Rua Alexandre Baraúna, 949 - Rodolfo Teófilo, CEP 60430-160, FortalezaCE, Brazil, e-mail [email protected]. Dr. Chaves is an assistant professor, Division of Stomatology and Oral Radiology, Federal University of Ceará, Sobral Campus, Sobral, Brazil. Dr. Alves is an associate professor, Division of Oral Pathology, Federal University of Ceará, Fortaleza, Brazil. Dr. Sousa is an associate professor, Division of Oral Pathology, Federal University of Ceará, Fortaleza, Brazil. Dr. Patrocínio is a pathologist, Division of Pathology, School of Medicine, Federal University of Ceará, Fortaleza, Brazil. Dr. Pereira is an adjunct professor, Division of Oral Pathology, Federal University of Ceará Sobral Campus, Sobral, Brazil. Disclosure. None of the authors reported any disclosures. Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine.
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ORIGINAL CONTRIBUTIONS
1. da Silva-Santos PS, Silva BS, Coracin FL, Yamamoto FP, PintoJunior DD, Magalhaes MG. Granulocytic sarcoma of the oral cavity in a chronic myeloid leukemia patient: an unusual presentation. Med Oral Patol Oral Cir Bucal. 2010;15(2):e350-e352. 2. 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(6): 689-693. 3. Brunning RD, Matutes E, Head D, et al. Acute myeloid leukaemia not otherwise categorized. In: Jaffe ES, Harris N, Stein H, Vardiman JW, eds. World Health Organization of Tumours: Pathology and Genetics—Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001: 104-105. 4. Audouin J, Comperat E, Le Tourneau A, et al. Myeloid sarcoma: clinical and morphologic criteria useful for diagnosis. Int J Surg Pathol. 2003;11(4):271-282. 5. 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(5):491-494. 6. 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(10):1514-1519. 7. Kim K, Velez I, Rubin D. A rare case of granulocytic sarcoma in the mandible of a 4-year-old child: a case report and review of the literature. J Oral Maxillofac Surg. 2009;67(2):410-416. 8. Bassichis B, McClay J, Wiatrak B. Chloroma of the masseteric muscle. Int J Pediatr Otorhinolaryngol. 2000;53(1):57-61. 9. Xie Z, Zhang F, Song E, Ge W, Zhu F, Hu J. Intraoral granulocytic sarcoma presenting as multiple maxillary and mandibular masses: a case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(6):e44-e48. 10. Srinivasan B, Ethunandan M, Anand R, Hussein K, Ilankovan V. Granulocytic sarcoma of the lips: report of an unusual case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(1):e34-e36. 11. Pau M, Beham-Schmid C, Zemann W, Kahr H, Karcher H. Intraoral granulocytic sarcoma: a case report and review of the literature. J Oral Maxillofac Surg. 2010;68(10):2569-2574.
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12. Canger EM, Celenk P, Kayipmaz S. Denture-related hyperplasia: a clinical study of a Turkish population group. Braz Dent J. 2009;20(3):243-248. 13. Naderi NJ, Eshghyar N, Esfehanian H. Reactive lesions of the oral cavity: a retrospective study on 2068 cases. Dent Res J (Isfahan). 2012;9(3): 251-255. 14. Jessri M, AbdulMajeed AA, Matias MA, Farah CS. A case of primary diffuse large B-cell non-Hodgkin’s lymphoma misdiagnosed as chronic periapical periodontitis. Aust Dent J. 2013;58(2):250-255. 15. Faitaroni LA, Bueno MR, De Carvalhosa AA, Bruehmueller Ale KA, Estrela C. Ameloblastoma suggesting large apical periodontitis. J Endod. 2008;34(2):216-219. 16. Estrela C, Decurcio DA, Silva JA, Mendonca EF, Estrela CR. Persistent apical periodontitis associated with a calcifying odontogenic cyst. Int Endod J. 2009;42(6):539-545. 17. Liesner RJ, Goldstone AH. ABC of clinical haematology: the acute leukaemias. BMJ. 1997;314(7082):733-736. 18. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:109-138. 19. de Santana Santos T, Martins-Filho PR, Piva MR, de Souza Andrade ES. Focal fibrous hyperplasia: a review of 193 cases. J Oral Maxillofac Pathol. 2014;18(suppl 1):S86-S89. 20. Amaya MP, Criado L, Blanco B, et al. Polymorphisms of proinflammatory cytokine genes and the risk for acute suppurative or chronic nonsuppurative apical periodontitis in a Colombian population. Int Endod J. 2013;46(1):71-78. 21. de Moraes Ramos-Perez FM, Soares UN, Silva-Sousa YT, da Cruz Perez DE. Ossifying fibroma misdiagnosed as chronic apical periodontitis. J Endod. 2010;36(3):546-548. 22. van der Waal RI, Huijgens PC, van der Valk P, van der Waal I. Characteristics of 40 primary extranodal non-Hodgkin lymphomas of the oral cavity in perspective of the new WHO classification and the International Prognostic Index. Int J Oral Maxillofac Surg. 2005;34(4):391-395. 23. Kemp S, Gallagher G, Kabani S, Noonan V, O’Hara C. Oral nonHodgkin’s lymphoma: review of the literature and World Health Organization classification with reference to 40 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105(2):194-201.
DIAGNOSTIC CHALLENGE
Intraoral mass in the posterior maxillary vestibule Francisco Samuel Rodrigues Carvalho, DDS; Fábio Wildson Gurgel Costa, DDS, PhD; Filipe Nobre Chaves, DDS; Ana Paula Negreiros Nunes Alves, DDS, PhD; Fabrício Bitu Sousa, DDS, PhD; Régia Maria do Socorro Vidal do Patrocínio, MD, MSc; Karuza Maria Alves Pereira, DDS, PhD
544 JADA 146(7) http://jada.ada.org
THE CHALLENGE
A
42-year-old woman came to our clinic for consultation regarding a painful swelling inside her mouth that had developed over approximately 1 month. During this time, the patient had no recurrent fever, generalized malaise, or weight loss. The patient reported that her most recent dental visit had been 15 days ago, and since that time, her oral discomfort had worsened. The patient’s primary care professional previously had prescribed amoxicillin (500 milligrams); however, after completing the 7-day drug regimen, the patient continued to have symptoms. An oral health care professional at our clinic observed a smooth, painful, soft, sessile nodular mass with well-defined margins in the posterior maxillary vestibule sulcus (Figure 1). The clinician also observed heavily decayed teeth and clinical signs of periodontal disease. The patient had a history of untreated myelodysplastic syndrome (MDS) and nonspecific heart murmur, and she was taking folic acid to treat severe anemia. In addition, the patient had no history of cancer, alcohol consumption, smoking, or hospitalizations. An overview of the patient’s panoramic radiograph revealed multiple lost teeth, root residues, heavily decayed teeth with periapical radiolucent lesions, horizontal bone resorption in the jaws, and bone sclerosis in the periapical area of tooth no. 34 (Figure 2). The clinician did not observe any radiographic changes in the area corresponding to the nodular lesion. The patient’s preoperative blood screening showed the following results (Table): low values for red blood cell count, hemoglobin, and hematocrit; increased mean corpuscular volume; low values for white blood cell and platelet counts; and increased clotting time. The clinician performed an oral incisional biopsy and submitted the specimen for histopathologic evaluation. The histopathologic analysis revealed diffuse sheets of large cells with ovoid and sometimes hyperchromatic nuclei, scarce cytoplasm, mild mitotic activity, and necrotic foci, resulting in a preliminary diagnosis of lymphoproliferative disorder (Figure 3). The clinician performed an immunohistochemical analysis using the antibodies PAX-5, terminal deoxynucleotidyl transferase (TdT), CD3, CD79a, CD34, CD117, and myeloperoxidase (MPO). The results were positive in 90% of cells for MPO (Figure 4), diffuse positive for CD117, focal positive in rare cells for CD3 and TdT, positive in plasmocytes for CD79a and in vessels for CD34, and negative for PAX-5. The results of a cytogenetic study showed deletion in the long arm of chromosome 11 in 4 metaphases (that is, del[11][q32]).
July 2015
ORIGINAL CONTRIBUTIONS
Figure 1. Intraoral aspect: a soft mass with well-defined margins in the posterior maxillary vestibule sulcus.
Figure 2. Panoramic radiograph showing lost teeth, root residues, heavily decayed teeth, periapical radiolucent lesions, generalized horizontal bone resorption, and tooth no. 34 with periapical bone sclerosis.
Figure 3. Diffuse sheets of large cells with ovoid and sometimes hyperchromatic nuclei in scarce cytoplasm, mild mitotic activity, and necrotic area (hematoxylin and eosin stain, original magnification 200).
Figure 4. Myeloperoxidase stain showing a strongly positive and diffuse cellular reaction (immunohistochemical staining, original magnification 400). mm, micrometer.
TABLE
Preoperative laboratory values. HEMATOLOGIC PARAMETERS
PATIENT VALUES
LABORATORY REFERENCE VALUES
2.39 million cells/mm3*
4.0-5.5 million cells/mm3
Hemoglobin
7.8 g/dL†
11.5-15.5 g/dL
Hematocrit
25.6%
36%-45%
Red Blood Cell
Mean Corpuscular Volume Leukocyte Segmented Lymphocyte Platelet
107.1 fL‡
80-96 fL
2,300 cells/mm3
3,600-11,000 cells/mm3
220 cells/mm3 125,000 units/mm
1,500-7,000 cells/mm3 3
150,000-400,000 units/mm3
7 min, 33 s
1-3 min
Prothrombin Time
16 s
11-14.6 s
Prothrombin Activity
76%
70%-100%
International Normalized Ratio
1.26
1.20
Serum Creatinine
0.6 mg/dL§
0.5-1.0 mg/dL
Fasting Blood Glucose
96 mg/dL
66-99 mg/dL
Clotting Time
* † ‡ §
cells/mm3: Cells per cubic millimeter. g/dL: Grams per deciliter. fL: Femtoliters. mg/dL: Milligrams per deciliter.
CAN YOU MAKE THE DIAGNOSIS? A. epulis fissuratum (inflammatory fibrous hyperplasia) B. chronic apical periodontitis with vestibular mucosa extension
C. extranodal non-Hodgkin lymphoma D. myeloid leukemia, extramedullary type
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July 2015 545
ORIGINAL CONTRIBUTIONS
THE DIAGNOSIS D. Myeloid leukemia, extramedullary type Myeloid leukemia, extramedullary type (MLET), is characterized by immature granulocytes (that is, immature neutrophils with a neutrophilic, acidophilic, or basophilic pattern), and it has been associated with myeloid leukemia, MDS, and other myeloproliferative disorders.1,2 Previously, this disease has been known as chloroma, granulocytic sarcoma,1 and extramedullary myeloid sarcoma3; however, it is more accurately called MLET.4 When we searched the PubMed database for intraoral MLET, we found a total of 81 cases reported from March 1970 through January 2015. In addition, investigators have described a small number of intraoral MLET cases occurring after the development of an acute myeloid leukemia (AML) process in patients with a previous diagnosis of MDS.5 MLET can affect people of any age, especially women,5,6 and intraoral lesions typically present as diffuse gingival enlargement most often in the mandible, followed by the maxilla, palate, gingiva, postextraction sites, and buccal region.7-9 The clinical findings for the patient described in this article allied with that of a woman with a history of MDS who had an intraoral mass that was suspected to have a possible diagnosis of MLET. In this article, we presented the case of a patient with an important oral lesion that is associated with systemic disease in the field of the hematopathology and that can be mistaken for a variety of benign or malignant processes. Clinically, MLET is an aggressive lesion that may be symptomatic9 or asymptomatic.8 Rapid growth with local bone destruction and invasion of adjacent tissues is a common finding.7 The most typical clinical sign is the presence of an enlargement in the oral mucosa. Other characteristics include color in a spectrum covering black, brown, red, and light gray, and the absence of ulcerations.1 Tumors can promote bone and radicular tooth resorption, whereas pressure on nerve structures may cause pain, facial nerve paralysis, deafness, and blindness.7 Our patient was symptomatic and had a soft-tissue lesion. MYELOID LEUKEMIA, EXTRAMEDULLARY TYPE
Investigators have observed MLET in association with myeloid leukemia and other myeloproliferative disorders such as polycythemia vera, hypereosinophilia, and myeloid metaplasia.9,10 Although clinicians have observed MLET most commonly in patients with myeloid leukemia, only 3.0% to 9.1% of patients diagnosed with chronic myeloid leukemia or AML have MLET.10 Intraoral MLET usually is associated with AML.9 According to Pau and colleagues,11 only 4 cases of MLET in patients with MDS have been reported, 3 of
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July 2015
whom developed AML; these findings support the diagnosis of the patient described in this article. Although oral manifestations of AML are common and patients with AML often have gingival and mucosal tissue enlargement, this finding is rare in patients with MLET.6 Our patient’s differential diagnosis list included an inflammatory oral mucosal disease; however, she did not have factors causing local trauma, such as dental prosthesis or parafunctional habits.12,13 Although periapical diseases of nonendodontic origin may resemble malignant neoplasms,14 our review of the patient’s case revealed a lack of the following important signs of chronic apical periodontitis: clinical radiographic evidence of bone involvement or vestibular cortical expansion, and negative pulp vitality testing.14-16 Extranodal non-Hodgkin lymphoma may occur in the jaws and is associated with nonspecific clinical signals or symptoms such as local discomfort, related cervical lymphadenopathy, swelling, pain, ulcer, and tooth mobility.14 Thus, clinicians should perform histopathologic analysis and immunohistochemistry to establish a definitive diagnosis of MLET.6 Investigators have described 4 histologic variants of MLET: a blastic variant (mainly with myeloblasts), an immature variant (with myeloblasts and promyelocytes), a differentiated variant (with myeloblasts, promyelocytes, and more mature granulocytes), and a variant with intracytoplasmic Auer bodies.4 For our patient, we confirmed the hematologic origin by noting positivity for CD117, which is associated with AML. We identified the myeloid lineage by noting a strong positivity for MPO, which indicates a granulocytic myeloperoxidase subtype.4 The presence of MLET suggests a poor prognosis: it may be an early manifestation of myeloid leukemia (as in the case described in this article) or a worsening of the clinical condition of a patient with leukemia.7 Our patient had MDS and, according to Kim and colleagues,7 the presence of MLET indicates the transformation of myeloproliferative disease into acute leukemia. Historically, AML was classified as follows: M0 (AML with minimal evidence of myeloid differentiation), M1 (acute myeloblastic leukemia without maturation), M2 (acute myeloblastic leukemia with maturation), M3 (acute promyelocytic leukemia), M4 (acute myelomonocytic leukemia), M5 (acute monocytic, monoblastic leukemia, or both), M6 (acute erythroleukemia), and M7 (acute megakaryoblastic leukemia).17,18 In 2008, a revision of the World Health Organization (WHO) classification for tumors of hematopoietic and lymphoid tissues included a new group called “AML with myelodysplasia-related
ORIGINAL CONTRIBUTIONS
changes.”18 Thus, in agreement with the WHO revision, our patient may be assigned to a group called “AML arising from previous myelodysplastic syndrome (MDS) or an MDS or myeloproliferative neoplasm.”18 Once MLET is diagnosed, aggressive therapy is warranted owing to the poor prognosis.10 After receiving the diagnosis of AML, our patient began chemotherapy (daunorubicin [87 mg], Ara-C [195 mg]) and prophylaxis (vancomycin, meropenem, piperacillin and tazobactam, and fluconazole); however, her condition rapidly evolved toward severe neutropenia, which was followed by septicemia and death (4 months after the diagnosis). DIFFERENTIAL DIAGNOSIS
Epulis fissuratum (inflammatory fibrous hyperplasia). Epulis fissuratum (that is, inflammatory fibrous hyperplasia) is an oral mucosal disease caused by low-intensity chronic trauma (for example, wearing ill-fitting dentures) or parafunctional habits.12 Lesions typically appear as a single or multiple hyperplastic tissue covered with stratified squamous ephithelium in the maxillary alveolar vestibule.12 The lesion size varies from a few millimeters to several centimeters, and the surface may be smooth or ulcerated (the latter often is associated with pain).12,13 According to Naderi and colleagues,13 these lesions have been reported to occur in patients aged 3 to 72 years (average, 34.7 years), and the lesions occur predominantly in males. In a Brazilian cross-sectional study of 1,290 soft-tissue reactive lesions, the prevalence of epulis fissuratum in the oral cavity was 15%, and the most commonly affected site was the buccal mucosa, followed by the lower lip and tongue.19 De Santana Santos and colleagues19 reported local trauma in 90.7% of the cases they studied. In our patient’s case, the clinical findings (for example, age, oral site, and soft-tissue aspect) we observed in the patient resembled an inflammatory fibrous hyperplasia. Chronic apical periodontitis with vestibular mucosa extension. Chronic apical periodontitis is a clinical form of apical periodontitis, which is characterized by an inflammatory disorder of periradicular tissues caused by microorganisms in the root canal system of an affected tooth, coupled with a local immune response.20 This inflammatory process involves bone resorption that is revealed as radiolucency on radiographic examinations.15,16 Clinically, chronic apical periodontitis is generally asymptomatic; however, a soft-tissue mass (that is, vestibular mucosa extension) can arise if the patient has symptoms similar to periodontitis, such as gingival inflammation and bleeding.14 Investigators have reported several lesions that suggest the diagnosis of apical periodontitis, such as benign odontogenic (for example, cysts and tumors) and nonodontogenic (for example, pseudocysts, infections, central giant cell lesions, fibro-osseous lesions, soft-tissue neoplasms) processes and malignant neoplasms.21 Our patient had a vestibular mucosal lesion
associated with signs of generalized periodontal disease that reinforced a possible diagnosis of chronic apical periodontitis with vestibular mucosa extension. Extranodal non-Hodgkin lymphoma. Lymphomas represent a distinct group of clonal malignant proliferative diseases that originate from a somatic mutation in a lymphocyte progenitor (B-, T-, or natural killer-cells phenotype) situated in lymph nodes or any organ.21 Lymphomas are categorized as Hodgkin and nonHodgkin diseases.22 Approximately 40% of non-Hodgkin lymphomas present as extranodal disease.23 The most common extranodal site is the gastrointestinal tract, but the oral cavity (mainly maxillary involvement) is a rare site of primary occurrence of disease.22 Clinically, nonHodgkin lymphoma may be characterized as a mass with or without superficial ulceration. Although it is uncommon, patients may have painful symptoms, fever, or weight loss.23 In the case described in this article, our patient’s maxillary involvement and clinical aspects could have represented possible signs of a malignant lesion, such as the extranodal non-Hodgkin lymphoma. CONCLUSIONS
Although the occurrence of MLET in the oral cavity is rare, it is important for clinicians to understand the oralsystemic connection of the condition. Knowing a patient’s medical history of MDS can alert the clinician to suspect MLET, because an oral lesion may be a manifestation of that pre-existing blood disorder. The laboratory finding of severe pancytopenia in a patient with a history of MDS should serve as a warning to the clinician that the concurrent presence of an ulcerated oral mucosal lesion for more than 1 month in duration can be a sign of a life-threatening medical condition. n http://dx.doi.org/10.1016/j.adaj.2015.02.009 Copyright ª 2015 American Dental Association. All rights reserved.
Dr. Carvalho is a postgraduate student and a resident in Oral and Maxillofacial Surgery, Walter Cantídio University Hospital, Fortaleza, Brazil. Dr. Costa is an adjunct professor, Division of Oral Radiology, Federal University of Ceará, Fortaleza, Brazil. Address correspondence to Dr. Costa at Rua Alexandre Baraúna, 949 - Rodolfo Teófilo, CEP 60430-160, FortalezaCE, Brazil, e-mail [email protected]. Dr. Chaves is an assistant professor, Division of Stomatology and Oral Radiology, Federal University of Ceará, Sobral Campus, Sobral, Brazil. Dr. Alves is an associate professor, Division of Oral Pathology, Federal University of Ceará, Fortaleza, Brazil. Dr. Sousa is an associate professor, Division of Oral Pathology, Federal University of Ceará, Fortaleza, Brazil. Dr. Patrocínio is a pathologist, Division of Pathology, School of Medicine, Federal University of Ceará, Fortaleza, Brazil. Dr. Pereira is an adjunct professor, Division of Oral Pathology, Federal University of Ceará Sobral Campus, Sobral, Brazil. Disclosure. None of the authors reported any disclosures. Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine.
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