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Primary non-Hodgkin’s lymphoma of the mandibular gingiva with maxillary gingival recurrence
Oral Oncology EXTRA (2006) 42, 123– 128
available at www.sciencedirect.com
journal homepage: http://intl.elsevierhealth.com/journal/ooex
CASE REPORT
Primary non-Hodgkin’s lymphoma of the mandibular gingiva with maxillary gingival recurrence F. Angiero a, M. Stefani
a,*
, R. Crippa
b
a
` degli Studi di Milano, Cattedra d’Istituzione di Anatomia Patologica, Via Della Commenda, 19, Universita 20122 Milano, Italy b Istituto Stomatologico Italiano, Dipartimento di Patologia Orale, Via Pace, 21, 20122 Milano, Italy Received 3 October 2005; accepted 5 October 2005
KEYWORDS
Summary Primary (extranodal) non-Hodgkin’s lymphoma (NHL) of the oral cavity is relatively rare. We report a case of NHL involving the left anterior mandibular gingiva of a 56-year-old man. He was initially treated with antibiotics and root canal therapy of the lower lateral incisor as there was a history of trauma to this area. The adjacent lateral incisor tested non-vital. However, after 2 weeks of antibiotic therapy the swelling increased in size and an incisional biopsy was performed. A diagnosis of non-Hodgkin’s lymphoma, large-B cell type was rendered. The patient was then referred to medical oncology for staging work-up and treatment. A course of six cycles of CHOP chemotherapy (Cyclophosphamide, Hydroxydoxorubicin, Oncovin, Prednisone) and radiotherapy were scheduled. There was a complete response upon completion of the combined chemotherapy and radiotherapy. One year later, the patient developed a 2 · 2-cm, painless, firm, fixed mass of the left anterior maxillary vestibule. No additional findings were noted clinically. Magnetic resonance imaging (MRI) confirmed the clinical findings and there was no suspicion of disease elsewhere. Pathologic examination revealed non-Hodgkin’s lymphoma, B-cell type. This lesion was identical morphologically and immunophenotypically to the initial mandibular lesion. Complete radiographic staging detected no other sites of disease. The bone marrow was not involved. The lesion rapidly normalized after six cycles of Fludara, Novantrone and Mabthera chemotherapy and one cycle of Cytarabine (Ara-C). Partial remission was achieved, but the patient died of disseminated disease, 12 months after relapse. There was an associated HCV infection, which may have played a role in the fatal outcome. c 2005 Elsevier Ltd. All rights reserved.
Lymphoma; Non-Hodgkin’s; Oral cavity; Large B-cell lymphoma
* Corresponding author. Tel.: +39 250 320807. E-mail address: [email protected] (M. Stefani).
1741-9409/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ooe.2005.10.008
124
F. Angiero et al.
Introduction Non-Hodgkin’s lymphoma (NHL) arises primarily within the lymph nodes, but approximately 24% affect extranodal locations.1,2 The most frequent extranodal sites include the gastrointestinal tract, skin, bones, and Waldeyer’s ring. The reported incidence of oral NHL ranges from 0.1% to 5%.2–7 In the oral cavity, NHL may occur within soft tissue or bone, affecting the paranasal sinuses, gingiva, floor of the mouth, buccal sulcus, salivary gland, or cheek. The most commonly affected sites are the Waldeyer’s ring and the palate.5,6 Few cases of gingival lymphomas have been reported: Gould and Alpert8 reported a case that involved the maxillary labial attached gingiva; Fukuda et al.9 reviewed 20 cases of malignant lymphoma of the oral cavity, 17 of which originated in the soft tissues and three involved the jaw bones; Park10 reported a case of NHL of the right anterior maxillary gingiva and antrum; Yasumoto et al.11 reported an MRI study of gingival lymphoma; Raut et al.12 reported an unusual gingival presentation; Epstein et al.13 reviewed 361 cases and reported seven gingival presentations; van der waal et al.14 reported 40 cases occurring in the oral cavity, 24 in the soft tissues and 16 intraosseous lesions; and in 2005 Kobler et al.15 reported one gingival case. Oral NHL lesions may develop in the soft tissues or centrally within the jaws, with or without nodal or marrow involvement. They appear as non-tender swellings commonly affecting the vestibule, gingiva or palatal mucosa; clinically the lesion may mimic inflammatory processes. The World Health Organization classification of lymphoma16 updates the Revised European American Classification of Lymphoid Neoplasms (REAL) classification. Non-Hodgkin’s lymphomas are subclassified by the Working Formulation17 into low, intermediate, and high-grade varieties. High-grade lymphomas are generally chemosensitive; central nervous system or bone marrow involvement adversely affects prognosis. The most widely used system for staging lymphomas is the Ann Arbor classification, initially introduced for Hodgkin’s lymphoma18,19 and later adopted to classify non-Hodgkin’s lymphomas. Stage I comprises lymphomas localized and confined to one side of the diaphragm with a single lesion; Stage IE indicates a single extralymphatic organ or site involved. Stage II implies the presence of 2 or more sites of involvement on the same side of the diaphragm; Stage IIE the localized involvement of an extra-lymphatic organ or site. Stage III indicates involvement of multiple lymph nodes on both sides of the diaphragm, including involvement of the spleen or localized involvement of an extra-lymphatic site. Stage IV is diffuse or disseminated involvement that may include one or more extra-lymphatic organs other than the spleen (i.e., liver or bone marrow). The prognosis generally worsens as the disease stage increases.
Figure 1 Photograph showing initial presentation of the lesion in the left anterior site of the mandible.
antibiotics and root canal therapy of the lower lateral incisor, as this tooth tested non-vital. However, after 14 days of antibiotic therapy the lesion continued to increase in size, and incisional biopsy was performed. No palpable cervical nodes were present (Fig. 2). The lesion was composed of diffuse predominantly large lymphocytes. The immunohistochemical panel revealed these to be B-cells, which showed a positive staining reaction for CD20 and Ki 67 (Figs. 3 and 4). Together, these findings led to a final diagnosis of malignant lymphoma; diffuse, large B-cell type. A computed tomographic scan of the patient’s mandible revealed loss of lamina dura and widening of periodontal ligament (Fig. 2). The patient was then referred to medical oncology for staging workup and treatment. Six courses of combination chemotherapy with, CHOP (cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone) and radiotherapy were scheduled. The sixth cycle of chemotherapy was stopped because of raised transaminase levels. There was complete remission (Fig. 5). The medical work-up identified
Case report A 56-year-old man presented with a rapidly progressive swelling of the left anterior mandibular buccal gingiva (Fig. 1). The panoramic radiograph was unremarkable. Clinical examination revealed a firm soft tissue swelling that measured 1.5 · 1.0 cm. He was initially treated with
Figure 2 A computed tomographic scan of the patient’s mandible shows loss of lamina dura and widening of periodontal ligament.
Primary NHL of the mandibular gingiva with maxillary gingival recurrence
Figure 3 Photomicrograph of immunohistochemical stain shows sheets of large mononuclear lymphoid cells positive for CD20 (original magnification ·20).
chronic hepatitis C virus (HCV). His complete blood count was normal; routine blood and urine chemistry was normal except for elevated liver enzyme levels. Anti-hepatitis C virus (HCV) antibodies were detected by recombinant immunoblot assay. Chest radiograph, abdominal CT scan, and nuclear bone scan were unremarkable. Bone marrow aspiration biopsy was normal. Remission was achieved. One year later he developed a swelling of the maxillary vestibule and gingiva (Fig. 6). Computerized tomography (CT) of the head and neck confirmed the anterior maxillary mass, measuring approximately 2.0 · 2.0 cm in diameter. MRI failed to reveal bone involvement (Fig. 7). The regional lymph nodes were not involved clinically nor were there any suspicious nodes on imaging of the neck. The maxillary mass was excised. Histological examination revealed a tumor identical to the prior mandibular gingival lesion (Figs. 8–10). In the postoperative period the patient was treated
125
Figure 5 Photograph shows a follow-up status after 5 treatments of systemic chemotherapy: good clinical response to treatment.
Figure 6 Photograph showing a recurrence in the left anterior site of the maxilla.
Figure 4 Photomicrograph of diffuse large B-cells with clear cytoplasm, prominent nucleoli, non-cleaved nuclei and rare mitotic figures. Immunohistochemical staining for CD3 showing negative staining around the tumor cells (original magnification ·40).
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Figure 7 RMI shows soft tissue involvement of the left anterior site of the maxilla.
F. Angiero et al.
Figure 10 Photomicrograph of immunohistochemical staining showing negative for ALK1 (original magnification ·20).
with six cycles of (Fludara, Novantrone plus Mabthera) chemotherapy and one cycle of Cytarabine (Ara-C). The patient died 12 months after relapse, despite an initial response. There was an associated HCV infection, which may have played a role in the fatal outcome.
Pathological finding
Figure 8 Photomicrograph showing large cells with vesicular nuclei, prominent nucleoli, basophilic cytoplasm, and mitotic figures. (hematoxylin–eosin, original magnification ·40).
Microscopically (hematoxylin and eosin stain) the lesion consisted of a diffuse proliferation of large atypical lymphoid cells with clear cytoplasm. Mitotic figures were infrequently identified. The cells were large, isolated or in small groups, demonstrating a moderate amount of cytoplasm with large, round-to-oval nuclei containing coarse chromatin and variably sized nucleoli. Focally, prominent nuclear irregularity and pleomorphism were evident. Some cells were binucleate. Immunohistochemical reactions showed these cells to belong to the B-lymphocyte line. The second biopsy specimen confirmed the diagnosis of B cell-nonHodgkin’s lymphoma; diffuse, large cell type.
Immunohistochemistry Immunohistochemistry was performed using standard techniques.20 We used a panel of monoclonal antibodies for the following markers: CD20 (selective marker that recognizes a subpopulation of B-cells); CD10 (marker for follicular center B-cells and granulocytes), CD3 (marker for T-cells and NK cells), CD30 (marker for activated T- and B-cells), ALK-1 (marker for anaplastic large cells) and Ki 67 (proliferation marker). Both biopsy specimens were positive for CD20 and Ki 67 and negative for CD3, CD10, CD30, and ALK-1. A diagnosis of non-Hodgkin’s lymphoma, diffuse, large B-cell type was rendered.
Discussion
Figure 9 Photomicrograph for immunohistochemical staining showing positive for CD20 (original magnification ·40).
Lymphoma is the second commonest neoplasm of the head and neck, following squamous cell carcinoma.13 Most occur in the Waldeyer’s ring, (e.g., tonsils, pharynx, base of the tongue). Occurrence in the oral cavity proper is rare.
Primary NHL of the mandibular gingiva with maxillary gingival recurrence Given an appropriate clinical setting, extranodal lymphoma must be considered in differential diagnosis. The first important factor in the diagnosis of extranodal lymphoma involving the oral cavity is to determine whether the lesion is a dental abscess, a periodontal infection, a primary lymphoma of the oral cavity or a manifestation of more disseminated disease. In the head and neck region, lymphoma should be considered when there is unexplained dental pain, numbness, tooth mobility, swelling, ulceration, a mass in an extraction socket, or any ill-defined lytic osseous changes. In our case, the gingiva was the first location and clinically the lesion appeared as a nodular mass, erythematous and inflamed, but without ulceration, associated with a non-vital tooth. There was a history of trauma to this area and the panoramic film showed no bone abnormalities. The general dentist applied endodontic treatment to the non-vital tooth. When the patient was seen for follow-up 2 weeks after his initial appointment the swelling had increased. An incisional biopsy was performed and a diagnosis of diffuse large B-cell lymphoma was rendered. The current staging procedures for extranodal oral lymphoma include a panoramic radiograph, abdominal and chest CT scan, bone scans, routine laboratory tests (hemogram, urine analysis, complete blood cell counts, lactate dehydrogenase and erythrocyte sedimentation rate), and bone marrow aspiration biopsy. A diagnosis of bone lymphoma cannot be established on the basis of radiography alone. Approximately 80% of bone lesions exhibit osteolytic erosive features, whereas the remaining 20% show sclerotic or mixed radiographic appearance.21–23 The medical evaluation of this patient revealed chronic hepatitis C virus (HCV), his complete blood count was normal; routine laboratory tests, chest radiograph, and bone marrow biopsy were normal. The diagnosis was established through histological examination of biopsy tissue, coupled with immunohistochemical phenotyping. Immunohistochemistry plays an important role in distinguishing cell types and differential diagnosis.24 We used CD20, CD10, CD3, CD30, ALK-1 and Ki 67 and found both biopsy specimens to be positive for CD20 and Ki 67 and negative for CD3, CD10, CD30, ALK-1. We consequently diagnosed diffuse large-B cell lymphoma. The concomitant HCV infection is of interest in this case. Recent epidemiological studies have revealed an association between HCV infection and the clonal proliferation of Bcells.23–25 It has been suggested26–31 that chronic antigenic stimulation (related to the Epstein–Barr virus, human immunodeficiency virus, human leukemia-lymphoma virus 1, human herpes virus 8 or hepatitis viruses B, C and G) acts on multiple B-cell clones, which may synchronously or metachronously undergo neoplastic transformation. In particular, B-cell lymphoma has been reported to be frequently associated with or related to HCV infection. In our case, which was clinically cured for NHL, a subsequent manifestation of B-cell lymphoma in the soft tissue vestibule of the maxilla, detected one year later and after complete remission, was considered to be a recurrence. Several studies have indicated that a second occurrence after a short period of time (<2–3 years), presenting the same histological properties as the primary lymphoma, should be considered a recurrence of the primary tumor, whereas
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different histopathology and longer time before recurrence are more indicative of a second primary lymphoma.32,33 The morphological characteristics of the second biopsy specimen were identical to those of the first specimen. The patient was treated as for a recurrence with chemotherapy; he did well for five months, but died two years after the initial diagnosis. Prognosis is influenced by clinical stage and histologic grade. Large cell lymphomas are considered aggressive and have a poorer prognosis.34–36 It is reported that diffuse large-cell types of NHL are considered high grade, with a 5year survival of about 30%, whereas the follicular, small cleaved-cell type are considered low grade, with a 5-year survival rate of 70%.37–41 The present case was high-grade diffuse large B-cell type lymphoma, as indicated in the REAL classification, and the clinical stage was IIE with soft tissue involvement; thus prognosis was poor; and in fact the patient died within a year. In brief, we report a case of primary non-Hodgkin’s lymphoma of the anterior vestibule of the mandible, with a recurrence at the left upper site in the maxillary vestibule that, to our knowledge, has not been reported previously. There was an associated HCV infection. The high potential for recurrence of this type of tumor, in addition to the role played by chemotherapeutic agents, and the role of chronic antigenic stimulation (specifically the hepatitis C virus) which has been linked to the development of some lymphoma subsets, can facilitate the development of a recurrence or of a second primary tumor. It appears that such an association may produce a recurrence that is more aggressive and, in this case, fatal.
References 1. Clark RM, Fitzpatrick PJ, Gospodarowitcz MK. Extranodal malignant lymphomas of the head and neck. J Otolaryngol 1983;12:239–45. 2. Spatafore CM, Keyes G, Skidmore AE. Lymphoma: an unusual presentation. J Endod 1989;15:438–41. 3. Ogden GR. Lymphoma of the oral soft tissues. Br Dent J 1986;161:9–12. 4. Nittayananta W, Chungpanich S, Pongpanich S, Mitarnun W. AIDS-related non-Hodgkin’s lymphoma presenting as delayed healing of an extraction wound. Br Dent J 1996;181:102–4. 5. Ratech H, Burke JS, Blayney DW, Sheibani K, Rappaport H. A clinicopathologic study of malignant lymphomas of the nose, paranasal sinuses, and hard palate, including cases of lethal midline granuloma. Cancer 1989;64:2525–31. 6. Wong DS, Fuller LM, Butler JJ, Shullenberg CC. Extranodal nonHodgkin’s lymphomas of the head and neck. Am J Roetgenol 1975;123:471–81. 7. Eisenbud L, Sciubba J, Mir R, Sachs SA. Oral presentation in non-Hodgkin’s lymphoma. A review of thirty-one cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1983;56:151–6. 8. Gould AR, Alpert B. Painless swelling of the anterior maxillary gingiva. J Oral Maxillofac Surg 1987;45:785–8. 9. Fukuda Y, Ishida T, Fujimoto M, Ueda T, Aozasa K. Malignant lymphoma of the oral cavity: clinicopathologic analysis of 20 cases. J Oral Pathol 1987;16:8–12. 10. Park YW. Non-Hodgkin’s lymphoma of the anterior maxillary gingiva. Arch Otolaryngol Head Neck Surg 1998;119:146. 11. Yasumoto M, Shibuya H, Fukuda H, Takeda M, Mukai T, Korenaga T. Malignant lymphoma of the gingiva: MR evaluation. Am J Neuroradiol 1998;19:723–7.
128 12. Raut A, Huryn J, Pollack A, Zlotolow I. Unusual gingival presentation of posttransplantation lymphoproliferative disorder: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:436–41. 13. Epstein JB, Epstein JD, Le ND, Gorsky M. Characteristics of oral and paraoral malignant lymphoma: a population based review of 361 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:519–25. 14. van der Waal RIF, 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;34:391–5. 15. Kobler P, Borcic J, Zore FI, Nola M, Sertic D. Primary non Hodgkins lymphoma of the oral cavity. Oral Oncol Extra 2005;1:12–4. 16. World Health Organization Classifications. Pathology & genetics. In: Jaffe ES, Harris NL, Stein H, Vardimar JW, editors. Tumors of haematopoietic and lymphoid tissues. IARC Press; 2001. 17. Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin’s disease. Cancer Res 1966;26:1063–83. 18. Bassi GS, Edin S, Glasg PS. An unusual presentation of nonHodgkin’s lymphoma in the head and neck. Am J Clin Oncol 2001;24(2):131–4. 19. Devita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology, vol. 2. 5th ed. New York: LippincottRaven; 1997., p. 2165–220. 20. Hsu SM, Raine L, Fanger H. Use of avidin–biotin–peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577–80. 21. Eideken-Monroe B, Edeiken J, Kim EE. Radiologic concepts of lymphoma of bone. Radiol Clin North Am 1990;28:411. 22. Castellino RA. The non-Hodgkin lymphomas: practical concepts for the diagnostic radiologist. Radiology 1991;178:315–21. 23. Marion J. Diagnosis and treatment of lymphomas. In: Thawley WR, Panje WR, Batsakis JG, editors. Comprehensive management of head neck tumors. Philadelphia: WB Saunders; 1999. p. 1840–53. 24. Biggar RJ, Rabkin CS. The epidemiology of acquired immunodeficiency virus related lymphomas. Curr Opin Oncol 1992;4:883–93. 25. Pavlova GP, Heinz R, Selim U, Bittermann E, Eder G. Association of GB virus C (GBV-C) hepatitis G virus (HGV) with hematological diseases of different malignant potential. J Med Virol 1999;57:361–6. 26. Santini GF, Crovatto M, Gianinni F, Bortolin MT, Mazzaro C, Invernizzi F. Hepatitis C virus and immunoglobulin gene rearrangements: an early step in lymphomagenesis? Acta Haematol 1998;100:117–22.
F. Angiero et al. 27. Divine M, Farcet JP. Adult T cell leukemia lymphoma: a model of retrovirus induced lymphomagenesis. In: Solal-Celigny P et al., editors. Non-Hodgkin’s lymphoma. London: Manson; 1993. p. 31–9. 28. Dupin N, Gorin I, Deleuze J, Agut H, Huraux JM, Escande JP. Herpes-like DNA sequences in AIDS-related tumors and Castleman’s disease. New Engl J Med 1995;333:799–800. 29. Ferri C, Caracciolo F, Zignego AL, La Civita L, Monti M, Longobardo G, et al. Hepatitis C virus infection in patients with non Hodgkins’s lymphoma. Br J Haematol 1994;88: 392–394. 30. Luppi M, Ferrari MG, Bonaccorsi G, Longo G, Narni F, Barozzi P, et al. Hepatitis C virus infection in subsets of neoplastic lymphoproliferations not associated with cryoglobulinemia. Leukemia 1996;10:351–5. 31. Zuckerman E, Zuckerman T, Levine A, Douer M, Gutekunst D, Mizokami K, et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Internal Med 1997;127: 423–8. 32. Coiffier B, Thieblemont C, Felman P, Salles G, Berger F. Indolent nonfollicular lymphomas: characteristics, treatment, and outcome. Sem Hematol 1999;36:198–208. 33. Shioyama Y, Nakamura K, Kunitake N, Kimura M, Terashima H, Masuda K. Relapsed non-Hodgkin’s lymphoma: detection and treatment. Radiat Med 2000;18:369–75. 34. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage—The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982; 49:2112–35. 35. Emanuel IA. Malignant lymphoma presenting as a parotid mass. J Laryngol Otol 1976;90:381–92. 36. Ho FC, Loke SL, Hui PK, Todd D, Ng RP, Khoo RK. Clinicopathological features of malignant lymphomas in 294 Hong Kong Chinese patients, retrospective study covering an eight-year period. Int J Cancer 1984;34:143–8. 37. Castellino RA. The non-Hodgkin lymphomas: practical concepts for the diagnostic radiologist. Radiology 1991;178:315–21. 38. Ostrowski ML, Unni KK, Banks PM, Shives TC, Evans RG, O’Connell MJ, et al. Malignant lymphoma of bone. Cancer 1986;58:2646–55. 39. Kirita T, Ohgi K, Shimooka K, Okamoto M, Yamanaka Y, Sugimura M. Primary non-Hodgkin’s lymphoma of the mandible treated with radiotherapy, chemotherapy, and autologous peripheral blood stem cell transplantation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:450–5. 40. Matthews JB, Basu MK. Primary extranodal lymphoma of the oral cavity: an immunohistochemical study. Br J Oral Surg 1983;21:159–63. 41. Barker GR. Unifocal lymphoma of the oral cavity. Br J Oral Maxillofac Surg 1984;22:426–31.
available at www.sciencedirect.com
journal homepage: http://intl.elsevierhealth.com/journal/ooex
CASE REPORT
Primary non-Hodgkin’s lymphoma of the mandibular gingiva with maxillary gingival recurrence F. Angiero a, M. Stefani
a,*
, R. Crippa
b
a
` degli Studi di Milano, Cattedra d’Istituzione di Anatomia Patologica, Via Della Commenda, 19, Universita 20122 Milano, Italy b Istituto Stomatologico Italiano, Dipartimento di Patologia Orale, Via Pace, 21, 20122 Milano, Italy Received 3 October 2005; accepted 5 October 2005
KEYWORDS
Summary Primary (extranodal) non-Hodgkin’s lymphoma (NHL) of the oral cavity is relatively rare. We report a case of NHL involving the left anterior mandibular gingiva of a 56-year-old man. He was initially treated with antibiotics and root canal therapy of the lower lateral incisor as there was a history of trauma to this area. The adjacent lateral incisor tested non-vital. However, after 2 weeks of antibiotic therapy the swelling increased in size and an incisional biopsy was performed. A diagnosis of non-Hodgkin’s lymphoma, large-B cell type was rendered. The patient was then referred to medical oncology for staging work-up and treatment. A course of six cycles of CHOP chemotherapy (Cyclophosphamide, Hydroxydoxorubicin, Oncovin, Prednisone) and radiotherapy were scheduled. There was a complete response upon completion of the combined chemotherapy and radiotherapy. One year later, the patient developed a 2 · 2-cm, painless, firm, fixed mass of the left anterior maxillary vestibule. No additional findings were noted clinically. Magnetic resonance imaging (MRI) confirmed the clinical findings and there was no suspicion of disease elsewhere. Pathologic examination revealed non-Hodgkin’s lymphoma, B-cell type. This lesion was identical morphologically and immunophenotypically to the initial mandibular lesion. Complete radiographic staging detected no other sites of disease. The bone marrow was not involved. The lesion rapidly normalized after six cycles of Fludara, Novantrone and Mabthera chemotherapy and one cycle of Cytarabine (Ara-C). Partial remission was achieved, but the patient died of disseminated disease, 12 months after relapse. There was an associated HCV infection, which may have played a role in the fatal outcome. c 2005 Elsevier Ltd. All rights reserved.
Lymphoma; Non-Hodgkin’s; Oral cavity; Large B-cell lymphoma
* Corresponding author. Tel.: +39 250 320807. E-mail address: [email protected] (M. Stefani).
1741-9409/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ooe.2005.10.008
124
F. Angiero et al.
Introduction Non-Hodgkin’s lymphoma (NHL) arises primarily within the lymph nodes, but approximately 24% affect extranodal locations.1,2 The most frequent extranodal sites include the gastrointestinal tract, skin, bones, and Waldeyer’s ring. The reported incidence of oral NHL ranges from 0.1% to 5%.2–7 In the oral cavity, NHL may occur within soft tissue or bone, affecting the paranasal sinuses, gingiva, floor of the mouth, buccal sulcus, salivary gland, or cheek. The most commonly affected sites are the Waldeyer’s ring and the palate.5,6 Few cases of gingival lymphomas have been reported: Gould and Alpert8 reported a case that involved the maxillary labial attached gingiva; Fukuda et al.9 reviewed 20 cases of malignant lymphoma of the oral cavity, 17 of which originated in the soft tissues and three involved the jaw bones; Park10 reported a case of NHL of the right anterior maxillary gingiva and antrum; Yasumoto et al.11 reported an MRI study of gingival lymphoma; Raut et al.12 reported an unusual gingival presentation; Epstein et al.13 reviewed 361 cases and reported seven gingival presentations; van der waal et al.14 reported 40 cases occurring in the oral cavity, 24 in the soft tissues and 16 intraosseous lesions; and in 2005 Kobler et al.15 reported one gingival case. Oral NHL lesions may develop in the soft tissues or centrally within the jaws, with or without nodal or marrow involvement. They appear as non-tender swellings commonly affecting the vestibule, gingiva or palatal mucosa; clinically the lesion may mimic inflammatory processes. The World Health Organization classification of lymphoma16 updates the Revised European American Classification of Lymphoid Neoplasms (REAL) classification. Non-Hodgkin’s lymphomas are subclassified by the Working Formulation17 into low, intermediate, and high-grade varieties. High-grade lymphomas are generally chemosensitive; central nervous system or bone marrow involvement adversely affects prognosis. The most widely used system for staging lymphomas is the Ann Arbor classification, initially introduced for Hodgkin’s lymphoma18,19 and later adopted to classify non-Hodgkin’s lymphomas. Stage I comprises lymphomas localized and confined to one side of the diaphragm with a single lesion; Stage IE indicates a single extralymphatic organ or site involved. Stage II implies the presence of 2 or more sites of involvement on the same side of the diaphragm; Stage IIE the localized involvement of an extra-lymphatic organ or site. Stage III indicates involvement of multiple lymph nodes on both sides of the diaphragm, including involvement of the spleen or localized involvement of an extra-lymphatic site. Stage IV is diffuse or disseminated involvement that may include one or more extra-lymphatic organs other than the spleen (i.e., liver or bone marrow). The prognosis generally worsens as the disease stage increases.
Figure 1 Photograph showing initial presentation of the lesion in the left anterior site of the mandible.
antibiotics and root canal therapy of the lower lateral incisor, as this tooth tested non-vital. However, after 14 days of antibiotic therapy the lesion continued to increase in size, and incisional biopsy was performed. No palpable cervical nodes were present (Fig. 2). The lesion was composed of diffuse predominantly large lymphocytes. The immunohistochemical panel revealed these to be B-cells, which showed a positive staining reaction for CD20 and Ki 67 (Figs. 3 and 4). Together, these findings led to a final diagnosis of malignant lymphoma; diffuse, large B-cell type. A computed tomographic scan of the patient’s mandible revealed loss of lamina dura and widening of periodontal ligament (Fig. 2). The patient was then referred to medical oncology for staging workup and treatment. Six courses of combination chemotherapy with, CHOP (cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone) and radiotherapy were scheduled. The sixth cycle of chemotherapy was stopped because of raised transaminase levels. There was complete remission (Fig. 5). The medical work-up identified
Case report A 56-year-old man presented with a rapidly progressive swelling of the left anterior mandibular buccal gingiva (Fig. 1). The panoramic radiograph was unremarkable. Clinical examination revealed a firm soft tissue swelling that measured 1.5 · 1.0 cm. He was initially treated with
Figure 2 A computed tomographic scan of the patient’s mandible shows loss of lamina dura and widening of periodontal ligament.
Primary NHL of the mandibular gingiva with maxillary gingival recurrence
Figure 3 Photomicrograph of immunohistochemical stain shows sheets of large mononuclear lymphoid cells positive for CD20 (original magnification ·20).
chronic hepatitis C virus (HCV). His complete blood count was normal; routine blood and urine chemistry was normal except for elevated liver enzyme levels. Anti-hepatitis C virus (HCV) antibodies were detected by recombinant immunoblot assay. Chest radiograph, abdominal CT scan, and nuclear bone scan were unremarkable. Bone marrow aspiration biopsy was normal. Remission was achieved. One year later he developed a swelling of the maxillary vestibule and gingiva (Fig. 6). Computerized tomography (CT) of the head and neck confirmed the anterior maxillary mass, measuring approximately 2.0 · 2.0 cm in diameter. MRI failed to reveal bone involvement (Fig. 7). The regional lymph nodes were not involved clinically nor were there any suspicious nodes on imaging of the neck. The maxillary mass was excised. Histological examination revealed a tumor identical to the prior mandibular gingival lesion (Figs. 8–10). In the postoperative period the patient was treated
125
Figure 5 Photograph shows a follow-up status after 5 treatments of systemic chemotherapy: good clinical response to treatment.
Figure 6 Photograph showing a recurrence in the left anterior site of the maxilla.
Figure 4 Photomicrograph of diffuse large B-cells with clear cytoplasm, prominent nucleoli, non-cleaved nuclei and rare mitotic figures. Immunohistochemical staining for CD3 showing negative staining around the tumor cells (original magnification ·40).
126
Figure 7 RMI shows soft tissue involvement of the left anterior site of the maxilla.
F. Angiero et al.
Figure 10 Photomicrograph of immunohistochemical staining showing negative for ALK1 (original magnification ·20).
with six cycles of (Fludara, Novantrone plus Mabthera) chemotherapy and one cycle of Cytarabine (Ara-C). The patient died 12 months after relapse, despite an initial response. There was an associated HCV infection, which may have played a role in the fatal outcome.
Pathological finding
Figure 8 Photomicrograph showing large cells with vesicular nuclei, prominent nucleoli, basophilic cytoplasm, and mitotic figures. (hematoxylin–eosin, original magnification ·40).
Microscopically (hematoxylin and eosin stain) the lesion consisted of a diffuse proliferation of large atypical lymphoid cells with clear cytoplasm. Mitotic figures were infrequently identified. The cells were large, isolated or in small groups, demonstrating a moderate amount of cytoplasm with large, round-to-oval nuclei containing coarse chromatin and variably sized nucleoli. Focally, prominent nuclear irregularity and pleomorphism were evident. Some cells were binucleate. Immunohistochemical reactions showed these cells to belong to the B-lymphocyte line. The second biopsy specimen confirmed the diagnosis of B cell-nonHodgkin’s lymphoma; diffuse, large cell type.
Immunohistochemistry Immunohistochemistry was performed using standard techniques.20 We used a panel of monoclonal antibodies for the following markers: CD20 (selective marker that recognizes a subpopulation of B-cells); CD10 (marker for follicular center B-cells and granulocytes), CD3 (marker for T-cells and NK cells), CD30 (marker for activated T- and B-cells), ALK-1 (marker for anaplastic large cells) and Ki 67 (proliferation marker). Both biopsy specimens were positive for CD20 and Ki 67 and negative for CD3, CD10, CD30, and ALK-1. A diagnosis of non-Hodgkin’s lymphoma, diffuse, large B-cell type was rendered.
Discussion
Figure 9 Photomicrograph for immunohistochemical staining showing positive for CD20 (original magnification ·40).
Lymphoma is the second commonest neoplasm of the head and neck, following squamous cell carcinoma.13 Most occur in the Waldeyer’s ring, (e.g., tonsils, pharynx, base of the tongue). Occurrence in the oral cavity proper is rare.
Primary NHL of the mandibular gingiva with maxillary gingival recurrence Given an appropriate clinical setting, extranodal lymphoma must be considered in differential diagnosis. The first important factor in the diagnosis of extranodal lymphoma involving the oral cavity is to determine whether the lesion is a dental abscess, a periodontal infection, a primary lymphoma of the oral cavity or a manifestation of more disseminated disease. In the head and neck region, lymphoma should be considered when there is unexplained dental pain, numbness, tooth mobility, swelling, ulceration, a mass in an extraction socket, or any ill-defined lytic osseous changes. In our case, the gingiva was the first location and clinically the lesion appeared as a nodular mass, erythematous and inflamed, but without ulceration, associated with a non-vital tooth. There was a history of trauma to this area and the panoramic film showed no bone abnormalities. The general dentist applied endodontic treatment to the non-vital tooth. When the patient was seen for follow-up 2 weeks after his initial appointment the swelling had increased. An incisional biopsy was performed and a diagnosis of diffuse large B-cell lymphoma was rendered. The current staging procedures for extranodal oral lymphoma include a panoramic radiograph, abdominal and chest CT scan, bone scans, routine laboratory tests (hemogram, urine analysis, complete blood cell counts, lactate dehydrogenase and erythrocyte sedimentation rate), and bone marrow aspiration biopsy. A diagnosis of bone lymphoma cannot be established on the basis of radiography alone. Approximately 80% of bone lesions exhibit osteolytic erosive features, whereas the remaining 20% show sclerotic or mixed radiographic appearance.21–23 The medical evaluation of this patient revealed chronic hepatitis C virus (HCV), his complete blood count was normal; routine laboratory tests, chest radiograph, and bone marrow biopsy were normal. The diagnosis was established through histological examination of biopsy tissue, coupled with immunohistochemical phenotyping. Immunohistochemistry plays an important role in distinguishing cell types and differential diagnosis.24 We used CD20, CD10, CD3, CD30, ALK-1 and Ki 67 and found both biopsy specimens to be positive for CD20 and Ki 67 and negative for CD3, CD10, CD30, ALK-1. We consequently diagnosed diffuse large-B cell lymphoma. The concomitant HCV infection is of interest in this case. Recent epidemiological studies have revealed an association between HCV infection and the clonal proliferation of Bcells.23–25 It has been suggested26–31 that chronic antigenic stimulation (related to the Epstein–Barr virus, human immunodeficiency virus, human leukemia-lymphoma virus 1, human herpes virus 8 or hepatitis viruses B, C and G) acts on multiple B-cell clones, which may synchronously or metachronously undergo neoplastic transformation. In particular, B-cell lymphoma has been reported to be frequently associated with or related to HCV infection. In our case, which was clinically cured for NHL, a subsequent manifestation of B-cell lymphoma in the soft tissue vestibule of the maxilla, detected one year later and after complete remission, was considered to be a recurrence. Several studies have indicated that a second occurrence after a short period of time (<2–3 years), presenting the same histological properties as the primary lymphoma, should be considered a recurrence of the primary tumor, whereas
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different histopathology and longer time before recurrence are more indicative of a second primary lymphoma.32,33 The morphological characteristics of the second biopsy specimen were identical to those of the first specimen. The patient was treated as for a recurrence with chemotherapy; he did well for five months, but died two years after the initial diagnosis. Prognosis is influenced by clinical stage and histologic grade. Large cell lymphomas are considered aggressive and have a poorer prognosis.34–36 It is reported that diffuse large-cell types of NHL are considered high grade, with a 5year survival of about 30%, whereas the follicular, small cleaved-cell type are considered low grade, with a 5-year survival rate of 70%.37–41 The present case was high-grade diffuse large B-cell type lymphoma, as indicated in the REAL classification, and the clinical stage was IIE with soft tissue involvement; thus prognosis was poor; and in fact the patient died within a year. In brief, we report a case of primary non-Hodgkin’s lymphoma of the anterior vestibule of the mandible, with a recurrence at the left upper site in the maxillary vestibule that, to our knowledge, has not been reported previously. There was an associated HCV infection. The high potential for recurrence of this type of tumor, in addition to the role played by chemotherapeutic agents, and the role of chronic antigenic stimulation (specifically the hepatitis C virus) which has been linked to the development of some lymphoma subsets, can facilitate the development of a recurrence or of a second primary tumor. It appears that such an association may produce a recurrence that is more aggressive and, in this case, fatal.
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