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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.43 No.1 pp.41-48

Primary Oral Diffuse Large B-cell Lymphoma Associated with Chronic Inflammatory Periodontal Iesions

Yeon Sook Kim1), Suk Keun Lee2)*
1)Department of Dental Hygiene, College of Health Sciences, Cheongju University, Cheongju
2)Department of Pathology, College of Dentistry, Gangneung-Wonju National University, Research Institute of Oral Science, Gangneung, Korea
Correspondence: Suk Keun Lee, Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 123 Chibyun-dong, Gangneung, 210-702, Korea Tel: +82-33-640-2228, Fax: +82-33-642-6410 E-mail:
February 8, 2019 February 15, 2019 February 22, 2019


Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma, and usually showed painless neck swelling, fever, sweat, and weight loss. Although about 5% of all lymphomas appeared in the oral area, the primary maxillofacial lymphomas were rare and sometimes clinically tended to be misdiagnosed such as chronic periodontitis, osteomyelitits, etc. This study demonstrated three cases of primary DLBCL mimicking localized osteomyelitis at mandible or maxilla. A series of histological and immunohistochemical examination using different biomarkers of lymphoreticular cells were performed to characterize the neoplastic cells of DLBCL. The first case occurred in a 45 years old male exhibiting mandibular osteomyelitis and neck swelling. The second case simply showed a gingival swelling at left upper premolar area in a 55 years old male. And the third case is from an 84 years old female who felt numbness at left lower lip and had severe periodontitis involving regional alveolar bone resorption. All of three cases had experienced no systemic manifestation of lymphoreticular malignancy before the diagnosis of oral lymphoma. Immunostainings of CD3, CD20, TNFα, BCL-2, Ki-67, PCNA, and c-Myc were strongly positive in these tumor cells, while those of p53 and CD31 were slightly positive, and CD56 immunoreaction was negative. These three cases were diagnosed as DLBCL and referred to the hemato-oncology unit for treatment. Therefore, every chronic granulomatous periodontal lesion hardly cured by simple medical treatment should be carefully explored through pathological examination, and it was presumed that DLBCL is closely related to the chronic inflammatory periodontal lesions recruiting mucosa-associated lymphoid cells in older patients. It was also suggested that DLBCL be differentially diagnosed from T-cell lymphoma, Burkitt’s lymphoma, and Hodgkin’s disease, etc. with immunohistochemical determination of tumor cell subtypes as soon as possible in order to be treated with appropriate therapy.

만성 염증성 치주병소들과 관련된 원발성 구강 미만성 거대 B-세포 림프종

김 연숙1), 이 석근2)*
1)청주대학교 보건의료과학대학 치위생학과
2)강릉원주대학교 치과대학 병리학교실 및 구강과학연구소



    The head and neck is the second most common region for the extra-nodal lymphomas after that of gastrointestinal tract. Approximately 2.5% of malignant lymphoma arises in the oral and para-oral region1). Lymphomas are the second most common non-epithelial malignant tumors in the oral and maxillofacial region. Non-Hodgkin's lymphoma (NHL) develops at extranodal sites. Diffuse large B cell lymphoma (DLBCL) is the most frequently diagnosed type of non-Hodgkin lymphoma, the fifth most frequent malignancy, accounting for about 40% of cases reported2,3).

    Among 122 cases in 63 publications, oral DLBCL was found as an asymptomatic gingival swelling and predominant in elderly male (61.5%), associated with human immunodeficiency virus (HIV)-negative (36.1%) and Epstein barr virus (EBV)- positive (3.3%)4). For the pathological diagnosis, histological subtyping of neoplastic lymphoid cells should be performed with the application of immunohistocheical staining using panel of antibodies, including CD3, CD10, CD20, CD30, CD45, CD138, PAX5, Bcl2, Ki-67, etc.5). DLBCL usually express pan-B markers with small percentage expressing T-cell markers. Few rare cases of DLBCL have shown CD3 expression, which is a most sensitive T-cell marker6).

    Actually, there appeared different variant of lymphoma like high grade B-cell lymphoma with MYC and BCL6 gene rearrangements, which had a predilection for rare extranodal sites such as the gastrointestinal tract, nasopharynx, tonsils, skull and adnexal structures and should be diagnosed promptly due to its aggressive nature7). T-cell/histiocyte-rich large B-cell lymphoma (THRBCL) is an uncommon subtype of non-Hodgkin's lymphoma. THRLBCL is an uncommon and aggressive malignant neoplasm that can involve the jaws, mimicking a periapical disease. It is a predominant nodal neoplasm; however, extranodal sites, such as the spleen, liver and bone marrow, can be involved at diagnosis8).

    DLBCL is usually treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy, producing high overall 5-year survival rate (83%)4). Rituximab, an anti- CD20 chimeric monoclonal antibody can specifically deplete mature B cells. Overall survival and disease-free survival rates were 91% in the rituximab plus CHOP group, compared with 83% and 60%, respectively, in the CHOP alone group (p=0.75 and p=0.24 for the differences between the groups, respectively). The rituximab plus CHOP therapy was generally well tolerated, with few adverse events reported9).

    The present study demonstrated three cases of DLBCL occurred at jaw in older patients, who showed clinical features of chronic periodontitis or osteomyelitis. Although DLBCL is one of aggressive malignant tumors and able to be rapidly disseminated systemically, it should be accurately diagnosed as soon as possible in order to get good response with improved chemotherapy, like rituximab and CHOP therapies.


    The first case (S2003-188) occurred in a 45 years old male complaining of gingival ulceration and neck swelling. The second case (S2011-201) simply showed severe gingival swelling at left upper premolar area in a 55 years old male. And the third case (S2013-071) is from an 84 years old female who felt numbness at left lower lip and had severe periodontitis involving regional alveolar bone resorption. All of three cases had experienced no systemic manifestation of lymphoreticular malignancy before the diagnosis of oral lymphoma. This case report has been approved by Institutional Review Board (GWNUDH-IRB2016–11)

    The incisional biopsy specimens were fixed in 10% neutral buffered formalin, processed routinely, and embedded with paraffin. Histological microsections in 4 μm thick were mounted on glass slides, stained with hematoxylin and eosin staining, and followed by histochemical and immunohistochemical staining using 13 antisera including Ki-67*, PCNA*, cMyc*, CD3*, CD20*, CD28&, CD31@, CD56&, and CD68*, p53*, BCL2*, IgK@, and TNFα&(*SantaCruz Inc. Biotech., USA; @ZYMED, CA, USA; &Abcam, Cambridge, UK).

    Immunohistochemistry reaction protocols varied according to the target antigen and manufacturers’ protocols. After deparaffinization and rehydration of the tissue sections in xylene followed by ethanol, sections were incubated with 0.5% hydrogen peroxide in phosphate-buffered saline (PBS) for 30 minutes. Primary anti-human polyclonal antibodies were diluted and added. Then, the tissues were incubated overnight at 4°C. Secondary biotinylated antibody was added for 30 min, followed by streptavidin peroxidase for 1 hour. The slides were visualized with diaminobenzidine (DAB). Sections were counterstained and then subjected to alcohol and xylene baths before being mounted for examination. Between each incubation steps all slides were rinsed twice in phosphate-buffered saline (PBS)10). Histochemical stains were observed under ordinary light microscope, and particularly, microscopic images of different IHC staining were captured by a digital camera (DP-70, Olympus Co., Japan).

    The first case of DLBCL showed a diffuse osteolytic lesion at left mandibular premolar to molar area mimicking chronic osteomyelitis and bony destruction advanced downward to mandibular body with rare peripheral radiopacity in panoramic X-ray view (Fig. 1A). The lymphoid tumor cells were proliferative and infiltrated into adjacent muscular tissue (Fig. 2A), resulted dull pain and induration. However, the incisional biopsy specimen was too small to get additional microsections for immunohistochemistry at this time.

    The second case of DLBCL showed severe gingival swelling with chronic periodontitis at left maxillary premolar area, where prosthetic crown bridge was applied ten years ago, but food debris under ponic area resulted chronic pyogenic granuloma and subsequently aggravated to periapical osteolytic lesion found in panoramic X-ray view (Fig. 1B). The tumor mass was grayish white in color, and showed granulomatous features heavily infiltrated with large lymphocytes (Fig. 2B), which were strongly positive for PCNA (about 60%) and CD20 (over 90%). Some T-cells infiltrated into the tumor tissue were strongly positive for CD3. Otherwise, the tumor cells were weakly positive for p53 and almost negative for CD56 (Fig. 3).

    The third case of DLBCL showed chronic periodontitis involving diffuse alveolar bone destruction at left mandibular premolar to molar area. The mandibular first molar was extracted recently due to severe periodontal destruction found in panoramic X-ray view (Fig. 1C). The tumor cells were monotonously polygonal in shape and mostly aggregated with frequent mitotic features (Fig. 2C), thereby, it was primarily diagnosed as malignant lymphoblastic lymphoma. In the immunohistochemistry, the tumor cells were strongly positive for Ki-67 (about 70%), CD20 (over 95%), TNFα, BCL2, cMyc, and slightly positive for IgK, CD31, and CD68, but weakly positive for CD28 and p53. Only a few T-cells infiltrated into the tumor tissue were positive for CD3 (Fig. 4). The tumor was finally diagnosed as DLBCL with cMyc dysregulation.


    DLBCL is the commonest extranodal non-Hodgkin lymphoma diagnosed in the oral and maxillofacial region4). It is an aggressive B-cell lymphoma histologically characterized by diffuse proliferation of large neoplastic B-lymphoid cells with a nuclear size equal to or exceeding normal histiocytic nuclei11). Primary extranodal non-Hodgkin's lymphomas of the head and neck account for 10-20% of all non-Hodgkin's lymphomas12). As the lesions frequently resemble other diseases such as chronic osteomyelitis, odontogenic or any secondary neoplasms, further evaluation and histopathologic examination allow early identification for appropriate treatment13). Non- Hodgkin lymphoma should be also a part of the differential diagnosis of other jaw lesions such as apical periodontitis14).

    In this study, the first case of DLBCL was clinically suspected for chronic localized osteomyelitis at left mandibular molar area in a 45 years old male patient, but its incisional biopsy revealed non-Hodgkin’s lymphoma according to the histological features with no immunohistochemical finding. Although the tumor cells were extensively infiltrated into adjacent muscular tissue, they were distributed as lymphoid architecture and exhibited undifferentiated large B-cells with cleaved nuclei, which were easily distinguishable from squamous cell carcinoma or other mesenchymal sarcomas.

    The second case of DLBCL showed diffuse gingival swelling and severe tooth mobility at left maxillary premolar area in a 55 years old male patient. The tumor tissue was a granulomatous lesion with the infiltration of macrophages and PMNs, but mostly composed of proliferative lymphoid cells. The tumor cells were subtyped into B-cells by strong positive immunoreactions of CD20, but they were negative for CD56. CD3-positive T-cells were frequently found in the tumor tissue, indicating that the T-cell might have some role for the transformation of DLBCL. The tumor cells were highly proliferative with overexpression of PCNA (about 60%) but silent for tumor suppressor protein, p53. Therefore, this case was diagnosed as DLBCL with aggressive growth potential.

    The third case of DLBCL showed diffuse chronic periodontitis and alveolar bone destruction at left mandibular premolar to molar area in an 84 years old female patient. The tumor tissue was filled with monotonous lymphoblasts exhibiting frequent mitosis, and gradually extended to mandibular body by destroying the central trabecular bones. In the immunohistochemical staining, the tumor cells were strongly positive for CD20 and IgK, and slight positive for CD31 and CD68. Only a few T-cells positive for CD3 and CD28 were found in the tumor tissue, which might be recruited by maturing B-cells among tumor cells. The tumor cells were strongly positive for oncogenic proteins, including cMyc, BCL2, and TNFα, but weakly positive for p53. Most of tumor cells (about 70%) were positive for proliferation marker, Ki-67. Therefore, this case was diagnosed as aggressive DLBCL with possible involvement of cMyc and BCL2 gene alteration.

    DLBCL was treated successfully with 7 of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2 d1, doxorubicine 50 mg/m2 d1, vincristine 1.4 mg/m2 d1, and prednisone 50 mg/m2 d1-5 (RCHOP) regimen15-17), although CD20 negative B-cells were not responsible to rituximab18). Dexamethasone, high-dose cytarabine, and carboplatin (DAC) therapy was administered at the beginning of the induction phase in 2 sequential cycles and incorporated throughout a continuation phase (modified from the ACOP+ regimen, which features doxorubicin, cyclophosphamide, vincristine, and prednisone) with doxorubicin, cyclophosphamide, vincristine, and dexamethasone19,20). Generally, CHOP therapy was the main treatment option (24.5%) and the overall 5-year survival rate achieved 83%. Therefore, oral DLBCL is known as an aggressive malignancy, but with a high survival rate4).

    As oral DLBCL is usually associated with chronic inflammatory periodontal lesions involving severe bony destruction, DLBCL is supposed to be stimulated by inflammatory cytokines, e.g., TNFα, interleukins, lymphokines, etc. Particularly, it was reported that genetic alterations, BCL6 and cMyc gene translocations were closely related to the pathogenesis of DLBCL, which was implicative for EBV and HIV infections. And more, DLBCL is usually found as a primary lesion in gastrointestinal tract and oral cavity, where numerous pathogenic micro-organisms are abundant.. Therefore, it was presumed that the antigenic stimulation derived from micro-organisms may give an important influence to DLBCL oncogenesis, and also suggest that the oral inflammatory lesions be preferentially treated by curettage and prevented by oral prophylaxis in order to reduce the sources for the immunological sensitization of lymphocytes and to ameliorate the anti-viral functions of oral mucosa. We thought the older people are needed to receive oral hygiene program routinely to prevent chronic inflammatory periodontal diseases.



    Panoramic radiographs of DLBCL. A: Case 1; osteolytic lesion mimicking osteomyelitis (arrows). B: Case 2; gingival swelling with periapical osteolytic lesion (arrows). C: Case 3; chronic periodontitis involving alveolar bone destruction (arrows).


    Photomicrographs of diffuse large B-cell lymphoma (DLBCL). A: Case 1; muscular infiltration of lymphocytes. B: Case 2; granulomatous infiltration of large lymphocytes. C: Case 3; aggregation of monotonous malignant lymphocytes.


    Immunohistochemical study of diffuse large B-cell lymphoma (DLBCL), case 2. A: CD3, some infiltrated T-cells were strongly positive, B: CD20, most of neoplastic lymphocytes (over 90%) were strongly positive. C: PCNA, many tumor cells (about 60%) were strongly positive. D: p53, tumor cells were weakly positive. E: CD56, negative in tumor cells. A-D: no counterstaining. E: hematoxylin


    Immunohistochemical study of diffuse large B-cell lymphoma (DLBCL), case 3. A: CD3, a few T-cells infiltrated into tumor tissue were strongly positive. B: CD20, most of tumor cells (over 95%) were strongly positive. C: Ki-67, many tumor cells (about 70%) were strongly positive. D: p53, weakly positive in tumor cells. E: IgK, slightly positive in tumor cells. F: TNFα, strongly positive in tumor cells. G: CD28, weakly positive in some lymphocytes. H: BCL2, strongly positive in tumor cells. I: cMyc, strongly positive in tumor cells. J: CD31, slightly positive in tumor cells. K: CD68, slightly positive in tumor cells. A-C: weak hematoxylin stain. D-K: no counterstaing.



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