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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.43 No.5 pp.209-215
DOI : https://doi.org/10.17779/KAOMP.2019.43.5.011

Solitary Lymphomatoid Granulomatosis at the Maxilla

Tae-Wook Ha1), Hussain I Al-Fadhel1), Dawool Han2), Woo Ick Yang3), Dong Wook Kim1), Eunae Sandra Cho2)*
1)Department of Oral and Maxillofacial Surgery
2)Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea
3)Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
Correspondence: Eunae Sandra Cho, Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea, 50-1 Yonsei-ro, Seodaemoon-Gu, Seoul, 03722, Korea. Tel: +82-2-2228-3036, E-mail: sandra@yuhs.ac
September 16, 2019 September 27, 2019 October 4, 2019

Abstract


Lymphomatoid granulomatosis (LYG) is an uncommon Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder distinct from lymphoma. LYG primarily occurs in the lung with or without accompanied lesions in the skin, central nervous system, kidney, gastrointestinal tract, nose, eyes, liver and oral cavity. Solitary extrapulmonary LYG is extremely rare, and whether solitary lesions progress onto pulmonary development and dysfunction is controversial. Herein, we report a case on a solitary LYG in the maxilla gingiva with bone exposure in a patient who had been taking methotrexate for rheumatoid arthritis.



상악의 단발 림프종모양육아종증

하 태욱1), 알 파델 후세인 이브라힘1), 한 다울2), 양 우익3), 김 동욱1), 조 은애산드라2)*
1)연세대학교 치과대학 구강악안면외과학교실
2)구강종양연구소 구강병리학교실
3)연세대학교 의과대학 병리학교실

초록


    Ⅰ. INTRODUCTION

    Lymphomatoid granulomatosis (LYG) is an uncommon type of EBV-associated B-cell lymphoproliferative disorder (LPD) which commonly arises in various immunosuppressive conditions1). It primarily affects the lung, while it may be concurrently present in other multiple sites such as the skin, central nervous system, kidney, gastrointestinal tract, nose, eyes, liver and oral cavity2,3). Solitary extrapulmonary lesions are extremely rare and are considered as an aspect of dissemination and systemic involvement1,2,4). There have been a few reports on nervous, cutaneous and oral LYG lesions without a pulmonary lesion development at the time of diagnosis5-7). Whether the extrapulmonary lesions represent an initial sign of systemic disease, or are a true solitary lesion is controversial.

    Herein, we report a solitary oral LYG in a patient taking methotrexate (MTX). The initial clinical impression for the oral lesion was Medication-related osteonecrosis of the jaw (MRONJ), while the primary pathologic diagnosis was natural killer (NK)/T-cell lymphoma. We discussed the differential diagnosis of LYG and reviewed the former literature.

    Ⅱ. CASE REPORT

    A 71-year-old female was referred to our hospital from a primary dental clinic for complaints of discomfort at the maxillary right first molar region. Oral examination revealed gingival necrosis with alveolar bone exposure at the posterior of right maxillary first molar (Fig. 1A). Redness and mild swelling were observed at the marginal gingiva of right maxillary second premolar and first molar. Both teeth had a history of root canal treatment received 5 months ago and showed bad periodontal condition with cortical bone loss and tooth mobility (Fig. 2A and B). The right maxillary second molar had been missing for more than 10 years.

    She was on medication for hypertension (amlodipine), rheumatoid arthritis (methotrexate [MTX], 10mg weekly for 14 years and bucillamine) and had been taking bisphosphonate by oral administration for 5 months. She had a past history of recurrent pulmonary tuberculosis treated 30 years ago. The possibility of MRONJ first came to our mind, because the patient was an elderly-women taking bisphosphonate and had signs of bone exposure and resorption. Additional radiologic and laboratory tests were made. Multi-detector computed tomography (MDCT) was taken on the maxilla, and C-terminal telopeptide (CTX) and osteocalcin serum level tests were evaluated. For her well-being, cefpodoxime, metronidazole and nonsteroidal anti-inflammatory drugs (NSAIDs) were prescribed to decrease the pain and inflammation.

    A week later, pain symptoms had reduced since the last visit and inflammation signs had been diminished at the site. The CTX level was 0.296 and osteocalcin level was 19.50. The CT image informed that there was cortical bone loss and adjacent soft tissue lesion on the right maxillary second premolar and first molar (Fig. 2C and D). The Department of Oral and Maxillofacial Radiology recommended a biopsy on the lesion to distinguish between inflammatory disease and malignancy. A biopsy was performed on the gingiva avoiding necrosis and necrosis-adjacent tissue. The biopsy specimen revealed chronic non-specific inflammation. The plan was to maintain the antibiotics and NSAIDs to reduce the inflammation.

    Four weeks after the first visit, bone exposure had decreased, and inflammatory signs were alleviated but not yet terminated at the lesion site (Fig. 1B). However, during the next two weeks, the lesion aggravated at the adjacent palatal gingiva with diffuse ulceration and necrosis (Fig. 1C) and re-biopsy was performed near the necrosis. The patient complained of severe pain and informed us that she had not been taking her MTX prescription after the first visit. MTX withdrawal had been directed by her primary dentist and rheumatologist in fear of MTX associated MRONJ which has been reported before8). The two clinicians were not aware of the bisphosphonate prescription which had been made in another hospital, so it had been maintained despite the possibility of MRONJ.

    Pathologic evaluation revealed areas of severe necrosis and cell-rich portions (Fig 3A). The cell-rich portions were composed of monocytes, predominantly lymphocytes infiltrating the adjacent tissue (Fig. 3B). Characteristically, the lymphocytes frequently displayed an angiocentric pattern and angioinvasive properties (Fig. 3C). The lymphocytes were a mixture of large atypical lymphocytes and small lymphocytes (Fig. 3D). Other than the lymphocytes, plasma cells and other inflammatory cells were seen in the background as well. NK/T-cell lymphoma was our primary pathologic diagnosis. To confirm our diagnosis, molecular pathology staining was proceeded.

    By immunohistochemistry, the large atypical lymphocytes were revealed to be CD20-positive B cells (Fig. 3E), while the small lymphocytes were CD3/T-cell intracytoplasmic antigen (TIA)-positive T cells (Fig. 3F and G). The atypical B cells were figured to be the main aspect of the lesion, while T cells were considered as reactive background. Epstein-Barr virus (EBV) infection was confirmed in the atypical B cells by in situ hybridization (Fig. 3H) CD56 was negative (not shown), which ruled out NK/T-cell lymphoma. The final diagnosis was lymphomatoid granulomatosis. It was given a grade 3 for the extensive amount of necrosis, aggregated large atypical CD20-positive B cells and high number of EBV positive cells (50>High power field)9,10).

    MTX was considered to be responsible for the immunosuppression causing LYG in our patient. The patient was referred to the Department of Hemato-oncology for proper management and MTX was replaced with tacrolimus. To evaluate presence of LYG lesions at other sites, especially the lung, a body CT was taken. There were no abnormal findings throughout the body CT, other than right kidney’s parenchymal thinning on abdomen-pelvis and a post- inflammatory sequela due to previous tuberculosis in the chest. There were no abnormal lymph nodes on the neck. On Positron emission tomography (PET)/CT, focal fludeoxyglucose (FDG) uptake was only observed in the right maxilla, regarded as post-operative changes (Fig. 2E).

    After replacing MTX to tacrolimus, the lesion gradually improved and was almost completely healed by the 2 month-follow up (Fig. 1D, E, F). Chemotherapy was not considered unless the lesion showed recurrence or pulmonary lesions occurred.

    Ⅲ. DISCUSSION

    Oral LYG is extremely rare and may be difficult to diagnose at first sight. There have been 11 cases of previously reported oral LYG 6,11-19). The clinical features previously reported of oral LYG were mainly non-specific (pain, granular tissue, ulceration and redness). Other systemic features, such as fever, weight loss, fatigue, cough, dysphagia, and dysphonia were generally seen in patients with synchronous pulmonary lesions6,11). Oral LYG lesions presenting as bone exposure with mucosal necrosis, as seen in our case, may be difficult to distinguish from MRONJ or deep fungal infections (i.e. aspergillosis and zygomycosis)20,21). Since the patient had a history of recurrent TB, recurrent pulmonary TB and secondary oral TB should had been considered for differential diagnosis as well22). Because of the low incidence and non-specific clinical features, pathologic confirmation is needed for diagnosis, yet pathologic differentiation may be challenging as well.

    LYG belongs to the EBV-associated LPD classification and needs pathological differentiation with various LPDs and other EBV-associated diseases. LYG presents pathologic features of large, sometimes atypical B cell infiltrates mixed with reactive T cells and other inflammatory cells. Angiocentric lymphocytic infiltration and necrosis are commonly observed. The large B cells are frequently infected with EBV23). The angiocentric and necrotic characteristics of LYG are similar to those of NK/T-cell lymphoma24). Abundant amounts of reactive T cells in LYG may be confused as T-cell lymphoma, especially in early grade 1 lesions with only very few large B cells25). The large atypical cells in LYG are CD20-positive and CD56-negative (NK-cell-associated marker), which distinguishes it from NK/T-cell lymphoma26,27).

    Mononuclear infiltrations with large CD20-positive and EBER-positive cells can give the differential diagnosis ranging from EBV-associated mucocutaneous ulcer to EBV-associated B-cell lymphoma28). The mononuclear infiltration in EBVassociated mucocutaneous ulcer is non-tumorous which supports the flat and clean clinical appearance of the ulcer. Furthermore, Reed-Sternberg like cells are routinely present which are not classically noticed in LYG29,30). Occasionally, there may be large lesion cells infiltrating blood vessels near the surface ulceration in EBV-associated mucocutaneous ulcer30).

    Whether EBV-associated B-cell lymphoma and high-grade LYG are a separate classification is a complicated issue. Presently, LYG is considered to be distinct from lymphoma, yet high-grade LYG does have pathological overlaps with subtypes of Diffuse Large B-Cell Lymphoma (DLBCL)23,31,32). Angiocentric feature, a characteristic finding of high-grade LYG, is not a regular feature of B-cell lymphoma. Lymphomas are considered to have a monomorphous cell infiltrate distribution compared to the polymorphous background of LYG, although polymorphous infiltrates have been noticed within certain lymphomas as well2,25,31,32). In deficient amounts of biopsy material, the monomorphous tumor cells-aggregated foci may not be included within the captured lesion. Therefore, to differentiate LYG from lymphoma a careful integrated evaluation of previous lymphoma or immunosuppression history, clinical settings (pulmonary and/or multiorgan involvement), cellular features and EBV infection status are needed9).

    LYG has a wide spectrum of prognosis, from indolent to highly progressive, which is difficult to predict at initial diagnosis. High-grade LYG resembles the clinical progress of lymphoma and generally requires immediate therapy. Moreover, further transformation to lymphoma has been reported in literature by a rate of 7~45% 1,25,33,34). Meanwhile, Katzenstein et al. proposed that grade 2, 3 LYG should be termed as “lymphoma” to guide the clinician to select active therapeutic options confirmed in lymphoma without risking clinical confusion due to the unpredictable biological behavior of LYG9). Corticosteroids, immunotherapy and combined chemotherapy are the known successful choices to improve symptoms of LYG and suspend progression to pulmonary dysfunction, the main cause of death3). A low proportion of LYG cases, mainly low-grade cases, go through spontaneous remission or remission after immunosuppressant discontinuance34,35).

    Persistent methotrexate use has been noticed in cases of LYG11,17,35-38). MTX is an anti-metabolic agent with complications of bone marrow suppression, and is known possible to induce various LPDs39). Among the 12 reported cases of oral LYG (including this case), 4 cases had a history of MTX prescription11,17). Three of the 4 cases showed complete remission after MTX withdrawal even in those with grade 3 LYG yet lacked long-term follow up data. Successful remission after MTX withdrawal has been presented in a few cases other than the oral cavity36-38). Nevertheless, continuous progression and relapse of LYG are ongoing problems in current cohorts and case reports despite the chemotherapeutic application in either MTX and non-MTXassociated cases11,40,41). Therefore, long term follow-up is essential in LYG patients.

    The prognosis of oral LYG patients depends on its pulmonary status. When an oral lesion is pathologically diagnosed as LYG, a periodic chest evaluation is required even in the absence of pulmonary involvement at initial examination. Cutaneous LYG lesion preceding its pulmonary lesion has been well described4,40,42). Moreover, cutaneous lesions are known to present as a first sign of relapse40). Our case of oral LYG had alleviated at the first withdrawal of MTX but had progressed once again in the adjacent tissue during the MTX-free period. The LYG lesion has spontaneously regressed since then yet alerts us of the importance of periodic check-ups of this disease. The biologic behavior of oral lesions is yet poorly understood and its association with pulmonary lesion needs further evidence.

    Figure

    KAOMP-43-5-209_F1.gif

    Clinical image of the right maxillary lesion. A. 1st visit. Ulceration and bone exposure were observed in the posterior of #16. Redness and swelling were seen in the palatal marginal gingiva. B. 4 weeks after the 1st visit. The lesion showed improvement with healing of the ulcer. C. 6 weeks after the 1st visit. The lesion was aggravated on the palatal side and re-biopsy was done. D. 9 weeks after the 1st visit. The necrotic area was partially reduced. E. 15weeks after the 1st visit. Necrosis had disappeared, and mild redness was observed. F. 18 weeks after the 1st visit. Only a mild indentation of the former lesion was observed.

    KAOMP-43-5-209_F2.gif

    A. Panoramic view taken on the 1st visit. B. Periapical view taken on the 1st visit. The right maxillary second premolar and first molar showed cortical bone loss. C. Bone window coronal view of maxillary computed tomography (CT) taken on the 1st visit. D. Bone window axial view of maxillary CT taken on the 1st visit. Cortical bone loss was observed at the buccal side of the right maxillary second premolar and first molar. E. F18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT axial view showed a hot spot at the right posterior maxilla.

    KAOMP-43-5-209_F3.gif

    Histopathologic examination and molecular pathology results of the surgical specimen. A. Lymphocytic infiltrated (Ly) on the submucosal area with extensive necrosis (Ne) and ulceration (Hematoxylin and eosin [HE], original magnification x12.5). B. The lymphocytes have infiltrated blood vessels (blue arrow) and submucosal adipose tissue. Necrosis was noticed (inset) (HE, original magnification x200, inset x40). C. Angiocentric and angioinvasive infiltration of lymphocytes in a blood vessel (BV). (HE, original magnification x200, inset x400). D. The lymphocytes were mainly large atypical lymphocytes (green arrow), and small reactive lymphocytes (yellow arrow), plasma cells and various inflammatory cells were admixed (HE, original magnification x400). E. Dense infiltration of CD20-positive large atypical lymphocytes (Immunohistochemistry staining [IHC], CD20, original magnification x200). F. Reactive CD3- positive small lymphocytes. (IHC, CD3, original magnification x200). G. Reactive lymphocytes are positive on TIA stain as well. (IHC, TIA, original magnification x200). H. High amounts of EBER-positive large lymphocytes are observed, indicating Epstein-Barr virus infection. (In situ hybridization, EBER, original magnification x200)

    Table

    Reference

    1. Fauci AS, Haynes BF, Costa J, Katz P, Wolff SM: Lymphomatoid Granulomatosis. Prospective clinical and therapeutic experience over 10 years. N Engl J Med 1982;306:68-74.
    2. Song JY, Pittaluga S, Dunleavy K et al.: Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations. The American journal of surgical pathology 2015;39:141-156.
    3. Roschewski M, Wilson WH: Lymphomatoid granulomatosis. Cancer J 2012;18:469-474.
    4. Beaty MW, Toro J, Sorbara L: Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol 2001;25:1111-1120.
    5. Wong DL-Y, Lehn AC: Central nervous system lymphomatoid granulomatosis without pulmonary involvement: a case report. Journal of Neurology, Neurosurgery Amp Psychiatry 2017;88:e1-e1.
    6. Pereira AAC, Ferreira CB, Hanemann JAC: Oral Manifestation of Lymphomatoid Granulomatosis. Head and Neck Pathology 2019;13:270-276.
    7. Kim J-Y, Jung KC, Park S-H, Choe J-Y, Kim JE: Primary lymphomatoid granulomatosis in the central nervous system: A report of three cases. 2018;38:331-336.
    8. Henien M, Carey B, Hullah E, Sproat C, Patel V: Methotrexateassociated osteonecrosis of the jaw: A report of two cases. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 2017;124:e283-e287.
    9. Katzenstein A-LA, Doxtader E, Narendra S: Lymphomatoid Granulomatosis: Insights Gained Over 4 Decades. 2010;34:e35-e48.
    10. Swerdlow SH, International Agency for Research on C, World Health O: WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer, 2017.
    11. Kidoguchi K, Yoshimura M, Kojima K: Oral ulceration: an unusual manifestation of lymphomatoid granulomatosis. Annals of Hematology 2019;98:1305-1307.
    12. Alinari L, Pant S, McNamara K: Lymphomatoid granulomatosis presenting with gingival involvement in an immune competent elderly male. Head Neck Pathol 2012;6:496-501.
    13. Ammannagari N, Srivali N, Price C, Ungprasert P, Leonardo J: Lymphomatoid granulomatosis masquerading as pneumonia. Ann Hematol 2013;92:981-983.
    14. Cabane J, Godeau P, Chomette G, Auriol M, Szpirglass H, Raphael M: Granulomatose lymphomatoïde buccale. La Revue de Médecine Interne 1990;11:69-72.
    15. Cargini P, Civica M, Sollima L, Di Cola E, Pontecorvi E, Cutilli T: Oral lymphomatoid granulomatosis, the first sign of a ‘rare disease’: a case report. Journal of Medical Case Reports 2014;8:152.
    16. Diez JSJ H-PB, De Paula JMP, Ortega EO: Granulomatosis linfomatoidea: caso clinico de uma enfermedad infrecuente com uma presentacion infrecuente. Revista Clinica Espanola 2000;200:461–463.
    17. Higashi Y, Yoshioka T, Kawai K: Lymphomatoid granulomatosis initially presenting as ulcerated subcutaneous and muscle lesions without pulmonary involvement. J Dermatology 2017;44:e107-e108.
    18. Shanti RM, Torres-Cabala CA, Jaffe ES, Wilson WH, Brahim JS: Lymphomatoid Granulomatosis With Involvement of the Hard Palate: A Case Report. J Oral Maxillofac Surg 2008; 66:2161-2163.
    19. Torrelo A, Martín M, Rocamora A, Allegue F, Ledo A: Lymphomatoid granulomatosis presenting as angioedema. Postgraduate Medical J 1992;68:366.
    20. Ruggiero SL, Dodson TB, Fantasia J: American Association of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw-2014 Update. Journal of Oral and Maxillofacial Surgery 2014;72:1938-1956.
    21. Scully C, Almeida OP: Orofacial manifestations of the systemic mycoses. J Oral Pathol Medicine 1992; 21:289-294.
    22. Eng H-L, Lu S-Y, Yang C-H, Chen W-J, Jaconson J, Van Dis M: Oral tuberculosis. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 1996;81:415-420.
    23. Colby TV: Current histological diagnosis of lymphomatoid granulomatosis. Mod Pathol 2012;25 Suppl 1:S39-42.
    24. Jaffe ES, Chan JK, Su IJ: Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20:103-111.
    25. Guinee D, Jr., Jaffe E, Kingma D: Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994;18:7 53-764.
    26. Chan JK, Sin VC, Wong KF: Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 1997;89:4501-4513.
    27. Guinee DG, Jr., Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN: Proliferation and cellular phenotype in lymphomatoid granulomatosis: implications of a higher proliferation index in B cells. Am J Surg Pathol 1998;22: 1093-1100.
    28. Rezk SA, Weiss LM: Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol 2007;38:1293-1304.
    29. Martin AW: Chapter 6 - Immunohistology of Non-Hodgkin Lymphoma. In: Dabbs DJ, editor. Diagnostic Immunohistochemistry (Third Edition). Philadelphia: W.B. Saunders; 2011:156-188.
    30. Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES: EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010;34:405-417.
    31. Colby TV, Carrington CB: Pulmonary lymphomas simulating lymphomatoid granulomatosis. Am J Surg Pathol 1982;6:19-32.
    32. Castillo JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM: EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2018 update on diagnosis, riskstratification and management. American Journal of Hematology 2018;93:953-962.
    33. Koss MN, Hochholzer L, Langloss JM, Wehunt WD, Lazarus AA, Nichols PW: Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients. Pathology 1986;18:283-288.
    34. Katzenstein AL, Carrington CB, Liebow AA: Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360-373.
    35. Kobayashi S, Kikuchi Y, Sato K: Reversible iatrogenic, MTX-associated EBV-driven lympho- proliferation with histopathological features of a lymphomatoid granulomatosis in a patient with rheumatoid arthritis. 2013;92:1561-1564.
    36. Shimada K, Matsui T, Kawakami M: Methotrexate‐related lymphomatoid granulomatosis: a case report of spontaneous regression of large tumours in multiple organs after cessation of methotrexate therapy in rheumatoid arthritis. Scandinavian J Rheumatology 2007;36:64-67.
    37. Oiwa H, Mihara K, Kan T et al.: Grade 3 Lymphomatoid Granulomatosis in a Patient Receiving Methotrexate Therapy for Rheumatoid Arthritis. Internal Medicine 2014;53:1873-1875.
    38. Ikeue T, Kawachi H, Yoshida H et al.: Endobronchial Manifestation of Methotrexate-induced Lymphoproliferative Disorder. Intern Med 2019;58:1597-1603.
    39. Rizzi R, Curci P, Delia M et al.: Spontaneous remission of “methotrexate-associated lymphoproliferative disorders” after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature. Medical Oncology 2009; 26:1-9.
    40. Sigamani E, Chandramohan J, Nair S et al.: Lymphomatoid granulomatosis: A case series from South India. 2018;61: 228-232.
    41. Jain P, Kanagal-Shamanna R, Ghorab A: Characteristics, Treatments, and Outcomes of Patients with Lymphomatoid Granulomatosis—MD Anderson Cancer Center Experience. 2017;130: 2852-2852.
    42. Carlson KC, Gibson LE: Cutaneous Signs of Lymphomatoid Granulomatosis. JAMA Dermatology 1991;127:1693-1698.
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