Address for correspondence : Ja Hyun Lee, MD, Department of Otorhinolayngology, National Health Insurance Corporation Ilsan Hospital, 100 Ilsan-ro, Ilsandong-gu, Goyang 410-719, Korea
Tel : +82-31-900-0049, Fax : +82-31-900-0049, E-mail : okas2000@daum.net 

INTRODUCTION

   Extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), also known as MALT lymphoma, is a distinctive group of B-cell lymphomas specified in the World Health Organization classification.¹⁾ The most common anatomic site of origin of MALT lymphoma is the stomach. Other common sites include the skin, salivary glands, ocular adnexa, intestines, and lung. However, it is known that virtually any extranodal anatomic site in the body can be involved by MALT lymphoma.²⁾ Because patient with MALT lymphoma exhibits an indolent natural history and a favorable prognosis, treatments like excision or radiotherapy or antibiotics should be chosen carefully. Results from radiotheraphy series have demonstrated relatively good local controls with a prolonged clinical course in patients with ocular adnexal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (ocular MALT lymphoma).^3,4)
   We report a case of recurrent extranodal marginal zone B-cell lymphoma that presented in the unusual location of the cheek after initial treatment with radiotherapy in ocular MALT lymphoma. To our knowledge, this presentation has not previously been reported in the literature.

Case

   A 65-year-old man presented with a 5 year history of a slow growing huge mass of his right-sided cheek. The mass on the cheek, 8×6 cm sized, was located between infra-ocular area and anterior margin of parotid gland, not likely to involve in parotid gland, orbital structure, nasal cavity and skin (Fig. 1). He did not have any symptoms or signs to suggest ocular or orbital disease and facial nerve problems. There were not body weight loss, night sweat and fever, so called as B-symptoms. The only symptom he had was a discomfort caused from a huge mass. He had had histories of treatments of radiotherapy on each eye before he came to our clinic because of both ocular MALT lymphomas, located in inferior rectus muscles extending to lateral rectus muscles around eyeballs; in left side with 25 Gy dose radiotherapy 15 years ago, in right side with 25 Gy dose 7 years ago. After radiotherapy on the left eye, he had spent complete remission period during about 8 years. Before 7 years, a newly developing MALT lymphoma had occurred in opposite right site on ocular adnexa again. The same dose of radiotherapy made him stay in the state of tumor free for about 2 years.
   At initial investigation in our clinic, there was no proptosis or diplopia. Ocular examination was unremarkable and vision was normal. There was no lymphadenopathy or hepatosplenomegaly. A computed tomography scan showed a non-enhanced well margined huge mass on masseter muscle, under Subcutaneous Musculo-Aponeurotic System, but no bone, muscle and skin involvement (Fig. 2). High standardized uptake value uptake on FDG-PET/CT on the main cheek mass was showed, but uptakes on any other multiorgan sites including both ocular adnexas were not visible. In a study of whole body bone scan, any evidences of invading to other sites were not noted (Fig. 3). To discriminate malignancy, we did fine-needle aspiration biopsy (FNAB) at clinic under local anesthesia, and we got the result of FNAB that it could be probable of lymphoma. After discussing with oncologist and pathologist, we concluded to perform an excisional biopsy because FNAB is not sufficient for a diagnosis of lymphoma.
   We performed excisional biopsy after elevating subcutaneous flap and got a 2×2 cm specimen from the huge mass. On surgery field, we confirmed that the mass was separated more than 1 cm far from parotid gland capsule and located separately on masseter muscle. We could not do excision of the mass completely because it was too huge and branches of facial nerve should be preserved. The specimen obtained was sent to histopathology department, and was done with immunohistochemical analysis indicated uniform presence of B-cell markers CD20 and Bcl2, the absence of CD3 (positive in only reactive T cells), CD10, Bcl6, cyclin D1 and Ki67 L.I less than 10% (Fig. 4). Therefore, the lesion was compatible with a MALT lymphoma.
   He recovered fully after surgery without facial weakness and was referred urgently to a radiotherapist for further management. He responded well to added radiotherapy with 36 Gy and has remained well at 6 months after his initial presentation. 

Discussion

   Extranodal marginal zone B-cell lymphoma of MALT (MALT lymphoma) is a distinctive type of malignant B-cell lymphoma. Initially defined by Isaacson¹⁾ and wright in 1983, the Revised European American Lymphoma and the World Health Organization classification systems have now incorporated this entity under the term MALT lymphoma. MALT lymphomas are believed to follow a relatively indolent course and show a tendency to remain localized within their original environment for a long period of time.⁵⁾ As used in the current study, the term ocular MALT lymphoma refers to lymphoma that arises in the extraocular orbital space and involves the conjuctiva, eyelids, lacrimal gland, or orbital soft tissue. MALT lymphomas in salivary gland related with autoimmune disease like Sjögren's syndrome are antigen-stimulated B-cell lymphomas characterized by localized stage, indolent clinical course, and similar recurrence in other extranodal sites.⁶⁾ The patient in our report had had ocular MALT lymphoma on each ocular adnexas, especially originated from inferior rectus muscles. He had good responses to local radiotherapy with 20 Gy dose in each treatment and no recurrence on ocular areas which were belonged to treatment field of radiotherapy until diagnosis in MALT lymphoma of cheek area. The huge cheek mass finally was reported as typical MALT lymphoma, but seemed to be completely separated from parotid gland, eye, skin and any suspicious mucosa-related tissue near the cheek area. It can be possible that after ocular adnexa biopsy, tumor seeds to surrounding tissues or radiotherapy induces and transforms atypical lymphoid cells.⁷⁾
   Immunohistochemically, MALT-lymphomas usually share the cytologic feature and immunophenotype (CD20+, CD21+, CD35+, IgM+, IgD-) of marginal zone B cells and CD10-, CD5-, and cyclin D1-, which is important for distinction from follicular lymphoma, small lymphocytic lymphoma/CLL, and matle cell lymphoma.⁸⁾ Our case is adequate to typical MALT lymphoma impression by the immunohistochemical staining of CD20+, Bcl2+, CD5-, CD10-, cyclinD1-. The neoplasm is composed predominantly of small lymphoid cells with mildly irregular nuclear contours and moderate cytoplasm. Also, the presence of lymphoepithelial lesions formed by the invasion of individual glands by aggregates of lymphoma cells is showed. CT and magnetic resonance tomography with contrast enhancement are the primary radiographic imaging tools in the evaluation of ocular adnexal proliferations. They aid in the assessment of location, size, and degree of infiltration. Positron emission tomography (PET) imaging may represent a valuable addition in the evaluation of MALT lymphoma, despite its low sensitivity (27%) in detecting orbital lesions. Several studies have indicated that PET has a higher sensitivity than CT scan in the detection of distant disease (86% vs. 72%) in patients with MALT lymphoma.⁹⁾
   Although there is no consensus regarding the optimal radiotherapy, in particular the optimal dose and target volume, most radiotherapy series report an absence of infield recurrence and very high local controls in patients with ocular MALT lymphoma.^3,10,11) In a view of long-term follow up, the therapeutic approach also was reported in 46 patients with ocular adnexal lymphomas by Auw-Haedrich et al.,¹²⁾ who found radiotherapy to be the predominant form of therapy in patients with MALT lymphoma. Current National Cancer Center Network guidelines recommend radiotherapy of 20 to 30 Gy for initial treatment of early stage nongastric MALT lymphoma of all sites and reirradiation for locally recurrent disease. Reirradiation in the setting of relapsed disease exceeds the maximum tolerable dose of the eye and should be avoided. The patient in our report had 20 Gy dose radiotherapies on ocular adnexas in each period. The lymphoma on the cheek was radiated with 36 Gy dose, but not including previous ocular field carefully. Since 6 months followed, he does not have any complication of radiotherapy, except of slight xerostomia. Adding to radiotherapy, various treatment modalities are available for the management of patients with OAML, including surgical resection, radiotherapy, single-agent or combination chemotherapy, and immunotherapy with monoclonal antibodies. However, no prospective clinical trials have been conducted to evaluate these therapeutic options or define the optimal treatment approach for these patients. Recently, antichlamydial antibiotic therapy was also proposed as a novel treatment option.¹³⁾
   In summary, our patient presented with a solid cheek mass and an excisional biopsy confirmed a MALT lymphoma occurring in subcutaneous cheek area in front of parotid gland, on masseter muscle, separated from ocular adnexa which previously diagnosed as ocular MALT lymphoma and treated with radiotherapy. Although we cannot be sure if it is originated from skin, salivary gland, ocular adnexa and any related mucosa tissue or not, the MALT lymphoma on the cheek is surely separated solely from previous ocular MALT lymphomas and parotid gland, skin and occurred unusually in the filled of subcutaneous area on cheek. We will need to observe a prognosis of the patient for long term closely.

1. Isaacson PG. Extranodalmarginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization Classification of Tumours: Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues. Lyon; IARC Press;2001. p.157-60.

2. Pelstring RJ, Essell JH, Kurtin PJ, Cohen AR, Banks PM. Diversity of organ site involvement among malignant lymphomas of mucosa-associated tissues. Am J Clin Pathol 1991;96(6):738-45.

3. Le QT, Eulau SM, George TI, Hildebrand R, Warnke RA, Donaldson SS, et al. Primary radiotherapy for localized orbital MALT lymphoma. Int J Radiat Oncol Biol Phys 2002;52(3):657-63.

4. Stafford SL, Kozelsky TF, Garrity JA, Kurtin PJ, Leavitt JA, Martenson JA, et al. Orbital lymphoma: radiotherapy outcome and complications. Radiother Oncol 2001;59(2):139-44.

5. Thieblemont C, Bastion Y, Berger F, Rieux C, Salles G, Dumontet C, et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 1997;15(4):1624-30.

6. Voulgarelis M, Moutsopoulos HM. Mucosa-associated lymphoid tissue lymphoma in Sjögren's syndrome: risks, management, and prognosis. Rheum Dis Clin North Am 2008;34(4):921-33, viii.

7. Akpek EK, Polcharoen W, Ferry JA, Foster CS. Conjunctival lymphoma masquerading as chronic conjunctivitis. Ophthalmology 1999;106(4):757-60.

8. Raderer M, Isaacson PG. Extranodal lymphoma of MALT-type: perspective at the beginning of the 21st century. Expert Rev Anticancer Ther 2001;1(1):53-64.

9. Sullivan TJ, Valenzuela AA. Imaging features of ocular adnexal lymphoproliferative disease. Eye (Lond). 2006;20(10):1189-95.

10. Baldini L, Blini M, Guffanti A, Fossati V, Colombi M, La Targia ML, et al. Treatment and prognosis in a series of primary extranodal lymphomas of the ocular adnexa. Ann Oncol 1998;9(7):779-81.

11. Bolek TW, Moyses HM, Marcus RB Jr, Gorden L 3rd, Maiese RL, Almasri NM, et al. Radiotherapy in the management of orbital lymphoma. Int J Radiat Oncol Biol Phys 1999;44(1):31-6.

12. Auw-Haedrich C, Coupland SE, Kapp A, Schmitt-Gräff A, Buchen R, Witschel H. Long term outcome of ocular adnexal lymphoma subtyped according to the REAL classification. Revised European and American Lymphoma. Br J Ophthalmol 2001;85(1):63-9.

13. Stefanovic A, Lossos IS. Extranodal marginal zone lymphoma of the ocular adnexa. Blood 2009;114(3):501-10.