Primary thyroid lymphoma is a rare condition accounting for 1 to 5% of all thyroid malignancies and approximately 2% of all malignant extranodal lymphomas [1]. Mucosa-associated lymphoid tissue (MALT) lymphoma is one of the rare variants, first described by Isaacson and Wright in 1984 [2]. Pure thyroid MALT lymphomas comprise about 6 to 28% of primary thyroid lymphomas, and are recognized as extranodal marginal zone B-cell lymphomas in the Revised European American Lymphoma classification of 1994 and the World Health Organization classification of 1999 [3-5]. Strictly, the thyroid gland is not a mucosal organ, being of foregut origin, and the lymphoid tissue that accumulates in the thyroid in Hashimoto's thyroiditis shares features with MALT. MALT lymphomas are thought to develop from lymphocytic tissue acquired during the course of a chronic inflammatory or autoimmune process. The thyroid is normally devoid of such lymphocytic tissue, and chronic autoimmune thyroiditis (Hashimoto's disease) has been associated with an increased risk of lymphoma, including MALT lymphoma [6]. The coexistence of reactive and neoplastic processes in the thyroid gland may render the cytological and histological diagnosis of MALT lymphoma difficult. Clinically, most patients present in the seventh decade of life and 30 to 50% of patients have compression symptoms, including dysphagia, dyspnea, stridor or hoarseness [7]. Primary thyroid MALT lymphomas are known to respond better to local treatments such as surgical resection and radiotherapy, compared to diffuse large B-cell lymphomas. Also, primary thyroid MALT lymphomas tend to run an indolent clinical course with excellent prognosis, whereas exclusive diffuse large B-cell types or mixed types display a more aggressive clinical course [8]. The present study aimed to evaluate the clinicopathological features and treatment outcomes of patients with primary thyroid MALT lymphoma.

We identified seven patients with a pathologic diagnosis of thyroid MALT lymphoma between January 1997 and December 2007, and reviewed their clinicopathological characteristics and treatment outcomes retrospectively. The diagnosis of MALT lymphoma was given in cases with the presence of CD20 immunoreactivity in immunohistochemically stained specimens from fine needle aspiration biopsy (FNAB), core biopsy and surgery, and the histologic presence of small lymphoid cells with variable proportions of centrocyte-like cells, plasma cells, lymphoplasmacytoid lymphocytes, monocytoid B-cells, and interspersed large transformed lymphocytes. Mixed types with simultaneous presence of both MALT lymphoma and diffuse large B-cell lymphoma were excluded. We also investigated the patients' stage (according to the Ann Arbor staging system) by examining the results from physical examination, blood counts, chemistry, chest X-rays, chest computed tomography (CT) scan, abdominal-pelvic CT, and bone marrow examination. This study was approved by our institutional review board. We adopted Musshoff's modification of the Ann Arbor staging system, and primary thyroid lymphomas were staged as follows: IE: primary thyroid lymphoma with or without extension into the perithyroidal soft tissue; IIE: primary thyroid lymphomas with involvement of lymph nodes on the same side of the diaphragm; IIIE: primary thyroid lymphomas with involvement of lymph nodes on both sides of the diaphragm and/or spleen; and IVE: primary thyroid lymphomas with dissemination to other extranodal sites [9]. Although this study was not primarily focused on staging, some authors insist that primary thyroid lymphoma is defined as a lymphoma that only involves the thyroid gland or the thyroid gland with its adjacent lymph nodes [10], restricting its stage to either stage IE or IIE under the Ann Arbor staging system. The mean follow-up period was 66 months (range, 10 to 148 months).

The patients' characteristics are listed in Table 1. There were five female and two male patients. At the time of diagnosis, the mean age of the patients was 73 years (range, 57 to 85 years). All patients complained of palpable neck masses, and two patients also had hoarseness and dyspnea. All patients had a history of autoimmune Hashimoto's thyroiditis, with a mean duration of 175 months (range, 60 to 360 months). One patient underwent FNAB, though the results were reported to be non-diagnostic. Core biopsy was performed in three cases for pathologic confirmation. Four cases, including the FNAB case, directly proceeded with curative surgery in the absence of preoperative pathologic confirmation because they displayed signs of acute enlargement as well as dysphagia and dyspnea during outpatient department follow-up, along with character changes in ultrasonography. Diagnosis was confirmed after surgery. The preoperative goitrous condition, postoperative gross specimen and microscopic feature (patient No.6) are shown in Fig. 1. As initial treatment, complete surgical resection was performed in five cases, radiotherapy alone in one case, and a combination of chemotherapy and radiotherapy was given in one case. Among the patients that underwent surgery, there were two cases of total thyroidectomy, two cases of total thyroidectomy with modified radical neck dissection, and one case of hemithyroidectomy. The radiotherapy-only case was performed using a dose of 4,500 cGy to the neck area. In the case of the patient that underwent combined chemotherapy and radiotherapy, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen was performed and the radiation dose was 4,500 cGy at the lesion. Using the Ann Arbor staging system, five patients were stage IE and two patients were stage IIE. All of the patients achieved complete remission. One patient expired due to an unrelated cause (pancreatic cancer), and there were no disease-specific mortalities.

MALT lymphomas are very rare, but account for 85% of extranodal non-Hodgkin's lymphomas [2]. Although the stomach is by far the most common site of MALT lymphomas, they have also been described in various non-gastrointestinal sites, such as the salivary gland, thyroid, skin, conjunctiva, orbit, lung, breast, kidney, liver and even in the intracranial dura [11-18].

Two types of MALT can be identified in disparate organs that do not correspond to peripheral sites of the immune system. The native type consists of lymphoid tissue physiologically present in the gut (e.g., Peyer's patches), whereas acquired MALT develops in sites of inflammation in response to either infectious conditions such as Helicobacter pylori gastritis, or autoimmune processes such as Hashimoto's thyroiditis [19,20]. In addition to being a causal factor of primary thyroid MALT lymphoma, it has been hypothesized that Hashimoto's thyroiditis may further develop into aggressive lymphomas [6,21]. This is the basis for treatment of primary thyroid MALT lymphomas, even though they have a better response to local treatment and a more favorable prognosis compared to diffuse large cell lymphomas.

Normally, FNAB is a widely accepted technique for the diagnosis of thyroid nodules. However, primary thyroid lymphomas can be difficult to diagnose with FNAB alone. While the diagnostic accuracy of FNAB is quite low for diffuse large B-cell lymphomas, it is even lower in the case of thyroid MALT lymphomas because the differentiation of MALT lymphomas from Hashimoto's thyroiditis can be difficult by cytomorphology alone [22]. Core needle biopsy, though not considered a first-line method for the diagnosis of lymphomas, has been reported to have a higher diagnostic yield, with a sensitivity of 94.3%, a specificity of 100%, and an accuracy of 95.2% [23]. As a method for diagnostic confirmation, core needle biopsy would be an alternative with a high priority along with FNAB. In our study, surgery was performed on a total of four cases prior to pathological confirmation, with a single case of FNAB and three cases of core needle biopsy. Clinically, when a patient with a past history of Hashimoto's thyroiditis displays signs of abrupt thyroid enlargement or compression symptoms, the possibility of thyroid MALT lymphoma should be considered. This is especially true for the patients with a history over 5 years.

The optimal treatment modality for primary thyroid MALT lymphoma remains yet to be defined. The benefits of surgical treatment in diffuse large B-cell lymphoma still remain in debate. While the combination of radiotherapy and chemotherapy is currently known as the standard treatment modality, local treatments such as total thyroidectomy, or sole radiotherapy have been reported to be effective as well in MALT lymphoma limited to the thyroid [3,24]. There are some authors who advocate that the treatment of neck lymph nodes with signs of metastasis from primary thyroid lymphoma should include adjuvant radiotherapy in addition to surgery such as functional neck dissection [8]. The five cases of MALT lymphoma in this study that were localized to the thyroid did not show recurrence or disease-related mortality regardless of treatment modality. Also, the two cases (stage IIE) that underwent modified radical neck dissection due to metastatic neck lymph nodes showed good outcome without additional adjuvant treatment. All of the patients remained recurrence free after 10 years. Considering the excellent prognosis achieved in the two cases with lateral neck node metastasis by complete surgical resection without adjuvant treatment, it can be said that complete surgical removal has significant value in treating primary thyroid MALT lymphomas even with regional lymph node metastasis. There are other similar reports where MALT lymphoma showed an indolent nature with an overall survival rate of more than 90% after only local control, whereas cases of diffuse large B-cell lymphoma had and overall survival rate of 30 to 50% even with both surgery and radiotherapy performed [7,25,26]. Considering the results of the current study and previous reports, the most important modality for the treatment of localized primary thyroid MALT lymphoma will be complete loco-regional control of disease including surgical removal and radiation therapy. Currently, there are no set protocols concerning follow-up evaluations after the treatment of primary thyroid MALT lymphoma. There are cases where fluorine-18 fluorodeoxyglucose-positron emission tomography scans were used in the evaluation of recurrences, but its utility is yet to be determined [27].

In conclusion, when primary thyroid MALT lymphoma is suspected, core needle biopsy along with FNAB should be considered as a first-line histologic diagnostic tool. As initial treatment, local treatment, such as complete surgical resection and radiotherapy, should be performed when the disease is localized in the thyroid or when the metastasis is limited to the regional lymph nodes. The role of adjuvant radiotherapy and chemotherapy is still undetermined and is in need of further research.