Long-Term Outcomes of 107 Cases of Primary Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma at a Single Medical Institution in Japan

Long-Term Outcomes of 107 Cases of Primary Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma at... Abstract Context Thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal lymphoma with a favorable prognosis. Objective To provide information on long-term outcomes that would facilitate establishment of the optimal management strategy for thyroid lymphoma. Design, Setting, and Participants Medical records of 107 patients (median age 67 years, 20 males, 87 females) who were diagnosed with localized thyroid MALT lymphoma stage IE or IIE at Ito Hospital were retrospectively reviewed. Main Outcome Measure Overall and event-free survival (EFS). Results Initial treatments included radiation therapy (RT) alone (n = 58), combined modality therapy (CMT) (n = 48), or chemotherapy alone (n = 1). All 107 patients responded to the treatment, six of whom experienced relapse. Only one patient died of lymphoma. The 5-year overall survival (OS) and EFS rates were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Of the 106 patients with information available on adverse events, 71 patients (67%) developed hypothyroidism after primary thyroid lymphoma treatment. The CMT group showed additional chemotherapy-induced adverse reactions in the form of neutropenia, neuropathy, constipation, and pneumonia. The 5-year OS rates of patients treated with CMT and RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively. Conclusions Long-term outcomes of localized thyroid MALT lymphoma are favorable with all initial treatment modalities. Primary thyroid lymphoma (PTL) accounts for 1% to 2% of extranodal lymphomas (1). PTL has a predilection for elderly women, with a female:male ratio of 4:1 and mean age of onset in the 60s (2–4). About 90% of PTL patients also have Hashimoto disease (HD), and the risk of PTL in patients with HD is ∼70 to 80 times higher than in the general population (5, 6). A retrospective analysis at our hospital found an incidence of PTL of 16 per 10,000 HD patients per year (3); this incidence is 10 times higher than previously reported. With advances in imaging and pathological diagnosis, as well as with aging of the population, the diagnostic frequency of PTL may continue to increase. PTLs are mainly classified as mucosa-associated lymphoid tissue (MALT) lymphoma (10% to 50%) and diffuse large B-cell lymphoma (50% to 70%) (3, 4, 7). Thyroid MALT lymphoma is an indolent B-cell–derived extranodal MALT lymphoma. Apart from the thyroid, extranodal MALT lymphomas also occur in organs such as the stomach, orbit, and salivary glands, and they usually have a good prognosis. Some researchers reported that the prognostic features differ according to the primary site. For example, primary gastric and thyroid MALT lymphomas have a better prognosis than salivary and orbital MALT lymphomas (8, 9). This may suggest the need to alter the treatment of MALT lymphomas based on the primary site. However, with the exception of localized gastric MALT lymphomas treated by Helicobacter pylori eradication, most MALT lymphomas are treated similarly. Involved site radiation therapy (RT) is usually considered as the initial treatment, but chemotherapy, including antibody treatment, and follow-up observation in stage IE patients without postoperative residual tumor have also been proposed (10). Because thyroid MALT lymphoma has a good prognosis (11), treatment-related adverse event is an important consideration when selecting treatment. In addition to general adverse events with antibody treatment and chemotherapy, the nearby salivary glands, oropharyngeal mucosa and esophageal mucosa (oropharyngolaryngitis/esophagitis), are sometimes damaged due to involved site RT. These adverse events specific to treatment of thyroid MALT lymphoma are important from a patient perspective. In particular, hypothyroidism after RT is a long-term adverse event that can markedly affect quality of life (QOL) in older individuals, who comprise the majority of patients with thyroid MALT lymphoma. Information about permanent long-term adverse events, such as hypothyroidism, is useful when selecting treatment, although, currently, data on the long-term outcomes of thyroid MALT lymphoma are very limited. Ito Hospital specializes in the treatment of thyroid diseases and has long collected clinical data on many patients with thyroid lymphoma (3, 12, 13). Therefore, this study used our clinical data to investigate long-term outcomes, including long-term adverse events, in patients with primary thyroid MALT lymphoma. The results of this study can provide useful information not only for treatment selection, but also for management of patients after they have undergone treatment. Patients and Methods Patient selection and clinical records We analyzed thyroid MALT lymphoma patients from January 1990, and, to obtain a long observation period, limited the analysis target to patients presenting before 2009. During the period, a total of 111 patients at Ito Hospital were histopathologically diagnosed with localized thyroid MALT lymphoma stage IE or IIE. The clinical records of these patients were retrospectively reviewed. Of these, four patients whose follow-up durations were within 100 days due to transfer to other hospitals and for whom treatment information was not available were excluded. Consequently, 107 patients with localized thyroid MALT lymphoma were included in this study. The clinical stage was evaluated by thyroid ultrasonography (n = 107), abdominal ultrasonography (n = 4), computed tomography (n = 104), 67Ga-citrate scintigraphy (n = 107), bone marrow aspiration biopsy (n = 98), and fluorine-18-fluorodeoxyglucose–positron emission tomography (n = 5), using the proposed criteria described by the Ann Arbor staging system for lymphomas (14, 15). Fluorine-18-fluorodeoxyglucose–positron emission tomography did not show any upstaging in any of the five patients in whom it was performed. Stage IE patients (n = 47) had localized involvement of the thyroid alone, whereas in stage IIE patients (n = 60) the major site of involvement was the thyroid gland, with associated regional lymph node involvement. Findings of ultrasonography were grouped into four classes according to the characteristics of the low-echoic lesion (Supplemental Fig. 1). The patients were also investigated for the presence of HD. A diagnosis of HD was based on the presence of elevated antithyroid peroxidase antibody and/or antithyroglobulin antibody levels, regardless of thyroid function. Patients without these antibodies, but with positive pathological findings, were also diagnosed with HD (3). Treatment of PTL At Ito Hospital, the treatment strategy for PTL was primarily based on the clinical stage; RT alone was given for stage IE, and combined modality therapy (CMT) was given for stage IIE PTL. The role of surgery was mainly for biopsies; generally, open incisional biopsy was performed. CMT usually included RT and multiple courses of cyclophosphamide, adriamycin, vincristine, and prednisolone (cyclophosphamide, 750 mg/m2; adriamycin, 40 mg/m2; vincristine, 1.4 mg/m2; and prednisolone, 100 mg/body)–based chemotherapy. With RT, the whole of the neck and upper mediastinum was encompassed by the treatment. In eight patients who were diagnosed after 2005, rituximab was added to cyclophosphamide, adriamycin, vincristine, and prednisolone therapy as CMT. To prevent an infusion reaction to rituximab (375 mg/m2), 400 mg acetaminophen and 30 mg diphenhydramine hydrochloride were administered as premedication. From 2012, the dosage of adriamycin was modified from 40 mg/m2 to 50 mg/m2. Adverse events Adverse events were graded based on the Common Terminology Criteria for Adverse Events version 4.0. Hypothyroidism after treatment of PTL was designated as follows: (1) started levothyroxine (LT4) after treatment of PTL and with increase in dosage thereafter; (2) started LT4 after treatment of PTL without increase in dosage; and (3) started LT4 before treatment of PTL, with increase in dosage of LT4 after treatment of PTL. Definitions and statistical analysis All of the 107 patients were diagnosed based on histological examination of the thyroid tissue specimens. Pathological diagnosis was based on the World Health Organization classification. Follow-up data were calculated from the time of the initial surgery for diagnosis of the thyroid pathology to the last follow-up. Clinical follow-up data were obtained from the patients’ records, communication with the patients and their families, and communication with the referring physicians. Relapse of PTL was defined as the involvement of new sites, recurrence at originally involved sites, or >25% increase in the size of the original tumor mass. A complete response was defined by the disappearance of all documented disease. Partial response was defined by a reduction of at least 50% in the largest diameter of every measurable lesion. Treatment success was defined as a partial response or better. This study was approved by the institutional review board of Ito Hospital. The data were analyzed as of February 2017. Overall survival (OS), event-free survival (EFS), and cause-specific survival (CSS) were estimated by the Kaplan–Meier method. OS was calculated from the time of initial surgery on the thyroid gland to death from any cause; EFS was calculated as the time from initial surgery on the thyroid gland to the absence of at least a partial response on the intermediate evaluation, relapse, or death in remission; and CSS was calculated from the time of initial surgery on the thyroid gland to death from lymphoma. For analysis of OS, data on patients who were alive at the last follow-up contact were censored. For the analysis of EFS, data on patients who were alive without any progression of the primary disease at the last follow-up were censored. JMP version 12.0.1 (SAS Institute, Cary, NC) was used for all statistical analyses. The poor prognostic factors investigated in the Cox proportional hazard model were age, sex, presence of HD, duration since diagnosis of HD, ESR, increase in lactate dehydrogenase and soluble interleukin-2 receptor levels, ultrasonography findings, i.e., bilaterality of lesion, disease stage, treatment, and operation. Backward stepwise modeling was used in multivariate analysis. A P value < 0.05 was considered to be statistically significant. Results Patients’ characteristics The patients’ characteristics at the time of diagnosis of MALT lymphoma are shown in Table 1. Of the 107 patients, 87 (81%) were women. The median age of the patients was 67 years (range, 28 to 88 years). HD was diagnosed in 100 (93%) patients. The median follow-up period of survivors was 9.7 years (range, 0.4 to 26.0 years). At the time of diagnosis, half of the patients had a unilateral low-echoic lesion (Table 1). As cytological atypia is mild in MALT lymphoma, final cytological diagnosis by fine-needle aspiration biopsy was highly suggestive of lymphoma in only 32% (Supplemental information). Table 1. Patients’ Characteristics Variables  Number (%)  No. of patients  107  Age, median [range], y  67 [28–88]  Sex (M/F)  20/87 (19/81)  Concomitant thyroid diseasea     HD  100 (93)   Adenomatous goiter  9 (8)   Othersb  8 (7)   None  4 (4)  Laboratory tests at diagnosis     Elevated LD  28 (26)   ESR, range, mm/h  18 [3–122]   sIL-2R, median [range], U/mL  592 [224–3654]   Free T3, median [range], pg/mL  3.0 [1.2–5.2]c   Free T4, median [range], ng/dL  1.1 [0.3–1.8]c   TSH, median [range], μU/mL  3.3 [0.5–113]c   TSH (decreased/normal range/elevated)  0/49/16 (0/75/25)c  Findings of low-echoic areas on ultrasonography     Unilateral  56 (52.3)    Right  29 (27.1)    Left  27 (25.2)   Bilateral  24 (22.4)   Single nodular  16 (15.0)   Multiple patchy low-echoic areas  8 (7.5)   Not availabled  3 (2.8)  Clinical stage (IE/IIE)  47/60 (44/56)  Treatment     CMT  48 (45)   RT  58 (54)   Chemotherapy  1 (1)  Outcome     Relapse  6 (5.6)   Death  12 (11)  Variables  Number (%)  No. of patients  107  Age, median [range], y  67 [28–88]  Sex (M/F)  20/87 (19/81)  Concomitant thyroid diseasea     HD  100 (93)   Adenomatous goiter  9 (8)   Othersb  8 (7)   None  4 (4)  Laboratory tests at diagnosis     Elevated LD  28 (26)   ESR, range, mm/h  18 [3–122]   sIL-2R, median [range], U/mL  592 [224–3654]   Free T3, median [range], pg/mL  3.0 [1.2–5.2]c   Free T4, median [range], ng/dL  1.1 [0.3–1.8]c   TSH, median [range], μU/mL  3.3 [0.5–113]c   TSH (decreased/normal range/elevated)  0/49/16 (0/75/25)c  Findings of low-echoic areas on ultrasonography     Unilateral  56 (52.3)    Right  29 (27.1)    Left  27 (25.2)   Bilateral  24 (22.4)   Single nodular  16 (15.0)   Multiple patchy low-echoic areas  8 (7.5)   Not availabled  3 (2.8)  Clinical stage (IE/IIE)  47/60 (44/56)  Treatment     CMT  48 (45)   RT  58 (54)   Chemotherapy  1 (1)  Outcome     Relapse  6 (5.6)   Death  12 (11)  Abbreviations: ESR, erythrocyte sedimentation rate; LD, lactate dehydrogenase; sIL-2R, soluble interleukin-2 receptor; TSH, thyroid-stimulating hormone. a There is some overlap between the diseases. b These included papillary carcinoma (n = 2), Graves’ disease (n = 5), and hyperthyroidism (n = 1). c Patients with thyroid hormone replacement therapy (n = 42) were excluded. d Three patients had no available ultrasonography images for re-evaluation. View Large Treatment Open incisional biopsy was performed in 85 patients; lobectomy was performed in 21 patients whose lesions were on the dorsal side or not large enough to identify the biopsy site by palpation during surgery; and total thyroidectomy was performed in one patient to relieve compression symptoms caused by the huge goiter. Although all of the patients first underwent surgery of some form, all 107 patients also received nonsurgical treatment. Of the 107 patients, 58 patients received RT alone (54%) with a median dose of 40 Gy, and 48 received chemotherapy and RT (45%) with a median dose of 36 Gy. One patient received chemotherapy alone (1%) (Table 1). As shown in Table 2, no significant differences in patients’ background characteristics were seen between those treated by CMT versus RT, except for clinical stage. According to the institutional treatment strategy of Ito Hospital, 42 of 47 patients with stage IE disease received RT alone, and 43 of 60 stage IIE patients received CMT. The proportion of patients with stage IIE disease was significantly higher among those who underwent CMT (90% versus 28% in CMT and RT patients, respectively, P < 0.0001) (Table 2). Table 2. Treatment and Outcome Variables [Number (%)]  CMT (n = 48)  RT (n = 58)  P Value  Age, median [range], y  66 [28–84]  69 [51–88]  0.08  Sex (M/F)  11/37 (23/77)  9/49 (16/84)  0.33  ESR, median [range], mm/h  18 [3–122]  18 [4–67]  0.50  Elevated LD  16 (33)  10 (17)  0.13  sIL-2R, median [range], U/mL  651 [276–3654]  551 [224–1661]  0.45  Findings of low-echoic areas on ultrasonographya      0.25   Unilateral  25 (52.0)  32 (55.2)     Bilateral  14 (29.2)  9 (15.5)     Single nodular  4 (8.3)  12 (20.7)     Multiple patchy low-echoic areas  4 (8.3)  4 (6.9)     Not available  1 (2.1)  2 (3.4)    Surgery      0.10   Open biopsy  41 (85)  43 (74)     Lobectomy  6 (13)  15 (26)     Total thyroidectomy  1 (2)  0 (0)    Clinical stage (IE/IIE)  5/43 (10/90)  42/16 (72/28)  <0.0001  Treatment         Irradiation dose, median [range], Gy  36 [21–45]  40 [30–50]  0.22   Chemotherapy      —    CHOP  39 (81)        RCHOP  8 (17)        COP-BLAM  1 (2)      Outcome         Relapse  1 (2)  5 (9)  0.14   Death  6 (13)  6 (10)  0.73  Variables [Number (%)]  CMT (n = 48)  RT (n = 58)  P Value  Age, median [range], y  66 [28–84]  69 [51–88]  0.08  Sex (M/F)  11/37 (23/77)  9/49 (16/84)  0.33  ESR, median [range], mm/h  18 [3–122]  18 [4–67]  0.50  Elevated LD  16 (33)  10 (17)  0.13  sIL-2R, median [range], U/mL  651 [276–3654]  551 [224–1661]  0.45  Findings of low-echoic areas on ultrasonographya      0.25   Unilateral  25 (52.0)  32 (55.2)     Bilateral  14 (29.2)  9 (15.5)     Single nodular  4 (8.3)  12 (20.7)     Multiple patchy low-echoic areas  4 (8.3)  4 (6.9)     Not available  1 (2.1)  2 (3.4)    Surgery      0.10   Open biopsy  41 (85)  43 (74)     Lobectomy  6 (13)  15 (26)     Total thyroidectomy  1 (2)  0 (0)    Clinical stage (IE/IIE)  5/43 (10/90)  42/16 (72/28)  <0.0001  Treatment         Irradiation dose, median [range], Gy  36 [21–45]  40 [30–50]  0.22   Chemotherapy      —    CHOP  39 (81)        RCHOP  8 (17)        COP-BLAM  1 (2)      Outcome         Relapse  1 (2)  5 (9)  0.14   Death  6 (13)  6 (10)  0.73  Abbreviations: CHOP, cyclophosphamide, adriamycin, vincristine, and prednisolone; COP-BLAM, cyclophosphamide, vincristine, prednisolone, bleomycin, adriamycin, and procarbazine; ESR, erythrocyte sedimentation rate; LD, lactate dehydrogenase; RCHOP, rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone; sIL-2R, soluble interleukin-2 receptor. a Three patients had no available ultrasonographic images for re-evaluation. View Large Disease relapse and causes of death Final follow-up data were obtained from the patients’ medical records (n = 72), communication with the patients (n = 3) and their families (n = 8), communication with the referring physicians (n = 23), and from an accident report by the police (n = 1). Treatment was successful (defined as a partial response or better) in all of the 107 patients. Of them, six patients experienced relapse. A 59-year-old woman with stage IE MALT lymphoma underwent radiotherapy and showed relapse in the spinal cord 4 years later. Despite the additional treatment, she died of lymphoma. The other five patients experienced relapse in the ipsilateral thyroid and/or lymph nodes after 3 (n = 1), 5 (n = 1), 7 (n = 1), and 9 years (n = 1), and in the epipharynx after 7 years (n = 1). At the time of relapse, MALT lymphoma had transformed to diffuse large B-cell lymphoma in three of the five patients. All five of the patients responded to additional treatment and remain alive without disease at the last follow-up (Supplemental Table 1). Twelve patients died during follow-up at the median age of 78 years (range, 62 to 95). Only one patient died of disease relapse, whereas the others died of other causes, including pneumonia (n = 1), adenocarcinoma (n = 1), subarachnoid hemorrhage (n = 1), acute liver dysfunction (n = 1), congestive heart failure (n = 1), and bladder tumor (n = 1). One patient died of an accident. Information regarding cause of death was not available in the remaining four patients. Survival rates The 5-year OS and EFS rates of localized thyroid MALT lymphoma were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. The CSS rate was 99% (95% CI, 93% to 100%) at both 5 and 10 years (Fig. 1). Figure 1. View largeDownload slide (A) OS and (B) EFS in the entire patient cohort. Figure 1. View largeDownload slide (A) OS and (B) EFS in the entire patient cohort. The characteristics of patients treated with RT and CMT are shown in Table 2. The proportion of stage IIE patients was significantly higher among patients treated with CMT than among those treated with RT (P < 0.0001). Five of the six patients with relapse were treated using RT. However, the difference in relapse rates was not statistically significant between patients treated with CMT and RT (P = 0.14). The Kaplan–Meier method also showed that the 5-year OS rates of patients treated with CMT and those with RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively, and the 10-year OS rates of patients treated with CMT and RT were 88% (95% CI, 75% to 95%) and 92% (95% CI, 81% to 97%) (log–rank test: P = 0.91), respectively. The Kaplan–Meier method also showed that the 5-year EFS rates of patients treated with CMT and those treated with RT were 93% (95% CI, 81% to 98%) and 91% (95% CI, 80% to 96%), respectively, and the 10-year EFS rates of patients treated with CMT and RT were 85% (95% CI, 70% to 93%) and 82% (95% CI, 68% to 91%) (log–rank test: P = 0.48), respectively (Fig. 2). The proportional hazard model revealed age as a significant poor prognostic factor in terms of OS [hazard ratio 1.13 (95% CI, 1.05 to 1.21), P = 0.001] and EFS [hazard ratio 1.09 (95% CI: 1.02 to 1.17), P = 0.006] (Supplemental Table 2); treatment modality (CMT versus RT) was not detected as a significant prognostic factor of outcome in our study. Figure 2. View largeDownload slide (A) OS and (B) EFS stratified according to treatment modality. Figure 2. View largeDownload slide (A) OS and (B) EFS stratified according to treatment modality. Adverse events Information regarding the adverse events related to treatment was available in 91 of 107 patients and is shown in Table 3. The CMT group showed additional adverse reactions secondary to chemotherapy in the form of neutropenia, neuropathy, constipation, and pneumonia. None of the eight patients treated with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone therapy developed infusion reactions. Table 3. Adverse Events and Hypothyroidism Related With Treatment   CMT No AE/Any AE/AE ≧ Grade 3  RT Any AE/AE ≧ Grade 3  Adverse events  (n = 47)  (n = 44)   Neutropenia, n (%)  11/36/36 (23/77/77)  —   Neuropathy, n (%)  38/ 9/0 (81/19/ 0)  —   Pneumonia, n (%)  37/10/2 (79/21/4)  —   Mucosal damage,a n (%)  23/24/5 (49/51/11)  12/32/5 (27/73/11)   Oral mucositis, n (%)  32/15/0 (68/32/0)  35/9/0 (80/20/0)   Dry mouth, n (%)  39/8/0 (83/17/0)  40/4/0 (91/9/0)   Dysgeusia, n (%)  44/3/0 (94/6/0)  40/4/0 (91/9/0)   Skin disorders, n (%)  44/3/0 (94/6/0)  39/5/0 (89/11/0)  Hypothyroidism  (n = 48)  (n = 58)   n (%)  14/34/0 (29/71/0)  21/37/0 (36/64/0)    CMT No AE/Any AE/AE ≧ Grade 3  RT Any AE/AE ≧ Grade 3  Adverse events  (n = 47)  (n = 44)   Neutropenia, n (%)  11/36/36 (23/77/77)  —   Neuropathy, n (%)  38/ 9/0 (81/19/ 0)  —   Pneumonia, n (%)  37/10/2 (79/21/4)  —   Mucosal damage,a n (%)  23/24/5 (49/51/11)  12/32/5 (27/73/11)   Oral mucositis, n (%)  32/15/0 (68/32/0)  35/9/0 (80/20/0)   Dry mouth, n (%)  39/8/0 (83/17/0)  40/4/0 (91/9/0)   Dysgeusia, n (%)  44/3/0 (94/6/0)  40/4/0 (91/9/0)   Skin disorders, n (%)  44/3/0 (94/6/0)  39/5/0 (89/11/0)  Hypothyroidism  (n = 48)  (n = 58)   n (%)  14/34/0 (29/71/0)  21/37/0 (36/64/0)  Adverse events and hypothyroidism were graded based on Common Terminology Criteria for Adverse Events, version 4.0. Abbreviation: AE, adverse events. a Oropharyngolaryngitis and/or esophagitis. View Large Thyroid function after the treatment of PTL Detailed information about thyroid function after treatment was available in 106 of 107 patients. Of them, 12 patients (11%) remained euthyroid without supplemental thyroid hormone therapy, and 71 patients (67%) developed hypothyroidism after the treatment of PTL. Three of the 106 patients (3%) showed postradiation painless thyroiditis 1 month (n = 2) and 11 months (n = 1) after the treatment, whereas one patient developed Graves’ disease, which was confirmed by high 24-hour radioiodine uptake (55%), 4 years after treatment. There was no significant difference in the frequency of hypothyroidism after treatment between the different treatment groups (70% after CMT versus 64% after RT, P = 0.48). Hypothyroidism during follow-up was well managed with levothyroxine supplementation. There was also no significant difference in the dosage of levothyroxine between treatment groups [median 100, range (50 to 150) μg/day in the CMT versus 100 (25 to 150) μg/day in the RT group, P = 0.80]. Discussion This study, a large-scale study on thyroid MALT lymphoma, showed favorable long-term outcomes in patients with thyroid MALT lymphoma with all initial treatment modalities. Previous research showed a 5-year OS of 91% in all MALT lymphoma cases, and although only 10 patients with thyroid lymphoma were investigated, the possibility that the prognosis of thyroid lymphoma is more favorable than that of other MALT lymphomas was shown (8, 9, 16). The present results confirmed previous data that the outcomes of thyroid MALT lymphoma are favorable over the long-term, up to nearly 10 years. Of particular note is the better long-term EFS in primary MALT lymphoma of the thyroid versus that of other organs (9). Although survival rates are usually favorable in MALT lymphoma, the relapse rate is reportedly high (9). However, despite long-term follow-up in this study, the relapse rate was remarkably low, occurring in only 6 of the 107 patients. A previous study of long-term outcomes in 10 patients with thyroid MALT lymphoma also reported no tumor relapse (9). Thus, the relapse rate of thyroid MALT lymphoma may be lower than that of MALT lymphoma in other organs. In addition, the survival rates are remarkably favorable as compared with those of other MALT lymphomas. Although the reasons for this are unclear, it may be related to the etiology of thyroid MALT lymphoma. Most cases of thyroid MALT lymphoma develop based on a background of chronic inflammation due to HD. The low relapse rate may be related to decreased activity of HD due to RT destroying not only the tumor, but also inflammatory cells. Future basic and clinical researches are warranted to investigate our speculation. In contrast, in 12 patients with stage IE MALT lymphoma in this study, the entire lesion was curatively resected by lobectomy (data not shown) before additional treatment was administered. All 12 patients received RT after the surgery, suggesting that these patients might have been overtreated. Hence, for patients with stage IE disease without residual tumor postoperatively, follow-up observation without additional RT might be an option. A comparison of relapse rates and HD activity between cases receiving RT after curative resection and no further treatment after curative resection should be performed. The effects of treatment of MALT lymphoma on thyroid function can also influence long-term posttreatment QOL in patients. This study examined the long-term effects of treatment of thyroid lymphoma on thyroid function, and found that hypothyroidism occurred in many cases, i.e., ∼70% of patients. It was previously reported that following treatment of Hodgkin disease by mainly RT and CMT, hypothyroidism was found in ∼30% of patients whose thyroid was irradiated (17). The frequency of hypothyroidism in our study was higher than this. Because 93% of the patients in our study also had HD, it is possible that RT and CMT might adversely affect thyroid hormone production from follicular cells, especially in HD patients, by some mechanism. Because hypothyroidism is a long-term adverse event, hematologists/oncologists should keep this in mind when managing patients previously treated for thyroid MALT lymphoma, and should conduct regular monitoring of thyroid function. In contrast, thyroid function can usually be well controlled with appropriate hormone replacement therapy, thus minimizing any adverse influence on long-term QOL of the patient. Localized thyroid MALT lymphomas show good responses to radio- and chemotherapy, and display a favorable prognosis with the current therapeutic regimens in many cases. Although RT resulted in slightly higher relapse rates than CMT in our study, there was no statistically significant difference between treatment groups and most relapsed patients could be adequately treated. The long-term adverse effects on thyroid function are similar with both types of treatment, but, because CMT resulted in additional adverse events, our study confirms RT as the preferred initial treatment of localized MALT lymphoma. In patients with a less favorable prognosis, in contrast, medical therapy as the initial treatment can be an option. The treatment strategy can also be individualized based on the patient’s preference. Some issues related to our study remain to be discussed. First, this study was conducted at a single institution specializing in thyroid disease, and hence, may have involved selection bias. Our findings should be confirmed in multicenter studies that involve hematology and oncology medical practice. Second, individualized therapy based on patient risk factors should be further investigated. Molecular biological markers may also be useful in individualizing treatment. For example, a previous small-scale study found that lack of expression of MUM1/IRF4 and Ki67 is associated with a favorable prognosis (18, 19). Considering the posttreatment QOL of patients who require the addition of chemotherapy, RT plus rituximab is another option due to the fewer adverse events. Further studies using bendamustine, a chemotherapeutic agent used for the treatment of indolent B cell non-Hodgkin lymphoma and mantle-cell lymphomas, which has a good tolerability profile, may also be worthwhile (20). Third, as some generic aberrations have been reported in MALT lymphomas at other sites (9, 21), it may be worth investigating genetic predisposition in relation to thyroid MALT lymphoma. Fourth, in our study, majority of patients with stage IE disease underwent RT alone, and those with stage IIE disease had CMT. Although univariate analysis using a proportional hazard model failed to detect a significant impact of the distribution of clinical stage on OS or EFS (P = 0.896 and P = 0.538, in Supplemental Table 2) in the two treatment groups, it might have affected the treatment outcome. Future studies should aim to study patient survival prospectively in a multi-institutional trial. Conclusion This study is the largest-scale study ever conducted, showing a favorable long-term prognosis in patients with localized thyroid MALT lymphoma with all initial treatment modalities. Abbreviations: CI confidence interval CMT combined modality therapy CSS cause-specific survival EFS event-free survival HD Hashimoto disease LT4 levothyroxine MALT mucosa-associated lymphoid tissue OS overall survival PTL primary thyroid lymphoma QOL quality of life RT radiation therapy. Acknowledgments Disclosure Summary: M.K. received a donation from AIN HOLDINGS and remuneration as the outside director of SBI Biotech and SBI Pharmaceuticals. H.N. received research grants from Takeda Pharmaceutical and Chugai Pharmaceutical. The other authors have nothing to disclose relevant to the content of this article. References 1. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer . 1972; 29( 1): 252– 260. Google Scholar CrossRef Search ADS PubMed  2. Zinzani PL, Magagnoli M, Galieni P, Martelli M, Poletti V, Zaja F, Molica S, Zaccaria A, Cantonetti AM, Gentilini P, Guardigni L, Gherlinzoni F, Ribersani M, Bendandi M, Albertini P, Tura S. 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Long-Term Outcomes of 107 Cases of Primary Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma at a Single Medical Institution in Japan

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Oxford University Press
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Copyright © 2018 Endocrine Society
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0021-972X
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1945-7197
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10.1210/jc.2017-01478
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Abstract

Abstract Context Thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal lymphoma with a favorable prognosis. Objective To provide information on long-term outcomes that would facilitate establishment of the optimal management strategy for thyroid lymphoma. Design, Setting, and Participants Medical records of 107 patients (median age 67 years, 20 males, 87 females) who were diagnosed with localized thyroid MALT lymphoma stage IE or IIE at Ito Hospital were retrospectively reviewed. Main Outcome Measure Overall and event-free survival (EFS). Results Initial treatments included radiation therapy (RT) alone (n = 58), combined modality therapy (CMT) (n = 48), or chemotherapy alone (n = 1). All 107 patients responded to the treatment, six of whom experienced relapse. Only one patient died of lymphoma. The 5-year overall survival (OS) and EFS rates were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Of the 106 patients with information available on adverse events, 71 patients (67%) developed hypothyroidism after primary thyroid lymphoma treatment. The CMT group showed additional chemotherapy-induced adverse reactions in the form of neutropenia, neuropathy, constipation, and pneumonia. The 5-year OS rates of patients treated with CMT and RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively. Conclusions Long-term outcomes of localized thyroid MALT lymphoma are favorable with all initial treatment modalities. Primary thyroid lymphoma (PTL) accounts for 1% to 2% of extranodal lymphomas (1). PTL has a predilection for elderly women, with a female:male ratio of 4:1 and mean age of onset in the 60s (2–4). About 90% of PTL patients also have Hashimoto disease (HD), and the risk of PTL in patients with HD is ∼70 to 80 times higher than in the general population (5, 6). A retrospective analysis at our hospital found an incidence of PTL of 16 per 10,000 HD patients per year (3); this incidence is 10 times higher than previously reported. With advances in imaging and pathological diagnosis, as well as with aging of the population, the diagnostic frequency of PTL may continue to increase. PTLs are mainly classified as mucosa-associated lymphoid tissue (MALT) lymphoma (10% to 50%) and diffuse large B-cell lymphoma (50% to 70%) (3, 4, 7). Thyroid MALT lymphoma is an indolent B-cell–derived extranodal MALT lymphoma. Apart from the thyroid, extranodal MALT lymphomas also occur in organs such as the stomach, orbit, and salivary glands, and they usually have a good prognosis. Some researchers reported that the prognostic features differ according to the primary site. For example, primary gastric and thyroid MALT lymphomas have a better prognosis than salivary and orbital MALT lymphomas (8, 9). This may suggest the need to alter the treatment of MALT lymphomas based on the primary site. However, with the exception of localized gastric MALT lymphomas treated by Helicobacter pylori eradication, most MALT lymphomas are treated similarly. Involved site radiation therapy (RT) is usually considered as the initial treatment, but chemotherapy, including antibody treatment, and follow-up observation in stage IE patients without postoperative residual tumor have also been proposed (10). Because thyroid MALT lymphoma has a good prognosis (11), treatment-related adverse event is an important consideration when selecting treatment. In addition to general adverse events with antibody treatment and chemotherapy, the nearby salivary glands, oropharyngeal mucosa and esophageal mucosa (oropharyngolaryngitis/esophagitis), are sometimes damaged due to involved site RT. These adverse events specific to treatment of thyroid MALT lymphoma are important from a patient perspective. In particular, hypothyroidism after RT is a long-term adverse event that can markedly affect quality of life (QOL) in older individuals, who comprise the majority of patients with thyroid MALT lymphoma. Information about permanent long-term adverse events, such as hypothyroidism, is useful when selecting treatment, although, currently, data on the long-term outcomes of thyroid MALT lymphoma are very limited. Ito Hospital specializes in the treatment of thyroid diseases and has long collected clinical data on many patients with thyroid lymphoma (3, 12, 13). Therefore, this study used our clinical data to investigate long-term outcomes, including long-term adverse events, in patients with primary thyroid MALT lymphoma. The results of this study can provide useful information not only for treatment selection, but also for management of patients after they have undergone treatment. Patients and Methods Patient selection and clinical records We analyzed thyroid MALT lymphoma patients from January 1990, and, to obtain a long observation period, limited the analysis target to patients presenting before 2009. During the period, a total of 111 patients at Ito Hospital were histopathologically diagnosed with localized thyroid MALT lymphoma stage IE or IIE. The clinical records of these patients were retrospectively reviewed. Of these, four patients whose follow-up durations were within 100 days due to transfer to other hospitals and for whom treatment information was not available were excluded. Consequently, 107 patients with localized thyroid MALT lymphoma were included in this study. The clinical stage was evaluated by thyroid ultrasonography (n = 107), abdominal ultrasonography (n = 4), computed tomography (n = 104), 67Ga-citrate scintigraphy (n = 107), bone marrow aspiration biopsy (n = 98), and fluorine-18-fluorodeoxyglucose–positron emission tomography (n = 5), using the proposed criteria described by the Ann Arbor staging system for lymphomas (14, 15). Fluorine-18-fluorodeoxyglucose–positron emission tomography did not show any upstaging in any of the five patients in whom it was performed. Stage IE patients (n = 47) had localized involvement of the thyroid alone, whereas in stage IIE patients (n = 60) the major site of involvement was the thyroid gland, with associated regional lymph node involvement. Findings of ultrasonography were grouped into four classes according to the characteristics of the low-echoic lesion (Supplemental Fig. 1). The patients were also investigated for the presence of HD. A diagnosis of HD was based on the presence of elevated antithyroid peroxidase antibody and/or antithyroglobulin antibody levels, regardless of thyroid function. Patients without these antibodies, but with positive pathological findings, were also diagnosed with HD (3). Treatment of PTL At Ito Hospital, the treatment strategy for PTL was primarily based on the clinical stage; RT alone was given for stage IE, and combined modality therapy (CMT) was given for stage IIE PTL. The role of surgery was mainly for biopsies; generally, open incisional biopsy was performed. CMT usually included RT and multiple courses of cyclophosphamide, adriamycin, vincristine, and prednisolone (cyclophosphamide, 750 mg/m2; adriamycin, 40 mg/m2; vincristine, 1.4 mg/m2; and prednisolone, 100 mg/body)–based chemotherapy. With RT, the whole of the neck and upper mediastinum was encompassed by the treatment. In eight patients who were diagnosed after 2005, rituximab was added to cyclophosphamide, adriamycin, vincristine, and prednisolone therapy as CMT. To prevent an infusion reaction to rituximab (375 mg/m2), 400 mg acetaminophen and 30 mg diphenhydramine hydrochloride were administered as premedication. From 2012, the dosage of adriamycin was modified from 40 mg/m2 to 50 mg/m2. Adverse events Adverse events were graded based on the Common Terminology Criteria for Adverse Events version 4.0. Hypothyroidism after treatment of PTL was designated as follows: (1) started levothyroxine (LT4) after treatment of PTL and with increase in dosage thereafter; (2) started LT4 after treatment of PTL without increase in dosage; and (3) started LT4 before treatment of PTL, with increase in dosage of LT4 after treatment of PTL. Definitions and statistical analysis All of the 107 patients were diagnosed based on histological examination of the thyroid tissue specimens. Pathological diagnosis was based on the World Health Organization classification. Follow-up data were calculated from the time of the initial surgery for diagnosis of the thyroid pathology to the last follow-up. Clinical follow-up data were obtained from the patients’ records, communication with the patients and their families, and communication with the referring physicians. Relapse of PTL was defined as the involvement of new sites, recurrence at originally involved sites, or >25% increase in the size of the original tumor mass. A complete response was defined by the disappearance of all documented disease. Partial response was defined by a reduction of at least 50% in the largest diameter of every measurable lesion. Treatment success was defined as a partial response or better. This study was approved by the institutional review board of Ito Hospital. The data were analyzed as of February 2017. Overall survival (OS), event-free survival (EFS), and cause-specific survival (CSS) were estimated by the Kaplan–Meier method. OS was calculated from the time of initial surgery on the thyroid gland to death from any cause; EFS was calculated as the time from initial surgery on the thyroid gland to the absence of at least a partial response on the intermediate evaluation, relapse, or death in remission; and CSS was calculated from the time of initial surgery on the thyroid gland to death from lymphoma. For analysis of OS, data on patients who were alive at the last follow-up contact were censored. For the analysis of EFS, data on patients who were alive without any progression of the primary disease at the last follow-up were censored. JMP version 12.0.1 (SAS Institute, Cary, NC) was used for all statistical analyses. The poor prognostic factors investigated in the Cox proportional hazard model were age, sex, presence of HD, duration since diagnosis of HD, ESR, increase in lactate dehydrogenase and soluble interleukin-2 receptor levels, ultrasonography findings, i.e., bilaterality of lesion, disease stage, treatment, and operation. Backward stepwise modeling was used in multivariate analysis. A P value < 0.05 was considered to be statistically significant. Results Patients’ characteristics The patients’ characteristics at the time of diagnosis of MALT lymphoma are shown in Table 1. Of the 107 patients, 87 (81%) were women. The median age of the patients was 67 years (range, 28 to 88 years). HD was diagnosed in 100 (93%) patients. The median follow-up period of survivors was 9.7 years (range, 0.4 to 26.0 years). At the time of diagnosis, half of the patients had a unilateral low-echoic lesion (Table 1). As cytological atypia is mild in MALT lymphoma, final cytological diagnosis by fine-needle aspiration biopsy was highly suggestive of lymphoma in only 32% (Supplemental information). Table 1. Patients’ Characteristics Variables  Number (%)  No. of patients  107  Age, median [range], y  67 [28–88]  Sex (M/F)  20/87 (19/81)  Concomitant thyroid diseasea     HD  100 (93)   Adenomatous goiter  9 (8)   Othersb  8 (7)   None  4 (4)  Laboratory tests at diagnosis     Elevated LD  28 (26)   ESR, range, mm/h  18 [3–122]   sIL-2R, median [range], U/mL  592 [224–3654]   Free T3, median [range], pg/mL  3.0 [1.2–5.2]c   Free T4, median [range], ng/dL  1.1 [0.3–1.8]c   TSH, median [range], μU/mL  3.3 [0.5–113]c   TSH (decreased/normal range/elevated)  0/49/16 (0/75/25)c  Findings of low-echoic areas on ultrasonography     Unilateral  56 (52.3)    Right  29 (27.1)    Left  27 (25.2)   Bilateral  24 (22.4)   Single nodular  16 (15.0)   Multiple patchy low-echoic areas  8 (7.5)   Not availabled  3 (2.8)  Clinical stage (IE/IIE)  47/60 (44/56)  Treatment     CMT  48 (45)   RT  58 (54)   Chemotherapy  1 (1)  Outcome     Relapse  6 (5.6)   Death  12 (11)  Variables  Number (%)  No. of patients  107  Age, median [range], y  67 [28–88]  Sex (M/F)  20/87 (19/81)  Concomitant thyroid diseasea     HD  100 (93)   Adenomatous goiter  9 (8)   Othersb  8 (7)   None  4 (4)  Laboratory tests at diagnosis     Elevated LD  28 (26)   ESR, range, mm/h  18 [3–122]   sIL-2R, median [range], U/mL  592 [224–3654]   Free T3, median [range], pg/mL  3.0 [1.2–5.2]c   Free T4, median [range], ng/dL  1.1 [0.3–1.8]c   TSH, median [range], μU/mL  3.3 [0.5–113]c   TSH (decreased/normal range/elevated)  0/49/16 (0/75/25)c  Findings of low-echoic areas on ultrasonography     Unilateral  56 (52.3)    Right  29 (27.1)    Left  27 (25.2)   Bilateral  24 (22.4)   Single nodular  16 (15.0)   Multiple patchy low-echoic areas  8 (7.5)   Not availabled  3 (2.8)  Clinical stage (IE/IIE)  47/60 (44/56)  Treatment     CMT  48 (45)   RT  58 (54)   Chemotherapy  1 (1)  Outcome     Relapse  6 (5.6)   Death  12 (11)  Abbreviations: ESR, erythrocyte sedimentation rate; LD, lactate dehydrogenase; sIL-2R, soluble interleukin-2 receptor; TSH, thyroid-stimulating hormone. a There is some overlap between the diseases. b These included papillary carcinoma (n = 2), Graves’ disease (n = 5), and hyperthyroidism (n = 1). c Patients with thyroid hormone replacement therapy (n = 42) were excluded. d Three patients had no available ultrasonography images for re-evaluation. View Large Treatment Open incisional biopsy was performed in 85 patients; lobectomy was performed in 21 patients whose lesions were on the dorsal side or not large enough to identify the biopsy site by palpation during surgery; and total thyroidectomy was performed in one patient to relieve compression symptoms caused by the huge goiter. Although all of the patients first underwent surgery of some form, all 107 patients also received nonsurgical treatment. Of the 107 patients, 58 patients received RT alone (54%) with a median dose of 40 Gy, and 48 received chemotherapy and RT (45%) with a median dose of 36 Gy. One patient received chemotherapy alone (1%) (Table 1). As shown in Table 2, no significant differences in patients’ background characteristics were seen between those treated by CMT versus RT, except for clinical stage. According to the institutional treatment strategy of Ito Hospital, 42 of 47 patients with stage IE disease received RT alone, and 43 of 60 stage IIE patients received CMT. The proportion of patients with stage IIE disease was significantly higher among those who underwent CMT (90% versus 28% in CMT and RT patients, respectively, P < 0.0001) (Table 2). Table 2. Treatment and Outcome Variables [Number (%)]  CMT (n = 48)  RT (n = 58)  P Value  Age, median [range], y  66 [28–84]  69 [51–88]  0.08  Sex (M/F)  11/37 (23/77)  9/49 (16/84)  0.33  ESR, median [range], mm/h  18 [3–122]  18 [4–67]  0.50  Elevated LD  16 (33)  10 (17)  0.13  sIL-2R, median [range], U/mL  651 [276–3654]  551 [224–1661]  0.45  Findings of low-echoic areas on ultrasonographya      0.25   Unilateral  25 (52.0)  32 (55.2)     Bilateral  14 (29.2)  9 (15.5)     Single nodular  4 (8.3)  12 (20.7)     Multiple patchy low-echoic areas  4 (8.3)  4 (6.9)     Not available  1 (2.1)  2 (3.4)    Surgery      0.10   Open biopsy  41 (85)  43 (74)     Lobectomy  6 (13)  15 (26)     Total thyroidectomy  1 (2)  0 (0)    Clinical stage (IE/IIE)  5/43 (10/90)  42/16 (72/28)  <0.0001  Treatment         Irradiation dose, median [range], Gy  36 [21–45]  40 [30–50]  0.22   Chemotherapy      —    CHOP  39 (81)        RCHOP  8 (17)        COP-BLAM  1 (2)      Outcome         Relapse  1 (2)  5 (9)  0.14   Death  6 (13)  6 (10)  0.73  Variables [Number (%)]  CMT (n = 48)  RT (n = 58)  P Value  Age, median [range], y  66 [28–84]  69 [51–88]  0.08  Sex (M/F)  11/37 (23/77)  9/49 (16/84)  0.33  ESR, median [range], mm/h  18 [3–122]  18 [4–67]  0.50  Elevated LD  16 (33)  10 (17)  0.13  sIL-2R, median [range], U/mL  651 [276–3654]  551 [224–1661]  0.45  Findings of low-echoic areas on ultrasonographya      0.25   Unilateral  25 (52.0)  32 (55.2)     Bilateral  14 (29.2)  9 (15.5)     Single nodular  4 (8.3)  12 (20.7)     Multiple patchy low-echoic areas  4 (8.3)  4 (6.9)     Not available  1 (2.1)  2 (3.4)    Surgery      0.10   Open biopsy  41 (85)  43 (74)     Lobectomy  6 (13)  15 (26)     Total thyroidectomy  1 (2)  0 (0)    Clinical stage (IE/IIE)  5/43 (10/90)  42/16 (72/28)  <0.0001  Treatment         Irradiation dose, median [range], Gy  36 [21–45]  40 [30–50]  0.22   Chemotherapy      —    CHOP  39 (81)        RCHOP  8 (17)        COP-BLAM  1 (2)      Outcome         Relapse  1 (2)  5 (9)  0.14   Death  6 (13)  6 (10)  0.73  Abbreviations: CHOP, cyclophosphamide, adriamycin, vincristine, and prednisolone; COP-BLAM, cyclophosphamide, vincristine, prednisolone, bleomycin, adriamycin, and procarbazine; ESR, erythrocyte sedimentation rate; LD, lactate dehydrogenase; RCHOP, rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone; sIL-2R, soluble interleukin-2 receptor. a Three patients had no available ultrasonographic images for re-evaluation. View Large Disease relapse and causes of death Final follow-up data were obtained from the patients’ medical records (n = 72), communication with the patients (n = 3) and their families (n = 8), communication with the referring physicians (n = 23), and from an accident report by the police (n = 1). Treatment was successful (defined as a partial response or better) in all of the 107 patients. Of them, six patients experienced relapse. A 59-year-old woman with stage IE MALT lymphoma underwent radiotherapy and showed relapse in the spinal cord 4 years later. Despite the additional treatment, she died of lymphoma. The other five patients experienced relapse in the ipsilateral thyroid and/or lymph nodes after 3 (n = 1), 5 (n = 1), 7 (n = 1), and 9 years (n = 1), and in the epipharynx after 7 years (n = 1). At the time of relapse, MALT lymphoma had transformed to diffuse large B-cell lymphoma in three of the five patients. All five of the patients responded to additional treatment and remain alive without disease at the last follow-up (Supplemental Table 1). Twelve patients died during follow-up at the median age of 78 years (range, 62 to 95). Only one patient died of disease relapse, whereas the others died of other causes, including pneumonia (n = 1), adenocarcinoma (n = 1), subarachnoid hemorrhage (n = 1), acute liver dysfunction (n = 1), congestive heart failure (n = 1), and bladder tumor (n = 1). One patient died of an accident. Information regarding cause of death was not available in the remaining four patients. Survival rates The 5-year OS and EFS rates of localized thyroid MALT lymphoma were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. The CSS rate was 99% (95% CI, 93% to 100%) at both 5 and 10 years (Fig. 1). Figure 1. View largeDownload slide (A) OS and (B) EFS in the entire patient cohort. Figure 1. View largeDownload slide (A) OS and (B) EFS in the entire patient cohort. The characteristics of patients treated with RT and CMT are shown in Table 2. The proportion of stage IIE patients was significantly higher among patients treated with CMT than among those treated with RT (P < 0.0001). Five of the six patients with relapse were treated using RT. However, the difference in relapse rates was not statistically significant between patients treated with CMT and RT (P = 0.14). The Kaplan–Meier method also showed that the 5-year OS rates of patients treated with CMT and those with RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively, and the 10-year OS rates of patients treated with CMT and RT were 88% (95% CI, 75% to 95%) and 92% (95% CI, 81% to 97%) (log–rank test: P = 0.91), respectively. The Kaplan–Meier method also showed that the 5-year EFS rates of patients treated with CMT and those treated with RT were 93% (95% CI, 81% to 98%) and 91% (95% CI, 80% to 96%), respectively, and the 10-year EFS rates of patients treated with CMT and RT were 85% (95% CI, 70% to 93%) and 82% (95% CI, 68% to 91%) (log–rank test: P = 0.48), respectively (Fig. 2). The proportional hazard model revealed age as a significant poor prognostic factor in terms of OS [hazard ratio 1.13 (95% CI, 1.05 to 1.21), P = 0.001] and EFS [hazard ratio 1.09 (95% CI: 1.02 to 1.17), P = 0.006] (Supplemental Table 2); treatment modality (CMT versus RT) was not detected as a significant prognostic factor of outcome in our study. Figure 2. View largeDownload slide (A) OS and (B) EFS stratified according to treatment modality. Figure 2. View largeDownload slide (A) OS and (B) EFS stratified according to treatment modality. Adverse events Information regarding the adverse events related to treatment was available in 91 of 107 patients and is shown in Table 3. The CMT group showed additional adverse reactions secondary to chemotherapy in the form of neutropenia, neuropathy, constipation, and pneumonia. None of the eight patients treated with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone therapy developed infusion reactions. Table 3. Adverse Events and Hypothyroidism Related With Treatment   CMT No AE/Any AE/AE ≧ Grade 3  RT Any AE/AE ≧ Grade 3  Adverse events  (n = 47)  (n = 44)   Neutropenia, n (%)  11/36/36 (23/77/77)  —   Neuropathy, n (%)  38/ 9/0 (81/19/ 0)  —   Pneumonia, n (%)  37/10/2 (79/21/4)  —   Mucosal damage,a n (%)  23/24/5 (49/51/11)  12/32/5 (27/73/11)   Oral mucositis, n (%)  32/15/0 (68/32/0)  35/9/0 (80/20/0)   Dry mouth, n (%)  39/8/0 (83/17/0)  40/4/0 (91/9/0)   Dysgeusia, n (%)  44/3/0 (94/6/0)  40/4/0 (91/9/0)   Skin disorders, n (%)  44/3/0 (94/6/0)  39/5/0 (89/11/0)  Hypothyroidism  (n = 48)  (n = 58)   n (%)  14/34/0 (29/71/0)  21/37/0 (36/64/0)    CMT No AE/Any AE/AE ≧ Grade 3  RT Any AE/AE ≧ Grade 3  Adverse events  (n = 47)  (n = 44)   Neutropenia, n (%)  11/36/36 (23/77/77)  —   Neuropathy, n (%)  38/ 9/0 (81/19/ 0)  —   Pneumonia, n (%)  37/10/2 (79/21/4)  —   Mucosal damage,a n (%)  23/24/5 (49/51/11)  12/32/5 (27/73/11)   Oral mucositis, n (%)  32/15/0 (68/32/0)  35/9/0 (80/20/0)   Dry mouth, n (%)  39/8/0 (83/17/0)  40/4/0 (91/9/0)   Dysgeusia, n (%)  44/3/0 (94/6/0)  40/4/0 (91/9/0)   Skin disorders, n (%)  44/3/0 (94/6/0)  39/5/0 (89/11/0)  Hypothyroidism  (n = 48)  (n = 58)   n (%)  14/34/0 (29/71/0)  21/37/0 (36/64/0)  Adverse events and hypothyroidism were graded based on Common Terminology Criteria for Adverse Events, version 4.0. Abbreviation: AE, adverse events. a Oropharyngolaryngitis and/or esophagitis. View Large Thyroid function after the treatment of PTL Detailed information about thyroid function after treatment was available in 106 of 107 patients. Of them, 12 patients (11%) remained euthyroid without supplemental thyroid hormone therapy, and 71 patients (67%) developed hypothyroidism after the treatment of PTL. Three of the 106 patients (3%) showed postradiation painless thyroiditis 1 month (n = 2) and 11 months (n = 1) after the treatment, whereas one patient developed Graves’ disease, which was confirmed by high 24-hour radioiodine uptake (55%), 4 years after treatment. There was no significant difference in the frequency of hypothyroidism after treatment between the different treatment groups (70% after CMT versus 64% after RT, P = 0.48). Hypothyroidism during follow-up was well managed with levothyroxine supplementation. There was also no significant difference in the dosage of levothyroxine between treatment groups [median 100, range (50 to 150) μg/day in the CMT versus 100 (25 to 150) μg/day in the RT group, P = 0.80]. Discussion This study, a large-scale study on thyroid MALT lymphoma, showed favorable long-term outcomes in patients with thyroid MALT lymphoma with all initial treatment modalities. Previous research showed a 5-year OS of 91% in all MALT lymphoma cases, and although only 10 patients with thyroid lymphoma were investigated, the possibility that the prognosis of thyroid lymphoma is more favorable than that of other MALT lymphomas was shown (8, 9, 16). The present results confirmed previous data that the outcomes of thyroid MALT lymphoma are favorable over the long-term, up to nearly 10 years. Of particular note is the better long-term EFS in primary MALT lymphoma of the thyroid versus that of other organs (9). Although survival rates are usually favorable in MALT lymphoma, the relapse rate is reportedly high (9). However, despite long-term follow-up in this study, the relapse rate was remarkably low, occurring in only 6 of the 107 patients. A previous study of long-term outcomes in 10 patients with thyroid MALT lymphoma also reported no tumor relapse (9). Thus, the relapse rate of thyroid MALT lymphoma may be lower than that of MALT lymphoma in other organs. In addition, the survival rates are remarkably favorable as compared with those of other MALT lymphomas. Although the reasons for this are unclear, it may be related to the etiology of thyroid MALT lymphoma. Most cases of thyroid MALT lymphoma develop based on a background of chronic inflammation due to HD. The low relapse rate may be related to decreased activity of HD due to RT destroying not only the tumor, but also inflammatory cells. Future basic and clinical researches are warranted to investigate our speculation. In contrast, in 12 patients with stage IE MALT lymphoma in this study, the entire lesion was curatively resected by lobectomy (data not shown) before additional treatment was administered. All 12 patients received RT after the surgery, suggesting that these patients might have been overtreated. Hence, for patients with stage IE disease without residual tumor postoperatively, follow-up observation without additional RT might be an option. A comparison of relapse rates and HD activity between cases receiving RT after curative resection and no further treatment after curative resection should be performed. The effects of treatment of MALT lymphoma on thyroid function can also influence long-term posttreatment QOL in patients. This study examined the long-term effects of treatment of thyroid lymphoma on thyroid function, and found that hypothyroidism occurred in many cases, i.e., ∼70% of patients. It was previously reported that following treatment of Hodgkin disease by mainly RT and CMT, hypothyroidism was found in ∼30% of patients whose thyroid was irradiated (17). The frequency of hypothyroidism in our study was higher than this. Because 93% of the patients in our study also had HD, it is possible that RT and CMT might adversely affect thyroid hormone production from follicular cells, especially in HD patients, by some mechanism. Because hypothyroidism is a long-term adverse event, hematologists/oncologists should keep this in mind when managing patients previously treated for thyroid MALT lymphoma, and should conduct regular monitoring of thyroid function. In contrast, thyroid function can usually be well controlled with appropriate hormone replacement therapy, thus minimizing any adverse influence on long-term QOL of the patient. Localized thyroid MALT lymphomas show good responses to radio- and chemotherapy, and display a favorable prognosis with the current therapeutic regimens in many cases. Although RT resulted in slightly higher relapse rates than CMT in our study, there was no statistically significant difference between treatment groups and most relapsed patients could be adequately treated. The long-term adverse effects on thyroid function are similar with both types of treatment, but, because CMT resulted in additional adverse events, our study confirms RT as the preferred initial treatment of localized MALT lymphoma. In patients with a less favorable prognosis, in contrast, medical therapy as the initial treatment can be an option. The treatment strategy can also be individualized based on the patient’s preference. Some issues related to our study remain to be discussed. First, this study was conducted at a single institution specializing in thyroid disease, and hence, may have involved selection bias. Our findings should be confirmed in multicenter studies that involve hematology and oncology medical practice. Second, individualized therapy based on patient risk factors should be further investigated. Molecular biological markers may also be useful in individualizing treatment. For example, a previous small-scale study found that lack of expression of MUM1/IRF4 and Ki67 is associated with a favorable prognosis (18, 19). Considering the posttreatment QOL of patients who require the addition of chemotherapy, RT plus rituximab is another option due to the fewer adverse events. Further studies using bendamustine, a chemotherapeutic agent used for the treatment of indolent B cell non-Hodgkin lymphoma and mantle-cell lymphomas, which has a good tolerability profile, may also be worthwhile (20). Third, as some generic aberrations have been reported in MALT lymphomas at other sites (9, 21), it may be worth investigating genetic predisposition in relation to thyroid MALT lymphoma. Fourth, in our study, majority of patients with stage IE disease underwent RT alone, and those with stage IIE disease had CMT. Although univariate analysis using a proportional hazard model failed to detect a significant impact of the distribution of clinical stage on OS or EFS (P = 0.896 and P = 0.538, in Supplemental Table 2) in the two treatment groups, it might have affected the treatment outcome. Future studies should aim to study patient survival prospectively in a multi-institutional trial. Conclusion This study is the largest-scale study ever conducted, showing a favorable long-term prognosis in patients with localized thyroid MALT lymphoma with all initial treatment modalities. Abbreviations: CI confidence interval CMT combined modality therapy CSS cause-specific survival EFS event-free survival HD Hashimoto disease LT4 levothyroxine MALT mucosa-associated lymphoid tissue OS overall survival PTL primary thyroid lymphoma QOL quality of life RT radiation therapy. Acknowledgments Disclosure Summary: M.K. received a donation from AIN HOLDINGS and remuneration as the outside director of SBI Biotech and SBI Pharmaceuticals. H.N. received research grants from Takeda Pharmaceutical and Chugai Pharmaceutical. The other authors have nothing to disclose relevant to the content of this article. References 1. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer . 1972; 29( 1): 252– 260. Google Scholar CrossRef Search ADS PubMed  2. Zinzani PL, Magagnoli M, Galieni P, Martelli M, Poletti V, Zaja F, Molica S, Zaccaria A, Cantonetti AM, Gentilini P, Guardigni L, Gherlinzoni F, Ribersani M, Bendandi M, Albertini P, Tura S. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Feb 1, 2018

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