Clinicopathological Characteristics and A20 (TNFAIP3) Mutation In Primary Thyroid Lymphoma

Primary thyroid lymphoma (PTL) is rare, composing approximately 5% of all thyroid malignancies, 1–2.5% of all malignant lymphomas, and fewer than 3% of all extranodal lymphomas. PTL frequently arises in a background of autoimmune thyroid disease, especially Hashimoto’s thyroiditis, but the genetic basis is largely unknown. The NF-κB negative regulator A20, also called tumor necrosis factor-α-induced protein 3 (TNFAIP3), has recently been reported to be frequently inactivated by deletion and/or mutation, which are involved in the pathogenesis of subsets of B-cell lymphomas, especially mucosa-associated lymphoid tissue (MALT) lymphoma. A20 deletion occurs more frequently in ocular adnexa and salivary MALT lymphoma, but there have been very few reports of it in PTL. In this study, we first analyzed the clinicopathologic characteristics of PTL and then investigated whether A20 inactivation by mutation or deletion was frequently detected in PTL.

We retrospectively analyzed 34 PTL patients treated from 2002 to 2013 in our institutions and diagnosed according to the 2008 WHO classification. A20 mutations were examined by directly sequencing genomic DNA using a set of primers.

The patients included 9 men and 25 women, median age 68 (range, 35–84) years, presenting with a rapidly growing nodular goiter with or without cervical adenopathy (n=30), hoarseness (n=1), or without symptoms related to lymphoma or hypothyroidism (n=3). The pathologic diagnosis of PTL included diffuse large B-cell lymphoma (DLBCL) (n=20), DLBCL with MALT (n=1), and MALT lymphoma (n=13). Twenty-one (62%) had a previous history of Hashimoto’s thyroiditis, and 6 were diagnosed with that condition concurrently with lymphoma. The majority of patients (n=23, 67%) had stage IE disease, although 8 (27%) had stage IIE disease and 3 advanced stage. Compared with MALT lymphoma, the patients with DLBCL presented with larger tumor size including bulky mass (>10 cm), elevated lactate dehydrogenase level, and poor prognosis (relapse rate, 25%) despite receiving THP-COP or CHOP combination therapy with rituximab. MALT lymphoma patients with total thyroidectomy had a good prognosis without chemotherapy; the disease-free survival rate was 100% in the median 40.5-month follow-up. We did not find any routine clinical or biological factors that predicted the evolution from Hashimoto’s thyroiditis to MALT lymphoma. Next, we analyzed A20 mutations in genomic DNA extracted from 16 samples. A20 mutations were identified in 2 of 13 PTL patients examined (15%): 1 of 6 (17%) with DLBCL and 1 of 7 (14%) with MALT lymphoma. Both patients with A20 mutations had Hashimoto’s thyroiditis. Interestingly, the 2 had a common missense mutation in exon 3 (rs2230926 380T>G; F127C), which reduces the ability of A20 to inhibit NF-kB signaling. In one patient, this missense mutation was newly acquired after chemotherapy and radiation.

We confirmed the histologic heterogeneity of PTL corresponding to different clinical presentations and different prognoses. A20 abnormalities may be related to PTL pathogenesis in some patients.

No relevant conflicts of interest to declare.