Primary thyroid mucosa-associated lymphoid tissue marginal zone lymphoma in a 46-year-old female: a case report

Introduction

Primary thyroid lymphoma (PTL) is a rare malignant tumor that originates from the lymphatic tissues of the thyroid gland. It accounts for only 1% to 5% of malignant tumors of the thyroid gland (1) and less than 2% of all lymphomas (2). The annual incidence rate is approximately 2 cases per 1 million people (3). The histologic types of PTL are diverse. The majority of PTL cases are non-Hodgkin’s lymphomas derived from B-cells. The two most commonly observed types of PTL are diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT).

Due to the rarity of PTL and the absence of distinct clinical features or imaging abnormalities, diagnosing this condition poses a significant challenge for clinicians. This paper presents a case study of PTL with a pathologic type of malt and documents the entire process of the patient’s experience, including onset, consultation, diagnosis, and treatment. The aim is to offer clinicians a valuable reference to enhance their understanding of this disease, thereby preventing misdiagnosis and inappropriate treatment. We present this article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-353/rc).

Case presentation

In February 2023, a 46-year-old woman was referred to the Department of Endocrinology at The First Affiliated Hospital of Xinjiang Medical University for treatment of an enlarged thyroid gland (Figure 1). The woman had noticed an enlargement in her neck nine months prior, without experiencing any other discomfort. She consulted her local doctor, who conducted a thyroid ultrasonography. The results indicated diffuse thyroid lesions and irregular hypoechoicity in both lobes, with measurements of 4.7 cm × 2.1 cm on the left side. Thyroid function indicated thyroglobulin antibodies (TgAb) of 132 IU/mL (reference range, 0–95 IU/mL), while other indicators in thyroid function were within the normal range. The patient did not receive treatment at the hospital during that time. Over eight months, she gradually experienced neck pressure and shortness of breath. As a result, she sought medical attention at another local hospital where she underwent thyroid ultrasound and thyroid function tests. The thyroid ultrasound revealed diffuse thyroid lesions with bilateral intralobular hypoechoic areas displaying lattice-like changes. The size of these lesions ranged from 5.7 cm × 2.6 cm × 4.8 cm in the left lobe to 1.2 cm × 0.6 cm in the right lobe. Otherwise, thyroid function was normal (Figure 2).

Figure 1 Comparison of treatment effects. In (A,B), the red arrows denote that the patient had a highly conspicuous neck mass prior to radiotherapy. In (C,D), the red arrows signify the patient’s appearance following radiotherapy, where the neck mass has vanished. This image is published with the patient’s consent.

Figure 2 Case timeline. MALT, mucosa-associated lymphoid tissue; FNAC, fine-needle aspiration cytology; FISH, fluorescence in situ hybridization; PET/CT, positron emission tomography/computed tomography; BMAB, bone marrow aspiration and biopsy; IGH, immunoglobulin H.

Thyroid color Doppler ultrasound revealed diffuse thyroid lesions, indicating enlargement of the left side of the thyroid gland and a hypoechoic nodule in the left lobe. The nodule measured approximately 7.0 cm × 3.5 cm × 5.7 cm and exhibited clear borders, regular morphology, and non-uniform echogenicity with a grid-like pattern within (Figure 3). Thyroid imaging revealed an enlarged right lobe of the thyroid gland with a non-uniform distribution of radioactivity. Additionally, the left lobe of the thyroid gland exhibited a clinical deficiency in radioactivity at the location of the mass, indicating a ‘cold’ nodule (Figure 4). Besides, the thyroid iodine 131 uptake rate and thyroid function were normal.

Figure 3 Thyroid color Doppler ultrasound: enlargement of the left side of the thyroid gland with hypoechoic nodules in the left lobe.

Figure 4 Thyroid imaging: Tc-99m 5mCi was injected intravenously, and thyroid planar imaging was performed 30 minutes later. Anteriorly, the right lobe of the thyroid gland was visualized, with increased volume and uneven distribution of radioactivity, while the left lobe of the thyroid gland showed an absence of radioactivity at the mass.

Thyroid computed tomography (CT) and enhancement scans revealed protrusion on the left side of the neck. The left lobe of the thyroid gland appeared enlarged with a rounded hypodense shadow, measuring approximately 4.27 cm × 4.35 cm. The enhancement scans indicated a significant strengthening of this area. The lesion did not have a clear demarcation from the mucous membrane of the esophageal wall at the opening of the esophagus. The bronchial tubes in each lobe were clear, showing no signs of stenosis or compression. Enlargement of some lymph nodes was observed in the left cervical root, submandibular region, and the two lateral regions of the neck. The largest lymph node measured approximately 1.21 cm × 0.7 cm in diameter (Figure 5).

Figure 5 Computed tomography scan showing anterior neck prominence and an irregular mass visible in the left thyroid gland (red arrows).

Ultrasound-guided fine-needle aspiration cytology (FNAC) revealed hyperplasia of small lymphoid cells in the punctured tissue, forming a vague nodular structure. The small lymphoid cells exhibited mononuclear-like, centrocytic morphology, along with a small amount of accompanying plasma cell-like differentiation. Immunohistochemical staining of the tumor cells indicated cytosolic CD20 and PAX5 positivity (Figure 6), as well as a 10% proliferation rate of Ki-67. Based on these pathological findings, the diagnosis leaned towards MALT extranodal marginal zone B-cell lymphoma. For further differential diagnosis, we performed fluorescence in situ hybridization (FISH) and immunoglobulin H (IGH) gene rearrangement test on thyroid tissues, which suggested FISH negative (Figure 7) IGH positive results. The above results further confirmed that the patient had MALT lymphoma.

Figure 6 Fine needle aspiration cytology. Small lymphoid cells were seen proliferating in the punctured tissue, forming a vague nodular structure; the small lymphoid cells showed a mononuclear, centrocytic pattern, with a small amount of plasma cell-like differentiation. The staining method adopted is HE staining, and the magnification is 200 times. HE, hematoxylin and eosin.

Figure 7 FISH. The magnification is achieved with a 100× objective lens. FISH, fluorescence in situ hybridization.

After the diagnosis was made, we conducted a whole-body positron emission tomography/CT (PET/CT) scan, gastroenteroscopy, and bone marrow aspiration and biopsy (BMAB) to further stage the patient’s lymphoma. The PET/CT results indicated significant enlargement of the left lobe of the thyroid gland with abnormal hypermetabolism, as well as multiple hypermetabolic lymph nodes in the left neck III, IV, and left clavicular region, which were consistent with lymphomatous changes (Figure 8). Additionally, both the gastroenteroscopy and BMAB did not reveal any evidence of lymphoma involving the bone marrow or gastrointestinal tract. Based on the Ann Arbor lymphoma staging criteria, the lymphoma of this patient has invaded a single extranodal organ and its regional lymph nodes, and there are no systemic clinical manifestations. Hence, the final staging is classified as stage IIE, Group A.

Figure 8 PET/CT. The red arrow represents that the left lobe of the thyroid gland is markedly enlarged and abnormally hypermetabolic, and there are multiple hypermetabolic lymph nodes in the left cervical region III, IV, and left clavicular region, consistent with lymphomatous changes. PET/CT, positron emission tomography/computed tomography.

According to the patient’s clinical stage, radiotherapy is appropriate for the patient. External beam radiotherapy was performed using 6 MV X-rays. The 6 MV X-rays have appropriate penetrating ability, which can effectively penetrate the tissues in the neck and focus on the set target area, accurately delivering energy to the tumor cells, destroying their DNA structure, and thereby inducing tumor cell apoptosis to achieve the therapeutic goal of tumor control. At the same time, its energy characteristics also enable a better balance between tumor killing and normal tissue protection during radiotherapy of the thyroid area. In this case, the total dose (DT) of radiotherapy was set at 30 Gy. This dose was determined based on a comprehensive consideration of various aspects such as the patient’s condition and physical tolerance, aiming to effectively control tumor progression while minimizing adverse effects on surrounding normal tissues as much as possible. The entire radiotherapy process was divided into 15 fractions (15 F) for irradiation, with a relatively balanced dose per fraction, which helps the body better adapt to the impact of radiotherapy. The target area covered the left IB area, the lower part of zone II, zone III, zone IV, and VB area. These areas were determined through precise imaging examinations (such as neck CT, etc.) combined with clinical judgment of the distribution characteristics of primary thyroid MALT lymphoma lesions, to ensure that the tumor tissue is encompassed as completely as possible within the radiotherapy irradiation range, while minimizing unnecessary irradiation of surrounding normal thyroid tissue, important blood vessels, nerves, and other structures in the neck.

The patient underwent 15 cycles of radiotherapy and was reviewed in November 2023. An enhanced CT of the neck conducted in comparison to February 2023 revealed an increased volume and abnormal enhancement of soft tissue nodules in the left lobe of the thyroid gland, although these nodules were significantly smaller than before. Additionally, scattered lymph nodes in the submandibular gland area bilaterally and in the cervical sheath vascular space bilaterally were found to be smaller and less numerous compared to previous findings (Figure 9). We have followed up with this patient for a duration of 2 years. During this period, through comprehensive clinical examinations, imaging studies (such as CT scans, etc.), and laboratory tests, we have found no evidence or indication of lymphoma recurrence.

Figure 9 According to the computed tomography scan, the mass within the left thyroid lobe of the patient (red arrows) has been conspicuously diminished in size following radiotherapy when contrasted with the previous state.

Ethical considerations

All procedures performed in this study were in accordance with the ethical standards of the institutional and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

PTL is a rare malignancy of the thyroid gland, primarily of B-cell origin. The most common types are DLBCL and MALT lymphoma (4). Lymphomas are malignant tumors that typically arise from lymphocytes or lymphoid tissue, although the thyroid gland does not normally contain lymphocytes. MALT is a B-cell lymphoma originating from extranodal MALT, and its pathogenesis remains incompletely understood. There seems to be a possible connection between thyroid lymphomas and autoimmune diseases, particularly Hashimoto’s thyroiditis (HT). It might be that the chronic inflammatory stimulation induced by autoantigens in patients with HT prompts lymphocytes to carry out clonal proliferation, facilitates the hyperplasia of thyroid lymphoid tissue, and subsequently leads to its transformation into lymphoma (5). In addition, chronic inflammation sustains and prolongs the proliferation of B cells. The constitutive activation of nuclear factor kappa B (NF-κB) may also lead to uncontrolled proliferation of B cells, ultimately resulting in the development of lymphoma (6). Although the risk of PTL is significantly higher (40–80 times) in patients with HT compared to the general population (7,8), only a small percentage (about 0.6%) of HT patients eventually develop PTL (9). Therefore, HT is considered a risk factor for PTL, but there is no direct causal relationship between the two. In the case of the patient mentioned, she underwent thyroid function tests at multiple hospitals, which showed normal thyroid-related antibodies and no evidence of HT.

The incidence of PTL is higher in females than males, with a male-to-female ratio of 1:2 to 4 (10). It predominantly occurs in middle-aged and elderly females (11). Patients typically present with a unilateral or bilateral neck mass that feels hard and has a smooth surface. They may also experience symptoms of neck compression, such as hoarseness, dysphagia, dyspnea, and occasionally pain. However, type B symptoms associated with lymphoma, such as fever, night sweats, and weight loss, are rare. Thyroid function can be normal, hypothyroid, or hyperthyroid (2). We describe the case of a middle-aged female patient who visited the clinic primarily due to a progressively enlarging thyroid mass, without significant pain, and with normal thyroid function. In clinical practice, if a middle-aged or elderly female patient with Hashimoto’s thyroiditis presents with a rapidly enlarging neck mass, the possibility of PTL should be considered to avoid misdiagnosis or underdiagnosis.

Ultrasound, as the preferred imaging examination for PTL, can provide information on the extent of lesions and the invasion situation. Meanwhile, it can also explore the conditions of the thyroid, neck and supraclavicular lymph nodes. However, the ultrasonic manifestations of PTL lack specificity and need to be differentiated from focal thyroiditis, nodular goiter and papillary thyroid carcinoma (12). PTL appears diffusely hypoechoic on ultrasound with slightly elevated echogenicity that resembles a ‘grid-like’ or ‘striated’ pattern. The gold standard for diagnosing PTL is a pathological biopsy of the mass. In our case, the diagnosis of MALT was confirmed through FNAC. MALT is a type of B-cell extranodal lymphoma that primarily occurs in the marginal zone. It consists of small cells with various morphologies, including marginal zone cells, monocytes, small lymphocytes, and scattered immunoblasts and centroblasts (13). In some cases, there may also be plasma cell differentiation. MALT commonly remains localized to the thyroid tissue, and the characteristic pathological changes of MALT are the formation of ‘lymphoepithelial lesions’ where tumor cells invade the epithelium. The Ki-67 index, which reflects cell proliferation, plays a crucial role in the differentiation of lymphomas. In comparison with DLBCL, the Ki-67 index of MALT lymphoma is typically lower. Consequently, a relatively higher Ki-67 index calls for greater consideration of high-grade lymphomas. Moreover, Ki-67 can be employed for prognostic prediction in PTL.

FNAC combined with flow cytology and immunohistochemistry, has been reported as a helpful method in diagnosing PTL (14). It highlights the significance of early puncture biopsy for pathologic immunohistochemistry, which is currently the sole preoperative approach for diagnosing the disease. Certain studies have revealed that the combination of flow cytometry and FNAC demonstrates a sensitivity as high as 97% and a specificity of 87% in the diagnosis of thyroid lymphoma (15,16). In this case, the patient’s B lymphoma showed positive results for Ig gene rearrangement. The tumor cells exhibited CD20 (+), CD3 (T+), Pax-5 (+), CD5 (T+), CD21 (follicular dendritic network +), CD23 (follicular dendritic network +), cyclin D1 (−), CD10 (+), Bc1-2 (+), Bcl-6 (+), Ki-67 (10%+), CD43 (T+), and Ki-67 (10%+). These findings were observed in the patient’s B lymphoma. CD43 (T+), AE1/AE3 (−), CD38 (small amount +), CD138 (small amount +), kappa (small amount +), and lambda (small amount +) were consistent with the diagnosis of MALT.

The optimal treatment for PTL is still controversial and there is no standardized approach. However, radiotherapy and chemotherapy are generally preferred. Surgery may be performed to relieve compression or to aid in diagnosis, but it does not improve survival rates. Aggressive surgery can also lead to complications such as recurrent nerve injury and parathyroid damage (17,18). Therefore, in the treatment of PTL, surgery is mostly used to make a definite diagnosis or relieve compressive symptoms. For MALT lymphoma, monotherapy is recommended. Currently, for patients with non-gastric MALT lymphoma at stage I to II, local radiotherapy is mostly adopted, while for those at stage III to IV, combined chemotherapy is the first choice. Several studies have shown that radiotherapy can improve the prognosis of early-stage (stage I and II) PTL, particularly in cases of MALT lymphoma (19). For patients with stage IE or stage IIE MALT lymphoma, the 5-year survival rate is 88% when radiotherapy is applied alone (2). In this particular case, there was no evidence of bone marrow, spleen, or systemic involvement, and the final stage was determined to be stage II. As a result, radiotherapy alone was chosen as the treatment. After the patient underwent three sessions of radiotherapy, a significant reduction in the size of the neck mass was observed, and the symptoms of dyspnea improved.

MALT lymphoma is considered one of the most favorable prognostic types due to its inert nature and good response to treatment. In a study conducted by Watanabe et al. in 2018, it was found that patients with primary thyroid MALT had excellent 5-year survival rates, regardless of the initial treatment method, with no statistical difference (20). Other studies have also reported 5-year survival rates and 10-year survival rates above 90% for MALT lymphoma (21,22).

Conclusions

This article presents a case of a rare form of MALT occurring in middle-aged women. PTL is a rare disease with nonspecific clinical manifestations, making it susceptible to underdiagnosis or misdiagnosis. Clinicians must enhance the screening of PTL, particularly through fine-needle aspiration for patients with rapidly growing neck masses, to minimize the pain and financial burden associated with misdiagnosis and mistreatment for both patients and their families. Since MALT lymphoma of the thyroid is clinically rare and lacks sufficient single-center or multicenter reports, it is essential to accumulate more cases for further verification.

Acknowledgments

Funding: This study was supported by the Xinjiang Uygur Autonomous Region Science and Technology Innovation Team (Tianshan Innovation Team) project (grant No. 2022TSCXTD0014).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-353/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-353/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-353/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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