A 58-Year-Old Man with a History of Autoimmune Thyroiditis Diagnosed with Mucosa-Associated Lymphoid Tissue Lymphoma and Papillary Carcinoma of the Thyroid

Introduction

The incidence of differentiated thyroid cancer in developed countries has increased 6-fold over the past 30 years, primarily due to advancements in detection [1]. Papillary thyroid carcinoma (PTC), a differentiated thyroid carcinoma, is the most common malignancy, accounting for approximately 80–90% of all thyroid malignancies [2]. Most patients have a good prognosis and experience almost no symptoms [3]. Diagnosis is performed using thyroid ultrasonography and ultrasound-guided fine-needle aspiration (FNA) [3]. Conversely, primary thyroid lymphoma (PTL) accounts for less than 5% of thyroid malignancies and 2% of extranodal lymphomas, with an estimated annual incidence of 2 per million, making it a markedly rare disease [4,5]. The most common subtype of PTL is diffuse large B-cell lymphoma (DLBCL), followed by mucosa-associated lymphoid tissue (MALT) lymphoma, accounting for more than 50% and 20% of all PTLs, respectively [5,6]. Thyroid MALT lymphoma is predominantly diagnosed by incisional biopsy and has a good prognosis [7]. In addition, most thyroid MALT lymphomas are associated with chronic inflammation due to Hashimoto’s disease [7].

Simultaneous diagnosis of PTC and MALT lymphoma in a single patient is markedly rare. A report on the long-term prognosis of 107 cases of thyroid MALT lymphoma has been published in Japan [7], and only 2 cases of PTC were included in the report; however, there was insufficient information on these cases. To date, several cases of PTC and MALT lymphoma diagnosed simultaneously have been reported [8–18], all of which were in stage IE of MALT lymphoma, indicating that the disease was localized within the thyroid gland.

When PTC and malignant lymphoma coexist in the thyroid gland, identifying the underlying cause of lymphadenopathy can be challenging, which poses a considerable diagnostic and therapeutic dilemma. This report presents a case of PTC and MALT lymphoma of the thyroid gland with lymphadenopathy.

Case Report

A 58-year-old man was referred to our hospital because of an enlarged thyroid gland and hoarseness that had persisted for approximately 6 months. He had a history of gallbladder stones treated by cholecystectomy at 55 years of age, with no other notable medical history. He had no family history of thyroid cancer or radiation exposure. Physical examination revealed a diffusely enlarged thyroid gland with no pain or tenderness. There were no palpable cervical lymph nodes or systemic findings other than a goiter. He had no B symptoms, such as weight loss, fever, or night sweats. Clinical parameters were as follows: body height, 164 cm; body weight, 91.0 kg; blood pressure, 138/89 mmHg; and heart rate, 79 beats/min.

The laboratory data from the initial examination are summarized in Table 1. Complete blood count and blood biochemical tests were unremarkable. The patient exhibited hypothyroidism; therefore, levothyroxine sodium hydrate was initiated. Antithyroglobulin and antithyroid peroxidase antibody levels were elevated. The tumor markers carcinoembryonic antigen and calcitonin were within the normal range, but soluble interleukin-2 receptor levels were elevated.

Based on thyroid ultrasound imaging findings, malignant lymphoma (Figure 1A) and thyroid cancer (Figure 1B) were suspected. Several enlarged lymph nodes of unknown origin were also noted. Computed tomography (CT) of the neck revealed a diffusely enlarged thyroid gland compressing the trachea (Figure 1C), along with calcification of the left lobe. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG; FDG-PET) revealed strong FDG uptake throughout the thyroid gland not confined to the mass in the left lobe (Figure 1D), suggesting a positive signal due to Hashimoto’s thyroiditis or malignant lymphoma. Additional FDG accumulation was observed in the left neck and near the pancreas. FNA of the left lobe mass with calcification revealed atypical cells with enlarged nuclei, irregular nuclear shapes, and intranuclear cytoplasmic inclusion bodies, indicating the possibility of PTC. FNA of the enlarged right lobe revealed the presence of lymphocytes only.

Based on these findings, the patient was diagnosed with 1) goiter with tracheal compression caused by Hashimoto’s thyroiditis (and/or possible malignant lymphoma), 2) PTC in the left lobe of the thyroid gland, and 3) lymph node metastasis (or enlarged lymph nodes) of the neck and near the pancreas because of PTC (and/or possible malignant lymphoma). Total thyroidectomy and neck lymph node dissection were performed to relieve tracheal compression and treat the PTC, with an excisional biopsy performed to address the malignant lymphoma. All parathyroid glands were excised along with the thyroid gland, and after resection, a parathyroid gland was implanted in the left sternocleidomastoid muscle.

Histopathological examination revealed Hashimoto’s thyroiditis (Figure 2) and PTC (15×15 mm) in the left thyroid gland (Figure 3), accompanied by a 90-mm mass consisting of MALT lymphoma that had spread to both lobes of the thyroid gland (Figure 4). The diagnosis of Hashimoto’s disease was established owing to the presence of atrophy of thyroid follicles with strong inflammatory cellular infiltration and loss of colloid, at a distance from the tumor (Figure 2). The mass in the left lobe showed cylindrical atypical epithelium with papillary and follicular growth and abnormal nuclear findings (Figure 3); thus, a diagnosis of PTC was established. Examination of the 90-mm mass revealed that a substantial portion of the normal thyroid architecture was replaced by dense, diffuse infiltrates of small, atypical lymphocytes (Figure 4). Immunostaining of the infiltrating cells showed CD20 (+), CD79α (+), IRTA1(+) (Figure 4B), Bcl-2 (±), Bcl-6 (−), CD10 (−), and CyclinD1 (−), and the number of κ-positive cells was 10 times greater than that of λ-positive cells (Figure 4C, 4D). Luminal accumulation of lymphoma cells and destructive lymphoepithelial lesions (LELs) were also observed. Based on these results, the patient was diagnosed with MALT lymphoma. Histopathological examination of the dissected lymph nodes (II, III, IV, and VI levels) was further performed, and no metastatic lymph nodes of PTC were detected; however, MALT lymphoma was detected (16 of 32 lymph nodes).

The patient was classified as stage III for the MALT lymphoma according to the Ann Arbor Staging, given that FDG-PET showed FDG accumulation near the pancreas. Remission induction therapy was selected for MALT lymphoma as an additional postoperative treatment. Because no lymph node metastasis of PTC was identified and postoperative serum thyroglobulin levels were lower than the measurement sensitivity, no additional treatment for PTC was administered. Four cycles of monotherapy with rituximab, an anti-CD20 monoclonal antibody, were administered and completed.

The patient’s postoperative course was uneventful. Treatment with oral levothyroxine sodium hydrate (150 µg/day) normalized thyroid function. Alfacalcidol (1 µg/day) was administered postoperatively to stabilize blood calcium levels. Serum parathyroid hormone was detectable gradually and within the normal range, along with normal serum calcium levels. Therefore, alfacalcidol therapy was discontinued. The postoperative blood thyroglobulin levels were lower than the measurement sensitivity. Antithyroglobulin antibody levels decreased to 29 IU/ml at 3 months postoperatively, normalizing to 15 IU/ml at 9 months postoperatively. Two years after completing rituximab treatment, FDG-PET detected no positive signals of FDG accumulation, including that near the pancreas, and there was no recurrence; therefore, the patient was considered to have achieved a complete response.

Discussion

In this case report, we discuss a patient with Hashimoto’s thyroiditis who presented with PTC (stage T1bN0M0) and MALT lymphoma (stage III) of the thyroid gland. The incidence of PTL in patients with Hashimoto’s thyroiditis is substantially higher than that in the general population, and given that approximately 90% of patients with PTL have Hashimoto’s thyroiditis, its etiology is believed to be associated with the long-term stimulation of chronic inflammation [2,19]. A high frequency of PTC has also been reported in patients with Hashimoto’s thyroiditis, possibly caused by cellular mediators produced by immune cells in a chronic inflammatory state or by elevated thyroid-stimulating hormone levels stimulating follicular epithelial proliferation [2,20]. Our patient also had Hashimoto’s thyroiditis, which can underlie the development of MALT lymphoma and PTC; however, the simultaneous occurrence of these 2 diseases is extremely rare. In our patient, the simultaneous discovery of the 2 malignancies was considered coincidental; however, owing to their rarity, there is no standardized approach to diagnose and treat this type of double malignancy, along with a lack of sufficient experience. Therefore, each case should be considered individually.

In the current case, the first consideration was whether the patient had malignant lymphoma of the thyroid gland and, if so, what was the pathological type. Malignant lymphoma was suspected based on the course of symptoms and thyroid echogenicity; however, FNA showed that the mass in the left lobe was PTC, and FNA from other sites failed to diagnose malignant lymphoma. Positive FDG signals near the pancreas were suspected to indicate malignant lymphoma, although the possibility of metastasis of PTC could not be dismissed. However, it should be noted that FDG accumulation observed via FDG-PET is difficult in highly differentiated carcinomas such as PTC [21]. Therefore, considering postoperative adjuvant isotope therapy, we did not consider an incisional biopsy for MALT lymphoma (thyroid lobectomy in this case) and selected a total thyroidectomy plus lymph node dissection for PTC, which simultaneously led to the diagnosis of malignant lymphoma and confirmed the origin of the enlarged lymph nodes. However, based on the observed results, an incisional biopsy with thyroid lobectomy may have been possible if the tracheal decompression was achieved by thyroid lobectomy, given the absence of metastatic findings of PTC in the present case.

Considering the presence of concurrent PTC and malignant lymphoma in the same patient, treatment should focus on the tumor with the worst stage and condition, although ideally, optimal treatment should be administered to address both tumors. PTC is the most common pathological type of thyroid malignancy and has a good prognosis. Our patient had stage T1bN0M0 PTC with no lymph node or distant metastases and was treated with surgical resection only, without postoperative radioiodine therapy. Surgery, either to relieve pressure symptoms or obtain specimens for the final diagnosis of malignant lymphoma, usually plays a limited role in malignant lymphoma. In the current case, the release of compression induced by the malignant lymphoma and thyroid tissue collection was completed simultaneously with PTC treatment.

Recent studies have shown that most thyroid MALT lymphomas classified as low grade are stage IE or IIE [7,22]. In addition, considering documented cases of concurrent diagnosis of PTC and thyroid MALT reported [8–18], all thyroid MALT lymphomas were stage IE, that is, confined within the thyroid gland without lymph node metastasis. One patient presented with concomitant DLBCL [9], and another case report did not describe the course of treatment [14]; hence, they were excluded from the analysis. Additionally, Lan et al [10] reported 3 cases. Accordingly, a total of 11 cases were considered. All patients underwent total thyroidectomy and were diagnosed with concomitant MALT lymphoma and papillary carcinoma. Five patients received additional radioiodine therapy, and 1 patient received radioiodine therapy and chemotherapy, all without recurrence. However, our patient had stage III thyroid MALT lymphoma. Therefore, we believe that the previous literature is not relevant to our case in terms of diagnosis and treatment, and further studies and reports are needed. Treatment strategies for thyroid MALT lymphoma include surgery alone with follow-up, radiation therapy, and chemotherapy with rituximab [4,23], and these strategies seem to vary from institution to institution with no firm agreement on the therapeutic approach [22]. In this case, the patient underwent postoperative chemotherapy with rituximab alone, and remission was maintained nearly 3 years after surgery. Given that the serum thyroglobulin level remained below the measurement sensitivity and no positive signal was detected on FDG-PET performed during the follow-up of malignant lymphoma (although the usefulness of FDG-PET in recurrent differentiated thyroid cancer is reported to be low if the thyroglobulin is below the sensitivity [24,25]), recurrence of PTC is also unlikely. It should be noted that the thyroid scintigraphy was not performed because the serum thyroglobulin level remained below measurement sensitivity.

In the present case, wherein PTC and MALT lymphoma were diagnosed simultaneously in the thyroid gland, the origin of the lymphadenopathy near the thyroid gland was attributed to MALT lymphoma alone. If the origin of the lymphadenopathy was PTC, both PTC and MALT lymphoma, or a high-grade lymphoma such as DLBCL [26,27], or if serum thyroglobulin was detected postoperatively, the optimal treatment would need to be reconsidered, and the treatment strategy would markedly differ from that reported in the current case. It is impossible to conduct a large-scale study on such rare cases, and accumulating knowledge by examining similar cases individually, as in the present report, will be valuable for future clinical practice.

Conclusions

This report highlights the association between autoimmune thyroiditis and thyroid MALT lymphoma, presents a rare finding of coexistent PTC and lymphadenopathy of initially unknown origin, and underscores the importance of histopathology in the diagnosis of these conditions.