Thyroid MALT lymphoma is extremely rare, accounting for 0.2% (11/5418) of thyroid malignancies and 29.7% (11/37) of thyroid lymphomas, within the range of 6%~46.8% reported in some studies [5, 6, 13]. Among 11 cases with thyroid MALT lymphoma, 72.7% (8/11) occurred in females, 81.8% (9/11) were older than 60 years, and 100% (11/11) arose in a background of Hashimoto thyroiditis, which are consistent with previous studies [3,14]. There are thyroid-specific sex differences with a female predominance in this study. Most patients with thyroid MALT lymphoma occur in adults, with a median age in the seventh decade of life. Hashimoto thyroiditis, i.e., a form of autoimmune-based chronic inflammation, is known to precede thyroid MALT lymphomas. In patients with Hashimoto thyroiditis, the risk of thyroid lymphoma is 70 times that in the general population, and approximately 85% are MALT lymphomas. Hashimoto thyroiditis is very common, but thyroid lymphoma is very rare, although it is associated with Hashimoto thyroiditis. It usually takes approximately 3-18 years to evolve into MALT lymphoma [15, 16]. The median age of patients with Hashimoto thyroiditis, 40 to 55 years, is younger than that of patients with thyroid MALT lymphoma [17]. Many MALT lymphoma cases have a history of chronic inflammatory disorder that results in the accumulation of extranodal lymphoid tissue (called acquired MALT). One postulated mechanism was a slow malignant transformation from chronic antigenic stimulation of marginal lymphocytes [18].
Thyroid MALT lymphoma commonly presents as a rapidly or gradually enlarged neck mass and goiter leading to local compressive symptoms. This neck mass rapidly grows in a short time, which is rarely observed in Hashimoto thyroiditis [19]. Dyspnea was the most common compressive symptom, presented in 3 cases (27.3%) due to tracheal stricture or deviation secondary to the diffusely enlarged thyroid lymphoma. The remaining symptoms, such as neck pain, dysphagia, and hoarseness, were not present in our cases. Classic B-type symptoms occurred in 2 cases (18.2%) with stage IVE disease, similar to that reported in approximately 20% of patients [20]. Most patients presented with stage I or II disease (7/11, 63.8%). Stage IIIE and IVE disease were seen in 36.4% (18.2%, respectively) of cases, higher than the incidence of 2%~7% of cases with primary thyroid lymphoma [5, 10], and similar to the incidence of 23%~40% of cases with thyroid MALT lymphoma involving multiple extranodal sites [14, 21]. Staging in patients with multiple extranodal lesions may be challenging because at least some cases with multiple site lesions perhaps constitute multiple clonally unrelated proliferations rather than truly disseminated disease [22].
Most thyroid MALT lymphoma presented as very hypoechoic solid enlarged nodules and/or goiter of tumor cell infiltration with enhanced posterior echoes on thyroid sonogram. Thyroid MALT lymphoma is composed of small B cells, including marginal zone cells with a prominent population of small and intermediate-sized lymphoid cells, accompanied by lymphoepithelial lesions and/or plasmacytic differentiation in some cases. The consistency of the tumor cells without any acoustic impedance results in enhanced posterior echoes. The rarest heterogeneous appearance of thyroid MALT lymphoma closely resembled Hashimoto thyroiditis, with multiple hypo/isoechoic micronodules (≤10 mm) interspersed within a normal sized left lobe gland. The pathological image and the sonogram showed the same size of the foci tumor cell infiltration. This is the first study to characterize the diffuse micronodular appearance of thyroid MALT lymphoma in the background of Hashimoto thyroiditis with normal-size gland. Diffuse micronodular disease with MALT lymphoma cannot be identified except with surgical pathology. Furthermore, from the dynamic perspective, the tumor developing course is the process of small single nodule or multiple tumor foci grow up to be nodular type, then progress to become mixed type and finally infiltrate throughout the thyroid to develop into diffuse type based on these patients’ serial ultrasound findings.
Serial ultrasound showed variable internal echoes of thyroid MALT lymphomas. The internal echoes were very low hypoechoic (i.e., pseudocystic), PEF of undetermined significance, and short linear, parallel linear, reticular/alveolate hyperechoic, sequentially appeared and increased as the tumor grew up. Due to the heterogeneous appearance of thyroid MALT lymphomas on sonograms, differentiation of these lymphomas from benign diseases such as Hashimoto thyroiditis, goiter, hemorrhage in adenoma, and even cysts is difficult for radiologists with insufficient awareness of thyroid MALT lymphoma. In some cases with the nodular type, pseudocystic appearance or concomitant PEF of undetermined significance were often misdiagnosed as cyst or hemorrhage. Increased vascularity detected by color Doppler flow imaging (CDFI) and pulsed wave (PW) can be helpful to identify the pseudocystic nodule as solid. Approximately 90% of MALT lymphoma cases demonstrated increased disordered vascularity.
In our study, only 2 cases of suspected lymphoma were reported by 2 radiologists with more than 10 years of experience. Therefore, there was a marked discrepancy in the clinical real-time ultrasound reports. Application of the 2017 ACR-TIRADS or 2020 C-TIRADS categories is very useful to address ultrasound diagnostic dilemmas and eliminate interobserver differences in terms of recommendations for FNA/CNB. Since CNB can yield a higher proportion of diagnostic results than conventional FNA [23], our patients underwent CNB instead of FNA. Eleven abnormalities(11/12, 91.67%) detected in two TIRADS’s were recommended for FNA/CNB. The one exception with the largest nodule ≤10 mm (Figure 1 A), which was categorized as TR3 and 4A nodules in ACR-TIRADS and C-TIRADS, was missed because the nodule size did not meet the recommended criteria for FNA. In such cases, active surveillance by follow-up ultrasound can substantially mitigate the possibility that significant malignancies remain undetected over time. Once the tumor size increases by more than 20% [24], biopsy is necessary for a precise diagnosis of the subtype, which affects subsequent therapeutic management. In addition, patients with debulking surgery should receive active surveillance by follow-up ultrasound to detect early local recurrence. Ultrasound revealed excisional tumor-infiltrated thyroid capsules in one case. The presence of extrathyroidal extension and abnormal lymph nodes increase the risk stratification of disease in TIRADS clinical practice [9]. Nevertheless, in our study, neck lymphadenopathy involvement was found in up to 90.9% (10/11) of the patients at diagnosis, possibly because most of these patients did not decide to perform biopsies until the presence of apparently enlarging neck masses.
MALT lymphomas have an indolent natural course and are slow to disseminate. Because of their insidious onset, precise diagnosis of thyroid MALT lymphomas is usually obtained after a long time (1 to 10 years) from the initial visit. In this study, serial sonograms showed the complicated natural course of thyroid MALT lymphoma, that is, thyroid MALT lymphoma behaved alternating or sequential self-limiting, progression or being unchanged on serial ultrasound for many years [25].
With regards to treatment strategy, MALT lymphomas are sensitive and have a better response to local thyroid radiotherapy, which is followed by prolonged disease-free intervals. Early-stage MALT lymphomas may be treated with radiotherapy alone without disease recurrence. The follow-up ultrasound showed thyroid reduced to normal size without the nodule in 2 cases after radiotherapy. Since radiotherapy may result in severe adverse events, observation or rituximab alone is also used. Stages III and IV refer to the treatment of rituximab combined with chemotherapy or observation [1]. The most common histologic subtype of thyroid lymphoma is diffuse large B-cell lymphoma (DLBCL) which accounts for 43.3%~70% of cases. And LCT or mixed MALT/DLBCL accounts for approximately 4%~7.6% [5, 26]. In patients with transformation into DLBCL, mixed subtypes, and/or extensive bulky local disease, multimodal treatment with rituximab, combination chemotherapy, and local radiotherapy provides the highest overall survival rates. One patient with stage IE disease (1/11, 9.1%) developed LCT in the contralateral half of the systemic lymphadenopathy at 1.5 years after left lobectomy and combined chemotherapy to achieve complete remission in the study. The prognosis for MALT lymphoma is excellent except for transformation into DLBCL with the clinical behavior being more similar to DLBCL (reported in < 10% of cases) [27, 28].
The role of surgical intervention remains controversial, and such intervention is typically incidental in the management of indolent MALT lymphomas for other indications, such as palliation in the setting of critical airway obstruction or stenosis, which can be replaced by corticosteroids and chemo/radiotherapy and temporary use of tracheal stent [29]. Among the 3 cases with debulking surgery, 2 cases (2/3, 66.7%) relapsed within a short time and 1 case developed aggressive LCT, then one case even developed second cancer (lung cancer). These unfavorable outcomes may be associated with autoimmune condition including persistence of Hashimoto thyroiditis. It raises a question of whether total thyroidectomy is a matter of better therapeutic efficacy due to absence of inflammatory stimuli of thyroiditis. Therefore, we propose that total thyroidectomy instead of debulking surgery is used in the clinical management in order to eradicate the strong risk factor of inflammation in Hashimoto thyroiditis. Regional radiotherapy and total thyroidectomy can avoid residual tumor relapse, LCT, and dissemination to multiple sites. However, the clinical benefits of extensive surgery are also controversial and need to be confirmed in large studies [6, 19, 30]. Some experts believe that surgery is contraindicated for the patients with thyroid MALT lymphomas higher than stage IE, bulky tumors greater than 10 cm in size, and mixed tumors.
In this study, the goiter reduced to a normal size and returned to hypo/isoechoic parenchyma after chemotherapy in 3 cases, complete remission was 100%. 2 cases went through a relative long period of remission (8, 9 years) and one case died, another relapsed. The third case with systemic dissemination, had a 6 years history of goiter, died of brain involvement and hemorrhage after 2.5 years. Combined chemotherapy for advanced-stage disease can achieve complete remission in 90%~100% of patients. However, relapses are unfortunately common within 3 to 6 years (10%~35%), which can occur after many years and may involve other extranodal sites. The 59-year female with a 7 years history of MZL, concomitant lymphocytic leukemia and bone marrow involvement, survived for 9 years after chemotherapy, then died of lung infection. In summary, mortality (3/11, 27.3%) was unfavorable, survival to date was 8.5 years (2-16 years) in our study.
In addition, three cases without treatment experienced a period of time (6 months, 2 years, and 3 years) with no significant change of tumor, survived for many years(4, 9, 10 years) with disease-specific to date. We found thyroid MALT lymphomas disappeared, appeared, increased, shrunk, even reoccurred on serial sonograms in 2 cases without treatment. And relapsed masses decreased in size in 1 case at 8 years after subtotal thyroidectomy during a long period of follow-up ultrasound. It is first time that the self-limiting changes of thyroid MALT lymphoma was demonstrated in the form of ultrasonic images, which has not been reported in the literatures we read.
Thyroid MALT lymphoma follows a relatively benign course and historically demonstrates a better response to treatment. The 5-year disease-free survival rates approach 96%~100%, higher than 71%~75% for DLBCL and the other histological subtypes [19, 31]. Poor prognostic factors include advanced age and stage, the presence of DLBCL, lack of treatment with radiation, greater tumor size, mediastinal involvement, rapid clinical growth, and the presence of B symptoms. However, there is the opposite opinion that involvement of multiple extranodal sites and even bone marrow involvement do not appear to confer a worse prognosis [27, 28]. In the end, the ideal treatment management should remain relative indolent and self-limiting conditions for many years and preserve the patients’ quality of life and longevity.
There are some shortcomings in the present study. Surgical excision in 3 cases had superior diagnostic accuracy in comparison with CNB in 8 cases. Biopsied tissue samples do not represent pathological features of entire tumor involvement with insufficient evidence, affecting the analysis of ultrasound characteristics. The other major limitation was the small sample size due to the morbidity and longer clinical course of thyroid MALT lymphoma, which failed to reach statistical significance. Further studies with large cohorts of patients and comprehensive analysis are needed to address this issue.