Introduction

Primary thyroid lymphoma is a rare hematological disease that represents 1-5% of all thyroid malignancies and 2-7% of extranodal lymphomas, with an estimated annual incidence 2 per 1 million [1, 2]. It is typically seen in women over 50 years old with Hashimoto’s autoimmune thyroiditis [3, 4]. Hashimoto’s thyroiditis increases the risk of thyroid lymphoma by 50-70 times, however primary thyroid lymphoma develops only in 0.5% of all Hashimoto’s thyroiditis cases [3, 4]. Patients usually present with a painless rapidly growing mass in the cervical region at the level of the thyroid gland. The patient may also have cervical lymphadenopathy, however, only 10 to 20% of patients present classical systemic symptoms of B-cell lymphoma, such as fever, night sweats, and weight loss. Due to the rapid expansion of the mass patients frequently develop obstruction of the upper respiratory and digestive tracts [2, 4]. Primary thyroid lymphomas are usually non-Hodgkin B-cell lymphomas; however, Hodgkin lymphomas are also possible [5]. The 5-year overall survival rate is 79–91% and it depends on age, stage of the disease, histology and treatment modality [5, 6].

There is a growing incidence of thyroid cancer worldwide. Therefore, a rapidly enlarging neck mass is always suspicious for aggressive type of thyroid carcinoma such as anaplastic carcinoma. Both anaplastic thyroid carcinoma and primary thyroid lymphoma represent rare thyroid malignancies, however their prognosis and treatment strategies are different. Current article describes a rare case of the primary thyroid lymphoma which developed during 1 month and required multidisciplinary treatment and gastrostomy due to a rapidly enlarged neck mass.

Case Report

In November, 2024 82-year-old female was urgently hospitalized with trouble breathing, dysphagia and hoarseness. On examination the patient had a neck deformity due to a large mass and enlarged cervical lymph nodes (Figure 1). Her vital signs were normal, laboratory tests demonstrated mild anemia (hemoglobin 98 g/l [normal range 120-140 g/l], hematocrit 27% [normal range 36-42%]). The patient stated that the mass appeared 1 month ago and rapidly enlarged. Her chest X-Ray revealed tracheal deviation (Figure 2).

Figure 1: The neck mass. A – anterior view; B – lateral view
	Figure 2: Chest X-Ray. The arrow indicates tracheal deviation due to mass

Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

The patient past medical history included postinfarction cardiosclerosis (2014), complex coronary lesions (coronary angiography in 2022), NYHA class I chronic heart failure, grade 3 arterial hypertension, diabetes mellitus type 2, multiple liver cysts and rectal cancer (2009). She received atorvastatin 20 mg, nebivolol 5 mg, perindopril 4 mg, isosorbide mononitrate 40 mg, trimetazidine 35 mg, metformin 750 mg for her medical conditions.

The patient was followed up by an endocrinologist for multinodular goiter and autoimmune thyroiditis. Previously in April, 2024 ultrasound showed multiple TI-RADS 3 masses in the right thyroid lobe, reaching 1.5 cm in size, and a single TI-RADS 4 lesion with the size of 5.6 x 3.6 x 4.2 cm, heterogeneous structure and mixed blood flow in the left lobe of the thyroid gland. The cervical lymph nodes were not increased in size and had no changes in corticomedullary differentiation. Thyroid cytology performed in May, 2024 revealed Bethesda II formation of the left thyroid lobe with no signs of malignancy.

Ultrasonography (USG) of the neck soft tissues on admission demonstrated large solid masses with clear, uneven contours and blood flow during color Doppler imaging on the anterior and lateral surfaces of the neck, with a pronounced heterogeneous, predominantly hypoechoic structure with foci of increased echogenicity (Figures 3, 4). The described masses invaded and deformed the tissues of both lobes and the isthmus of the thyroid gland. The common carotid artery on the right was displaced laterally but patent. The internal jugular vein on the right was had signs of compression. Multiple hypoechoic lymph nodes of irregular shape with impaired corticomedullary differentiation were noted along the common carotid artery. The common carotid artery on the left was displaced laterally but patent. The internal jugular vein on the right was compressed. Along the common carotid artery, multiple hypoechoic lymph nodes of irregular shape with impaired corticomedullary differentiation were noted. No data on delimited and undelimited fluid accumulations of the neck were found. Against the background of the formation, the esophagus was not clearly visible, pushed to the right, with altered thickened walls.

Figure 3: USG of the neck soft tissues, B-mode. A – large thyroid mass (red arrow indicates the mass, yellow arrow indicates the trachea); B – thyroid mass and jugular lymph nodes ((red arrow indicates the mass, yellow arrow indicates the enlarged lymph nodes with lack of corticomedullary differentiation); C – large multinodular mass; D – posterior portion of the mass adjacent to the vertebral column (red arrow indicates the mass, yellow arrow indicates the vertebral column)

Figure 4: USG of the neck with Doppler imaging. A – the mass encircles the carotid artery; B – the mass has abundant vascular supply; C – esophageal displacement (red arrow indicates the trachea, yellow arrow indicates the esophagus); D – carotid artery displacement; E – multinodular mass compressing the carotid artery; F – multinodular mass compressing the carotid artery

Abdomen ultrasonography identified multiple hypoechogenic loci in the liver up to 1.2 cm and a solid mass in the head of the pancreas with distinct, even contours and the size of 7.7 x 8.2 cm. Contrast-enhanced neck CT scan showed significant increase in size of the left thyroid lobe up to 11.5 cm in diameter due to numerous hypovascular nodules. The tumor had bumpy contours, accumulates contrast heterogeneously with hypodense inclusions in the structure. The formation displaces the larynx and trachea to the right, lying along their left and posterior contours; invasion of the esophagus could not be excluded. In the lower sections, the structure of the formation contained a deformed left lobe of the thyroid gland, 41 * 23 mm in size, with hypodense foci in the structure. Along the left contour, the formation was closely adjacent to the medial wall of the proximal third of the left common carotid artery. In the right lobe of the thyroid gland, multiple hypovascular nodes were noted, up to 14 mm in diameter. Supraclavicular lymph nodes on the left were enlarged to 17 mm along the short axis, with a hypodense central part when contrasted. The previous CT scan did not indicate thyroid gland enlargement (Figures 5, 6).

	Figure 5: CT scan of the neck with contrast enhancement (arrow indicates the thyroid). A – thyroid gland with multiple nodes, September 2024; B – enlarged thyroid gland, November 2024
Figure 6: CT scan with contrast enhancement demonstrating a large neck mass (arrow indicates the thyroid mass). A – sagittal section. B – coronal section.

The thyroid mass had spread into laryngopharynx and led to trachea and esophagus upper third displacement and constriction. In the left subclavicular area two lymph nodes accumulating contrast agent with the size of 1.4 cm and 1.7 cm were identified. Bronchoscopy confirmed invasion into the pharynx. Upper GI endoscopy performed in the first day of hospitalization exposed narrowing of the esophagus upper third due to external compression and signs of chronic atrophic gastritis. Percutaneous endoscopic gastrostomy was performed for adequate nutrition. Biopsy specimen was taken for histological verification. Pathology report revealed diffuse large B-cell lymphoma cells. Immunohistochemistry showed CD20, bcl6, Ki67 80% expression and absence of cyclinD1, CD10, CD3, CD30, EBV. She was diagnosed with primary B-cell thyroid lymphoma IIE stage, low-intermediate risk. Pre-phase treatment with cyclophosphamide and dexamethasone was initiated following after R-miniCHOP (rituximab 500mg, cyclophosphamide 600mg, doxorubicin 37 mg, vincristine 1mg, dexamethasone 9 mg). During the pre-phase, the patient noted a decrease in discomfort when swallowing and improvement of the passage of liquid. The patient was scheduled for 6 courses of R-miniCHOP and is currently undergoing her second cycle of treatment.

Discussion

Thyroid gland nodules are prevalent in the population and can be encountered during USG in 20-75% of cases [7]. Thyroid gland mass is a benign lesion in up to 90% of cases and thyroid cancer is seen only in 4-6.5% of cases [8]. FNA under USG guidance for suspicious nodules is considered the golden standard for evaluation, although up to 25% are classified into Bethesda III and IV categories, which are considered cytologically indeterminate [9]. Recent studies implement core-needle biopsy (CNB) in selected cases as the obtained histological material is superior to cytology [10, 11]. Moreover, several guidelines propose using CNB for malignant tumors such as lymphoma, anaplastic thyroid carcinoma and metastasis [10,12]. CNB also allows to differentiate a number of tumors when cytology usually classifies them into Bethesda III or IV [13]. A large thyroid mass usually requires cytological (FNA) or histological (CNB) verification. A meta-analysis of 17 studies of 166 patients demonstrated that CNB has a sensitivity and positive predictive value of 94,3% and 100% for thyroid lymphoma and 80,1% and 100% for anaplastic thyroid carcinoma respectively. For comparison the reported sensitivity of FNA was 48% for thyroid lymphoma and 61% for anaplastic thyroid carcinoma. Therefore, a rapidly enlarging thyroid mass should undergo CNB as it allows to save time as compared to stepped diagnostic pathway using FNA first and awaiting the result before doing CNB [14]. CNB also provides possibility for immunohistochemical staining.

A thyroid mass that rapidly increases in size is suspicious for aggressive type of thyroid cancer such as anaplastic carcinoma or thyroid lymphoma [15, 16]. Both are rare, anaplastic carcinoma represents 2-3% of all thyroid malignancies, while primary thyroid lymphoma is seen in around 5% of cases [15, 16]. The differential diagnosis is presented in the Table 1.

The prevailing PTL histological types are diffuse large B-cell lymphoma (DLBCL) (68%) and MALT lymphoma (24%). According to SEER database analysis, DLBCL and MALT PTL 10-year disease-specific death rates are 20% and 5%, respectively [22]. Over 80-90% of patients present with local disease (56% stage IE or 32% IIE), while about 10-20% of patients have advanced stage (2% stage IIIE or 11% stage IV) (Table 2) [23, 24].

First of all, prognosis depends on the stage of the disease, histology and the age at the diagnosis. It was shown that the anterior-posterior diameter >2.5 cm measured via ultrasonography is associated with a high risk of disease progression [25]. The highest death risk is associated with age ≥ 60 years (hazard ratio [HR], 3.94; 95% CI 3.31-4.69; P < 0.001), unmarried status (HR, 1.55; 95% CI 1.37-1.75; P < 0.001), Ann Arbor stage III-IV (HR, 1.55; 95% CI 1.37-1.75; P = 0.020), diffuse large B-cell lymphoma (DLBCL) (HR, 2.60; 95% CI 1.15-5.87; P = 0.022), and T cell non-Hodgkin lymphoma (HR, 3.53 95% CI 1.12-11.10; P = 0.031) [26]. Patients with International Prognosis Index (IPI) index ≥3 and high β2-MG (>3 mg/L) tend to have worse OS and progression-free survival [27].

Secondly, Hashimoto thyroiditis (HT) is known to increase the risk of primary thyroid lymphoma (PTL) up to 80 times, albeit PTL develops only in 0.5% of all HT cases [3, 4]. The pathogenesis is still unknown, nevertheless, almost 80% of the PTL patients have evidence of HT. (28) In MALT thyroid lymphoma TET2 (85.5%), CD274 (PD-L1) (53%) and TNFRSF14 (53%) mutations are frequently seen. TET2 mutations affect DNA methylation and transcriptional factors important for B-cell maturation. CD274 missense mutations lead to deregulation of T-helper cells, which activate malignant B-cells. Interestingly, CD274 and TNFRSF14 gene alterations are associated with Hashimoto’s thyroiditis (p = 0.01, p = 0.04, respectively) [29].

Thirdly, treatment modalities used may alter significantly survival outcomes. Extranodal DLBCL have remarkably higher 5-year OS (62%) compared with nodal DLBC (43%) [30]. Curiously, extranodal involvement is seen more often in ABC subtype [31]. Origin site does not affect dramatically treatment outcomes [32]. The most significant response rates in primary thyroid lymphoma patients are observed after combined treatment when surgery is followed after chemotherapy and radiotherapy [33]. The role of surgery is limited, though surgical operations still play a role in diagnosis, early-stage disease or in palliative treatment for tumors affecting trachea and adjacent structures [34].

Surgery alone (HR =0.547, 95% CI =0.348–0.859, P=0.009) or combined surgery and radiotherapy (HR =0.491, 95% CI =0.314–0.769, P=0.002) are found to improve the disease-specific survival (DSS) of DLBCL patients effectively. Thyroid lobectomy (HR =0.57, 95% CI =0.361–0.900, P=0.016) and near-total/total thyroidectomy (HR =0.597, 95% CI =0.384–0.929, P=0.022), are associated with better prognosis for these patients [34].

Chemotherapy with or without radiotherapy is the main treatment strategy for advanced DLBCL stages (III, IV). However, multiagent chemotherapy combined with radiotherapy also can be a possible option for I and II stage of DLBCL, since it results in better OS results [35]. As for primary thyroid lymphoma chemotherapy, the standard DLBCL protocols are applied, such as cyclophosphamide, doxorubicin, vincristine, and prednisone with adding of anti-CD20 agent rituximab (R-CHOP regimen). Compared with DLBCL patients without extranodal involvement, patients with extranodal sites are 5.3 times more prone to R-CHOP chemotherapy regimen resistance [36].

As for MALT lymphomas, they are characterized by indolent growth pattern and more favorable treatment response compared with DLBCL. Mostly, patients with primary MALT lymphoma are younger, have lower stage and longer DSS compared with DLBCL. (34) Surgery-first approach is applicable for localized PTL in case of radical resection feasibility. Otherwise, RCHOP chemotherapy regimen or its modifications are used [37].

The nutritional status of PTL patients deserves a separate attention. Patients with the head and neck tumors having esophageal compression should be referred early for endoscopic gastrostomy to maintain their nutritional and metabolic status [38].

Conclusions

The treatment of primary thyroid lymphoma patients often requires a multidisciplinary team involving oncologist, endocrine surgeon, endocrinologist and other specialists. Despite the favorable prognosis in early-stage disease, treatment modalities used may alter significantly survival outcomes.

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