Multimodal ultrasound evaluation of refractory primary thyroid lymphoma: a case report and literature review

Introduction

Primary thyroid lymphoma (PTL) is a rare malignant tumor, accounting for less than 5% of primary thyroid malignancies and less than 2% of all extranodal lymphomas (1). It is defined as lymphoma originating in the thyroid gland, with or without involvement of regional lymph nodes, and has no contiguous extension or distant metastases when diagnosed (2), while secondary thyroid lymphoma usually occurs in thyroid involvement by systemic lymphoma (3). PTL has no specific clinical manifestations. It commonly occurs in elderly individuals with an average age of over 60 years, typically presenting as rapid enlargement of a neck mass accompanied by cervical lymphadenopathy (4). More than 60% of patients experience compression symptoms such as dyspnea, dysphagia, wheezing, and hoarseness (1,5). PTL is primarily composed of B-cell-derived non-Hodgkin lymphoma (NHL), with the most common subtypes including diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma (1,3,6). At present, combined chemotherapy and radiotherapy have become the first-line treatment for this disease. However, some patients show poor response to first-line treatment and may experience early recurrence and refractoriness.

Due to the rarity of PTL, there are relatively few studies on this type of disease, and there are limited examination methods to assess whether the disease is refractory or recurrent. This article presents a case of refractory PTL evaluated by multimodal ultrasound and documents the patient’s entire medical journey. The purpose is to provide clinicians with valuable imaging references to reduce missed diagnoses and misdiagnoses, as well as evaluating the clinical role of multimodal ultrasound in the diagnosis and efficacy assessment of such diseases. We present this article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-526/rc).

Case presentation

A 33-year-old female presented to West China Hospital with “progressive enlargement of a neck mass one month prior” and had no symptoms such as tenderness, fever, or night sweats. No relevant examinations or treatments had been conducted previously. The patient had a history of hepatitis B, was 6 years post-cesarean section, and had no history of other infectious diseases, other surgeries, or cardiovascular and cerebrovascular diseases. Laboratory test results were as follows: thyroid stimulating hormone (TSH): 5.320 mIU/L (reference range, 0.27–4.2 mIU/L); free triiodothyronine (FT3): 3.91 pmol/L (reference range, 3.60–7.50 pmol/L); free thyroxine (FT4): 13.20 pmol/L (reference range, 12.0–22.0 pmol/L); thyroglobulin antibody (Tg-Ab): 1,295.00 IU/mL (reference range, <115 IU/mL); thyroid peroxidase antibody (TPO-Ab): <9.00 IU/mL (reference range, <34 IU/mL); lactate dehydrogenase: 171 IU/L (reference range, 120–250 IU/L). All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Pre-treatment thyroid ultrasound examination is as follows (Figure 1): solid lesions were detected in the middle-inferior parts of both thyroid lobes and the isthmus, adjacent to the surrounding capsule. The nodule showed heterogeneous extremely hypoechogenicity, with a size of approximately 62 mm × 23 mm × 44 mm, an aspect ratio <1, ill-defined borders, irregular shape, and posterior acoustic enhancement, classified as American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) category 4. Adler blood flow grade: grade 1. Shear-wave elastography of the nodule: E-max (61.4 kPa), E-min (22.3 kPa), E-mean (44.5 kPa), E-ratio (1.38). Contrast-enhanced ultrasound (CEUS) showed centripetal perfusion, mainly heterogeneous hypoenhancement, with non-enhancement in some areas.

Figure 1 Pre-treatment ultrasound examination revealed lesions in both lobes and the isthmus of the thyroid gland. (A) A heterogeneous, marked hypoechoic mass within the thyroid parenchyma, adjacent to the surrounding capsule. (B) Color Doppler flow imaging of the mass in the left thyroid lobe. (C,D) The contrast-enhanced ultrasound of the mass in the left thyroid lobe, demonstrating uneven centripetal hypoenhancement of the mass in the left thyroid lobe. (E) The elastography of the mass in the left thyroid lobe.

Due to the large size of the mass, rapid growth, and high clinical suspicion for lymphoma, a core needle biopsy (CNB) of the left thyroid lobe (using a BARD MN16G needle) was performed instead of fine-needle aspiration cytology (FNAC). Pathological results (Figure 2) confirmed NHL, specifically aggressive B-cell lymphoma consistent with DLBCL. Hans classification indicated a non-germinal center B-cell (non-GCB) origin, with double expression of Bcl-2 and c-Myc proteins.

Figure 2 Pathology results of the first thyroid core needle biopsy. (A) Thyroid lymphoma (×400; HE staining). (B) Immunohistochemical slide for Ki-67 (×400). (C) Immunohistochemical slide for Bcl-6 (×400). (D) Immunohistochemical slide for c-Myc (×400). HE, hematoxylin-eosin.

Subsequently, a positron emission tomography-computed tomography (PET/CT) (Figure 3) scan revealed soft tissue masses in both lobes of the thyroid gland, as well as enlarged lymph nodes in the bilateral middle-lower neck and supraclavicular regions with abnormally increased glucose metabolism. Combined with the pathological findings, these manifestations are consistent with lymphoma invasion. Based on the above examination results, the patient is classified as stage IIE, group A according to the Ann Arbor staging system and has a National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) score of 0.

Figure 3 Pre-treatment PET/CT scan showed masses in both lobes of the thyroid gland with abnormal metabolism, as well as bilateral cervical lymphadenopathy accompanied by increased metabolism. PET/CT, positron emission tomography-computed tomography.

Subsequently, the patient received 3 cycles of R-CHOP chemotherapy, which consists of rituximab, cyclophosphamide, pirarubicin, vindesine, and prednisone. The second PET/CT scan (Figure 4) showed: significant reduction in the volume of both thyroid lobes, but the lesion still had relatively active metabolism (Deauville score: 5 points). Combined with the PET/CT report, tumor residue was suspected, the treatment response was evaluated as stable disease (SD), and the patient was diagnosed with refractory thyroid lymphoma.

Figure 4 The second PET/CT showed a significant reduction in the volume of both thyroid lobes, while the metabolic activity of the lesions remained relatively active (Deauville score, 5 points). PET/CT, positron emission tomography-computed tomography.

After adjusting the treatment plan, one cycle of chemotherapy with brentuximab vedotin, lenalidomide and rituximab was administered. However, due to coronavirus disease 2019 (COVID-19) infection, lenalidomide was taken for only 3 days. The patient reported that the neck mass initially shrank but gradually enlarged afterward.

Thyroid ultrasound examination after the above treatment is as follows (Figure 5): solid lesions remained in the middle-inferior parts of both thyroid lobes and the isthmus, adjacent to the surrounding capsule, with a size of approximately 56 mm × 20 mm × 51 mm, an aspect ratio <1, irregular shape, ill-defined borders, heterogeneous extremely hypoechogenicity, and posterior acoustic enhancement, classified as ACR-TIRADS category 4. Adler blood flow grade: grade 1. Shear-wave elastography of the nodule: E-max (194 kPa), E-min (41.0 kPa), E-mean (111.7 kPa), E-ratio (2.0). CEUS pattern: mainly heterogeneous hypoenhancement, with non-enhancement in some areas and centripetal enhancement.

Figure 5 The second ultrasound examination showed a slight reduction in the volume of the thyroid mass. (A) Transverse section of the thyroid gland. (B) Color Doppler flow imaging of the mass in the left thyroid lobe. (C,D) The contrast-enhanced ultrasound of the mass in the left thyroid lobe, demonstrating uneven centripetal hypoenhancement of the mass in the left thyroid lobe. (E) The elastography of the mass in the right thyroid lobe.

Ultrasound-guided CNB of the right thyroid lobe was performed again. Pathological results supported the diagnosis of NHL (aggressive B-cell lymphoma), most consistent with DLBCL, of non-GCB origin, with double expression of Bcl-2 and c-Myc proteins. A very small number of atypical follicular epithelial cells were additionally identified on cytological examination. Scattered rare suspicious cells were noted on serial sections of immunohistochemical staining, and the possibility of papillary carcinoma cannot be excluded. Table 1 presents a comparison of the pathological results from the two biopsies.

The treatment regimen was adjusted, and the patient received 3 cycles of chemotherapy of new regime, which consists of rituximab, brentuximab vedotin, ibrutinib. Post-treatment PET/CT (Figure 6) showed that the thyroid tended to achieve complete remission after treatment: the volume was smaller than before, and glucose metabolism was significantly reduced (Deauville score: 2 points). Thyroid ultrasound (Figure 7) showed reduced thyroid volume compared with previous scans, with ultrasound features consistent with Hashimoto’s thyroiditis and no definite NHL lesions. The patient subsequently underwent total thyroidectomy (Figure 8). Surgical treatment is recommended given that the possibility of papillary carcinoma cannot be excluded from the second CNB. Postoperative pathology showed follicular atrophy in some areas, accompanied by fibrous tissue hyperplasia and infiltrating reactive lymphocytic hyperplasia. The patient was followed up for 15 months after surgery, during which thyroid ultrasound showed no recurrence of neck tumors.

Figure 6 Post-treatment PET/CT showed that the thyroid gland tends to achieve a complete response after treatment (Deauville score, 2 points). PET/CT, positron emission tomography-computed tomography.

Figure 7 Post-treatment ultrasound showed that the internal echo of the thyroid gland presented changes consistent with Hashimoto’s thyroiditis, and no definite space-occupying lesion was observed. (A-C) Gray-scale ultrasound examination. (D) Color Doppler flow imaging.

Figure 8 The clinical diagnosis and treatment process of this patient. CNB, core needle biopsy; COVID-19, coronavirus disease 2019; DLBCL, diffuse large B-cell lymphoma; PET/CT, positron emission tomography-computed tomography; R-CHOP, rituximab, cyclophosphamide, pirarubicin, vindesine, and prednisone.

Discussion

The diagnosis of PTL is mainly based on clinical manifestations and imaging examinations, and confirmed by cytology and histopathology. Thyroid lymphoma exhibits significant clinical heterogeneity, and the diagnosis of PTL is often delayed due to overlapping features other thyroid malignancies (7).

For diagnostic and follow-up imaging, PET/CT is currently recognized as the key examination for evaluating treatment responses in lymphoma, yet it has limitations in terms of cost, accessibility and radiation exposure. In comparison with PET/CT, multimodal ultrasound offers the following advantages: (I) cost-effectiveness: the cost of an ultrasound examination is significantly lower, alleviating the economic burden of long-term follow-up for patients; (II) high accessibility: ultrasound equipment is widely available in primary and secondary medical institutions, enabling timely follow-up in non-tertiary medical facilities; (III) radiation-free: unlike PET/CT, ultrasound involves no ionizing radiation and is suitable for repeated examinations. Nevertheless, PET/CT demonstrates superior sensitivity in detecting distant metastases, and a combination of the two modalities may represent the optimal option for comprehensive follow-up in patients with refractory PTL.

Imaging and cytology may provide an initial indication of a malignant tumor, but a definitive diagnosis usually requires a CNB or surgical tissue sampling to confirm the subtype and perform immunohistochemistry (3,7).

NHL is the predominant pathological type of PTL, among which DLBCL is the most common pathological subtype. The treatment strategies for PTL vary according to its histological subtypes and disease stages: the R-CHOP regimen is the first-line systemic therapy for DLBCL; radiotherapy is required for local control in early-stage disease; and surgical treatment is generally reserved for cases with local residual disease, compressive symptoms or suspected concurrent thyroid cancer (3,7). Immunotherapy has also been introduced for the treatment of refractory cases (7).

Most patients respond well to treatment. However, the recurrence rate due to chemotherapy-resistant diseases can be as high as 40% (8). Primary refractory DLBCL was defined as failure to achieve response (SD) or progressive disease (PD) during, or by the end of, first-line (1L) immunochemotherapy (IC) (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving complete response (CR) at EOT to 1L IC (9).

This case involves a 33-year-old young female patient diagnosed with refractory DLBCL of the thyroid gland, staged IIE, with an NCCN-IPI score of 0. Hans classification indicates that the lymphoma cells are derived from multi-lineage non-GCB, and there is co-expression of Bcl-2 and c-Myc. In terms of traditional prognostic assessment indicators, the patient has a low Ann Arbor-Costwolds stage and an IPI score categorized as low-risk. However, based on the analysis of pathological features and molecular biological characteristics, her condition is still classified as a refractory case. The reasons may lie in the following molecular features: first, the patient’s lymphoma subtype is non-GCB type; second, there is co-expression of Bcl-2 and c-Myc, both of which meet the definition of a molecular high-risk subtype.

Clinical studies have shown that Bcl-2/c-Myc co-expression is closely associated with poor efficacy of the R-CHOP regimen. Patients with this feature have significantly lower 3-year overall survival (OS) and 3-year progression-free survival (PFS) compared to non-co-expressing patients (10-12). Additional studies have confirmed that even with a low NCCN-IPI score, the co-expression status may still lead to chemotherapy resistance and an increased risk of early recurrence in patients (13). The poor actual treatment outcome of this patient further suggests that the impact of tumor molecular characteristics on prognosis may surpass the prognostic predictive ability of traditional scoring systems (such as IPI and NCCN-IPI).

Ultrasonography is the preferred imaging modality for thyroid diseases. Based on ultrasound findings including internal echogenicity, margin, and posterior echotexture, PTL can be classified into nodular, diffuse, or mixed types (14). Patients with Hashimoto’s thyroiditis have an increased risk of developing lymphoma (15). In our case, the patient also presented with elevated thyroglobulin antibodies. Studies have shown an overlapping clonal pattern between PTL and Hashimoto’s thyroiditis (3). Both conditions can present with diffuse or nodular changes. On ultrasound images, it is difficult to distinguish some cases of thyroid lymphoma from Hashimoto’s thyroiditis. For nodular changes, ultrasonic features such as hypoechogenicity and posterior acoustic enhancement are helpful for predicting thyroid lymphoma. Based on CEUS imaging, Yang et al. proposed that centripetal heterogeneous hypo-enhancement should be recognized as a CEUS feature predictive of malignancy (16). In contrast, for diffuse changes, ultrasonography has limited diagnostic value, while Ota et al. indicated that posterior acoustic enhancement of lesions is the only useful sonographic sign for diagnosing PTL (14). Currently, there are few reports on multimodal ultrasound assessment of PTL, and no large-sample studies evaluating the ultrasonic features of relapsed/refractory thyroid lymphoma have been reported.

In this case, the ultrasonic features of thyroid lymphoma included heterogeneous hypoechogenicity, posterior acoustic enhancement, and echo strands within the hypoechoic lesions. These findings are consistent with the typical features of PTL reported in the literature (2,14,16,17). A study reported that PTL patients with both anterior-posterior diameters of the bilateral thyroid lobes exceeding 2.5 cm may be prone to refractory/local recurrence events (17). This patient partially conformed to the conclusion of this study (the anterior-posterior diameter of the left thyroid lobe was 2.5 cm, and that of the right thyroid lobe was 2.7 cm). Onal et al. also observed that PTL patients with larger tumors had poorer relapse-free survival (18). The sparse blood flow signals inside the lesions may be associated with the invasive destruction of microvessels by the tumor. The texture of the lesions was slightly harder than that of the surrounding thyroid tissue, with an elasticity ratio of 1.38 between the two. Although malignant nodules are generally harder than benign ones, there are currently few studies on ultrasonic elastography of PTL, so it is more suitable as supplementary information for diagnostic indication. CEUS mainly showed heterogeneous centripetal hypoenhancement, with non-enhancement in some areas. This imaging feature of CEUS is consistent with the conclusion reported by Yang et al. (16).

After 1–3 cycles of R-CHOP regimen and one cycle of second-line treatment, the volume of the lesions decreased while the texture became harder, and no significant change was observed in blood flow signals. The increased hardness detected by elastography may reflect post-treatment fibrosis or residual tumor tissue, whereas the persistent hypoenhanced areas suggest residual active tumors. This was confirmed by the results of needle biopsy, which proves that multimodal ultrasound has important value in monitoring the therapeutic effect of thyroid lymphoma.

Multimodal ultrasound played a critical role in guiding clinical decision-making throughout the patient’s management. Initially, B-mode ultrasound findings prompted CNB for definitive diagnosis, avoiding delays associated with FNAC which has limited utility for lymphoma classification. After first-line therapy, residual mass on B-mode ultrasound and heterogeneous enhancement on CEUS collectively indicated residual viable disease, prompting repeat CNB and subsequent clinical intervention. Postoperatively, ultrasound has been used for radiation-free long-term follow-up, with no recurrence detected at 15 months. These findings demonstrate the value of multimodal ultrasound in integrating imaging with clinical decision-making in refractory PTL.

There are limitations in this case report. Firstly, this is a single case report. Therefore, conclusions regarding the diagnostic and prognostic value of elastography and CEUS in refractory PTL cannot be generalized to a larger population. Prospective multicenter studies with larger sample sizes are required to validate the utility of multimodal ultrasound in this setting. Secondly, during the patient’s treatment, multimodal ultrasound was not used for assessment in every follow-up visit. Instead, ultrasound examinations and PET/CT scans were mostly conducted alternately. Moreover, after the completion of the final treatment, CEUS was not performed to evaluate residual tumors, and PET/CT was used instead. Thirdly, during the patient’s second-line treatment, the patient stopped taking medications on her own due to a COVID-19 infection, which may have affected the treatment efficacy and the conclusions of imaging assessments.

Conclusions

Refractory PTL has a low incidence rate, and multimodal ultrasound is one of the important methods for its diagnosis and efficacy evaluation. Ultrasound features including internal hypoecho or marked hypoecho, and posterior echo enhancement are helpful for predicting thyroid lymphoma. CEUS mainly presents an uneven centripetal hypoenhancement pattern, which serves as a reference for evaluating the presence of residual tumors. The final diagnosis depends on needle biopsy or excisional biopsy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-526/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-526/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-526/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/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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