Introduction
Primary thyroid lymphoma (PTL), an uncommon
malignancy accounting for 1–5% of thyroid neoplasms and <2.5–7%
of extranodal lymphoma, typically manifests as a rapidly enlarging
neck mass that causes compressive symptoms such as dysphagia,
dyspnea and hoarseness in >70% of patients at diagnosis
(1–5).
The predominant histopathological subtypes of
thyroid lymphoma include diffuse large B-cell lymphoma (DLBCL) and
mucosa-associated lymphoid tissue (MALT) lymphoma (6). Other subtypes, such as follicular
lymphoma, small lymphocytic lymphoma and Burkitt lymphoma, are
infrequently observed, whilst mantle cell lymphoma, T-cell lymphoma
and Hodgkin's lymphoma constitute rare exceptions (7).
Hashimoto's thyroiditis (HT), the most prevalent
autoimmune thyroid disorder, affects 1–2% of the global population
with a 10:1 female predominance (8,9). A
triad of features pathologically defines HT: Diffuse
lymphoplasmacytic infiltration with germinal center formation,
progressive thyroid parenchymal destruction leading to
hypothyroidism and detectable serum antibodies against thyroid
peroxidase (sensitivity, ~95%) and thyroglobulin (specificity,
~80%) (10).
PTL has a pathophysiological association with
autoimmune thyroid disorders, most notably HT (11). Patients with HT demonstrate an
increased risk of developing PTL (12). The low incidence of PTL contributes
to a lack of standardized diagnostic and therapeutic guidelines.
This results in a lack of consensus regarding the diagnosis and
treatment of affected individuals, primarily due to its low
prevalence. Furthermore, the coexistence of PTL and HT is
exceedingly rare. A case of concurrent primary thyroid PTL lymphoma
and HT is described in the present report.
Case report
An 86-year-old female patient with no prior medical
history was admitted to the Department of Cervicothoracic Surgery
at the 331 Hospital (Zhuzhou, China) in October 2024, presenting
with a recurrent cough, shortness of breath, stridor and neck
swelling persisting for ~2 months. Contrast-enhanced CT
demonstrated suspected thyroid malignancy with invasion into the
strap muscles, trachea and right jugular vein, accompanied by
tracheal stenosis, tumor thrombus in the right jugular vein and
bilateral metastatic lymphadenopathy in the central and lateral
cervical regions (predominantly on the right side) (Fig. 1A). A clinical exam confirmed a
palpable, large nodule on the neck. Blood analysis revealed normal
free triiodothyronine (3.56 pmol/l; normal range, 3.10–6.80 pmol/l)
and free thyroxine levels (15.6 pmol/l; normal range, 12.00–22.00
pmol/l). Both anti-thyroglobulin antibodies (915 IU/ml; normal
range, 0–115 IU/ml) and thyroid peroxidase antibodies (73.6 IU/ml;
normal range, 0–34 IU/ml) were elevated, as was thyroid stimulating
hormone (12.2 µIU/ml; normal range, 0.27–4.20 µIU/ml).
Ultrasonography of the thyroid gland exhibited a reduced volume
with diffuse parenchymal alterations, suggestive of HT and
potential atrophy. In the right lobe, a hypoechoic lesion exhibited
ill-defined borders with the trachea, disruption of tracheal rings
and associated right cervical lymphadenopathy with soft tissue
edema (Fig. 1B-D).
The diagnostic challenges in this case primarily
stemmed from the clinical and radiological mimicry of a far more
common aggressive malignancy, anaplastic thyroid carcinoma,
compounded by the underlying background of HT. Due to diagnostic
challenges, a needle biopsy was performed, and the diagnosis was
confirmed by histological examination. The harvested thyroid tissue
was fixed in 10% neutral buffered formalin at room temperature for
24 h and subsequently embedded in paraffin. Sections were cut at a
thickness of 4 µm. For hematoxylin and eosin (H&E) staining,
sections were stained with Mayer's haematoxylin for 5 min and eosin
for 2 min at room temperature. For immunohistochemistry (IHC),
heat-induced antigen retrieval was performed using EDTA buffer (pH
9.0) in a pressure cooker (120°C for 3 min). Endogenous peroxidase
activity was blocked with 3% hydrogen peroxide for 10 min.
Following incubation with primary antibodies [including CD20 (cat.
no. ZM-0039; Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.),
CD10 (cat. no. MAB-0668; Fuzhou Maixin Biotechnology Development
Co., Ltd.), BCL-6 (cat. no. ZM-0011; Beijing Zhongshan Jinqiao
Biotechnology Co., Ltd.), MYC (cat. no. ZA-0555; Beijing Zhongshan
Jinqiao Biotechnology Co., Ltd.) and Ki-67 (cat. no. (10)N17369; Roche Diagnostics GmbH)] at 4°C
overnight and an enzyme-labeled goat anti-mouse/rabbit IgG
conjugate (cat. no. PV-9000; Beijing Zhongshan Jinqiao
Biotechnology Co., Ltd.) system, chromogen detection was performed
using DAB. Sections were counterstained with haematoxylin and
examined under a light microscope at ×400 magnification. The
results of the histopathological analysis of the thyroid lesion
biopsy, combined with immunophenotypic profiling, were consistent
with high-grade B-cell lymphoma, most suggestive of DLBCL of
germinal center origin. The immunophenotypic profile showed the
following negative markers: Thyroglobulin, cytokeratin, thyroid
transcription factor-1, Vimentin, CD3, CD5, Cyclin D1, BCL-2,
anaplastic lymphoma kinase, CD21 and CD30, and the following
positive markers: CD20 (strong/diffuse), Ki-67 (proliferation
index, ~90%), CD10, BCL-6 and MYC (~20% nuclear positivity)
(Fig. 2). The diagnosis of DLBCL
with a germinal center B-cell lineage per the Hans classification
(13)] was conclusively established
by combined morphological assessment, immunophenotypic profiling
and molecular studies (14).
The treatment strategy prioritized the zuberitamab
plus mini-CHOP regimen based on a comprehensive geriatric
assessment, given the patient's advanced age and anticipated
treatment tolerance. zuberitamab (also known as
Anruixi®) is a novel, humanized anti-CD20 monoclonal
antibody independently developed in China (15). It was approved by the National
Medical Products Administration (NMPA) for the treatment of
CD20-positive diffuse large B-cell lymphoma in combination with
chemotherapy, providing a new treatment option in clinical
practice. The patient received four cycles of targeted therapy for
DLBCL, including zuberitamab plus mini-CHOP. In November 2024, the
patient received the first cycle of the zuberitamab plus mini-CHOP
regimen. The specific doses were as follows: 500 mg zuberitamab on
day 0; 600 mg cyclophosphamide on day 1; 20 mg doxorubicin
hydrochloride liposome on day 1; 1.3 mg vincristine (Oncovin) on
day 1; and 50 mg prednisone orally on days 1–5. The chemotherapy
course proceeded smoothly without any specific discomfort and the
patient requested discharge. A total of 24 days after the beginning
the first cycle of the zuberitamab plus mini-CHOP regimen, the
patient began the second cycle. The specific doses were as follows:
500 mg zuberitamab on day 0; 600 mg cyclophosphamide on day 1; 20
mg doxorubicin hydrochloride liposome on day 1; 1.3 mg vincristine
on day 1; and 50 mg prednisone tablets orally on days 1–5. This
chemotherapy course proceeded smoothly without any specific
discomfort and the patient requested discharge.
After two treatment cycles, a repeat neck CT scan
revealed tracheal reopening compared to prior imaging (Fig. 3A). Although the patient experienced
a treatment delay for personal reasons, consolidation therapy with
zuberitamab plus mini-CHOP was subsequently administered in January
and February 2025 at the same doses. A follow-up CT scan in
February 2025 showed mild residual tracheal narrowing (Fig. 3B). The patient is currently
undergoing regular follow-up examinations every 3 months. The
follow-up protocol includes outpatient physical examinations and
neck/chest CT scans to monitor the local and systemic response,
supplemented by monthly telephone consultations to assess the
patient's general well-being. The condition has remained stable
without any further progression.
Discussion
PTL is a rare malignancy, representing 1–5% of
thyroid neoplasms (16). HT,
characterized by lymphocytic infiltration and elevated thyroid
autoantibodies, creates a pro-inflammatory microenvironment
conducive to B-cell clonal expansion (9).
The development of PTL within the inflammatory
milieu of HT is a paradigmatic example of lymphomagenesis driven by
chronic antigenic stimulation. Clinical data underscore this strong
association; studies indicate that HT is present in ~40 to 90% of
PTL cases, who have a nearly 40- to 80-fold increased risk of
developing thyroid lymphoma compared to the general population
(12,14). The present case reinforces the
critical need to consider PTL in patients with HT presenting with a
rapidly enlarging neck mass. A prompt and definitive diagnosis via
ultrasound-guided core needle biopsy (CNB) with
immunohistochemistry is essential to distinguish PTL from thyroid
carcinoma. This distinction is clinically paramount as it dictates
the entire management strategy: While thyroid carcinoma often
necessitates aggressive surgical intervention, PTL is primarily a
systemic disease that responds remarkably well to
immunochemotherapy. Relying solely on clinical presentation or
suboptimal sampling may lead to unnecessary radical surgery for a
condition that could be effectively managed with systemic agents.
As demonstrated in the present case, the rapid initiation of
systemic therapy post-CNB diagnosis can provide immediate relief of
compressive symptoms and avoid the morbidity associated with
high-risk thyroidectomy in elderly patients. A persistent
autoimmune attack leads to the accumulation of lymphoid tissue and
the formation of acquired MALT within the thyroid gland (17,18).
Chronic antigenic stimulation leads to the accumulation of acquired
MALT and potential transformation into aggressive DLBCL, often
driven by MYC or BCL2/BCL6 alterations (19). The immunophenotype of the case in
the present report (germinal center B-cell origin with high Ki-67)
underscores this aggressive potential.
While R-CHOP remains the standard of care for
DLBCL-PTL, the choice of anti-CD20 antibody is evolving.
Zuberitamab, a novel fully humanized anti-CD20 antibody,
demonstrated non-inferiority and superior complete response (CR)
rates in GCB-subtype patients in the Hi-CHOP trial (20). In this study, the zuberitamab plus
CHOP regimen demonstrated non-inferiority to rituximab plus CHOP in
terms of tumor response, with superiority in the CR rate as
assessed by blinded independent central review in the per-protocol
set. With a median follow-up of 29.6 months (range, 0.07–39.1
months), patients treated with the Hi-CHOP regimen showed
marginally improved survival. Notably, patients with the germinal
center B-cell (GCB) subtype appeared to benefit more from Hi-CHOP
compared with those with the non-GCB subtype. The Hi-CHOP regimen
was well tolerated, with no new significant safety signals
detected. Based on these efficacy and safety data, the NMPA of
China approved zuberitamab as an initial therapy for CD20-positive
DLBCL on May 17, 2023. Additionally, a phase 2 study has shown its
activity in primary immune thrombocytopenia, another
B-cell-mediated disorder (15).
However, PTL, a rare extranodal presentation of
DLBCL, has not been specifically evaluated in these trials, and to
date, no dedicated studies or case reports have documented the use
of zuberitamab in PTL. Compared to the traditional Rituximab-based
regimens used in historical cases, zuberitamab offers distinct
clinical advantages and specific limitations. The primary
advantages include its potentially superior response rates in
GCB-subtype patients and its reduced immunogenicity as a fully
humanized antibody, which may minimize infusion-related reactions
in patients with autoimmune dysregulation such as HT (15,20).
Furthermore, the present case demonstrates the feasibility of
combining zuberitamab with dose-adjusted ‘mini-CHOP’ to achieve
rapid tracheal re-expansion in an 86-year-old patient. However, a
notable disadvantage is that zuberitamab, approved in 2023,
currently lacks the extensive decades-long longitudinal data and
global clinical footprint that support the use of Rituximab. The
present case therefore represents, to the best of our knowledge,
the first reported clinical application of zuberitamab in primary
thyroid DLBCL arising from HT. Given that the present patient's
disease falls within the approved indication for zuberitamab and
that the patient's immunophenotype was of GCB origin-a subgroup
that appeared to derive enhanced benefit in the Hi-CHOP trial-its
use is both clinically justified and biologically rational
(20). In this frail, elderly
patient with life-threatening tracheal compression, the zuberitamab
plus mini-CHOP regimen achieved rapid symptomatic relief and
sustained disease control without significant adverse events,
providing preliminary real-world evidence supporting the
feasibility and effectiveness of this novel agent in the
dose-adjusted management of high-risk PTL. Beyond the selection of
specific anti-CD20 antibodies, the therapeutic landscape for DLBCL
is rapidly evolving. Novel agents such as Bruton's tyrosine kinase
inhibitors, BCL-2 antagonists and immunomodulatory drugs are
expanding options for relapsed/refractory disease (21–23).
Furthermore, breakthrough immunotherapies, including bispecific
T-cell engagers (e.g., glofitamab) and chimeric antigen receptor
T-cell therapy, are reshaping outcomes in aggressive B-cell
lymphomas and warrant exploration in PTL (24,25).
Future management will increasingly rely on molecular profiling for
risk stratification and precision-based approaches.
The present case reinforces the need to consider PTL
in patients with HT presenting with a rapidly enlarging neck mass.
Prompt diagnosis via core needle biopsy with immunohistochemistry
is critical for distinguishing it from carcinoma and initiate
appropriate, potentially life-saving systemic therapy. In addition,
the present case highlights several clinically significant aspects
of primary thyroid DLBCL in elderly patients, particularly its
diagnostic challenges, therapeutic considerations in geriatric
oncology and the importance of multimodal management. Bergsma et
al (26) evaluated a
70-year-old female with PTL and HT who achieved confirmed complete
remission after 6 cycles of standard R-CHOP chemotherapy. In a
single-center study of 171 patients with PTL, 90% had concurrent
HT, with CHOP-based regimens yielding a 5-year overall survival
rate of 85% (27). Similarly, in a
multi-center study, 48.4% of PTL patients had HT, with an OS rate
of ~84% following CHOP-based therapy and/or radiation (28). Furthermore, Gu et al
(29) reported the case of a
48-year-old woman admitted with dyspnea and diagnosed with thyroid
lymphoma via fine-needle aspiration (FNA), whose respiratory
distress resolved after 1 day of chemotherapy. Sharma et al
(30) evaluated 75 patients with
thyroid lymphoma, whose main symptoms included neck mass (88.0%),
dysphagia (45.3%) and hoarseness (37.3%), with 70.7% showing
abnormal FNA biopsy results. Finally, Karabachev et al
(31) evaluated three cases of
symptomatic thyroid masses and demonstrated that FNA cytology was a
viable diagnostic modality for PTL. The novelty and new knowledge
contributed by the present case are threefold: i) It is the first
reported use of Zuberitamab, a novel anti-CD20 monoclonal antibody
approved in China for DLBCL, in primary thyroid DLBCL arising from
HT; ii) it demonstrates successful treatment with dose-adjusted
mini-CHOP plus zuberitamab in an advanced-age patient (86 years),
proving feasibility and tolerability in frail, high-risk
individuals; and iii) this case serves as a translation of pivotal
trial data into an ultra-rare extranodal DLBCL subset, offering the
first real-world evidence for this novel agent in the specific
context of PTL with HT. These elements collectively distinguish the
present case from prior reports and advance the literature by
introducing a new treatment option, demonstrating its applicability
in a geriatric GCB-subtype patient and providing a framework for
future investigation.
In conclusion, whilst a limitation of the present
study is that, as a case report, it is inherently biased, it
overall demonstrates that thyroid lymphoma is associated with HT.
As HT is a well-established risk factor for lymphoma development,
close monitoring of affected patients is essential, particularly
for those presenting with a rapidly enlarging neck mass, dysphagia
and/or hoarseness. In such cases, an urgent ultrasound-guided core
needle biopsy should be performed to confirm the diagnosis of
thyroid lymphoma and to maximize diagnostic accuracy and facilitate
the timely initiation of appropriate therapy. In this elderly,
high-risk patient, the zuberitamab plus mini-CHOP regimen
demonstrated notable efficacy and tolerability, underscoring the
clinical relevance of this novel anti-CD20 monoclonal antibody as a
valuable component of first-line immunochemotherapy in such
challenging presentations. With prompt diagnosis and tailored
treatment, patients with PTL can achieve favorable therapeutic
outcomes and encouraging survival rates.
Acknowledgements
Not applicable.
Funding
Funding for this work was provided by Hunan Provincial Natural
Science Foundation-Regional Joint Fund (grant no. 2024JJ7654).
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
FSL conceived the study, performed the primary
clinical data acquisition, and was responsible for the initial
drafting of the manuscript. XYX and KT performed the comprehensive
analysis and interpretation of the patient's clinical course and
conducted the systematic literature review to establish the case's
novelty. XNC provided critical diagnostic resources, specifically
in the acquisition and professional interpretation of the
histopathological and immunohistochemical findings essential for
the definitive diagnosis of primary thyroid lymphoma. CJS and QHY
provided expert clinical guidance, supervised the patient's
diagnostic and treatment strategy, and critically revised the
manuscript for important intellectual content. QHY and CJS confirm
the authenticity of all the raw data and performed the final
verification of clinical records. All authors have read and
approved the final manuscript, and agree to be accountable for all
aspects of the work, ensuring its accuracy and integrity.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the
patient for the publication of their clinical data and any
associated medical images.
Competing interests
The authors declare that they have no competing
interests.
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