Concurrent papillary thyroid carcinoma and incidental cervical lymph node indolent B cell non-Hodgkin lymphoma: clinicopathological features, outcomes, and potential relationships

Abstract

Objective

Concurrent cases of papillary thyroid carcinoma (PTC) and non-Hodgkin lymphoma are infrequent, especially when both are diagnosed simultaneously. This study aims to investigate the clinicopathological characteristics and immunophenotypic features, and clinical outcomes of patients diagnosed with both PTC and incidental cervical lymph node indolent B cell non-Hodgkin lymphoma (CLN-B-NHL), and to explore potential relationships between these two conditions.

Methods

A retrospective analysis was conducted on patients who underwent thyroid lobectomy and were diagnosed with PTC and incidental CLN-B-NHL based on final pathological assessments at a single cancer center from 2015 to 2018. Immunohistochemistry(IHC) staining for BCL-2 and Cyclin D1 was performed, followed by fluorescence in situ hybridization (FISH) for validation. Clinicopathological characteristics and treatment outcomes were systematically recorded and analyzed.

Results

The incidence of incidental CLN-B-NHL among 17,196 PTC patients was 0.04%. The cohort included 7 patients (3 males, 4 females; median age: 50 years), with 5 presenting asymptomatic thyroid/neck masses and 2 detected incidentally. All patients had PTC (American Joint Committee on Cancer, AJCC stage I), and 4 exhibited lymph node metastases. CLN-B-NHL subtypes included 5 follicular lymphomas (FL), 1 mantle cell lymphoma (MCL), and 1 nodal marginal zone lymphoma (NMZL). Notably, 3 patients had both PTC metastases and lymphoma within the same lymph node. IHC revealed weak BCL-2 expression in 4/7 cases of PTC and strong Cyclin D1 positivity in all 7 cases, contrasting with normal tissues. FISH analysis identified BCL2/IGH rearrangements in 4 FL cases and a CCND1/IGH translocation in 1 MCL case, but no such alterations were found in PTC. Treatment included R-CHOP in 4 cases and VR-CAP in 1 case, with 5 patients achieving complete remission and 2 achieving partial remission. The 5-year overall survival rate was 100%.

Conclusions

The concurrent diagnosis of PTC and indolent CLN-B-NHL is extremely rare, with distinct clinicopathological and immunophenotypic features. A subset of cases exhibited coexisting PTC metastases and lymphoma within the same lymph node, though no direct molecular link (e.g., shared BCL2/IGH or CCND1/IGH alterations) was identified. Despite favorable treatment responses and 100% 5-year survival rate in this cohort, the small sample size limits definitive conclusions regarding long-term outcomes. Comprehensive pathological evaluation is critical for PTC with atypical lymph node involvement, and further studies are needed to validate the role of aggressive management in this population.

Introduction

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, predominantly affecting young women, and is generally associated with an excellent prognosis and long-term survival [1, 2]. During routine pathological examination of resected thyroid specimens and dissected lymph nodes, pathologists occasionally identify cases of primary lymphoma involving cervical lymph nodes. These cases typically present as thyroid masses, often without accompanying B symptoms such as low-grade fever, night sweats, or weight loss. While the concurrent presence of PTC and Hodgkin lymphoma (HL) can be readily diagnosed morphologically, non-Hodgkin lymphoma (NHL) is often overlooked. Although coexisting PTC and primary thyroid non-Hodgkin lymphoma (NHL) have been reported [3, 4], their prognosis varies significantly depending on pathological and clinical features, as well as biological behavior [5].

The coexistence of PTC and cervical lymph node indolent B cell non-Hodgkin lymphoma (CLN-B-NHL) is exceedingly rare, particularly when both malignancies are diagnosed simultaneously. While some experts attribute these cases to the random occurrence of two independent cancer entities, whether these represent true collision tumors or incidental coexistence remains debated. This phenomenon warrants further investigation to elucidate potential underlying mechanisms and clinical implications.

In this study, we present a series of 7 cases of concurrent PTC and CLN-B-NHL, providing a comprehensive analysis of their clinicopathological characteristics, immunophenotypic profiles, and genetic features. We also explore treatment outcomes, prognosis, and preliminary correlations between PTC and CLN-B-NHL, aiming to contribute to a better understanding of this rare clinical entity.

Materials and methods

Case selection

With institutional review board approval, we retrospectively reviewed a database of 17,196 patients who underwent initial surgery for thyroid cancer between January 2015 and May 2018. From this cohort, we identified 7 patients diagnosed with CLN-B-NHL based on final pathological analysis.

All patients were initially diagnosed with thyroid nodules and multiple enlarged cervical lymph nodes via ultrasound. They all underwent thyroidectomy and lymph node dissection at the time of diagnosis. None had received preoperative radiotherapy or chemotherapy. Patients with primary thyroid lymphoma were excluded from the study.

The diagnoses and histological classifications of PTC and lymphoma were independently reviewed by two pathologists in accordance with the latest World Health Organization Classification of Tumours [6, 7]. PTC staging was performed using the American Joint Committee on Cancer(AJCC) Staging Manual, 8th Edition [8], while the Ann Arbor staging system was used to evaluate lymphoma prognosis [9]. Due to the small cohort size, we employed descriptive statistics rather than inferential analyses.

Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)

Tissue specimens were fixed in 10% neutral-buffered formalin, dehydrated, and embedded in paraffin. IHC was performed on formalin-fixed, paraffin-embedded tissue sections, either at the time of diagnosis or retrospectively for this study. The following prediluted antibodies were used: CD3, CD5, CD20, CD21, CD23, BCL-6, CD10, Cyclin D1, Ki67, BCL-2, and SOX-11, all obtained from ZSGB-BIO (Beijing, China).

FISH analysis was carried out on formalin-fixed, paraffin-embedded tissue sections according to the manufacturer’s protocols. The FISH probes used included the Vysis IGH/CCND1 DF FISH probe kit and the Vysis BCL2 break-apart FISH probe kit, both obtained from Abbott Molecular Inc. (Downers Grove, IL).

Evaluation of treatment response

Treatment response was assessed using positron emission tomography-computed tomography (PET-CT) or enhanced computed tomography (CT) of the neck, chest, abdomen, and pelvis. Responses were categorized according to the 2014 Lugano criteria [10] into one of the following categories: complete remission (CR), partial remission (PR), stable disease, or progressive disease.

Follow-up

Patient follow-up data were obtained from electronic medical records and telephone communication. The last follow-up date was conducted on December 31, 2023. Follow-up time was defined as the from the patient’s initial visit to the last follow-up. Overall survival time was calculated from the date of diagnosis to the last follow-up date.

Results

Clinical characteristics

The crude incidence rate of incidental CLN-B-NHL among the 17,196 patients diagnosed with PTC was 0.04%. This study included 7 patients (3 males and 4 females) aged between 28 and 56 years (median age: 50 years; mean age: 48.4 years). Five patients presented with asymptomatic thyroid or neck masses (cases 1, 4, 5, 6, and 7), while 2 cases were incidentally detected during physical examination (cases 2 and 3). None of the patients exhibited symptoms typical of lymphohematopoietic tumors, such as fever, night sweats, or weight loss (B symptoms). Neck ultrasound revealed multiple lymphadenopathies in all cases. Surgical procedures included: total thyroidectomy with bilateral cervical lymph node dissection (1 case); thyroidectomy with modified radical neck dissection (3 cases); thyroidectomy with cervical lymph node dissection (3 cases). Clinical data, treatment, pathological assessment, and follow-up details are provided in Table 1.

Table 1 The clinicopathologic characteristics of 7 cases

All patients were diagnosed with PTC (AJCC stage I). Four patients (cases 2, 4, 5, and 7) had lymph node metastases of PTC. The CLN-B-NHL cases consisted of 5 follicular lymphomas (FL), 1 mantle cell lymphoma (MCL), and 1 nodal marginal zone lymphoma (NMZL). Six patients were diagnosed with both PTC and lymphoma at initial presentation. Postoperative 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scans of the head, neck, chest, abdomen, and pelvis were performed within one month. One MCL patient was initially missed and diagnosed two years later following a recurrence of a neck mass. Lymphoma staging revealed stage IIIA disease (involving nodes on both sides of the diaphragm) in 6 patients (85.7%) and stage IVA disease (with bone marrow involvement) in 1 patient (case 1, 14.3%).

Pathological features

For PTC, the thyroid tumors ranged in size from 0.5 cm to 1.7 cm macroscopically. Five cases were confined to the thyroid, with minimal extrathyroid extension in two cases. Microscopic examination revealed two patients with multifocal PTC and five with unifocal disease. Only one patient had a history of Hashimoto thyroiditis. PTC was characterized by papillary structures, ground-glass nuclei, nuclear grooves, overlapping nuclei, intranuclear pseudoinclusions, psammoma bodies (Fig. 1A), and fibrotic sclerosis. IHC confirmed the diagnosis in all cases, with PTC tissues and lymph node metastases testing positive for CK19 and TTF-1. BCL-2 was weakly expressed in 4 PTC cases (4/7, Fig. 1B) but strongly expressed in normal tissues. Cyclin D1 showed strong positivity in all PTC cases (Fig. 1C), contrasting with its low expression in normal tissues. Thus, BCL-2 expression was decreased, and Cyclin D1 expression was increased in PTC compared to normal thyroid tissue.

Fig. 1

(case 4) Morphological characteristics of PTC (H&E, 100x): (A) PTC exhibiting follicular and papillary structures, psammoma bodies (arrow), ground-glass nuclei, intranuclear pseudo inclusion bodies, and nuclear grooves; (B) Weak BCL-2 expression in PTC, in contrast to relatively strong expression in normal tissues; (C) Strong Cyclin D1 expression in PTC, with low expression in normal tissues.

For lymphoma, lymph node capsules were intact in most cases, except for two (cases 1 and 4, Fig. 2A), where neoplastic cells extended beyond the capsule. Lymph node structures were partially preserved in some cases, while others showed complete destruction by neoplastic follicles. Case 2 exhibited preserved paracortical areas, subcapsular sinuses, and medullary sinuses (Fig. 2B). All cases showed strong CD20 expression, confirming a B-cell origin.

Fig. 2

Morphological characteristics for lymphoma(H&E, 100x): (A) Neoplastic cells extending outside the capsule, the normal lymph node architecture was completely effaced (case 1); (B) Lymph node structure showing a neoplastic follicle (arrow), subcapsular sinus, and medullary sinus (case 2), presenting a diagnostic challenge that could easily lead to misdiagnosis; (C) Neoplastic follicle with relatively large cells and frequent nuclear division (arrow). (case 3)

Four cases exhibited follicular or nodular patterns, with small to medium-sized, uniform lymphoid cells lacking mantle zones and polarization. FL-1-2 was diagnosed in cases with lower stages and rare mitotic figures, while FL-3 A (case 3, Fig. 2C) was diagnosed in one case with larger cells, frequent mitoses, and a higher stage. IHC staining for CD10, BCL-6, and BCL-2 was positive (Fig. 3). MCL showed Lymphoid cell hyperplasia consisted of small to medium-sized cells with mildly to markedly irregular nuclei and pathological mitotic figures. Residual germinal centers were observed. IHC showed positivity for Cyclin D1 and SOX-11 (Fig. 4). NMZL showed destruction of the lymph node structure, with narrowed and thinned mantle areas of germinal centers. Nodules consisted of diffusely distributed monocyte-like B cells with moderate cellular atypia, empty cytoplasm, and a slightly hyaline appearance. IHC results included positive staining for Bcl-2 and CD21 (FDC network positive) but negative staining for CD10 and Cyclin D1 (Fig. 5).

Fig. 3

(Case 4) H&E, immunohistochemical, and FISH analysis of PTC coexisting with FL(100x) (red arrow: PTC, black arrow: FL). PTC shows weak positivity for BCL-2. FL had a low Ki67 proliferation rate. (A) H&E; positive for (B) CD20, (C) BCL2, (E) CD10, (F) BCL6, (G) Ki67. FISH reveals BCL2 (yellow arrow) rearrangements in FL (D), with no genetic rearrangements in PTC (H).

Fig. 4

(Case 5) H&E, immunohistochemical, and FISH analysis of PTC coexisting with MCL(100x) (red arrow, PTC; black arrow, MCL). (A): PTC coexisting with MCL (H&E). (B) MCL shows positivity for Cyclin D1. (C) FISH shows CCND1/IGH(yellow arrow) translocation in MCL. (D) MCL shows positivity for SOX-11. (E) H&E for PTC. (F) PTC shows high positive for Cyclin D1. (G) FISH shows no genetic rearrangements in PTC(yellow arrow). (H) Low Ki-67 proliferation rate in MCL.

Fig. 5

(Case 7) H&E, and immunohistochemical analysis of NMZL (100x). (A) H&E. (B) IHC staining for CD20. (C) Low Ki-67 proliferation rate. (D) Positive for CD43, (E) Positive for BCL2. (F) Positive for CD21(FDC positive). (G) Negative for CD10 (H) Negative for Cyclin D1.

Indolent lymphomas predominated (5/7), including 4 low-grade FL cases and 1 NMZL case, with Ki67 proliferation indices of 10–20% (Figs. 2 and 4). Aggressive tumors included one FL-3 A case (Ki67: 50%) and one MCL case (Ki67: 10%) with aggressive progression (Fig. 4).

Four cases showed PTC metastases in cervical lymph nodes. In three patients, metastatic PTC components (Figs. 3 and 4, H, amp and E, red arrow) and lymphoma components (Figs. 3 and 4, H, amp and E, black arrow) were observed within the same lymph node. Case 2 had one metastatic lymph node with FL involvement, case 4 had 10 of 13 metastatic lymph nodes with FL involvement, and case 5 had one of three metastatic lymph nodes with MCL involvement.

Molecular features

To investigate the relationship between PTC and coexisting FL/MCL, FISH was performed to detect BCL2 and Cyclin D1 translocations. t(14;18)/IGH:: BCL2 gene rearrangement was identified in 4 FL cases (Fig. 3), and t(11;14)/IGH::CCND1 translocation was found in 1 MCL case (Fig. 4). No BCL2/IGH or CCND1/IGH translocations were detected in PTC cases. IHC and FISH results are summarized in Table 2.

Table 2 Immunohistochemistry (IHC) and FISH (BCL-2/CCND1) of 7 cases

Treatment and Follow-up

Four patients received the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; cases 1, 4, 6, and 7). One MCL patient was treated with VR-CAP (similar to R-CHOP but with bortezomib replacing vincristine; case 5). Two patients did not receive treatment. Clinical follow-up ranged from 68 to 120 months. PET scans showed no persistence or recurrence of either neoplasm. Five patients achieved complete remission, while two achieved partial remission (cases 4 and 5). The 5-year overall survival, disease-specific survival, and recurrence-free survival rates were all 100%.

Discussion

In this case series, we report seven patients who underwent thyroidectomy for localized well-differentiated thyroid cancer and were incidentally diagnosed with CLN-B-NHL on final pathological analysis. Our findings contrast with previous studies that have reported the rare coexistence of PTC and thyroid lymphoma, albeit rarely. Notably, studies have shown an association between primary thyroid lymphoma and chronic lymphocytic thyroiditis, whereas our cases did not exhibit such a correlation. Furthermore, the predominance of indolent B-cell lymphomas, particularly FL, in our cohort is in contrast to the aggressive subtypes (e.g., diffuse large B-cell lymphoma [DLBCL]) commonly observed in primary thyroid lymphoma [11,12,13]. These differences highlight the importance of distinguishing between primary thyroid lymphoma and CLN-B-NHL coexisting with PTC.

Most patients in our study were diagnosed at advanced stages, which highlights the need for pathologists and clinicians to carefully evaluate clinical history and imaging findings when encountering such rare cases. In particular, the presence of small-B cell lymphoma can be easily overlooked. Pathologists should exercise caution when evaluating lymph nodes for PTC metastasis, particular in cases where normal germinal centers are nearly absent. IHC should be utilized for confirmation. All our cases were diagnosed in this manner. In the MCL case, residual germinal centers were observed, suggesting later nodal involvement, and the diagnosis was only established upon retrospective review.

The selection of BCL-2 and Cyclin D1 as targets for investigative was driven by their established roles in both PTC and NHL pathogenesis. Our study identified decreased BCL-2 expression and increased Cyclin D1 expression in PTC tissues, consistent with previous findings by Liu et al. [14]. This confirmed the critical role of these molecules in PTC progression. Notably, BCL2/IGH rearrangements are pathognomonic for FL [15], while CCND1/IGH translocations define MCL [17]. This dual relevance in both epithelial and lymphoid malignancies prompted us to investigate whether shared molecular alterations could underlie the coexistence of PTC and CLN-B-NHL. However, FISH analysis revealed that neither BCL 2/IGH rearrangement in FL or CCND1/IGH translocation in MCL were present in PTC cases, suggesting that despite phenotypic coexistence, the molecular mechanisms of PTC and NHL may operate independently.

Recent studies have demonstrated distinct molecular mechanisms underlying BCL-2 and cyclin D1 dysregulation in FL and PTC. In FL, BCL-2 overexpression is primarily driven by chromosomal rearrangements, particularly the characteristic t(14;18)(q32;q21) translocation leading to BCL2/IGH gene fusion [15]. In contrast, BCL-2 expression in PTC is more frequently associated with gene polymorphisms or transcriptional regulation mechanisms [16]. Similarly, while cyclin D1 overexpression in MCL is linked to the t(11;14)(q13;q32) translocation resulting in CCND1/IGH rearrangement CCND1/IGH translocation [17], in PTC, it primarily occurs through alternative mechanisms such as gene amplification [18] or epigenetic modifications [19]. These differential molecular profiles highlight the distinct oncogenic pathways involved in lymphoid versus epithelial malignancies.

Our findings revealed tissue-specific dysregulation, with reduced BCL-2 and elevated Cyclin D1 in PTC, contrasting with translocation-driven overexpression in NHL. This indicates independent oncogenic mechanisms rather than a unified molecular pathway, supporting the collision tumor hypothesis [20] but also suggesting the potential for microenvironmental interactions that warrant further investigation [21]. Recent studies have demonstrated that PTC development is closely associated with BRAF gene mutations and environmental factors such as radiation exposure, while the pathogenesis of intranodal non-Hodgkin lymphoma may be linked to immune dysregulation, chronic inflammation, and viral infections [22, 23]. Although no common environmental etiology has been identified for both PTC and CLN-B-NHL, environmental factors may serve as shared risk factors for these malignancies. Chronic inflammation and immune dysregulation may provide a microenvironment conducive to tumorigenesis, while prolonged exposure to certain chemicals and pollutants may also increase disease risk.

Moreover, the Ki67 proliferation index plays a crucial role in assessing the grade and prognosis of CLN-B-NHL [24]. Among the cases studied, four low-grade FL cases exhibited Ki67 proliferation index of 10–20%, one MCL case showed a Ki67 index of 10%, and one FL-3 A case without PTC metastasis had a Ki67 index of 50%. This findings suggest that PTC is more likely to metastasize to cervical lymph nodes containing primary NHL with low or stable low proliferation index. Close follow-up is recommended, particularly for patients with aggressive subtypes or high Ki67 indices.

Notably, we found that three patients exhibited both PTC metastases and lymphoma within the same lymph node, of which two cases were FL and one was classic MCL. Awareness of this potentially confounding genetic combination is critical to avoid misinterpreting these features as disease progression or resistance to treatment, which could significantly affect disease management and patient prognosis.

Individualized treatment strategies should be implemented for patients with coexisting PTC and NHL. Surgical resection of the thyroid and affected lymph nodes remains the primary treatment, with the need for adjuvant chemotherapy determined by the aggressiveness of lymphoma. For instance, Case 3, with FL-3 A (Ki67 index: 50%) received post-operative R-CHOP chemotherapy, while Case 2, with low-grade FL, did not. Treatment regimens should be tailored according to lymphoma subtype and stage, as shown in Case 5, where VR-CAP was administered instead of R-CHOP for MCL. Although all patients achieved favorable outcomes in this series, the lack of standardized treatment protocols and heterogeneity in lymphoma subtypes (indolent vs. aggressive) limits the generalizability of these findings. The observed 100% survival rate may reflect the predominance of low-grade lymphomas (5/7 cases) rather than therapeutic efficacy. Additionally, the median follow-up of 68–120 months may not be long enough to detect late recurrences or secondary malignancies.

This study has several limitations. First, its retrospective design and single-center cohort introduce potential selection bias. Second, the extremely low incidence (0.04%) and small sample size (n = 7) restrict statistical power to detect subtle associations. Third, the absence of molecular profiling beyond BCL2 and CCND1 limits mechanistic insights. Finally, long-term outcomes beyond 5 years remain uncertain, particularly for indolent lymphomas with potential late recurrences. The rarity of PTC and CLN-B-NHL coexistence necessitates larger, multicenter studies to validate our findings. Future research should focus on: (1) Elucidating the molecular mechanisms underlying the coexistence of PTC and CLN-B-NHL, using techniques such as single-cell sequencing and spatial transcriptomics, and (2) Investigating the role of the tumor microenvironment in promoting the simultaneous development of these malignancies.

Conclusions

This study highlights the rare coexistence of PTC with primary lymph node lymphoma. During cervical lymph node dissection for metastatic evaluation, lymphoma may be overlooked or misdiagnosed as reactive hyperplasia or lymphadenitis. Given the diagnostic challenges posed by this uncommon dual pathology, accurate recognition is critical. We emphasize the need for heightened vigilance among pathologists—particularly those without specialized hematopathology training—when assessing lymphadenopathy in thyroid cancer patients.

In conclusion, while our findings underscore the diagnostic challenges and clinicopathological uniqueness of concurrent PTC and CLN-B-NHL, the incidental nature of these cases and favorable survival outcomes emphasize the need for cautious interpretation. Future multicenter studies with extended follow-up and integrated multi-omics approaches are essential to clarify the biological interplay between these malignancies and optimize management strategies.