Diagnostic Challenge of Contralateral Intranodal Thyroid Inclusions in a Patient With Synchronous Oropharyngeal and Papillary Thyroid Carcinoma: A Case Report

ABSTRACT

Distinguishing benign intranodal thyroid inclusions from metastatic papillary thyroid carcinoma is vital in synchronous malignancies to prevent overstaging. Integrating morphological analysis with BRAF VE1 immunohistochemistry ensures diagnostic precision to align management with the true pathological stage, avoiding unnecessary aggressive interventions like total thyroidectomy and radioactive iodine therapy.

1. Introduction

The development of second primary malignancies in head and neck cancer patients occurs at an annual rate of 2%–4%, with synchronous primaries defined as those identified within 6 months of the initial diagnosis [1]. Human papillomavirus (HPV)‐associated oropharyngeal squamous cell carcinoma (OPSCC) now accounts for up to 70% of cases in certain regions [2]. Concurrently, papillary thyroid carcinoma (PTC) is the most prevalent endocrine malignancy, often identified incidentally during staging for unrelated head and neck cancers [3, 4]. When thyroid tissue is discovered within cervical lymph nodes in the setting of known PTC, it is traditionally interpreted as regional metastasis, which significantly alters clinical staging and dictates aggressive intervention.

However, benign intranodal thyroid inclusions (ITIs) represent a critical diagnostic pitfall that can mimic metastatic disease [5]. Differentiating ITIs from true metastasis is challenging in patients with synchronous primaries, as dual malignancies complicate nodal interpretation. While recent guidelines emphasize treatment de‐escalation for low‐risk thyroid cancers, the risk of overstaging due to ITIs remains a concern. There is limited literature on integrating specific molecular markers and morphological criteria to resolve such diagnostic challenges. We report a rare case of synchronous HPV‐positive oropharyngeal and PTC presenting with a significant diagnostic dilemma regarding contralateral cervical lymphadenopathy.

2. Case Presentation

A 52‐year‐old female presented in September 2024 with a two‐month history of left infra‐auricular pain and swelling. Initially managed as an infectious mass with antibiotics, the lesion remained refractory. Physical examination revealed an indurated mass at the left tonsillar fossa. A punch biopsy confirmed non‐keratinizing squamous cell carcinoma (SCC) with positive p16 immunohistochemical (IHC) staining. Head and neck CT showed a 3.0 cm enhancing mass in the left tonsil (Figure 1a,b) and an enlarged ipsilateral Level II lymph node with cystic degeneration (Figure 1c,d). PET/CT confirmed a hypermetabolic left tonsil lesion (SUV max: 17.15) and a necrotic left Level II lymph node (SUV max: 10.50). Furthermore, PET/CT incidentally identified a 1.0 cm hypermetabolic nodular lesion (SUV max: 50.89) in the right thyroid lobe, suspected to be a synchronous primary malignant tumor (Figure 2).

FIGURE 1.

Pretreatment contrast‐enhanced CT images. (a) Axial and (b) coronal views demonstrating asymmetric enlargement of the left tonsil (white arrow); the lesion measures approximately 3.0 cm in its maximal diameter. (c) Axial and (d) coronal views revealing a 3.6‐cm lymph node with prominent cystic degeneration at the left cervical Level II (white arrow), highly suggestive of regional metastasis.

FIGURE 2.

Axial PET/CT image demonstrating a hypermetabolic nodule in the right thyroid lobe (white arrow), measuring approximately 1.0 cm with a maximum standardized uptake value (SUV_max) of 50.89. PET/CT: Positron emission tomography/computed tomography.

3. Management and Course

The clinical stage for the p16‐positive OPSCC was established as cT2N1M0 [6]. The patient underwent five cycles of induction chemotherapy (cetuximab, cisplatin, and docetaxel) starting October 2024. During treatment, antiviral prophylaxis with entecavir was initiated for chronic hepatitis B. The course was complicated by an episode of febrile neutropenia, requiring hospitalization and a dose reduction of docetaxel. A follow‐up CT on December 26, 2024, evaluated the therapeutic response using RECIST 1.1 criteria [7]. Imaging revealed complete resolution of the left tonsillar mass (Figure 3b, compared to baseline in Figure 3a) and the left Level II lymph node (Figure 3d, compared to baseline in Figure 3c).

FIGURE 3.

Contrast‐enhanced CT scans demonstrating response to induction chemotherapy. (a) Baseline axial image showing the primary tumor in the left palatine tonsil (white arrow). (b) Follow‐up scan after induction chemotherapy demonstrating complete interval resolution of the mass. (c) Pretreatment view of a cystic metastatic lymph node at left cervical Level II (white arrow). (d) Posttreatment image confirming resolution of the regional lymphadenopathy.

To further evaluate the thyroid lesion, neck ultrasonography was performed on January 2, 2025, which revealed an ill‐defined, hypoechoic, and heterogeneous solid nodule measuring 10.1 × 10.2 × 11.2 mm in the right lobe (Figure 4a,b). Fine‐needle aspiration (FNA) indicated atypia of undetermined significance (AUS), Bethesda Category III [8]. Following a multidisciplinary discussion involving a hematology‐oncology specialist and the patient, a decision was made to prioritize the management of the oropharyngeal cancer. The patient subsequently underwent transoral robotic surgery (TORS) for the left tonsillar carcinoma and a left modified radical neck dissection on January 18, 2025. Pathological analysis confirmed residual HPV‐associated SCC in the tonsil, while all resected regional lymph nodes were negative for SCC. The pathological stage for the OPSCC was ypT1N0, cM0 (Stage I) [6].

FIGURE 4.

Preoperative thyroid ultrasonography. Images in both (a) transverse and (b) longitudinal planes of the right thyroid lobe demonstrate an ill‐defined, hypoechoic, and heterogeneous solid nodule. The lesion measures approximately 10.1 × 10.2 × 11.2 mm, with sonographic features highly suggestive of malignancy.

Intriguingly, one lymph node at Level II and one at Level III contained microscopic foci of thyroid tissue in the subcapsular sinuses, consisting of follicles with colloid production (Figure 5a). No definitive cytological features of conventional PTC or psammoma bodies were identified. IHC staining for TTF‐1 and PAX‐8 confirmed thyroid origin (Figure 5b,c), but BRAF VE1 staining was negative. Because the primary thyroid lesion was right‐sided and the nodal tissue was contralateral with mild atypia, regional metastasis (N1b) was suspected. Following shared decision‐making, a total thyroidectomy was performed on February 19, 2025. Pathological examination identified a nodule measuring 0.7 × 0.5 × 0.4 cm in the right thyroid lobe, which was histologically confirmed as a classic PTC (Figure 6a,b). Initially, the synchronous PTC was classified as pT1aN1bM0 (Stage I) [9]. The patient completed adjuvant radiotherapy (60 Gy) from March to April 2025. Adjuvant radioactive iodine (RAI) therapy (90 mCi) was administered on July 4, 2025.

FIGURE 5.

Histopathological and immunohistochemical findings of the resected cervical lymph nodes. (a) H&E staining (100×) revealing microscopic foci of thyroid follicles within the subcapsular sinus; the follicles are well‐formed with intraluminal colloid and lack the classic features of papillary thyroid carcinoma, such as papillary structures or psammoma bodies. (b, c) Immunohistochemical analysis (200×) confirms the thyroid origin of these cells, demonstrating strong nuclear expression of (b) TTF‐1 and (c) PAX‐8.

FIGURE 6.

Histopathological analysis of the total thyroidectomy specimen. (a) Low‐power magnification (H&E, 40×) showing the tumor nodule located in the right thyroid lobe. (b) High‐power view (H&E, 400×) demonstrating classic histopathological features of papillary thyroid carcinoma, including intranuclear pseudoinclusions, nuclear elongation, and nuclear grooves. These morphological findings are consistent with the diagnosis of classic papillary thyroid carcinoma.

4. Pathological Reexamination

Guided by recent insights on ITIs by Chuang et al. [10], the medical team reevaluated the left Level II and III nodes. The reassessment led to the reclassification of the nodal follicles as benign ITIs. This conclusion was supported by the lack of nuclear hallmarks in the nodes compared to the primary tumor (Figure 7a,b). IHC discordance was definitive: the primary tumor exhibited strong BRAF VE1 positivity, while the ITIs were negative (Figure 7c,d). Consequently, the PTC was revised to pT1aN0M0 [9].

FIGURE 7.

Comparative analysis of the primary thyroid tumor and thyroid follicles within the resected cervical lymph node. (a, b) Hematoxylin and eosin (H&E) staining (400×). (b) The primary thyroid tumor demonstrates classic histopathological features of papillary thyroid carcinoma, including nuclear elongation, grooves, and intranuclear pseudoinclusions. In contrast, (a) the thyroid follicles within the lymph node lack these diagnostic nuclear features. (c, d) BRAF VE1 immunohistochemistry (400×). (d) The primary tumor exhibits diffuse cytoplasmic positivity for BRAF VE1, whereas (c) the intranodal thyroid tissue is entirely negative. This immunohistochemical discordance provides definitive evidence to reclassify the nodal findings as benign intranodal thyroid inclusions rather than metastatic disease.

5. Conclusion and Results (Outcome and Follow‐Up)

At the most recent clinical follow‐up, a comprehensive evaluation confirmed a favorable prognosis for both primary malignancies. Surveillance head and neck CT imaging and PET/CT scan demonstrated no evidence of local recurrence or distant metastasis in the oropharynx, the thyroid bed, or the cervical lymph nodes. The patient remains clinically stable and continues on thyroid hormone replacement therapy under regular surveillance by a multidisciplinary team.

6. Discussion

Management of synchronous head and neck malignancies requires a nuanced approach. Our patient presented a complex challenge involving p16‐positive OPSCC and synchronous PTC, centered on the nature of contralateral thyroid tissue. For HPV‐positive OPSCC, TORS is favored for T1–T2 tumors to optimize functional recovery in speech and swallowing. Induction chemotherapy (docetaxel, cisplatin, and cetuximab) can effectively downsize primary tumors and regional metastases, potentially allowing for treatment de‐escalation [11]. Our patient achieved near‐complete remission following this regimen.

Beyond the primary oropharyngeal tumor, the management of the synchronous thyroid lesion required a detailed evaluation of its molecular profile. BRAF mutations are identified in approximately 60% of PTC cases [12], a figure that increases to 70% in Asian populations [13]. The BRAF V600E mutation accounts for over 90% of all BRAF mutations in thyroid cancer [12, 14], and the BRAF VE1 IHC stain serves as a highly specific tool for detecting this mutant protein in tissue samples. While thyroid follicles in contralateral nodes initially suggested metastasis (N1b), Chuang et al. [10] established that ITIs can occur in lateral nodes regardless of primary PTC status. The diagnostic hallmarks of ITIs include the absence of nuclear pseudoinclusions and negative IHC for BRAF VE1, HBME‐1, and galectin‐3 [10]. In this case, the IHC discordance between the primary tumor (BRAF positive) and nodes (BRAF negative) confirmed the benign nature of the inclusions.

Accurately differentiating N0 from N1 status is vital to avoid overtreatment. According to the ATA 2025 guidelines, thyroid lobectomy is the recommended initial procedure for low‐risk cT1N0M0 tumors [15]. The initial decision for total thyroidectomy and RAI was driven by N1b suspicion. However, re‐evaluation revised the stage to pT1aN0, for which RAI is not routinely recommended [15]. Had the benign nature of the ITIs been established preoperatively through molecular testing or second‐look FNA with thyroglobulin washout, a conservative lobectomy would have preserved thyroid function. Integrating morphological analysis with markers like BRAF VE1 is essential for preventing overstaging. In summary, a cautious diagnostic approach is fundamental to tailoring individualized management strategies and adhering to the latest evidence‐based treatment guidelines.

Author Contributions

Bo‐Cheng Rau: conceptualization, data curation, formal analysis, writing – original draft, writing – review and editing, methodology. Yun‐An Chen: conceptualization, methodology, data curation, formal analysis, supervision, writing – original draft, writing – review and editing. Chun‐Wei Huang: conceptualization, methodology, data curation, formal analysis, supervision, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Consent

Written informed consent for publication of clinical details and images was obtained.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.