Is classic papillary thyroid carcinoma definitely an “indolent cancer”?—a case of locally advanced classic occult papillary thyroid carcinoma: a case report

Introduction

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy with growing slowly, a low degree of malignancy, and a favorable prognosis, which considered as an “indolent cancer”; especially, classic PTC, accounting for approximately 80% of thyroid malignancies, is classified as non-invasive subtype and has a better prognosis than other subtypes (1). However, some low-risk PTCs still have disease progression at an early stage. Herein, we report a case of classic occult PTC less than 1 cm in diameter with an enlarged lymph node in neck as the primary symptom. The complete clinical diagnosing and treating process of this case are present, as well as our discussion and reflections on the approach to the diagnosis and treatment of PTC less than 1 cm in diameter. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-81/rc).

Case presentation

A 55-year-old male was admitted to the Qinghai University Affiliated Hospital on June 13, 2023 complaining an enlarged lymph node in right neck for 3 days. The patient reported that a right-sided neck mass was noticed himself incidentally 3 days ago without pain, fever and other special discomfort, and there was no history of exposure to ionizing radiation and family history of thyroid cancer.

Physical examination showed no abnormalities in the thyroid glands, but a hard 3 cm × 2 cm mass was palpated in right neck with poor mobility and no tenderness. Blood routine tests showed total white blood cell count was 5.65×10⁹/L (normal range: 3.50–9.50 ×10⁹/L); neutrophil count was 3.83×10⁹/L (normal range: 1.80–6.30 ×10⁹/L); lymphocyte count was 1.36×10⁹/L (normal range: 1.10–3.20×10⁹/L); and blood platelet count was 134×10⁹/L (normal range: 125–350 ×10⁹/L); thyroid function showed thyroid stimulating hormone (TSH) was 2.93 uIU/mL (normal range: 0.35–4.94 µIU/mL); free triiodothyronine (FT3) was 2.77 pg/mL (normal range: 1.71–3.71 pg/mL); free thyroxin (FT4) was 1.09 ng/dL (normal range: 0.7–1.48 ng/dL); thyroglobulin (Tg) was 75.39 ng/mL (normal range: 3.5–77 ng/mL); thyroglobulin antibody (TgAb) was 1.62 IU/mL (normal range: 0–4.11 IU/mL); and thyroid peroxidase antibody (TPOAb) was 3.03 IU/mL (normal range: 0–5.61 IU/mL); both two tests showed no abnormalities.

Neck ultrasound (US) showed a 36 mm × 29 mm enlarged lymph node (Figure 1A) detected in III region of right neck with unclear cortico-medullary demarcation and lymph node hilum structure disappearing and no abnormalities in thyroid glands (Figure 1B); neck computed tomography (CT) and contrast-enhanced CT showed a 28 mm × 25 mm low-density enlarged lymph node in the medial aspect of the right sternocleidomastoid muscle, which was poorly demarcated from the surrounding tissues (Figure 2A), and there were no abnormalities in thyroid glands (Figure 2B); the patient had underwent fine needle aspiration cytology (FNAC) of the enlarged right cervical lymph node on June 10, 2023 in our Thyroid Surgery Clinic and the pathology of FNAC showed a large number of adenoidally arranged cell clusters with well-differentiated cells, and metastatic carcinoma was first considered. In order to further determine the primary lesion, fine-needle aspiration biopsy (FNAB) of the enlarged lymph node was performed on June 16, 2023 and the pathology showed tumor cells infiltration in the connective tissue, and immunohistochemistry (IHC) and histomorphology were consistent with metastatic carcinoma with a high likelihood of follicular epithelial origin of thyroid gland (Figure 3A,3B); IHC revealed that tumor cells were positive for AE1/AE3, CK7, Tg (Figure 3C), Galectin-3, TTF-1 (Figure 3D), CD34 (vascular), CK19 and PAX8 (Figure 3E), and negative for NapsinA, CK20, Villin, TRPS 1, NKX 3.1 and P504s; the Ki67 was 10%. Therefore, preoperative diagnosis was lymph node metastasis, which originated from thyroid possibly.

Figure 1 Neck ultrasound: (A) showed an enlarged lymph node detected in III region of right neck with unclear cortico-medullary demarcation and lymph node hilum structure disappearing; (B) showed no abnormalities detected in thyroid glands.

Figure 2 Neck contrast-enhanced CT: (A) showed an enlarged lymph node in the medial aspect of the right sternocleidomastoid muscle, which was poorly demarcated from the surrounding tissues; the red arrow refers to the enlarged lymph node; (B) showed no abnormality detected in the thyroid glands. CT, computed tomography.

Figure 3 HE and IHC staining of the enlarged lymph node: (A) showed tumor cells infiltration in the connective tissue (×40); (B) showed tumor cells infiltration in the connective tissue (×100); (C) showed Tg(+) (×100); (D) showed TTF-1(+) (×100); (E) showed PAX8(+) (×100). HE, hematoxylin-eosin; IHC, immunohistochemistry.

Then the enlarged lymph node resection in right neck + right thyroid lobectomy + freezing were performed; intraoperatively, we observed the enlarged lymph node invaded the right internal jugular vein and right sternocleidomastoid muscle; freezing pathology of right thyroid lobe showed a gray nodule with 0.3 cm at a distance of 0.5 cm from the thyroid capsule, and histomorphology considered malignant; hence, further left thyroid lobectomy + isthmus resection + lymph nodes and adipose tissue dissection in II, III, IV, V and VI regions in right neck + complete resection of the invaded right sternocleidomastoid muscle and right internal jugular vein were performed. Postoperative pathology diagnosis was PTC (classic) (Figure 4A-4C) without thyroid capsule invasion; lymph node metastasis (Figure 4D) in II, III, IV and V regions was (3/6), and vessels and striated muscle tissues involved (Figure 4E); lymph node metastasis in region VI was (1/6). According to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging of thyroid cancer, the pathological staging of this patient was pT1aN1bM0, stage II. Polymerase chain reaction (PCR) revealed mutation of the BRAF V600E gene.

Figure 4 Postoperative HE staining: (A) showed classic PTC (×40); (B) showed classic PTC (×100); (C) showed tumor cells of classic PTC (×400); (D) showed metastatic lymph node (×40); (E) showed metastatic lymph node invaded surrounding striated muscle tissues (×100). HE, hematoxylin-eosin; PTC, papillary thyroid carcinoma.

After surgery, calcium supplements were given immediately. The patient was given 150 mCi ¹³¹l remnant ablation + adjuvant therapy at 3-week postoperatively. The post-therapy whole-body scan (WBS) showed small amount of radionuclide slightly concentrated in the neck and no obvious concentration of radionuclides in lungs and bones (Figure 5). And then taking levothyroxine tablets orally (100 µg, QD) for TSH suppression. At 6-week follow-up postoperatively, the thyroid function showed Tg was 0.21 ng/mL, TSH was 64.5 µIU/mL, FT3 was 0.95 pg/mL and FT4 was 0.4 ng/dL; then the dose of levothyroxine tablets was adjusted to 150 µg, QD. Six months post-operative, the patient had a fair general condition with no obvious discomfort; and his outpatient review of thyroid function showed Tg was 0.04 ng/mL, TSH was 0.09 µIU/L, FT3 was 2.79 pg/mL, FT4 was at 1.22 ng/dL and parathyroid hormone (PTH) was 56.20 pg/mL (normal range: 15–65 pg/mL).

Figure 5 The post-therapy WBS showed small amount of radionuclide slightly concentrated in the neck and no obvious concentration of radionuclides in lungs and bones. WBS, whole-body scan.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). 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.

Timeline

The patient was admitted to the Department of Oncology Surgery of Qinghai University Affiliated Hospital on June 13, 2023. During the 1^st–12^th days after hospitalization, laboratory examination and preoperative evaluation were performed. He underwent surgery on June 26, 2023. The 14th–16th days were postoperative duration. The duration from four weeks after operation to six months is follow-up period (Figure 6).

Figure 6 Timeline of the case.

Discussion

As recommended in current guidelines (2-5), active surveillance (AS) is considered an alternative to immediate surgery for some low-risk PTCs less than 1 cm. However, 4.7% of the low-risk PTC patients less than 1 cm who performed AS at Kuma Hospital still presented tumor progression during AS (124 cases showed tumor enlarging, 27 cases showed new lymph nodes metastasis and 1 showed distant metastasis). It is rare, but a very small portion do progress. In this case, the patient’s first symptom was an enlarged lateral cervical lymph node, but no thyroid lesions were detected by US and CT preoperatively, and the postoperative pathology confirmed classic PTC, which indicated that this patient was a case of occult PTC; moreover, even though the tumor was classic occult PTC, the metastatic lymph node had invaded the internal jugular vein and the sternocleidomastoid muscle and progressed to a locally advanced stage before detecting the primary thyroid foci, suggesting its high malignant potential. Therefore, is classic PTC absolutely an “indolent cancer”? Before localized progression occurs, how to properly evaluate the malignant degree of classic PTC less than 1 cm and accurately judge the disease progression is a significant challenge for thyroid surgeons in developing management measures.

In recent years, the incidence of PTC in China has increased rapidly, and in order to avoid overtreatment and missing surgery timing, early determining the biological parameters of PTC with invasive biological behavior is crucial to its therapeutic management. According to the latest World Health Organization classification of PTC (6), tall cell, hobnail and columnar cell PTC subtypes are classified as invasive subtypes and surgical resection is the preferred treatment; although classic PTC is classified as non-invasive subtype, its potential malignant biological behaviors cannot be ignored, especially how to identify the malignancy of classic PTC less than 1 cm and how to avoid overtreatment deserve further study. Thyroid Imaging Reporting and Data System (TI-RADS) of American College of Radiology (ACR) and Fine Needle Aspiration Cytology (FNAC) are effective evaluation tools for detecting PTC preoperatively. Scappaticcio et al. (7) reported a significant difference in ACR TI-RADS categorization between classical and non-classical PTC subtypes, and this was mainly for PTCs ≥1 cm. In contrast, when only considering invasive or noninvasive PTC subtypes, preoperative cytology examination reliably predicted classical PTC versus non-classical PTC subtypes, regardless of PTC diameter. Therefore, clinicians have a high likelihood of finding classic PTC on postoperative histology when they faced with high-risk thyroid nodules and suspected classic PTC cytologically, and this likelihood guides their choice of early treatment modalities.

At present, the malignancy of classic PTC less than 1 cm is mainly evaluated by detecting specific molecular markers, and identifying molecular markers, which can predict early progression to late adverse outcome of classic PTC, is crucial for precise therapy. Mutations of BRAF gene, RAS gene and TERT promoter and RET gene rearrangements in PTC indicate a high degree of malignancy and poor prognosis, and surgery is recommended as soon as possible (8). Besides, novel molecular markers associated with the malignancy of PTC have been reported recently. Some scholars suggested that the preoperative detection of overexpression of calcium binding protein S100A4, cyclin D1 and C-myc may be very valuable in determining the treatment choice of PTC (9,10); Beck et al. concluded that a molecular subtype of classic PTC characterized by high PROM1 expression, high ALDH1A3 expression and low CD24 expression has a high degree of malignancy and even an lower recurrence-free survival rate (11); Napoli et al. showed that detecting the abnormal expression of several microRNAs (such as miR-154-3p, miR-299-5p, miR-376a-3p, etc.) in PTC could be valuable in predicting the presence or absence of lymph nodes metastasis at an early stage (12); the findings of di Masi et al. showed that carotenoid accumulation is a specific marker of PTC, and the downregulation of retinoic acid (RA)-related pathways may also be associated with the progression and severity of PTC (13). We have selected 10 classic PTC patients less than 1 cm in diameter without lymph node metastasis, and used immunohistochemistry to detect the expression of the above genes; the results suggesting that compared with these 10 patients, the expression of Cyclin D1 and C-myc in this case was significantly higher while the expression of CD24 was clearly lower, which, in combination with the BRAF V600E gene mutation, indicated that the degree of malignancy in this classic PTC patient was still high. This may suggest that detecting molecular markers and their specific combinations preoperatively related to the degree of malignancy is of great significance for treatment options for classic PTC <1 cm.

Conclusions

In a word, it has been routinely widely accepted that classic PTC is an indolent cancer with a low degree of aggressiveness and slow progression, resulting in some patients whose lesions were less than 1 cm in diameter not being operated on immediately and losing the best opportunity for treatment. This case implies that some classic PTC also have a high malignant potential, and the traditional examination techniques combined with relevant molecular marker detection are helpful to determine the degree of malignancy, so as to develop a precise and individualized treatment plan (early operation or AS) for patients with low-risk PTC <1 cm.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (No. 82060485).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-81/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-81/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-81/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) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the 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/.

References

1. Hahn LD, Kunder CA, Chen MM, et al. Indolent thyroid cancer: knowns and unknowns. Cancers Head Neck 2017;2:1. [Crossref] [PubMed]
2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26:1-133. [Crossref] [PubMed]
3. Miyauchi A, Ito Y, Fujishima M, et al. Long-Term Outcomes of Active Surveillance and Immediate Surgery for Adult Patients with Low-Risk Papillary Thyroid Microcarcinoma: 30-Year Experience. Thyroid 2023;33:817-25. [Crossref] [PubMed]
4. Sugitani I, Ito Y, Takeuchi D, et al. Indications and Strategy for Active Surveillance of Adult Low-Risk Papillary Thyroid Microcarcinoma: Consensus Statements from the Japan Association of Endocrine Surgery Task Force on Management for Papillary Thyroid Microcarcinoma. Thyroid 2021;31:183-92. [Crossref] [PubMed]
5. Molinaro E, Campopiano MC, Elisei R. MANAGEMENT OF ENDOCRINE DISEASE: Papillary thyroid microcarcinoma: toward an active surveillance strategy. Eur J Endocrinol 2021;185:R23-34. [Crossref] [PubMed]
6. Jung CK, Bychkov A, Kakudo K. Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach. Endocrinol Metab (Seoul) 2022;37:703-18. [Crossref] [PubMed]
7. Scappaticcio L, Trimboli P, Bellastella G, et al. Prediction of classical versus non classical papillary thyroid carcinoma subtypes from cytology of nodules classified according to TIRADS. Endocrine 2024;84:560-70. [Crossref] [PubMed]
8. Eszlinger M, Lau L, Ghaznavi S, et al. Molecular profiling of thyroid nodule fine-needle aspiration cytology. Nat Rev Endocrinol 2017;13:415-24. [Crossref] [PubMed]
9. Zou M, Al-Baradie RS, Al-Hindi H, et al. S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma. Br J Cancer 2005;93:1277-84. [Crossref] [PubMed]
10. Sanjari M, Kordestani Z, Safavi M, et al. Enhanced expression of Cyclin D1 and C-myc, a prognostic factor and possible mechanism for recurrence of papillary thyroid carcinoma. Sci Rep 2020;10:5100. [Crossref] [PubMed]
11. Beck AC, Rajan A, Landers S, et al. Expression of cancer stem cell markers in tall cell variant papillary thyroid cancer identifies a molecular profile predictive of recurrence in classic papillary thyroid cancer. Surgery 2022;171:245-51. [Crossref] [PubMed]
12. Napoli F, Rapa I, Mortara U, et al. MicroRNA profiling predicts positive nodal status in papillary thyroid carcinoma in the preoperative setting. Cancer Cytopathol 2022;130:695-704. [Crossref] [PubMed]
13. di Masi A, Sessa RL, Cerrato Y, et al. Unraveling the Effects of Carotenoids Accumulation in Human Papillary Thyroid Carcinoma. Antioxidants (Basel) 2022;11:1463. [Crossref] [PubMed]