Clinicopathological and molecular characteristics of papillary thyroid carcinoma in adolescent and young adult patients

Abstract

Adolescent and young adult (AYA, 15–39 years old) patients with papillary thyroid carcinoma (PTC) experience significant psychological distress and place great importance on obtaining information regarding the disease; however, their demands remain unmet. We aimed to investigate clinicopathological and molecular features of PTC in AYA patients and compare them to those of PTC in older patients (≥40 years). This retrospective study enrolled 1,677 patients diagnosed with PTC from January 2018 to December 2022, with 400 AYA patients and 1,277 older adults. At the time of diagnosis, AYA patients with PTC had higher rates of presentation in females, larger tumor size (>2.0 cm), lymphatic vessel invasion, chronic thyroiditis, clinical lymph node metastasis, and pathologic lymph node metastasis, but lower rates of multifocality and extrathyroidal extension compared with PTC in older adults. The two groups had no significant differences regarding surgical method and distant metastasis. The prevalences of BRAF p.V600E and TERT promoter mutations of PTC were significantly lower in AYA patients (69.1% vs. 82.6% and 1.3% vs. 18.8%, respectively; both p < 0.001). In conclusion, PTC in AYA patients differed from PTC in older patients. Particularly, BRAF p.V600E and TERT promoter mutations in AYA with PTC were less frequently observed than in older adults.

Introduction

Thyroid cancer accounts for 13% of all invasive neoplasms in adolescents and young adults (AYA, 15–39 years old) [1] and is the most common head and neck carcinoma, with an increasing incidence rate in several countries [2, 3]. Papillary thyroid carcinoma (PTC) is the predominant pathological type of all thyroid cancers encountered in AYA [1, 4]. More than half of Japanese AYA cancer survivors experience significant psychological distress [5]. They have a threefold higher risk for major depressive disorder compared with cancer-free controls [6]. Indeed, AYA patients with thyroid cancer often face unique educational, socioeconomic, and mental health issues [4, 7, 8]. They place great importance on obtaining information regarding the disease [9]. AYA patients with cancer should be considered as a distinct age group that has unique medical and psychosocial requirements [10]. However, only a few studies to date assessed PTC in AYA [11-13]; thus, characteristics of PTC in AYA remain to be elucidated [9]. In particular, data on genetic alterations in this group is limited [11, 12]. Therefore, we aimed to investigate clinicopathological and molecular features of PTC in AYA patients and statistically compare them with those in older adults (≥40 years).

Materials and Methods

Participants

We obtained clinicopathological data from 1,691 patients who were pathologically diagnosed with PTC at the Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Japan from January 2018 to December 2022. All the patients underwent thyroidectomy as the initial treatment at Yamashita Thyroid Hospital, Fukuoka, Japan. We excluded 4 patients who were aged younger than 15 years and 10 patients with a history of thyroid surgery. A total of 1,677 consecutive patients were included in this study, consisting of 400 AYA and 1,277 older patients.

This study was approved by the Institutional Ethical Committee for Medical Research at Nagasaki University (#15062617-6) and conducted in accordance with the tenets of the Declaration of Helsinki. Informed consent was obtained from all participants involved in the study in the form of opt-outs.

Surgical treatment

The indication of surgical treatment was determined by the following criteria [14, 15]. Total thyroidectomy was performed if any of the following was present: tumor larger than 4.0 cm, bilateral multifocality, extrathyroidal extension (ETE), size of clinical lymph node metastasis (LNM) larger than 3.0 cm, extranodal tumor extension in LNM, or distant metastasis. Lobectomy plus isthmectomy was performed if the tumor was ≤2.0 cm, there was no ETE, no LNM, and no distant metastasis. In other patients, total thyroidectomy or lobectomy was decided individually based on the prognostic factors and patient background [14, 15]. Central lymph node dissection (LND) was routinely performed [14, 15]. Lateral LND was performed if lateral LNM was preoperatively demonstrated by fine-needle aspiration cytology (FNAC) or highly suspected as seen in ultrasonographic (US) examination.

Data collection of clinicopathological features

In our institute, the pathological features of thyroid tumors were routinely confirmed by at least three thyroid pathology specialists. All the clinicopathological features were recorded in our system specifically designed for pathological diagnosis together with clinical information at our department (Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University). Clinical information, including age, sex, medical history, thyroid biochemical tests, preoperative diagnosis, and surgical procedure, were provided by Yamashita Thyroid Hospital. Clinicopathological features, including age, sex, tumor size, multifocality, ETE, lymphatic vessel invasion (LVI), chronic thyroiditis, clinical LNM, pathologic LNM, and distant metastasis, were collected from medical records. In patients with PTC, younger ages (<30 years) and tumors larger than 2 cm are well-known as the significant risk factors for recurrences [16-18]. Therefore, we divided patients into subgroups based on the cutoff points of tumors sized 2 cm or 30 years of age. Multifocality was recorded when two or more tumors were identified preoperatively in the thyroid gland by imaging examinations and FNAC. ETE was reported intraoperatively when the tumor invaded the major neck structures, including larynx, trachea, esophagus, recurrent laryngeal nerve, mediastinal vessels, carotid artery or prevertebral fascia (excluding sternothyroid or sternohyoid muscle) [19]. LVI was confirmed by the presence of cancer cells or psammoma bodies in lymphatic channels as seen with D2-40 immunohistochemistry [20]. Clinical LNM was diagnosed by image analyses and physical examinations, and occasionally with FNAC. Pathologic LNM was diagnosed by surgically dissected specimens. Tumor recurrence was histologically confirmed by surgically resected specimens at least 6 months after the first surgery [21, 22].

Molecular analyses

DNA was extracted from formalin-fixed and paraffin-embedded (FFPE) tumor tissues using the Maxwell RSC DNA FFPE Kit (Promega, Madison, WI, USA) in a previous study [23]. Mutations for BRAF p.V600E and TERT promoter hot spot mutations C228T and C250T were analyzed using a droplet digital polymerase chain reaction as in the previous description [22-24].

Statistical analyses

Categorical variables were presented as numbers and percentages. For continuous variables, medians and interquartile ranges (IQRs) were reported. Differences between study groups were analyzed using the chi-square test or Fisher’s exact test. The Mann-Whitney U test was used for continuous data. We used the IBM SPSS Statistics software version 29.0 (IBM Corp., Armonk, NY, USA) for statistical analysis, and statistical significance was set at p < 0.05.

Results

Comparison of clinicopathological and molecular features of PTC between AYA and older adults

The clinicopathological characteristics of PTC in AYA and older adults are shown in Table 1. There were significantly more female patients in the AYA group (86.0% vs. 80.7%, p = 0.017). Although the median tumor size was similar between both groups (1.2 cm vs. 1.2 cm, p > 0.05), tumors larger than 2 cm were significantly more frequent among AYA patients (27.0% vs. 18.9%, p < 0.001). The rates of LVI, chronic thyroiditis, clinical LNM, and pathologic LNM were significantly higher in the AYA group (32.5% vs. 12.5%, p < 0.001; 36.5% vs. 29.5%, p = 0.009; 41.5% vs. 34.7%, p = 0.013; 65.3% vs. 59.2%, p = 0.031, respectively). Conversely, the rates of multifocality and ETE were significantly higher in the older adult group (18.3% vs. 25.9%, p = 0.002; 3.3% vs. 6.9%, p = 0.008). There were no significant differences in the prevalences of total thyroidectomy and distant metastasis between the two groups. Among 1,255 patients with follow-up information, tumor recurrences were histologically confirmed in 18 cases during the median follow-up duration of 43 months. Of these patients, there was only one patient from the AYA group.

Table 1 Comparison of clinicopathological and molecular features of PTC between AYA and older adult patients

Features	All (n = 1,677)	AYA (n = 400)	Older (n = 1,277)	p-value
Age, median (IQR)	51 (40–64)	33 (28–36)	57 (48–67.5)	<0.001
Female, n (%)	1,375 (82.0)	344 (86.0)	1,031 (80.7)	0.017
Total thyroidectomy, n (%)	835 (49.8)	185 (46.3)	650 (50.9)	0.105
Tumor size (cm), median (IQR)	1.2 (0.8–1.9)	1.2 (0.8–2.1)	1.2 (0.8–1.7)	0.156
Tumor size >2.0 cm, n (%)	349 (20.8)	108 (27.0)	241 (18.9)	<0.001
Multifocality, n (%)	404 (24.1)	73 (18.3)	331 (25.9)	0.002
Extrathyroidal extension, n (%)	101 (6.0)	13 (3.3)	88 (6.9)	0.008
Lymphatic vessel invasion, n (%)	290 (17.3)	130 (32.5)	160 (12.5)	<0.001
Chronic thyroiditis, n (%)	523 (31.2)	146 (36.5)	377 (29.5)	0.009
Clinical LNM, n (%)	609 (36.3)	166 (41.5)	443 (34.7)	0.013
Pathologic LNM, n (%)	1,017 (60.6)	261 (65.3)	756 (59.2)	0.031
Distant metastasis, n (%)	12 (0.7)	3 (0.8)	9 (0.7)	1.000
Outcomes (n = 1,255)
Follow-up, median (IQR)	43 (27–58)	40 (27–55)	44 (26–59)	0.119
Recurrence, n (%)	18 (1.4)	1 (0.3)	17 (1.8)	0.091

AYA, adolescents and young adults; PTC, papillary thyroid carcinoma; LNM, lymph node metastasis; IQR, interquartile range

In the subgroup of 582 patients with PTC with available mutation results, the prevalences of BRAF p.V600E and TERT promoter mutations in AYA patients were significantly lower than those in the older patients (69.1% vs. 82.6% and 1.3% vs. 18.8%, respectively; both p < 0.001) (Table 2).

Table 2 Comparison of molecular features of PTC between AYA and older adult patients in the subgroup of 582 patients with available genetic mutation results

Molecular features	AYA (n = 152)	Older (n = 430)	p-value
BRAF p.V600E mutation
Absent	47 (30.9%)	75 (17.4%)	<0.001
Present	105 (69.1%)	355 (82.6%)
TERT promoter mutation
Absent	150 (98.7%)	349 (81.2%)	<0.001
C228T	2 (1.3%)	67 (15.6%)
C250T	0	14 (3.2%)

AYA, adolescents and young adults; PTC, papillary thyroid carcinoma

Association of pathological features and age group of PTC in AYA patients

The association of pathological features and age groups of PTC in AYA patients is presented in Table 3. In comparisons between two age groups in AYA, such as younger ages between 15 and 29 years (n = 128) and older ages between 30 and 39 years (n = 272), both the median tumor size and rate of LVI were significantly larger in the younger than in the older age group (1.4 cm vs. 1.2 cm and 42.2% vs. 27.9%, respectively; both p = 0.005). Conversely, the rate of multifocality was significantly higher in the older than in the younger age group (21.3% vs. 11.7%, p = 0.02). No significant differences were found in total thyroidectomy, ETE, chronic thyroiditis, clinical LNM, pathological LNM, and distant metastasis between the younger and older age AYA groups.

Table 3 Association of pathological features and age group of PTC in AYA patients

Features	Age (years)		p-value
	15–29 (n = 128)	30–39 (n = 272)
Total thyroidectomy, n (%)	56 (43.8)	129 (47.4)	0.491
Tumor size (cm), median (IQR)	1.4 (1.0–2.4)	1.2 (0.8–2.0)	0.005
Tumor size >2.0 cm, n (%)	44 (34.4)	64 (23.5)	0.023
Multifocality, n (%)	15 (11.7)	58 (21.3)	0.020
Extrathyroidal extension, n (%)	5 (3.9)	8 (2.9)	0.763
Lymphatic vessel invasion, n (%)	54 (42.2)	76 (27.9)	0.005
Chronic thyroiditis, n (%)	50 (39.1)	96 (35.3)	0.465
Clinical LNM, n (%)	59 (46.1)	107 (39.3)	0.201
Pathologic LNM, n (%)	89 (69.5)	172 (63.2)	0.217
Distant metastasis, n (%)	2 (1.6)	1 (0.4)	0.241

AYA, adolescents and young adults; PTC, papillary thyroid carcinoma; LNM, lymph node metastasis; IQR, interquartile range

Discussion

It is well-known that AYA patients with cancer face unique challenges, including unique educational, socioeconomic, and mental health issues, as compared with other age groups [10, 25, 26]. We aimed to understand PTC in AYA patients. Our investigation revealed that PTC in AYA patients had different features from that in older adults at the time of diagnosis. PTC in AYA patients was characterized by a higher rate of female patients, tumor size larger than 2 cm, LVI, chronic thyroiditis, clinical LNM, and pathologic LNM, but lower frequencies of ETE, multifocality, BRAF p.V600E mutation, and TERT promoter mutation in comparison with older adults (Graphical Abstract).

Graphical Abstract 

Although the median tumor size was similar between the two age groups, tumor sizes larger than 2 cm, which have more aggressive biological features than those ≤2 cm [16, 17], were more frequent in AYA patients. Our results also showed more frequent cervical LNM in AYA patients, which was in line with the reports describing that younger age is a risk factor for cervical LNM [27-29]. Conversely, our results showed significantly lower prevalences of ETE and multifocality in the AYA group. Several studies reported that older age is associated with ETE and multifocality in PTC [30-32], indicating a consistency of our results with previous reports. Our study also demonstrated no significant differences in several factors such as ETE, clinical LNM, pathologic LNM, and distant metastasis between both age groups in the AYA group. These findings suggest that it is not necessary to apply unique treatment approaches based on age categories in AYA patients with PTC.

Several previous studies consistently demonstrated that the prevalence of BRAF mutation is significantly lower in children than in adults with PTC [33-36]. In the present study, AYA patients had a lower frequency of BRAF p.V600E mutation in comparison with older adults. Additionally, previous studies also reported that frequency of TERT promoter mutations is very rare or absent in pediatric PTCs [34, 35]. However, no previous study has reported the incidence of TERT-p mutation in PTC from AYA patients. This study revealed only 1.3% (2/152) TERT promoter mutations in AYA patients, including a 32-year-old woman and 39-year-old man with PTC showing ETE and LNM. TERT promoter hot spot mutations are known to be significant prognostic factors and are found in 10% to 20% of thyroid cancers, particularly in those older than 45 years [37-41]. The data suggest that TERT promoter mutation has a limited role in younger patients with PTC.

To the best of our knowledge, this is the first study to investigate clinicopathological and molecular features of PTC in Japanese AYA patients. Although PTC in the AYA patients had distinct clinicopathological and molecular features compared to the older adult patients at the time of presentation, short-term outcomes were excellent in both groups. Sun et al. reported that locoregional recurrence was found in 20 (6.08%) of 329 AYA cases of PTC with cervical LNM at the initial surgery during the median follow-up time of 57 months [13]. Vriens et al. demonstrated that median disease-free and overall survival in AYA with PTC were significantly higher than in the older group [11], suggesting that AYA with PTC has an excellent prognosis. Consistent with previous studies, only one patient showed recurrence in the cervical LN at 15 months after initial surgery in our cohort. This patient was a 37-year-old woman with a tumor measuring 1.3 cm, central LNM, no ETE, and neither BRAF p.V600E nor TERT promoter mutations. Although there was no statistically significant difference in recurrence rates between the two groups, the rate of recurrence in the older group was 6 times higher than that in the AYA group.

Our study has some limitations. First, we could not compare PTC between AYA and pediatric patients because of the small number of pediatric patients (four patients). Second, the molecular features were not investigated for all the patients. In addition, due to the rare TERT promoter mutations in AYA patients, it was not possible to assess the associations between TERT promoter mutation and clinicopathological features. Third, due to the low rate of tumor recurrences during the short median follow-up duration (43 months), the analysis for disease-free survival was not performed. Multicenter prospective studies with long-term outcomes are needed to explore our findings.

In conclusion, clinicopathological features of PTC in AYA patients differed from that in older adult patients. Particularly, AYA patients had lower frequencies of BRAF p.V600E and TERT promoter mutations in comparison with older adults.

Authors’ Disclosure

None of the authors have any potential conflicts of interest associated with this research.

Funding Information

This work was funded by the Atomic Bomb Disease Institute, Nagasaki University and the Program of the Network-Type Joint Usage/Research Center for Radiation Disaster Medical Science.

Author Contributions

All the authors contributed significantly in the different aspects of this study, such as data collection, design, statistical analyses, molecular analyses, interpretation of results, and manuscript writing. All the authors read and agreed to the final version of the manuscript.

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