Analysis of the concurrent occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma: A dual center, retrospective study in China

Abstract

This study examines the clinicopathological characteristics of patients with coexistent medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC). A retrospective analysis was conducted on 169 patients who underwent surgical treatment for MTC at 2 medical centers between 2010 and 2019. The clinicopathological characteristics were documented, and associations between MTC/PTC and MTC were evaluated. Among the 169 MTC patients, 16 (9.5%) exhibited concomitant histological characteristics of both MTC and PTC. Three patterns of carcinoma distribution were identified: mixed carcinoma, tumors confined to the ipsilateral glandular lobe, and MTC/PTC lesions dispersed across both glandular lobes. Of these 16 patients, 9 were female and 7 were male, with a mean age of 50.6 years. The PTC lesions had a maximum diameter of 0.40 ± 0.21 cm, whereas the MTC lesions measured 1.73 ± 1.86 cm in maximum diameter. Additionally, 9 cases exhibited lymph node metastases, but no distant metastases were observed. Univariate analysis indicated no significant associations between MTC/PTC and MTC (P > .05), with no differences in survival or prognosis between the groups.

1. Introduction

Thyroid cancer is among the most rapidly increasing malignancies globally. Medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) represent 2 biologically distinct entities. MTC originates from parafollicular C cells, is predominantly driven by RET mutations, and often demonstrates greater aggressiveness with a higher propensity for metastasis; it accounts for ~1% to 2% of all thyroid malignancies.^[1-4] In contrast, PTC arises from follicular epithelial cells, is commonly associated with BRAF or RAS mutations, and typically follows a more indolent clinical course, constituting the vast majority of cases. Despite differences in origin, molecular characteristics, and treatment strategies, MTC and PTC can coexist within the thyroid gland of the same patient.^[5-8] The reported incidence of this coexistence is low, generally below 1%,^[9] yet it presents unique diagnostic and management challenges. Current understanding is primarily derived from case reports or small, single-center retrospective studies.^[10,11] These reports, however, primarily document the co-occurrence phenomenon, leaving critical questions unresolved – particularly concerning whether the pathogenesis constitutes a “collision” of independent tumors or a monoclonal event, and what its actual implications are for patient prognosis. There is a notable lack of large-scale, multi-center clinicopathological studies, particularly in specific populations such as in China, where epidemiological and genetic backgrounds may influence disease characteristics. To address this gap, we conducted a retrospective dual-center study analyzing all consecutive cases of concurrent MTC and PTC over a 10-year period. Our aims were to elucidate the clinicopathological features of this rare entity within our patient population and to establish a robust dataset to guide clinical management and future research.

2. Patients and methods

2.1. Patient inclusion criteria and characteristics

A retrospective review was conducted on cases of MTC in patients who underwent surgical intervention between January 2010 and December 2019 at 2 medical centers. The study sample comprised 169 patients with MTC confirmed through surgical and pathological evaluation, all of whom had no prior medical history of other malignant tumors. Among these 169 patients, 16 cases (9.5%) exhibited an association with PTC. Demographic data, including gender and age, as well as histopathological data such as tumor size, extent of tumor invasion, and lymph node metastasis, were extracted from the clinicopathological records. Additionally, clinical parameters such as thyroid stimulating hormone (TSH), thyroglobulin (TG), calcitonin (Ctn), and carcinoembryonic antigen (CEA) levels were collected. All diagnoses were collaboratively determined by 2 senior pathologists, and in instances of discrepant results, a third pathologist was consulted to reach a consensus. Ethical approval, which included a waiver of informed consent, was granted by the institutional Ethics Committee for this retrospective study using anonymized data.

2.2. Peripheral blood measurement methods

Peripheral venous blood samples, each with a volume of 4 mL, were collected from patients who were required to fast prior to surgery. Following collection, the samples were allowed to stand for 30 to 60 minutes before being centrifuged for 10 minutes to separate the serum. Subsequently, levels of Ctn, CEA, TG, and TSH were measured using identical detection methods at both institutions. Specifically, Ctn levels were assessed using the Siemens IMMULITE 2000 XPi Electrochemiluminescence Immunoassay Analyzer, with an assay range of 2 to 2000 pg/mL; results falling outside this range were reported as “<2 pg/mL” or “>2000 pg/mL.” CEA levels were determined using the Abbott ARCHITECT i4000SR Analyzer, TG levels were measured with the Roche Cobas e 601 Analyzer, and TSH levels were assessed using the Siemens ADVIA Centaur XP Analyzer. All procedures were conducted in strict accordance with the operational manuals provided by the manufacturers. In this study, we established the upper limit of the acceptable range for Ctn as 8.4 pg/mL for males and 5.0 pg/mL for females, and for CEA as 5.0 ng/mL for both males and females.

2.3. Surgical methods

Open surgery was employed for all patients, with thyroidectomy and cervical lymphadenectomy conducted concurrently in a single procedure. The choice of surgical approach was guided by the American Thyroid Association Guidelines.^[12] Specifically, total thyroidectomy was performed for patients with a family history of MTC, tumor extension, multifocality, or bilateral cervical LNM. Conversely, subtotal thyroidectomy was performed for patients with tumors confined to one side of the glandular lobe, with or without the presence of benign contralateral nodules. During cervical lymphadenectomy, central lymph node dissection was routinely carried out. In cases where enlarged lateral cervical lymph nodes or tumor metastasis were confirmed through fine-needle aspiration or imaging studies, dissection of lateral lymph node was undertaken. Additionally, in the absence of clinical evidence of thyroid tumor metastasis, region I was not included in the surgical procedure. Furthermore, in cases where imaging revealed enlarged superior mediastinal lymph nodes, a mediastinal lymph node dissection in region VII was performed. During this procedure, it is imperative to safeguard critical structures, including the accessory nerve, sternocleidomastoid muscles, internal carotid artery, and internal jugular veins. Additionally, care must be taken to avoid traction-induced nerve stimulation, and the in situ blood supply to the parathyroid glands should be preserved.

2.4. Follow-up methods

Patients were stratified into 3 distinct categories based on their most recent evaluation outcomes. The first category, termed “biochemically cured,” is characterized by a negative postoperative basal Ctn test result, with serum Ctn levels falling within the normal range for healthy individuals, and the absence of tumors or other abnormalities as determined by imaging studies. The second category, “biochemical abnormality,” encompasses patients who exhibit negative postoperative basal Ctn and no detectable tumors via imaging, yet present with serum Ctn levels that exceed the normal range, although these levels remain manageable. The final category, “relapsing,” includes patients who demonstrate positive postoperative basal Ctn levels, increasing serum Ctn concentrations, and imaging abnormalities.^[5,13] Upon detection of relapse symptoms, patients are subjected to reoperation. Postoperative follow-up evaluations are conducted at 1, 3, and 6 months following surgery. These evaluations comprise CEA and Ctn measurements, assessments of thyroid function, and thyroid ultrasound examinations.

2.5. Statistical methods

In this study, statistical analyses were conducted utilizing the SPSS software package (Version 25.0, IBM SPSS Statistics; IBM Corporation, Armonk). Results were deemed statistically significant if the P-value was <.05. Furthermore, the chi-square (χ²) test and unpaired t-test were employed, and certain demographic data were reported using means and standard deviations.

3. Results

3.1. Clinicopathological characteristics of MTC/PTC retrospective chart review

Among the 169 patients diagnosed with MTC, 16 individuals (9.5%) exhibited concurrent MTC and PTC, forming the focal cohort of this study. This group comprised 7 males and 9 females, with ages ranging from 40 to 59 years (mean age: 50.6 ± 6.1 years). A comprehensive summary of their clinical characteristics is presented in Table 1.

Table 1.

Demographic and clinicopathologic characteristics of 16 patients.

Number	Gender	Age (yr)	Complaints	Type of surgery	Tumor size (laterality)		Lymph node metastasis	HT	131I	Outcome
					MTC (cm)	PTC (cm)
1	F	57	Increased CEA	TX, CentrD, LaterD	3.2 (L)	0.1 (R)	None	–	–	C
2	F	59	Thyroid nodules for 1 mo	HX, CentrD	0.3 (R)	0.05 (R)	None	–	–	C
3	M	59	Thyroid nodules for half a month	HX, CentrD, LaterD	4.2 (R)	0.6 (L)	CLN; LLN	–	–	BA
4	F	51	Increased CEA	TX, CentrD, LaterD	1.2 (R)	0.6 (R)	CLN; LLN	–	–	R
5	F	53	Thyroid nodules for 10 yr	TX, CentrD, LaterD, mediastinalD	7.5 (R)	0.25 (L)	CLN; LLN; MLN	–	–	C
6	M	48	Thyroid nodules for 2 mo	TX, CentrD, LaterD, mediastinalD	1.8 (L)	0.6 (R)	CLN;LLN; MLN	–	–	R
7	M	59	Thyroid nodules for 1 wk	TX, CentrD	1.2 (R)	0.2 (L)	None	–	–	C
8	M	40	Thyroid nodules for 1 and a half years	TX, CentrD	0.5 (R)	0.2 (L)	None	–	–	C
9	M	47	Thyroid nodules for 1 wk	TX, CentrD, LaterD	0.7 (mixed)	0.7 (mixed), 0.2 (R), 0.1 (L)	CLN	–	–	C
10	F	54	Thyroid nodules for 20 yr	TX, CentrD, LaterD	1.8 (R)	0.4 (L)	CLN	–	–	C
11	M	51	Thyroid nodules for 20 d	TX, CentrD	1.1 (R)	0.5 (L)	CLN	–	131I	C
12	F	49	Thyroid nodules for 4 yr	TX, CentrD, LaterD, mediastinalD	0.6 (R)	0.3 (L)	None	HT	–	C
13	F	41	Thyroid nodules for 20 d	TX, CentrD	0.7 (mixed)	0.7 (mixed), 0.15 (R)	CLN	–	–	BA
14	F	49	Thyroid nodules for 3 yr	TX, CentrD	0.6 (L)	0.2 (R)	None	–	–	C
15	M	50	Thyroid nodules for 4 yr	TX, CentrD	0.7 (R)	0.3 (L)	None	–	–	C
16	F	43	Thyroid nodules for 2 yr	HX, CentrD	1.7 (L)	0.4 (R)	CLN	–	–	BA

BA = biochemical abnormality, C = cured, CentrD = central lymph node dissection, F = female, LaterD = lateral lymph node dissection, M = male, MediastinalD = mediastinal lymph node dissection, MTC = medullary thyroid carcinoma, R = relapse, ST = subtotal thyroidectomy, TX = total thyroidectomy.

The detection of MTC/PTC varied across cases. Two patients were identified through thyroid nodules discovered during examinations initiated due to elevated CEA levels. The remaining 14 patients were diagnosed following the identification of thyroid nodules during routine health checkups, with detection intervals spanning from several days to several years. With the exception of 1 patient who also had Hashimoto’s thyroiditis, none had preexisting thyroid conditions. Additionally, no patient had a prior history of other tumors before the diagnosis of MTC/PTC.

3.2. Clinicopathologic data review

Among the 16 cases with concomitant MTC and PTC, 2 cases (12.5%) demonstrated both histologically distinct components within the same tumor nodule (Fig. 1). In 3 patients, including the 2 with mixed carcinoma, all tumor foci were localized to a single thyroid lobe. The remaining 13 patients exhibited multifocal tumors affecting both thyroid lobes.

Figure 1.

Pathological features of concurrent MTC and PTC. (A) H&E staining showing the mixed morphological patterns of the 2 tumors (black arrow indicates MTC; red arrow indicates PTC). (B) Thyroglobulin IHC: positive staining in the PTC area (red arrow) and negative expression in the MTC area (black arrow). (C) Calcitonin IHC: diffuse cytoplasmic positivity within the MTC component. (D) Congo red staining: demonstrating characteristic amyloid deposits within the MTC stroma. (E) Synaptophysin IHC: positive expression in the MTC area and negative in the PTC area. (F) CK19 IHC: strong immunoreactivity in the PTC area, while the MTC area is negative (original magnification: ×40). MTC = medullary thyroid carcinoma, PTC = papillary thyroid carcinoma.

Tumor size varied among patients; however, in each instance, the maximum diameter of the PTC component was smaller than that of the coexisting MTC. The maximum diameter of MTC tumors ranged from 0.3 to 7.5 cm, with a mean ± standard deviation of 1.73 ± 1.86 cm. Conversely, the PTC lesions were significantly smaller, ranging from 0.05 to 0.7 cm, with a mean ± standard deviation of 0.37 ± 0.20 cm. Consequently, the maximum diameter of all PTC lesions was ≤1 cm.

LNM was present in 9 out of the 16 patients (56.3%). The sites of metastasis were distributed as follows: central lymph node metastasis in 9 patients, lateral lymph node metastasis in 4 patients, and mediastinal lymph node metastasis in 2 patients. No distant metastases were detected in this cohort (Table 1).

3.3. Treatment and prognosis review

In this study, all 16 cases underwent central neck dissection; of these, 3 patients received a subtotal thyroidectomy, while 13 underwent a total thyroidectomy. Among those who had a subtotal thyroidectomy, 1 patient also had an ipsilateral lateral neck dissection. In the group that underwent total thyroidectomy, 7 patients received lateral neck dissection. Additionally, 3 patients underwent mediastinal lymph node dissection, as detailed in Table 1. Following surgical intervention, all patients, with 1 exception, were administered levothyroxine supplementation and TSH suppressive therapy. The exception was a patient who, upon pathological evaluation 1 week postoperatively, was found to have metastases in 6 out of 14 central lymph nodes. This patient subsequently received adjuvant radioiodine (¹³¹I) therapy. Pathological analysis confirmed that the metastatic deposits were predominantly PTC, with 1 lymph node also exhibiting a MTC component. Post-¹³¹I therapy, the patient achieved biochemical remission.

Serum Ctn and CEA levels were monitored to evaluate the response to treatment. Preoperative assessments indicated elevated CEA and Ctn levels in 9 and 13 patients, respectively, with baseline data unavailable for 1 patient. Two additional patients exhibited normal Ctn and CEA levels both pre- and postoperatively. Postoperative measurements were taken on day 1 and at 1 month, revealing a significant decline in both markers on day 1. At the 6-month follow-up, 6 patients fulfilled the criteria for biochemical remission (Table 2).

Table 2.

CEA and Ctn levels observed with surgery (before, after 1 day, after 1 month).

Number	Gender	CEA			CT			Outcome
		Preoperative	1 d	1 mo	Preoperative	1 d	1 mo
1	F	–	–	–	–	–	–	C
2	F	1.85	1.11	1.76	6.12	1.66	2.12	C
3	M	95.87	53.12	17.19	>2000	237.3	14.9	BA
4	F	219.6	174.4	75.45	>2000	550	232	R:55.8 mo
5	F	1629.24	1057.19	46.59	>2000	2004	246	C
6	M	293.65	193.92	64.27	>2000	214.1	272.3	R: 14.2 mo
7	M	14.74	12.43	3.45	287	15.46	2	C
8	M	2.35	2.39	2.43	3.5	3.4	<0.5	C
9	M	5.2	3.02	2.10	14.28	4.50	<0.5	C
10	F	76.35	58.95	17.5	709.60	24.79	0.77	C
11	M	11.50	7.36	4.55	89.80	4.06	<2	C
12	F	11.34	5.69	1.22	109.00	2.14	<2	C
13	F	3.5	2.3	1.7	46.38	11.94	12.98	BA
14	F	3.55	2.61	2.67	148.00	3.72	<2	C
15	M	2.81	2.62	1.62	82.30	<2	<2	C
16	F	55.28	34.21	13.8	678.00	173	209	BA

One day, 1 month these indexes were postoperation.

BA = biochemical abnormality, C = cured, F = female, M = male, R = relapse.

At the most recent follow-up, 11 out of 16 patients with MTC/PTC achieved biochemical remission. Three patients exhibited persistently elevated tumor markers without any imaging evidence of disease, while 2 patients experienced disease recurrence and subsequently underwent reoperation. Pathological analysis confirmed that the recurrence in both cases originated from the MTC component. Following the second surgery, one of these patients attained biochemical remission.

All 16 patients in the MTC/PTC subgroup were alive at their last follow-up. In the broader MTC cohort, 2 out of 169 patients were excluded from survival analysis due to loss to follow-up, resulting in an analysis set of 167 patients for overall survival and recurrence-free survival. The median follow-up duration for this cohort was 35 months. Among these 167 patients, 132 (79.0%) remained disease-free, while 35 (21.0%) experienced disease recurrence. A total of 7 patients (4.2%) succumbed to MTC-related causes, whereas 160 patients (95.8%) were alive at the last follow-up. Kaplan–Meier analysis comparing the MTC/PTC subgroup (n = 16) with the MTC patients (n = 151) in this analyzable set revealed no statistically significant difference (Fig. 2).

Figure 2.

Kaplan–Meier survival analysis comparing the MTC/PTC cohort with the MTC cohort. (A) Overall survival (OS). (B) Recurrence-free survival (RFS). No significant differences were observed between the 2 groups in either OS (P = .441) or RFS (P = .452). MTC = medullary thyroid carcinoma, OS = overall survival, PTC = papillary thyroid carcinoma, RFS = recurrence-free survival.

3.4. Univariate analysis results for MTC/PTC and MTC

The MTC cohort (n = 153) consisted of 80 females and 73 males, with a mean age at diagnosis of 48.89 ± 13.55 years. In contrast, the MTC/PTC cohort (n = 16) comprised 9 females and 7 males, with a mean age of 50.63 ± 6.10 years. Comparative analysis of the demographic characteristics between the MTC and MTC/PTC cohorts indicated no significant differences. Furthermore, no statistically significant differences were observed in the clinicopathological characteristics. Preoperative measurements of TSH and TG similarly exhibited no significant differences between the groups. Overall, the 2 cohorts were comparable at baseline, with no statistically significant differences in either demographic or clinicopathological characteristics (P > .05; refer to Table 3 for detailed information).

Table 3.

Univariate analysis results for MTC/PTC and MTC.

Clinical parameters	MTC/PTC (n = 16)	MTC (n = 153)	t/χ2	P
Age (yr)	50.63 ± 6.10	48.89 ± 13.55	−0.935	.356
Gender
Female	9	80	0.091	.763
Male	7	73
(MTC) Maximal diameter (cm)	1.74 ± 1.86	2.03 ± 1.37	0.771	.442
Capsular invasion	3	54	1.774	.183
Extrathyroidal extension	1	29	1.601	.206
Lymph node metastasis
CLN	9	82	0.031	.860
LLN	4	68	2.303	.129
MLN	2	20	0.006	.941
TSH	1.79 ± 1.01	2.27 ± 2.54	0.668	.493
TG	20.88 ± 20.50	19.76 ± 21.83	−0.181	.856
Biochemical cured	11	102	0.465	.495
Biochemical abnormality	5	65

Data are presented as mean ± SD or number.

Comparisons: Student t test for continuous variables, χ² test for categorical variables.

CLN = central lymph node, LLN = lateral lymph node, MLN = mediastinal lymph node, MTC = medullary thyroid carcinoma, PTC = papillary thyroid carcinoma.

4. Discussion

We performed a focused review of the literature on the coexistence of MTC and PTC to better contextualize our findings. The characteristics of representative studies are summarized in Table 4. Across the literature, several consistent patterns can be identified. Where the PTC component is often small – frequently presenting as papillary microcarcinoma (≤1 cm) – it is commonly detected incidentally after surgery.^[11,14,15] In contrast, the MTC component is typically larger and serves as the dominant pathological driver in terms of both tumor burden and clinical behavior.^[14,16] Lymph node metastases, when present, are predominantly associated with the MTC component,^[17] although rare cases of mixed or dual-component metastases have been reported.^[18] In terms of prognosis, most studies indicate that clinical outcomes are primarily determined by the MTC component rather than the coexisting PTC.^[11,16] Moreover, several reports suggest that the coexistence of these 2 tumors may represent either a coincidental finding or a “collision tumor” phenomenon rather than a biologically unified entity.^[15,17]

Table 4.

Summary of characteristics of representative studies with coexistent MTC and PTC.

Study	Year	Study type	Sample size (MTC/PTC)	Incidence	PTC size	Key findings
Alandejani et al	2024	Case report	1	–	Variable	Incidental finding, diagnosis postoperatively
Yang et al	2024	Case + review	1	Rare	Not specified	Mixed tumor with dual lymph node metastasis
Thomas et al	2021	Case series	21	4.7% of MTC	Mostly microPTC	Supports “collision theory”
Calapkulu et al	2022	Case series	3	<1%	Variable	Prognosis depends on dominant component
Zhang et al	2024	Retrospective cohort	30	~24.6% (in MTC cohort)	Variable	Differences in Ctn/CEA and pathology
Akgun et al	2023	Retrospective study	13	<1%	Not specified	No survival difference by location
Fallahi et al	2023	Case series + review	5	0.70%	Mostly microPTC	High prevalence of incidental microPTC

CEA = Carcinoembryonic antigen, Ctn = Calcitonin, MTC = medullary thyroid carcinoma, PTC = papillary thyroid carcinoma.

Although the coexistence of MTC and PTC is not an exceptional event (reported incidences among MTC cohorts range from 3.6% to 19%;^[5-7,19] in our study, the proportion was 9.5%), the diagnosis of MTC/PTC predominantly relies on postoperative pathological evaluation. This reliance is attributed to the nature of concomitant PTC, as the majority of concurrent PTC lesions in our cohort were smaller than 1 cm. Such diminutive size poses challenges for preoperative detection via ultrasound, as corroborated by previous studies.^[20] In alignment with the findings of Biscolla et al,^[5] who reported that 21 out of 27 combined cases involved subcentimeter lesions, all sixteen PTC lesions in our study were <1 cm, with 9 measuring even smaller than 0.5 cm at the time of diagnosis. This diminutive size contributes to an increased risk of preoperative diagnostic oversight. Furthermore, advancements in pathological and immunohistochemical techniques have enhanced the accuracy of diagnosing combined MTC/PTC cases, leading to more frequent detection during postoperative clinical evaluations.

In 13 out of 16 documented cases of MTC/PTC in this study, the tumors were located in separate lobes, suggesting a limited direct anatomical association between the 2. Although mixed tumors have been frequently reported in the literature,^[21-25] there is ongoing debate regarding their origin; they may either represent a collision of 2 distinct neoplasms or constitute a unique pathological entity.^[8,26] Given the anatomical distribution and the fact that all PTC lesions were microcarcinomas, 1 interpretation is that these PTC components represent incidental papillary microcarcinomas – a common finding in the general population. However, an alternative possibility is that an underlying biological association between the 2 tumor types exists, which cannot be entirely excluded given the lack of molecular characterization in this retrospective cohort.

The present study did not identify a significant impact of concurrent MTC and PTC on the prognosis of patients with MTC, a finding that differs from some previous reports. Several factors may explain this discrepancy. The study by Sandilos et al focused on mixed medullary-PTC, defined by the presence of both components within the same tumor lesion and associated with more aggressive behavior.^[27] The prognosis of mixed tumors is likely influenced by the biological behavior of the predominant component^[28,29] or shaped by a unique tumor immune microenvironment.^[30,31] In contrast, the majority of cases in the present cohort were anatomically distinct lesions, a pattern consistent with the collision tumor hypothesis and similar to those reported by Biscolla et al, Kim et al, and Machens et al^[5-7] Additionally, the limited sample size (n = 16) in this study may have reduced statistical power to detect modest survival differences. Differences in clinicopathological characteristics may also contribute: in this study, age and MTC tumor size did not differ significantly between groups, whereas Kim et al and Machens et al reported significant differences.^[6,7] As noted above, all PTC lesions in this study were microcarcinomas, which typically have an indolent course. Furthermore, the absence of RET mutation testing precluded adjustment for hereditary versus sporadic MTC, a factor that may influence both the prevalence of concurrent PTC and prognosis.^[7] Despite comparable surgical management and follow-up duration across groups, the combined influence of differences in pathological definition, sample size, clinicopathological features, and genetic background likely accounts for the divergent survival findings. In summary, the findings of the present study are consistent with the interpretation that concurrent papillary microcarcinoma does not adversely affect the prognosis of patients with MTC when the 2 tumors present as anatomically distinct lesions, although this finding does not imply equivalence in outcomes between the 2 diseases.

Lymph node metastasis in concurrent MTC and PTC is predominantly associated with the MTC component, although rare cases of mixed or dual-component metastases have been reported.^[18] However, when guiding adjuvant therapy, the histologic composition of lymph node metastases provides critical information. In our study, 1 patient received ¹³¹I treatment following total thyroidectomy because pathological analysis revealed that the lymph node metastases were predominantly of PTC origin – despite the primary PTC lesion measuring only 0.5 cm.^[32] This case illustrates that accurate identification of nodal histology is essential for treatment decision-making: when PTC dominates nodal involvement, ¹³¹I therapy is warranted even if the primary PTC is small. Consistent with Biscolla’s study, 12 out of 27 patients with MTC/PTC received ¹³¹I treatment, resulting in biochemical cure in 9 patients, biochemical abnormality in 1 patient, and distant metastases in 2 patients, although these metastases were not attributable to PTC.^[13] Although the ATA guidelines do not provide specific recommendations for the management of concurrent PTC/MTC,^[12] the NCCN guidelines offer more concrete guidance: when PTC and MTC co-occur, adequate surgical resection should be performed in accordance with MTC standards, followed by PTC relapse risk assessment and adjuvant treatment post-surgery.^[19,33]

This study is subject to several limitations. Firstly, despite the dual-center design, the sample size of the MTC/PTC cohort remains limited, which restricts the statistical power and precludes the use of more complex multivariable modeling. As a result, the findings are predominantly descriptive and require validation in larger cohorts. Secondly, the absence of molecular clonality analysis represents a significant limitation, as it prevents definitive distinction between anatomically distinct concurrent tumors and true mixed carcinomas based solely on morphology and immunohistochemistry. This distinction is relevant because mixed carcinomas may exhibit different biological behavior and prognosis. Thirdly, this retrospective study did not include a systematic evaluation of genetic or family history, nor did it account for prior radiation exposure. Consequently, we are unable to determine whether specific clinicopathological characteristics influence prognosis in this patient population or to derive definitive clinical management recommendations from the present data. Future research should involve prospective, multi-center studies with larger sample sizes to incorporate comprehensive genomic profiling and facilitate robust statistical modeling, thereby identifying independent prognostic factors.

5. Conclusion

In summary, our study found no significant differences in clinicopathological characteristics between MTC/PTC and MTC. Further studies are warranted to explore the underlying pathogenesis of MTC/PTC, as its etiology remains unclear.

Author contributions

Data curation: Xiaogang Qi, Zhongkai Ni, Lihua Hong, Jinwang Ding.

Funding acquisition: Tianhan Zhou.

Investigation: Xiaogang Qi.

Methodology: Zhongkai Ni.

Resources: Tianhan Zhou.

Writing – original draft: Xiaogang Qi.

Writing – review & editing: Tianhan Zhou.