Abstract
Objective
Concurrent papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) is a rare entity. We aimed to investigate the clinicopathological features, treatment, and prognosis of this coexistence.
Methods
We retrospectively studied 23 patients with concurrent PTC and MTC presenting as collision tumors (referred to as PTC/MTC) between 2011 and 2023 at our center.
Results
Among 197 MTC patients, 23 (11.7%) had PTC/MTC. Preoperative assessments revealed an 88.9% positivity rate for calcitonin and a 54.5% positivity rate for carcinoembryonic antigen. Thyroid ultrasonography showed more than one nodule suspicious of malignancy in 73.9% of the patients and detected nodal metastases in 63.9%. The MTC component had a higher frequency of abundant blood-flow signals than the PTC component (p = 0.009). Fine-needle aspiration cytology (FNAC) diagnosed only one tumor component in 75.0% cases. Among the 23 cases with PTC/MTC, 15 (65.2%) were identified as medullary thyroid microcarcinoma (micro-MTC), 19 cases (82.6%) as papillary thyroid microcarcinoma (micro-PTC). The proportion of micro-MTC in collision tumors was significantly higher than that in all MTC cases (p < 0.001). Further comparison between micro-MTCs in PTC/MTC and those not associated with PTC demonstrated no significant differences in clinicopathological features and prognosis.
Conclusions
In this cohort, PTC/MTC was found in approximately 1 in 10 MTC patients. Multiple suspicious malignant thyroid nodules with abundant blood-flow signals warrant vigilance for concurrent PTC and MTC, even if FNAC detects only one tumor component. Micro-MTC accounts for a high proportion of PTC/MTC cases, and its clinicopathological features are not influenced by the presence of a PTC component.
Keywords: Thyroid, Collision tumor, Medullary thyroid carcinoma, Papillary thyroid carcinoma, Microcarcinoma, Fine-needle aspiration
Introduction
Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer, originating from the thyroid follicular epithelial cells [1]. Medullary thyroid carcinoma (MTC), a rare subtype that accounts for 1%–2% of all thyroid cancers, arises from parafollicular neuroendocrine cells [1]. Although PTC and MTC are histologically different entities, they can co-occur in the same thyroid gland in rare cases [2–5].
The co-occurrence of PTC and MTC in the same thyroid can be categorized into the following two types: collision tumors (referred to as PTC/MTC) and mixed medullary/papillary thyroid carcinoma (MMPTC) [3]. Collision tumors are defined as the coexistence of two adjacent but histologically distinct tumors in the same organ without any histological admixture between the two [4]. The presence of admixed tumor cells of MTC and PTC in the same lesion, accompanied by positive immunohistochemistry staining for both calcitonin and thyroglobulin, are features of MMPTC [6]. The incidence of PTC/MTC is significantly higher than that of MMPTC [7].
The features of PTC/MTC have been described in several monocentric studies and case reports. Nevertheless, the diagnosis and management of this condition remain challenging owing to its rarity. Frequently, only one tumor component might be detected preoperatively, whereas the other is unexpectedly discovered during postoperative pathological examinations [4]. The failure to recognize both tumor components, particularly the more aggressive MTC component, can profoundly affect a patient’s management and prognosis. Therefore, understanding the clinicopathological features of concurrent PTC and MTC is crucial.
This study aimed to summarize preoperative evaluations, pathological features, treatment, and prognosis of patients with PTC/MTC diagnosed between 2011 and 2023 at our center.
Materials and methods
Patients
We retrospectively searched the medical database of the Peking Union Medical College Hospital for data from January 2011 to January 2023 to retrieve information regarding inpatients diagnosed with MTC. Overall, 197 patients had MTC during the study. Of these, 24 patients were found to have concurrent PTC and MTC. One patient was diagnosed with MMPTC, characterized by admixed tumor cells of MTC and PTC within the same lesion accompanied by positive immunohistochemistry staining for both calcitonin and thyroglobulin, and was excluded from this study. The remaining 23 patients who presented with collision tumors were included in this study.
Definitions
Two experienced pathologists confirmed the pathological diagnoses of PTC and MTC. Papillary thyroid microcarcinoma (micro-PTC) and medullary thyroid microcarcinoma (micro-MTC) were defined as tumors whose greatest dimension measured ≤ 1 cm [8, 9]. Multifocality was defined as the presence of two or more tumor sites in the thyroid gland. Tumor-node-metastasis (TNM) staging of PTC and MTC was performed according to the 8th edition of the American Joint Committee of Cancer [10, 11]. MTC components were graded according to the International MTC Grading System (IMTCGS) from the 2022 WHO classification of thyroid tumors [6]. The grading system incorporates three parameters: Ki-67 proliferation index (≥ 5% vs. < 5%), mitotic count (≥ 5 vs. < 5 per 2 mm²), and presence of tumor necrosis. High-grade MTC is defined by at least one of the following: Ki-67 ≥ 5%, mitotic count ≥ 5 per 2 mm², or presence of necrosis [6, 12]. The diagnosis of multiple endocrine neoplasia type 2 (MEN2) can be established through the identification of one or more of the following criteria: the presence of a germline mutation in the RET gene, the manifestation of at least two characteristic clinical components of MEN2, or one or more first-degree relatives with characteristic clinical features of the entity [13]. Structural recurrence (SR) was verified by means of fine-needle aspiration (FNA) biopsy, additional neck surgery, or the emergence of new imaging evidence following the initial surgery [14]. A biochemical cure is characterized by a postoperative calcitonin level falling within the normal reference range [15].
Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, N.Y., USA). Continuous variables were compared between groups using two independent-sample Student’s t-tests. Chi-square and Fisher’s exact tests were used to analyze categorical variables. Statistical significance was set at p < 0.05.
Results
Patients
Overall, 197 patients had MTC during the study. Synchronous PTC and MTC presenting as collision tumors were identified in 23 patients, accounting for 11.7% of the total cases with MTC. All 23 patients underwent initial thyroid surgery at our hospital.
The mean age of the patients was 51.3 years (range: 26–70 years), with a male-to-female ratio of 0.44:1 (7 men and 16 women). Detailed demographic characteristics are presented in Table 1. Two of the 23 patients were identified with MEN2 (cases 2 and 10). Case 2 had pheochromocytoma, PTC/MTC collision tumor, and a germline RET p.C634G (c.1900T > G) mutation. The patient’s family history included two paternal aunts with pheochromocytoma, but no confirmed MTC in them or other family members. Case 10 had a father with MTC and a paternal aunt with thyroid cancer of unknown histology. Genetic testing was recommended but not performed due to loss to follow-up.
Table 1.
Preoperative evaluation, pathological findings, treatment, and prognosis of cases with concurrent PTC and MTC
| Case number | Age (years)/gender | Preoperative evaluation | Location and size (cm) | NM | TNM staging | Surgery | Other treatment | Outcomes | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ctn (pg/mL) |
CEA (ng/mL) |
FNAC | MTC | PTC | MTC | PTC | ||||||
| Case 1 | 45/F | NA | 0.59 | NA | R, 0.2 | B, 1.8 | PTC | I | I | TT + biCND | RAI | BC |
| Case 2 | 26/F | 62 | 1.2 | NA | R, 0.3 | L, 0.3 | N | I | I | TT + uniCND | N | BC |
| Case 3 | 57/F | NA | NA | NA | R, 0.3 | R, 0.3 | N | I | II | TT + uniCND | N | Lost |
| Case 4 | 55/F | NA | NA | NA | L, 0.4 | R, 0.2 | N | I | I | TT + biCND | N | BC |
| Case 5 | 40/F | NA | NA | NA | L,0.4 | B, 0.8 | PTC | I | I | TT + biCND + uniLND | RAI | NSR |
| Case 6 | 62/M | NA | NA | NA | R, 0.5 | L, 0.1 | N | I | I | TT + biCND | N | BC |
| Case 7 | 56/M | NA | 1.54 | PTC | L, 0.5 | R, 3 | PTC | I | II | TT + biCND | NA | Lost |
| Case 8 | 53/F | NA | NA | NA | L, 0.6 | R, 0.6 | N | I | I | TT + uniCND | N | NSR |
| Case 9 | 48/F | NA | NA | PTC | L, 0.6 | L, 0.6 | N | I | I | TT + uniCND | RAI | BC |
| Case 10 | 27/F | NA | NA | AUS | R, 0.7 | L, 0.8 | N | I | I | TT + uniCND | N | Lost |
| Case 11 | 64/F | 2 | 1.99 | MTC | R, 0.8 | L, 0.3 | N | I | I | TT + biCND + uniLND | N | NSR |
| Case 12 | 45/M | NA | NA | NA | L, 0.9 | R, 0.1 | MTC | IV | I | TT + uniCND + uniLND | N | BC |
| Case 13 | 37/F | 202 | 4.6 | NA | L, 1.0 | B, 0.3 | MTC | III | I | TT + biCND | N | BC |
| Case 14 | 42/F | NA | NA | PTC | L, 1.0 | L, 0.9 | N | I | I | HT + uniCND | N | BC |
| Case 15 | 57/M | NA | NA | NA | R, 1.0 | B, 1.0 | MTC | III | I | TT + uniCND | N | BC |
| Case 16 | 57/M | 32 | 33 | MTC | R, 1.5 | R, 0.1 | PTC | I | II | TT + biCND | N | BC |
| Case 17 | 59/F | NA | NA | NA | B, 1.8 | B, 0.8 | N | I | I | TT + biCND | N | BC |
| Case 18 | 54/M | 1256 | 279 | MTC | L, 2.5 | R, 0.6 |
MTC+ PTC |
IV | I | TT + biCND + biLND | Radiotherapy | SR |
| Case 19 | 60/F | NA | NA | NA | R, 2.5 | B, 1.6 | N | II | I | TT + biCND | RAI | NSR |
| Case 20 | 67/F | 483 | 100 | NA | L, 2.6 | R, 0.3 | N | II | I | TT + biCND | N | BC |
| Case 21 | 39/F | 822 | 72.9 | NA | L, 3.5 | B, 1.5 | MTC | III | I | TT + uniCND | N | Lost |
| Case 22 | 70/M | 1476 | 324.3 | MTC + PTC | L, 4.5 | R, 0.2 | MTC | IV | I | TT + biCND + uniLND | N | Lost |
| Case 23 | 60/F | 1490 | 245.7 | NA | B, NA | R, 0.2 | MTC | IV | I | TT + biCND + biLND | N | SR |
PTC, papillary thyroid carcinoma; MTC, medullary thyroid carcinoma; Ctn, calcitonin; CEA, carcinoembryonic antigen; FNAC, fine-needle aspiration cytology; NM, nodal metastases; TNM, Tumor-node-metastasis; F, female; NA, not available; R, right lobe; B, both lobes; TT, total thyroidectomy; bi, bilateral; CND, central lymph node dissection; RAI, radioiodine therapy; BC, biochemical cure; L, left lobe; N, negative; uni, unilateral; LND, lateral lymph node dissection; NSR, no evidence of structural recurrence; M, male; AUS, atypia of undetermined significance; HT, hemithyroidectomy; SR, structural recurrence.
The reference range for calcitonin is within 0–10 pg/mL. The reference range for CEA is within 0–5 ng/mL.
Preoperative evaluation
Clinical manifestations
Most patients exhibited no clinical symptoms. Seventeen (73.9%) patients had thyroid nodules incidentally discovered during routine health examinations. One patient presented with hyperthyroidism as an initial manifestation (case 10). The remaining patients had various complaints, including diarrhea, facial flushing, cough, hoarseness, and neck mass. Of the 21 patients with sporadic MTC, three had a familial history of cancer (including differentiated thyroid cancer, lung cancer, and lymphoma), and one had a previous occurrence of endometrial cancer.
Laboratory findings
Twenty-one patients underwent thyroid function tests during diagnosis. Among them, 19 (90.5%) patients were euthyroid, one had hyperthyroidism which developed into subclinical hyperthyroidism after treatment with antithyroid drugs (case 10), and one had subclinical hypothyroidism (case 18). Preoperative levels of calcitonin, carcinoembryonic antigen (CEA), and thyroglobulin were tested in 9, 11, and 10 patients, respectively (Table 1). Calcitonin levels were invariably elevated in eight (88.9%) patients, ranging from 32 to 1,490 pg/mL (reference range: < 10 pg/mL). CEA levels were elevated in 6/11 (54.5%) patients, whereas 1/10 (10.0%) had elevated thyroglobulin levels. Twenty-one patients were assessed for anti-thyroglobulin (TG-Ab) and antithyroid peroxidase (TPO-Ab) antibodies. Among these, two patients were positive for both antibodies, two were solely positive for TPO-Ab, and three were solely positive for TG-Ab.
Thyroid ultrasonography and ultrasound-guided fine-needle aspiration
Twenty-three patients underwent preoperative thyroid ultrasonography, with 17 (73.9%) having more than one nodule suspected of being malignant on one or both the thyroid lobe(s). Detailed ultrasonographic features of MTC and PTC were available for 18 and 15 patients, respectively (Table 2). Both MTC and PTC are hypoechoic on ultrasonography. The MTC component had a higher frequency of abundant blood-flow signals than the PTC component (50.0% vs. 6.7%, p = 0.009), whereas no significant differences were found in features like calcification, irregular contour, obscure border, or aspect ratio > 1. Suspicious lymphadenopathy was found on ultrasound in 7/11 (63.7%) patients with lymph node metastasis.
Table 2.
Ultrasonographic features of MTC and PTC in collision tumors
| MTC (n = 18) | PTC (n = 15) | P value | |
|---|---|---|---|
| Hypoecho, % (n) | 100 (18) | 100 (15) | - |
| Irregular contour or obscure border, % (n) | 61.1 (11) | 86.7 (13) | 0.134 |
| Calcification, % (n) | 50 (9) | 60 (9) | 0.566 |
| Abundant blood flow signals, % (n) | 50 (9) | 6.7 (1) | 0.009 |
| Aspect ratio > 1, % (n) | 16.7 (3) | 33.3 (5) | 0.418 |
MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma
Eight patients underwent ultrasound-guided FNA; seven of the eight patients had FNA performed on thyroid nodules, while the remaining patient had it conducted on the supraclavicular lymph nodes. Cytological diagnosis showed one (12.5%) case with both MTC and PTC, six (75.0%) with a single tumor type (three with PTC and three with MTC), and one (12.5%) with atypia of undetermined significance (Table 1).
Diagnostic timeline of collision tumors
Preoperatively, at least one tumor component was identified in 12 patients (52.2%). The MTC component was identified in eight patients (34.8%), including three diagnosed through FNA cytology (FNAC) and five based on elevated serum calcitonin levels. The PTC component was identified in three patients (13.0%) by FNAC. Both MTC and PTC components were identified by FNAC in one patient (4.3%). Intraoperatively, nine patients (39.1%) had one component diagnosed through frozen section examination: PTC in seven patients (30.4%) and MTC in two patients (8.7%). Frozen section examination did not identify both components simultaneously in any patient in our cohort. Postoperatively, both MTC and PTC components were identified in the final pathology specimens in two patients (8.7%). These patients underwent surgery based on ultrasound findings suspicious for malignancy, and neither preoperative FNA nor frozen section examination was performed. The diagnostic timeline of collision tumors is shown in Fig. 1.
Fig. 1.
Diagnostic timeline of PTC/MTC collision tumors
Pathological findings
Medullary thyroid carcinoma component in collision tumors
MTC occurred most frequently in the left lobe (n = 12, 52.2%), followed by the right lobe (n = 9, 39.1%) and both lobes (n = 2, 8.7%). The mean size of MTC tumors was 1.3 cm (range: 0.2–4.5 cm). Extrathyroidal extension, capsular invasion, and multifocality were observed in three (13.0%), four (17.4%), and three (13.0%) cases, respectively. Seven (30.4%) patients had nodal metastases, one of whom had coexisting PTC metastases. None of the patients had developed distant metastases during their diagnoses. Regarding TNM staging, 14/23 (60.9%), 4/23 (17.4%), 2/23 (8.7%), and 3/23 (13.0%) patients had stages I, IV, II, and III disease, respectively (Table 3). For immunohistochemistry, calcitonin staining was available for 22 of 23 patients, with all showing positive staining (100%). Additionally, chromogranin (16/16) and synaptophysin (13/13) demonstrated 100% positivity, while thyroid transcription factor-1 and CEA showed positivity rates of 93.3% (14/15) and 90.0% (9/10), respectively. All 14 cases tested for thyroglobulin were negative.
Table 3.
Pathological features of collision tumors
| MTC | PTC | |
|---|---|---|
| Left lobe, % (n) | 52.2 (12) | 27.1 (6) |
| Right lobe, % (n) | 39.1 (9) | 43.5 (10) |
| Both lobes, % (n) | 8.7 (2) | 30.4 (7) |
| Mean size, cm | 1.3 | 0.7 |
| Extrathyroidal extension, % (n) | 13.0 (3) | 4.3 (1) |
| Capsular invasion, % (n) | 17.4 (4) | 47.8 (11) |
| Multifocality, % (n) | 13.0 (3) | 34.8 (8) |
| Nodal metastases, % (n) | 30.4 (7) | 21.7 (5) |
| TNM staging | ||
| Stage IV, % (n) | 17.4 (4) | 0 |
| Stage I, % (n) | 60.9 (14) | 87.0 (20) |
MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma; TNM, Tumor-node-metastasis
Treatment and prognosis
MTC grading using the IMTCGS was performed in 19 cases with available tissue. The Ki-67 index was 1% in 6 cases, 2% in 4 cases, 3% in 6 cases, 4% in 1 case (case 18), 5% in 1 case (case 13), and 6% in 1 case (case 20). All cases demonstrated mitotic counts < 5 per 2 mm² with no tumor necrosis. Based on the IMTCGS, two patients were classified as high-grade MTC (cases 13 and 20), and 17 patients as low-grade.
Papillary thyroid carcinoma component in collision tumors
PTC occurred in the right lobe in 10 (43.5%) cases, and in seven (30.4%), it was present in both lobes. The following two histological types were found: classic PTC (17/23, 73.9%) and the follicular variant (6/23, 26.1%). The average PTC size was 0.7 cm (range: 0.1–3.0 cm). Eleven (47.8%) and eight (34.8%) cases showed capsular invasion and multifocality, respectively. Nodal metastases were observed in five (21.7%) cases. Twenty of the 23 (87.0%) patients had stage I disease, and the remaining three (13.0%) had stage II (Table 3).
Pathological features of collision tumors
Twelve of the 23 collision tumors (52.2%) occurred in the same lobe, with the MTC and PTC components being separated by normal thyroid parenchyma.
The pathological characteristics of each component are summarized in Table 3. The MTC component was more common in the left lobe, whereas PTC tended to occur in the right lobe. MTC had more aggressive features in some respects, including larger mean size, as well as higher frequencies of extrathyroidal extensions and nodal metastases than the PTC component. The incidences of capsular invasion and multifocality were higher in the PTC components. The MTC stage in 20 of the 23 patients was higher than (9/20, 45.0%) or equal to (11/20, 55.0%) the PTC stage. The remaining three patients (13.0%) had a higher PTC stage.
Ten of the 23 collision tumors were complicated by primary thyroid disease, including five cases (21.7%) with chronic lymphocytic thyroiditis and five (21.7%) with nodular goiters.
Treatment and prognosis
Twenty-two patients underwent total thyroidectomy and central cervical lymph node dissection, with six of them also undergoing simultaneous lateral lymph node dissection. Additionally, one patient underwent hemithyroidectomy and central cervical lymph node dissection. Postoperatively, radioiodine therapy was administered to four patients. One patient underwent radiotherapy postoperatively due to extensive neck diseases.
Outcome data were accessible for 18 patients after excluding those lost to follow-up (n = 5) (Table 1). The median duration of follow-up was 26.5 months, ranging from 8 to 135 months. In the cohort, 16 (88.9%) cases had no evidence of SR after their initial treatment, and the median follow-up duration was 29 months (8–135 months). Of these cases, 12 (66.7%) achieved biochemical cure within a median duration of 32 months (8–135 months). Moreover, two (11.1%) patients experienced SR after 18 and 24 months, respectively. No cases of distant metastasis or reported deaths were recorded.
Microcarcinomas in collision tumors
Among the 23 cases with collision tumors, 15 (65.2%) were identified as micro-MTCs, 19 (82.6%) as micro-PTCs, and 13 (56.5%) contained both micro-MTC and micro-PTC components. Among the 197 MTC cases documented during the study, 54 (27.4%) presented with micro-MTCs. The proportion of micro-MTCs was significantly higher in MTCs concurrent with PTC compared to the overall MTC cases (65.2% vs. 27.4%, p < 0.001).
Micro-MTCs in collision tumors were compared to classic micro-MTCs (those not associated with PTC), and no significant differences were observed between the two groups regarding age, sex distribution, tumor size, multifocality, nodal metastasis, TNM stage, and biochemical cure rates (Table 4).
Table 4.
Characteristics of classic micro-MTC and micro-MTC linked with PTC
| Classic micro-MTC (n = 39) | Micro-MTC linked with PTC (n = 15) | P value | |
|---|---|---|---|
| Mean age, years (range) | 47.6 (13–82) | 50.0 (27–70) | 0.605 |
| Sex, male, % (n) | 43.6 (17) | 26.7 (4) | 0.253 |
| Pathological findings | |||
| Mean size, cm | 0.77 | 0.61 | 0.067 |
| Multifocality, % (n) | 23.1 (9) | 6.7 (1) | 0.252 |
| Capsular invasion, % (n) | 23.1 (9) | 13.3 (2) | 0.708 |
| Extrathyroidal extension, %(n) | 23.1 (4) | 0 (0) | - |
| Nodal metastases, % (n) | 48.7 (19) | 20.0 (3) | 0.054 |
| Stage IV (TNM staging), % (n) | 23.1 (9) | 6.7 (1) | 0.252 |
| Stage I (TNM staging), % (n) | 48.7 (19) | 80.0 (12) | 0.054 |
| Prognosis | n = 33 | n = 12 | |
| BC, % (n) | 75.8 (25) | 75.0 (9) | 1.000 |
MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma; TNM, Tumor-node-metastasis; BC, biochemical cure.
Discussion
Within our cohort of 197 MTC cases, 23 (11.7%) had PTC/MTC. The presence of multiple thyroid nodules on ultrasound displaying suspicious malignancy features, particularly abundant blood flow, may indicate potential PTC/MTC. However, the capacity of FNA biopsy to identify both tumor components is limited. The prevalence of micro-MTC in PTC/MTC cases was higher than that in all MTC cases, and no differences were observed in clinicopathological features and prognosis between micro-MTC concurrent with PTC and classic micro-MTC.
Concurrent PTC and MTC have been reported in several monocentric studies, with a maximum of 30 cases [16]. In previous studies, concurrent PTC and MTC were classified as collision tumors and MMPTCs, respectively. Recently, Zhang et al. categorized cases with synchronous PTC and MTC into four subtypes based on the positional relationship between the two tumor components [16]. No histological admixture between the two tumor components is the most common, regardless of the classification method. The proportion of PTC/MTC among patients treated for MTC ranges from 3.6% to 19.0% [2, 4, 17, 18]. In our study, the proportion was 11.7% (23/197), which falls within the previously reported ranges. The varying incidences in different centers may be attributed to differences in pathological examination protocols and detection sensitivity. Given the high proportion of micro-MTC in PTC/MTC cases (65.2% in our cohort), small MTC lesions may be overlooked during gross examination and sampling of thyroidectomy specimens if not carefully searched for. This underscores the importance of heightened awareness among clinicians and pathologists regarding this rare entity. Additionally, variations in the recognition of MTC variants and other histological features may also contribute to these differences.
Several hypotheses have been proposed regarding the pathogenesis of PTC/MTC [19, 20]. The chance theory states that the simultaneous occurrence of PTC and MTC is a random event [17]. Unsurprisingly, PTCs are combined with MTC since the incidence of PTC is high in the general population [21]. According to this study and some previous research, more than 80% of MTC cases are associated with micro-PTC [4, 16], which is the main subtype of PTC [22]. This supports the chance theory to some extent. Another theory suggests that when a common stem cell harbors two different driver mutations, it can result in the occurrence of two independent tumors. However, some studies have contradicted this theory [3, 23, 24]. Rossi et al. performed a genetic analysis of three patients with PTC/MTC and identified RET mutations in the MTC component, whereas a BRAF mutation was detected in the PTC component [23]. Similarly, Ciampi et al. investigated 24 patients with PTC/MTC and found that the co-occurrence of PTC and MTC may not be attributable to classical gene mutations commonly associated with the pathogenesis of the two tumors, including RAS, BRAF, and RET mutations [3]. Therefore, further studies exploring the mechanisms of PTC/MTC should be conducted to clarify these notions.
Identifying both tumor components, particularly the preoperative identification of the MTC component, poses one of the clinical challenges in cases of PTC/MTC. In this study, the presence of the MTC component was preoperatively detected in 39.1% of patients, whereas it was postoperatively identified in 52.2% of patients. Preoperative assessments, which encompass serum calcitonin tests, thyroid ultrasonography, and FNAC, could enhance the detection of the MTC component. Serum calcitonin is a biomarker known for its specificity and high sensitivity in detecting MTC [25]. In our study, elevated calcitonin levels were observed in eight of the nine (88.9%) patients, indicating a similarly good sensitivity in collision tumors. Regarding ultrasonographic features, most patients exhibited more than one nodule that was suspected of being malignant on thyroid lobe(s), with many cases accompanied by suspicious lymphadenopathy. The identified malignant features comprised hypoechogenicity, irregular contour, obscure border, calcification, abundant blood flow, and an aspect ratio of > 1. Notably, the MTC component exhibited a significantly higher frequency of abundant blood-flow signals than the PTC component. The role of FNAC, a commonly used diagnostic method for thyroid nodules [26], has been examined in cases of PTC/MTC. However, FNAC is limited to identifying only one tumor component, usually the MTC, as indicated in previous case reports and research findings [4, 27, 28]. Of the eight patients in this study, FNAC detected both PTC and MTC in only one case. Therefore, when ultrasound detects multiple nodules with characteristics of malignancy, the possibility of PTC/MTC should be considered even if the FNAC identifies only a single tumor component. In these situations, calcitonin examination can provide essential evidence of the MTC component.
Our study revealed a substantial presence of microcarcinomas within collision tumors, including micro-PTC and micro-MTC. Micro-MTC accounted for 65.2% of all PTC/MTC cases. Several other studies have also reported a notable prevalence of micro-MTC among concurrent PTC and MTC, ranging from 47% to 60%.3, 16, 29 We further compared the prevalence of micro-MTC in PTC/MTC cases with its presence in all MTC cases during the study. The results showed a notably higher proportion of micro-MTC within the PTC/MTC group. One possible explanation for this trend is that the coexistence of another tumor component (in this case, PTC) may enhance the detection rate of micro-MTC. Moreover, to clarify whether the presence of a PTC component influences the characteristics of micro-MTC, we conducted a comparative analysis between micro-MTC cases associated with PTC and classic micro-MTC cases. The results indicated no significant differences in age, sex distribution, tumor size, multifocality, nodal metastasis, TNM stage, and biochemical cure rates between the two groups. Additionally, a few studies have explored the differences between MTC combined with PTC and classic MTC, and a consensus on this issue has not been reached. Biscolla et al. found no difference in the pathological features and outcomes between these two types [2]. According to Negura et al., the MTC component is more aggressive in PTC/MTC compared to classic MTC without concurrent PTC [30]. Another multicenter research observed a relatively good prognosis for patients with concomitant PTC and MTC, with 97% and 66% survival and progression-free rates, respectively. However, when calcitonin levels and TNM staging were considered, the analysis indicated that the prognosis of patients with concurrent PTC and MTC was worse than that of those with classic MTC [29]. Therefore, more research involving a larger and more diverse population is warranted to further investigate this issue.
IMTCGS was proposed in 2021 as a universal grading system for MTC [6]. We performed grading of MTC components according to the IMTCGS in 19 available PTC/MTC cases, with 17 (89.5%) classified as low-grade and two as high-grade. This proportion of high-grade MTC is lower than the 30.3% (20/66) reported in a previous study [31], which may be attributed to the predominance of micro-MTC in our cohort. Furthermore, no tumor necrosis or mitotic counts > 5 per 2 mm² were observed in our cases, largely consistent with previous reports where 17 of 20 high-grade tumors were classified solely by Ki-67 index ≥ 5%, while only 3 exhibited tumor necrosis or mitotic counts > 5 per 2 mm² [31]. Given the limited sample size, our findings are preliminary and require validation in larger cohorts. The prognostic significance of MTC grading in PTC/MTC patients remains to be determined in future studies.
In our cohort, TNM staging frequently differed between the MTC and PTC components in collision tumors, raising challenges in determining which staging should be applied and how subsequent treatment should be planned. There is no consensus or guideline for treating concurrent PTC and MTC, owing to the rarity of the condition. However, it is generally acknowledged that in the case of a collision tumor, both entities should be treated as separate primaries [4, 32]. Accordingly, staging the MTC and PTC components separately is more consistent with this treatment approach and aligns with the principles of precision medicine in managing such rare and complex diseases [33]. Due to the aggressive nature of the MTC component, which frequently necessitates complete gland removal, total thyroidectomy and central neck dissection are the preferred surgical approaches for treating the primary disease. The decision to perform lateral neck dissection is typically determined based on metastasis to the regional lymph nodes and calcitonin levels. Based on the risk stratification of PTC components, thyroid-stimulating hormone (TSH) suppression treatment should be initiated postoperatively, and adjuvant radioiodine therapy is necessary for PTC components classified as high- or intermediate-risk. According to the guidelines, radiotherapy should be indicated if high-risk features are present in any component. In this study, 22 patients underwent total thyroidectomy and central neck dissection in accordance with the recommended treatment guidelines for MTC. Four patients received radioiodine therapy for the PTC component, and one underwent radiotherapy for extensive neck diseases caused by MTC. Therefore, identifying both tumor components in PTC/MTC is crucial for tailoring the management strategies. Particularly, the preoperative identification of MTC is important as it frequently influences the extent of surgery. Furthermore, the possibility of combined PTC should not be overlooked during pathological diagnosis to ensure appropriate implementation of TSH suppression treatment and radioiodine therapy postoperatively.
Our retrospective analysis had some inherent limitations. Because of the rarity of PTC/MTC, the limited sample size in this study makes it insufficient to compare the differences in clinicopathological features and prognosis between MTC linked with PTC and classic MTC. Although we performed grading of MTC components using the IMTCGS, our findings are preliminary and require validation in larger cohorts. The small number of high-grade cases limited our ability to assess the prognostic significance of MTC grading in PTC/MTC patients, which warrants further investigation. Additionally, comprehensive molecular data for these patients are lacking. Larger studies integrating genetic profiling, IMTCGS grading, and long-term outcomes are needed to optimize risk stratification and treatment strategies for PTC/MTC collision tumors.
In conclusion, PTC/MTC was identified in 23 of 197 (11.7%) MTC patients in our cohort. Ultrasound showing multiple suspicious thyroid nodules, especially with abundant blood flow signals, should prompt consideration of concurrent PTC and MTC even if FNAC reveals only one malignancy. Preoperative calcitonin testing is recommended to identify MTC in these cases. Micro-MTCs account for more than half of PTC/MTC cases, a higher proportion than their prevalence in general MTC cases. The coexistence of the PTC component does not appear to impact the clinicopathological features or prognosis of micro-MTC.
Acknowledgements
We would like to thank every patient for participating in this study.
Author contributions
YL and Xiaofeng Chai collected and analyzed the data. YL wrote the paper. HL, YX, and HZ verified and interpreted the patient data. Xiaoyi Li, BL, and Xingming Chen investigated the data and interpreted the results. NL, WZ, and Xiaolan Lian conceived the study and edited the paper. All authors have read and approved the submitted version of the manuscript.
Funding
This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2021-I2M-1-001), the Preferred Research Foundation for the Returned Overseas Scholars from Ministry of Human Resources and Social Security of China (Key Category) (2014), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT320-10), and Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202515).
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study protocol was approved by the Ethics Committee of Peking Union Medical College Hospital (approval number: I-23YJ889), in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants involved in this study.
Consent for publication
Not applicable. All data presented are fully anonymized with no identifiable patient information.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yuanmeng Li and Xiaofeng Chai contributed equally to this work as co-first authors. Naishi Li, Weigang Zhao and Xiaolan Lian contributed equally to this work as co-corresponding authors.
Contributor Information
Naishi Li, Email: linaishi@pumch.cn.
Weigang Zhao, Email: xiehezhaoweigang@163.com.
Xiaolan Lian, Email: lianxl@pumch.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.