Case 1

A 32-year-old male presents with a rapidly growing cervical mass with locoregional symptoms. Physical examination reveals marfanoid habitus, mucosal neuromas and grade II goiter. The FNAB reports Bethesda VI. A total thyroidectomy (TT) is performed and pathology reveals combined papillary and medullary thyroid carcinoma. Postoperative calcitonin (CT) level is 2600 pg/ml. Due to the papillary component, an ablative dose of 80 mCi of I-131 is administered. During follow-up, lymph node metastases are detected with elevated thyroglobulin (Tg) and calcitonin levels; two lateral and central lymphadenectomies are performed, confirming lymph node metastases, including paratracheal (12 positive out of 24) mixed carcinoma metastases (Figure 1). Mutated RET gene, diagnosed with MEN2B. Negative metanephrines.

Figure 1: Neck with several scars from lymph node dissections

Case 2
A 46-year-old female presents with a mass in the anterior neck region and dysphagia of one year’s duration. She has grade II goiter. Ultrasound reveals a solid, homogeneous and well-defined nodule in the left lobe measuring 38×27×22 mm, with central vascularization and another similar nodule (Figure 2) in the right lobe measuring 10×11×7 mm. In the VI lymph node group, a hyperechoic, rounded lymphadenopathy without fatty hilum is identified. The FNAB of the larger nodule reports Bethesda VI and Tg from needle wash of the lymph node is 1050 ng/ml. With a diagnosis of PTC, TT with central lymphadenectomy is performed. Pathology reports combined, multifocal carcinoma, composed of a medullary thyroid carcinoma (MTC) measuring 35x25x24 mm and three foci of PTC, the largest being 7x5 mm with solitary central lymph vascular invasion. Postoperatively, calcitonin (5.2 pg/mL) and carcinoembryonic antigen (CEA: 18.37 ng/mL) levels were low, indicating excellent biochemical response. The patient starts treatment with levothyroxine for TSH suppression due to the papillary component, without requiring radioiodine, given the estimated low risk of recurrence (Figure 3).
                               a                                                                                                       b                                                                                                         c
                                                  

Figure 2: Cytology of thyroid nodule (a and b), adenopathy (c). High cellularity is observed with thyroid cells arranged in patches. Some have a spindle-shaped appearance.

Figure 3: HE 100x microphotography shows 2 areas with very different architecture. Green arrow shows a solid, nested, proliferation and black arrow shows an area of carcinoma with follifollicular pattern

Figure 4: The solid area shows fusiform and epithelioid cells with salt and pepper chromatin nuclei and granular, eosinophilic cytoplasm. There is amyloid substance in the stroma.

Jin Yao et al. report that in the last 30 years, only 18 cases have been documented in the literature and only 2 in Latin America^4,5. The age of presentation varies between 27 and 70 years; both presented patients fall within this age range. In most cases, diagnosis is made after the appearance of a cervical mass, as in the described cases⁴

The pathogenesis is not entirely clear, as these tumors result from the conjunction of two neoplasia’s of different embryonic and histological origins. PTC originates from the follicular cells of the thyroid, of endodermal origin, whereas MTC derives from parafollicular C cells, of neuroectodermal origin. Various theories have been proposed involving genetic mutations, local and environmental factors³. The tumor collision theory suggests the independent and contiguous development of two primary neoplasia’s, while the divergent differentiation theory from a common progenitor cell proposes that a progenitor cell capable of dual differentiation gives rise to both cell lines and the metaplastic transformation proposes a trans differentiation of one subtype to another, although this is less accepted.

Shared genetic and molecular factors: Common mutations have been found in mixed cases, such as RET, RAS or TERT, suggesting a clonal origin in some patients^3,6. In the first case, the finding of a RET mutation and the marfanoid phenotype are consistent with a type 2B multiple endocrine neoplasia syndrome (MEN2B), which adds a relevant genetic component for diagnosis and family follow-up (Figure 5)

Figure 5: The follicular area shows epithelial cells with clear nuclei, grooves and pseudoinclusions. Other foci chowed papillary pattern.

Preoperative diagnosis is crucial as it influences surgical methods and prognosis It requires a thorough clinical evaluation, including history, physical examination, blood tests (TSH, calcitonin) and imaging studies (ultrasound)^4,7. Cytological diagnosis via FNAB is complex, as medullary carcinoma can mimic other neoplasia’s and histology is variable². Immunohistochemical staining for calcitonin is essential to confirm or rule out medullary carcinoma⁴. In the two presented cases, a definitive diagnosis was established in the postoperative histopathological analysis, reinforcing the difficulty in identifying this entity at the preoperative stage. In our setting, routine measurement of baseline calcitonin is not requested for all nodules, aligned with what most guidelines suggest 

Lymphatic metastases are often present at the time of diagnosis, as in the second case presented. These lymph nodes may present pure cell populations or mixed components within the same node². This coincides with observations in the described cases, where the first patient presented mixed metastases and the second patient had pure papillary metastases (Figure 6)

Figure 6 (a): Immunohistochemistry for thyroglobulin was positive in the papillary carcinoma and negative in the medullary carcinoma (solid). INSM1 (b), synaptophysin (c) and calcitonin (d) were positive in the medullary carcinoma.

Chromogranin and TTF1 were also positive in the medullary component. TTF1 was positive in the papillary component.

 
Understanding the synchronous coexistence of these tumors is important for appropriate therapeutic management, although preoperative diagnosis is difficult due to low incidence and diagnostic complexity, as occurred in both cases, where the definitive diagnosis was made post-thyroidectomy^2,7.

Treatment is primarily guided by the medullary component, as it is the most aggressive and determinant of prognosis. Total thyroidectomy and central lymphadenectomy constitute the standard^4,7. Preoperative identification of lymph node metastases is key to planning surgery. Total thyroidectomy with central lymphadenectomy is the surgical approach of choice for MTC and should also be considered when mixed variants or multifocality are suspected.

From a pathological standpoint, the medullary component presents tumor cells with disordered arrangement, granular cytoplasm and organization in sheets, nests or rows and may present a papillary pattern. The papillary component does not differ from classical papillary carcinoma².

Although radioactive iodine ablation and TSH suppression are not effective for medullary carcinoma due to the absence of iodine uptake in parafollicular cells, they are useful for the coexisting papillary carcinoma⁸. The indication for radioiodine treatment is based on the assessment of recurrence risk, as observed in the first case (moderate risk) that received radioiodine and in the second case (low risk) that did not require it^4,8.

It is difficult to comment on the prognosis of these combined thyroid carcinomas, as few cases have been reported⁴. Patients with papillary carcinoma have the highest 10-year relative survival, while MTC is considered to have a worse prognosis, difficult to cure and with a higher likelihood of recurrence⁴. However, according to the WHO⁴, the prognosis of mixed medullary and follicular thyroid carcinoma depends on the medullary component. Therefore, the presence of the medullary component worsens the prognosis compared to pure papillary carcinoma.

The prognosis is determined by the presence or absence of metastases and age (older age, worse prognosis). In this case, there is a young middle-aged patient who has lymph node metastases of large proportions and in large numbers, which persist to date¹⁰.

References

1.                Roman BR, Morris LG, Davies L. La epidemia de cáncer de tiroides: perspectiva de 2017. Curr Opin Endocrinol Diabetes Obes 2017;24(5):332-336.

2.                Nangue C, Bron L, Portmann L, et al. Mixed medullary-papillary carcinoma of the thyroid: report of a case and review of the literature. Head Neck 2009;31(7):968-974.

3.                Yang Y, Zhang J, Wang J. Mixed Medullary-Papillary Thyroid Carcinoma with Mixed Lymph Node Metastases: A Case Report and Review of the Literature. Cancer Manag Res 2024;16:1285-1291.

4.                Yao J, Li CF, Wang JJ, et al. Medullary thyroid carcinoma combined with papillary thyroid carcinoma: case report and literature review. Int J Clin Exp Pathol 2020;13(10):2710-2717.

5.                Quiroz Y, Fermín E, Castro A, et al. Carcinomas sincrónicos papilar y medular de tiroides, a propósito de un caso. Acta Médica Peruana 2024;41(2):122-126.

6.                Ciampi R, Romei C, Pieruzzi L, et al. Classical point mutations of RET, BRAF and RAS oncogenes are not shared in papillary and medullary thyroid cancer occurring simultaneously in the same gland. J Endocrinol Invest 2017;40(1):55-62.

7.                Wong RL, Kazaure HS, Roman SA, Sosa JA. Simultaneous medullary and differentiated thyroid cancer: a population-level analysis of an increasingly common entity. Ann Surg Oncol 2012;19(9):2635-2642.

8.                Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Thyroid Carcinoma. Version 1.2020. Plymouth Meeting, PA: NCCN 2020.

9.                Katoh H, Yamashita K, Enomoto T, Watanabe M. Classification and general considerations of thyroid cancer. Ann Clin Pathol 2015;3(1):1045.

10.             Martínez Z, Cristiani A, Centurion D, Mendoza B, Mintegui G. Case report: combined pattern thyroid carcinoma. Endocrinol Metab Int J 2022;10(2):54-56.