Synchronous Presence of Papillary, Medullary, and Anaplastic Thyroid Tumors in a Single Patient: A Rare Case Report

Introduction

Papillary thyroid carcinoma (PTC) is the most prevalent subtype of differentiated thyroid carcinoma, accounting for approximately 85% of all differentiated thyroid carcinomas. It arises from thyroid follicular cells and typically demonstrates indolent growth, often remaining localized for years, though it frequently metastasizes to the cervical lymph nodes [1,2]. In contrast, medullary thyroid carcinoma (MTC) represents about 4% of all thyroid cancers and originates from the parafollicular cells, which are of neuroendocrine origin. Approximately 75% of MTC cases occur sporadically and the remaining 25% are hereditary [2]. Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive, accounting for less than 5% of all thyroid malignancies while contributing disproportionately to thyroid cancer-related mortality [3]. Although ATC can arise de novo, it more commonly develops from pre-existing differentiated thyroid carcinoma, most often PTC. Genetic alterations, including p53 and Ki-67 overexpression, are believed to contribute to this transformation [4,5].

The coexistence of multiple distinct thyroid malignancies within a single patient is infrequent but well recognized, representing cases in which 2 or more histologically different thyroid cancers occur simultaneously – most notably ATC, MTC, and PTC. Because these malignancies originate from different cellular lineages, their synchronous occurrence is of considerable clinical and pathological interest. Moreover, ATC typically arises within the thyroid gland itself, and transformation occurring in metastatic sites is exceedingly rare [3]. Here, we present a case of a 68-year-old female patient with metastatic PTC, anaplastic transformation in lymph nodes, and an incidental finding of medullary thyroid microcarcinoma.

Case Report

A 68-year-old woman with a history of comorbidities including semaglutide-managed morbid obesity, diabetes, hypertension, hypothyroidism, bronchial asthma, heart failure, hearing loss, obstructive sleep apnea on continuous positive airway pressure (CPAP), and history of pulmonary embolism. She initially presented in primary health care with an enlarging neck mass and neck pain that lasted for 2 months, which progressed upon follow-up, with fever and tenderness in the neck area. This condition was initially investigated with thyroid ultrasound, which showed heterogeneous bilateral thyroid lobes suggestive of chronic thyroid disease, along with a large cystic structure (2.5×4.2 cm) in the right submandibular area, raising suspicion of a necrotic lymph node. However, she denied symptoms such as dysphagia, odynophagia, respiratory distress, hoarseness, hematemesis, nausea, vomiting, weight loss, or night sweats. There was no significant family history of head and neck malignancy or prior radiation exposure. She was urgently referred to head and neck surgery; on examination, a large, firm swelling was noted at level II on the right side of the neck with local discomfort yet without overlying skin changes or palpable lymphadenopathy. The oral cavity and oropharynx were clear, and there were no signs of trismus. A cranial nerve assessment, including the facial nerve, was intact. Flexible nasopharyngoscopy revealed unremarkable nasal cavities, nasopharynx, oropharynx, hypopharynx, supraglottis, and glottis, with bilaterally mobile vocal cords. Further investigations included a non-contrasted computed tomography (CT) scan of the neck that revealed a lobulated lesion (5.6×3.8×4.7 cm) in the right carotid space with hyperenhancement and cystic changes as shown in Figures 1 and 2, causing compression of the internal jugular vein and complete occlusion at the level of the lesion. Additionally, a necrotic lymph node was noted anterior to the mass, along with calcifications in the right thyroid lobe. Other imaging modalities were performed such as magnetic resonance imaging (MRI), and magnetic resonance angiography, and the results confirmed a large, lobulated, T2-heterogeneous necrotic/cystic mass in the right neck with post-contrast enhancement but no suspicious lymphadenopathy elsewhere. A core needle biopsy of the right neck mass confirmed PTC, with tumor cells positive for TTF-1, PAX-8, and focal thyroglobulin, confirming a thyroid origin. Given the diagnosis of metastatic PTC, the patient underwent a total thyroidectomy with right radical neck dissection. In addition, dissection of the left neck level VI lymph nodes was performed, based on intraoperative assessment and the known tendency of well-differentiated thyroid carcinoma to accompany occult central lymph nodal disease. Although there was no clinical, radiological, or pathological evidence of metastasis present at that time, the nodes were easily accessible within the operative field. Thus, proceeding with the dissection during the initial surgery was considered safer and more appropriate than subjecting an older patient with multiple comorbidities to a potential second surgery, which could carry substantially higher morbidity. The tumor was completely excised with all margins negative for carcinoma. There was no evidence of vascular, lymphatic, perineural, extrathyroidal, or muscle invasion.

Pathological analysis examined a total of 58 lymph nodes from the right cervical region, right thyroid lobe, left thyroid lobe, and left neck level VI. The right cervical lymph nodes (48 in total) at levels II, III, and IV revealed metastatic ATC arising from PTC in 3 of the lymph nodes (3/48); with extranodal extension identified at levels II and III. The largest metastatic node measured 5.7 cm in diameter. The parotid gland was not involved; therefore, level I lymph nodes were preserved. The right thyroid lobe contained 1 benign lymph node (0/1), and the left side showed 3 benign lymph nodes (0/3). Additionally, the contralateral level VI neck dissection revealed 6 benign lymph nodes with no evidence of metastasis (0/6).

Histopathology of the right thyroid lobe identified a collision tumor composed of PTC, infiltrative follicular subtype, and a medullary thyroid microcarcinoma. However, no anaplastic transformation was found within the thyroid tissue itself. Chronic lymphocytic (Hashimoto’s) thyroiditis was also present. The left thyroid lobe similarly exhibited chronic lymphocytic thyroiditis with no malignancies identified.

Immunohistochemistry supported the diagnoses: PTC stained positive for Galectin-3, HMBE-1, and CK19 but negative for CD56; anaplastic carcinoma in the lymph nodes stained positive for Pan-CK, CK7, and TTF1 but negative for CD45, CD30, and Chromogranin A; and medullary thyroid microcarcinoma stained positive for Chromogranin A, Synaptophysin, CD56, and calcitonin. Molecular testing confirmed the presence of a BRAF mutation. Both RET and TRET were tested as well; however, both of them were negative. During the patient’s first postoperative visit, she was doing well, with no active complaints except for mild right-sided neck discomfort. Postoperative laboratory evaluation included calcitonin (CTN) and carcinoembryonic antigen (CEA), both of which were low (CTN <2 pg/mL; CEA <1.7 ng/mL). The patient developed transient postoperative hypocalcemia, an expected risk following central neck dissection; however, the potential oncologic benefit outweighed this risk. Her hypocalcemia responded well to supplementation, and calcium levels normalized within 2 months without any lasting impact on her quality of life. Also, postoperative surveillance included serial measurements of thyroglobulin and thyroglobulin antibodies (TgAb). Thyroglobulin levels remained very low: 0.124 ng/mL at 3 months and 0.068 ng/mL at 6 months, indicating an excellent biochemical response. TgAb levels were stable (12.05 IU/mL and 12.29 IU/mL, respectively), with no biochemical evidence of residual or recurrent disease. In addition, the patient’s thyroid stimulating hormone was maintained within the recommended low-to-normal range for low-risk well-differentiated thyroid carcinoma, in accordance with current postoperative follow-up guidelines. Postoperative care centered on supportive care with routine clinical monitoring, pain control, and scheduled laboratory and imaging follow-up. The patient was morbidly obese, with a body mass index (BMI) of 51, and she also scored 3 on the Eastern Cooperative Oncology Group Performance Status (ECOG-PS), indicating limited mobility and partial self-care ability for the majority of the day. The patient’s family favored observation over adjuvant therapy. Given the absence of disease on follow-up CT scans, this approach was deemed appropriate.

A whole-body iodine scan was deferred due to the inability to ensure appropriate patient isolation, as she required assistance for standing and had restricted right shoulder mobility. Additionally, clinical priority was directed toward managing the anaplastic component, which represented the most aggressive pathology.

Discussion

Thyroid malignancies typically follow well-established histopathological patterns, with PTC being the most common and MTC and ATC occurring far less frequently [1–3]. While synchronous occurrences of 2 thyroid malignancies, particularly PTC with either MTC or ATC, have been documented [6–8], the coexistence of all 3 in a single patient has been infrequently reported.

Throughout the literature, some articles have described case reports with mixed MTC and PTC occurring in the same lymph node, highlighting the potential for simultaneous tumor development within the thyroid and its metastatic sites [6,9]. Additionally, synchronous PTC and ATC have been documented, often presenting with aggressive features and poor prognosis [4]. The coexistence of PTC and MTC in patients with underlying thyroid pathology, such as Hashimoto’s thyroiditis, further supports the hypothesis of a shared microenvironment conducive to multiple tumor development [7].

A review of the literature describing cases with coexisting thyroid malignancies and similar clinical presentations shows that most patients typically present with a neck mass rather than other symptoms. In nearly all reported cases, the initial diagnostic approach involved ultrasound evaluation followed by fine-needle aspiration. Surgical management was the primary treatment modality, often complemented by adjuvant radiotherapy or chemotherapy. In contrast, our patient was not a suitable candidate for such therapies due to her clinical condition.

In one case, a 65-year-old man presented with a progressive multinodular goiter. Ultrasound revealed bilateral thyroid nodules, and fine-needle aspiration (FNA) of the left dominant nodule showed atypia of undetermined significance with atypical microfollicles and follicular cells. He underwent total thyroidectomy, and histopathology revealed synchronous multicentric papillary and medullary thyroid microcarcinomas without extrathyroidal, vascular, or lymphatic invasion. Postoperative radioactive iodine ablation was performed [1].

In another case, a 40-year-old man presented with a firm, painless right neck mass that had been present for 3 months. Ultrasound was normal, yet CT showed a calcified solid lesion in the right posterior triangle. FNA confirmed PTC. He underwent right lobectomy with lymphadenectomy, and histopathology revealed papillary and follicular variants with anaplastic transformation. Adjuvant radiotherapy followed [10].

In a final case, a 77-year-old woman presented with a right neck mass. FNA suggested PTC. Surgical pathology revealed PTC with focal anaplastic transformation (0.4 cm) invading adjacent soft tissue. She underwent total thyroidectomy without postoperative radioactive iodine. Later, recurrence with cervical lymph node and pulmonary metastases was confirmed as anaplastic carcinoma. BRAF mutation was detected, and dabrafenib/trametinib therapy was initiated [11].

Our patient’s presentation is distinct in that she had ATC, MTC, and PTC concurrently. While ATC is known for its aggressive course and rapid progression, the presence of MTC adds another layer of complexity due to its neuroendocrine differentiation and potential for distant metastasis [1–3]. PTC, though generally indolent, has been reported to coexist with other malignancies, but its synchronous presentation with ATC and MTC has not been widely reported [2,3].

The pathogenesis underlying synchronous thyroid malignancies remains unclear. Some hypotheses suggest a common genetic or molecular pathway leading to tumor dedifferentiation and transformation [5]. Recent studies have indicated unique molecular alterations in patients with synchronous thyroid neoplasms, which could provide insight into potential shared oncogenic mechanisms [8]. Additionally, environmental, and immunological factors may contribute to the development of multiple primary tumors within the thyroid gland [3,9].

Synchronous thyroid malignancies present unique diagnostic and therapeutic challenges. Treatment is typically guided by the most aggressive tumor subtype present [2].

Surgical management, primarily total thyroidectomy with central or modified neck dissection, is the standard initial approach in most cases [3,6,12]. For PTC components, postoperative radioactive iodine ablation and thyroid stimulating hormone suppression are commonly applied. However, these methods are ineffective for MTC or ATC due to the lack of iodine uptake [1].

Preoperative evaluation for MTC typically includes serum CTN, CEA, and RET mutation testing. In advanced or recurrent cases, targeted systemic therapies such as vandetanib and cabozantinib have shown success [2]. Similarly, BRAF-targeted treatments like dabrafenib and trametinib have demonstrated efficacy in mutation-positive, metastatic disease [4]. Despite these advances, personalized treatment remains limited by the rarity of these tumors. Integration of molecular profiling into routine practice may help improve outcomes in the future [12].

This case highlights the infrequent synchronous occurrence of ATC, MTC, and PTC within a single patient, underscoring the importance of a comprehensive diagnostic evaluation and individualized therapeutic planning. Future research should focus on elucidating the molecular and genetic mechanisms underlying the concurrent development of these distinct thyroid malignancies, which may guide earlier detection, improve risk stratification, and identify targeted therapy. Furthermore, systematic collection and analysis of similar cases could contribute to the development of evidence-based clinical guidelines for managing patients presenting with multiple synchronous thyroid carcinomas. Although PTC, MTC, and ATC have been extensively characterized individually, their combined occurrence remains poorly understood and presents unique diagnostic and treatment challenges that underscore the need for further studies and collaborative research efforts to define optimal management strategies.

Conclusions

This case illustrates the occurrence of synchronous PTC, MTC, and ATC in a single patient, each arising from distinct cellular lineages. The anaplastic transformation within metastatic lymph nodes, without involvement of the thyroid gland itself, adds to the uniqueness of the presentation. Given the aggressive nature of ATC, the neuroendocrine complexity of MTC, and the typically indolent course of PTC, this case highlights the importance of thorough histopathological evaluation, molecular profiling, and a multidisciplinary approach to management. It also highlights the need for further research into the molecular pathways and microenvironmental factors that may drive the concurrent development of multiple thyroid malignancies. Understanding these mechanisms may enhance early detection and inform more effective, personalized therapeutic strategies in similarly complex cases.