Non-secretory medullary thyroid carcinoma with laryngotracheal invasion: a case report and review of the literature

Introduction

Thyroid cancer is a common thyroid disease worldwide and one of the most frequent endocrine malignancies (1). It is the second most prevalent neoplasm among females in Saudi Arabia (SA) (2). Between 2001 and 2013, the Saudi Cancer Registry recorded 7,670 instances of thyroid cancer, with females being more frequently affected than males. From 2001 through 2012, there were progressively more incidences of thyroid cancer, peaking at 893 cases in 2012 (2). Over 90% of malignant thyroid tumors are primary differentiated thyroid carcinomas (i.e., papillary, follicular, or Hurthle cell) and have an overall excellent prognosis. On the other hand, undifferentiated thyroid carcinomas are rare and usually progress rapidly (3). Medullary thyroid carcinoma (MTC) accounts for only 2–3% of all thyroid carcinomas and is responsible for up to 13.4% of all deaths associated with this disease (1,4,5). We describe a case of non-secretory MTC with laryngotracheal invasion in a middle-aged patient who underwent total thyroidectomy, total laryngectomy, and bilateral neck dissection, which was complicated by pharyngocutaneous fistula (PCF) postoperatively, in addition to a review of the literature. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-45/rc).

Case presentation

A 47-year-old male was referred to the otolaryngology clinic at King Abdulaziz Medical City (KAMC) as a case of undifferentiated thyroid cancer. The patient’s medical history included type 2 diabetes mellitus, hypertension, obesity, and depression. The patient was already on tracheostomy, which was performed as an emergency surgery in a different hospital due to airway compressive symptoms. During the preoperative evaluation, the patient exhibited no symptoms or signs of difficulty breathing or swallowing. The patient maintained good oxygen saturation (>95%) on room air, without signs of respiratory distress or oxygen requirement. Neck examination showed a 5 cm × 5 cm hard thyromegaly on the right side with right-sided level IV lymphadenopathy, measuring approximately 2 cm, with a healthy tracheal stoma. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A contrast-enhanced neck computed tomography (CT) scan revealed a large heterogeneous mass in the right thyroid gland, measuring 6 cm × 5 cm × 4 cm, extending to the right supraglottic, glottic, and subglottic regions. The mass was invading the thyroid, cricoid, and arytenoid cartilages and encasing the trachea and esophagus (Figure 1). A right level 4 metastatic necrotic lymph node measuring 2 cm was also observed. A tru-cut biopsy of the thyroid mass showed a neuroendocrine tumor consistent with MTC. A chest CT scan revealed bilateral highly suspicious pulmonary nodules (Figure 2), whereas an abdominal CT scan excluded the presence of pheochromocytoma. A positron emission tomography (PET) scan of the head and neck showed an intensely heterogeneous hypermetabolic thyroid mass with fludeoxyglucose (FDG) avidity, multiple hypermetabolic metastatic cervical lymph nodes, and multiple basilar-predominant sub-centimetric solid pulmonary nodules. No evidence of metabolically active metastatic disease was observed (Figure 3). Serum laboratory testing revealed a high thyroid stimulating hormone (TSH) level of 88.8 IU/L, normal calcitonin level of 14.5 pg/mL, and a T4 level at the lower border of the normal range, measuring 9.26 pmol/L, with an elevated carcinoembryonic antigen of 15.8 ng/mL, which is triple the normal limit.

Figure 1 A contrasted neck CT scan showing: a 6 cm × 5 cm × 4 cm right thyroid mass with right level 4 metastatic lymph nodes. (A) Coronal view. (B) Axial view. (C) Circumferential encasement of the trachea and esophagus. CT, computed tomography.

Figure 2 A contrasted chest CT scan showing: (A) bilateral pulmonary nodules in the right lower lobe. White arrow indicates the largest nodule. (B) An enlarged right hilar 1.5 cm and prominent mediastinal lymph nodes. CT, computed tomography.

Figure 3 PET scan of the head and neck showing: (A) heterogeneous hypermetabolic thyroid mass with ¹⁸F-FDG avidity. (B) Hypermetabolic metastatic cervical lymph nodes. (C) Basilar predominant sub-centimetric solid pulmonary nodules. PET, positron emission tomography; FDG, fludeoxyglucose.

A diagnosis of non-secretory MTC was established. The management options were discussed in the tumor board meeting and with the patient. Surgical management, including total thyroidectomy, total laryngectomy, and bilateral level II–IV neck dissection and central neck dissection, was performed after obtaining patient approval. Intraoperative findings revealed a hard right thyroid mass invading the strap muscles and trachea and abutting the esophagus. Pathological lymph nodes were identified in right levels 2, 3, and 4. The preservation of the major vessels and cranial nerves in the neck was ensured. The mass was meticulously dissected off the esophagus with a clear intact surgical plane. Anterior hypopharyngeal wall was closed with good tension-free mucosal coverage utilizing inverted Connel sutures after ensuring a negative surgical margin. The final histopathology report confirmed the diagnosis of non-secretory MTC T4aN1bM1 (stage IV).

Shortly during his inpatient stay, he developed hypocalcemia, reaching 1.85 mEq/L, and was treated with multiple intravenous infusions of calcium gluconate. After 2 weeks, the patient developed a right-sided neck abscess and PCF, which showed no improvement with conservative management. Subsequently, the patient underwent incision and drainage (I&D) of the neck abscess with right neck exploration. Intraoperatively, a right-sided neck abscess with an excessive greenish discharge was drained. The PCF, measuring approximately 2 cm, was closed primarily with absorbable single interrupted sutures. However, the PCF persisted with moderate pus and minimal erythema. Then, the patient underwent a third surgery for PCF repair using a pectoralis major myocutaneous flap. This included primary closure of the pharyngeal mucosa using a horizontal mattress suture aided by fibrin sealants (TISSEEL and tachoSil), followed by flap application. The fistula healed successfully after surgery.

The patient was discharged in a stable condition with a completely healed PCF and resolved hypocalcemia after 128 days of inpatient stay. To optimize fistula healing, the patient was discharged with a percutaneous endoscopic gastrostomy (PEG) feeding tube, which was removed in the clinic 4 months after discharge. He started adjuvant radiotherapy following discharge and successfully completed 33 sessions. No evidence of local recurrence while the lung nodule is still the same without any progression 6 months after completion of radiotherapy evident by clinical and radiological imaging. Table 1 demonstrates the chronological events of the case.

Discussion

MTC is a rare and aggressive type of thyroid cancer (1). Most MTCs occur in a sporadic form, while the familial form accounts for only 25% of the cases (3). Familial MTC can be classified into multiple endocrine neoplasia (MEN) type IIA, MEN type IIB, and non-MEN familial MTC. MTC arises from the parafollicular cells (C cells of the thyroid gland) in 5–10% of cases of thyroid malignancies (3,5). It occurs almost equally in both genders with no difference between the sporadic and hereditary forms (5). As MTC arises from parafollicular cells, calcitonin secreting cells, most of these carcinomas secrete calcitonin which is a highly specific and sensitive serum tumor biomarker (6). However, non-secretory forms of MTC are a well identified entity and very rare, accounting for less than 1% of the cases (7,8). Thyroid tumors can be labeled as non-secretory MTC based on histological and biochemical findings (3,8). Histologically, a biopsy typically reveals solid nests of ovoid or spindled cells within a fibrous stroma (5,6). Additionally, immunohistochemical stains show reactivity to neuroendocrine markers, such as synaptophysin, chromogranin, and CD56 as parafollicular cells have neuroendocrine origin (6). Calcitonin is often positive in immunostaining even in non-secretory MTC. However, as observed in our case, negative staining can occur. Immunohistochemical stains also demonstrate reactivity to thyroid markers, confirming thyroid origin, including thyroid transcription factor (TTF01) and paired-box gene 8 (PAX-8) (6).

MTC can present with a variety of symptoms, mostly as a palpable thyroid swelling that is similar in appearance to other thyroid nodules (4,5). Approximately 50% of MTC patients show signs of neck lymph node metastasis during clinical examination. Other signs and symptoms of thyroid cancer may include difficulty breathing, dysphagia, dysphonia, and coughing (5,9). In some cases, MTC may be detected incidentally in imaging studies or during surgery for a different condition (9).

Extracapsular invasion can be demonstrated in well-differentiated thyroid carcinoma patients, accounting for 5% to 15% of cases. This is mainly due to the direct extension of the primary tumor or extracapsular extension of the involved lymph nodes, resulting in invasive spread. In contrast, there are no reports of laryngeal or esophageal invasion in MTC (10,11). Abboud et al. conducted a retrospective study that included 197 patients diagnosed with thyroid cancer and treated via total thyroidectomy. Around 9% of patients were identified to have invasion of at least one adjacent structure. The most frequently reported signs and symptoms of upper aerodigestive tract invasion were hemoptysis, stridor, hoarseness, dysphagia, and aspiration. The most common sites of involvement were the overlying striated muscle (83%), recurrent laryngeal nerve (31%), larynx (35%), trachea (29%) followed by esophagus (17%) (10). In our case, the patient showed involvement of both the larynx and the trachea. The significant extent of the disease resulted in a crucial need for total thyroidectomy, total laryngectomy, and bilateral neck dissection. Martínez-Montoro et al. reported an early stage non-secretory MTC managed with total thyroidectomy alone without evidence of recurrence or persistence within 6 months follow-up (6). A systemic review by Gambardella et al. including 19 studies of non-secretory MTC with a total of 49 patients (11). The stage of disease was not mentioned in the review, and in majority of patients, type of surgery was not specified. Of those specified, five patients underwent total thyroidectomy, and seven underwent total thyroidectomy with neck dissection while one had a hemithyroidectomy. No adjuvant treatment was mentioned. Recurrence was recorded in seven patients with mean follow-up of 41 months.

Patients with suspected or confirmed MTC should undergo pre-operative staging to determine the extent of the disease and to identify comorbid conditions. Biochemical evaluation and neck ultrasound should be performed in all patients (12). Moreover, patients with confirmed lymph node metastases or high serum calcitonin levels should undergo preoperative chest and neck CT, three-phase contrast-enhanced multidetector liver CT, or contrast-enhanced magnetic resonance imaging (MRI) (8). Surgery is the mainstay of treatment for MTC because of its effectiveness. Systemic therapy has been recently incorporated as part of medical management in advanced disease. If rearranged during transfection (RET) protooncogene mutation is present, after establishing the diagnosis, RET mutations are evaluated to determine the possibility of medical management. As RET is considered a protooncogene and has an essential role in cellular regulation, RET-inhibitors use has good effect on patients with positive mutations. RET mutation is reported in around 50% of sporadic MTCs and in around 85% of advanced MTC cases (13). In advanced stages of disease, systemic therapy such as RET-inhibitors may be used to control disease progression. First- and second-generation RET-inhibitors have been developed with improved anti-tumor efficacy and safety profile in the second generation (13,14). Unfortunately, our patient was not a candidate for RET-inhibitors as next-generation sequencing was negative for any RET genetic alteration. As the patient is having a non-functioning larynx due to tumor invasion, a comprehensive discussion on treatment options ensued. Ultimately, the decision was made to proceed with surgery followed by postoperative radiotherapy to mitigate further local destruction and optimize disease control, after a thorough explanation of the procedure, potential adverse effects, and alternative options. A second line systemic therapy involves the use of chemotherapeutic in cases of progressively advancing MTC where patients fail or unable to tolerate RET-inhibitors (15). In addition, postoperative radiotherapy showed effective locoregional control (10,15). However, a study by Kukulska et al. found no overall survival benefit (16).

Patients may develop postoperative complications following total thyroidectomy. The observed complications include infection, temporary or permanent nerve injury, bleeding, and hypocalcemia (10,17). More extensive surgeries, including laryngectomy, may lead to additional complications, such as PCF, wound infection, flap necrosis, and aspiration pneumonia (18,19). These complications are significant and require close monitoring and treatment to ensure proper healing and recovery.

Hypocalcemia is a common complication following total thyroidectomy, accounting for 30–60%, with an increased incidence when performed in conjunction with total laryngectomy (17,19). In a study conducted by Phalke et al., it was observed that patients undergoing total laryngectomy with total thyroidectomy were 10.7 times more likely to develop hypocalcemia than those undergoing total thyroidectomy only (20). An additional risk of postoperative hypocalcemia in our patient includes central neck dissection as described by multiple authors (21,22). Furthermore, certain identification of all parathyroid glands was difficult with the large tumor which increased the risk of hypoparathyroidism. Hypocalcemia can occur transiently, persisting for 6–12 months, or permanently, accounting for only 3% of postoperative hypocalcemia cases (23,24). Various patient-related and surgical factors, including gender, age, thyrotoxicosis duration (<10 years before surgery), number of parathyroid glands identified, preoperative calcium and ionized calcium levels, parathyroid hormone levels post-surgery, and ligation of the inferior thyroid artery trunk, may increase the risk of developing hypocalcemia (24). Our patient developed transient hypocalcemia, which was managed with multiple intravenous infusions of calcium carbonate and oral cholecalciferol D3 tablets upon discharge.

PCF is a frequent complication post total laryngectomy, defined as an abnormal connection between the pharynx and the skin of the neck with clinical evidence of salivary leak (25). The incidence of PCF after total laryngectomy varies and is generally reported to fall within the range of 8–25% in the literature (25,26). The predisposing factors of PCF include patient-related factors (i.e., age more than 65 years, smoking, alcohol consumption, and malnutrition), systemic diseases (i.e., diabetes, coronary artery disease, and chronic kidney disease), and surgical factors (i.e., preoperative radiotherapy, previous tracheostomy, neck dissection and extended total laryngectomy) (25,27). The management of PCF includes conservative measures, such as wound care, nutritional support, and control of contributing factors (28). In more persistent cases, vacuum assisted closure (VAC) and surgical interventions, including the application of regional flaps, may be considered (28). The use of a prophylactic muscular flap in comparison to primary pharyngeal closure for prevention of PCF is controversial. Sanabria et al. report no significant difference between the two groups in the incidence of post-operative PCF while a systemic review by Guimarães et al., report a lower incidence in patient with pectoralis major flap after total laryngectomy (29,30). Our case exemplifies the complexity of PCF management, as our patient developed persistent PCF, which was managed surgically due to the failure of conservative management.

Conclusions

MTC is a rare type of thyroid neoplasia that can manifest with various symptoms resulting from either the primary lesion or secondary invasion. Surgery remains the mainstay of treatment, however, there are limited options and no approved adjuvant therapies for patients with disseminated MTC. Complications that arise after total thyroidectomy and laryngectomy can be noteworthy and demand careful surveillance and immediate treatment to prevent further deterioration.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-45/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-45/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-45/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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