A Case Report of Ret Negative Metastatic Medullary Thyroid Carcinoma: So Close Yet So Far

CASE DESCRIPTION

A 61-year-old gentleman presented with neck swelling of 6 months duration which was gradually progressive in size. It was not associated with pain, compressive symptoms or voice changes. He had no symptoms of hypothyroidism or hyperthyroidism. He had frequent loose stools for the last 3 months which were only controlled with anti-motility medications. For the above-mentioned complaints, he consulted a nearby doctor, and a workup was done. His thyroid function reports were within normal limits. Ultrasound of the neck showed a TIRADS 5 lesion in the left lobe of the thyroid with significant cervical lymphadenopathy. Fine needle aspiration cytology (FNAC) was done from outside reported as anaplastic thyroid carcinoma and so he was referred to our department. He had no family history of goiter on examination, he had grade 2 Goiter and a hard nodule with restricted mobility on the left side. There was multiple level 2–5 cervical lymph nodes on the left side. Carotids were normal in position on the right side and displaced on the left side. Lower border was palpable. We did a slide review of the same and also send serum calcitonin (CTN) and carcino-embryonic antigen (CEA). Calcitonin was reported as 37818 pg/mL (0–10.2) and CEA levels 1525 ng/mL (<3). His FNAC slide review came as medullary thyroid carcinoma. So, he was further evaluated for metastasis and to rule out multiple endocrine neoplasias 2 (MEN 2A). Rearranged during Transfection (RET) mutation analysis was planned. His plasma metanephrines and nor metanephrines were normal (Table 1). Computerized tomography of the neck, chest, and abdomen showed thyroid malignancy with bilateral cervical and mediastinal lymphadenopathy with no other metastasis (Fig. 1). So, he underwent total thyroidectomy + central compartment lymphadenopathy + bilateral neck dissection + sternotomy + mediastinal lymph node dissection with the help of intraoperative neuro monitoring a few months back. Intraoperatively left lobe of the thyroid (5 cm × 4 cm × 2 cm) was hard in consistency with dense adherence to the tracheal perichondrium and adherent to the cervical esophagus. The central compartment nodes on the left were large, and bulky and engulfed the left recurrent laryngeal nerve (RLN) which was sacrificed. Central compartment nodes on the left tracheoesophageal groove were extending down into the mediastinum. The Left Level 2–5 nodes were enlarged extending from level 2 in submandibular fossa region down to the internal jugular vein (IJV), subclavian confluence and also extending posteriorly to the confluence. Level 3 node was the largest (6 cm × 3 cm × 2 cm) which was densely adherent to the IJV, the resulting rent of IJV was closed with prolene. The right Level 2–5 region also contained nodes, smaller in size, largest 1.5 cm × 1 cm. The lowermost central compartment nodes, Pre and post brachiocephalic vessel nodal mass with fat cleared. The para-aortic nodes excised. The nodes around the phrenic nerve on the left side were separated out. The nodes near the pulmonary artery and the aortopulmonary window were also excised. Thymectomy and anterior mediastinal fat and nodes also cleared (Fig. 2). Postoperatively he had left RLN palsy and left phrenic nerve neuropraxia. Postoperative period was uneventful, with corrected calcium of 8.2 mg/dL on postoperative day 1 (POD1). Neck and chest drains were removed on days 4 and 5 and discharged. His histopathology report came as medullary thyroid carcinoma with lymph node metastasis pT3a N1b (Fig. 3). Out of total of 64 lymph nodes dissected, 46 were positive. After 2 months of surgery, Serum CTN was done which was dropped to 1676 pg/mL from 37818 pg/mL. His CEA levels also dropped to 45 ng/mL. As he had elevated CTN levels, Ga⁶⁸ DOTATOC PET CT was done which showed Subcentimetric lung nodules-suspicious lung metastasis (Fig. 4). He was started on tyrosine kinase inhibitor, cabozantinib 40 mg once daily dose for 2 weeks and then increased to 80 mg per day. But he didn’t tolerate the cabozantinib as he developed severe painful peeling and erythema of skin especially in hands and foot (Hand foot syndrome) (Fig. 5). Meanwhile RET mutation analysis report came as negative. After 4 months of surgery, his calcitonin dropped further to 420 pg/mL (Fig. 6). As he was RET negative and not tolerating cabozantinib, he kept under close follow-up with CTN and CEA level monitoring which was stable.

DISCUSSION

Medullary thyroid carcinoma is a rare neuroendocrine tumor of the thyroid gland, which causes high levels of calcitonin in blood.¹ It comprises of <5% of all thyroid malignancies. Around 25% of MTC is associated with a hereditary syndrome like multiple endocrine neoplasia 2.² Diagnosis and management of sporadic MTC is based on ultrasound neck, fine needle aspiration cytology, and staining for calcitonin, Serum calcitonin and carcinoembryonic antigen (CEA) levels and also rearranged during transfection (RET) gene mutation analysis. Medullary thyroid carcinoma is also diagnosed after thyroidectomy for indeterminate FNA results.³ Complete surgical resection of the tumor and locoregional metastasis is the only curative option for MTC. For metastatic or recurrent MTC, treatment options include surgical resection, external beam radiation therapy and systemic therapies or directed local therapies.⁴

Initial tumor burden and normalization of serum CTN levels post-operatively are the most important prognostic factors in patients with MTC after curative indent. There is no consensus regarding the time taken for CTN level to reach its minimum levels. However, patients with CTN >1000 pg/mL and >10 lymph nodes have prolonged time to normalize CTN levels which averages about 57.7 days.⁵ It should be kept in mind before planning of first post-operative CTN as in this case.

Medullary thyroid carcinoma is 75% sporadic and 25% familial. There are differences in the presentation of sporadic MTC compared to hereditary MTC. Sporadic MTC patients had more invasion and distant metastasis compared to hereditary MTC. Progression will be more in metastatic sporadic MTC compared to hereditary MTC. Hereditary MTC had a more microscopic disease, multifocality, smaller tumor size, and c-cell hyperplasia compared to sporadic variant.⁶

Complete surgical resection of thyroid and lymph node mass is the only curative option for MTC. As per the guidelines, the initial treatment of MTC was total thyroidectomy and central compartment lymph node dissection. In cases of MTC with no evidence of neck node metastasis ultrasound is based on CTN level. American Thyroid Association 2015 recommended the excision of involved lateral cervical lymph nodes with total thyroidectomy and central compartment lymph node dissection. From a recent study done by Niederle et al., MTC is subdivided into tumors with or without desmoplastic stromal reaction (DSR). They suggested intraoperative assessment of DSR in tumors and in DSR negative tumors, they did not require lymph node dissection.⁷ Primary tumors resection in patients with metastatic disease is controversial. To avoid adverse side effects, 2015 revised ATA guidelines recommended less aggressive surgery. As per the study from Zhuang et al., resection of primary tumors prolongs their median overall survival rather than palliation.

For patients with progressive or metastatic or symptomatic loco regional MTC, targeted therapies are an option. But they have issues of toxic side effects and development of tumor resistance as in our case. Vandetanib or cabozantinib as systemic therapy should be considered in patients with unresectable loco-regional metastasis and distant metastasis. As per phase III trials named ZETA and EXAM trial, they increased progression-free survival. In patients taking cabozantinib, around 50% discontinued the treatment due to adverse side effects.⁸ The recommended dose of cabozantinib was 140 mg/day, but in this case, he could not even tolerate 40 mg. Other multi-kinase inhibitors used in MTC are selpercatinib and pralsetinib. These two specific RET-kinase inhibitors were approved for RET mutant MTC.

CONCLUSION

The diagnostic and therapeutic strategies are different for medullary thyroid carcinoma patients from well-differentiated thyroid cancer. As per recent guidelines, individualized treatment options and follow-up strategies are adapted for medullary thyroid carcinoma. Extensive careful surgery is the only option for localized MTC. Vandetanib or cabozantinib should be primarily considered in patients with metastatic MTC. However, multi-kinase inhibitors are having significant side effects which can lead to poor quality of life. Molecular testing for RET mutation will be essential for finding an appropriate candidate who may benefit from selpercatinib or praseltinib, because these kinase inhibitors have favorable safety and complete response in a few cases.

ORCID

Shikhil Puzhakkal https://orcid.org/0000-0003-0302-0958

Pradeep Puthen Veetil https://orcid.org/0000-0002-2415-9644

REFERENCES

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