Thyroid carcinoma metastasizing to the submandibular gland: Sonographic findings

Abstract

Metastases to the submandibular gland are extremely rare; a literature search retuned only three previously reported cases from a thyroid gland primary site. Herein, we report two cases of metastatic thyroid carcinoma to the submandibular gland in a 64-year-old woman with PTC and a 70-year-old-woman with medullary thyroid carcinoma (MTC). The metastases were identified on CT and PET/CT in one case and on CT in the other case, but both were diagnosed with ultrasound-guided fine-needle aspiration. Our cases highlight that while rare, both PTC and MTC can metastasize to the submandibular gland.

1 ∣. INTRODUCTION

Metastases to the submandibular glands are extremely rare. Of the salivary glands, most metastases occur in the parotid gland from squamous cell carcinomas and melanomas of the head and neck area.¹ A literature search returned only three previous reported cases of metastases to the submandibular gland from a thyroid gland primary site, which included papillary microcarcinoma and occult papillary thyroid cancer (PTC).^2-4 In all three of these previously reported cases, the patients presented with a swollen submandibular gland which was subsequently biopsied using US-guided FNA to reveal metastatic papillary thyroid carcinoma. Herein, we present a case of PTC and, to the best of our knowledge, the first case of medullary thyroid carcinoma (MTC) metastasizing to the submandibular gland and describe the positron emission tomography (PET), computed tomography (CT), and ultrasound (US) appearances of each case.

2 ∣. CASE REPORTS

2.1 ∣. Patient 1

A 64-year-old woman with bilateral PTC (Stage IV T4aN1a) underwent a total thyroidectomy followed by radioactive iodine treatment at an outside institution. Approximately 6 months after treatment, her thyroglobulin (TG) level was 219 ng/mL. An outside PET/CT scan showed a 6 mm ¹⁸fluorodeoxyglucose (⁸FDG)-avid mass in the left trapezius (not shown) which was proven to represent metastatic PTC on subsequent tissue biopsy. Additional ¹⁸FDG uptake was present in the right neck but misinterpreted to be in a lymph node (Figure 1A). A CT scan of the neck with contrast retrospectively revealed a subtle 0.7 cm nodule in the inferior right submandibular gland (Figure 1B). US with power Doppler was performed to evaluate the FDG-avid node inferior to the right thyroid gland and demonstrated an avascular hypoechoic nodule (Figure 1C). An US-guided fine-needle aspiration (FNA) of this lesion revealed metastatic PTC (Figure 2A,B).

FIGURE 1.

A 64-year-old woman with papillary thyroid carcinoma metastatic to the right submandibular gland. (A) PET/CT reveals an FDG-avid focus in the right neck/submandibular gland (arrow). (B) CT scan shows a subtle hypodense mass in the anterior right submandibular gland originally thought to be a lymph node but retrospectively determined to be a metastasis (arrow). (C) Doppler US demonstrates an avascular, well-circumscribed slightly hypodense mass in the right submandibular gland which was biopsied to reveal metastatic PTC (arrows)

FIGURE 2.

Papillary thyroid carcinoma (patient 1). (A) Cell block preparation showing the papillary architecture and classic features of PTC (Cell block section, hematoxylin and eosin stain, ×100). (B) Characteristic cytomorphologic features of PTC in the aspirate smear with intranuclear pseudoinclusions (arrows) nuclear grooves (arrowheads; Cytologic smear, Papanicolau stain, ×400)

In both cases, US examinations were performed using a high-frequency linear transducer (5-18 MHz) attached to a Hitachi Aloka Arietta 850-SE Premium scanner (Hitachi Healthcare, Twinsburg, Ohio, USA) with color and/or power Doppler. The FNA was performed using a 20-gauge needle attached to a 20 cc syringe and one pass was performed in both cases. The specimens were immediately sent to the cytology lab where the diagnosis was made. This patient had a BRAF V600E mutation and thus was treated with dabrafenib and trametinib.

2.2 ∣. Patient 2

A 70-year-old woman underwent total thyroidectomy for MTC with somatic RET M918T mutation. Surveillance laboratory tests approximately 4 years later revealed markedly elevated levels of carcinoembryonic antigen (CEA; 171.3 ng/mL; normal <3.8 ng/mL) and elevated calcitonin (18 897 pg/mL; normal ≤7.6 pg/mL). CT scan of the neck with contrast demonstrated an exophytic left submandibular mass (Figure 3A). US, performed to evaluate the left submandibular mass, revealed a 1.2 cm multi-lobulated hypoechoic nodule in the left submandibular gland (Figure 3B,C) and an US-guided FNA was performed. Cytology interpretation of the FNA aspirate was consistent with metastatic MTC and confirmed by positive calcitonin expression by immunoperoxidase stain (Figure 4). The patient was subsequently treated with targeted systemic chemotherapy due to progressive distant metastases.

FIGURE 3.

A 70-year-old woman with medullary thyroid carcinoma metastatic to the left submandibular gland. (A) CT scan reveals an exophytic, peripherally enhancing left submandibular gland mass (arrow). (B) US shows a well-circumscribed hypodense mass in the left submandibular gland (arrows). (C) Power Doppler US demonstrates flow within the central portion of the mass (arrow)

FIGURE 4.

Medullary thyroid carcinoma (patient 2). MTC showing positive calcitonin expression assessed by immunoperoxidase stain (Cytologic smear, ×400)

3 ∣. DISCUSSION

Papillary thyroid carcinoma is the most common form of thyroid cancer, representing 80% of cases.⁵ Other types of thyroid carcinomas include medullary thyroid carcinoma, follicular thyroid carcinoma and undifferentiated (anaplastic) carcinoma. When thyroid cancer metastasizes, it typically spreads first to the cervical lymph nodes, followed by the lungs, liver and bone. In rare cases, thyroid cancer metastasizes to the parotid gland.^6-8 Herein, we present two rare cases of thyroid cancer, one PTC and one MTC that metastasized to the submandibular glands. Only three cases of PTC with submandibular gland metastases have been described in the literature. Similar to our study, one of these was from the contralateral thyroid lobe.³ To the best of our knowledge, our case of MTC metastasizing to the thyroid is the first case reported in the literature. In addition, our report shows that US may detect a submandibular metastasis even when the lesion is subtle (patient 1) and that US-guided FNA is a useful tool for diagnosis.

Characteristic cytologic features of PTC include nuclear enlargement, irregular nuclear contours, fine powdery chromatin, nuclear crowding, nuclear grooves, and intranuclear pseudoinclusions.^9,10 Thick colloid and psammomatous calcifications may be present. In addition, “clear” nuclei, termed “Orphan Annie Eye” nuclei may be seen in paraffin-embedded tissue sections.¹¹ In the majority of cases, US-guided FNA provides a rapid evaluation and diagnosis of suspicious nodules with PTC with minimal risk to the patient.

MTC arises from parafollicular C cells located adjacent to thyroidal epithelium. Parafollicular C cells are a type of neuroendocrine cells that secrete calcitonin. When these cells proliferate, as in the case of MTC, an abnormally high level of calcitonin can be detected in the serum. In addition, calcitonin may deposit in the thyroid stroma in the form of amyloid. The cytomorphologic features of MTC may be variable, but they commonly show oval to spindle cells with round nuclei and finely stippled chromatin. While rare and only comprising approximately 5% of thyroid carcinomas, MTC can be widely metastatic even at diagnosis.⁵

Germline mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with multiple endocrine neoplasia type 2 (MEN 2), which includes MTC. The RET M918T mutation is the most common somatic RET mutation associated with non-hereditary MTC.¹² Cabozantinib and vandetanib are currently approved by the Food and Drug Administration in the United States and internationally. MTC with the RET mutation can be treated with RET inhibitors such as BLU-667 and LOXO-292 which are now being studied in multi-institutional clinical trials.¹³

At our institution, a tertiary referral center for patients with cancer, surveillance imaging studies for patients with a history of treated thyroid cancer often undergo US, CT and PET to assess for tumor recurrence in the soft tissue of the thyroid bed, neck and distant metastases. Our US imaging protocol includes imaging of the thyroid bed, the submental, pre-laryngeal and suprasternal spaces, the submandibular glands, and the bilateral neck. Power Doppler is subsequently performed on all suspicious nodes and nodules. Suspicious nodes or nodules seen on US may undergo an US-guided FNA to exclude a new primary or metastatic tumor. This case report demonstrates that while rare, both PTC and MTC can potentially metastasize to the submandibular glands. Further study may be performed to evaluate the role of including the submandibular glands in the US surveillance of patients with thyroid cancer.

Abbreviations:

¹⁸FDG

¹⁸fluorodeoxyglucose

CT

computed tomography

FNA

fine needle aspiration

MTC

medullary thyroid carcinoma

PET/CT

positron emission tomography-computed tomography

PTC

papillary thyroid carcinoma

US

ultrasound