Metastatic Thyroid Neoplasm

1. Cause and Etiology

Metastatic thyroid neoplasms refer to malignancies that originate outside the thyroid gland and secondarily involve the thyroid, either by direct extension or, more commonly, via hematogenous or lymphatic spread. These are secondary tumors and must be distinguished from primary thyroid cancers such as papillary or follicular thyroid carcinoma.

Common primary tumors that metastasize to the thyroid:

Renal cell carcinoma (RCC) – most frequent
Lung carcinoma
Breast carcinoma
Gastrointestinal malignancies (especially colorectal)
Melanoma
Head and neck squamous cell carcinomas

Rarely, thyroid metastasis may be the first indication of an occult primary cancer elsewhere.

2. Pathophysiology

The mechanisms of thyroid metastasis include:

Hematogenous spread: Rich vascular supply makes the thyroid a theoretically common site for metastasis, though in practice, it's rare.
Lymphatic spread: Less common; usually seen with nearby malignancies.
Direct invasion: Seen in local extension from adjacent cancers (e.g., laryngeal, esophageal).
Despite the thyroid gland's rich blood supply, factors such as high iodine content, high oxygenation, and rapid blood flow may inhibit the seeding of metastatic tumor cells.

Once cancer cells seed in the thyroid parenchyma, they may:

Grow as discrete nodules, mimicking primary thyroid neoplasms
Infiltrate diffusely, which is less common

3. Epidemiology

Metastases to the thyroid are rare, accounting for 1–3% of all thyroid malignancies in surgical series, though autopsy studies suggest a higher prevalence (up to 24%).
More common in elderly patients, usually with a known history of malignancy.
The most common primary tumor is renal cell carcinoma, followed by lung and breast carcinomas.

4. Clinical Presentation

Metastatic thyroid lesions may be:

Asymptomatic, discovered incidentally on imaging or surgery
Presented as a rapidly enlarging neck mass
Associated with:

Dysphagia
Hoarseness (if recurrent laryngeal nerve involved)
Neck discomfort or pressure
Occasionally, hyperthyroidism or hypothyroidism, though most patients are euthyroid

Patients often have a known history of prior malignancy, although in some cases, thyroid involvement is the first manifestation of systemic disease

5. Imaging Features

Ultrasound (US)

Hypoechoic or heterogeneous nodules
Irregular margins
Microcalcifications (rare)
Increased vascularity
Nodules may mimic primary thyroid malignancies

CT/MRI

Useful in assessing the extent of disease, including extrathyroidal extension and regional lymphadenopathy
May show solid enhancing lesions, occasionally with necrosis

PET-CT

FDG-avid lesions in the thyroid may be metastatic
Useful for detecting other metastatic sites or locating an unknown primary

Scintigraphy

Most metastatic lesions are cold nodules on radioiodine scans, since they do not take up iodine

Histopathology and Immunohistochemistry

Core biopsy or FNA (fine-needle aspiration) is essential
Immunoprofiling helps differentiate metastasis from primary thyroid neoplasms:

Thyroglobulin, TTF-1 positive → primary thyroid cancer
PAX8, CD10, RCC marker → metastatic renal cell carcinoma
CK7/CK20, GCDFP-15, ER/PR → breast
S100, HMB-45 → melanoma

6. Treatment

Treatment depends on:

The primary site of the tumor
The extent of systemic disease
Whether the metastasis is isolated or part of disseminated disease

Options include:

Surgical excision (thyroidectomy): Considered in cases of isolated thyroid metastasis or for symptomatic relief (e.g., compressive symptoms)
Radiotherapy: For palliation or local control
Systemic therapy: Based on the primary cancer (e.g., targeted therapy for RCC, chemotherapy for breast/lung cancer)
Radioiodine therapy: Not effective for metastatic lesions, as most are non-iodine avid

7. Prognosis

Prognosis is generally poor, as thyroid metastasis usually reflects advanced systemic disease
Isolated thyroid metastasis, especially from renal cell carcinoma, may have a better prognosis following complete surgical resection
Median survival varies depending on:

Primary tumor type
Burden of disease
Response to systemic treatment

Reported survival post-thyroid metastasis diagnosis:

RCC: 4–5 years (if resected)
Lung or GI cancers: Often less than 1 year

Summary Table

Aspect	Details
Cause	Hematogenous spread from a distant primary malignancy
Common Primary Sites	Renal cell carcinoma, lung, breast, GI, melanoma
Pathophysiology	True parenchymal metastasis via blood or lymphatics; occasionally, direct invasion
Epidemiology	1–3% of thyroid malignancies (surgical series); more in autopsies
Clinical Signs	Neck mass, hoarseness, dysphagia, or asymptomatic
Imaging Features	Solid hypoechoic nodules, FDG-avid, cold on radioiodine scan
Diagnosis	Core biopsy or FNA with immunohistochemistry
Treatment	Surgery (select cases), systemic therapy, palliative radiation
Prognosis	Poor overall; better if isolated metastasis (e.g., from RCC)

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Case study: Progressive Neck Mass in a 53-Year-Old Man
Metastatic Thyroid Neoplasm

History and Imaging Findings

A 53-year-old man presented with a progressively enlarging neck mass.
A complete blood count (CBC) and comprehensive metabolic panel (CMP) revealed no abnormalities and were within normal limits.
A chest radiograph was subsequently obtained.

Quiz 1:

Which of the following is the most prominent finding on the chest radiograph?
(1) Bilateral multifocal pulmonary nodules
(2) Right upper lobe consolidation
(3) Bilateral pneumothoraces
(4) Right rib fracture
On the patient’s chest radiograph, a right-sided paratracheal soft tissue prominence may suggest an anterior mediastinal mass. Which of the following should be included in the differential diagnosis?
(1) Thymoma
(2) Teratoma
(3) Thyroid neoplasm
(4) Lymphoma
(5) All of the above

Additional Imaging
Contrast-enhanced CT images are shown below.

Quiz 2:

Which of the following is the most prominent finding on the chest CT scan?
(1) Right lower paratracheal mass with central necrosis
(2) Multiple bilateral pulmonary nodules
(3) Numerous pulmonary nodules in a random (miliary) distribution
(4) Large saddle embolus with multiple segmental and subsegmental emboli
(5) Both (1) and (2)
(6) Both (1) and (3)
(7) None of the above

Additional Imaging and Workup

Additional blood work revealed a significantly elevated thyroglobulin level of 310 ng/mL (reference range: 1.6–50 ng/mL).
The patient subsequently underwent total thyroidectomy.
Histopathological examination and molecular analysis revealed papillary thyroid carcinoma harboring both BRAF V600E and TERT promoter mutations.
Pre-therapy I-123 scan and post-therapy I-131 scintigraphy performed one week after treatment are shown below.

Quiz 3:

What is the key finding on the pre-therapy I-123 and post-therapy I-131 scintigraphy scans?
(1) No uptake related to pulmonary metastases in both lungs
(2) Multifocal uptake in both lungs is consistent with pulmonary metastases
(3) Uptake in the stomach is consistent with gastric metastasis
(4) None of the above
Is radioactive iodine ablation an effective treatment for this patient’s pulmonary metastases?
(1) Yes
(2) No

Findings and Diagnosis

Findings
Chest radiograph: Multiple diffuse pulmonary nodules suggestive of metastatic disease. Right paratracheal soft tissue prominence with leftward tracheal deviation.

Chest CT:
Multiple bilateral pulmonary metastases are present. A large mass arising from the right paratracheal thyroid region is observed, demonstrating central necrosis and mass effect, with leftward deviation of the trachea.

I-123 and I-131 Whole-Body Scintigraphy:
The I-131 scan demonstrates tracer uptake at the thyroidectomy bed. No focal tracer uptake is observed in the lungs to indicate metastatic nodules. Physiological uptake is noted in the salivary glands, gastrointestinal tract, genitourinary system, and liver.

Differential Diagnosis:

Thymoma
Metastatic teratoma
Metastatic thyroid neoplasm
Lymphoma

Final Diagnosis:
Metastatic thyroid neoplasm

Discussion

Metastatic Thyroid Neoplasm

Pathophysiology
Uncontrolled proliferation of papillary thyroid cells.
Mutations in the mitogen-activated protein kinase (MAPK) signaling pathway play a key role in tumorigenesis.
Independent genetic mutations, such as BRAF V600E and TERT promoter mutations, are associated with an increased risk of distant metastasis and reduced iodine avidity.

Epidemiology
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, accounting for approximately 85% of all thyroid cancers.
It is more common in females than males, with a female-to-male ratio of approximately 2.5:1.
Risk factors include a family history of syndromes such as Werner syndrome, Cowden syndrome, familial adenomatous polyposis (FAP), and multiple endocrine neoplasia type 2 (MEN2), as well as a history of head and neck radiation exposure.

Clinical Presentation

Palpable thyroid nodule or neck mass
Enlarged anterior cervical lymph nodes
At the time of diagnosis, up to 2–10% of patients exhibit extrathyroidal spread
Of these, approximately two-thirds have pulmonary metastases, and one-third have skeletal metastases

Imaging Features

CT is ideal for nodal staging, detection of distant pulmonary metastases (as nodules), and identifying osseous metastases from non-iodine-avid disease.
I-123 and I-131 whole-body scintigraphy: Papillary thyroid carcinoma concentrates radioactive iodine but not pertechnetate. However, in cases with specific genetic alterations such as BRAF V600E or TERT promoter mutations, distant metastases may lose iodine avidity.

Treatment

Surgical resection
Radioactive iodine ablation
Chemotherapy for non-iodine-avid metastases

References

(1) Choudhury PS, Gupta M. Differentiated thyroid cancer theranostics: Radioiodine and beyond. Br J Radiol. 2018;91(1091):20180136.

(2) Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133.

(3) Hoang JK, Sosa JA, Nguyen XV, Galvin PL, Oldan JD. Imaging thyroid disease: Updates, imaging approach, and management pearls. Radiol Clin North Am. 2015;53(1):145-161.

(4) Perros P, Boelaert K, Colley S, et al. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf). 2014;81 Suppl 1:1-122.

(5) Soe MH, Chiang JM, Flavell RR, et al. Non-iodine-avid disease is highly prevalent in distant metastatic differentiated thyroid cancer with papillary histology. J Clin Endocrinol Metab. 2022;107(8):e3206-e3216.

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