Diagnostic Workup for Thyroid Nodules

Initial Assessment

The National Comprehensive Cancer Network recommends that the diagnostic workup for thyroid nodules should begin with ultrasound-guided fine needle aspiration (FNA) of the nodule and clinically suspicious lymph nodes as the first diagnostic test, along with measurement of serum thyroid-stimulating hormone (TSH) 1, 2
Ultrasound (US) of the thyroid and central neck should be performed for all thyroid nodules, as it is essential for detecting and characterizing nodular thyroid disease 1, 3
Serum TSH measurement should ideally be obtained before FNA, as higher TSH levels are associated with increased risk of differentiated thyroid cancer 1
FNA should be performed in any thyroid nodule >1 cm and in those <1 cm if there are suspicious clinical or ultrasonographic features 3, 4

Suspicious ultrasound features that warrant FNA include microcalcifications 1, 3
Central hypervascularity is a suspicious ultrasound feature that warrants FNA 1, 2
Absence of peripheral halo is a suspicious ultrasound feature that warrants FNA 3
Shape (taller than wide) is a suspicious ultrasound feature that warrants FNA 3

The probability of malignancy increases with age <15 years and male gender 1
Family history of thyroid cancer increases the probability of malignancy 1
History of head and neck irradiation increases the probability of malignancy 1, 3
Firm nodule fixed to adjacent structures increases the probability of malignancy 1
Rapidly growing nodule increases the probability of malignancy 1
Enlarged regional lymph nodes increase the probability of malignancy 1
Vocal cord paralysis increases the probability of malignancy 1
History of diseases associated with thyroid carcinoma (familial adenomatous polyposis, Carney complex, Cowden's syndrome, MEN 2A or 2B) increases the probability of malignancy 1

US-guided FNA is more accurate, economical, safe, and effective than palpation-guided FNA 5
FNA specimens should be categorized according to the Bethesda System for Reporting Thyroid Cytopathology 2, 5
Cytologic examination typically categorizes specimens as: carcinoma or suspicious for malignancy; follicular or Hürthle cell neoplasm; follicular lesion of undetermined significance; thyroid lymphoma; benign; or insufficient biopsy 1

For indeterminate cytology results, molecular testing (BRAF/RAS, TERT, PIK3CA, TP53) can assist in diagnosis of benign versus malignant subtypes 3, 5
Serum calcitonin measurement should be considered as part of the diagnostic evaluation to detect medullary thyroid cancer, which has higher sensitivity compared with FNA 3, 4
Cervical lymph nodes should be evaluated by US when thyroid nodules are found 5

If FNA is inadequate or nondiagnostic, it should be repeated 3
For follicular neoplasia with normal TSH and "cold" appearance on thyroid scan, surgery should be considered 3
Pathology and cytopathology slides should be reviewed at the treating institution by a pathologist with expertise in diagnosing thyroid disorders 1

For benign nodules, follow-up with ultrasound is recommended at regular intervals 6, 7
For malignant nodules, treatment planning should include careful exploration of the neck by ultrasound to assess lymph node chains 4, 8

A reassuring FNA should not override concerns in the presence of worrisome clinical findings, as false-negative results can occur 1
Neither FNAB nor CNB can distinguish thyroid follicular adenoma from adenocarcinoma 5