Evaluation and Management of Indeterminate Thyroid Nodules: The Revolution of Risk Stratification Beyond Cytological Diagnosis

Abstract

In accordance with National Guidelines, we currently follow a linear approach to the diagnosis of thyroid nodules, with management decision based primarily on a cytological diagnosis following fine-needle aspiration biopsy. However, 25% of these biopsies render an indeterminate cytology, leaving uncertainty regarding appropriate management. Individualizing the risk of malignancy of these nodules could improve their management significantly. We summarize the current evidence on the relevance of clinical information, radiological features, cytological features, and molecular markers tests results and describe how these can be integrated to personalize the management of thyroid nodules with indeterminate cytology. Several factors can be used to stratify the risk of malignancy in thyroid nodules with indeterminate cytology. Male gender, large tumors (>4 cm), suspicious sonographic patterns, and the presence of nuclear atypia on the cytology are all associated with an increased cancer prevalence. The added value of current molecular markers in the risk stratification process needs further study because their performance seems compromised in some clinical settings and remains to be validated in others. Risk stratification is possible in thyroid nodules with indeterminate cytology using data that are often underused by current guidelines. Future guidelines should integrate these factors and personalize the recommended diagnostic and therapeutic approaches accordingly.

Keywords: biomarkers; cytology; diagnostic imaging; differential diagnosis; histology; oncogenes; thyroid nodule.

Figure 1.

Current diagnostic approach for a newly diagnosed thyroid nodule.

Figure 2.

Theoretical performance of molecular marker tests for indeterminate thyroid nodules with either high-suspicion sonographic pattern or nuclear atypia. The sensitivity (Sn) and specificity (Sp) of the tests were calculated for cytologically indeterminate thyroid nodules (Bethesda III and IV) with the information provided in the original validation studies. The expected negative (solid red line) and positive (solid blue line) predictive values were calculated using a prevalence of malignancy of 45% (dashed purple line).^,, NPV indicates negative predictive value; PPV, positive predictive value.

Figure 3.

Proposed algorithm for evaluation and management of indeterminate thyroid nodules. Prevalence of malignancy in parenthesis and most frequent malignancies for each scenario derived from Moffitt retrospective data. Note that other institutions could have different findings. Non-ATA suspicion sonographic pattern includes heteroechoic nodules and iso or hyperechoic nodules with at least 1 suspicious sonographic feature. ^aConsider surgery if large (>4 cm), symptomatic or patient preference. Consider repeating FNA if cytological specimen was of limited quality (scant cellularity/ preparation artifact) in a solid nodule. ^bRepeat FNA is the preferred approach for A/FLUS unless management is already decided and unlikely to change with a different cytological diagnosis. Consider diagnostic surgery if large (>4 cm), symptomatic, patient preference, or if molecular markers are not available. Molecular markers could be helpful if surgery is not already indicated for other reasons, but their performance has not been validated in specific sonographic or cytologic scenarios, and negative results might need to be interpreted with caution. ^cIn the absence of other indications for total thyroidectomy, a lobectomy is usually appropriate for A/FLUS or F/HN even if mutations are identified with oncogene panels. Consider repeating biopsy before surgery in A/FLUS. A/FLUS indicates atypia/follicular lesion of undetermined significance, ATA, American Thyroid Association; FC, follicular cell predominance without nuclear atypia; FNA, fine needle aspiration; F/HN, follicular/Hürthle cell neoplasm; FTC, follicular thyroid carcinoma; FVPTC, follicular variant of papillary thyroid carcinoma, includes encapsulated noninvasive tumors (NIFTP, asterisk denotes when NIFTP are the most frequent tumors); NA, nuclear atypia; OF, oncocytic features; OTA, other types of atypia such as air drying or clotting artifacts, atypical lymphocytes, atypical cyst-lining cells, reactive changes. Other, nonfollicular cell-derived malignancies (in our series lymphoma); PTC, conventional papillary thyroid carcinoma.

Figure 4.

Thyroid cytology–histology correlation. (A) Traditional view of thyroid cytology–histology correlation. (B) Current view of thyroid cytology–histology correlation. Borderline/precursor lesions include neoplastic lesions without clear evidence of invasion or minimally invasive, with or without papillary-like nuclear features.