Cases are presented in light of the current diagnostic and therapeutic trends in management of thyroid nodules and well-differentiated cancers. Demographic, historical, and population-based risk factors are used to risk stratify cases. Ultrasonographic features and other imaging are discussed with regard to appropriateness of utilization and impact on management. The role of traditional cytologic and histopathologic analysis with fine-needle aspiration and intraoperative frozen sections is discussed, including diagnostic nuances and limitations. The emerging role of biomarkers such as Braf are evaluated regarding their role in contemporary assessment of thyroid nodules by reviewing practical cases.
Key points
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Assessment of risk of thyroid nodules requires understanding of clinical, demographic, imaging, cytopathologic, and now biomarker profiles; none of these factors alone represents a sufficient decision-making factor.
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Ultrasonography represents an accurate and cost-effective imaging modality for evaluating the thyroid, cervical lymphatics, and postoperative thyroid bed.
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Most solid or mixed thyroid nodules greater than 1 cm should undergo cytologic evaluation before surgery with increasing consideration for universal or selective use of biomarker assays.
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Biomarkers such as Braf add value to standard cytopathology in identifying suspected well-differentiated thyroid cancers.
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Biomarkers have prognostic value and with additional confirmatory information may help decision making regarding extent of surgical treatment and application of adjuvant treatments.
Introduction
In 2013, in the United States, it was estimated that 60,220 new cases of thyroid cancer would be diagnosed and 1850 deaths would be caused by thyroid cancer. Thyroid cancer affects women more often than men and usually occurs in people between the ages of 25 and 65 years. The incidence of this malignancy has been increasing over the last decade. Approximately 60,000 thyroid surgeries are performed annually, of which 33% (20,000) are thyroid lobectomies.
Thyroid cancer risk factors include a history of radiation, goiter, a family history of thyroid disease, the female gender, and the Asian race. Established clinical prognostic factors in well-differentiated thyroid cancer include age greater than 40 years, extrathyroidal/extracapsular invasion, vascular invasion, male gender, follicular disease, and tumors greater than 4 cm. Lymph node status does not seem to affect disease-free survival.
Risk of a nodule being malignant include size, cold nodule status, ultrasonographic (US) features (microcalcifications and increased nodular vascularity), a neck radiation exposure history, a family history in 1 or more first-degree relatives, associated lymphadenopathy on presentation, cytopathology (Bethesda grade) ( Box 1 , Table 1 ), and biomarker results (Afirma [Gene Expression Classifier Veracyte, Inc, San Francisco, CA, USA], MiRInform Thyroid [Asuragen, Inc, Austin, TX, USA], Thyroseq [University of Pittsburgh, Pittsburgh, PA, USA], microRNA).
- I.
Nondiagnostic or unsatisfactory
Cyst fluid only
Virtually acellular specimen
Other (eg, obscuring blood, clotting artifact)
- II.
Benign
Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule)
Consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context
Consistent with granulomatous (subacute) thyroiditis
Other
- III.
Atypia of undetermined significance or follicular lesion of undetermined significance
- IV.
Follicular neoplasm or suspicious for a follicular neoplasm
Specify if Hürthle cell (oncocytic) type
- V.
Suspicious for malignancy
Suspicious for papillary carcinoma
Suspicious for medullary carcinoma
Suspicious for metastatic carcinoma
Suspicious for lymphoma
Other
- VI.
Malignant
Papillary thyroid carcinoma
Poorly differentiated carcinoma
Medullary thyroid carcinoma
Undifferentiated (anaplastic) carcinoma
Squamous cell carcinoma
Carcinoma with mixed features (specify)
Metastatic carcinoma
Non-Hodgkin lymphoma
Other
| Diagnostic Category | Risk of Malignancy (%) | Usual Management a |
|---|---|---|
| Nondiagnostic or unsatisfactory | 1–4 | Repeat FNA with US guidance |
| Benign | 0–3 | Clinical follow-up |
| Atypia of undetermined significance or follicular lesion of undetermined Significance | ∼5–15 b | Repeat FNA |
| Follicular neoplasm or suspicious for a follicular neoplasm | 15–30 | Surgical lobectomy |
| Suspicious for malignancy | 60–75 | Near-tota1 thyroidectomy or sugica1 lobectomy c |
| Malignant | 97–99 | Near-total thyroidectomy c |
a Management may depend on other factors (eg, clinical, sonographic) besides the FNA interpretation.
b Estimate extrapolated from histopathologic data from patients with repeated atypicals.
c In the case of suspicious for metastatic tumor or a malignant interpretation indicating metastatic tumor rather than a primary thyroid malignancy, surgery may not be indicated.
Molecular testing is a developing modality to be used judiciously in clinical practice. Much needs to be studied and reported regarding optimal and cost-effective use of molecular testing in the context of nodular thyroid disease ( Table 2 ). This article includes cases that we hope show how molecular biomarker testing of thyroid nodule fine-needle aspirates (FNA) may be appropriately leveraged in a thyroid surgical practice ( Table 3 ).
| Component | Description | Optimization |
|---|---|---|
| Pathology | Follicular-derived lesions and neoplasms have overlapping features Certain neoplasms (eg, classic papillary carcinoma) have characteristic features | Development of tests distinguishing the pathobiological nature of lesions |
| FNA operator | Aspiration technique Capillary (nonaspiration) technique | Cellular specimen reflecting the architectural pattern of cell proliferation |
| Specimen processing | Direct smears Liquid-based slides Cell block Collection in molecular preservative | Slides: monolayer of well-preserved and well-stained cells without artifacts Ancillary studies: preservation of nucleic acid and protein molecules |
| Interpretation and reporting | Bethesda classification (6 tiered) | Standardization and application of criteria for uniform diagnostic practice |
| Ancillary studies | Molecular markers: BRAF, RAS, RET/PTC, PAX8/PPAR-γ Immunohistochemical markers: HBME-1, galectin-3, CITED-1 Others under development | High sensitivity and specificity for malignant neoplasms |
| Thyroid Cytology | |
|---|---|
| Classes of FNA Results | Usefulness of Molecular Testing |
| Negative (II) | Not useful |
| Rule out follicular neoplasm (III) | Useful |
| Follicular neoplasm (IV) | Most useful |
| Suspicious for malignancy (V) | Probably useful (30%–40% still benign at pathology) |
| Positive (VI) | Not useful |
Introduction
In 2013, in the United States, it was estimated that 60,220 new cases of thyroid cancer would be diagnosed and 1850 deaths would be caused by thyroid cancer. Thyroid cancer affects women more often than men and usually occurs in people between the ages of 25 and 65 years. The incidence of this malignancy has been increasing over the last decade. Approximately 60,000 thyroid surgeries are performed annually, of which 33% (20,000) are thyroid lobectomies.
Thyroid cancer risk factors include a history of radiation, goiter, a family history of thyroid disease, the female gender, and the Asian race. Established clinical prognostic factors in well-differentiated thyroid cancer include age greater than 40 years, extrathyroidal/extracapsular invasion, vascular invasion, male gender, follicular disease, and tumors greater than 4 cm. Lymph node status does not seem to affect disease-free survival.
Risk of a nodule being malignant include size, cold nodule status, ultrasonographic (US) features (microcalcifications and increased nodular vascularity), a neck radiation exposure history, a family history in 1 or more first-degree relatives, associated lymphadenopathy on presentation, cytopathology (Bethesda grade) ( Box 1 , Table 1 ), and biomarker results (Afirma [Gene Expression Classifier Veracyte, Inc, San Francisco, CA, USA], MiRInform Thyroid [Asuragen, Inc, Austin, TX, USA], Thyroseq [University of Pittsburgh, Pittsburgh, PA, USA], microRNA).
- I.
Nondiagnostic or unsatisfactory
Cyst fluid only
Virtually acellular specimen
Other (eg, obscuring blood, clotting artifact)
- II.
Benign
Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule)
Consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context
Consistent with granulomatous (subacute) thyroiditis
Other
- III.
Atypia of undetermined significance or follicular lesion of undetermined significance
- IV.
Follicular neoplasm or suspicious for a follicular neoplasm
Specify if Hürthle cell (oncocytic) type
- V.
Suspicious for malignancy
Suspicious for papillary carcinoma
Suspicious for medullary carcinoma
Suspicious for metastatic carcinoma
Suspicious for lymphoma
Other
- VI.
Malignant
Papillary thyroid carcinoma
Poorly differentiated carcinoma
Medullary thyroid carcinoma
Undifferentiated (anaplastic) carcinoma
Squamous cell carcinoma
Carcinoma with mixed features (specify)
Metastatic carcinoma
Non-Hodgkin lymphoma
Other
| Diagnostic Category | Risk of Malignancy (%) | Usual Management a |
|---|---|---|
| Nondiagnostic or unsatisfactory | 1–4 | Repeat FNA with US guidance |
| Benign | 0–3 | Clinical follow-up |
| Atypia of undetermined significance or follicular lesion of undetermined Significance | ∼5–15 b | Repeat FNA |
| Follicular neoplasm or suspicious for a follicular neoplasm | 15–30 | Surgical lobectomy |
| Suspicious for malignancy | 60–75 | Near-tota1 thyroidectomy or sugica1 lobectomy c |
| Malignant | 97–99 | Near-total thyroidectomy c |
a Management may depend on other factors (eg, clinical, sonographic) besides the FNA interpretation.
b Estimate extrapolated from histopathologic data from patients with repeated atypicals.
c In the case of suspicious for metastatic tumor or a malignant interpretation indicating metastatic tumor rather than a primary thyroid malignancy, surgery may not be indicated.
Molecular testing is a developing modality to be used judiciously in clinical practice. Much needs to be studied and reported regarding optimal and cost-effective use of molecular testing in the context of nodular thyroid disease ( Table 2 ). This article includes cases that we hope show how molecular biomarker testing of thyroid nodule fine-needle aspirates (FNA) may be appropriately leveraged in a thyroid surgical practice ( Table 3 ).
