The Diagnostic Work-Up of Thyroid Nodules: Ruling out Papillary Thyroid Cancer

  • When to Evaluate Thyroid Nodules

    When to Evaluate Thyroid Nodules

    The ATA defines a thyroid nodule as “a discrete lesion within the thyroid gland that is radiologically distinct from the surrounding thyroid parenchyma.”<sup>2</sup> In iodine-sufficient countries, approximately 1% of men and 5% of women have a palpable thyroid nodule. However, prevalence rates with the use of high-resolution ultrasonography (US) range from 19% to 68%. Thyroid nodules are often detected incidentally during US, computed tomography (CT) scanning, or other imaging; these are called <i>incidentalomas.</i><sup>1,2</sup> More than 85% of thyroid nodules are benign. Nodules can be solitary or multiple. Patients with a solitary nodule have the same thyroid cancer risk as patients with multiple nodules.<sup>1,2</sup> Nodules >1 cm are more likely to be malignant and should be evaluated.<sup>2</sup> Nodules <1 cm should be evaluated if a patient has clinical symptoms or lymphadenopathy. Rarely, an asymptomatic nodule <1 cm that presents without lymphadenopathy will undergo malignant transformation.<sup>2</sup>

  • Physical Examination and History

    Physical Examination and History

    Nodules are more likely to be malignant in women or in people younger than 14 years or older than 70 years.<sup>1</sup> A detailed history and physical examination can identify other factors that increase the risk of thyroid cancer. These include radiation exposure from treatment or fallout during childhood or adolescence, thyroid cancer/thyroid cancer syndrome in a first-degree relative, a personal history of thyroid cancer, or prior positive nodules on [18F]fluorodeoxyglucose positron emission tomography (18FDG-PET).<sup>1,2</sup> Physical findings suggestive of malignancy include pain, dysphagia, vocal cord paralysis, significant voice changes, hoarseness, coughing, rapid nodule growth, cervical lymphadenopathy, and fixation of the nodule to surrounding tissue.<sup>2</sup> Evidence does not support routine thyroid cancer screening.<sup>2</sup> People with a family history of familial follicular cell-derived DTC may have an increased risk for this disease, but no evidence shows screening would improve patient outcomes.<sup>2</sup>

  • Initial Laboratory Testing

    Initial Laboratory Testing

    It is important to measure the serum thyrotropin (TSH) level in patients with a nodule >1 cm or who have clinical symptoms or lymphadenopathy. Further evaluation is required in patients with hyperthyroidism (overt or subclinical) or elevated TSH levels, which correspond with an increased risk of malignancy.<sup>2</sup> In anyone with a subnormal TSH concentration, a radionuclide thyroid scan (preferably 123Iodine) is indicated to assess the nodule’s functionality. (Note that radionuclide scanning is contraindicated in pregnant or lactating women.)<sup>2</sup> Hyperfunctioning nodules are rarely malignant and do not require cytologic evaluation. For the initial evaluation, ATA guidelines advise against measuring serum thyroglobulin (Tg), which is not sensitive or specific for thyroid cancer.<sup>2</sup> Data associate unstimulated serum calcitonin levels >50 to 100 pg/mL with medullary thyroid cancer (MTC), but ATA does not recommend this test unless an elevated level would affect the diagnostic or surgical approach.<sup>2</sup>

  • Ultrasonography in Diagnosis

    Ultrasonography in Diagnosis

    Gray-scale or Doppler US should be performed, preferably by an experienced operator, to assess the thyroid and anterior cervical lymph nodes in any patient with a known or suspected thyroid nodule.<sup>1,2</sup> Findings can help assess malignancy risk and plan FNA biopsy.<sup>2</sup> Nodules should be measured in 3 dimensions. The US report should describe the nodule’s location, composition, and features. The more suspicious features are present, the more likely it is to be malignant.<sup>1,2</sup> The following are features suspicious for malignancy: • Microcalcifications • Greater intramodular vascularity • Hypoechongenicity (82% to 91% of thyroid cancers are solid) • Irregular or infiltrative margins • Taller-than-wide on transverse view • Extrathyroidal extension • Cervical lymph node metastases. If a patient has multiple nodules, the sonographic pattern should be provided for each nodule. In patients with low TSH levels, radionuclide thyroid scan results should be compared with US images to assess functionality of nodules ≥1 cm.

  • When Fine-Needle Aspiration Is Indicated

    When Fine-Needle Aspiration Is Indicated

    When US findings suggest the need for further evaluation, FNA biopsy is preferred because of its accuracy and cost-effectiveness.<sup>2</sup> It has a false-negative rate of 1% to 3%.<sup>7</sup> Each nodule >1 cm carries the same risk of malignancy, so each suspicious nodule should be aspirated. Thyroid cytology is reported per the Bethesda system, which has 6 diagnostic categories: nondiagnostic/unsatisfactory, benign, atypia/follicular lesion of undetermined significance, follicular neoplasm/suspicious for follicular neoplasm, suspicious for malignancy, and malignant. Benign nodules need no further workup or treatment. If cytology is nondiagnostic (insufficient follicular cells for a diagnosis), guidelines call for US-guided FNA, which is more sensitive and specific than palpation-guided FNA. Waiting 3 months between initial and follow-up FNA is unnecessary.<sup>2</sup> 18FDG-PET scanning is not typically recommended for lesions with indeterminate cytology.

  • Thyroid Nodules and Malignancy

    Thyroid Nodules and Malignancy

    Almost all (>90%) thyroid cancers are well-differentiated, and they fall broadly into 2 categories: papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). PTC accounts for approximately 90% of DTC and has a 10-year survival rate >95%.<sup>5</sup> FTC has a 10-year survival rate of 85%. Less common types of thyroid cancer are medullary, which has a 10-year survival rate of 75%, and anaplastic carcinoma, an aggressive undifferentiated cancer with a 5-year survival rate of 7%.<sup>5</sup> Nodules with a high suspicious US pattern are likely PTC.<sup>2</sup> If FNA confirms PTC, surgery is generally advised. At diagnosis, approximately 30% of patients with PTC have cervical lymph node metastases vs 2% of patients with FTC.<sup>7</sup> Initial surgery involves excising the primary tumor, any extrathyroidal disease, and clinically significant lymph node metastases.<sup>2</sup> Preoperative CT or MRI with contrast are useful.2 In patients with PTC, cervical lymph node or distant metastases, age >45 years, and larger tumor size are associated with a worse prognosis.<sup>2</sup><i>Image Credit: Biophoto Associates/Science Source</i>

  • Aggressive Variants of PTC

    Aggressive Variants of PTC

    Histologically, PTC is a well-differentiated tumor that usually has a papillary growth pattern.<sup>2</sup> At least 10 microscopic variants of PTC exist.<sup>2,7</sup> Tall cell, columnar cell, and hobnail variants are more aggressive with worse survival outcomes than classical PTC. In tall-cell PTC, >50% of cells are 3 times taller than they are wide.<sup>2</sup> The tumors are often necrotic with a high mitotic index.<sup>7</sup> Tall-cell PTC is more common in older patients and has a higher recurrence rate.<sup>2</sup> The columnar-cell variant has mostly columnar cells with pronounced nuclear stratification and confers a greater risk of distant metastases. The hobnail variant is rare; cells have a hobnail appearance, atypically placed nuclei, and a bulging apical surface.<sup>2</sup> Lung metastases are more common with hobnail PTC. The solid and diffuse-sclerosing variants are also more aggressive than classical PTC.<sup>7</sup> It is critical to distinguish solid PTC from poorly differentiated thyroid carcinoma as they share many pathologic features.<sup>2</sup> <i>Image Credit: Steve Gschmeissner/Science Source.</i>

  • Less-Aggressive Variants of PTC

    Less-Aggressive Variants of PTC

    The follicular, oxyphilic, and cribriform-morular are less-aggressive PTC subtypes.<sup>7</sup> Follicular variant PTC (FVPTC) is the most common subtype of PTC. It has a follicular growth pattern, but its nuclear features are characteristic of PTC.<sup>2,7</sup> Distant metastases are uncommon with FVPTC tumors <2 cm.<sup>2</sup> FVPTC can be infiltrative or encapsulated.<sup>6</sup> The nomenclature for encapsulated FVPTC, which accounts for one-half to two-thirds of FVPTCs, was recently changed to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).<sup>6</sup> These tumors are indolent with a low risk of metastases and a recurrence rate <1%.<sup>2,6,8</sup> NIFTP excludes tumors with a high mitotic rate, tumor necrosis, more than one-third of solid growth, or the presence of psammoma bodies and >1% papillae.<sup>8</sup> The rationale for rebranding encapsulated FVPTC as NIFTP is that eliminating the word carcinoma would reduce the risk of unnecessary treatment for what is essentially a clinically benign tumor.<sup>8</sup> <i>Image Credit: Steve Gschmeissner/Science Source.</i>

  • Mutational Testing

    Mutational Testing

    Studies have linked several gene mutations to PTC.<sup>2,7</sup> For example, an Italian study found a BRAF mutation in 40% of PTC cases.<sup>9</sup> Nonencapsulated FVPTC tumors often contain BRAF mutations, whereas NIFTP tumors commonly harbor RAS mutations. In addition, approximately 80% of tall-cell PTCs and one-third of columnar-cell PTCs have a BRAF mutation.<sup>2</sup> BRAF mutations are also frequently found in hobnail PTC. Data show BRAF mutations in thyroid nodules are highly specific for malignancy but not highly sensitive.<sup>2</sup> A retrospective study tested a 7-gene panel that included BRAF, HRAS, NRAS, KRAS, and 2 RET/PTC rearrangements.<sup>7</sup> The panel had a positive predictive value of 80% to 95% in suspicious nodules.<sup>2,7</sup> Several studies evaluated a 167-gene expression classifier for presurgical diagnosis with inconsistent results. The ATA concluded that presurgical molecular testing may be helpful when results might affect decisions, but data are insufficient to recommend routine mutation profiling.<sup>2</sup>

  • Conclusion


    Many thyroid cancers can be effectively treated and therefore most patients with DTC have a favorable prognosis, even when they have lymph node metastases at diagnosis.<sup>2</sup> For low-risk PTC, total thyroidectomy is not always necessary; thyroid lobectomy alone may be sufficient. Radioactive iodine ablation is not routinely recommended for low-risk PTC.<sup>2</sup> Progress in understanding the genetic mechanisms of thyroid cancer may lead to the discovery of molecular markers or molecular signatures that could allow identification of thyroid cancers at greater risk of progression or recurrence or with less favorable survival outcomes. These molecular markers could potentially be used to identify therapeutic targets or existing targeted therapies that may prove effective in higher-risk PTC.<sup>2</sup>

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Almost half of people older than 40 years have a thyroid nodule.1 Most are benign and present little risk; only 7% to 15% are malignant. 2 In 2016, an estimated 64,300 cases of thyroid cancer were diagnosed, which is approximately double the number of cases diagnosed in 2002.3,4 Despite the rising incidence of thyroid cancer, mortality rates have remained relatively stable, and epidemiology experts say this points to overdiagnosis of subclinical disease.4,5

Recent studies have shown that most excess cases of thyroid cancer involved small indolent tumors that would likely have never been detected were it not for advances in imaging technologies and fine-needle aspiration (FNA).1,4,6 Many people received aggressive, risky, and costly treatments for these harmless tumors, previously known as encapsulated follicular variant of papillary thyroid carcinomas (EFVPTCs).6

In 2016, an Endocrine Pathology Society working group proposed revising the nomenclature for EFVPTC to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).6 Also in 2016, the American Thyroid Association (ATA) published updated evidence-based guidelines for diagnosing and managing adults with thyroid nodules and differentiated thyroid cancer (DTC).2 These changes should help clinicians and pathologists understand the variants of thyroid cancer better and improve their ability to communicate with one another and with patients about prognosis and treatment  needs.2


  1. Cosgrove D, Barr R, Bojunga J, et al. WFUMB guidelines and recommendations on the clinical use of ultrasound elastography: part 4. Thyroid. Ultrasound Med Biol. 2017;43:4-26.
  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;26:1-133.
  3. American Cancer Society. Cancer Statistics Center: 2016 estimates. Available at: Published 2016. Accessed December 12, 2016.
  4. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-2167.
  5. Hoang JK, Nguyen XV, Davies L. Overdiagnosis of thyroid cancer: answers to five key questions. Acad Radiol. 2015;22:1024-1029.
  6. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023-1029.
  7. Schneider S, Chen H. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J Clin. 2013;63:373-394.
  8. Tallini G, Tuttle RM, Ghossein RA. The history of the follicular variant of papillary thyroid carcinoma [published online October 12, 2016]. J Clin Endocrinol Metab. jc20162976
  9. Fugazzola L, Puxeddu E, Avenia N, et al. Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr Relat Cancer. 2006;13:455-464.

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