A 41-year-old male with a history of hypertension and multinodular goiter was found to have concerning features on a follow-up thyroid ultrasound. His thyroid ultrasound showed bilateral enlarging nodules with calcifications. The nodule in the right upper pole was 2.8 × 2.0 × 2.0 cm and in the left lower pole was 3.0 × 1.7 × 1.1 cm. He subsequently underwent ultrasound guided fine-needle aspiration of these nodules, revealing cellular adenomatoid nodule in the right nodule and findings highly suspicious for papillary carcinoma in the left nodule (i.e., areas of moderate cellularity, enlarged cells with focal nuclear pleomorphism, and single cells with dense cytoplasm, intranuclear inclusions, multinucleated giant cells, and psammoma bodies). Physical exam was notable for palpable bilateral thyroid nodules. He had no known family history of thyroid disease or malignancy and no personal history of radiation exposure. He also denied neck compressive symptoms or symptoms of hyper-or hypothyroidism. CBC-d and CMP were normal. Thyroid-stimulating hormone was 1.6 mU/L and free thyroxine (FT₄) was 1.5 ng/dL, both within the normal range.

A total thyroidectomy was recommended. Pathology from the total thyroidectomy showed the right side contained an adenomatoid nodule and the left side contained a 2.8 cm papillary thyroid cancer (PTC) with extrathyroidal extension, inked surgical margin, and skeletal muscle negative for malignancy; and 3 cm PTC on the left side, 10/28 lymph nodes positive (4 of 14 positive right level 3; 6/14 positive left level 3). Patient has Stage I PTC (T3N1). He proceeded to receive 150 mCi radioactive iodine ablation therapy under rhTSH stimulation. He was administered suppressive doses of levothyroxine to maintain a TSH of <0.01 mIU/L. His post-therapy whole body 131-I scan noted two foci of radioiodine uptake in the thyroid bed which were unchanged from his pretherapy scan. His stimulated thyroglobulin was 2.0 ng/mL and thyroglobulin antibody was <20 IU/mL.

One year after his initial surgery, his laboratory studies revealed TSH of <0.01 mU/L (at goal) and FT4 1.8 ng/dL with unstimulated serum thyroglobulin level of 0.4 ng/mL and the absence of thyroglobulin antibodies. He then underwent a rhTSH stimulated whole body scan, which showed no evidence of local recurrence or distant metastases. Neck ultrasound was also unremarkable. However, his stimulated thyroglobulin increased to 5.0 ng/mL, which will be followed closely.

Thyroid cancer is the most common endocrine malignancy, and its incidence and prevalence are on the rise. According to the American Cancer Society, the projected incidence of thyroid cancer for 2013 is 60,220 new cases (45,310 in women, and 14,910 in men) with 1,850 deaths from thyroid cancer (1,040 women and 810 men) [1]. Differentiated thyroid cancer includes both papillary and follicular thyroid cancer, which accounts for more than 90 % of all thyroid cancers, with papillary thyroid cancer prevailing (about 80–90 % of differentiated thyroid cancer are PTC). The higher incidence of papillary thyroid cancer, in part, is attributed to increased detection of small papillary thyroid carcinomas and more frequent use of neck and chest imaging leading to incidentally found thyroid nodules [2]. In the Unites States, there is no significant difference in the risk of thyroid cancer between solitary nodules and multinodular goiter [3]. Therefore, patients with multinodular goiter should be monitored closely as well, as in the case described above. However, the increasing frequency is not thought to be related to enhanced detection alone. If detection alone was the predominant factor, it is expected that most of the detected thyroid cancers would be Stage 1 disease. Yet, the mortality rate of older men with differentiated thyroid cancer is increasing at an alarming rate. Further, a recent molecular analysis of the frequency of BRAF mutations in PTC tissues samples has increased over the last 10–15 years [4].

There are several risk factors associated with PTC. These include female gender (three times more common in women), previous exposure to ionizing radiation, and rare hereditary conditions (e.g., Cowden’s syndrome). Approximately 5 % of patients with PTC will have familial PTC; the exact genetic cause has not yet been determined. Although mortality from thyroid cancer is low, the recurrence rate is 25–35 %, making risk stratification a priority. Prognostic factors such as age <15 or ≥45 years, male gender, tumor size >4 cm, follicular histology or tall and columnar cell variants, multifocality, initial local tumor invasion, and regional lymph node metastasis are associated with increased risk of recurrence [5]. Staging is an extremely important tool in management of patients with malignancy. Currently, the TMN (tumor, node, and metastasis) staging system is used which was proposed by the American Joint Committee on Cancer (AJCC) and the International Union against Cancer Committee (UICC). Patients under the age of 45 are subdivided into stage I or II, with the only difference being the presence of distant metastasis (stage II).

In patients 45 years and older: Stage I: Cancer is located only within the thyroid gland and is 2 cm or less. Stage II: intrathyroidal cancer larger than 2 cm and less than 4 cm. Stage III: Either the tumor is larger than 4 cm and only in the thyroid or the tumor is any size and cancer has spread to tissues just outside the thyroid, but not to lymph nodes; or the tumor is any size and cancer may have spread to tissues just outside the thyroid and has spread to lymph nodes near the trachea or the larynx. Stage IVA: Either the tumor is any size and cancer has spread outside the thyroid to tissues under the skin, the trachea, the esophagus, the larynx, and/or the recurrent laryngeal nerve; cancer may have spread to nearby lymph nodes; or the tumor is any size and cancer may have spread to tissues just outside the thyroid. Cancer has spread to lymph nodes on one or both sides of the neck or between the lungs. Stage IVB: cancer has spread to tissue anterior to the spinal column or has surrounded the carotid artery or the blood vessels in the area between the lungs; cancer may have spread to lymph node. Stage IVC: the tumor is any size and cancer has spread to distant sites, such as the lungs and bones, and may have spread to lymph nodes.

The American Thyroid Association (ATA) has developed a risk stratification system into low, intermediate, and high-risk patients. Low-risk patients have no metastases, all their macroscopic tumor has been resected, there is no tumor invasion of locoregional tissues or structures, the tumor lacks aggressive histology, and if I-131 remnant ablation is performed, there is no uptake outside the thyroid bed on the first post-treatment whole-body scan. The characteristics for intermediate-risk patients include either microscopic tumor invasion into the perithyroidal soft tissue, cervical lymph node metastases, I-131 uptake outside the thyroid bed on the first post-treatment whole-body scan, or tumor with aggressive histology or vascular invasion. High-risk patients have macroscopic tumor invasion, incomplete tumor resection, distant metastases, and elevated thyroglobulin levels out of proportion to what is seen on the post-treatment scan [6]. Patients can also be restratified based on their response to initial therapy following thyroidectomy and radioactive iodine remnant ablation and potentially be downstaged. This allows a more individualized risk assessment strategy. Based on clinical outcomes during the first 2 years of follow-up including suppressed Tg, stimulated Tg, and imaging studies patients are further re-staged according to their initial response into three groups: excellent response, acceptable response, or incomplete response. This has been proven to be especially useful in intermediate and high-risk patients since those who have an initial excellent response have a very low likelihood of disease recurrence [7].

Recently, advances have been made in identifying molecular markers from FNA samples that carry both diagnostic and prognostic value in the management of PTC. BRAF gene mutations occur in PTC, and in several other carcinomas as well, such as pulmonary carcinoma, although the exact BRAF mutations may vary. BRAF is a B-type Raf kinase, which is located in chromosome 7 and plays a role in regulating the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MEK–ERK) pathway, which affects cell division, differentiation, and secretion [8]. The incidence of BRAF gene mutations in patients with sporadic PTC ranges from about 40 % to 70 %. The most common BRAF mutation is a change in valine to glutamic acid at codon 600, designated BRAF^V600E, and accounts for more than 90 % of occurrences. BRAF mutations often insinuate a poorer prognosis and are associated with older age, tall cell variant, extrathyroidal extension, and later disease stage presentation (stage III and IV) [9]. In a recent retrospective, multicenter study by Xing, et al., 1,849 patients with PTC were studied and the presence of BRAF^V600E mutation was significantly associated with increased cancer-related mortality (5.3 % in the mutation-positive group vs. 1.1 % in the mutation-negative patients) [10]. Additionally, nearly 40 % of patients with micropapillary carcinoma (<10 mm) have the BRAF^V600E mutation, suggesting that it could be a useful tool for staging in the future [11]. However, some studies suggest that BRAF mutation is a rare clonal event, indicating that using BRAF separately as a prognostic factor remains controversial [12]. BRAF is not the only genetic variation found in PTC, as many as 70 % of patients with non-familial PTC have some type of gene mutation (ex. RET, Ras genes, NTRK1, Ret/PTC).

Several commercial molecular genetic tests are now available that purport to have improved diagnostic sensitivity and specificity for indeterminate thyroid FNAs. There are presently two commercially available tests currently on the market that may be used in conjunction with fine-needle aspiration: Veracyte Afirma ^® gene classifier and Asuragen miRInform™ thyroid panel. Veracyte uses a multigene expression classifier that compares gene expression from mRNA isolated from needle washings during a standard FNA to 167 genes that have been identified by Veracyte as characteristic of the genetic signatures of both benign and malignant thyroid nodules. These specific genes analyzed in this assay are not identified in their publications. In one study, the sensitivity is 92 % and specificity is 52 %, making this a useful rule-out test that can effectively identify benign nodules [13]. However, the clinical applicability of this test needs further confirmation. For example, does this high sensitivity to detect benign nodules apply in select groups of patients (e.g., older patients with a 5 cm nodule). The Asuragen panel, on the other hand, detects several of the key mutations involved with PTC, including BRAF, Ras, RET, and PAX8/PPar gamma. It is primarily used as a rule-in test with a high predictive specificity (98 %), meaning a positive test is likely malignant [14]. However, perhaps 50–70 % of PTC does not harbor one of these mutations. Therefore, a test that identifies a mutation is helpful whereas a negative test does not exclude the presence of thyroid cancer. These tests have promising roles in the management of PTC, but experience with molecular genetics remains limited, and should be interpreted on a case by case basis. At present, most clinicians may use one of these molecular tests and there are limited studies assessing the utility of using both tests in the same patient. There are, of course, additional cost considerations.

According to the American Thyroid Association (ATA) revised guidelines on the management and treatment of differentiated thyroid cancer from 2009, the initial surgical option for those with a tumor size of >1 cm, is a near-total or total thyroidectomy, as was done in the case of this patient. Thyroid lobectomy should be reserved for those with low risk disease, micropapillary carcinoma, unifocality, absence of lymph nodes, and no personal history of head and neck irradiation. All patients with FNA-proven differentiated thyroid cancer should be staged pre-operatively and undergo a neck ultrasound with node mapping evaluating the contralateral lobe and lymph nodes for the presence of disease [6]. Performing lymph node dissection at the time of thyroidectomy is controversial, and surgical expertise is warranted. Postoperatively, serum thyroglobulin and thyroglobulin antibodies should be monitored serially on all patients.