PAPILLARY THYROID MICROCARCINOMA
The vast majority of thyroid cancers are differentiated, and pathological examination reveals that most of these are papillary thyroid cancers (PTCs). The long-term prognosis and recommended treatment for patients with PTC are dependent on the stage of disease. Papillary thyroid microcarcinoma (PTMC) is defined by the World Health Organization (WHO) as a PTC 1.0 cm or smaller . These small lesions are being identified with greater frequency via ultrasonography and other imaging modalities, and frequently are identified incidentally at surgery for benign thyroid disorders. Recently, Hughes et al.  showed that PTMC is the most common thyroid malignancy in patients older than 45 years, based on the United States population.
Within the group of patients with PTMC, prognostic factors have not been well defined, and the clinical management of patients with PTMC remains nonstandardized. However, recent studies have explored clinical, sonographic, and pathological findings to determine which risk factors are associated with aggressive behavior. Niemeier et al. [3▪] delineated a clinical risk stratification system based on molecular marker status in combination with several histopathologic features. A number of studies have demonstrated that microcarcinomas have a more favorable prognosis than larger tumors; risk of mortality is generally between 0 and 1%. However, recurrent or persistent disease surprisingly is common. Several studies support the conclusion that total thyroidectomy is the procedure of choice for PTMC, as long as it can be performed safely.
Diagnosis and surgical approach
The increasing use of imaging procedures, such as ultrasonography of the neck, is identifying a large number of small thyroid nodules or ‘incidentalomas’. The first decision point for the clinician is whether to perform fine-needle aspiration (FNA) biopsy. Guidelines of the American Thyroid Association (ATA) are clear on this point with the recommendations that nodules greater than 1 cm should undergo FNA cytology . Smaller nodules should be biopsied on the basis of suspicious ultrasonographic findings, including calcification, increased intranodular vascularity by Doppler flow, solid or hypoechoic appearance, irregular or blurred margins, or a taller than wide shape . Other indications for biopsy of subcentimeter nodules are a patient history of radiation exposure or a family history of thyroid malignancy .
PTMCs are thought to have a different tumor biology than larger lesions in that they can remain indolent with minimal morbidity for decades. In a recent observational trial for PTMC, Ito et al.  studied 162 patients with PTMC based on FNA cytology. Approximately 70% of the patients were found to have stable tumors during an observational period of about 4 years with no intervention. However, although these tumors generally are considered clinically innocuous, some have an aggressive clinical behavior. The clinical significance of these small tumors is clarified by the series of 900 PTMCs reported by Hay et al. . The median tumor size was 7 mm, and 98% were histologically grade 1 tumors with no apparent local invasion. However, three patients did have distant metastases at presentation, and one-third of the patients who had positive lymph nodes at presentation were noted to have a higher risk of recurrence. A meta-analysis encompassing more than 4000 PTMCs demonstrated that 28% of tumors had lymph node metastases, 0.6% had distant metastases, 3.3% of patients experienced disease recurrence, and tumor-related mortality was 0.3% .
The risk factors associated with aggressive behavior of PTMCs are not well defined. However, as the clinician is faced with conflicting data bearing on the potential management of PTMC, it would seem logical that some form of risk stratification is required to determine which course of action to take . Clinical characteristics and parameters, such as patient age, sex, tumor size, tumor multifocality, vascular or capsular invasion, extrathyroidal extension, lymph node metastases, histological variants of PTMC, or the presence of molecular markers that may require more aggressive management, need to be considered to achieve minimal morbidity while still anticipating optimal outcomes [3▪,10].
In a study of 933 patients with PTMC, Lombardi et al.  identified several independent risk factors for extracapsular extension, including tumor size and cervical node metastases. The largest series of PTMC patients reviewed came from the Surveillance, Epidemiology, and End Results (SEER) Cancer Database of 18 445 patients [12▪]. Although the general consensus is that PTMC has an indolent course, 92 of these patients (0.5%) died of the disease. Risk factors of recurrence included age greater than 45 years, male sex, non-Caucasian race, extrathyroidal extension, and both lymph node and distant metastases. The authors found that the presence of two or more risk factors was associated strongly with disease-related mortality and could help to identify patients who should be considered for more aggressive management.
More recently, genetic markers have been explored to assess tumor behavior in PTC. Many studies have demonstrated the association between the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) valine-to-glutamic acid mutation at codon 600 (V600E) (BRAF V600E) and aggressive histopathologic features of PTC, risk of tumor recurrence, and cancer-related mortality . Niemeier et al. [3▪] analyzed a group of aggressive PTMC selected based on the presence of lymph node metastases or tumor recurrence, and compared it with a group of nonaggressive PTMC. The groups were matched for sex, age, and tumor size, but with no extrathyroidal extension. Importantly, the authors detected BRAF V600E in 77% of aggressive and 32% of nonaggressive PTMC, suggesting that the V600E mutation may be a marker of invasiveness and, together with histopathologic features of aggressiveness, may allow for clinical risk stratification of PTMCs.
The presence or absence of risk factors and aggressive features are important indicators in planning thyroid surgery of PTMC. Controversy continues regarding the optimal extent of thyroid resection in these subcentimeter cancers. Treatment of PTMC has been addressed in both ATA and European Thyroid Association (ETA) guidelines [4,14]. When PTMC is diagnosed preoperatively, routine total or near-total thyroidectomy is the main treatment to eradicate multifocal disease and decrease overall recurrence rate. Mercante et al.  reported on the course of 445 patients with PTMC followed for a median 5.3 years, of whom 404 had total thyroidectomy and 389 had radioactive iodine (RAI) ablation. Multifocality was present in 35%, extrathyroidal extension in 30%, and lymph node metastases in 41%. Neck recurrence or distant metastases was observed in 3.8%, with the significant independent risk factors of capsular invasion, lymph node metastases at presentation, or extrathyroidal extension.
Routine central compartment (Level VI) neck dissection also is an area of controversy. Recent studies from Korea addressed the role of prophylactic central lymphadenectomy for PTMC. One study supported prophylactic central neck dissection and recommended that the clinicopathologic features, such as male sex, tumor multifocality, and extrathyroidal extension, be considered for the determination of prophylactic dissection . However, a second study demonstrated that although prophylactic central neck dissection decreased postoperative thyroglobulin level, it was not helpful in decreasing short-term locoregional recurrence in patients with clinically node-negative PTMC . Although there are ample data that micrometastases are not infrequent, central lymphadenectomy comes with increased attendant risk of recurrent laryngeal nerve injury and hypoparathyroidism. If there are palpable, biopsy-proven, or grossly apparent metastases at the time of surgery, lymphadenectomy should be performed. However, if these conditions are not present and if postoperative RAI ablation is planned, dissection of nonpalpable lymph nodes probably is not essential .
Adjuvant therapy and clinical outcomes
Total or near-total thyroidectomy facilitates the postoperative administration of RAI for the purposes of thyroid remnant ablation and treatment. Pellegriti et al.  presented a retrospective cohort of 299 patients with PTMC. During follow-up of these patients, persistent disease was found in 26%, locoregional metastases in 23%, and distant disease in 3%. Tumor size was not predictive of recurrent disease. Although the initial management of PTMC often has been either subtotal or near-total thyroidectomy but without RAI ablation, the study authors supported total thyroidectomy followed by RAI ablation, particularly in patients with multifocal tumors, lymph node metastases, or vascular or capsular invasion. This was supported by Creach et al. , who retrospectively analyzed the therapies and outcomes of 407 patients with PTMC. Clinical characteristics that predicted for recurrent disease were greater tumor size, affected cervical lymph nodes, and lack of iodine-131 therapy. They recommended that patients with PTMC, particularly those with involved lymph nodes, be treated with thyroidectomy followed by thyroid remnant ablation with RAI.
The presence of the BRAF V600E mutation in PTMC has been shown to be associated with extrathyroidal extension, lateral neck lymph node metastases, multifocality, and tumor stages III and IV [3▪,20]. Targeted therapies with selective and nonselective inhibitors of BRAF V600E recently have begun clinical trials in patients with melanoma. Selective pharmacologic targeting of BRAF V600E may prove effective for treating patients with PTMC harboring this mutation .
MEDULLARY THYROID MICROCARCINOMA
Medullary thyroid microcarcinoma (MTMC) accounts for a growing number of thyroid tumors, particularly in thyroids removed prophylactically in patients with known RET proto-oncogene mutations (MEN IIa, MEN IIb, and familial medullary carcinoma syndromes), which carry an increased risk for medullary thyroid cancer (MTC) development . The majority of cases of MTC are sporadic; however, heritable forms account for approximately 25–30% of cases. In these cases of hereditary MTC, it is known that C-cell hyperplasia progresses to MTMC and later to MTC [23,24]. It is in these high-risk patients undergoing prophylactic thyroidectomies in whom most MTMCs are found.
Diagnosis, surgical management, and outcomes
Similarly to PTMC, the clinical management of MTMC is not clearly defined and remains nonstandardized. Establishing uniform guidelines for the management of MTMC is further complicated by the varying clinical presentations: patients mainly present either as the relative of a proband with MTC, or with incidental detection on imaging studies or thyroidectomy performed for other indications (and may or may not have a diagnosis of MTMC at the time of initial surgery). According to the ATA Medullary Thyroid Cancer Guidelines, all patients with a personal history of primary C-cell hyperplasia, MTC (including MTMC), or MENII, and all people with a family history consistent with MENII or FMTC should be offered RET testing . Timing of prophylactic thyroidectomy for RET mutation carriers depends on the level of risk of aggressive MTC associated with specific exon mutations, which are categorized A (high risk) through D (highest risk) in the ATA Medullary Thyroid Cancer Guidelines. Those carriers with the highest risk mutations are recommended to undergo prophylactic total thyroidectomy within the first year of life, and are often found to have MTMC despite early surgical treatment. Those with less high-risk mutations may delay prophylactic total thyroidectomy beyond 5 years of age if they have a normal serum calcitonin, normal annual cervical neck ultrasound, and a less aggressive family history.
Extent of prophylactic thyroidectomy in MENII carrier states is also unclear. Current evidence suggests that level VI central neck dissection may not be necessary unless there is clinical or radiologic evidence of lymph node metastases, nodules greater than 5 mm on ultrasound, or a basal serum calcitonin greater than 40 pg/ml (in patients older than 6 months) [25–29]. Children undergoing thyroidectomy suffer higher complication rates than adults; they have better outcomes when operated on by high-volume surgeons and should be referred appropriately to an experienced tertiary care center . High suspicion for concomitant pheochromocytoma must always be maintained, and biochemical screening for pheochromocytoma should be performed for any patient with MTC who is older than 10 years before any surgery is performed [25,31].
The increasing use of imaging procedures, including neck ultrasound, combined with the increased sensitivity of current imaging tests has led to increased detection of subcentimeter, nonpalpable nodules. In the absence of suspicious nodular features, family history of thyroid cancer, or history of radiation exposure, nodules less than 1 cm in size generally are not recommended for biopsy . Partly because of the low prevalence of MTC overall, there are no well defined ultrasound characteristics of MTC, and recent evidence indicates that preoperative diagnosis of MTMC is often difficult. A recent study by Trimboli et al.  showed a low frequency of ultrasound features commonly associated with PTC such as hypoechogenicity, microcalcifications, margin irregularity, and nodular vascularization in MTC, making predictions based on ultrasound findings difficult. Additionally, a recent study by Choi et al.  examined the difference in ultrasound characteristics of MTCs according to tumor size. Ultrasound findings were correlated with FNA biopsy and pathology results, and they found that MTMCs more frequently had spiculated margins, whereas MTCs (>1 cm) more commonly had smooth margins. They concluded that small MTC size (≤1 cm) and a smooth margin may be factors predicting false-negative FNA results.
Ultrasound-guided FNA biopsy is a cornerstone of evaluation of thyroid nodules. Diagnosis of MTC on FNA cytology is usually straightforward; however, there are potential pitfalls unique to MTMCs, as Yang et al.  have described. The cytological diagnosis rate was 66.6% for MTMC and 100% for MTC. When compared, the cytological features in MTMC were more subtle, with more colloid, less amyloid, more cohesion, more round cells and less discohesive single, spindle, or giant cell types. Needle washings for calcitonin may be helpful if there is suspicion for MTC or MTMC at the time of biopsy.
Somatic mutations of the RET proto-oncogene in sporadic cases of MTC are present in approximately 40–60% of patients . Recently, a high prevalence of H-ras and K-ras mutations has been described in RET-negative MTCs, and there is hope that further clarification of the genotype–phenotype relationship may allow for tailored treatment based on aggressiveness of specific mutations and targeted molecular adjuvant treatment in the future . Several types of somatic RET mutations have been reported in sporadic MTC, but the most common mutation is M918T in exon 16, with a prevalence of approximately 90% in those with somatic RET mutations and known correlation with an advanced stage at diagnosis and poorer prognosis [37,38]. Romei et al.  recently described a lower than expected prevalence of the M918T mutation in MTMC relative to MTC, suggesting that a separate oncogene mutation may be responsible for the majority of MTMC, or that this mutation may occur late in tumor proliferation, as it is rarely found in tumors less than 2 cm in size. Further investigation is needed to draw specific conclusions from these findings regarding treatment and prognosis.
Serum calcitonin is a sensitive marker for MTC, and a basal level greater than 10 pg/ml is generally considered abnormal in most studies that screen for MTC . Mild elevations (<30 pg/ml basal) may indicate MTMC, C cell hyperplasia, or benign disease . Although routine calcitonin screening of patients with nodular thyroid disease is not widely practiced in the United States, European studies have shown improved outcomes for patients with MTC detected by serum calcitonin screening. This has been shown to be cost-effective in the United States [41,42]. There are no standard guidelines for calcitonin specific to MTMC, but use of calcitonin levels to personalize timing of prophylactic thyroidectomy in RET mutation carriers has been described by Elisei et al. .
The extent of surgery in patients with sporadic MTMC is controversial. Unfortunately, MTC is known for its propensity to spread to lymph nodes and distant organs. Surgical extirpation of the primary tumor and involved lymph nodes is the only possibility of cure, and MTC is notoriously difficult to cure if not treated early [26,27]. Controversy exists regarding the clinical significance of MTMCs and the extent of appropriate surgical management, with some groups arguing that tumors less than 0.5 cm in patients with RET-negative MTMC do not require completion thyroidectomy, while others continue to treat MTMC aggressively with a minimum of total thyroidectomy and central compartment lymphadenectomy [44,45]. New data indicate that MTMCs carry a significant risk of lymph node metastasis and elevation of postoperative serum calcitonin (a surrogate marker of persistent disease). Machens and Dralle  retrospectively analyzed 233 patients with hereditary and sporadic MTMC and found that with increasing incremental tumor diameter, there was an increase in lymph node metastases and a decrease in biochemical cure rates, with up to 62% of patients with hereditary disease and 43% of patients with sporadic disease harboring lymph node metastases.
Furthermore, even with tumors less than 1 cm in size, there is debate on size criteria which predicts lymph node metastasis. Previously, Pillarisetty et al.  reviewed 18 patients with sporadic MTMC. They reported that tumors less than 0.5 cm were associated with a complete absence of clinically detectable nodal disease or elevated postoperative calcitonin levels, and therefore argued that completion thyroidectomy may not be necessary in these circumstances. In contrast, Kazaure et al.  recently performed an analysis of 310 MTMC patients from the SEER database found that approximately 37% of patients with examined lymph nodes had metastases and 12% had greater than 10 positive lymph nodes. Notably, MTMCs less than 5 mm in size had a 23% probability of lymph node metastases, and that probability was higher for tumors greater than 5 mm in diameter. More than 5% of patients with MTMC had distant metastases at the time of diagnosis.
RAI treatment is not indicated for MTMC. External beam radiation treatment and systemic treatment may be useful in the subset of MTMC patients with persistent unresectable disease or distant metastasis. Not specific to MTMC, new strategies to treat metastatic MTC are being developed and include targeted kinase inhibitors, radioimmunotherapy, and vaccine-based therapies [48,49].
In summary, total or near-total thyroidectomy is the treatment of choice in patients with PTMC in order to eradicate multifocal disease and decrease overall recurrence rate. If there are palpable, biopsy-proven, or grossly apparent metastases at the time of surgery, central lymphadenectomy should be performed. However, if these conditions are not present and if postoperative RAI ablation is planned, dissection of nonpalpable lymph nodes probably is not essential. Patients with PTMC, particularly those with involved lymph nodes, should be offered postoperative administration of RAI for the purposes of thyroid remnant ablation and treatment. For PTMC with BRAF V600E-positive testing, targeted therapies based on selective inhibitors of BRAF V600E could be effective in the near future.
MTMC may present as part of a hereditary syndrome or as sporadic disease. The biological significance of MTMC is uncertain, but recent studies indicate that a number of patients will present with nodal and distant metastasis, and that some patients will have persistent elevated calcitonin postoperatively despite seemingly adequate surgery. Prophylactic thyroidectomy in hereditary cases may be guided by knowledge of specific exon mutations and calcitonin levels. Extent of surgery for both hereditary and sporadic cases is unstandardized, and further studies are needed to clarify this issue. Treatment of metastatic or recurrent disease is similar to that for MTC and newer treatments are in development.
Conflicts of interest
L.S.W. and S.A.M. report that no competing financial interests exist.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 100).
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