Papillary thyroid microcarcinoma: the significance of high risk features

Multiple reports have identified a rising incidence of thyroid cancer over the past several decades, primarily due to the diagnosis of small papillary carcinomas [1, 2]. According to the World Health Organization, papillary carcinomas that measure 1.0cm or less are diagnosed as papillary thyroid microcarcinomas (PTMs) [3]. Recent work has suggested that PTMs are the most commonly diagnosed thyroid cancers in individuals who are older than 45 years, and accounts for almost one quarter of new diagnoses [1]. The clinical significance and recommendations for management of these PTMs is still evolving. In general, PTM is considered a clinically very low risk cancer type that uncommonly causes mortality, with a greater than 90% disease-free survival after long term follow up [2, 4, 5]. Reported rates for distant metastases and mortality from PTM are <0.05% [6]. However, some PTMs exhibit aggressive behaviour, including the development of a regional and distant metastases, and even death [7, 8].

The rising incidence of PTM, and its associated morbidity, requires risk stratification and guidelines for treatment. Currently, treatment of PTM is based upon stratification of cancer risk for aggressive behaviour, which is based on patient and cancer characteristics [2, 4]. Cancers considered high risk include those that are: multifocal, have extrathyroidal extension, have vascular invasion, are incompletely resected, have lymph node metastases, especially if multiple nodes are involved, nodes are > 3cm in largest dimension, or if extra-nodal cancer extension is present, and if distant metastases are present. The presence of these high risk features in a PTM influences the extent of surgery required for treatment [9]. Small PTM size (< 5mm versus ≥ 5mm) has also been suggested as being important for risk stratification, with some reports identifying PTMs ≥ 5mm as being more likely to have high risk features [8, 10, 11].

The objective of this study was to determine if small PTMs (size < 5mm) are clinically and pathologically different from larger PTMs (size 5mm- ≤ 10mm).

One hundred thirty-two of 1459 patients (9%) met study inclusion criteria and made up the study patient population.

PTM diagnosis is very common with almost half of all new papillary thyroid cancer (PTC) diagnoses being a PTM. Following thyroid surgery, pathologic identification of PTM ranges from 1–24% of surgical specimens [2, 5, 10], and 6–36% of autopsy specimens [2, 5]. Analysis of the Surveillance, Epidemiology and End Results database revealed that PTM in patients older than 45 years is now the most commonly diagnosed PTC [1]. Our observed rate of PTM diagnosed from surgical specimens in the absence of a thyroid macrocarcinoma was 9%, and was consistent with Canadian autopsy (6%) [12], international autopsy (3–18%) [2] and pathology data (1–24%) depending on the extent of surgical resection [2, 11].

Guidelines regarding the surgical management of PTC have continued to evolve and are currently based on clinical and pathological characteristics of the diagnosed individual and their thyroid cancer, respectively [9}. However, debate still exists regarding whether PTM should be managed in a manner similar to larger PTC [4]. PTM usually has an excellent prognosis and current American Thyroid Association Guidelines recommend that thyroid lobectomy alone is adequate treatment for unifocal intrathyroiodal cancers in the absence of a prior history of head and neck irradiation, familial thyroid carcinoma, or clinically detectable cervical metastases. As there are no features of PTM that can reliably identify the small subset of patients who will go on to develop clinically significant cancer progression, an active surveillance approach that involves close clinical and ultrasound PTM follow up, has currently not been adopted by the vast majority of centers [9]. An observational study, with non-surgical management of PTM, reported 3mm of growth in 6% of patients, with 1.4% of patients developing lateral lymph node metastases at 5 years of follow-up. These authors have suggested non-operative management of PTM in the absence of high risk features [13]. However, other groups have encouraged a surgical approach, which has shifted from thyroid lobectomy to total thyroidectomy, and some groups even recommend nodal dissection of the central neck. Proponents of the latter approach recognize the relationship between high risk features and disease recurrence [14, 15].

High risk features are often present in PTM and one-third of our patients had at least 1 high risk feature identified after pathological examination. While distant metastases were uncommon in our series (< 1%), consistent with other reports [6], multifocality was observed in almost a third of cases (28%) and 27% of these cases had bilateral disease. Reported multifocality rates for PTM have ranged from 15–43% [2, 15], with contralateral malignancy identified in up to 53% of cases [16]. Interestingly, multifocality is believed to reflect multiple independent tumors of different clonal origin, as opposed to intraglandular cancer metastases [17]. While the incidence of PTC multifocality is not related to tumor size [18] as we observed in the current study, it has been reported to be an independent risk factor for cancer recurrence [6, 17]. However, the prognostic significance of contralateral PTM is controversial. Given that only 5–10% of the PTCs recur, some investigators have suggested that recurrence can be treated when detected clinically, while other investigators have argued that reoperative surgery carries additional risks that need to be weighted appropriately [14]. The presence of lymph node metastases at the time of diagnosis also influences cancer recurrence risk and has been reported in 5–51% of cases [2, 15]. The current study observed a 7% rate of nodal disease at the time of PTC diagnosis is at the lower end of this range, but is consistent with the 9% nodal disease risk that has been recently associated with PTM [15]. This low rate of lymph node metastases may be an underestimate as the practice of central neck dissection for these cases is variable. Long-term follow-up of PTM has found that the presence of multifocality and lymph node metastases at diagnoses increases the risk of developing subsequent nodal disease, 11% of multifocal PTM recurred compared with 4% of unifocal PTM tumors [19].

Three of nine patients diagnosed with lymph node metastases at the time of their diagnosis had no other high risk features present. The presence of nodal metastasis in association with PTM is believed to represent different underlying cancer biology when compared with PTM not associated with nodal metastases [5]. Aggressive biological behavior may be related to molecular characteristics not yet well understood. Recent reports have identified molecular BRAF mutations, present in 17–52% of PTM, as potential early genetic lesions in PTC [2, 20]. Presence of BRAF mutations are associated with high risk features, including extrathyroidal cancer extension (ETE) and multifocality, and are also predictive of an increased risk of lateral compartment nodal disease [20]. Lin and colleagues have suggested that pre-operative screening for BRAF mutation using fine needle aspirate biopsy could potentially guide the initial treatment of PTM, with positive BRAF status requiring more aggressive therapy [20]. Other recent studies have found that combining BRAF mutations with a panel of other molecular prognosticators may improve its clinical utility [9].

Some investigators have reported that the tumor size of PTM (< 5 vs ≥ 5mm) may be related to aggressive cancer behavior, with larger PTMs being more likely to have high risk features and nodal metastasis [10, 21]. Other groups have found no relationship between PTM size and the presence of high risk features [22, 23]. Our study found that the size of PTM had little relationship with the presence of high risk features. Only ETE was significantly more commonly present in larger than smaller PTM. While the overall rate of ETE was low (5%), these observations were consistent with prior reports (2–21%) [2, 5]. Kim et al. [24] found that the presence of ETE was directly related to the PTM size but not with the risk of cancer recurrence. Other groups have evaluated the relationship between cancer size and high risk features concluded that PTM size did not influence patient outcomes [10, 21].

The current study has several limitations. It is a retrospective analysis from a single institution and results may not be generalizable to all populations. However, the prospective data collection from a multi-cultural catchment area in a publically funded health care system provides support of the representative nature of the sample. The incidental identification of PTC after surgery for benign disease implies that lymph nodes could be under-sampled, and presence of metastatic disease may be higher than our results suggest. As well, outcome and follow-up data is not available and thus no prognostic information can be inferred from this analysis.

The diagnosis of PTM after thyroid surgery presents the thyroid cancer management team with a dilemma. Neither PTM size, nor the absence of high risk features, excluded the possibility of synchronous lymph node metastases. While some argue that high risk features should prompt surgical management consistent with PTC >1cm, further study that includes the evaluation of the role of thyroid cancer molecular prognostications is required in order to identify the optimal management algorithm for this common endocrine malignancy.