Incidence and Clinical Impact in Papillary Thyroid Microcarcinoma With Lateral Cervical Node Metastasis


 BackgroundsLateral lymph node metastasis (LNM), which significantly impacts papillary thyroid carcinoma (PTC) patients’ prognosis. Papillary thyroid microcarcinoma (PTMC) is known to have a much better prognosis than non-PTMC, but it has not been known whether there is such a difference even with lateral LNM. MethodsThis retrospective study included a series of 3336 consecutive PTC patients who underwent thyroidectomy. Of them, 206 had lateral LNM and were divided into the PTMC and non-PTMC groups by tumor size (1-cm) for comparing the prevalence of prognostic factors. ResultsLNM was in 157/1131 (13.9%) non-PTMC patients and 49/2205 (2.2%) PTMC patients. Eleven of the 206 (5.3%) lateral LNM cases not found on US were only seen on computed tomography. The prevalence of prognostic factors which include an age of >55 years, >5 metastatic lymph nodes (LNs), high metastatic-to-examined LN ratio, and large metastatic LNs (>3 cm) were not significantly different between PTMC and non-PTMC group. ConclusionIn PTC with lateral LNM, the prognosis is likely to be similar regardless of tumor size. Considering the modest risk of lateral LNM in PTMC, FNA for small thyroid tumor and radiologic tests for lateral LNM should be encouraged.


Introduction
Papillary thyroid carcinoma (PTC) accounts for 90% of all thyroid carcinomas, and its prevalence is increasing owing to the recent development and dissemination of ultrasonography (US) and US-guided ne needle aspiration (FNA) [1,2]. Papillary thyroid microcarcinoma (PTMC) refers to a cancer with a maximum tumor diameter of ≤10 mm; most PTMCs have been reported to have a good prognosis [3]. In the recently published 2015 American Thyroid Association (ATA) guidelines, if the size of the nodule is <1cm, FNA should not be performed even if the US ndings are highly suspicious of malignancy [4]. In addition, some studies have suggested that active surveillance is a better option for patients with PTMC than immediate surgery [5,6].PTC is characterized by frequent lymphatic metastases. It has been reported that lymph node metastasis (LNM) develops in approximately 30% to 80% of patients with PTC [7]. The incidence of LNM in PTMC is known to range from 3.1% to 81%, although it differs among studies [8]. In particular, lateral LNM has a signi cant impact on patients' prognosis [9,10] and is present in ~3.7-55% of PTMC [8,[11][12][13][14][15][16]. PTMC is known to have a much better prognosis than non-PTMC, but it has not been known whether there is such a difference even with lateral LNM.We supposed that if tumors <1-cm was not performed histologic examination according to the current guidelines, LNM may not be detected considering that most clinicians do not make enough effort, such as performing US and computed tomography (CT) for lateral neck node assessment. As such, the appropriate timing of the diagnosis and treatment of lateral LNM is likely to be missed, and the patients' prognosis may be adversely affected.The number and size of metastatic lymph nodes (LNs) in the neck are known as important predictors of the prognosis of patients with PTC with lateral LNM [17]. In addition, the ratio of metastatic LNs to the examined LNs (LNR) has been proposed as an important predictor of recurrence [18][19][20].Therefore, we investigated the incidence of lateral LNM in PTMC in our center and compared the prevalence of factors, which were previously known as a high risk of recurrence in previous studies, between PTMC and non-PTMC in PTC with lateral LNM. We also investigated the detection rate of lateral LNM in US and CT. Ultimately, this study was intended to examine the necessity of histological con rmation of small thyroid nodules and evaluation of lateral LNs.

Materials And Methods
We retrospectively collected the clinico-pathologic data of 3,392 patients diagnosed with PTC who underwent thyroidectomy in our center from January 2008 to December 2015. The exclusion criteria consisted of history of thyroidectomy (n=38), concurrent medullary or anaplastic thyroid carcinoma (n=4), and follow-up loss (n=14). Finally, 3,336 patients were enrolled in this study. Of them, 206 patients underwent prophylactic/therapeutic bilateral central compartment neck (level VI; pretracheal, prelaryngeal, and paraesophageal LNs) dissection and therapeutic lateral cervical neck (levels IIa, III, IV, and Vb, not including the sternocleidomastoid, jugular vein, and accessory nerve) dissection (LCND) after lateral LNM was diagnosed on the basis of the preoperative examination ndings. These patients were divided into the PTMC and non-PTMC groups. All patients were diagnosed using US-guided FNA biopsy for thyroid nodules before surgery. To con rm the presence of LNM, real-time US and contrast-enhanced CT were performed; all images were assessed by 1 of 3 radiologists who specialize in diseases of the neck and thyroid with >5 years of experience. FNA was performed on the suspicious lateral neck LN for metastasis assessment on US, which was de ned as follows: hyper-echogenicity (higher than the surrounding muscles), cystic change, loss of fatty hilum, calci cation, round shape, and abnormal vascular pattern [21][22][23]. If the cytology for FNA revealed metastatic LNs or thyroglobulin in the LNs with a washout uid level of ≥10 ng/dL, the condition was diagnosed as a metastatic LN. If not visible on US but strongly suspected on CT, the selective node that was grossly enlarged or had a suspicious feature was excised; intraoperative frozen biopsy before LCND then followed. The suspicious CT features were as follows: presence of calci cations, central necrosis or cystic change, and heterogeneous cortical enhancement or enhancement more than that of the adjacent muscle [21][22][23]. As recommended in the ATA guidelines [4], prophylactic LCND was not performed. This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital (KBSMC 2017-04-037).

Clinico-pathologic analysis
We compared the incidence of lateral LNM between the PTMC and non-PTMC groups and analyzed their clinico-pathologic factors. In addition, the prognostic difference between the 2 groups was indirectly analyzed by comparing the differences in the factors affecting the prognosis, which were demonstrated in previous studies [19,20,24]. Ito et al. [24] reported that patients under the N1b stage who underwent LCND had a high recurrence rate if they were older than 55 years or had a metastatic node size of ≥3 cm. In other patients, the LNR was helpful in predicting the prognosis in addition to the number and size of metastatic LNs. Lee et al. [19] reported that the LNR (levels II-VI) had a cutoff value of 0.5, which was associated with patients' prognosis. Park et al. [20] reported that the loco-regional recurrence-free survival was affected by the presence of >6 metastatic nodes and by a cutoff value of 0.22 for the LNR. Based on these previous results, the differences between the 2 groups were compared using the clinico-pathologic data of the patients in this study.

Statistical analysis
All statistical analyses were performed using R version 3.3.2 [22,23,[25][26][27][28]. For comparison between the PTMC and non-PTMC groups, the t-test for continuous variables and Fisher's exact test or Chi-square test for categorical variables were used.

Results
Of the total 3,336 patients with PTC, 2,205 (66.1%) had PTMC, and 1,131 (33.9%) had non-PTMC. Further, 206 patients (6.2%) had lateral LNM and consequently underwent therapeutic LCND. LCND was performed in 157 of the 1,131 (13.9%) non-PTMC patients and 49 of the 2,205 (2.2%) PTMC patients ( Figure 1). These patients who underwent LCND were divided into the PTMC and non-PTMC groups; the differences in the clinico-pathologic factors are summarized in Table 1. The proportion of men tended to be higher in the PTMC group (PTMC: 42.9% vs non-PTMC: 27.4%, p=0.062). The pathologic tumor size of the PTMC group was 0.7±0.3 cm, and that of the non-PTMC group was 1.9±0.8 cm. The largest size of the metastatic LNs was 1.1-cm in the PTMC group and 1.3 cm in the non-PTMC group; however, the difference was not signi cant (p=0.188). The multifocality, bilaterality, vascular invasion, and BRAF mutation were not signi cantly different between the 2 groups as well. Only the percentages of gross extrathyroidal extension (p<0.001) and lymphatic invasion (p=0.047) were signi cantly higher in the non-PTMC group.

Comparison of the clinico-pathologic factors affecting the prognosis
We compared the differences in the predictive factors of recurrence, which were demonstrated to be associated with patients' prognosis in previous studies on patients who underwent LCND with lateral LNM and the 2015 ATA guidelines [4,19,20,24]. An age of >55 years, >5 metastatic LNs, high LNRs (cutoff value: 0.22 and 0.5), and large metastatic LNs (>3 cm), which were factors related to a poor prognosis, were slightly more in the non-PTMC group; however, the difference was not signi cant ( Table   2).
3.2. Necessity for detailed imaging studiesIn our institution, radiologists with an experience of >5 years and a specialization in thyroid imaging performed US and assessed the CT images. Neck US and CT for preoperative staging were performed in all patients diagnosed with thyroid cancer after FNA.
Nevertheless, the number of patients with lateral LNM not found on US was 4 (8.2%) in the PTMC group and 7 (4.5%) in the non-PTMC group; that of patients with lateral LNM not found on CT was 5 (10.2%) in the PTMC group and 21 (13.4%) in the non-PTMC group. The sensitivity of US was 94.9% and that of CT was 87.4%.

Discussion
Because of the recent rapid increase in the number of diagnoses and surgeries performed for thyroid cancer, several studies have questioned the need for indolent PTMC surgery, and there has been a controversy regarding the clinical necessity for FNA for small thyroid nodules [29,30]. The 2015 ATA guidelines recommended against FNA for thyroid nodules smaller than 1-cm, even for those with highly suspicious US patterns [4]. Although this is limited to cases not accompanied by extrathyroidal extension or suspicious cervical LN, many clinicians questioned this guideline.Although PTMC is a small-sized cancer of <1-cm in diameter and is an indolent cancer, it has been reported that 3.1% to 18.2% of lateral LNM and up to 20% of loco-regional recurrences exist [31][32][33]. We reported that the incidence of lateral LNM in PTMC was 2.2%, which is lower than previously reported results, but is thought to be a relatively high value when considering the known indolent nature of PTMC. Lateral LNM requires patients to undergo a wide-extent surgical procedure, resulting in a higher morbidity [9,34]. In addition, it is a crucial risk factor for distant metastasis, which is associated with increased mortality [10,35]. In our study, An age of >55 years, >5 metastatic LNs, high LNRs, and large metastatic LNs (>3 cm), which were factors related to a poor prognosis, [17][18][19][20] were not signi cantly different between non-PTMC and PTMC. Therefore, even for PTMC, evaluation of lateral LNM is important. However, although there is a difference among institutions, careful examination of the lateral nodes is not always performed in patients without a pathologic diagnosis of malignancy. There is a possibility that the diagnosis of lateral LNM can be missed if <1-cm tumors are not pathologically con rmed, which may be the reason for encouraging FNA of suspicious ≤1-cm nodules.The ATA guidelines recommend preoperative neck US for cervical (central and especially lateral neck compartment) LNs for all patients undergoing thyroidectomy for malignant or suspicious for malignant cytologic or molecular ndings [4]. US is a very useful test for the detection of thyroid diseases and cervical lymphadenopathy and the most recommended technique for detecting LNM. However, the accuracy rate of cervical LN evaluation has been known to be ~48.1% [36], and the diagnostic values for lateral LNM showed a wide range in various studies (sensitivity, 64-95%; speci city, 50-97.9%) [21-23, 28, 37]. It is because US is an operator-dependent examination and utilized by physicians in various specialties, including radiologists, endocrinologists, and surgeons. In our study, sensitivity of US for lateral LNM was relatively high as 94.9%, probably because neck US was always performed to evaluate cervical LNs after diagnosis of cancer. The consensus on the usefulness of using neck CT in addition to US in detecting lateral LNM remains unclear. CT is not recommended for routine use for preoperative staging of differentiated thyroid cancer and is only considered if advanced cancer is suspected [4,21,38]. Kim et al. [21] demonstrated that US/CT combination was superior to US alone in the detection of metastatic LNs in the lateral neck. Conversely, Yoon et al. [28] proved that CT does not provide additional diagnostic values when combined with US in the diagnosis of LNM. In our study, 11 of the 206 (5.3%) cases of lateral LNM not found on US were only seen on CT. Therefore, CT added to US may have a higher diagnostic accuracy, so further research on the usefulness of CT in PTC is needed.To the best of our knowledge, this is the rst study to compare the clinical features of PTMC and non-PTMC among PTC with lateral LNM. The strength of this study is that it minimized selection bias because both CT and US were performed for preoperative staging in all patients diagnosed with thyroid cancer in our institution. In addition, US and CT readings were performed by experienced specialists in thyroid disease. Conversely, the limitation of this study is the indirect prognostic analysis through comparison of known prognostic factors. This is because, due to the relatively short follow-up period and a small number of recurrent events, no signi cant value could be obtained by survival analysis. In the future, it will be necessary to con rm these results by performing further analysis with survival data.

Conclusions
The incidence of lateral LNM in PTMC was 2.2%, which was thought to be a relatively high value when considering the known indolent nature of PTMC. There was also no signi cant difference in the prevalence of clinico-pathologic factors with prognostic values between the PTMC and non-PTMC groups with lateral LNM. This suggests that lateral LNM in PTMC is likely to have a poor prognosis, despite the small tumor size. Therefore, if suspicious <1-cm thyroid nodules are found, it may be necessary to consider FNA, and if diagnosed with cancer, US and CT for evaluating lateral LNM should be encouraged.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
None declared.
Authors' contributions EYK, YLP and JSY collected and interpreted the patient data, and KHL was a major contributor in writing the manuscript. CHP inspired the topic selection and led the authors. All authors read and approved the nal manuscript. Data are expressed as means±standard deviations or n (%). Data are expressed as n (%). Figure 1 Comparison of the incidence of lateral lymph node metastasis between the PTMC and non-PTMC groups.

Figure 1
Comparison of the incidence of lateral lymph node metastasis between the PTMC and non-PTMC groups.