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Year : 2014  |  Volume : 10  |  Issue : 1  |  Page : 50-55

Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma

1 Department of Surgery, Korea University College of Medicine, Guro Hospital, Seoul, Korea
2 Department of Surgery, Anam Hospital, Seoul, Korea
3 Department of Surgery, Korea University College of Medicine, Ansan Hospital, GyeongGi-Do, Korea

Date of Web Publication23-Apr-2014

Correspondence Address:
Jae Bok Lee
Department of Surgery, Korea University College of Medicine Guro Hospital 97 Guro-dong gil, Guro-gu, Seoul, 152-703
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.131366

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 > Abstract 

Background and Aims: Extrathyroidal extension (ETE) is one of the most important factors correlated to poor outcome of papillary thyroid carcinoma (PTC). However, the role of ETE in the prognosis of papillary thyroid microcarcinoma (PTMC) and the factor associated with ETE of PTMC are unclear. We investigated clinicopathological, immunohistochemical factors associated with ETE of PTMC to identify whether PTMC with ETE would have more adverse prognostic factors and higher risk for recurrence.
Setting and Design: We enrolled patients performed thyroidectomy due to PTC between January 2003 and June 2008 and selected patients diagnosed with PTMC among them. We investigated numerous clinicopathological, immunohistochemical factors of selected patients.
Materials and Methods: Data from 325 patients diagnosed with conventional PTMC by intraoperative frozen section and final pathology were recorded retrospectively.
Statistical Analysis Used: A χ2 test or an independent two-sample t-test, multiple logistic regression analysis, the Kaplan-Meier method, and log-rank test.
Results: Thirty-four percent of patients (325 of 952) had PTMC on final pathology. Among them, the number of patients with and without ETE was 91 and 234, respectively. On both univariate and multivariate analysis; ETE of PTMC correlated with size (P < 0.001); tumor, node, and metastasis (TNM) staging (P = 0.001); multifocality (P = 0.001); lymph node metastasis (P < 0.001); radioactive iodine (RAI) therapy (P = 0.001); and recurrence (P = 0.037).
Conclusions: ETE of conventional PTMC is associated with size, multifocality, lymph node metastasis, and recurrence. More extensive surgery should be considered for patients having ETE identified by intraoperative frozen sections, preoperative imaging, and intraoperative finding and other high risk factors.

 > Abstract in Chinese 

统计分析方法: χ2 检测或独立双样本t-检测,多元回归分析,Kaplan-Meier法,以及对数检测。
结果:34%病例(325/952)最终病理报告为甲状腺微小乳头状癌。他们当中,有和没有ETE的分别为91例和234例。同时运用单变量和多变量分析; ETE和PTMC相关因素:大小(P<0.001);TNM分期(P=0.001);多病灶(P=0.001);淋巴结转移(P<0.001); 放射性碘(RAI)治疗(P=0.001);复发(P=0.037)。

Keywords: Extrathyroidal extension, lymph node metastasis, multifocality, papillary thyroid microcarcinoma, size

How to cite this article:
Kim WY, Kim HY, Son GS, Bae JW, Lee JB. Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma. J Can Res Ther 2014;10:50-5

How to cite this URL:
Kim WY, Kim HY, Son GS, Bae JW, Lee JB. Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma. J Can Res Ther [serial online] 2014 [cited 2021 Jul 28];10:50-5. Available from: https://www.cancerjournal.net/text.asp?2014/10/1/50/131366

 > Introduction Top

Extrathyroidal extension (ETE) is a negative predictor of outcome in patients with papillary thyroid carcinoma (PTC). [1],[2],[3],[4] Patients with ETE have a significantly increased mortality rate ranging from 6 to 71% and rate of recurrence ranging from 37 to 64%. [1],[3],[4],[5],[6],[7],[8] However, ETE in papillary thyroid microcarcinoma (PTMC) as a poor prognostic factor is not well-defined. The prognosis of PTMC is generally favorable. However, some recent studies have reported recurrence rate up to 20%, and many cases of distant metastases with fatal outcome have been described. [9],[10],[11],[12],[13] These observations suggest that PTMC diagnosed by imaging modalities that include small PTC might represent an early phase in the development of PTC, and that ETE in PTMC would be also a risk factor for poor outcome.

We hypothesized that we could identify patients having PTMC with ETE would have more adverse prognostic factors and higher risk for recurrence. To assess the hypothesis, the study compared the clinicopathological and immunohistochemical characteristics between patients with and without ETE in conventional PTMC, whether ETE in PTMC was adverse prognostic factor or not, and which adverse prognostic factors might coexist with ETE in PTMC.

 > Materials and Methods Top

Analysis of clinicopathological features and recurrence and/or persistence

From January 2003 to June 2008, 952 patients underwent thyroid surgery for PTC at our institution. Among them, 325 had conventional PTMC (53.3%; 31 males, 294 females). For evaluation of ETE, pathologists reported the presence of ETE; 91 of the 325 PTMC patients (28.0%; 4 males, 87 females) had ETE. We reviewed the medical records, pathology reports, and subsequent clinical course of all patients. We also investigated various clinicopathological factors of patients with and without ETE (pT3 or pT4); such as sex, age, tumor size, cervical lymph node metastasis, multifocality, extent of surgery, preoperative thyroid stimulating hormone (TSH), coexisting lymphocytic thyroiditis, body mass index (BMI), recurrence, and RAI treatment. Long-term prognosis was analyzed in all 325 patients (mean follow-up duration, 67.4 ± 27.9 months). Four patients showed recurrent and/or persistent disease on their follow-up at the hospital (mean disease free survival, 24.5 ± 6.8 months). Recurrent and or persistent disease was diagnosed based on the results of the operation, and neck ultrasonography (US) and I-131 whole body scan examinations, and all were confirmed by fine needle aspiration biopsy (FNAB). Informed consent was obtained from all the patients. This study was approved by institutional review board.


Of the 325 PTMC patients, 180 (55.4%) underwent total or near-total thyroidectomy, 52 (16.0%) underwent subtotal thyroidectomy, and 30 (28.6%) underwent hemithyroidectomy. Total or near-total thyroidectomy was performed in patients with multiple tumors, ETE, or lymph node metastasis on preoperative or intraoperative findings. Hemithyroidectomy was performed in patients without multiple tumors, ETE, or lymph node metastasis.


We performed immunohistochemical staining of molecules associated with PTMC, including galectin-3 (n = 99, ETE; no ETE = 57:42), epidermal growth factor receptor (EGFR) (n = 80, ETE; no ETE = 46:34), and p53 (n = 96, ETE; no ETE = 56:40). The immunohistochemical staining categorized as the cells as negative or positive. Positive staining was defined as ≥ 10% of the cells stained with antibodies and negative staining as <10%.

Statistical analyses

Descriptive statistics were used to summarize study data. The continuous variables are expressed as mean ± standard deviation (SD). Univariate analysis was performed by using a χ2 test (for nonparametric categorical variable) or an independent two-sample t-test (for continuous variable). Significant variables at univariate analysis were further assessed for evaluating their independence with multiple logistic regression analysis. Disease-free survival between patients with and without ETE was calculated by the Kaplan-Meier method and log-rank test. A P < 0.05 was considered to indicate a significant difference. Statistical analyses were performed by Statistical Packages for Social Sciences (SPSS) version 12.0 for Windows (SPSS, Chicago, IL).

 > Results Top

Three hundred and twenty-five of the 952 patients (34.1%) who underwent thyroidectomy were diagnosed with PTMC and 91 of the 325 patients (28.0%) had ETE. The two groups (ETE and no ETE) did not differ in the distribution of men and women (M: F = 4:87 for ETE vs M: F = 27:207 for no ETE) or age (48.2 ± 11.0 years for ETE vs 47.2 ± 10.6 years for no ETE). However, the tumor size (0.72 ± 0.21 cm for ETE vs 0.56 ± 0.26 cm for no ETE) was significantly different (P < 0.001). The frequency of ETE increased with increasing tumor size [Figure 1]. Lymph node metastasis (P < 0.001), multifocality (P = 0.001), recurrence (P = 0.037), RAI (P = 0.001), and TNM stage (P = 0.001) were found more frequently and higher in patients with ETE. However; extent of surgery, preoperative TSH, alone or coexisting with lymphocytic thyroiditis or BMI, was not significantly associated with ETE [Table 1].
Figure 1: The frequency of extrathyroidal extension in papillary thyroid microcarcinoma (PTMC) according to tumor size

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Table 1: Clinicopathological features of PTMC with or without ETE

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We also analyzed the prognosis of all 325 patients with ETE (median age, 48.2 ± 11.0 years; mean disease free survival, 66.3 ± 26.2 months) and without ETE (median age, 47.2 ± 10.6 years; mean disease free survival, 68.4 ± 29.5 months). The number of patients with recurrent disease was significantly larger in the group with ETE (n = 4, 4.3%) than in the group without ETE (n = 0) (P = 0.037). The tumor size in one patient with recurrent disease was 0.3 cm and was each 0.8 cm in three patients. All patients with recurrent disease were female and had ETE, RAI treatment, total thyroidectomy (one had a total thyroidectomy and modified radical neck dissection), neck lymph node metastasis (one had central and lateral neck lymph node metastasis), and had been diagnosed using US and FNAB (one patient was diagnosed by a 131-I whole body scan with US and FNAB). They all had recurrence in the neck lymph node (level II, IV, and VI and operation bed, respectively). One patient had multifocality and two had lymphocytic thyroiditis; the other patients did not. No patients had distant metastases. All recurrent patients were alive at the last follow-up [Table 2]. The mean interval from initial surgery to recurrence was 24.5 ± 6.8 months. By Kaplan-Meier survival analysis, recurrence was significantly different in patients with and without ETE (P = 0.045) [Figure 2].
Figure 2: Disease-free survival between patients with and without ETE. Recurrence was significantly different in patients with and without ETE (P = 0.045). ETE: Extrathyroidal extension, 0: without ETE, 1: with ETE

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Table 2: Clinicopathological features of recurrent patients

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We tried to determine whether the expression of several molecules associated with the biological behavior of PTMC differed between patients with ETE and no ETE. Immunohistochemical analysis revealed that the expressions of galectin-3, EGFR, and p53 did not differ between either groups [Table 3].
Table 3: Immunohistochemical features of PTMC with or without ETE

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 > Discussion Top

The presence of ETE is a convincing predictor of negative outcomes in patients with well-differentiated thyroid carcinoma. [1],[2],[3],[4] In various staging systems for differentiated thyroid carcinoma including the seventh edition of TNM classification by the American Joint Committee on Cancer; the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS) criteria of the Mayo Clinic; and the European Organization for Research and Treatment of Cancer; ETE is considered as a prognostic factor for differentiated thyroid carcinoma. [14],[15] The reported prevalence of PTC with ETE varies, ranging from 2 to 45%, with progressively bigger tumors in PTC being associated with increased likelihood of ETE. [1],[3],[4],[5],[7],[8],[16],[17],[18] Similarly, an increasing number of studies support the present finding that PTMC displays evidence of ETE and/or nodal metastasis. [19],[20],[21],[22] The prevalence of ETE in PTMC is similar to PTC, ranging from 2 to 52% and the increasing frequency of ETE is accompanied by the increasing tumor size in PTMC, as in PTC. [9],[12],[18],[23],[24],[25],[26],[27],[28],[29],[30] In this study, the prevalence was 28.0% (91/325) and the frequency of ETE also increased with increasing tumor size. The collective observations suggest that PTMC may be an early-detected form of PTC, rather than a different disease entity, which may have been described previously as an indolent tumor. [24],[31],[32] On the other hand, some studies have been unable to identify independent prognostic indicators including ETE in PTMC, noting that PTMC should be managed like conventional PTC. [21],[33],[34]

ETE in PTMC is associated with larger size, lymph node metastasis, TNM staging, multifocality, and locoregional recurrence. [13],[19],[22],[35],[36] Presently, the mean size of ETE-associated tumors was larger than that of tumor without ETE, consistent with other studies [14],[24] . Moreover, the frequency of ETE also increased with increasing tumor size [Figure 1]. In PTMC, the prevalence of lymph node metastasis at diagnosis ranges between 0 and 64%. [37] Lymph node metastasis at diagnosis is a predictive factor for locoregional recurrence and distant metastasis. [19],[20],[21] Although our study had a small portion of patients who had undergone prophylactic central lymph node dissection (CLND) and did not include aggressive cancer types, PTMC with ETE had lymph node metastasis more frequently than PTMC without ETE (P = 0.001), consistent with previous studies. [14],[21] All PTMC recurrent patients with ETE had lymph node metastasis in this study.

Papillary carcinoma is frequently multifocal. [38] Our data also shows that a considerable percentage of cancers presented with multifocality (n = 41; 45.1% of ETE, 12.6% of all patients) and PTMC with ETE more often had multifocality than PTMC without ETE (P = 0.001). Two PTMC patients with ETE who had recurrence (n = 4) showed multifocality. Examination of a series of patients affected by differentiated thyroid microcarcinoma has clearly established that the presence of multifocality and lymph node metastasis influences the prognosis and recurrence rate. [19],[20],[21],[22],[28],[39] But, in two studies, the presence of multifocality did not correlate with prognosis or with disease recurrence. [38],[40]

In patients with PTMC, the recurrence rate ranges from 0.3 to 37%. [19],[20],[21],[37],[40] The recurrence rate of PTMC with ETE one of these studies (7.7%) is comparable with the presently-observed rate of 2.6%. [19] All four patients with PTMC who had recurrence in this study had ETE (P = 0.037). This is consistent with the idea that ETE is a poor prognostic factor for recurrence, which is consistent with other studies. [19],[22],[28] However, one meta-analysis showed that the presence of ETE in PTMC was not related to recurrence. [37] Also, our study had a limitation that follow-up period (3-8 years) was too short to evaluate postsurgical outcomes for PTMC.

We also investigated some molecular markers of papillary carcinoma, such as galectin-3, EGFR, and p53. The expression of these molecular markers did not differ between samples of ETE and no ETE. Galectin-3 plays an important role in cell-cell and cell-matrix interaction, and in the control of cell growth, neoplastic transformation, and metastasis by conferring resistance to apoptosis. [41-43] Overexpression of EGFR has been related to cancer recurrence. [44] The p53 protein is capable of inhibiting cell proliferation and transformation. Several studies have shown a correlation between mutated p53 gene expression and degree of tumor differentiation. [45],[46] It has also been reported that p53 gene expression is an indicator of poor prognosis, and might be important for planning the treatment of PTMC. [47] Presently, staining of tumors for these immunohistochemical markers showed no difference in the expression pattern in relation to ETE. However, the staining was not performed in all patients.

Although computed tomography (CT) or US may show high sensitivity and accuracy for ETE; [45],[48],[49] ETE, tumor size, and whether papillary carcinoma is or not can be directly identified by intraoperative frozen sections although it is not complete. So, the factors identified by intraoperative frozen section may be helpful for deciding the extent of surgery intraoperatively, such as total thyroidectomy or subtotal thyroidectomy, or hemithyroidectomy, or central lymph node dissection.

We consider that therapeutic CLND for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. [50] Prevalence of the central lymph node metastasis in clinically node negative PTMC has been reported to be as great as 30-65% and there may be some impact on recurrence in the neck requiring further surgical treatment, although the presence of microscopic nodal metastasis has not been shown to have a major impact on outcome. [51],[52],[53] Prophylactic CLND may be performed in patients with clinically node negative PTMC for clinicopathological features; such as the advanced tumor (T3, T4) including ETE, old age, male gender, multifocality although it may cause permanent morbidities such as hypoparathyroidism and recurrent laryngeal nerve injury, infrequently. [50],[52],[54],[55]

In conclusion, ETE of conventional PTMC is associated with tumor size, multifocality, and cervical lymph node metastasis. Therefore, ETE of PTMC is an important factor in determining the extent of needed surgery; this is especially true with PTMC with fewer known prognostic factors. More extensive surgery including prophylactic central lymph node dissection and more aggressive treatment should be considered in case of patients having ETE and other high risk factors identified by intraoperative frozen section, preoperative imaging, and intraoperative finding.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]

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