World J Surg (2015) 39:187–193 DOI 10.1007/s00268-014-2795-5
ORIGINAL SCIENTIFIC REPORT
Intraoperative Frozen Section for the Evaluation of Extrathyroidal Extension in Papillary Thyroid Cancer Young Min Park • Soo-Geun Wang Jin Young Goh • Dong Hoon Shin • In-Ju Kim • Byung-Joo Lee
•
Published online: 18 September 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background We investigated extrathyroidal extension (ETE) through frozen biopsy for intraoperative decision making in patients with papillary thyroid cancer (PTC). Methods During the period of the study an operation was performed in 268 patients with PTC and ETE was evaluated using intraoperative frozen biopsies of thyroid tissue. Results Extrathyroidal extension was confirmed in 54 patients (20 %) on frozen biopsy. Fifty-three patients among 54 patients showing ETE on frozen biopsy were confirmed on permanent pathologic analysis. Accordingly, frozen biopsy had a sensitivity of 66 %, a specificity of 99 %, a positive predictive value of 98 %, and a negative predictive value of 87 %. Tumor size (OR 4.373; CI 2.257–8.475, p = \0.001) was an independent factor for predicting ETE on frozen biopsy. Conclusions Intraoperative frozen biopsy can be an useful tool in identifying the presence of ETE. It can also help the operator decide the extent of surgery and central neck dissection in patients with PTC.
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MEST) (No. NRF-2012R1A1A4A01009912). Y. M. Park Department of Otorhinolaryngology, Pundang Jesaeng Hospital, Deajin Medical Center, Seongnam, Gyeonggi, Korea S.-G. Wang B.-J. Lee (&) Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea e-mail: [email protected]
D. H. Shin Department of Pathology, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea I.-J. Kim Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea
J. Y. Goh Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea
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Introduction Papillary thyroid carcinoma (PTC) is the most common malignancy originating from the thyroid. Patients with PTC usually have an excellent prognosis due to its generally indolent course. However, there has been still controversy on the extent of surgery in the treatment of PTC. Several investigators have reported that a total thyroidectomy improves overall survival and decreases recurrence rates compared to lobectomy [1, 2]. On the other hand, some studies have shown that a patient’s survival and treatment outcomes are not influenced by total thyroidectomy compared to lobectomy [3–5]. Although a definite treatment guideline has not been established, some surgeons have decided that the extent of surgery (total thyroidectomy vs lobectomy) should be based on several factors including tumor size, multifocality, extrathyroidal extension (ETE), patient age, and lymph node metastasis [6, 7]. Thus, in order to make a surgical plan for patient with PTC, it is important to determine the presence or absence of the above-mentioned risk factors before the operation. Extrathyroidal extension has been observed in as many as 31.9 % of patients with PTC, including small tumors, so the ability to detect ETE is especially important when deciding the extent of surgery [8–13]. There have been some debates on clinical implication of ETE related to overall survival and recurrence rate. Some investigator said ETE did not impact disease recurrence, even though it was associated with large tumor size and multifocality [14, 15]. However, Kim et al. reported that ETE of micro PTC was associated with increased tumor recurrence rate [16]. Therefore, they insisted that more extensive surgery was required in patients having ETE [16]. Thus, even small tumors may necessitate a total thyroidectomy if ETE is confirmed in patients with PTC [6]. ETE may also require prophylactic central lymph node dissection because of an increased risk of central nodal metastasis [17]. There have been some researches to detect ETE preoperatively using imaging modalities including computed tomography (CT) and US [18–20]. Among them, investigators have usually tried to find preoperative US findings of ETE because US was more accurate than CT in prediction of the presence of ETE [19]. Kwak et al. insisted that the presence and degree of contact between tumor and the adjacent capsule as found on US could predict ETE preoperatively [18]. Kim et al. reported that tumor echogenicity of preoperative US were predictive for the presence of ETE [20]. However, preoperative US showed the limitation for the evaluation of ETE because the diagnostic performance of it was not enough powerful to be applied (60 % sensitivity, 80 % specificity, 70 % positive predictive value, and 77 % negative predictive value) [18]. However, to our knowledge, there has been no study to
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investigate the clinical usefulness of frozen biopsy for evaluating ETE. We performed intraoperative frozen biopsy of surgical specimens and investigated ETE of tumors through pathologic analysis to determine the utility of frozen biopsy for intraoperative decision making in patients with PTC.
Materials and methods Patients Between March 2013 and May 2013, 268 patients who were diagnosed with PTC were enrolled in the study. The Institutional Review Board of Pusan National University Hospital approved the study and informed consent was obtained from all patients. All 268 patients with PTC were evaluated for ETE using intraoperative frozen biopsy. Study procedure All patients received US, fine needle aspiration biopsy, and CT to evaluate the exact extent of the primary thyroid tumor and lymph node metastasis before the operation. In this study, we did not assess the accuracy of US to find the ETE of PTC, separately. However, in previous study, we showed the performance of US (70 % of sensitivity and 77 % of specificity) to find ETE on the basis of the contact with thyroid capsule [20]. US did not show performance enough to find ETE, preoperatively. Although preoperative CT scan is usually not performed, in our institution, it was performed to evaluate the lymph node status because it was superior to US for the assessing of lymph node status of central, upper mediastinum, and level IIb compartment. Based on our previous research, we routinely performed frozen section of ipsilateral central neck compartment to evaluate lymph node metastasis during operation [21]. If lymph node metastasis was found in the specimen, we preferred total thyroidectomy. In addition to the above, we wanted to utilize frozen section for the evaluation of ETE and confirm the accuracy of it compared to permanent section. In our institution, in cases with lymph node metastasis and ETE, we preferred total thyroidectomy and both central neck dissection. Frozen biopsy process Surgical thyroid specimens were marked with ink to delineate the lesion. Pathologists then evaluated the specimen grossly and dissected it. Samples were frozen, sectioned, and stained with hematoxylin-eosin. The specimen was bisected irrespective of the size of primary lesion. Pathologists determined the presence or absence of ETE
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using light microscopy and reported the results back to the surgical team within 30 min on average.
Table 2 Diagnostic accuracy of frozen biopsy in the evaluation of ETE Frozen ETE (?)
Statistical analysis Chi squared analysis or Fisher’s exact test were used to compare categorical variables between two independent groups. An independent two-sample t test was used to compare continuous variables between two independent groups. Multivariate logistic regression analysis was performed to control for patients’ demographic and tumor characteristics when determining risk factors for ETE. The diagnostic performance including sensitivity, specificity, positive predictive value, and negative predictive value of frozen biopsy were calculated. A p value \0.05 was considered statistically significant. Statistical analyses were performed with SPSS 18.0 for Windows (SPSS, Chicago, IL, USA).
Results Among 268 patients who were diagnosed with PTC and underwent surgical resection, 240 patients (90 %) were female and 28 patients (10 %) were male. The average age of patients was 51.6 years and 203 patients (76 %) were 45 years of age or older. The mean size of the primary thyroid tumor was 0.75 cm. There was temporary hypocalcemia in two cases and temporary vocal cord palsy in one case after the operation. However, all cases recovered with conservative management within 6 months and there were no patients with permanent complications. Other patient information is summarized in Table 1. Table 1 Patient demographics and tumor characteristics Characteristics
No. of patients
Permanent ETE (?)
80 (30 %)
ETE (-) Sex
188 (70 %)
Male Female
C45 years
203 (76 %)
Primary tumor
80
187
188
Total Sensitivity
Central neck
85 (32 %)
Lateral neck
10 (4 %)
54
214 66 %
Specificity
99 %
Positive predictive value
98 %
Negative predictive value
87 %
ETE extrathyroidal extension
A total thyroidectomy was performed in 259 patients while a lobectomy was performed in the remaining nine patients. The initial extent of surgery was determined using several factors including tumor size, multifocality, ETE, and lymph node metastasis. All patients received ipsilateral central neck dissection and nodal specimens were sent to pathology with the resected thyroid lobe. Surgical specimens, including the thyroid lobe and central neck node, were analyzed through frozen biopsy for ETE and nodal metastasis. Unilateral central neck dissection was performed in 151 patients and bilateral central neck dissection was performed in other 117 patients. Ten patients received lateral neck dissection for the removal of metastatic neck node in the lateral neck. Of the 268 patients enrolled, ETE was confirmed in 54 patients (20 %) on frozen biopsy. On permanent pathologic examination, ETE was ultimately confirmed in 80 patients (30 %). Of those 80 patients, tumors extended to the perithyroidal soft tissue in 73 patients and to the sternothyroid muscle in the other seven patients. There were no cases showing extension to a major organ. Fifty-three patients among 54 patients showing ETE on frozen biopsy were also shown to have local extension on permanent Table 3 Diagnostic accuracy of frozen biopsy in the evaluation of ETE in micro PTC
Permanent ETE (-) Total Sensitivity
7.5 (2–28)
Lymph node metastasis
ETE extrathyroidal extension
27
1
Permanent ETE (?) 65 (24 %)
Size, mm (range)
53
Permanent ETE (-)
28 (10 %)
\45 years
Total
Permanent ETE (?)
240 (90 %)
Age
Frozen ETE (-)
Frozen ETE (?)
Frozen ETE (-)
Total
28
15
43
1
159
160
29
174 65 %
Specificity
99 %
Positive predictive value
97 %
Negative predictive value
91 %
PTC papillary thyroid carcinoma, ETE extrathyroidal extension
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World J Surg (2015) 39:187–193
Table 4 Clinical and pathologic information of patients in the frozen ETE (?) group and ETE (-) group Frozen ETE (?) group
Frozen ETE (-) group
Age
p value
Table 6 The difference between frozen ETE (?) and (-) groups in patients with ETE on the permanent pathologic examination (total = 80 patients) Frozen ETE (?) group (n = 53)
0.374
\45 years
10
55
C45 years Sex
44
159
8
20
46
194
Female
\0.001 28
172
C1 cm
26
42
Yes
26
69
No
28
145
0.038
Number of metastatic central lymph nodes 145 52
C3
9
17
5
5
49
209
43
19 0.742
Male
8
3
45
24
\1 cm
27
15
C1 cm
26
12
26
8
27
19
Female
0.814
0.151
No
0.031
No
C45 years
Number of metastatic central lymph nodes
Lateral neck metastasis Yes
8
Central neck metastasis Yes
0.05 28 17
10
Primary tumor size
Central neck metastasis
0 B2
0.396
\45 years Sex
Primary tumor size \1 cm
p value
Age 0.317
Male
Frozen ETE (-) group (n = 27)
0.189
0
27
B2
17
19 4
C3
9
4
Lateral neck metastasis
ETE extrathyroidal extension
pathologic analysis. Accordingly, the diagnostic performance of frozen biopsy was as follows: 66 % sensitivity, 99 % specificity, 98 % positive predictive value, and 87 % negative predictive value (Table 2). In the study, two hundred three patients (76 %) were diagnosed with micro PTC (\1 cm) and received the operation. The diagnostic performance of frozen biopsy was calculated in the evaluation of ETE for micro PTC: 65 % sensitivity, 99 % specificity, 97 % positive predictive value, and 91 % negative predictive value (Table 3).
0.999
Yes
5
3
No
48
24
ETE extrathyroidal extension
The primary tumor size in patients with ETE on frozen biopsy was significantly larger than in other patients (p = \0.001) (Table 4). Central lymph node and lateral lymph node metastasis was significantly associated with ETE on frozen biopsy, respectively (p = 0.038 and p = 0.031). Tumor size (OR 4.373; CI 2.257–8.475, p = \0.001) was an independent factor for predicting ETE on frozen biopsy by multivariate logistic analysis after
Table 5 Multi-variative analysis for the evaluation of relationship between ETE and other clinical characteristics B
Age
S.E.
0.018
0.015
Sex
0.283
0.5
Size
1.476
0.338
Wald
df
p value*
0.215
Exp (b)a
1.019
Confident interval Lower
Upper
0.989
1.049
1.537
1
0.321
1
0.571
1.327
0.498
3.534
19.107
1
\0.001
4.373
2.257
8.475
Central LN
0.256
0.360
0.505
1
0.477
1.292
0.638
2.615
Lateral LN
0.432
0.743
0.338
1
0.561
1.541
0.359
6.614
ETE extrathyroidal extension, LN lymph node *
p \ 0.05, statistically significant
a
Odds ratio
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Fig. 1 Patients A. Tumor was confined within thyroid parenchymal tissue. The ETE was not detected on frozen biopsy (a) and permanent examination (b)
Fig. 2 Patient D. The extrathyroidal extension was not detected on frozen biopsy (a). However, perithyroidal fat tissue extension was detected on other sectioned permanent specimen (b) (arrow: ETE)
controlling for age, sex, and other clinical aspects (Table 5). To detect clinical and pathologic factors related to false negative results of frozen biopsy, the difference between frozen (?) and (-) groups in patients with ETE on permanent pathologic examination was analyzed. Age, sex, tumor size, central and lateral lymph node metastasis were not significantly associated with false negative results of frozen biopsy for the evaluation of ETE (Table 6). Histologic findings of frozen and permanent section were analyzed in all patients. Tumors were confined inside the thyroid parenchymal tissue on both frozen and permanent section in patient A (Fig. 1). ETE was not detected on frozen biopsy, however perithyroidal fat tissue was involved by tumor and detected on other sectioned permanent specimen in patient D (Fig. 2). In this study, among total 268 patients with PTC, 254 patients were planned to receive total thyroidectomy and 14 patients were planned to receive lobectomy based on several clinical factors before operation. However, using intraoperative frozen section to evaluate ETE, 5 among 14 patients who were planned to receive lobectomy and
ipsilateral central neck dissection before operation converted to total thyroidectomy based on positive results of intraoperative frozen section (Fig. 3).
Discussion In this study, we evaluated ETE through frozen biopsy intraoperatively with a diagnostic performance of 66 % sensitivity, 99 % specificity, 98 % positive predictive value, and 87 % negative predictive value. Although the sensitivity of frozen biopsy was similar to US, the specificity, positive predictive value, and negative predictive value were superior compared to US. Accordingly, in cases showing ETE on intraoperative frozen biopsy a more aggressive treatment strategy is merited. Even if the size of tumor was less than 1 cm, the diagnostic performance of frozen biopsy showed comparable results for the evaluation of ETE (65 % sensitivity, 99 % specificity, 97 % positive predictive value, and 91 % negative predictive value). In the study, 29 (14 %) of 203 patients with micro PTC (\ 1 cm) were confirmed ETE on the frozen biopsy during
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Fig. 3 Among total 268 patients with PTC, 254 patients were planned to receive total thyroidectomy and 14 patients were planned to receive lobectomy based on several clinical factors before operation. However, 5 patients among 14 patient who were planned to receive lobectomy converted to total thyroidectomy, as ETE was confirmed on intraoperative frozen section
the operation. Thus, frozen biopsy could help the surgeon decide the extent of surgery (total thyroidectomy vs lobectomy and central neck dissection) even in patients with small tumors. To find clinical and pathologic factors related to false negative results of frozen biopsy, we analyzed the difference between frozen (?) and (-) groups in patients with ETE on permanent results. However, any clinical factors were not significantly associated with false negative results. Technically, pathologic section was generally performed only once in the specimen on the frozen biopsy. Based on a pathologic frozen section, pathologists evaluated malignancy and the presence of ETE in this study. If ETE was observed on the frozen biopsy, it was also confirmed on the permanent pathologic examination in almost cases. However, as multiple pathologic sections were performed on permanent pathologic examination, ETE could be detected on the other portion of tumor which was not sectioned on the frozen biopsy. This is the reason why the accuracy of the frozen biopsy was different from that of permanent pathologic examination in the prediction of ETE. In the case of false positive results, as the specimen was incompletely sectioned on the frozen biopsy, ETE was suspected. However, ETE was not finally confirmed on the permanent examination. In previous work, we performed frozen biopsy for quantitative analysis of the central neck node and reported that it is an useful tool for the evaluation of central lymphatic status intraoperatively with a high sensitivity and specificity [21]. Because central nodal status and ETE are known to be negative predictive factors for PTC, a more aggressive surgical approach may be required in patients with these risk factors [22]. According to the present study and previously published work, frozen biopsy is useful in
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the evaluation of central nodal status and ETE and helps inform the surgeon’s operative plan regarding the extent of surgery and the need for central neck dissection in patients with PTC. Our study did have several limitations. First, because the pathologists were not blinded to results of frozen section, the problem of bias could not be avoided and it could influence the study’s outcomes. Second, more aggressive operations were performed in our institution even for micro PTC. In this study, total thyroidectomy was performed in almost all patients (96.6 %) and central lymph node dissections were performed in all patients. This treatment policy can be a source of controversies over the extent of surgery, especially in micro PTC. Third, frozen section could induce additional costs because of operation time and use of hospital resources. However, in South Korea, national insurance system covered almost patients, especially cancer patients. Therefore, frozen section of surgical specimen did not demand additional costs to patients. Because the results were reported to surgical team within 30 min on average, it was not significant burden to our facility. Intraoperative frozen biopsy can be an useful tool in identifying the presence of ETE. It can also help the surgeon decide the extent of surgery and the need for central neck dissection in patients with PTC during the operation. Conflict of interest
None.
References 1. Mazzaferri EL, Young RL (1981) Papillary thyroid carcinoma: a 10 year follow-up report of the impact of therapy in 576 patients. Am J Med 70:511–518
World J Surg (2015) 39:187–193 2. Samaan NA, Schultz PN, Hickey RC et al (1992) The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients. J Clin Endocrinol Metab 75:714–720 3. Haigh PI, Urbach DR, Rotstein LE (2005) Extent of thyroidectomy is not a major determinant of survival in low- or high-risk papillary thyroid cancer. Ann Surg Oncol 12:81–89 4. Hundahl SA, Fleming ID, Fremgen AM et al (1998) A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer 83:2638–2648 5. Wanebo H, Coburn M, Teates D et al (1998) Total thyroidectomy does not enhance disease control or survival even in high-risk patients with differentiated thyroid cancer. Ann Surg 227:912–921 6. Sundram F, Robinson BG, Kung A et al (2006) Well-differentiated epithelial thyroid cancer management in the Asia Pacific region: a report and clinical practice guideline. Thyroid 16:461–469 7. Erdem E, Gu¨lc¸elik MA, Kuru B et al (2003) Comparison of completion thyroidectomy and primary surgery for differentiated thyroid carcinoma. Eur J Surg Oncol 29:747–749 8. Chow SM, Law SC, Chan JK et al (2003) Papillary microcarcinoma of the thyroid-prognostic significance of lymph node metastasis and multifocality. Cancer 98:31–40 9. Arora N, Turbendian HK, Kato MA et al (2009) Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 19:473–477 10. Mercante G, Frasoldati A, Pedroni C et al (2009) Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients. Thyroid 19:707–716 11. Besic N, Pilko G, Petric R et al (2008) Papillary thyroid microcarcinoma: prognostic factors and treatment. J Surg Oncol 97:221–225 12. Lim DJ, Baek KH, Lee YS et al (2007) Clinical, histopathological, and molecular characteristics of papillary thyroid microcarcinoma. Thyroid 17:883–888
193 13. Lombardi CP, Bellantone R, De Crea C et al (2010) Papillary thyroid microcarcinoma: extrathyroidal extension, lymph node metastases, and risk factors for recurrence in a high prevalence of goiter area. World J Surg 34:1214–1221. doi:10.1007/s00268009-0375-x 14. Ahn D, Sohn JH, Jeon JH et al (2014) Clinical impact of microscopic extrathyroidal extension in patients with papillary thyroid microcarcinoma treated with hemithyroidectomy. J Endocrinol Invest 37:167–173 15. Shin JH, Ha TK, Park HK et al (2013) Implication of minimal extrathyroidal extension as a prognostic factor in papillary thyroid carcinoma. Int J Surg 11:944–947 16. Kim WY, Kim HY, Son GS et al (2014) Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma. J Cancer Res Ther 10:50–55 17. Kim YS, Park WC (2012) Clinical predictors of right upper paraesophageal lymph node metastasis from papillary thyroid carcinoma. World J Surg Oncol 10:164 18. Kwak JY, Kim EK, Youk JH et al (2008) Extrathyroid extension of well-differentiated papillary thyroid microcarcinoma on US. Thyroid 18:609–614 19. Choi JS, Kim J, Kwak JY et al (2009) Preoperative staging of papillary thyroid carcinoma: comparison of ultrasound imaging and CT. AJR Am J Roentgenol 193:871–878 20. Kim SS, Lee BJ, Lee JC et al (2011) Preoperative ultrasonographic tumor characteristics as a predictive factor of tumor stage in papillary thyroid carcinoma. Head Neck 33:1719–1726 21. Lim YS, Choi SW, Lee YS et al (2013) Frozen biopsy of central compartment in papillary thyroid cancer: quantitative nodal analysis. Head Neck 35:1319–1322 22. Lee YS, Lim YS, Lee JC et al (2010) Clinical implication of the number of central lymph node metastasis in papillary thyroid carcinoma: preliminary report. World J Surg 34:2558–2563. doi:10.1007/s00268-010-0749-0
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ORIGINAL SCIENTIFIC REPORT
Intraoperative Frozen Section for the Evaluation of Extrathyroidal Extension in Papillary Thyroid Cancer Young Min Park • Soo-Geun Wang Jin Young Goh • Dong Hoon Shin • In-Ju Kim • Byung-Joo Lee
•
Published online: 18 September 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background We investigated extrathyroidal extension (ETE) through frozen biopsy for intraoperative decision making in patients with papillary thyroid cancer (PTC). Methods During the period of the study an operation was performed in 268 patients with PTC and ETE was evaluated using intraoperative frozen biopsies of thyroid tissue. Results Extrathyroidal extension was confirmed in 54 patients (20 %) on frozen biopsy. Fifty-three patients among 54 patients showing ETE on frozen biopsy were confirmed on permanent pathologic analysis. Accordingly, frozen biopsy had a sensitivity of 66 %, a specificity of 99 %, a positive predictive value of 98 %, and a negative predictive value of 87 %. Tumor size (OR 4.373; CI 2.257–8.475, p = \0.001) was an independent factor for predicting ETE on frozen biopsy. Conclusions Intraoperative frozen biopsy can be an useful tool in identifying the presence of ETE. It can also help the operator decide the extent of surgery and central neck dissection in patients with PTC.
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MEST) (No. NRF-2012R1A1A4A01009912). Y. M. Park Department of Otorhinolaryngology, Pundang Jesaeng Hospital, Deajin Medical Center, Seongnam, Gyeonggi, Korea S.-G. Wang B.-J. Lee (&) Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea e-mail: [email protected]
D. H. Shin Department of Pathology, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea I.-J. Kim Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea
J. Y. Goh Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Kyeongnam, Korea
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Introduction Papillary thyroid carcinoma (PTC) is the most common malignancy originating from the thyroid. Patients with PTC usually have an excellent prognosis due to its generally indolent course. However, there has been still controversy on the extent of surgery in the treatment of PTC. Several investigators have reported that a total thyroidectomy improves overall survival and decreases recurrence rates compared to lobectomy [1, 2]. On the other hand, some studies have shown that a patient’s survival and treatment outcomes are not influenced by total thyroidectomy compared to lobectomy [3–5]. Although a definite treatment guideline has not been established, some surgeons have decided that the extent of surgery (total thyroidectomy vs lobectomy) should be based on several factors including tumor size, multifocality, extrathyroidal extension (ETE), patient age, and lymph node metastasis [6, 7]. Thus, in order to make a surgical plan for patient with PTC, it is important to determine the presence or absence of the above-mentioned risk factors before the operation. Extrathyroidal extension has been observed in as many as 31.9 % of patients with PTC, including small tumors, so the ability to detect ETE is especially important when deciding the extent of surgery [8–13]. There have been some debates on clinical implication of ETE related to overall survival and recurrence rate. Some investigator said ETE did not impact disease recurrence, even though it was associated with large tumor size and multifocality [14, 15]. However, Kim et al. reported that ETE of micro PTC was associated with increased tumor recurrence rate [16]. Therefore, they insisted that more extensive surgery was required in patients having ETE [16]. Thus, even small tumors may necessitate a total thyroidectomy if ETE is confirmed in patients with PTC [6]. ETE may also require prophylactic central lymph node dissection because of an increased risk of central nodal metastasis [17]. There have been some researches to detect ETE preoperatively using imaging modalities including computed tomography (CT) and US [18–20]. Among them, investigators have usually tried to find preoperative US findings of ETE because US was more accurate than CT in prediction of the presence of ETE [19]. Kwak et al. insisted that the presence and degree of contact between tumor and the adjacent capsule as found on US could predict ETE preoperatively [18]. Kim et al. reported that tumor echogenicity of preoperative US were predictive for the presence of ETE [20]. However, preoperative US showed the limitation for the evaluation of ETE because the diagnostic performance of it was not enough powerful to be applied (60 % sensitivity, 80 % specificity, 70 % positive predictive value, and 77 % negative predictive value) [18]. However, to our knowledge, there has been no study to
123
World J Surg (2015) 39:187–193
investigate the clinical usefulness of frozen biopsy for evaluating ETE. We performed intraoperative frozen biopsy of surgical specimens and investigated ETE of tumors through pathologic analysis to determine the utility of frozen biopsy for intraoperative decision making in patients with PTC.
Materials and methods Patients Between March 2013 and May 2013, 268 patients who were diagnosed with PTC were enrolled in the study. The Institutional Review Board of Pusan National University Hospital approved the study and informed consent was obtained from all patients. All 268 patients with PTC were evaluated for ETE using intraoperative frozen biopsy. Study procedure All patients received US, fine needle aspiration biopsy, and CT to evaluate the exact extent of the primary thyroid tumor and lymph node metastasis before the operation. In this study, we did not assess the accuracy of US to find the ETE of PTC, separately. However, in previous study, we showed the performance of US (70 % of sensitivity and 77 % of specificity) to find ETE on the basis of the contact with thyroid capsule [20]. US did not show performance enough to find ETE, preoperatively. Although preoperative CT scan is usually not performed, in our institution, it was performed to evaluate the lymph node status because it was superior to US for the assessing of lymph node status of central, upper mediastinum, and level IIb compartment. Based on our previous research, we routinely performed frozen section of ipsilateral central neck compartment to evaluate lymph node metastasis during operation [21]. If lymph node metastasis was found in the specimen, we preferred total thyroidectomy. In addition to the above, we wanted to utilize frozen section for the evaluation of ETE and confirm the accuracy of it compared to permanent section. In our institution, in cases with lymph node metastasis and ETE, we preferred total thyroidectomy and both central neck dissection. Frozen biopsy process Surgical thyroid specimens were marked with ink to delineate the lesion. Pathologists then evaluated the specimen grossly and dissected it. Samples were frozen, sectioned, and stained with hematoxylin-eosin. The specimen was bisected irrespective of the size of primary lesion. Pathologists determined the presence or absence of ETE
World J Surg (2015) 39:187–193
189
using light microscopy and reported the results back to the surgical team within 30 min on average.
Table 2 Diagnostic accuracy of frozen biopsy in the evaluation of ETE Frozen ETE (?)
Statistical analysis Chi squared analysis or Fisher’s exact test were used to compare categorical variables between two independent groups. An independent two-sample t test was used to compare continuous variables between two independent groups. Multivariate logistic regression analysis was performed to control for patients’ demographic and tumor characteristics when determining risk factors for ETE. The diagnostic performance including sensitivity, specificity, positive predictive value, and negative predictive value of frozen biopsy were calculated. A p value \0.05 was considered statistically significant. Statistical analyses were performed with SPSS 18.0 for Windows (SPSS, Chicago, IL, USA).
Results Among 268 patients who were diagnosed with PTC and underwent surgical resection, 240 patients (90 %) were female and 28 patients (10 %) were male. The average age of patients was 51.6 years and 203 patients (76 %) were 45 years of age or older. The mean size of the primary thyroid tumor was 0.75 cm. There was temporary hypocalcemia in two cases and temporary vocal cord palsy in one case after the operation. However, all cases recovered with conservative management within 6 months and there were no patients with permanent complications. Other patient information is summarized in Table 1. Table 1 Patient demographics and tumor characteristics Characteristics
No. of patients
Permanent ETE (?)
80 (30 %)
ETE (-) Sex
188 (70 %)
Male Female
C45 years
203 (76 %)
Primary tumor
80
187
188
Total Sensitivity
Central neck
85 (32 %)
Lateral neck
10 (4 %)
54
214 66 %
Specificity
99 %
Positive predictive value
98 %
Negative predictive value
87 %
ETE extrathyroidal extension
A total thyroidectomy was performed in 259 patients while a lobectomy was performed in the remaining nine patients. The initial extent of surgery was determined using several factors including tumor size, multifocality, ETE, and lymph node metastasis. All patients received ipsilateral central neck dissection and nodal specimens were sent to pathology with the resected thyroid lobe. Surgical specimens, including the thyroid lobe and central neck node, were analyzed through frozen biopsy for ETE and nodal metastasis. Unilateral central neck dissection was performed in 151 patients and bilateral central neck dissection was performed in other 117 patients. Ten patients received lateral neck dissection for the removal of metastatic neck node in the lateral neck. Of the 268 patients enrolled, ETE was confirmed in 54 patients (20 %) on frozen biopsy. On permanent pathologic examination, ETE was ultimately confirmed in 80 patients (30 %). Of those 80 patients, tumors extended to the perithyroidal soft tissue in 73 patients and to the sternothyroid muscle in the other seven patients. There were no cases showing extension to a major organ. Fifty-three patients among 54 patients showing ETE on frozen biopsy were also shown to have local extension on permanent Table 3 Diagnostic accuracy of frozen biopsy in the evaluation of ETE in micro PTC
Permanent ETE (-) Total Sensitivity
7.5 (2–28)
Lymph node metastasis
ETE extrathyroidal extension
27
1
Permanent ETE (?) 65 (24 %)
Size, mm (range)
53
Permanent ETE (-)
28 (10 %)
\45 years
Total
Permanent ETE (?)
240 (90 %)
Age
Frozen ETE (-)
Frozen ETE (?)
Frozen ETE (-)
Total
28
15
43
1
159
160
29
174 65 %
Specificity
99 %
Positive predictive value
97 %
Negative predictive value
91 %
PTC papillary thyroid carcinoma, ETE extrathyroidal extension
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Table 4 Clinical and pathologic information of patients in the frozen ETE (?) group and ETE (-) group Frozen ETE (?) group
Frozen ETE (-) group
Age
p value
Table 6 The difference between frozen ETE (?) and (-) groups in patients with ETE on the permanent pathologic examination (total = 80 patients) Frozen ETE (?) group (n = 53)
0.374
\45 years
10
55
C45 years Sex
44
159
8
20
46
194
Female
\0.001 28
172
C1 cm
26
42
Yes
26
69
No
28
145
0.038
Number of metastatic central lymph nodes 145 52
C3
9
17
5
5
49
209
43
19 0.742
Male
8
3
45
24
\1 cm
27
15
C1 cm
26
12
26
8
27
19
Female
0.814
0.151
No
0.031
No
C45 years
Number of metastatic central lymph nodes
Lateral neck metastasis Yes
8
Central neck metastasis Yes
0.05 28 17
10
Primary tumor size
Central neck metastasis
0 B2
0.396
\45 years Sex
Primary tumor size \1 cm
p value
Age 0.317
Male
Frozen ETE (-) group (n = 27)
0.189
0
27
B2
17
19 4
C3
9
4
Lateral neck metastasis
ETE extrathyroidal extension
pathologic analysis. Accordingly, the diagnostic performance of frozen biopsy was as follows: 66 % sensitivity, 99 % specificity, 98 % positive predictive value, and 87 % negative predictive value (Table 2). In the study, two hundred three patients (76 %) were diagnosed with micro PTC (\1 cm) and received the operation. The diagnostic performance of frozen biopsy was calculated in the evaluation of ETE for micro PTC: 65 % sensitivity, 99 % specificity, 97 % positive predictive value, and 91 % negative predictive value (Table 3).
0.999
Yes
5
3
No
48
24
ETE extrathyroidal extension
The primary tumor size in patients with ETE on frozen biopsy was significantly larger than in other patients (p = \0.001) (Table 4). Central lymph node and lateral lymph node metastasis was significantly associated with ETE on frozen biopsy, respectively (p = 0.038 and p = 0.031). Tumor size (OR 4.373; CI 2.257–8.475, p = \0.001) was an independent factor for predicting ETE on frozen biopsy by multivariate logistic analysis after
Table 5 Multi-variative analysis for the evaluation of relationship between ETE and other clinical characteristics B
Age
S.E.
0.018
0.015
Sex
0.283
0.5
Size
1.476
0.338
Wald
df
p value*
0.215
Exp (b)a
1.019
Confident interval Lower
Upper
0.989
1.049
1.537
1
0.321
1
0.571
1.327
0.498
3.534
19.107
1
\0.001
4.373
2.257
8.475
Central LN
0.256
0.360
0.505
1
0.477
1.292
0.638
2.615
Lateral LN
0.432
0.743
0.338
1
0.561
1.541
0.359
6.614
ETE extrathyroidal extension, LN lymph node *
p \ 0.05, statistically significant
a
Odds ratio
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Fig. 1 Patients A. Tumor was confined within thyroid parenchymal tissue. The ETE was not detected on frozen biopsy (a) and permanent examination (b)
Fig. 2 Patient D. The extrathyroidal extension was not detected on frozen biopsy (a). However, perithyroidal fat tissue extension was detected on other sectioned permanent specimen (b) (arrow: ETE)
controlling for age, sex, and other clinical aspects (Table 5). To detect clinical and pathologic factors related to false negative results of frozen biopsy, the difference between frozen (?) and (-) groups in patients with ETE on permanent pathologic examination was analyzed. Age, sex, tumor size, central and lateral lymph node metastasis were not significantly associated with false negative results of frozen biopsy for the evaluation of ETE (Table 6). Histologic findings of frozen and permanent section were analyzed in all patients. Tumors were confined inside the thyroid parenchymal tissue on both frozen and permanent section in patient A (Fig. 1). ETE was not detected on frozen biopsy, however perithyroidal fat tissue was involved by tumor and detected on other sectioned permanent specimen in patient D (Fig. 2). In this study, among total 268 patients with PTC, 254 patients were planned to receive total thyroidectomy and 14 patients were planned to receive lobectomy based on several clinical factors before operation. However, using intraoperative frozen section to evaluate ETE, 5 among 14 patients who were planned to receive lobectomy and
ipsilateral central neck dissection before operation converted to total thyroidectomy based on positive results of intraoperative frozen section (Fig. 3).
Discussion In this study, we evaluated ETE through frozen biopsy intraoperatively with a diagnostic performance of 66 % sensitivity, 99 % specificity, 98 % positive predictive value, and 87 % negative predictive value. Although the sensitivity of frozen biopsy was similar to US, the specificity, positive predictive value, and negative predictive value were superior compared to US. Accordingly, in cases showing ETE on intraoperative frozen biopsy a more aggressive treatment strategy is merited. Even if the size of tumor was less than 1 cm, the diagnostic performance of frozen biopsy showed comparable results for the evaluation of ETE (65 % sensitivity, 99 % specificity, 97 % positive predictive value, and 91 % negative predictive value). In the study, 29 (14 %) of 203 patients with micro PTC (\ 1 cm) were confirmed ETE on the frozen biopsy during
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Fig. 3 Among total 268 patients with PTC, 254 patients were planned to receive total thyroidectomy and 14 patients were planned to receive lobectomy based on several clinical factors before operation. However, 5 patients among 14 patient who were planned to receive lobectomy converted to total thyroidectomy, as ETE was confirmed on intraoperative frozen section
the operation. Thus, frozen biopsy could help the surgeon decide the extent of surgery (total thyroidectomy vs lobectomy and central neck dissection) even in patients with small tumors. To find clinical and pathologic factors related to false negative results of frozen biopsy, we analyzed the difference between frozen (?) and (-) groups in patients with ETE on permanent results. However, any clinical factors were not significantly associated with false negative results. Technically, pathologic section was generally performed only once in the specimen on the frozen biopsy. Based on a pathologic frozen section, pathologists evaluated malignancy and the presence of ETE in this study. If ETE was observed on the frozen biopsy, it was also confirmed on the permanent pathologic examination in almost cases. However, as multiple pathologic sections were performed on permanent pathologic examination, ETE could be detected on the other portion of tumor which was not sectioned on the frozen biopsy. This is the reason why the accuracy of the frozen biopsy was different from that of permanent pathologic examination in the prediction of ETE. In the case of false positive results, as the specimen was incompletely sectioned on the frozen biopsy, ETE was suspected. However, ETE was not finally confirmed on the permanent examination. In previous work, we performed frozen biopsy for quantitative analysis of the central neck node and reported that it is an useful tool for the evaluation of central lymphatic status intraoperatively with a high sensitivity and specificity [21]. Because central nodal status and ETE are known to be negative predictive factors for PTC, a more aggressive surgical approach may be required in patients with these risk factors [22]. According to the present study and previously published work, frozen biopsy is useful in
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the evaluation of central nodal status and ETE and helps inform the surgeon’s operative plan regarding the extent of surgery and the need for central neck dissection in patients with PTC. Our study did have several limitations. First, because the pathologists were not blinded to results of frozen section, the problem of bias could not be avoided and it could influence the study’s outcomes. Second, more aggressive operations were performed in our institution even for micro PTC. In this study, total thyroidectomy was performed in almost all patients (96.6 %) and central lymph node dissections were performed in all patients. This treatment policy can be a source of controversies over the extent of surgery, especially in micro PTC. Third, frozen section could induce additional costs because of operation time and use of hospital resources. However, in South Korea, national insurance system covered almost patients, especially cancer patients. Therefore, frozen section of surgical specimen did not demand additional costs to patients. Because the results were reported to surgical team within 30 min on average, it was not significant burden to our facility. Intraoperative frozen biopsy can be an useful tool in identifying the presence of ETE. It can also help the surgeon decide the extent of surgery and the need for central neck dissection in patients with PTC during the operation. Conflict of interest
None.
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