The Effect of Surgeon Experience on the Detection of Metastatic Lymph Nodes in the Central Compartment and the Pathologic Features of Clinically Unapparent Metastatic Lymph Nodes: What Are We Missing When We Don't Perform a Prophylactic Dissection of Central Compartment Lymph Nodes in Papillary Thyroid Cancer?

Abstract

Background:

Prophylactic central neck dissection (PCND) for papillary thyroid cancer (PTC) is controversial. Recent publications suggest that the number and size of nodes and the presence of extranodal extension (ENE) are important features for risk stratification of lymph node metastases. We analyzed these features in clinically unapparent nodes that would not otherwise be removed. We also investigated the impact of surgeon experience on the ability to detect metastatic lymph nodes intraoperatively.

Methods:

Forty-seven patients with well-differentiated PTC, with no preoperative evidence of central metastases, were included in this study. Intraoperatively, clinically apparent disease was determined by inspection and palpation by the senior surgeon and a fellow/senior resident, and recorded in a blinded fashion. Rate of occult metastases based on intraoperative evaluation were tabulated for each group of surgeons. Histopathologic features of occult nodes were analyzed to determine what clinicians would be missing by foregoing a PCND, and how that would have impacted the patient management.

Results:

The rate of occult metastases, based on senior surgeon assessment, was 26%, and did not differ significantly from fellow/senior resident assessment. The level of agreement between these two surgeon groups was moderate (k=0.665). Analysis of the false negative cases revealed that the size of the largest undetected node ranged from 0.1 to 1.3 cm; 36% of patients with occult metastases demonstrated five or more positive nodes, and 27% showed ENE.

Discussion:

Clinical assessment based on intraoperative inspection and palpation had poor sensitivity and specificity in identifying metastatic central nodes, regardless of the level of experience of the surgeon. There was moderate agreement between surgeons of different experience levels. Sensitivity improved significantly with larger size of positive nodes, but not with the presence of multiple positive nodes or presence of ENE. In foregoing PCND in this patient population, our results suggest that treating clinicians miss potentially virulent disease with a large number of occult positive central nodes and occult nodes with ENE. This is the first report to address the pathologic features of clinically nonevident central nodes showing a high incidence of clinically relevant, adverse histologic features, as well as the impact of surgeon experience in performing the important intraoperative determination of whether there are clinically evident nodes that require removal.

Introduction

The management of central compartment lymph nodes (CCLNs) in patients with papillary thyroid cancer (PTC), without clinical evidence of metastatic nodal disease (cN0), is controversial (1 –6). Studies have shown the rate of occult metastases in levels VI and VII to be as high as 82% (7). Proponents of prophylactic central neck dissection (PCND) have reported that the results of PCND affect up to a third of patients with respect to their radioactive iodine (RAI) treatment recommendations, and up to a third of patients are reported to experience a reduction in recurrent disease (5,8). The impact of the addition of PCND to total thyroidectomy (TT) has reduced the thyroglobulin (Tg) in some series while having no affect in others (8 –10).

Arguments against PCND are based on studies that have shown an increased risk of permanent hypoparathyroidism and permanent nerve injury in patients who undergo CCLN dissection. (2,3,8,9) Studies that show the safety of PCND are typically done at institutions that perform a high volume of thyroid surgery by experienced surgeons. However, the level of experience of the surgeons performing the majority of thyroidectomies in the United States varies considerably (10 –12).

The most recent clinical management guidelines of the American Thyroid Association (ATA) do not recommend for or against a PCND in the absence of clinically apparent disease (13). Clinically apparent, or clinically evident, lymph nodes are defined as suspicious for metastatic disease based on preoperative imaging, intraoperative palpation, and/or intraoperative inspection (14). The startling low number of thyroid operations performed annually by the majority of surgeons performing thyroid surgery in the United States raises concerns for the overall safety of performing that surgery in less experienced hands. It has further implications when considering the performance of a PCND. However, to date, no study has looked at the impact of the level of surgeon experience in determining whether clinically evident nodes are present in the central compartment at the time of performing the thyroid surgery.

In a meta-analysis by Randolph et al., an attempt was made to stratify lymph nodes according to the risk of recurrence based on clinical evidence, nodal size, number of involved nodes, and the presence of ENE. The stratification of pathologically positive nodes proposed in that publication, which further defines clinically “relevant” or “significant” lymph nodes, provides a construct for determining the importance of the information gained from a PCND with respect to staging and therapeutic decision making.

The objectives of this study were to: (a) assess surgeon accuracy in identifying positive CCLNs based on intraoperative palpation and inspection; (b) determine whether the level of surgeon experience impacts the accuracy of detecting clinically evident CCLNs; (c) determine whether the coexistence of Hashimoto's thyroiditis with thyroid cancer leads to a higher incidence of false positive central compartment assessment, and (d) analyze characteristics of occult positive CCLNs in order to understand whether they are clinically significant and thereby what the clinical team is missing by not performing a PCND.

Materials and Methods

Following Institutional Review Board approval, we gathered data on 47 consecutive patients who underwent thyroidectomy with PCND for PTC by two senior surgeons (MLU and MP) at a single tertiary care institution between April 2012 and June 2013.

All patients had cytologic or pathologically proven well-differentiated PTC, and had no evidence of suspicious CCLNs based on preoperative evaluation, which included ultrasound in all cases and cross-sectional imaging in 14 cases. Patients were excluded if there was preoperative clinical or radiographic evidence of CCLNs and/or if the number of CCLNs removed was fewer than five (unless one or more of those nodes was positive).

Assessment of clinically evident CCLNs was carried out in each case by a senior surgeon who had at least 27 years of post-training experience in performing thyroid surgery (MLU and MP). In addition, a fellow or senior resident (3rd, 4th, or 5th year of training) provided an independent assessment of the clinically evident nodes in each case. The latter group of surgeons was intended to reflect the less experienced surgeons performing thyroid surgery in the United States. The assessment was carried out by inspection and palpation of CCLNs after retraction of the strap muscles and exposure of the thyroid gland and the entire central compartment. Surgeon evaluation was carried out in a single blinded fashion and was recorded at the time of the operation by writing on a sterile piece of paper, prior to the removal of the thyroid and the central nodes.

After clinical assessment, a thyroidectomy (the extent of which is shown in Table 1) was carried out with a bilateral central compartment lymph node dissection (CCLND). With the exception of two patients, a CCLND included removal of all level VI and a portion of level VII lymph nodes bilaterally (15). All but two patients underwent a TT and CCLND as the primary treatment. One patient, with a micropapillary carcinoma, underwent a hemithyroidectomy and unilateral PCND. In this case, the ipsilateral central compartment was evaluated and lymph nodes prophylactically removed. In another patient, a completion thyroidectomy and CCLND was performed. In both of these cases, the process of clinical assessment was identical to the larger cohort of patients who underwent a TT, except that the evaluation and lymph node dissection was limited to the ipsilateral side.

Table 1.

Patient and Surgical Characteristics (n=47)

	Number	% of total cases
Patient characteristics
Age
Median (range), years	41 (16–83)
<45 years	31	66%
≥45 years	16	34%
Sex
Female	36	77%
Male	11	23%
Preoperative CT/MRI	14	30%
Extent of surgery
Total thyroidectomy	45	96%
Hemithyroidectomy	1	2.1%
Completion	1	2.1%
Bilateral CCLND	46	98%
Lateral ND	7	15%

CCLND, central compartment lymph node dissection; ND, neck dissection.

The pathologic features of the primary tumor and CCLNs were reviewed by a pathologist who was blinded to the surgeons' assessments. In addition, the presence of thyroiditis based on histology and/or preoperative antibodies was recorded in a database, along with the specific histologic features of the primary tumor and the lymph nodes, as well as postoperative complications of surgery, including permanent hypoparathyroidism and vocal cord dysfunction. Vocal cord assessment was based on either fiber optic or indirect laryngoscopy performed at the time of the postsurgical visit.

Sensitivity, specificity, negative predictive value, and positive predictive value of intra-operative assessment were calculated for the two levels of experience: senior surgeons and fellow/senior residents. Tumor factors associated with differences in false negative rates and differences in sensitivity were compared using Fischer's exact test with significance set at p<0.05 to identify factors that improve the accuracy of clinical evaluation.

The kappa test was used to assess clinical assessment concordance rates between surgeon groups stratified by experience level. Poor concordance was defined as kappa <0.20, fair was 0.21–0.40, moderate 0.41–0.60, and good >0.61.

Results

The patient cohort was 77% female and had a median age of 41 years (range 16–83 years). All patients were diagnosed with PTC. One patient with suspicious cytology underwent a hemithyroidectomy with a subsequent completion thyroidectomy for multifocal PTC and positive lymph nodes that were diagnosed on permanent section. One additional patient underwent a completion thyroidectomy 12 years following initial surgery in another country. Interestingly, this patient was found to have a multifocal PTC with the largest focus being 3 mm but manifesting ETE, and there were five positive of eight CCLNs with the largest node measuring 4 mm and demonstrating ENE. All remaining patients underwent a TT and CCLND. As noted above, in the two patients who underwent a hemithyroidectomy and a completion thyroidectomy, the process of intraoperative assessment was identical to the patients who underwent a TT. Patient and surgical characteristics are shown in Table 1. One patient was identified as having a 1 mm PTC associated with a larger benign nodule that had suspicious cytologic features identified on fine-needle aspiration.

All cases demonstrated classical PTC on final pathology. Forty-three percent of cases demonstrated multifocality, of which 45% were unilateral and 55% bilateral. Primary tumor characteristics are shown in Table 2. Of the 47 cases, 29 (62%) had one or more CCLNs positive for metastatic PTC. Ten out of 11 (91%) cases with a T3 primary tumor were also found to have positive CCLNs. Clinical assessment of the central compartment by the senior surgeons based on intraoperative assessment resulted in 17 (36%) true positive and 6 (13%) false positive determinations with a positive predictive value (PPV) of 0.74. Additionally, there were 12 (26%) true negative and 12 (26%) false negative results (occult metastases) with a negative predictive value (NPV) of 0.50 (sensitivity was 0.59 and specificity was 0.67). The sensitivity of senior surgeon assessment increased with the number of positive nodes and size of the largest positive node. However, only the size of the largest node was significant, with larger lymph nodes resulting in greater sensitivity (p=0.027).

Table 2.

Primary Tumor Characteristics

	Number	% of total cases
Size
Average (range), cm	1.27 (0.1–6)
Stage
T1a	21	45%
T1b	13	28%
T2	2	4.3%
T3	11	23%
T4a	0	0%
Papillary thyroid carcinoma
Classical	47	100%
Multifocal
None	27	57%
Unilateral	9	19%
Bilateral	11	23%
ETE
None	37	79%
Minimal	10	21%
Extensive	0	0%
Lymphovascular invasion
None	40	85%
Present	7	15%
Thyroiditis
None	30	64%
Present	17	36%

ETE, extra thyroidal extension.

Of the 29 cases that had positive CCLNs, there were 12 cases that were not clinically evident to the senior surgeon, resulting in a false negative (or occult metastasis) rate of 26%. In this group of false negative determinations, 42% of cases had five or more positive nodes. The size of the largest clinically nonevident positive node ranged from 0.1 to 1.3 cm, and was between 2 and 10 mm in eight patients, while two patients had nodes that were between 10 and 30 mm. Three cases (25% of the false negative cohort) had CCLNs with ENE.

Of the 29 cases that had positive CCLNs, these were not clinically evident to the fellow or senior resident in 16 cases, resulting in a false negative rate of 34%. In cases of false negative assessment by the fellow/senior resident, 44% of cases had five or more positive nodes. Three patients had nodes that demonstrated ENE. The overall false negative rate for senior surgeon and fellow/senior resident combined, following elimination of overlapping cases, was 36%. To evaluate the impact of surgeon experience on the accuracy of identifying clinically evident lymph nodes, we calculated the sensitivity, specificity, and false negative rates stratified by level of surgeon experience as shown in Table 3. There was no statistically significant difference in any of the measured rates stratified by experience level (p=0.074). The level of agreement between the senior surgeon and fellow/senior resident was moderate with a kappa value of 0.665 (p=0.000). Seventeen patients (36%) had evidence of thyroiditis. The false positive rate in this group of patients was 17.6% for both senior surgeon and fellow/senior resident, which was not significantly higher than the overall false positive rates of 13% and 6% respectively (p=0.565). The average number and range of nodes harvested in patients with thyroiditis was almost identical to the rest of the cohort (12.4 compared to 11.9 and a range of 4–25 compared with 3–25).

Table 3.

Accuracy, Error Rates, Sensitivity, and Specificity of Clinical Assessment Stratified by Surgeon Experience

		True positive (accuracy)		True negative		False positive (error rate)		False negative
	n	#	% of total cases	#	% of total cases	#	% of total cases	#	% of total cases	Sensitivity	Specificity
Senior surgeon	47	17	36%	12	26%	6	13%	12	26%	0.59	0.67
Fellow/senior resident	47	14	30%	15	32%	3	6%	15	32%	0.48	0.83

Accuracy, error rates, sensitivity, and specificity of clinical assessment stratified by surgeon experience shows no statistically significant difference in ability to identify positive CCLNs based on surgeon experience. Accuracy=number of true positive. Error rate=number of false negative. For sensitivity levels, senior surgeon, p=0.135, and fellow/senior resident, p=0.137.

Complications were comprised of one case (2%) of persistent hypoparathyroidism at six months after surgery. There were no cases of temporary or permanent vocal cord paralysis, wound infections, and chyle leaks.

Discussion

While the ATA guidelines do not recommend for or against PCND, there are a wide range of management strategies, including: (a) never performing PCND, (b) only performing a PCND if there is metastatic lateral compartment disease, and (c) performing intraoperative frozen section analysis of suspicious CCLNs and proceeding with therapeutic CND only in cases of biopsy-proven disease. Furthermore, there is variation in the extent of PCND, ranging from bilateral to unilateral PCND (16).

Opponents of PCND argue that lymph node dissection in WDTC does not improve survival (17), and lymph nodes that are not clinically evident are probably not clinically significant with respect to their impact on disease prognosis and risk of recurrence (18,19). Furthermore, bilateral CCLND can increase the rate of complications of recurrent laryngeal nerve injury and hypoparathyroidism.

However, the sensitivity and specificity of the surgeon's assessment of what constitutes clinically evident nodal disease can vary widely (20). Prior studies have demonstrated up to an 82% rate of missed CCLNs based on clinical evidence alone (21). However, these studies did not document lymph node features beyond the presence or absence of positive nodes.

The current study was conducted to elucidate further the prevalence of more detailed nodal characteristics in the cN0 neck. Clinical evaluation based on intraoperative inspection and palpation resulted in a sensitivity and specificity of only 0.59 and 0.67 for a senior surgeon, and 0.48 and 0.83 for a fellow/senior resident respectively. Moreover, the type II error rate (false negatives) for senior surgeon and/or fellow/senior resident was 36%.

The number of thyroid surgeries needed for adequate training is unknown (21), yet there is significant disparity in surgeon experience among those performing thyroid surgery in the United States. Studies by Sosa et al. and Saunders et al. demonstrate that the majority of thyroid surgeries are done by surgeons who perform fewer than 10 thyroidectomies annually (22,23).

The challenge for a governing body such as the ATA to advise for or against PCND must account for the varying levels of experience among surgeons. Therefore, it seemed important to determine whether surgeons with varying experience levels are able to detect metastatic nodes with equal accuracy. We found that surgeon experience did not significantly impact sensitivity, specificity, or the false negative rate. However, there appeared to be a trend toward a higher level of false negative cases among less experienced surgeons. The “junior surgeon” cohort, defined as a head and neck fellow/senior resident, was meant to represent surgeons performing a small number of thyroid operations each year. While this may not be a perfect substitution, it is difficult to engage that cohort of surgeons in a similar structured manner as the current study design. The head and neck fellow/senior resident cohort is less experienced than a board-certified practicing surgeon. However during training, fellows/senior residents are exposed to a significant volume of thyroid operations under the tutelage of an attending surgeon and do so more often than the community-based surgeon performing a few thyroid surgeries each year. We deemed the combined assessment of both the senior and junior surgeons that is summarized in Table 4 to be reflective of the cross-section of the population of thyroid surgeons in the country.

Table 4.

Combined False Negative Cohort for Both Senior Surgeon and Fellow/Senior Resident (n=47)

	Positive CCLNs		False negative
	Number	% of total cases	Number	% of total cases
Cases with positive CCLNs	29	62%	17	36%
Average number of positive nodes	5.1		3.6
		% of cases with (+) nodes		% of false negative cases
1–4 nodes	14	48%	10	59%
5–9 nodes	10	35%	6	35%
≥10 nodes	5	17%	1	5.9%
Size of largest node
Average (cm)	0.71		0.48
		% of cases with (+) nodes		% of false negative cases
0.2–1 cm	16	55%	14	82%
1–3 cm	10	35%	3	18%
>3 cm	0	0%	0	0%
Presence of ENE	4	14%	3	18%

CCLNs, central compartment lymph nodes; ENE, extranodal extension.

Therefore, we speculated that the presence of thyroiditis might result in a higher rate of false positive determination. However, the number of CCLNs removed and the rate of false positive clinical evaluations in patients with thyroiditis were similar to the entire cohort.

This analysis also showed that neither the number of positive nodes nor the presence of ENE were associated with significantly better sensitivity, better specificity, or lower false negative rates. However, as anticipated, as nodes increased in size, they were less likely to be missed.

In their meta-analysis, Randolph et al. proposed that lymph node metastases be stratified on the basis of number of affected nodes, nodal size, and the presence of ENE. Patients with more than five positive nodes were reported to have a 19% risk of recurrence, while fewer than five positive nodes conferred a risk of 3–8% (14). In a series by Ito et al., patients with lymph nodes >1.5 cm carried an increased risk of lymph node recurrence as well as a worse disease-free survival rate (24). ENE has also been associated with an elevated risk of recurrence ranging from 15% to 32% and a worse disease-specific survival rate (14).

We applied the lymph node risk factors identified by Randolph et al. to the occult lymph nodes removed in PCND in this study to determine their clinical significance with respect to risk assessment, surveillance strategies, and the decision to administer remnant ablation. The ATA guidelines recommend “selective use of RAI ablation” in cases of 1–4 cm intrathyroidal tumors with lymph node metastases and other high risk factors (13). Using these criteria, we identified 12 patients (50% of cN0 patients) with tumors <4 cm and without clinically apparent nodes, in whom PCND revealed metastatic nodes, making them potential candidates for RAI therapy based on senior surgeon opinion alone (Table 5).

Table 5.

False Negative Cases for Senior Surgeon and Fellow/Senior Resident

Case number	Number of central compartment nodes sampled	Number of central compartment nodes positive	Size of largest positive lymph node (cm)	ENE	Role for RAI treatment based on positive lymph node characteristics
1	24	11	0.4	Absent	Yes
2	15	6	1	Absent	Yes
3	7	1	0.2	Absent	No
4	5	3	0.5	Absent	No
5	3	1	0.1	Absent	No
6	9	5	1.3	Present	Yes
7	8	5	0.4	Present	Yes
8	18	2	0.3	Absent	No
9	16	7	0.3	Absent	Yes
10	16	1	0.6	Absent	No
11	11	2	0.35	Present	Yes
12	4	1	0.1	Absent	No
Only fellow/senior resident false negative cases
13	20	5	0.7	Absent	Yes
14	12	6	0.4	Absent	Yes
15	6	2	0.25	Absent	No
16	23	2	0.9	Absent	No
17	14	4	0.35	Absent	No

Features of undetected lymph nodes in the central compartment and the resulting radioactive iodine (RAI) therapy recommendation for each case. Highlighted rows indicate patients with at least one of the lymph node characteristics indicating a worse disease prognosis or a higher risk of recurrence.

PCND, prophylactic central neck dissection.

The 2009 ATA clinical practice guidelines did not stratify “positive lymph nodes” based on nodal characteristics in their recommendations for RAI therapy. With the growing conservatism in advising RAI therapy, we selected the following criteria that might make a patient a candidate for selective use of RAI: patients with a single node with ENE, a node ≥1 cm, or five or more metastatic nodes.

Prior studies using pN1 as the criterion for remnant ablation, identified that the decision to administer remnant ablation was extended to 21.7% and 28.6% of patients on the basis of PCND results (25). Interestingly, using our stricter criteria for remnant ablation based on lymph node characteristics noted above, 8 of the total cohort of 47 (17%) patients had their disease management altered. This represents 47% of the 17 patients with positive nodes who would not have undergone PCND based on clinical evidence.

Finally, three of four patients with ENE did not have clinically evident central compartment disease. Additionally, ENE was found in lymph nodes measuring as small as 3.5 mm. ENE has been significantly correlated with aggressive disease biology, recurrence, disease persistence, decreased chance of biochemical remission and even disease-specific survival (26,27). Three out of the four patients with ENE were older than 45 years of age. Twenty-five percent of the false negative cohort, a slightly higher value than reported by Joo et al. (18.2%), demonstrated at least one lymph node with ENE, suggesting that without a PCND, clinicians are potentially missing virulent disease (29).

The complications in this study are in accordance with others that have shown central compartment lymphadenectomy does not greatly increase morbidity (13). A meta-analysis of PCND by Lang et al. reported a 1.2% incidence of permanent vocal cord paralysis and 2.0% incidence for permanent hypoparathyroidism (5).

Conclusion

There is a significant risk of not detecting pathologically positive, nonclinically evident CCLNs. The size and number of positive nodes and the presence of ENE that indicate a higher risk of recurrence occur in 25% of patients with clinically unapparent nodes operated upon by experienced and less experienced surgeons. Therefore, in foregoing PCND in this patient population, clinicians will be missing virulent nodal disease that would influence disease staging, risk assessment, surveillance strategies, and the decision to administer remnant ablation. Only moderate agreement was observed between surgeons of different experience levels when evaluating the clinically negative central neck. The incidence of false negative assessment in patients with positive nodes was higher in less experienced surgeons but will require a larger study to determine if that difference is statistically significant.

Footnotes

Acknowledgment

We would like to thank the Mount Sinai Health System for their generous support of this research project.

Author Disclosure Statement

We have nothing to disclose.

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