Wolf in Sheep’s Clothing: Papillary Thyroid Microcarcinoma in the US

Abstract

BACKGROUND:

The presumptive overdiagnosis of papillary thyroid microcarcinoma (PTMC) has led to an emerging trend of less-extensive operation and an inclination toward active surveillance when possible. In this study, we aimed to examine the risk of advanced PTMC at presentation.

STUDY DESIGN:

We conducted a retrospective analysis using the National Cancer Database (2010 to 2014). Patients with PTMC who underwent surgical intervention were included and patients with a history of any cancer were excluded.

RESULTS:

A total of 30,180 adult patients with PTMC were identified; 5,628 patients (18.7%) presented with advanced features, including central lymph node (LN) metastasis (8.0%), lateral LN metastasis (4.4%), microscopic extrathyroidal extension (ETE; 6.7%), gross ETE (0.3%), lymphovascular invasion (LVI; 4.4%), and distant metastasis (0.4%). All of those features were associated with a significantly lower survival rate (p < 0.05 each) except for microscopic ETE and LVI. There was a significant interrelation among those features, distant metastasis was associated with central LN metastasis (odds ratio [OR] 2.44; 95% CI, 1.48 to 4.23; p < 0.001), lateral LN metastasis (OR 3.18; 95% CI, 1.77 to 5.71; p < 0.001), and gross ETE (OR 9.91; 95% Cl, 3.83 to 25.64; p < 0.001). In turn, nodal metastasis was associated with microscopic ETE (OR 4.23; 95% CI, 3.82 to 4.70; p < 0.001) and LVI (OR 7.17; 95% CI, 6.36 to 8.08; p < 0.001).

CONCLUSIONS:

PTMC could exhibit advanced features in 19% of patients who underwent operation and some of those, such as LVI and microscopic ETE, are undetectable with preoperative workup. Clinicians need to be cognizant of this considerable risk in the era of less-aggressive management of PTMC.

Small-sized papillary thyroid carcinoma (PTC) was found to represent a distinct clinical and pathologic entity of thyroid cancer more than 5 decades ago; however, its nomenclature, definition, and management have endured multiple changes during the years. Woolner and colleagues¹ were the first to coin the term occult papillary carcinoma, indicating PTC ≤1.5 cm, in their study published in 1960. The study highlighted the nonaggressive course of occult papillary carcinoma. An autopsy study by Harach and colleagues² of 101 individuals not previously diagnosed with thyroid cancer found the prevalence of occult papillary carcinoma could be as high as 36%, of which 67% had a tumor <1 cm. In 1989, the WHO introduced the term papillary microcarcinoma to replace occult papillary carcinoma, and it was defined as PTC ≤1 cm.³ Currently, the prevalence of papillary thyroid microcarcinoma (PTMC) of all sizes of PTC tumors is estimated to be 30%, and it is responsible for 3% of all thyroid cancer mortality and 5% of PTC mortality.^4,5

Multiple studies have reported a good prognosis associated with PTMC.^4,6 The indolent nature of these tumors is supported by the relatively high prevalence of PTMC on autopsies (6% to 36%) of individuals who died of something other than thyroid cancer.⁴ It is also supported by prospective clinical studies of active surveillance of patients with PTMC who did not undergo surgical intervention primarily. Those studies demonstrated clinical outcomes comparable with those of patients who had undergone surgical intervention.^6–8

The 2015 American Thyroid Association guidelines generally recommend lobectomy for patients with a differentiated thyroid carcinoma <1 cm with no evidence of extrathyroidal extension (ETE), nodal or distant metastasis, and no history that places the patient at high risk of recurrence.⁹ However, the guidelines also discuss the role of active surveillance for those patients, in light of the evidence alluded to earlier. The guidelines indicate that there is a subset of PTMC that would exhibit locoregional and distant metastases and that there are no clinically reliable criteria yet to identify those patients at presentation.⁹

In this study, we aimed, through the use of a large population database of patients with PTMC, to investigate the incidence of advanced pathologic features (nodal metastasis, ETE, lymphovascular invasion [LVI], and distant metastasis) at presentation and the interrelation between those features. Ultimately, understanding this subset of patients with PTMC could lead to counseling and prognostication tools that could guide management discussion for patients presenting with PTMC.

METHODS

The study was a retrospective cohort analysis using the National Cancer Database (NCDB, 2010 to 2014).¹⁰ The NCDB is a joint program of the Commission on Cancer of the American College of Surgeons and the American Cancer Society.¹⁰ The American College of Surgeons has executed a business associate agreement that includes a data use agreement with each of its Commission on Cancer-accredited hospitals.¹⁰ The NCDB, established in 1989, is a nationwide, facility-based, comprehensive clinical surveillance resource oncology data set that currently captures 70% of all newly diagnosed malignancies in the US annually.¹⁰ The NCDB contains de-identified data that do not meet the criteria of human subject research and IRB approval is not required.¹⁰

The first study objective was to provide an epidemiologic perspective on PTMC in the US and the prevalence of associated advanced pathologic features at presentation. The pathologic features examined are central and lateral nodal metastases, microscopic and gross ETE, LVI, and distant metastasis. The second study objective was to examine the association of each of the pathologic features with overall survival. The third study objective aimed to elucidate the association among the described pathologic features with distant metastasis in a multivariate logistic regression model. Pathologic features that demonstrated a significant association were considered independent predictors of distant metastasis. Pathologic features that did not demonstrate significant association with distant metastasis were tested again for their association with the independent predictors of distant metastasis identified in the previous step.

The study population included adult patients (18 years and older) who had a primary diagnosis of PTMC and had undergone thyroid operation. Patients with a history of any cancer were excluded. International Classification of Diseases for Oncology, 3rd edition codes were used to identify PTC (8050, 8260, 8340, 8341, 8342, 8343, and 8344). The NCDB has data on the size of the tumor; only tumors ≤1 cm were included. The data were checked for completeness, patients with missing values for any of the study parameters were excluded.

Independent factors that were assessed for their association with the presentation of PTMC patients with advanced pathologic features and overall survival included age (younger than 55 years, 55 years and older), sex (female, male), race (white, black, Hispanic, other), Charlson/Deyo comorbidity score (as classified by NCDB: 0, 1, 2, ≥3), type of thyroidectomy (lobectomy, total), lymph node (LN) dissection (not performed, performed), radioactive iodine therapy (not performed, performed), and hospital volume. Hospital volume was determined based on the number of PTMCs treated annually in a given hospital and categorized by applying quartile classification with rounding to the closest 10, as follows: low volume: ≤25th percentile, 1 to 10 PTMCs/y, intermediate volume: >25th to ≤75th percentiles: 11 to 30 PTMCs/y, and high volume: >75th percentile, ≥31 PTMCs/y).

The association between each independent factor and the risk of presenting with advanced pathologic features was tested using the chi-square test. Factors that demonstrated significant association were included in the multivariate logistic regression model. Log-rank and Kaplan-Meier tests were used to assess the association of each factor with overall survival. Factors that were significantly associated with survival were included in the multivariate Cox hazard ratio (HR) model. Significance level was set as α = 0.05. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute).

RESULTS

A total of 30,180 patients with PTMC were identified per the study inclusion criteria (Table 1). Of the study sample, 5,628 patients (18.65%) had at least LN metastasis, ETE, LVI, or distant metastasis. Table 2 presents the individual risk of association of each of those pathologic features with PTMC at presentation for surgical intervention. The mean ± SD age of the study population was 49.89 ± 13.68 years, 81.83% were women, and 85.60% of patients were white. The median follow-up time was 38.93 months (interquartile range 25.63 to 54.44 months). The 5-year overall survival rate of patients without any of the advanced pathologic features was 98.40%, similar to that of patients with 1 or more of the advanced features (98.45%). The majority of the study sample (82.00%) did not have any other medical comorbidities at presentation. Total thyroidectomy was performed in 82.63% of the patients, and the rest (17.37%) had lobectomy only. Concomitant neck dissection was performed in 52.22% of patients with PTMC. A total of 7,672 patients (25.42%) received radioactive iodine therapy.

Table 1.

Characteristics of the Study Population Who Presented with Papillary Thyroid Microcarcinoma and Underwent Thyroid Operations (National Cancer Database, 2010 to 2014)

			Advanced features*
	Study population (n = 30,180†)		Not present (n = 24.552†)		Present (n = 5.628†)
Characteristic	n %		n %		n %		p Value‡
Age							<0.001
18–54 y	18,838	62.42	14,843	60.46	3,995	70.98
55 y or older	11,342	37.58	9,709	39.54	1,633	29.02
Sex							<0.001
Male	5,485	18.17	4,116	16.76	1,369	24.32
Female	24,695	81.83	20,436	83.24	4,259	75.68
Race							<0.001
White	25,834	85.6	20,907	85.15	4,927	87.54
Black	2,209	7.32	1,993	8.12	216	3.84
Hispanic	240	0.8	198	0.81	42	0.75
Other	1,897	6.29	1,454	5.92	443	7.87
Charlson/Deyo score							<0.001
0	24,748	82	19,965	81.32	4,783	84.99
1	4,520	14.98	3,823	15.57	697	12.38
2	744	2.47	629	2.56	115	2.04
≥3	168	0.56	135	0.55	33	0.59
Operation							<0.001
Lobectomy	5,242	17.37	4,972	20.25	270	4.8
Total thyroidectomy	24,938	82.63	19,580	79.75	5,358	95.2
Neck dissection							<0.001
Not performed	14,420	47.78	13,578	55.3	842	14.96
Performed	15,760	52.22	10,974	44.7	4,786	85.04
Radioactive iodine therapy							<0.001
Not performed	22,508	74.58	20,668	84.18	1,840	32.69
Performed	7,672	25.42	3,884	15.82	3,788	67.31
Hospital volume							<0.001
Low: 1–10 PTMCs/y	13,398	44.39	11,253	45.83	2,145	38.11
Intermediate: 11–30 PTMCs/y	10,070	33.37	8,184	33.33	1,886	33.51
High: ≥31 PTMCs/y	6,712	22.24	5,115	20.83	1,597	28.38

^*Lymph node metastasis, extrathyroidal extension, lymphovascular invasion, and/or distant metastasis.

^†Percentage values might not add up to 100% due to rounding.

^‡Chi-square test.

PTMC, papillary thyroid microcarcinoma.

Table 2.

Risk of Advanced Pathologic Features in Patients with Papillary Thyroid Microcarcinoma (National Cancer Database, 2010 to 2014)

Variable	Study population (n = 30,180)
	n	%
Nodal metastasis
Not identified	26,455	87.66
Central compartment	2,399	7.95
Lateral compartment	1,326	4.39
Extrathyroidal extension
Not identified	28,053	92.95
Microscopic extension	2,035	6.74
Gross extension	92	0.3
Lymphovascular invasion
Not identified	28,862	95.63
Identified	1,318	4.37
Distant metastasis
Not identified	30,054	99.58
Identified	126	0.42

Patients who were likely to present with at least LN metastasis, ETE, LVI, or distant metastasis were more likely to be younger than 55 years, male, and white (p < 0.05 each) (Table 3). Patients with PTMC with advanced pathologic features were more likely to be managed in high-volume hospitals (p < 0.001). The same analysis was performed for only the pathologic features that are not easily identifiable on preoperative workup, namely, central LN metastasis, microscopic ETE, and/or LVI. The analysis demonstrated the same risk factors from the overall model (Table 4).

Table 3.

Characteristics of Patients Who Presented with Papillary Thyroid Microcarcinoma with Advanced Pathologic Features (n = 30,180)

Characteristic	Advanced pathologic feature,* %	Adjusted odds ratio†	95% CI	p Value
Age
18–54 y	21.21	1.63	1.52–1.73	<0.001
55 y or older	14.40	Reference	—	—
Sex
Male	24.96	1.66	1.54–1.78	<0.001
Female	17.25	Reference	—	—
Race
White	19.07	Reference	—	—
Black	9.78	0.47	0.41–0.55	<0.001
Hispanic	17.50	0.85	0.61–1.20	0.35
Other	23.35	1.19	1.06–1.33	0.003
Charlson/Deyo score
0	19.33	Reference	—	—
1	15.42	0.83	0.76–0.91	<0.001
2	15.46	0.90	0.73–1.10	0.29
≥3	19.64	1.35	0.91–1.99	0.14
Hospital volume
Low: 1–10 PTMCs/y	16.01	0.62	0.58–0.67	<0.001
Intermediate: 11–30 PTMCs/y	18.73	0.75	0.69–0.81	<0.001
High: ≥31 PTMCs/y	23.79	Reference	—	—

^*Central or lateral lymph node metastasis, extrathyroidal extension, lymphovascular invasion, and/or distant metastasis).

^†The multivariate model includes all the factors listed in the table.

PTMC, papillary thyroid microcarcinoma.

Table 4.

Characteristics of Patients Who Presented with Papillary Thyroid Microcarcinoma with Advanced Pathologic Features Not Easily Identifiable on Preoperative Workup (n = 30,180)

Characteristic	Advanced pathologic features,* %	Adjusted odds ratio†	95% CI	p Value
Age
18–54 y	18.16	1.60	1.49–1.72	<0.001
55 y or older	12.29	Reference	—	—
Sex
Male	20.34	1.49	1.38–1.61	<0.001
Female	14.99	Reference	—	—
Race
White	16.28	Reference	—	—
Black	8.16	0.46	0.40–0.54	<0.001
Hispanic	15.38	0.88	0.61–1.26	0.47
Other	20.50	1.21	1.08–1.37	0.002
Charlson/Deyo score
0	16.50	Reference	—	—
1	13.09	0.84	0.76–0.92	<0.001
2	14.19	0.99	0.80–1.22	0.90
≥3	18.18	1.50	1.00–2.25	0.05
Hospital volume
Low: 1–10 PTMCs/y	13.43	0.58	0.54–0.63	<0.001
Intermediate: 11–30 PTMCs/y	15.74	0.70	0.65–0.76	<0.001
High: ≥31 PTMCs/y	21.25	Reference	—	—

^*Central lymph node metastasis, microscopic extrathyroidal extension, and/or lymphovascular invasion.

^†he multivariate model includes all the factors listed in the table.

PTMC, papillary thyroid microcarcinoma.

Pathologic features of interest were examined for their association with overall survival (Table 5). In patients with PTMC, both central (HR 2.06; 95% CI, 1.20 to 3.55; p < 0.001) and lateral (HR 3.64; 95% CI, 1.74 to 7.61; p < 0.001) nodal metastases were associated with poor overall survival. Presence of gross ETE was also associated with lower overall survival (HR 6.73; 95% CI, 1.88 to 24.19; p = 0.004). Distant metastasis, expectedly, also lowered overall survival (HR 3.49; 95% CI, 1.63 to 7.45; p = 0.001). Microscopic ETE and LVI were not associated with a significant change in overall survival.

Table 5.

Impact of Papillary Thyroid Microcarcinoma Pathologic Features on Overall Survival (n = 30,180)

Variable	Adjusted hazard ratio*	95% CI	p Value
Nodal metastasis
Not identified	Reference	—	—
Central compartment	2.06	1.20–3.55	<0.001
Lateral compartment	3.64	1.74–7.61	<0.001
Extrathyroidal extension
Not identified	Reference	—	—
Microscopic extension	1.87	0.99–3.53	0.05
Gross extension	6.73	1.88–24.19	0.004
Lymphovascular invasion
Not identified	Reference	—	—
Identified	1.32	0.82–2.14	0.26
Distant metastasis
Not identified	Reference	—	—
Identified	3.49	1.63–7.45	0.001

^*Multivariate model include the following factors: age, sex, race, Charlson/Deyo score, thyroidectomy, neck dissection, radioactive iodine, nodal metastasis, extrathyroidal extension, lymphovascular invasion, distant metastasis, and hospital volume.

Pathologic features that were associated with distant metastasis per the analysis protocol described in the Methods section were central and lateral LN metastasis and gross ETE (Fig. 1). LVI and microscopic ETE were not associated with distant metastasis directly, but we found they had an association with nodal metastasis and gross ETE, suggesting indirect association with distant metastasis.

Figure 1.

The interrelation of selected pathologic features with distant metastasis in patients with papillary thyroid microcarcinoma. The diagram only displays positive association found per the study protocol.

DISCUSSION

This was a retrospective analysis of patients with PTMC using the NCDB. The study identified a total of 30,180 patients with PTMC who underwent surgical intervention in the US from 2010 to 2014. This is one of the largest populations and most recent to be analyzed. Most of the study sample were patients younger than 55 years, female, white, and with no history of other comorbidities. The composition of the study sample resembles that of previous studies, ensuring the generaliz-ability of our results.^4,11,12

This study was designed to describe the pathologic features of PTMC at presentation for surgical intervention. The current American Thyroid Association guidelines recommend against a biopsy of subcentimeter nodules, and active surveillance is proposed for selected patients with PTMC.⁹ Therefore, awareness of the risk of associated advanced pathologic features is imperative. Some of these features, such as with LVI and ETE, are usually undetectable with preoperative ultrasound and cytologic studies alone, and other features might be missed with routine workup. Most patients with advanced PTMC were more likely to be identified in high-volume hospitals, likely a reflection of resources and the expertise available to better characterize these tumors. This study demonstrated that 18.65% of PTMC patients presented with advanced pathologic features. It was interesting to find that even features such as microscopic ETE and LVI, which might not affect overall survival directly, have a strong correlation with distant metastasis, which will ultimately lead to poor overall survival. We did not investigate the risk of recurrence, data that are not available in NCDB, rather we highlighted the important findings of how aggressive PTMC could be. Physicians should be able to counsel patients that active surveillance would miss significant survival predictors at presentation. Mazza- ferri and Jhiang¹³ reported, in their prospective cohort study of patients with differentiated thyroid carcinoma, that a delay from diagnosis to therapy >12 months increased the likelihood of cancer mortality by 130%.

In the absence of highly sensitive and reliable tests that could identify high-risk PTMC on presentation, primary operation is a favorable prognostication and therapeutic option. Previous studies have demonstrated a risk of locoregional recurrence of 2% to 6% with PTMC, and distant recurrence risk of 1% to 2%.⁹ However, it has long been recognized that there is a subset of those tumors that would exhibit a more aggressive clinical course.⁶‘¹⁴ Identifying this subset of high-risk PTMC at presentation has been a challenging task. Previous studies have investigated the association of demographic, clinical, pathologic, and molecular characteristics with PTMC behavior. In this study, we found patients who are younger than 55 years, male, and white were more likely to have PTMC with advanced pathologic features. Similarly, a study by Ito and colleagues⁶ identified younger age with PTMC to be associated with a higher risk for progression. Other factors that have been identified previously to be associated with advanced PTMC included multifocality and capsular invasion identified on histopathologic examination.¹⁵ Molecular analysis of PTMC was also investigated in pursuit of identifying PTMC with aggressive features. BRAF^V600E mutation was found to predict the aggressive behavior of PTMC, however, it was not associated with a higher recurrence rate because those patients with the mutation identified often had a more extensive operative intervention.^16,17 However, another study by Niemeier and colleagues¹⁸ reported that the sensitivity of BRAF ^V600E mutation alone was 77% for predicting advanced PTMC. Niemeier and colleagues proposed a scoring system that, in addition to BRAF mutation, would also account for the presence of superficial tumor location, intraglandular tumor spread and multifocality, and tumor fibrosis, the proposed scoring system increased the sensitivity to 96% for identifying PTMC with high risk of recurrence. It is worth noting from the study by Niemeier and colleagues that the calculation of the score was based on the availability of histopathologic specimens, limiting the application of the scoring system to patients who had undergone thyroid operations.¹⁸ Yabuta and colleagues¹⁴ investigated the TERT mutation for its use in active surveillance of patients with PTMC. They found that in 15 PTMC patients who showed disease progression, none had TERT mutation, putting its use as a predictive surveillance marker in doubt.

The 2015 American Thyroid Association guidelines discuss the role of active surveillance in carefully selected PTMC patients when there is no evidence of extrathyroidal extension, nodal or distant metastasis, and no history that identifies the patient at a high risk of recurrence.⁹ The notion of a cautious observation of a cancer is a novelty in the oncologic management that has stimulated not only a clinical debate but an ethical one as well. Stack and Angelos¹⁹ argued that active surveillance should only be performed with the implementation of an IRB-approved protocol or “surveillance contract.” From the patients’ perspective, active surveillance could place that patient under psychological stress. Prospective active surveillance studies have reported that some patients who were undergoing active surveillance elected to switch into treatment groups based on anxiety.^7,20 Additionally, there is a concern for compliance with active surveillance over time, as has been observed in low-risk prostate cancer patients who were followed prospectively with active surveillance and have demonstrated a decrease in compliance over time, from 81% at 1 year after diagnosis to 33% at 10 years after diagnosis.²¹

This study has several limitations. The NCDB does not have follow-up information on recurrence and there is no information on the preoperative workup findings of ultrasound examination and cytology reports. The NCDB also does not include information on history of radiation exposure and family history of thyroid cancer. The follow-up time is also relatively short. Nonetheless, the NCDB provides a large sample size of patients with PTMC with detailed histopathologic information.

CONCLUSIONS

Patients with PTMC could harbor advanced pathologic features that are not easily detectable with routine preoperative workup and can only be identified on histopathologic examination after operation. Therefore, in patients presenting with PTMC with no evidence of ETE, nodal or distant metastasis, and no history that places them at a high risk of recurrence, lobectomy seems to be a more appropriate course of management. Patients should be counseled that lobectomy would serve as a diagnostic and therapeutic intervention, minimizing the risk of identifying advanced pathologic features later. This would ultimately decrease the risk of delaying appropriate treatment and likely improve survival.

Discussion

DR GREGORY D KENNEDY on behalf of DR MICHAEL CHEN (Birmingham, AL): In the spirit of full disclosure, I would like to say that I am a colorectal surgeon, and I know nothing about papillary thyroid microcarcinoma. I have been asked by Dr Chen to read his comments and questions. The surgical management of papillary thyroid cancer (PTC) continues to evolve, especially in tumors that are less than 1 cm, often called papillary thyroid microcarcinomas, or micro-PTCs. Most surgeons would treat micro-PTCs with a thyroid lobectomy or active surveillance; that is, no surgery, just observation.

In this study, Dr Kandil and colleagues analyzed the National Cancer Database (NCDB) years 2010 to 2014, focusing on patients with micro-PTC who underwent surgical intervention. Most micro-PTCs are either managed conservatively or never come to diagnosis because we generally do not do thyroid fine needle aspirations on thyroid nodules less than 1 cm. Furthermore, we know from autopsy studies that many people who die of non-thyroid cancer-related causes have a micro-PTC in their thyroid which never manifested. The patients in your study are a highly selected group of patients with micro-PTC who underwent operation for some reason and are likely to have more aggressive disease than patients who did not undergo operation.

In your study, 19% of patients undergoing operation had an aggressive phenotype. Do you have an estimate of what percent of all patients with micro-PTC, including those who did not undergo operation, which are the majority, would have an aggressive phenotype? Survival for the group with aggressive features is the same as for those without: 98.4% at 5 years postoperation. Do you have a thought on why that is? Would you change the current American Thyroid Association (ATA), or Thyroid Imaging Reporting and Data System guideline, which, in general, do not recommend thyroid biopsy of nodules less than 1 cm?

DR GERARD M DOHERTY (Boston, MA): Papillary thyroid cancer overall has an excellent prognosis, as we have heard. For isolated tumors less than 1 cm, they are essentially nonthreatening, with a 10-year survival of more than 99%. There is a subset of patients who present with more advanced disease even though the primary tumor is small, but those are usually evident when the patients come in.

The trend in our field over the last decade and a half, as reflected in the ATA treatment guidelines, has been to deintensify treatment of this low-risk disease. The primary treatment choice throughout the time period covered by the guidelines in 2006, 2009, and 2015 for tumors < 1 cm in size has essentially remained the same, and that has been lobectomy, unless there was some compelling reason to remove the other lobe. The field is now moving to extend lobectomy to patients with even bigger tumors and to omit radioiodine therapy for those patients as well. We are deintensifying across the spectrum of thyroid cancer treatment.

Against that backdrop, our colleagues have shown us that a not insubstantial minority of patients do have some negative prognostic pathologic features in this group. They have surmised that we may be putting people at risk of undertreatment by our strategies of not performing biopsy on small tumors, and then not treating them aggressively. What is the harm of undertreatment in a disease that has more than 99% survival? How would we know if we undertreated it?

Abbreviations and Acronyms

ETE

extrathyroidal extension

HR

hazard ratio

LN

lymph node

LVI

lymphovascular invasion

NCDB

National Cancer Database

PTC

papillary thyroid carcinoma

PTMC

papillary thyroid microcarcinoma