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REVIEW ARTICLE
Ahead of print publication  

Overdiagnosis and overtreatment of papillary thyroid carcinoma: A multidisciplinary review


1 Department of Pathology, King Salman Armed Forces Hospital, Kingdom of Saudi Arabia, Tabuk, Kingdom of Saudi Arabia
2 Department of Surgery, King Salman Armed Forces Hospital, Kingdom of Saudi Arabia, Tabuk, Kingdom of Saudi Arabia
3 Pathology Department, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
4 Department of Radiation oncology, King Salman Armed Forces Hospital, Kingdom of Saudi Arabia, Tabuk, Saudi Arabia

Date of Submission27-Jun-2022
Date of Acceptance14-Oct-2022
Date of Web Publication14-Nov-2022

Correspondence Address:
Laila Moharram,
Department of Pathology, King Salman Armed Forces Hospital, Kingdom of Saudi Arabia, Tabuk
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/trp.trp_10_22

  Abstract 


Objectives: Thyroid cancer is one of the most common cancers and its incidence continues to grow in high-income countries. Combined with an excellent survival and stable mortality rate, this increase in incidence is due to overdiagnosis, particularly with the wide use of ultrasonography and other imaging modalities. This study aims to address the issue of thyroid cancer overdiagnosis, and how the recent guidelines can reduce the burden of diagnosis of incidental and indolent lesions, as well as de-escalating the treatment.
Materials and Methods: All thyroid cancer cases diagnosed at King Salman Armed Forces Hospital from 2012 to 2020 were reviewed. A descriptive analysis was performed on the clinicopathologic relevant variables, including age, gender, tumor type, pathologic variant type, tumor size, stage, papillary micro-carcinoma, extra-thyroid extension, tumor focality, lymphovascular invasion, recurrence, and baseline thyroglobulin. We excluded subjects with nay (not applicable or missing) data points to get accurate statistical results and were left with pure papillary carcinoma cases
Results: Of the cases of papillary thyroid carcinoma, a significant proportion of which (23%) are microcarcinoma (≤1 cm), a tumor usually found incidentally and rarely causes clinical symptoms. Only two cases out of the microcarcinomas have shown regional lymph node metastasis (4%). No distant metastasis or tumor-related death is encountered. A similar proportion of our cases is the previously called noninvasive follicular variant of papillary thyroid carcinoma encapsulated follicular variant papillary thyroid carcinomas (PTC).
Conclusions: Awareness of thyroid cancer overdiagnosis is important to reduce the unnecessary surgical interventions, patient psychological distress, and postoperative complications.

Keywords: American thyroid association, encapsulated follicular variant, lobectomy, noninvasive follicular thyroid tumor with papillary-like nuclear feature, papillary thyroid carcinoma



How to cite this URL:
Moharram L, Al-Alawi Y, Hariri N, Ghorbel I, Hamoud E. Overdiagnosis and overtreatment of papillary thyroid carcinoma: A multidisciplinary review. Thyroid Res Pract [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.thetrp.net/preprintarticle.asp?id=361150




  Introduction Top


Thyroid cancer is one of the most rapidly growing cancers in the high-income countries. This has been attributed to the wide use of ultrasonography and other imaging modalities, more fine-needle aspirations (FNAs), and variability in the criteria and threshold of diagnosing certain variant of papillary thyroid carcinoma among pathologists. The steady increase in thyroid cancer incidence (mostly small papillary thyroid carcinomas PTC), combined with stable thyroid cancer-associated mortality, is pathognomonic of overdiagnosis. Overdiagnosis is defined as the detection of a medical condition that, if left undiagnosed, would cause no harm.


  Materials and Methods Top


All thyroid cancer cases diagnosed at our institution from 2012 to February 2020 were listed in a spreadsheet. A descriptive analysis was performed on all the clinicopathologic relevant variables, including age, gender, tumor type, pathologic variant type, tumor size, tumor stage, papillary microcarcinoma (i.e., ≤1 cm), extrathyroid extension, tumor focality, lymphovascular invasion, recurrence, and baseline thyroglobulin. We used the term (aggressive PTC variant) to describe the few cases we had that showed tall-cell or diffuse sclerosing variant.

A new variable was created (noninvasive encapsulated follicular variant [EFV] of papillary carcinoma “EFV” vs. not EFV of papillary carcinoma “EFV”). A descriptive analysis of both groups was performed on all of the relevant variables.

We excluded the subjects with nay (not applicable or missing) data points to get accurate statistical results.

Statistical analysis was then performed on the newly created variable (EFV-PTC vs. non-EFV-PTC) with all clinicopathological relevant variables. For the categorical variables, a Chi-square test was performed. For continuous variables, an analysis of variance test was performed. The statistical significance level was set on a P < 0.05.

All analysis was performed on JMP®, Version 15.2.1. SAS Institute Inc., Cary, NC, USA 1989–2019.


  Results Top


The dataset included 170 subjects with thyroid cancer. The overwhelming majority of cases are papillary thyroid carcinoma. Two cases are follicular carcinoma, two are medullary carcinoma, two are poorly differentiated (insular) carcinoma, and four cases are diffuse large B-cell lymphoma.

We excluded 44 subjects for having one or more missing data points. All the remaining 126 subjects have papillary thyroid cancer (PTC), and about half of them are classic PTC (46%). Most of the patients were female (79%), the mean age for both genders was 40 years old. The noninvasive EFV of papillary thyroid carcinoma [EFV] was found in (23%) of all cases. The papillary microcarcinoma variant accounted for another 23% of the cases. The remaining cases were EFV with capsular invasion, aggressive papillary thyroid carcinoma (referred here to tall cell and diffuse sclerosing variant), oncocytic papillary thyroid carcinoma, and invasive follicular variant of papillary thyroid carcinoma (4%, 2%, 2%, and 1%, respectively) [Table 1].
Table 1: A descriptive analysis of all the clinicopathologic relevant variables

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After performing a comparison analysis between EFV and no EFV groups, we found that both groups had similar findings while comparing gender, tumor stage, ETE, the presence of LVI, tumor size, and recurrence, with P > 0.05. We could not find any statistically significant difference between the two groups while studying the aforementioned variables. However, tumor focality and additional incidental microcarcinoma were different between the two groups, where the latter showed a statistically significant result with a P < 0.001 [Table 2].
Table 2: EFV-PTC: Encapsulated follicular variant of papillary thyroid carcinoma

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Only two cases out of the microcarcinomas have shown regional lymph node metastasis (4%). No distant metastasis or tumor-related death is encountered.

Additional to the main tumor of interest, incidental microcarcinomas were also seen in the background thyroid in 66 cases (52% of cases).

Of all the 29 cases of noninvasive encapsulated/well-demarcated follicular variant of papillary carcinoma EFV-PTC, none had lymph node metastasis. These cases can be potentially re-classified into noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) to avoid overtreatment of an exceedingly indolent tumor. However, a barrier to such reclassification is that these tumors were not examined completely microscopically, one of the prerequisites for classifying a tumor as NIFTP.

The median follow-up was 24 months (range, 2–96 months). No tumor-related death is encountered in the cases of differentiated papillary carcinoma.


  Discussion Top


Epidemic of diagnosis

Thyroid cancer has become one of the most rapidly growing cancers in high-income countries. The International Agency for Research on Cancer (IARC) has cited the increase in thyroid cancer incidence in five countries reported in the New England Journal of Medicine.[1]

The most remarkable example of overdiagnosis due to indiscriminate mass screening was reported in South Korea, where people were offered screening ultrasonography for the neck starting in 1999. This has resulted in a massive 15-fold increase in thyroid cancer incidence in South Korea from 1993 to 2011.[2] In the United States, since 1975, the incidence of thyroid cancer has approximately tripled, from 4.9 to 14.3 per 100,000 individuals.[3] In the Kingdom of Saudi Arabia, the incidence of thyroid cancer in Saudi females has increased from 1994 to 2012 (5.5–8.3 per 10,000 individuals), according to data from the Saudi Cancer Registry.[4] In the 1982–1986 period, thyroid cancer cases made up 4.4% of the total cancer cases seen in the largest referral cancer center in the Kingdom of Saudi Arabia, and 9.4% of the total cases seen by the same center in 2012–2014.[5] The overall age-standardized rate was 4.4/100,000 (2/100,000 for males and 6.8/100,000 for females) in KSA according to the National Cancer Registry in 2008.[6]

Caution against indiscriminate imaging screening

The United States Preventive Services Task Force (USPSTF) recommends against the screening by either US or palpation, for thyroid cancer in asymptomatic adults.[7] The USPSTF concludes with moderate certainty that screening for thyroid cancer in asymptomatic persons results in harms that outweigh the benefits. This does not apply to people who have hoarseness of voice, predisposing genetic abnormality, neck swelling, or other clear indications of neck ultrasound.

Likewise, the IARC report recommends against screening of the thyroid gland and workup of small nodules and advocates careful monitoring as a preferable option for patients affected by low-risk tumors.[1]

Autopsy studies

Due to increased access to healthcare, ultrasound, and FNA, the number of thyroid cancer cases is continuing to increase. Many of these cancers are “Incidentalomas” that if left untreated, would not clinically manifest or cause harm to the patient. A meta-analysis has shown that incidental thyroid differentiated carcinoma in autopsies with partial and whole thyroid examination was 4.1% (95% confidence interval [CI], 3.0%–5.4%) and 11.2% (95% CI, 6.7%–16.1%), respectively.[8] An autopsy study from Finland has shown a prevalence rate of 35.6% of occult papillary carcinoma, suggesting that these are “normalomas” that will not progress clinically.[9]

Radiology

Ultrasonography is important in the evaluation of thyroid nodules. First, it confirms the presence of thyroid nodule, since some palpable lumps or enlargements do not correspond to a sonographically well-defined nodule, distinct from the surrounding parenchyma. The American Thyroid Association (ATA) scheme of reporting ultrasonographic patterns of thyroid nodules provides a stratification for nodules based on pattern recognition. The features evaluated are solid versus cystic, echogenicity, margins, microcalcifications, and taller-than-wide shape. The recommendation to proceed for FNA depends on the pattern and in some cases, also the size of the nodule. As an example, purely cystic nodules need not be biopsied, as they have a very low risk of malignancy.[10]

The American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS) is a point system given to multiple features (composition, echogenicity, shape, margin, and echogenic foci). The total points determine the nodule's ACR TI-RADS level, which ranges from TR1 (benign) to TR5 (high suspicion of malignancy). The decision to proceed with FNA depends on the total points and nodule size.[11]

Several other radiographic classification systems exist, the ATA and ACR TI-RADS being more commonly used in clinical practice. These algorithms are expected to reduce the number of unnecessary FNA and therefore, reduce the number of unnecessary surgical resections. The ATA guidelines state that FNA is not required for thyroid nodules <1 cm that appears to be confined to the thyroid.[10]

Pathology

The previously called “EFV” of papillary thyroid carcinoma EFV-PTC is a problematic entity, with low interobserver reproducibility.[12] Labarge et al. showed that defensive medicine might have an impact on the overdiagnosis of thyroid cancer, they found that states with higher malpractice risk have a higher incidence of thyroid cancer, when controlling for healthcare access and other factors. [12,13] The previously called “EFV” of papillary thyroid carcinoma EFV-PTC was noted to be associated with excellent outcome with no to extremely rare lymph node metastasis.

Noninvasive follicular thyroid tumor with papillary-like nuclear feature

In 2016, an expert panel consensus meeting led to the introduction of the nomenclature “noninvasive follicular thyroid tumor with papillary-like nuclear feature, NIFTP” to replace the EFV-PTC term. This is aimed at reducing the burden of overdiagnosis and overtreatment of a common, very indolent thyroid lesion.[14] Strict inclusion and exclusion criteria are required before assigning a tumor as NIFTP. The tumor has to show encapsulation/clear demarcation, follicular growth pattern, and papillary-like nuclear features. The exclusion criteria are psammoma bodies, vascular and capsular invasion, tumor necrosis, high mitotic activity, 30% or more solid growth pattern, and papillae of any percentage. The panel recommended an adequate microscopic examination of the nodule. Defined as such, NIFTP has RAS or RAS-like mutation, while the classic papillary carcinoma shows BRAF V600E mutation. Secondary criteria were added which were stated as “helpful, but not required for the NIFTP diagnosis,” are lack of BRAF V600E mutation detected by molecular assays or immunohistochemistry and lack of BRAF V600E-like mutations or other high-risk mutations (TERT, TP53).[15]

Treatment options

Observation instead of surgery for microcarcinomas, a new approach

Three hundred and forty Japanese patients with papillary microcarcinomas were offered active surveillance rather than immediate surgery (given that they lack high-risk features, such as proximity of tumor to trachea, dorsal location, high-grade cytology, apparent nodal metastasis).[16] None of these patients had cancer death and few developed nodal metastases at 10 years (3.4%). A proportion eventually underwent surgery, none had cancer recurrence.

Another Japanese study of 1235 patients with papillary microcarcinomas who chose active surveillance instead of immediate surgery showed that tumor enlargement occurred in 8% of patients, and 3.8% developed metastatic nodes at 10 years. None of those who underwent rescue surgery after slight progression of their PTMCs showed life-threatening recurrence or died of thyroid carcinoma.[17] The authors concluded an inverse relationship between disease progression and patient age. Multivariate analyses for disease progression showed that only young age (≤40 years) was a significant prognostic factor, whereas family history of differentiated thyroid carcinoma and multiple foci were not.

In the United States, Memorial Sloan Kettering Cancer Center offered a cohort of 291 patients an active surveillance for low-risk PTC (intrathyroidal tumors ≤1.5 m) with serial tumor measurements through ultrasonography. During a median (range) active surveillance of 25 (6–166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance.[18]

For the first time, the ATA recognized active surveillance as a potential management approach for patients with low-risk thyroid cancer.[10] This option can be considered also in patients at high surgical risk due to comorbid conditions, patients with short life expectancy (e.g., severe cardiopulmonary disease, other malignancies, and very advanced age), or patients who have medical or surgical issues that required to be addressed before thyroid surgery.

Reducing the number of total thyroidectomies

A paper from Memorial Sloan Kettering Cancer Center showed no significant difference in overall survival by extent of surgical resection between lobectomy and total thyroidectomy in 361 patients with differentiated pT1 N0 and T2N0.[19]

For patients with thyroid cancer >1 cm and <4 cm without extrathyroidal extension, and without clinical evidence of any lymph node metastases (cN0), the ATA recommends that the initial surgical approach can be either a bilateral (near-total or total thyroidectomy) or a unilateral procedure (lobectomy).[10]


  Conclusion Top


The elimination of the word “carcinoma” from the EFV-PTC and replacing the term with NIFTP has led to de-escalating the treatment of an indolent and relatively common lesion, and removing the cancer “stigma” and the resulting patient psychological stress. At our institution, all our cases of previously called EFV-PTC did not show lymph node metastasis. Microcarcinoma accounted for 23% of our cases, a tumor variant usually found either by ultrasound or other radiologic examination or as an incidental finding in thyroids removed for unrelated pathology and rarely causes clinical symptoms. Awareness of the problem of thyroid cancer overdiagnosis and discussing this issue with other disciplines will help reduce this burden.[20] Rare aggressive thyroid carcinomas do exist, and the clinical team has to identify those and separate them from the more common indolent variants, for proper management.

Ethical approval

The research was approved by the Research Ethics Committee of our institution, Ethics ID Number: KSAFH-REC-2020–322.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors have no conflict of interest.



 
  References Top

1.
Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L. Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. N Engl J Med 2016;375:614-7.  Back to cited text no. 1
    
2.
Ahn HS, Kim HJ, Welch HG. Korea's thyroid-cancer “epidemic” – Screening and overdiagnosis. N Engl J Med 2014;371:1765-7.  Back to cited text no. 2
    
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Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 2014;140:317-22.  Back to cited text no. 3
    
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Bazarbashi S, Al Eid H, Minguet J. Cancer incidence in Saudi Arabia: 2012 data from the Saudi Cancer Registry. Asian Pac J Cancer Prev 2017;18:2437-44.  Back to cited text no. 4
    
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KFSH & RC, Tumor Registry Annual Report; 2014. Available from: https://www.kfshrc.edu.sa/store/media/8ek.pdf.  Back to cited text no. 5
    
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Hussain F, Iqbal S, Mehmood A, Bazarbashi S, ElHassan T, Chaudhri N. Incidence of thyroid cancer in the Kingdom of Saudi Arabia, 2000–2010. Hematol Oncol Stem Cell Ther 2013;6:58-64.  Back to cited text no. 6
    
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US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Barry MJ, Davidson KW, et al. Screening for thyroid cancer: US preventive services task force recommendation statement. JAMA 2017;317:1882-7.  Back to cited text no. 7
    
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Furuya-Kanamori L, Bell KJ, Clark J, Glasziou P, Doi SA. Prevalence of differentiated thyroid cancer in autopsy studies over six decades: A meta-analysis. J Clin Oncol 2016;34:3672-9.  Back to cited text no. 8
    
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Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 1985;56:531-8.  Back to cited text no. 9
    
10.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133.  Back to cited text no. 10
    
11.
Tessler FN, Middleton WD, Grant EG, Hoang JK, Berland LL, Teefey SA, et al. ACR thyroid imaging, reporting and data system (TI-RADS): White paper of the ACR TI-RADS committee. J Am Coll Radiol 2017;14:587-95.  Back to cited text no. 11
    
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Liu J, Singh B, Tallini G, Carlson DL, Katabi N, Shaha A, et al. Follicular variant of papillary thyroid carcinoma: A clinicopathologic study of a problematic entity. Cancer 2006;107:1255-64.  Back to cited text no. 12
    
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Labarge B, Walter V, Lengerich EJ, Crist H, Karamchandani D, Williams N, et al. Evidence of a positive association between malpractice climate and thyroid cancer incidence in the United States. PLoS One. 2018;13:e0199862.  Back to cited text no. 13
    
14.
Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: A paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol 2016;2:1023-9.  Back to cited text no. 14
    
15.
Nikiforov YE, Baloch ZW, Hodak SP, Giordano TJ, Lloyd RV, Seethala RR, et al. Change in diagnostic criteria for noninvasive follicular thyroid neoplasm with papillarylike nuclear features. JAMA Oncol 2018;4:1125-6.  Back to cited text no. 15
    
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Ito Y, Miyauchi A, Inoue H, Fukushima M, Kihara M, Higashiyama T, et al. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg 2010;34:28-35.  Back to cited text no. 16
    
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Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A. Patient age is significantly related to the progression of papillary microcarcinoma of the thyroid under observation. Thyroid 2014;24:27-34.  Back to cited text no. 17
    
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Tuttle RM, Fagin JA, Minkowitz G, Wong RJ, Roman B, Patel S, et al. Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol Head Neck Surg 2017;143:1015-20.  Back to cited text no. 18
    
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Nixon IJ, Ganly I, Patel SG, Palmer FL, Whitcher MM, Tuttle RM, et al. Thyroid lobectomy for treatment of well differentiated intrathyroid malignancy. Surgery 2012;151:571-9.  Back to cited text no. 19
    
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Schnadig VJ. Overdiagnosis of thyroid cancer: Is this not an ethical issue for pathologists as well as radiologists and clinicians? Arch Pathol Lab Med 2018;142:1018-20.  Back to cited text no. 20
    



 
 
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