Guidelines from the Brazilian society of surgical oncology regarding indications and technical aspects of neck dissection in papillary, follicular, and medullary thyroid cancers

ABSTRACT

Objective:

The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas.

Materials and methods:

Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians’ Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection?

Results/conclusion:

Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II–V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; “berry node picking” is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

Keywords
Thyroid carcinoma; surgical treatment; papillary thyroid cancer; medullary thyroid cancer; follicular thyroid cancer; lymph node metastasis; elective neck dissection; therapeutic neck dissection; molecular tests; indications; guidelines

INTRODUCTION

Thyroid nodules are frequent in the adult population. The prevalence of palpable thyroid nodules is about 5% in women and 1% in men ( ¹ , ² ). However, high-resolution ultrasound can detect these nodules in up to 19%-68% of the cases, with this frequency being even higher in women and elderly individuals ( ³ , ⁴ ).

The main concern during an investigation of a thyroid nodule is to exclude or identify the presence of thyroid cancer, which is found in 7%-15% of the cases ( ⁵ , ⁶ ). Papillary (most frequent) and follicular carcinomas account for more than 90% of all cases of thyroid cancer ( ⁷ ).

With advances and widespread use of ultrasound and fine-needle aspiration biopsy, the incidence of thyroid cancer has been increasing. The frequency of tumors < 1 cm in new cases of thyroid cancer increased from 25% in 1988-1989 to 39% in 2008-2009. Additionally, the incidence of new cases tripled between 1975 and 2009, increasing from 4.9 to 14.3 per 100,000 individuals ( ⁸ ).

Notably, papillary thyroid carcinoma is often asymptomatic and incidentally detected in autopsy specimens ( ⁹ – ¹⁵ ). The highest prevalence ever reported of incidentally discovered papillary thyroid carcinomas in autopsies is 35.6% ( ⁹ ). In Brazil, the frequency of this finding is estimated at 1%-8% ( ¹⁶ ). Some authors in Japan even consider these incidentalomas to be normal findings; for them, papillary microcarcinomas (tumors < 5 mm) do not require treatment and should only be followed up ( ⁹ – ¹⁵ ). Indeed, according to some specialists, single papillary thyroid microcarcinomas < 10 mm without lymph node metastases or extrathyroidal extension can be managed without surgical treatment and with active surveillance alone ( ¹⁶ ). Another important finding in patients with papillary thyroid carcinoma is the presence of lymph node metastases; these can occur in 14%-64% of the cases overall and in up to 28% of the patients with tumors smaller than 1 cm ( ¹⁷ ).

The incidence of neck metastases is very low in follicular carcinomas, ranging in some studies from 2.1%-3.3% ( ¹⁸ – ¹⁹ ), but are more frequent in medullary thyroid carcinomas, ranging from 44%-81% ( ²⁰ – ²¹ ).

Lymph node metastases are present in most patients with papillary thyroid carcinoma and are rare in those with follicular thyroid carcinoma ( ²² ). In papillary thyroid carcinoma, lymph node metastases have no prognostic significance in patients with low-risk disease but are predictive of poor survival in those with high-risk disease ( ²³ ).

Neck metastases from papillary thyroid carcinomas occur most frequently to level VI. Central neck dissection includes the pre-laryngeal, pre-tracheal, and at least the paratracheal chains homolateral to the tumor. The dissection can include the retropharyngeal, retroesophageal, and para-laryngopharyngeal areas and the superior mediastinum and may extend inferiorly from the cricoid cartilage to the brachiocephalic vein. Intraoperative care should include the identification and preservation of the inferior laryngeal nerves (which must be dissected using an atraumatic technique) and inferior parathyroid glands. Intraoperative frozen section analysis is important to distinguish between parathyroid glands and lymph nodes, and if one or more parathyroids are accidentally resected, reimplantation should be performed ( ²⁴ , ²⁵ ).

A growing interest is to individualize the management of thyroid cancer based on risk stratification, establishing therapy and follow-up according to the estimated risk. The primary concern is to select the best therapeutic strategy to reduce morbidity and mortality and avoid overtreatment and its potential side effects. Thus, the surgical extent of the thyroidectomy and the neck dissection in patients with thyroid cancer must be carefully planned and individualized ( ²⁶ , ²⁷ ).

This document is the result of efforts by the Committee of Head and Neck Surgery of the Brazilian Society of Surgical Oncology to develop recommendations based on the current evidence available in the scientific literature regarding the indications and technical aspects of neck dissection in papillary, follicular, and medullary thyroid carcinomas, specifically:

1. Indications for elective central compartment neck dissection in papillary, follicular, and medullary thyroid carcinomas.

2. Indications for elective lateral neck dissection in papillary, follicular, and medullary thyroid carcinomas.

3. Indications for therapeutic modified radical neck dissection in papillary, follicular, and medullary thyroid carcinomas.

4. Management of lymph node recurrence after selective or therapeutic neck dissection in thyroid carcinomas.

5. Recommendation regarding the use of molecular tests in guiding the extent of the neck dissection.

MATERIALS AND METHODS

The development of the recommendations in the present guidelines was based on research of scientific articles published in English, including meta-analyses and guidelines from international societies such as the American Thyroid Association (ATA), the Japan Association of Endocrine Surgeons, and the European Thyroid Association (ETA). The research was carried out in the databases PubMed ( www.ncbi.nlm.nih.gov/pubmed ), SciELO ( www.scielo.org ), and LILACS (Bireme). The search was conducted manually or via the Internet.

The American College of Physicians’ Guideline Grading System was used as the grading system to determine the levels of evidence and grades of recommendations ( ²⁸ ) ( Tables 1 and 2 ).

Table 1
Interpretation of the American College of Physicians’ Guideline Grading System ( ²⁸ )

Grade of recommendation	Benefits versus risks and burdens	Implications
Strong recommendation	Benefits clearly outweigh risks and burden or vice versa	For patients, most would want the recommended course of action and only a small proportion would not; a person should request discussion if the intervention was not offered. For clinicians, most patients should receive the recommended course of action. For policymakers, the recommendation can be adopted as a policy in most situations.
Weak recommendation	Benefits closely balanced with risks and burden	For patients, most would want the recommended course of action but some would not – a decision may depend on an individual's circumstances. For clinicians, different choices will be appropriate for different patients, and a management decision consistent with a patient's values, preferences, and circumstances should be reached. For policymakers, policymaking will require substantial debate and involvement of many stakeholders.
Insufficient	Balance of benefits and risks cannot be determined	Decisions based on evidence from scientific studies cannot be made.

Table 2
Recommendation based on quality of evidence ( ²⁸ )

Grade of recommendation/Quality of evidence	Methodological quality of supporting evidence	Interpretation
Strong recommendation
High-quality evidence	Without important limitations or overwhelming evidence from observational studies	Can apply to most patients in most circumstances without reservation
Moderate-quality evidence	Important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies	Can apply to most patients in most circumstances without reservation
Low-quality evidence	Observational studies or case series	May change when higher quality evidence becomes available
Weak recommendation
High-quality evidence	Without important limitations or overwhelming evidence from observational studies	Best action may differ depending on circumstances
Moderate-quality evidence	Important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies	Best action may differ depending on circumstances
Low-quality evidence	Observational studies or case series	Alternatives may be equally reasonable
Insufficient	Evidence is conflicting, poor quality, or lacking	Insufficient evidence to recommend for or against routinely providing the service

Based on the study of all the scientific articles surveyed, we propose the following questions to address the recommendations:

1. Is elective neck dissection recommended in the treatment of patients with papillary or follicular thyroid carcinoma?

2. Is elective neck dissection recommended in the treatment of patients with medullary thyroid carcinoma?

3. Is therapeutic posterior lateral neck dissection indicated in the presence of clinically detected metastases?

4. How should neck dissection be performed in recurrent disease after elective or therapeutic neck dissection in thyroid cancer?

5. Are molecular tests indicated to guide the extent of neck dissection?

RESULTS

Question 1:

Is elective central neck dissection recommended in the treatment of patients with cN0 well-differentiated thyroid carcinoma?

The 2020 revised guidelines of the Japan Association of Endocrine Surgeons ( ²⁹ ) recommend elective central neck dissection in all cases of cN0 well-differentiated thyroid carcinoma. This recommendation was based on low scientific evidence but had good consensus-based approval. The recommendation was primarily based on a meta-analysis of 17 studies including 4,437 patients, in which elective central neck dissection along with total thyroidectomy was associated with a very low incidence of regional recurrence (0.66%; 95% confidence interval 0.49%-0.90%). Of note, the difference in recurrence rates with and without dissection was only 2.3%. This meta-analysis included three prospective and 14 retrospective studies, and the patients in both groups (with versus without dissection) had several differences. The authors further argued that the incidence of complications such as hypocalcemia was low, with odds ratios of 2.37 and 1.93 in patients who did and did not undergo dissection, respectively ( ³⁰ ). They also recommended elective mediastinal dissection ( ³¹ ) on the basis that these lymph nodes are very difficult to identify before surgery using imaging tests ( ³¹ , ³² ); this recommendation is further supported by high complication rates in reoperations, e.g. , recurrent nerve injury ( ³³ ).

The presence of lymph node metastases in papillary thyroid carcinoma has a low risk of recurrence (2.3%) and, according to one study ( ²³ ) including 9,904 patients, has only a negative effect on survival when associated with other prognostic factors such as age above 45 years, distant metastases, and tumor size; indeed, the survival rates over 14 years have been described as 82% and 79% in the absence and presence of lymph node metastases, respectively.

Several studies have shown that elective central neck dissection does not improve survival rates or risk of recurrence and increases the risk of complications such as temporary hypocalcemia and dysphonia ( ³⁴ – ³⁹ ). These observations have also been shown in a Brazilian study by Ywata de Carvalho and cols. ( ⁴⁰ ).

Elective resection of level VI lymph nodes in patients with cN0 neck staging identifies many patients with pN1 disease, but the direct long-term benefit of this approach is very small ( ⁴⁰ – ⁴² ). Most groups only agree with this approach in high-risk cases (very old or very young patients, T3-T4 bulky tumors, multifocal aggressive disease, extrathyroidal extension, presence of lymph node metastases from levels II to V), in which staging influences decisions about adjuvant therapy. The use of currently available imaging methods prevents unnecessary elective neck dissections ( ³⁴ , ³⁸ , ⁴¹ – ⁴⁴ ).

The presence of microscopic central lymph node disease is not a risk factor for macroscopic recurrence; this knowledge may prevent the misuse of radioiodine therapy ( ⁴⁵ ). Following this same line of avoiding unnecessary treatment, Momesso and cols. suggest that radioiodine therapy should be avoided not only in patients with microscopic lymph node disease but also in those with primary tumors smaller than 2 cm without unfavorable factors (such as multifocal disease, extrathyroidal extension, positive lymph nodes or distant metastases). Therefore, radioiodine therapy should not be used indiscriminately ( ⁴⁶ ). Vaisman & Tuttle have further emphasized that the management of these cases should be individualized and that stratification of risk groups is essential to help identify whether treatment should be implemented more or less aggressively ( ²⁶ ).

Recommendation 1: Elective central neck dissection is NOT recommended in the treatment of patients with cN0 papillary or follicular thyroid carcinoma.

Thyroidectomy without elective central neck dissection is appropriate for T1-T2 noninvasive tumors in patients with cN0 papillary thyroid carcinoma or follicular carcinoma.

Strong recommendation/moderate-quality evidence.

Elective central neck dissection in patients with cN0 papillary or follicular thyroid carcinomas should be considered only in those with advanced tumors (if papillary carcinoma), T3-T4 disease, in the presence of metastases in the lateral neck levels (II-V), or if this procedure is essential in planning adjuvant therapies.

Weak recommendation/low-quality evidence.

Question 2:

Is elective neck dissection recommended in medullary thyroid carcinoma?

The indication of total thyroidectomy with dissection of the central compartments depends on serum calcitonin levels and ultrasound findings. This is the standard treatment for sporadic or hereditary medullary thyroid carcinoma.

Patients with palpable tumors are at high risk for lymph node metastases. Nonetheless, several studies have reported that elective neck dissection is not associated with improved survival rates in medullary carcinoma. Kebebew and cols. and Grozinsky-Glasberg and cols. observed no differences in survival curves in studies including, respectively, 104 and 51 patients with medullary thyroid carcinoma ( ⁴⁷ , ⁴⁸ ). Of note, biochemical cure ( i.e. , negative calcitonin test) is more likely in patients who undergo elective neck dissection than in those who do not undergo this procedure.

The rates of levels VI or II-V neck metastases in patients without versus with neck dissection according to serum calcitonin values are, respectively, 12% versus 0% for calcitonin values 20-200 pg/mL, 43% versus 14% for values 200-2,000 pg/mL, 74% versus 44% for values 2,000-10,000 pg/mL, and 90% versus 80% for values above 10,000 pg/mL ( ⁴⁹ ). Among patients with established metastases at level VI, the risk of metastases at levels II-V increases significantly, as does the incidence of contralateral metastases ( ⁵⁰ ).

A question remains whether the extent of neck dissection influences prognosis in patients with medullary thyroid carcinoma. However, considering the rates of positive lymph nodes in these patients and the decrease in quality and survival time associated with recurrence, dissection of at least the central neck compartment (level VI) is indicated, an approach that is worthwhile for tumors > 5 mm or patients with calcitonin levels > 20 pg/mL. According to Wells ( ⁵¹ ), the encounter of metastases is very unlikely with preoperative calcitonin levels < 20 pg/mL. In the same publication, and based on expert opinion, the authors recommend contralateral neck dissection when calcitonin levels are > 200 pg/mL and preoperative imaging is positive in the ipsilateral neck compartment ( ⁵¹ ).

Recommendation 2: Elective neck dissection of level VI (central) is indicated in all patients with medullary thyroid carcinoma.

Moderate recommendation/moderate-quality evidence.

Based on calcitonin levels: for levels between 20-200 pg/mL, dissection of the central compartment (level VI) is recommended; for levels above 200 pg/mL, bilateral modified radical neck dissection may be indicated when preoperative imaging is positive in the ipsilateral neck compartment.

Weak recommendation/low-quality evidence.

Question 3:

Can therapeutic modified radical neck dissection be performed?

A recent analysis of data from the US National Cancer Centers Network (NCCN) ( ⁵² ) has shown a small but significantly increased risk of death in patients with papillary thyroid cancer who are younger than 45 years. The study emphasized the importance of a more rigorous screening for neck metastases in this group of patients. Independent from other factors, the presence or absence of lymph node metastases has a small effect on the overall survival rates in patients with well-differentiated carcinoma. Still, there is a consensus that therapeutic neck dissection (levels II to VI) should be indicated in cases with neck metastases (cN1) ( ²³ , ³⁴ ).

Lymph node metastases occur most frequently in levels II-V (lateral and latero-posterior compartments), while level I is rarely affected ( ⁵³ , ⁵⁴ ). Neck dissection should be restricted to patients with clinically evident metastases or in whom metastases are observed on preoperative ultrasound and confirmed by cytological analysis of material collected by fine-needle aspiration and measurement of thyroglobulin in the aspirated wash. Also, in cases where suspicious lymph nodes are observed during surgery and lymph node metastasis is confirmed by frozen section examination, neck dissection (levels II-VI) can reduce the risk of recurrence and mortality ( ⁵⁵ – ⁵⁷ ).

Barbosa and cols. have shown that an elevated number of large metastatic lymph nodes in the lateral compartment and extracapsular leakage decrease the likelihood of an excellent response to initial treatment and are associated with neck lymph node recurrence or persistence and distant metastases ( ⁵⁸ ).

The 2013 update of a Brazilian consensus of clinical endocrinologists on differentiated thyroid cancer recommended prophylactic dissection of the central compartment only when lymph node metastases are strongly suspected or confirmed on histopathology during surgery or in the presence of metastases in the lateral neck compartment. If metastatic lymph nodes are found in the lateral compartment but not in the central compartment, the central compartment (level VI) should also be dissected ( ⁵⁹ ). Therefore, therapeutic neck dissection (sparing level I because of its low incidence of metastatic involvement) is mandatory when cervical metastasis is confirmed.

Recommendation 3: Therapeutic lateral and central neck dissection (levels II-VI) must be performed in patients with papillary thyroid carcinoma in the presence of detected neck metastases confirmed by cytology, frozen section, or thyroglobulin measurement on aspirate wash. This approach decreases the risk of locoregional recurrence and mortality.

• -

  Strong recommendation/moderate-quality evidence.

Question 4:

What is the surgical treatment for lymph node recurrence after elective or therapeutic neck dissection in thyroid cancer?

Some prognostic factors may influence the risk of neck lymph node recurrence or persistence, even in patients who have undergone more comprehensive types of elective neck dissections and in the hands of expert surgeons. These prognostic factors include age above 55 years, male sex, tumors with extrathyroidal extension, tumors larger than 3 cm, and lymph node characteristics such as number, size, location, and extranodal extension ( ⁴⁶ , ⁵⁸ , ⁶⁰ – ⁶² )

Evidence from some observational studies suggests that disease recurrence affecting only a few lymph nodes can be managed conservatively (without surgery) under strict observation ( ⁶³ , ⁶⁴ ), but if the recurrence is large, invasive, or involves multiple lymph nodes, the treatment of choice is surgery ( ⁶⁵ – ⁶⁷ ).

Several factors must be considered in therapeutic decisions, such as the risks of a second surgery (since normal anatomic features may be distorted, especially when fibrosis is extensive) and damage to the parathyroid glands, inferior laryngeal nerves, carotid artery, internal jugular vein, and lymphatic duct, among others. Still, surgical resection is the treatment of choice for recurrent macroscopic lymph node disease ( ⁶⁸ ).

The surgical indication should be based on clinical (structural disease) or radiological (ultrasound or computed tomography [CT] scanning) evidence of recurrence and confirmed by fine-needle aspiration (cytological evaluation or thyroglobulin measurement in the aspirate wash), instead of relying on increased serum thyroglobulin levels alone. Of note, confirmation of recurrence by cytopathology alone can be challenging ( ⁶⁹ , ⁷⁰ ).

Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (¹⁸F-FDG PET/CT) or radioiodine s ingle-photon emission computed tomography with integrated CT (RAI-SPECT/CT) may be used to improve the accuracy of the method for identification of recurrence. Lymph node tattooing with ultrasound-guided injection of activated charcoal can also be used ( ⁶⁹ ).

Some authors advocate surgical treatment even in patients with few lymph nodes, regardless of risk level, in those with high-grade tumors, in cases with thyroglobulin doubling time (doubling of thyroglobulin values over time), in radioiodine-avid tumors (tumors with good radioactive iodine uptake) or those with good ¹⁸F-FDG-PET/CT uptake, and in the presence of molecular markers of aggressive behavior. The procedure known as “berry picking” (nodulectomy) is not recommended due to high recurrence rates, and compartmental surgery is indicated preferably ( ⁷¹ , ⁷² ).

Surgery, if indicated, should be safe and restricted to the affected compartment since the neck area with the recurrence has already been approached in previous neck dissection. The lateral compartment should be dissected if the recurrence is localized and restricted to this location and the compartment has not been dissected before. After compartmental dissection, baseline thyroglobulin levels decrease by 60%-90%, although a 30%-50% reduction has been described in some studies. Notably, the prediction of which patients will respond after salvage surgery is challenging. To minimize lesions to cervical structures, neurostimulators may be used to identify the inferior laryngeal nerve, and lymph nodes may be marked with technetium (^99mTc)-sestamibi for radioguided surgery or tattooed with charcoal ( ⁷³ – ⁷⁸ ).

Recommendation 4: Surgical management of lymph node recurrence after elective or therapeutic neck dissection in thyroid cancer: central compartment neck dissection (level VI) should be performed, preferably sparing important anatomic structures. “Berry node picking” is not recommended. Standard therapeutic neck dissection is strongly recommended, if already not done, in cases of recurrence in the lateral compartments (levels II-V). The surgical approach should be restricted to the affected compartment.

Strong recommendation/ moderate-quality evidence.

Question 5:

Could molecular tests guide the extent of neck dissection?

A greater understanding of molecular signaling pathways could be used to stratify better patients who may benefit from prophylactic central neck dissection. Mitogen-activated protein kinase (MAPK) pathway mutations are well-known frequent driver mutations in papillary thyroid carcinomas. The most common genetic abnormality in papillary thyroid carcinomas is the BRAF V600E mutation, which has a reported frequency of 40%-70% ( ⁷⁹ ). In a retrospective review by Tufano and cols., BRAF V600E mutations were reported in 75% of 120 patients who underwent central neck dissection due to disease recurrence in this compartment ( ⁸⁰ ). Additionally, Howell and cols. have shown that, among preoperative clinical endpoints commonly used to determine prophylactic central neck dissection, only BRAF V600E mutation was an independent predictor of the presence of metastases in a cohort of 156 patients ( ⁸¹ ).

A study from four institutions in the United States ( ⁸² ) has shown that the detection of BRAF V600E mutation was not superior to intraoperative examination in predicting the presence of metastatic lymph nodes in the central compartment. Recently, patients carrying a BRAF V600E mutation combined with a telomerase reverse transcriptase (TERT) promoter mutation have been shown to present a significantly shorter progression-free survival, clearly suggesting a more aggressive tumor biology in these cases. Still, based on current evidence, no definitive molecular marker – not even the BRAF V600E mutation – can reliably predict the presence of metastases in the central compartment, and no data have shown that prophylactic resection changes the outcome in patients carrying these mutations ( ⁸³ ).

Recommendation 5: The use of molecular tests to guide the extent of neck dissection in patients with thyroid cancer is not recommended.

Strong recommendation/moderate-quality evidence.

REFERENCES

• ¹
  Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15- year study of the incidence of thyroid malignancy. Ann Intern Med. 1968;69:537-40.
• ²
  Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977;7:481-93.
• ³
  Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med. 1997;126:226-31.
• ⁴
  Guth S, Theune U, Aberle J, Galach A, Bamberger CM. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest. 2009;39:699-706.
• ⁵
  Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351:1764-71.
• ⁶
  Mandel SJ. A 64-year-old woman with a thyroid nodule. JAMA. 2004;292:2632-42.
• ⁷
  Sherman SI. Thyroid carcinoma. Lancet. 2003;361:501-11.
• ⁸
  Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.
• ⁹
  Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid: A “normal” finding in Finland. Cancer. 1985;56:531-8.
• ¹⁰
  Fukunaga FH, Yatani R. Geographic pathology of occult thyroid carcinomas. Cancer. 1975;36:1095-9.
• ¹¹
  Samson RJ. Prevalence and significance of occult thyroid cancer. In: DeGroot LJ, ed. Radiation-associated thyroid carcinoma. New York: Grune & Stratton; 1977. p. 137-53.
• ¹²
  Nishiyama RH, Ludwig GK, Thompson NW. The prevalence of small papillary thyroid carcinomas in 100 consecutive necropsies in an American population. In: DeGroot LJ, ed. Radiation-associated thyroid carcinoma. New York: Grune & Stratton; 1977. p. 123-35.
• ¹³
  Thorvaldsson SE, Tulinius H, Bjornsson J, Bjarnason O. Latent thyroid carcinoma in Iceland at autopsy. Pathol Res Pract. 1992;188:747-50.
• ¹⁴
  Lang W, Borrusch G, Bauer L. Occult carcinomas of the thyroid. Am J Clin Pathol. 1988;90:72-6.
• ¹⁵
  Yamamoto Y, Toshiharu M, Izumi K, Otsuka H. Occult papillary carcinoma of the thyroid. Cancer. 1990;65:1173-9.
• ¹⁶
  Rosário PW, Ward LS, Graf H, Vaisman F, Mourão GF, Vaisman M. Thyroid nodules ≤ 1 cm and papillary microcarcinomas: Brazilian experts opinion. Arch Endocrinol Metab. 2019;63(5).
• ¹⁷
  Sampson RJ, Key CR. Smallest forms of papillary carcinoma of the thyroid. Arch Pathol. 1970;91:334-9.
• ¹⁸
  Witte J, Goretzki PE, Dieken J, Simon D, Roher HD. Importance of lymph node metastasis in follicular thyroid cancer. World J Surg. 2002;26:1017-22.
• ¹⁹
  Chow SM, Law SCK, Mendenhall WM, Au SK, Yau S, Yuen KT, et al. Follicular thyroid carcinoma. Cancer. 200295:488-98.
• ²⁰
  McGovern MM, Elles R, Beretta I, Somerville MJ, Hoefler G, Keinanen M, et al. Report of an international survey of molecular genetic testing laboratories. Community Genet. 2007;10:123-31.
• ²¹
  Krane JF, Nayar R, Renshaw AA. Atypia of undetermined significance/follicular lesion of undetermined significance. In: Ali SZ, Cibas ES (Eds). The Bethesda System for Reporting Thyroid Cytopathology. New York, NY: Springer; 2010. p. 37-49
• ²²
  Hughes DT, White ML, Miller BS, Gauger PG, Burney RE, Doherty GM. Influence of prophylactic central lymph node dissection on postoperative thyroglobulin levels and radioiodine treatment in papillary thyroid cancer. Surgery. 2010;148:1100-6.
• ²³
  Podnos YD, Smith D, Wagman LD, Ellenhorn JD. The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer. Am Surg. 2005;71:731-4.
• ²⁴
  Robbins KT, Shaha AR, Medina JE, Califano JA, Wolf GT, Ferlito A, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg. 2008;134:536-8.
• ²⁵
  Hartl DM, Leboulleux S, Al Ghuzlan A, Baudin E, Chami L, Schlumberger M, et al. Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann Surg. 2012;255:777-83.
• ²⁶
  Vaisman F, Tuttle R. Clinical Assessment and Risk Stratification in Differentiated Thyroid Cancer. Endocrinol Metab Clin North Am. 2019;48(1):99-108.
• ²⁷
  Tuttle RM, Ganly I, Risk stratification in medullary thyroid cancer : moving beyond static anatomic staging. Oral Oncol. 2003;49:695-701.
• ²⁸
  Qaseem A, Snow V, Owens DK, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. The Development of Clinical Practice Guidelines and Guidance Statements of the American College of Physicians: Summary of Methods Ann Intern Med. 2010;153:194-9.
• ²⁹
  Ito Y, Onoda N, Okamoto T. The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer. Endocr J. 2020;67(7):669-717.
• ³⁰
  Zhao W, You L, Hou X, Chen X, Ren X, Chen G, et al. The effect of prophylactic central neck dissection on locoregional recurrence in papillary thyroid cancer after total thyroidectomy: a systematic review and meta-analysis: pCND for the Locoregional Recurrence of Papillary Thyroid Cancer. Ann Surg Oncol. 2017;24(8):2189-98.
• ³¹
  Iihara M, Yamashita T, Okamoto T, Kanbe M, Yamazaki K, Egawa S, et al. A nationwide clinical survey of patients with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma in Japan. Jpn J Clin Oncol. 1997;27(3):128-34.
• ³²
  Miyazawa Y, Sakata H, Kawashima T, Ochiai T. Diagnosis and treatment of sporadic medullary thyroid carcinoma. J Clin Surg (Rinsho Geka). 2004;59:413-7. (Japanese)
• ³³
  Rodrigues KC, Toledo RA, Coutinho FL, Nunes AB, Maciel RMB, Hoff AO, et al. Assessment of depression, anxiety, quality of life, and coping in long-standing multiple endocrine neoplasia type 2 patients. Thyroid. 2017;27:693-706.
• ³⁴
  Popadich A, Levin O, Lee JC, Smooke-Praw S, Ro K, Fazel M, et al. A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer. Surgery. 2011;150:1048-57.
• ³⁵
  Lang BH, Wong KP, Wan KY, Lo CY. Impact of routine unilateral central neck dissection on preablative and postablative stimulated thyroglobulin levels after total thyroidectomy in papillary thyroid carcinoma. Ann Surg Oncol. 2012;19:60-7.
• ³⁶
  Wang TS, Evans DB, Fareau GG, Carroll T, Yen TW. Effect of prophylactic central compartment neck dissection on serum thyroglobulin and recommendations for adjuvant radioactive iodine in patients with differentiated thyroid cancer. Ann Surg Oncol. 2012;19:4217-22.
• ³⁷
  Chisholm EJ, Kulinskaya E, Tolley NS. Systematic review and meta-analysis of the adverse effects of thyroidectomy combined with central neck dissection as compared with thyroidectomy alone. Laryngoscope. 2009;119:1135-9.
• ³⁸
  Sancho JJ, Lennard TW, Paunovic I, Triponez F, SitgesSerra A. Prophylactic central neck disection in papillary thyroid cancer: a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg. 2014;399:155-63.
• ³⁹
  Moreno MA, Edeiken-Monroe BS, Siegel ER, Sherman SI, Clayman GL. In papillary thyroid cancer, preoperative central neck ultrasound detects only macroscopic surgical disease, but negative findings predict excellent long-term regional control and survival. Thyroid. 2012;22:347-55.
• ⁴⁰
  Ywata de Carvalho A, Chulam TC, Kowalski LP. Long-term Results of Observation vs Prophylactic Selective Level VI Neck Dissection for Papillary Thyroid Carcinoma at a Cancer Center. JAMA Otolaryngol Head Neck Surg. 2015;141(7):599-606.
• ⁴¹
  Lang BH, Ng SH, Lau LL, Cowling BJ, Wong KP, Wan KY. A systematic review and meta-analysis of prophylactic central neck dissection on short-term locoregional recurrence in papillary thyroid carcinoma after total thyroidectomy. Thyroid. 2013;23:1087-98.
• ⁴²
  Wang TS, Cheung K, Farrokhyar F, Roman SA, Sosa JA. A meta-analysis of the effect of prophylactic central compartment neck dissection on locoregional recurrence rates in patients with papillary thyroid cancer. Ann Surg Oncol. 2013;20:3477-83.
• ⁴³
  Bonnet S, Hartl D, Leboulleux S, Baudin E, Lumbroso JD, Al Ghuzlan A, et al. Prophylactic lymph node dissection for papillary thyroid cancer less than 2 cm: implications for radioiodine treatment. J Clin Endocrinol Metab. 2009;94:1162-7.
• ⁴⁴
  Laird AM, Gauger PG, Miller BS, Doherty GM. Evaluation of postoperative radioactive iodine scans in patients who underwent prophylactic central lymph node dissection. World J Surg. 2012;36:1268-73.
• ⁴⁵
  Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, et al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 2012;22:1144-52.
• ⁴⁶
  Momesso DP, Vaisman F, Caminha LS, Pessoa CH, Corbo R, Vaisman M. Surgical approach and radioactive iodine therapy for small well-differentiated thyroid cancer. J Endocrinol Invest. 2014;37(1):57-64.
• ⁴⁷
  Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88:1139-48.
• ⁴⁸
  Grozinsky-Glasberg S, Benbassat CA, Tsvetov G, Feinmesser R, Peretz H, et al. Medullary thyroid cancer: a retrospective analysis of a cohort treated at a single tertiary care center between 1970 and 2005. Thyroid. 2007;17:549-56.
• ⁴⁹
  Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid carcinoma. J Clin Endocrinol Metab. 2010;95:2655-63.
• ⁵⁰
  Machens A, Hauptmann S, Dralle H. Prediction of lateral lymph node metastases in medullary thyroid cancer. Br J Surg. 2008;95:586-91.
• ⁵¹
  Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610.
• ⁵²
  Adam MA, Pura J, Goffredo P, Dinan MA, Reed SD, Scheri RP, et al. Presence and number of lymph node metastases are associated with compromised survival for patients younger than age 45 years with papillary thyroid cancer. J Clin Oncol. 2015;33:2370-5.
• ⁵³
  Scheumann GF, Gimm O, Wegener G, Hundeshagen H, Dralle H. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg. 1994;18:559-67.
• ⁵⁴
  Sugitani I, Fujimoto Y, Yamada K, Yamamoto N. Prospective outcomes of selective lymph node dissection for papillary thyroid carcinoma based on preoperative ultrasonography. World J Surg. 2008;32:2494-502.
• ⁵⁵
  Gemsenjager E, Perren A, Seifert B, Schuler G, Schweizer I, Heitz PU. Lymph node surgery in papillary thyroid carcinoma. J Am Coll Surg. 2003;197:182-90.
• ⁵⁶
  Kouvaraki MA, Lee JE, Shapiro SE, Sherman SI, Evans DB. Preventable reoperations for persistent and recurrent papillary thyroid carcinoma. Surgery. 2004;136:1183-91.
• ⁵⁷
  Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Preoperative ultrasonographic examination for lymph node metastasis: usefulness when designing lymph node dissection for papillary microcarcinoma of the thyroid. World J Surg. 2004;28:498-501.
• ⁵⁸
  Barbosa MP, Momesso D, Bulzico DA, Farias T, Dias F, Lima RA, et al. Metastatic lymph node characteristics as predictors of recurrence/persistence in the neck and distant metastases in differentiated thyroid cancer. Arch Endocrinol Metab. 2017;61(6):584-9.
• ⁵⁹
  Rosário PW, Ward LS, Carvalho GA, Graf H, Maciel RM, Maciel LM, et al. Thyroid nodules and differentiated thyroid cancer: an update on the Brazilian consensus. Arch Bras Endocrinol Metabol. 2013;57(4):240-64.
• ⁶⁰
  Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, et al. Risk factors for recurrence to the lymph node in papillary thyroid carcinoma patients without preoperatively detectable lateral node metastasis: validity of prophylactic modified radical neck dissection. World J Surg. 2007;31(11):2085-91.
• ⁶¹
  Bonnet S, Hartl D, Leboulleux S, Baudin E, Lumbroso JD, Al Ghuzlan A, et al. Prophylactic lymph node dissection for papillary thyroid cancer less than 2 cm: implications for radioiodine treatment. J Clin Endocrinol Metab. 2009;94(4):1162-7.
• ⁶²
  Ducoudray R, Trésallet C, Godiris-Petit G, Tissier F, Leenhardt L, Menegaux F. Prophylactic lymph node dissection in papillary thyroid carcinoma: is there a place for lateral neck dissection? World J Surg. 2013;37(7):1584-91.
• ⁶³
  Rondeau G, Fish S, Hann LE, Fagin JA, Tuttle RM. Ultrasonographically detected small thyroid bed nodules identified after total thyroidectomy for differentiated thyroid cancer seldom show clinically significant structural progression. Thyroid. 2011;21:845-53.
• ⁶⁴
  Robenshtok E, Fish S, Bach A, Dominguez JM, Shaha A, Tuttle RM. Suspicious cervical lymph nodes detected after thyroidectomy for papillary thyroid cancer usually remain stable over years in properly selected patients. J Clin Endocrinol Metab. 2012;97:2706-13.
• ⁶⁵
  Ito Y, Higashiyama T, Takamura Y, Kobayashi K, Miya A, Miyauchi A. Prognosis of patients with papillary thyroid carcinoma showing postoperative recurrence to the central neck. World J Surg. 2011;35:767-72.
• ⁶⁶
  Uchida H, Imai T, Kikumori T, Hayashi H, Sato S, Noda S, et al. Long-term results of surgery for papillary thyroid carcinoma with local recurrence. Surg Today. 2013;43:848-53.
• ⁶⁷
  Newman KD, Black T, Heller G, Azizkhan RG, Holcomb GW 3rd, Sklar C, et al. Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children's Cancer Group. Ann Surg. 1998;227(4):533-41.
• ⁶⁸
  Chadwick D, Kinsman R, Walton P. The British Association of Endocrine and Thyroid Surgeons 2012. 4th ed. Oxfordshire: Dendrite Clinical Systems, Ltd; 2012. p. 3-188.
• ⁶⁹
  Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, et al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 2012;22:1144-52.
• ⁷⁰
  Lesnik D, Cunnane ME, Zurakowski D, Acar GO, Ecevit C, Mace A, et al. Papillary thyroid carcinoma nodal surgery directed by a preoperative radiographic map utilizing CT scan and ultrasound in all primary and reoperative patients. Head Neck. 2014;36:191-202.
• ⁷¹
  Yeh M, Bernet V, Ferris R, Loevner L, Mandel S, Orloff L, et al. American Thyroid Association statement on preoperative imaging for thyroid cancer surgery. Thyroid. 2015;25:3-14.
• ⁷²
  Eskander A, Merdad M, Freeman JL, Witterick IJ. Pattern of spread to the lateral neck in metastatic well differentiated thyroid cancer: a systematic review and meta-analysis. Thyroid. 2013;23:583-92.
• ⁷³
  Al-Saif O, Farrar WB, Bloomston M, Porter K, Ringel MD, Kloos RT. Long-term efficacy of lymph node reoperation for persistent papillary thyroid cancer. J Clin Endocrinol Metab. 2010;95:2187-94.
• ⁷⁴
  Yim JH, Kim WB, Kim EY, Kim WG, Kim TY, Ryu JS, et al. The outcomes of first reoperation for locoregionally recurrent/persistent papillary thyroid carcinoma in patients who initially underwent total thyroidectomy and remnant ablation. J Clin Endocrinol Metab. 2011;96:2049-56.
• ⁷⁵
  Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC, et al. Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:1440-5.
• ⁷⁶
  Phelan E, Kamani D, Shin J, Randolph GW. Neural monitored revision thyroid cancer surgery: surgical safety and thyroglobulin response. Otolaryngol Head Neck Surg. 2013;149:47-52.
• ⁷⁷
  Schuff KG. Management of recurrent/persistent papillary thyroid carcinoma: efficacy of the surgical option. J Clin Endocrinol Metab. 2011;96:2038-9.
• ⁷⁸
  Rubello D, Salvatori M, Casara D, Piotto A, Toniato A, Gross MD, et al. 99mTc-sestamibi radio-guided surgery of loco-regional 131Iodine-negative recurrent thyroid cancer. Eur J Surg Oncol. 2007;33:902-6.
• ⁷⁹
  Caronia LM, Phay JE, Shah MH. Role of BRAF in thyroid oncogenesis. Clin Cancer. Res. 2011;17(24):7511-7.
• ⁸⁰
  Tufano RP, Bishop J, Wu G. Reoperative central compartment dissection for patients with recurrent/persistent papillary thyroid cancer: efficacy, safety, and association of the BRAF mutation. Laryngoscope. 2012;122:1634-40.
• ⁸¹
  Howell GM, Nikiforova MN, Carty SE, Armstrong MJ, Hodak SP, Stang MT, et al. BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer. Ann Surg Oncol. 2013;20(1):47-52.
• ⁸²
  Han PA, Kim HS, Cho S, Fazeli R, Najafian A, Khawaja H, et al. Association of BRAF V600E mutation and microRNA expression with central lymph node metastases in papillary thyroid cancer: a prospective study from four endocrine surgery centers. Thyroid. 2016;26(4):532-42.
• ⁸³
  Shirley LA, Jones NB, Phay JE. The Role of Central Neck Lymph Node Dissection in the Management of Papillary Thyroid Cancer. Front Oncol. 2017;7:122.

Publication Dates

• Publication in this collection
  29 May 2023
• Date of issue
  2023

History

• Received
  15 May 2022
• Accepted
  12 Oct 2022