Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Excellent Response to Therapy:
  • Patients with no biochemical (unstimulated serum thyroglobulin (Tg) < 0.2 or stimulated Tg < 1.0 ng/mL) or radiographic evidence of disease are classified as having an excellent response to therapy
  • Patients with an initial low to intermediate risk of recurrence who meet these criteria:
    • Are recommended to have serum Tg monitored every 12 to 24 months
  • Patients with initially high-risk disease:
    • Should continue to have a serum Tg measurement at least every 6 to 12 months
• Biochemical Incomplete Response to Therapy:
  • Patients who have undergone total thyroidectomy and remnant ablation and have an unstimulated serum Tg > 1 ng/mL or a stimulated Tg > 10 ng/mL or a rising thyroglobulin antibody (TgAb) titer with negative imaging:
    • Are classified as having a biochemical incomplete response to therapy
  • Such patients should undergo imaging with sonography of the neck:
    • If the disease is unable to be located:
      • Cross-sectional imaging of the neck and chest should be performed
  • Serum Tg should be followed at least every 6 to 12 months.
• Structural Incomplete Response to Therapy:
  • Those patients with structurally or functionally (on diagnostic whole-body scan [DxWBS] or 18(FDG-PET) evident disease are classified as:
    • Having a structural incomplete response to therapy
  • Unfortunately, the majority of patients in this category will have persistent disease in spite of additional treatments
  • Disease-specific death rates are high in this group:
    • 11% with locoregional metastases
    • 50% with distant metastases
• Indeterminate Response to Therapy:
  • Patients with biochemical or structural findings that cannot be confidently classified as either excellent response or persistent disease:
    • Are deemed as having an indeterminate response to therapy
  • Such patients may be carefully followed with biochemical testing and serial imaging to better delineate which category is ultimately appropriate
  • It is estimated that up to 20% of these patients will eventually develop conclusive evidence of disease requiring additional therapy

• Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC):
  • Is now considered a separate entity and no longer a subtype of PTC
• IEFVPTC has a RAS-like mutational and transcriptomic profile:
  • Similar to that of follicular adenoma (FA) and follicular thyroid carcinoma (FTC) (Figure):
    • Whereas classic PTC and the infiltrative follicular subtype of PTC:
      • Have BRAF V600E-like molecular profiles
• IEFVPTCs:
  • Have a fibrous capsule or well-defined border and lack the histologic features of infiltrative follicular PTC
• Like FTC:
  • IEFVPTC can invade vessels in the capsule and develop distant metastasis

• Risk stratification in differentiated thyroid cancer has traditionally used a relatively small set of clinical and pathological factors to create models that predict disease-specific mortality or overall survival:
  • Although clinically useful, these models provided static estimates of risk with information available within the first few months of initial therapy and demonstrated suboptimal, long-term outcome predictions for any individual patient

• Over the last decade, additional models have been developed that provide predictive information with regard to other clinically relevant outcomes, such as:
  • The risk of having persistent disease after initial therapy
  • The risk of structural or biochemical disease recurrence
  • The likelihood of going into remission following initial therapy in adult patients with thyroid cancer

• Furthermore, rather than using information that is only available at one particular point in time, these new models emphasize the importance of dynamic risk assessment:
  • Where the initial risk assessment is modified over time as new data become available
• These dynamic risk assessments allow us to:
  • Integrate response to therapy assessments with the underlying individual tumor biology:
    • To provide real-time risk assessments at any point in the course of the patient’s disease
• Thus, the modern view of risk stratification begins with:
  • The identification of a suspicious nodule (peri-diagnostic period) and continues through the phases of:
    • Diagnosis
    • Treatment
    • Adjuvant therapy
    • Follow-up

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• Asymptomatic, small thyroid nodules (usually ≤ 1 cm maximal diameter, 1 cm³, or 1 mL volume) confined to the thyroid and surrounded by normal thyroid parenchyma:
  • Can be followed with active surveillance:
    • With or without cytologic confirmation:
      • In patients who value their normal thyroid function and who desire avoidance of thyroid surgery
• Patients who demonstrate tumors larger than 1.5 to 2.0 cm; tumors in subcapsular locations adjacent to important structures, such as the trachea and recurrent laryngeal nerve; or tumors with documented growth rate doubling times of < 2 years:
  • Are generally considered inappropriate for observation and would be considered to have actionable disease
• If the tumor growth rate is unknown at the time of nodule detection:
  • Then this can be established with serial ultrasound evaluations done approximately every 6 months for 1 to 2 years
• The frequency of ultrasound evaluations and long-term follow-up:
  • Depends on the tumor size, location, and established growth rate
• With the use of this paradigm:
  • Active surveillance continues until:
    • There is a 3-mm increase in tumor diameter:
      • Which corresponds to a 100% increase in tumor volume
    • Identification of metastatic disease
    • Direct invasion into surrounding structures of the thyroid
    • A decision to discontinue active surveillance based on patient preference
• This risk-stratified, minimalistic management approach to very low-risk thyroid cancers has been shown to be safe and effective over 5 to 10 years of follow-up in studies from Japan, Korea, and the United States:
  • In the first 10 years of active surveillance follow-up:
    • Only 2% to 8% of papillary microcarcinomas:
      • Increase ≥ 3 mm in maximum diameter
    • 12% to 14% demonstrate an increase in tumor volume of > 50%:
      • The smallest change in nodule volume that can be reproducibly measured
    • Novel lymph node metastases:
      • Are detected in 2% to 4%
  • The likelihood of disease progression is higher in younger patients than in older patients
• Importantly, at the time of disease progression:
  • Deferred surgical intervention is quite effective with excellent outcomes and no disease-specific mortality
• References:
  • Ito Y, Miyauchi A. Active surveillance as first-line management of papillary microcarcinoma. Annu Rev Med. 2019;70:369–379.
  • Ito Y, Miyauchi A, Kudo T, Oda H, Yamamoto M, Sasai H, Masuoka H, Fukushima M, Higashiyama T, Kihara M, Miya A.. Trends in the implementation of active surveillance for low-risk papillary thyroid microcarcinomas at Kuma Hospital: gradual increase and heterogeneity in the acceptance of this new management option. Thyroid. 2018;28(4):488–495.
  • Tuttle RM, Zhang L, Shaha A. A clinical framework to facilitate selection of patients with differentiated thyroid cancer for active surveillance or less aggressive initial surgical management. Expert Rev Endocrinol Metab. 2018;13(2):77–85. 
  • Tuttle RM, Fagin JA, Minkowitz G, Wong RJ, Roman B, Patel S, Untch B, Ganly I, Shaha AR, Shah JP, Pace M, Li D, Bach A, Lin O, Whiting A, Ghossein R, Landa I, Sabra M, Boucai L, Fish S, Morris LGT. Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol Head Neck Surg. 2017;143(10):1015–1020. 
  • Tuttle RM, Zhang L, Shaha A. A clinical framework to facilitate selection of patients with differentiated thyroid cancer for active surveillance or less aggressive initial surgical management. Expert Rev Endocrinol Metab. 2018;13(2):77–85.
  • D’Agostino TA, Shuk E, Maloney EK, Zeuren R, Tuttle RM, Bylund CL. Treatment decision making in early-stage papillary thyroid cancer. Psychooncology. 2018;27(1):61–68.
  • Groopman J, Hartzband P.. Your Medical Mind. How to Decide What Is Right for You. New York, NY: Penguin Books.
  • Ito Y, Miyauchi A. Prognostic factors and therapeutic strategies for differentiated carcinomas of the thyroid. Endocr J. 2009;56(2):177–192.

• The 2015 ATA guidelines:
  • Now accept a minimalistic surgical approach (thyroid lobectomy without neck dissection):
    • To treat intrathyroidal papillary thyroid carcinomas < 4 cm in properly selected patients
  • Careful peri-diagnosis, preoperative, and intraoperative risk stratification:
    • Are the keys to successful use of thyroid lobectomy:
      • Without having to perform an unacceptable rate of early-completion thyroidectomies
• Patients classified as being ideal for lobectomy:
  • Would have papillary microcarcinomas:
    • That appeared to be confined to the thyroid in the setting of an otherwise normal thyroid ultrasound and clinical N0 neck
• We classify patients as appropriate for lobectomy:
  • If the tumor is 1 to 4 cm in maximum dimension, if the contralateral lobe is normal, or if there are other abnormalities on the ultrasound, such as thyroiditis or benign-appearing nodules (again, in the setting of the clinical N0 neck)
• Patients with extrathyroidal extension, clinical N1 disease, or distant metastasis:
  • Would be considered inappropriate for thyroid lobectomy as initial therapy
• In addition to the relevance of peri-diagnostic and preoperative risk stratification with respect to the selection of thyroid lobectomy as initial therapy:
  • It is important to recognize that there are intraoperative findings that should alter that recommendation and lead to an immediate total thyroidectomy:
    • We encourage patients to find a surgeon who they trust and to empower the surgeon to make a final decision in the operating room regarding the extent of initial surgery that should be performed, which can vary from lobectomy to total thyroidectomy, with or without neck dissection
    • However, even with appropriate preoperative and intraoperative risk stratification:
      • As many as 6% to 20% of patients will have unexpected findings on the final pathology report:
        • That may lead to a completion thyroidectomy and usually, radioactive iodine
      • An additional 5% to 10% may require completion thyroidectomy:
        • At some later point during follow-up for diagnostic or therapeutic purposes
          
      • The rate of early-completion thyroidectomy, performed following review of the initial pathology report, will vary, depending on how aggressive each management team is with regard to the use of radioactive iodine for either remnant ablation or adjuvant treatment
      • If minor factors, such as minor extrathyroidal extension, very small-volume lymph node metastasis, or small tumors with aggressive histologic features usually lead to radioactive iodine therapy, then the completion thyroidectomy rate may be as high as 20%
      • In our hands, the completion thyroidectomy rate is much lower, as we have a much more restricted use of radioactive iodine:
        • The most common reason for completion thyroidectomy in our hands is unanticipated, extensive vascular invasion documented on the pathology report that obviously could not be visualized preoperatively or intraoperatively
• Thus, patients need to understand that the final determination of whether a thyroid lobectomy is the appropriate initial therapy can only be achieved by:
  • The integration of preoperative, intraoperative, and postoperative risk stratification
• Patients who are uncomfortable with this approach will often choose a total thyroidectomy as initial therapy
• Patients motivated to keep part of the thyroid will often accept that uncertainty, recognizing that the final decision regarding the completeness of initial therapy cannot be completely known until several weeks after the surgery is completed when more complete risk stratification can be accomplished
• References:
  • Tuttle RM, Zhang L, Shaha A. A clinical framework to facilitate selection of patients with differentiated thyroid cancer for active surveillance or less aggressive initial surgical management. Expert Rev Endocrinol Metab. 2018;13(2):77–85. 
  • Carty SE, Doherty GM, Inabnet WB III, Pasieka JL, Randolph GW, Shaha AR, Terris DJ, Tufano RP, Tuttle RM; Surgical Affairs Committee Of The American Thyroid Association. American Thyroid Association statement on the essential elements of interdisciplinary communication of perioperative information for patients undergoing thyroid cancer surgery. Thyroid. 2012;22(4):395–399.

Beahrs Triangle or Riddle’s triangle

• This is one of the most important triangles in relation with thyroid surgery
• This triangle is named after O.H. Beahrs:
  • Its synonymous with Riddle’s triangle
• Baehr’s triangle is bounded by:
  • Base:
    • Common carotid artery
  • Superior:
    • Inferior thyroid artery
  • Medial:
    • Recurrent laryngeal nerve
• The triangle lies:
  • Posterior to the thyroid gland:
    • In the tracheo-esophageal groove
• Boundaries of Baehr’s triangle:
  • Can be identified after retracting the ipsilateral thyroid lobe medially:
    • To safe guard the recurrent laryngeal nerve

• RLN Triangle:
  • This is an inverted triangle with:
    • Apex formed inferiorly by:
      • Thoracic inlet
    • Medially:
      • Trachea
    • Lateral Margin:
      • The medial edge of retracted strap muscles
    • The superior border is:
      • The lower edge of the inferior pole of the gland
• Recurrent laryngeal nerve exits as a single trunk here at thoracic inlet
• Triangle of Concern:
  • The commonest site for bleeding in thyroidectomy:
    • Is the ‘triangle of concern’, comprising the:
      • Trachea medially
      • RLN nerve laterally
      • With the thyrothymic ligament and loose fat above the sternum at the base
      • Berry’s ligament at the apex
• This triangle has the small branches of the inferior thyroid artery that require meticulous hemostasis with in the vicinity of RLN, which can cause injury to nerve

• Classically, the RLN is identified intraoperatively in Simon’s triangle, which  is formed by:
  • The common carotid artery laterally
  • The esophagus medially
  • The inferior thyroid artery superiorly
• The recurrent laryngeal nerve  crosses the triangle

• Thyroid neoplasms are classified as two or three molecular groups based on the mutational and gene expression profiles:
  • Two molecular groups:
    • BRAF V600E-like
    • RAS-like
  • Three molecular groups:
    • BRAF V600E-like
    • RAS-like
    • Non-BRAF V600E / non-RAS-like
• The BRAF V600E group:
  • Is most commonly represented by:
    • Papillary thyroid carcinoma (PTC)
• The BRAF V600E-like molecular profile includes:
  • The BRAF V600E mutation
  • Gene fusions involving:
    • BRAF, RET, and neurotrophic receptor tyrosine kinase 1/3 (NTRK1/3)
• RAS-like molecular profiles include:
  • NRAS, HRAS, KRAS, EIF1AX, enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1), Dicer 1, ribonuclease III (DICER1), phosphatase and tensin homolog (PTEN) mutations, BRAF K601E, and gene fusions involving peroxisome proliferator-activated receptor gamma (PPARG) and THADA
• When the three-group molecular classification is applied:
  • PAX8::PPARG gene fusion and mutations of EIF1AX, EZH1, IDH1, SOS1, SPOP, DICER1, and PTEN genes are classified as a non-BRAFV600E-/non-RAS-like group
• Encapsulated / circumscribed thyroid tumors with a predominant follicular growth pattern:
  • Generally have a RAS-like molecular profile
• High grade is histologically defined:
  • As the presence of ≥ 5 mitoses per 2 mm2 and / or tumor necrosis.
• Y, yes; N, no; Q, questionable; PDTC, poorly differentiated thyroid carcinoma; ATC, anaplastic thyroid carcinoma; DHGTC, dif- ferentiated high-grade thyroid carcinoma; IEFVPTC, invasive encapsulated follicular variant of papillary thyroid carcinoma; WDT-UMP, well-differentiated tumor of uncertain malignant potential; NIFTP, non-invasive follicular thyroid neoplasm with papillary-like nuclear fea- tures; FT-UMP, follicular tumor of uncertain malignant potential; FTC, follicular thyroid carcinoma; OCA, oncocytic carcinoma of the thy- roid; TERT, telomerase reverse transcriptase; TP53, tumor protein p53; PAX8, paired box 8

• Patients with ILC have worse surgical outcomes compared to patients with invasive ductal carcinoma (IDC):
  • Measured by positive margin rates
  • Mastectomy rates
  • Axillary dissection rates
• Many potential causes:
  • Higher stage at presentation
  • Higher discordance between clinical stage and pathologic stage
  • Lower sensitivity of standard imaging tools
• Patients with ILC have higher positive margin rates compared to patients with IDC:
  • Secondary to:
    • Diffuse growth pattern
    • Low Imaging Sensitivity:
      • Leading to higher positive margin rates

• Positive margins have negative consequences:
  • Significant lower breast satisfaction and sexual well-being at two years among those who require re-excision after breast conservation surgery (BCS)
  • Significant higher rates of surgical site infection (SSI), seroma / hematoma, and fat necrosis
  • Healthcare costs increased 4-fold for patients requiring re-excision
  • Increased risk of recurrence if two addressed
• ILC:
  • Mammographically occult disease
  • MRI significantly underestimates size
  • Positive margins
• Should patients with ILC always choose mastectomy?
  • Historically mastectomy was recommended for ILC specifically because of the diffuse growth pattern
  • More modern series show similar rates of recurrence between BCS with radiation vs. mastectomy for ILC
• Rates of BCS for ILC have increased over time:
  • However the rate for BCS for ILC is lower that for IDC:
    • This is despite large series showing improved outcomes with breast conservation surgery compared to mastectomy:
      • US National Cancer Database Analysis of > 160,000 patients showed same or better overall survival (OS) with BCS compared to mastectomy
      • A Swedish study of nearly 50,000 patients showed improved OS with BCS compared to mastectomy (included 5,893 patients with ILC)
      • The higher rates of nodal positivity in ILC leads to increased likelihood of needing postmastectomy radiation:
        • Implications for radiation and reconstructive complications

• BCS for patients with ILC > 4 cm:
  • BCS trial excluded patients with tumors > 4 cm
  • Retrospective analysis have shown BCT to be safe in IDC greater than 4 cm:
    • But not studied in ILC
  • Patients with ILC are more likely to present with larger tumors than IDC

• In multivariable logistic regression model having larger tumors, higher N stage, HER2+ or triple negative subtype:
  • Were associated with significantly higher risk of recurrence:
    • The type of surgery does not affect these long-term outcomes
  • If negative margins are achieved:
    • There is no difference in recurrence rates for BCT vs mastectomy in ILC cases > 4 cm:
      • Important to note that over 50% of BCT group had positive margins and needed re-excision
• Surgical approaches to reduce positive margin rates in ILC:
  • Oncoplastic surgery:
    • Level 1: local tissue rearrangement only
    • Level 2: parenchymal flaps and skin resection
  • Selective shave margins
• Success rates for re-excision of positive margins after BCS in ILC:
  • Roughly 75%
• Factors associated with successful re-excison

• Positive margins after mastectomy for ILC