Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

¿Quién debe realizar cirugía de tiroides?

•  Su entrenamiento es el siguiente:

  • Tumores de Cabeza y Cuello / Cirugía Endocrina: Fox Chase Cancer Center

• Tumores de Cabeza y Cuello / Cirugía Endocrina:IFHNOS / Memorial Sloan Kettering Cancer Center

 

Cirugía Oncológica Compleja: Fox Chase Cancer Center

 

• Cirugia General y Gastrointestinal:
  • Michigan State University

• Maestría en Ciencias de Investigación:Drexel University

• Differentiated thyroid cancer (DTC) includes papillary, follicular, and oncocytic carcinomas:
  • Comprising the vast majority (> 90%) of all thyroid cancers
• In the United States:
  • It is estimated that there were 44,020 new cases of thyroid cancer in 2024:
    • Compared with 37,200 in 2015 when the last American Thyroid Association (ATA) guidelines were published
• The yearly incidence tripled from 4.9 per 100,000 in 1975 to:
  • 14.3 per 100,000 in 2015
• Approximately 25% of the new thyroid cancers diagnosed in 1988 to 1989 were < 1 cm:
  • Compared with 39% of the new thyroid cancer diagnoses in 2008 to 2009:
    • This shift to earlier detection / diagnosis correlates with the increasing use of neck ultrasonography and other imaging along with the advent of ultrasound-guided fine needle aspiration (FNA)
• The incidence of thyroid cancer, and particularly small thyroid cancers:
  • Has reduced in the United States since 2014:
    • This change in incidence trajectory is likely a reflection of the adoption of guidelines’ recommendations from the ATA and other organizations discouraging FNA of small nodules < 1 cm in the absence of abnormal lymph nodes or local invasion:
      • Due to the overall outstanding prognosis associated with these tumors and weighed against the potential risks of unnecessary treatment
• In addition to changes in the management of early-stage thyroid cancer:
  • Prior guidelines introduced criteria to enhance initial decision-making and a response framework following interventions to facilitate further management decisions:
    • These have been validated since the prior guidelines, enabling adoption in clinical practice
• There have been major advances in understanding the molecular causes of thyroid cancer development and progression that have created newly approved treatment options for subsets of patients:
  • Published data in these and other areas require serial updates of existing guidelines to facilitate clinical care
• In the current guidelines, an approach to clinical decision-making is introduced based upon the individual patient and clinician journey with thyroid cancer:
  • Which they term DATA:
    • Diagnosis
    • Risk / benefit Assessment
    • Treatment decisions
    • Response Assessment
• This approach begins at the initial diagnosis of thyroid cancer, the diagnosis of residual disease or a clinical recurrence:
  • It includes assessment to determine whether a particular intervention is appropriate based on risks and benefits as well as individual patient factors:
    • When multiple possible management strategies are available, the framework supports identification of the best treatment option
• Then, after intervention, an assessment of response using the 2025 ATA risk assessment tool is deployed to determine whether more treatment or monitoring is appropriate
• The clinician and the patient can use this DATA framework to help make clinical decisions from diagnosis through the patient’s entire disease course.

• In 1996, the ATA published treatment guidelines for patients with thyroid nodules and DTC:
  • Over the last 25 to 30 years, there have been remarkable advances in knowledge affecting the diagnosis and treatment of DTC, but clinical controversy continues to exist in many areas
  • In the end, the goal is to provide individualized therapy for each patient based on the best application of clinical data to their unique case:
    • For example, a less aggressive approach would be recommended for individuals with early stage DTC who have an excellent prognosis or for individuals at higher risk of side effects, while a more aggressive approach would be recommended for those patients with higher risk disease or those with inadequate response to initial therapy

• American Thyroid Association Thyroid Cancer Management 2025 Guidelines
• Recommendation 6:
  • Due to lower complication rates and improved outcomes on average associated with high volume thyroid surgeons (> 25 to 50 thyroidectomies / year):
    • Patients with thyroid cancer should be offered referral to a high-volume surgeon;
      • Particularly for tumors requiring more extensive surgery:
        • Strong recommendation, Moderate certainty evidence
  • Physician experience and expertise have long been revered in patient care:
    • But quantifying the benefits can be challenging, particularly at an individual provider level
  • There are many aspects of care where physician expertise is important in the diagnosis, staging, and management of patients with
    thyroid cancer, including sonography, pathology, surgery, endocrinology, nuclear medicine, oncology, and radiation
    therapy
  • Ultrasound of the neck is a prime example, due to its well-documented dependence on the skill and experience of the sonographer coupled with its importance for preoperative diagnosis, staging, and surveillance
  • The experience of the cytopathologist also has been demonstrated to improve the accuracy of ultrasound-guided FNA biopsy diagnosis
  • The evidence supporting improved outcomes at the hands of experienced surgeons is most compelling
  • The relationship between thyroid surgery case volume and patient outcomes has been studied extensively during the past 20 years:
    • In one of the recent studies examining the relationship between surgeon volume and thyroidectomy outcomes:
      • Sosa et al. found a strong association between higher surgeon volume and favorable patient outcomes:
        • Especially with respect to recurrent laryngeal nerve injury and wound complications
        • This was most pronounced for patients undergoing total thyroidectomy for thyroid cancer
    • Others have made similar observations on a larger scale:
      • In a study of the Health Care Utilization Project Nationwide Inpatient Sample (HCUP-NIS);
        • Over 80% of thyroidectomies were performed by low- and intermediate-volume surgeons (< 29 thyroidectomies /year)
        • On average, high-volume surgeons (> 30 thyroidectomies / year) had the lowest
          complication rates for patients who underwent total thyroidectomy for cancer (high 7.5% vs. intermediate 13.4% vs. low 18.9%; p < 0.001)
    • A recent meta-analysis including 22 studies found unanimity in the association of lower complication rates with higher thyroid surgery volume
  • When hospital volume and surgeon volume are both considered:
    • On average, high-volume surgeons are associated with lower complication rates, lower hospital mortality, and lower cost:
      • Whereas high-volume centers are associated primarily with lower cost and shorter lengths of stay
  • Estimates of the annual thyroid surgical volume necessary to achieve lower complication rates range from 25 to 50:
    • With one series suggesting > 50 cases for more advanced thyroid
      cancer
• A study specically designed to address this number concluded that annual total thyroidectomy case volume > 25 / year was associated with improved outcomes
• Patients have an 87% increase in the odds of having a complication if the surgeon performed just 1 case / year:
  • 68% for 2 to 5 cases / year
  • 42% for 6 to 10 cases / year
  • 22% for 11 to 15 cases / year
  • 10% for 16 to 20 cases / year
  • 3% for 21 to 25 cases / year
• Patients undergoing total thyroidectomy for cancer at the hands of high-volume surgeons also are reported to have signicantly less thyroid remnant tissue after resection:
  • Resulting in a reduced radioiodine dose requirement for remnant ablation (if indicated)
• Finally, patients having thyroid cancer surgery at low-volume centers were signicantly more
  likely to have an involved tumor margin compared to those treated at high-volume centers.
• An overwhelming body of evidence demonstrates improved outcomes for patients undergoing thyroid cancer surgery with higher-volume surgeons
• Referral of patients to high-volume thyroid surgeons is associated with, on average, superior outcomes:
  • However, referral is not always possible, in view of the relative scarcity of high-volume surgeons and their geographic concentration in larger urban areas
• Conclusions at an overall population level cannot
  always be applied to individual surgeons and patient circumstances:
  • It seems reasonable to encourage referral of patients with grossly invasive and/or extensive disease to a high-volume surgeon experienced in the management of advanced thyroid cancer, and perhaps even to refer those patients undergoing
    total thyroidectomy for low- to intermediate-risk cancers

• Mechanism of Action:
  • Target:
    • Cetuximab is a chimeric monoclonal IgG1 antibody directed against the epidermal growth factor receptor (EGFR / ErbB1)
  • Binding: 
    • It binds with higher affinity than natural ligands (EGF, TGF-α):
      • Blocking ligand-induced EGFR activation
  • Downstream effects:
    • Inhibition of EGFR autophosphorylation → suppression of downstream pathways (RAS / RAF / MEK / ERK and PI3K / AKT) → reduced proliferation and survival
    • Induces cell cycle arrest and apoptosis.
    • Inhibits angiogenesis:
      • Via VEGF downregulation
    • Enhances radiosensitivity and chemosensitivity
    • Triggers antibody-dependent cellular cytotoxicity (ADCC):
      • Due to IgG1 Fc interaction with NK cells
• Indications in Head & Neck Oncology:
  • Locally Advanced Head & Neck Squamous Cell Carcinoma (HNSCC):
    • In combination with definitive radiotherapy in patients not suitable for high-dose cisplatin
    • Based on the Bonner trial (NEJM 2006):
      • Cetuximab + RT improved locoregional control and OS compared with RT alone
  • Recurrent or Metastatic HNSCC:
    • First-line (EXTREME regimen): 
      • Cetuximab + platinum (cisplatin / carboplatin) + 5-FU:
        • Demonstrated OS benefit (Vermorken et al., NEJM 2008)
    • As monotherapy or maintenance:
      • In platinum-refractory or palliative setting
  • Special Situations:
    • Considered for cisplatin-ineligible patients
    • Investigated in combination with immunotherapy (e.g., PD-1 inhibitors), though data are evolving
• Adverse Effects:
  • Dermatologic (most common):
    • Acneiform rash (papulopustular eruption) in ~ 80%:
      • Correlates with better response
    • Xerosis, pruritus, paronychia
  • Infusion-related reactions:
    • Fever, chills, bronchospasm, hypotension
    • Severe (anaphylaxis-like) reactions more common in the Southeastern US:
      • Linked to preexisting IgE antibodies against galactose-α-1,3-galactose from tick bites
  • Electrolyte disturbances:
    • Hypomagnesemia:
      • Due to renal Mg wasting
    • Hypokalemia
    • Hypocalcemia
  • Other:
    • Diarrhea, mucositis, fatigue
  • Rare:
    • Interstitial lung disease, cardiotoxicity
• Management of Adverse Effects:
  • Skin toxicities:
    • Prophylaxis:
      • Sunscreen, moisturizers, topical steroids, oral tetracyclines (doxycycline / minocycline)
    • Management:
      • Topical antibiotics (clindamycin), systemic tetracyclines; dose modification for grade ≥ 3 rash
  • Infusion reactions:
    • Premedication:
      • H1 antihistamines ± corticosteroids
    • Severe reactions:
      • Immediate discontinuation, epinephrine, airway support
  • Electrolyte disturbances:
    • Routine monitoring of Mg, K, Ca during therapy and up to 8 weeks post-treatment
    • Oral / IV replacement as needed
• References:
  • Bonner JA et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. NEJM. 2006;354:567–78.
  • Vermorken JB et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. NEJM. 2008;359:1116–27.
  • NCCN Guidelines: Head and Neck Cancers. Version 2025.
    Cohen EEW et al. Cetuximab in HNSCC: updated evidence. JCO.

• Ductal carcinoma in situ (DCIS):
  • Is a noninvasive carcinoma of the breast
  • It is defined as the proliferation of malignant epithelial cells:
    • Confined to the mammary ducts and without evidence of invasion through the basement membrane
  • Because it is noninvasive:
    • DCIS does not pose a risk of metastasis
• Lobular carcinoma in situ (LCIS):
  • Was previously considered a form of noninvasive carcinoma:
    • But is now understood to be a benign entity that is a pathologic marker of increased breast cancer risk:
      • In either breast
  • Atypical lobular hyperplasia (ALH) and LCIS:
    • Are both forms of lobular neoplasia and, together with atypical ductal hyperplasia (ADH):
      • Represent proliferative nonmalignant breast lesions

• Mechanisms of Action:
  • 5-Fluorouracil (5-FU):
    • Converted intracellularly to:
      • Fluorodeoxyuridine monophosphate (FdUMP), which forms a ternary complex with thymidylate synthase (TS) and reduced folate:
        • Blocks deoxythymidine monophosphate (dTMP) synthesis, leading to “thymineless death”
    • Other metabolites (fluorouridine triphosphate, FUTP; fluorodeoxyuridine triphosphate, FdUTP):
      • Misincorporate into RNA and DNA, contributing to cytotoxicity
    • Leucovorin:
      • Enhances TS inhibition
  • Methotrexate (MTX):
    • Antifolate:
      • That inhibits dihydrofolate reductase (DHFR)
    • Intracellular polyglutamation increases potency and extends inhibition to other folate-dependent enzymes:
      • Impairing purine and pyrimidine synthesis:
        • Leading to cell death
• Indications in Head and Neck Squamous Cell Carcinoma (HNSCC):
  • 5-Fluorouracil (5-FU):
    • Induction therapy:
      • Used in docetaxel + cisplatin + 5-FU (TPF) regimen:
        • Which improved progression-free survival (PFS) and overall survival (OS) vs. cisplatin + 5-FU (PF) in TAX 323 / 324
    • Concurrent chemoradiation (CRT):
      • Carboplatin + 5-FU with radiation therapy (RT):
        • Is an option for cisplatin-ineligible patients
    • Recurrent / Metastatic (R/M):
      • Backbone of the EXTREME regimen (platinum + 5-FU + cetuximab):
      • Which improved OS compared to platinum + 5-FU alone
  • Methotrexate (MTX):
    • Single-agent palliative therapy:
      • Historically a standard for recurrent / metastatic HNSCC:
      • Often given weekly intravenous (IV) 40 mg/m², with activity and tolerability in frail or heavily pretreated patients
    • Combination therapy:
      • Sometimes paired with cetuximab in cisplatin-unfit patients
• Adverse Effects and Management:
  • 5-Fluorouracil (5-FU):
    • Mucositis, diarrhea, myelosuppression, hand-foot syndrome (HFS):
      • Supportive care; oral cryotherapy may reduce mucositis (bolus 5-FU)
    • Cardiotoxicity (vasospasm, ischemia):
      • Discontinue 5-FU
      • Treat as vasospastic angina with nitrates and / or calcium channel blockers
    • Neurotoxicity (cerebellar syndrome, hyperammonemic encephalopathy):
      • Stop 5-FU
      • Hydrate, correct metabolic derangements
    • Dihydropyrimidine dehydrogenase (DPD) deficiency:
      • Screen with DPYD testing where available:
        • Poor metabolizers should avoid fluoropyrimidines
      • Antidote:
        • Uridine triacetate (Vistogard) within 96 hours of overdose or early severe toxicity
  • Methotrexate (MTX):
    • Mucositis, myelosuppression, hepatotoxicity:
      • Monitor complete blood count (CBC) and liver function tests (LFTs); hold dose for grade ≥3 toxicity.
      • Folinic acid (leucovorin) rescue may be used for high-dose or severe toxicity
    • Renal elimination:
      • Requires dose adjustment in renal impairment
      • Avoid interactions with trimethoprim-sulfamethoxazole (TMP-SMX), nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and some penicillins, which increase MTX toxicity
• Key References:
  • Vermorken JB et al., NEJM 2007; Posner MR et al., NEJM 2007; Lorch JH et al., Lancet Oncol 2011 – TPF vs PF in induction therapy.
  • Vermorken JB et al., NEJM 2008 – EXTREME regimen in R/M HNSCC.
  • NCCN Guidelines: Head and Neck Cancers, 2025 Insights.
  • Amstutz U, Froehlich TK, Largiadèr CR. Clin Pharmacol Ther 2011 – DPD deficiency and 5-FU toxicity.
  • US FDA Label: Uridine triacetate (Vistogard).
    Specenier P, Vermorken JB. Oral Oncol 2009 – Methotrexate in head and neck cancer.

• Mechanism of Action:
  • Paclitaxel and docetaxel:
    • Are microtubule-stabilizing agents:
      • They bind to the β-subunit of tubulin:
        • Promoting microtubule assembly while inhibiting depolymerization
      • This leads to stabilization of the mitotic spindle:
        • Blocking cell cycle progression in the G2 /M phase, ultimately triggering apoptosis
    • Additional effects:
      • Anti-angiogenic activity at low doses
      • Modulation of apoptotic pathways:
        • Bcl-2 phosphorylation
      • Potential immune-modulatory effects
• Indications in Head and Neck Squamous Cell Carcinoma (HNSCC):
  • Locally Advanced / Induction Therapy
    TPF regimen (Docetaxel + Cisplatin + 5-FU) has demonstrated improved survival and locoregional control compared with PF (cisplatin + 5-FU)
    • TAX 323 and TAX 324 trials showed significant OS and PFS benefit with TPF in unresectable or locally advanced disease
• Concurrent Chemoradiation:
  • Weekly paclitaxel or docetaxel (often combined with carboplatin) is used as an alternative for patients ineligible for cisplatin
  • Demonstrated radiosensitizing effects.
• Recurrent / Metastatic HNSCC:
  • Single-agent docetaxel or paclitaxel provides palliative benefit with response rates ~ 20% to 30%
  • Often used as part of combination chemotherapy (e.g., taxane + platinum + cetuximab)
• Adverse Effects:
  • Hematologic:
    • Neutropenia (dose-limiting, especially with docetaxel)
    • Febrile neutropenia
  • Neurologic:
    • Peripheral neuropathy (sensory > motor), cumulative and dose-dependent
    • Hypersensitivity Reactions:
      • Due to the lipid solvent:
        • Cremophor EL in paclitaxel
        • Polysorbate 80 in docetaxel
      • Flushing, rash, bronchospasm, anaphylaxis
    • Other:
      • Mucositis
      • Stomatitis
      • Alopecia
      • Fluid retention:
        • More with docetaxel
      • Onycholysis
      • Skin / nail changes
      • Fatigue
      • Myalgia / arthralgia
• Management of Adverse Events:
  • Premedication:
    • Paclitaxel:
      • Corticosteroids + H1/H2 antagonists (e.g., dexamethasone, diphenhydramine, ranitidine)
    • Docetaxel:
      • Dexamethasone to reduce hypersensitivity and fluid retention
  • Neutropenia:
    • Dose reduction, prophylactic G-CSF for high-risk regimens (especially TPF)
  • Neuropathy:
    • Dose modification or discontinuation
    • Supportive care:
      • Duloxetine may help with painful neuropathy
  • Mucositis:
    • Oral hygiene, saline rinses, cryotherapy, topical analgesics
  • Fluid Retention (docetaxel):
    • Steroid premedication, diuretics if symptomatic
• Key References:
  • Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–704. 【TAX 323】
  • Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–15. 【TAX 324】
  • NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 2.2025.
  • Hitt R, et al. Phase III study comparing TPF with PF in locally advanced head and neck cancer. J Clin Oncol. 2005;23(34):8636–45.
  • Colevas AD, et al. Chemotherapy options for patients with cisplatin-ineligible head and neck cancer. J Clin Oncol. 2018;36(19):1942–50.

• What each test is built to do:
  • Afirma GSC (± Xpression Atlas): 
    • RNA whole-transcriptome classifier optimized as a rule-out test:
      • XA adds variants / fusions if GSC is Suspicious PMCVeracyte
  • ThyroSeq v3 GC: 
    • DNA / RNA next-gen panel across many genes (mutations, fusions, copy-number alterations, helpful in oncocytic cell lesions / Hürthle cell lesions) designed for rule-out + rule-in and therapy-relevant profiling JAMA NetworkThyroSeq
  • ThyGeNEXT + ThyraMIR v2 (Interpace): 
    • Two-step oncogene panel → reflex miRNA classifier; aims for balanced rule-out with stronger rule-in when driver / miRNA high-risk pattern is present PMCThygenext Thyramir
• Performance (typical ranges in Bethesda III–IV):
  • Afirma GSC: 
    • High sensitivity / NPV in VS and real-world cohorts:
      • PPV modest to moderate
    • Many studies report:
      • NPV ~ 94% to 97%
      • PPV ~ 45% to 65%
    • Real-world series show improved yield vs validation PMCScienceDirect
  • ThyroSeq v3: 
    • Validation and multi-center series show high sensitivity / NPV with higher PPV than Afirma in several cohorts:
      • PPV ~ 60% to 65%
    • Institutional data show sensitivity ~ 92% to 95% (Bethesda III to IV) JAMA NetworkACS Publications
  • ThyGeNEXT/ThyraMIR v2: 
    • Reported NPV ~ 93% to 96%
    • Useful PPV when drivers / miRNA risk present
    • 2025 systematic review suggests high surgical avoidance rates among platforms PMCResearchGate
• Prognostic/management information (actionability):
  • Afirma GSC + XA: 
    • If Suspicious, XA reports fusions / variants (e.g., RET, NTRK, ALK):
      • Which can guide targeted therapy decisions down the line
    • GSC itself primarily aids avoiding surgery Veracyte
  • ThyroSeq v3: 
    • Reports BRAF, RAS, TERT-p, RET / NTRK/ ALK, gene expression and copy-number profiles:
      • Useful for risk stratification (e.g., TERT / BRAF V600E for aggressiveness) and for operative planning (extent, LN assessment) and potential targeted options
      • Particularly helpful in Hürthle-predominant nodules JAMA NetworkThyroSeq
  • ThyGeNEXT/ThyraMIR v2: 
    • Calls out high-risk drivers (BRAF V600E, TERT, ALK, etc.) and refines intermediate results with miRNA pairs:
      • Useful for deciding between surveillance vs diagnostic lobectomy when imaging / clinical risk is equivocal PMCInterpace Biosciences®, Inc.
• Independent comparisons and guidelines:
  • Contemporary reviews / meta-analyses: 
    • Afirma GSC and ThyroSeq v3 both excel as rule-out tests (high sensitivity / NPV), with ThyroSeq often showing higher PPV (rule-in)
    • Interpace’s combined platform performs comparably on NPV with strong rule-in behavior in some studies ScienceDirect+1PMC
• Societal guidance (ETA 2023):
  • Molecular tests can reduce diagnostic surgery and should be selected to match pretest risk and clinical goals rather than “one best test for all.” PMC
• Bottom line (how to choose today):
  • If your primary goal is to avoid surgery (rule-out) in Bethesda III to IV with low–intermediate pretest risk:
    • Afirma GSC or ThyroSeq v3 are both appropriate:
      • Real-world data support high NPV for both PMCJAMA Network
  • If you want both strong rule-out and richer “what kind of cancer is this if positive?” detail to guide extent of surgery and future therapy:
    • ThyroSeq v3 generally provides more granular prognostic / actionable data (TERT/driver profile, CNA burden, Hürthle copy-number signature) and often a higher PPV than Afirma
    • This makes it my usual pick when operative planning may hinge on genotype JAMA NetworkThyroSeq
  • If you favor a stepwise, cost-conscious approach with meaningful rule-in capability when drivers /miRNA are high-risk:
    • ThyGeNEXT + ThyraMIR v2 is reasonable:
      • Pooled data show competitive NPV and good surgical-avoidance rates PMCResearchGate
• Practical take for your clinic:
  • For Bethesda III to IV nodules with indeterminate US where you want to minimize unnecessary operations and inform extent if positive: 
    • ThyroSeq v3 is the most versatile single test today
  • For surgeon’s “rule-out first” workflows with straightforward nodules and low pretest risk: 
    • Afirma GSC is perfectly acceptable:
      • Add XA if suspicious and you want therapy targets.
  • For equivocal cases where a rule-in signal would materially change from surveillance to surgery, or when prior testing is ambiguous: 
    • ThyGeNEXT + ThyraMIR v2 is a solid option

Interpretation & Take-Home

• Best Rule-Out (Highest NPV and Sensitivity):
  • Afirma GSC (real-world meta-analysis: SN ~97%, NPV ~99%) and ThyroSeq v3 (UCLA trial: SN 97%, NPV 99%) are essentially neck-and-neck in ruling out malignancy. Both demonstrate excellent reliability in avoiding unnecessary surgeries.
• Better Rule-In (Higher PPV):
  • ThyroSeq v3 edges ahead slightly with PPV ~64% versus Afirma’s ~57% in comparable settings, meaning a positive result is more likely to indicate true malignancy.
• Manufacturer-Reported MPTX (ThyGeNEXT + ThyraMIR):
  • Claims very strong performance (SN ~ 95%, SP ~ 90%, NPV ~ 97%, PPV ~ 75%):
    • But these results may reflect idealized cohorts with prevalence adjustments
    • Real-world studies show more conservative metrics:
      • SN ~ 76%, SP ~ 75%, NPV ~ 83%, PPV ~ 67%).
• In Summary:
  • For maximum confidence in rule-out:
    • Afirma GSC and ThyroSeq v3 are clearly superior
  • If positive actionable findings (e.g., higher PPV, molecular prognostic detail) are crucial:
    • ThyroSeq v3 offers an advantage
  • MPTX is promising, especially if you value a modular approach, but real-world validation remains less robust than for the other two

• ThyroSeq® test results refine cancer probability in thyroid nodules with indeterminate cytology, informing the most appropriate management of these patients

• Negative Results:
  • According to NCCN guidelines, if molecular testing, in conjunction with clinical and ultrasound features, predicts a risk of cancer comparable to the risk of malignancy seen in a benign FNA cytology (roughly 5% or less):
    • Active surveillance can be considered
  • Therefore, in those clinical situations where the pretest probability of cancer in nodules with Bethesda III and IV cytology is less than 44%:
    • A negative ThyroSeq test results would confer the cancer probability of 5% or less:
      • Justifying observation in lieu of surgical management in appropriately selected cases
    • Because the probability of cancer in such nodules is comparable to benign FNA cytology, the management of patients may follow the recommendations for nodules with benign cytology:
      • Which, based on the 2015 ATA guidelines, should be determined based on ultrasound (US) pattern (Recommendation #23)
  • In nodules with Bethesda V cytology and negative ThyroSeq result:
    • The residual cancer risk of ~20% does not allow to avoid surgical management:
      • Thyroid lobectomy may be sufficient initial treatment for many of these patients
• Currently Negative Results:
  • Test results are reported as currently negative:
    • When the sample is found positive for a low risk and / or low-level gene mutation, DNA copy number alterations (CNA) or gene expression alterations (GEA) that alone is not sufficient for full cancer development
  • Although at the time of sampling most of these nodules are benign:
    • Some of them may undergo clonal expansion and acquire additional mutations
  • In the absence of suspicious US features or other clinical risk factors:
    • Many of these patients are likely to benefit from active surveillance with repeat of clinical exam and potentially FNA and molecular testing in 1 year
• Positive RAS-Like or GEA Results:
  • ThyroSeq test positive for an isolated RAS mutation or RAS-like alteration (e.g. BRAF K601E mutation, THADA fusion, RAS-like GEA):
    • Indicates that the nodule is a tumor (not hyperplasia) and predicts, depending on the specific alteration:
      • A 30% to 80% probability of either a low-risk cancer or a pre-cancerous tumor, NIFTP
  • Many of these nodules may be managed by therapeutic lobectomy:
    • Which is currently recommended by the ATA guidelines for low-risk papillary and follicular carcinomas (Recommendation #35) and NIFTP
• Positive BRAF-Like of GEA Results:
  • ThyroSeq test positive for an isolated BRAF V600E or BRAF V600E-like alteration (e.g. RET / PTC, BRAF fusions, BRAF V600E-like GEA):
    • Confers a very high (greater than 95%) probability of cancer
  • According to the ATA guidelines:
    • BRAF-mutated unifocal intrathyroidal carcinoma less than 1 cm in size has low risk for recurrence:
      • Therefore may be treated with thyroid lobectomy alone
    • Whereas 1 cm to 4 cm BRAF-positive PTC is an intermediate-risk tumor:
      • Where total thyroidectomy or lobectomy should be considered based on clinical and US findings
• Postive Oncocytic Cell Type (formely Hurthle Cell Type) CNA Results:
  • ThyroSeq test positive for isolated oncocytic cell type / Hürthle cell-type copy number alterations (CNA) confers, in different nodule size groups:
    • A 40% to 80% probability of Hürthle Cell carcinoma:
      • Whereas the rest of these nodules are benign Hurthle Cell adenomas
• Positive High Risk Mutations Results:
  • ThyroSeq test positive for multiple high-risk mutations (e.g. BRAF V600E and TERT) confers a very high probability of cancer and predicts an increased risk of disease recurrence by the ATA guidelines and of tumor-related mortality
  • Most of these patients would likely benefit from total thyroidectomy, with possible consideration for regional lymph node dissection if one of the mutations is BRAFV600E