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• The second most common type of thyroid cancer:
  • Is follicular thyroid carcinoma (FTC):
    • 4.6% of the cases based on the SEER database between 2010 and 2014
• Fundamentally all follicular carcinomas are:
  • RAS-like tumors:
    • There profile is different from classic PTC because they do not have BRAF mutations:
      • Most of them have RAS and RAS-like mutations
  • Yoo S.K et al, from Korea showed that the genetic profile of follicular carcinomas:
    • Is very similar to follicular adenomas (FA) because they are related tumors:
      • Most FTC originate from a FA and eventually break through the capsule and become carcinomas
  • Encapsulated follicular variant of PTC:
    • Their molecular profile is much closer to a FA and FTC than to classic PTC
  • Infiltrative follicular variant of PTC has a molecular profile:
    • That is more like classic PTC than FTC
  • The biologic difference between
    follicular pattern RAS-like tumors and classic PTC:
    • Is the infiltrative growth pattern (Figure)
  • The difference between these tumors is not only phenotypically based on gross pattern, but also based on biological and clinical differences:
    • Because follicular pattern RAS-like tumors:
      • Retain avidity to radioactive iodine
    • BRAF-like tumors (classic PTC and infiltrative follicular variant of PTC) have the classic features of PTC:
      • They are infiltrative, they spread to lymph nodes first and later to distant sites, and they lose the expression of genes associated with thyroid differentiation
    • RAS-like tumors (FA, FTC, NIFTP, and invasive encapsulated follicular variant of PTC):
      • May or may not have nuclear features of PTC, they are encapsulated, they spread to distant sites (rarely to lymph nodes), and they retain expression of genes associated with thyroid differentiation
• The RAS genes (HRAS, KRAS and NRAS):
  • Encode for the interconnected G-proteins:
    • That play a critical role in the intracellular transduction of signals arising from cell membrane receptors
• RAS protein in its inactive state:
  • Is bound to guanosine diphosphate (GDP):
    • Upon activation, it releases GDP and binds guanosine triphosphate (GTP):
      • Thus activating the MAPK and other signaling pathways, such as PI3K/AKT
  • Typically, the activated RAS / GTP protein becomes promptly inactive:
    • Due to its intrinsic GTPase activity and the action of cytoplasmic GTPase-activating proteins:
      • Point mutations in the domains of the RAS gene either increase its affinity for GTP (mutations in codons 12 and 13) or inactivate its autocatalytic GTPase activity (mutation in codon 61):
        • The consequence of this is that the mutant protein becomes permanently switched in the active position and continuously activates its downstream targets
  • Mutations in the RAS genes are believed play
    an early role in the cellular transformation and may predispose to the progression benign tumors to malignant tumors
  • Point mutations involving the specific sites (codons 12, 13 and 61) of the NRAS, HRAS or KRAS genes:
    • Are identified in roughly 10% to 20% of PTC:
      • PTC holding RAS mutation invariably have follicular subtype histology:
        • This mutation also correlates with significantly less prominent nuclear features of PTC, more common
          thyroid encapsulation, and a lower rate of lymph node metastases
      • A few studies have linked RAS
        mutations with PTC:
        • That have a more aggressive behavior, such as a higher frequency of distant metastases
      • Mutations in the RAS gene are not limited to PTC and also found in other benign and malignant thyroid neoplasms, as well as in tumors from other tissues
      • RAS gene mutations are identified in approximately:
        • 20% to 40% of follicular thyroid adenomas (FTA)
        • 40% to 50% of FTC
        • 20% to 40% of anaplastic thyroid carcinoma (ATC)
    • When a FNA cytology is indetermined and the molecular profile identifies a RAS mutation:
      • The risk of malignancy varies
        between the type of mutation:
        • HRAS = 71%
        • NRAS = 63%
        • KRAS = 33%
• The concept of progression from benign to malignant tumors is supported by the molecular profile shared by these different tumors:
  • More evidence supporting this concept of cancer progression is the similar morphology that these lesions have, along with experimental mouse data showing very similar results
• Pathologist observing thyroid nodules have detected this step wise progression
• The nodule in Figure developed from a single cell driven by the RAS mutation, it continued to grow and grow, it eventually forms a capsule, looking microscopically like a benign adenoma (goiter), then it continues to progress, it accumulates more genetic alterations (micro mRNA, and it involves other molecular pathways), it becomes a tumor, it eventually breaks through the capsule, and it will give you invasive encapsulated follicular variant of PTC:
  • If an FNA is performed of area A it would come back as Bethesda II, in area B it would come back as a Bethesda IV, and in area C as Bethesda V:
    • This has changed the practice of cytopathology with molecular
      testing helping us understand better the biological nature of these tumors

• Papillary thyroid carcinoma (PTC):
  • Is one of the best molecularly understood cancers:
    • With more that 97% of the driver mutations identified
• One of the main goals of the cancer genome atlas research network study (TCGA) thyroid project:
  • Was to detect cancer-initiating mutations, i.e., driver mutations:
    • In those cases that lacked the well-known PTC driver mutations (BRAF V600E, point mutations of RAS genes, and gene fusions involving RET and NTRK):
      • These cases are referred to by computational biologists as “dark matter” cases
  • These very important studies under the umbrella of NCI and NIH analyzed 496 PTCs that permitted several analyses:
    • That showed that approximately 75% of all PTC:
      • Developed through the molecular mechanism of point mutation:
      • The most common been the:
        • BRAF V600E mutation
      • The second most common the:
        • RAS mutation
      • The thyroid most common the:
        • TERT mutation – That constituted a small percentage of tumors but was found to be a marker of aggressive disease
    • Roughly 15% of PTC develop through the mechanism of gene fusions:
      • The most common been RET / PTC,
        NTRK 1/3, ALK, BRAF, PAX8 / PPARG
      • The RET / PTC, NTRK 1/3, ALK have very important therapeutic implications for advanced thyroid cancer:
        • Because of the availability of targeted inhibitors with low toxicity and
          high efficacy for the management of these tumors
    • Roughly 7% of PTC develop exclusively from the molecular mechanism of copy number alterations (CNA) (Figure)

• Roughly 45% to 75% of PTC (29% to 83%) have a mutation in the BRAF gene:
  • Making it the most frequently known genetic
    alteration in PTC
  • Practically all mutations involve:
    • Nucleotide 1799 and result in a valine-to-glutamate substitution at residue 600 (V600E):
      • This point mutation leads to constitutive activation of BRAF kinase:
        • Resulting in a constant phosphorylation of MEK and downstream effectors of the MAPK pathway (Figure)
    • Other mechanisms of BRAF activation in PTC include:
      • K601E point mutation:
        • Small in-frame insertions or deletions surrounding codon 600
      • AKAP9-BRAF rearrangement:
        • Which is more common in PTC associated with radiation exposure
• BRAF V600E mutation:
  • Is the prevailing mutation in PTC:
    • With classical histology and in the tall cell subtype:
      • But is rare in follicular subtypes tumors
  • In multiple studies, the existence of the BRAF mutation:
    • Has been linked with aggressive tumor biology such as:
      • Advanced stage at presentation
      • Extrathyroidal extension (infiltrative)
      • Recurrence
      • Lymph node or distant metastases
  • BRAF V600E mutation:
    • Is an independent predictor of tumor recurrence:
      • Even in patients with stage I to stage II disease
  • The ability of thyroid cancers to trap
    radioiodine:
    • Has been identified to be decreased in tumors with the BRAF V600E mutations and this may lead to treatment failures of the recurrent disease:
      • Which is due to the dysregulation of the function of sodium iodide
        symporter (NIS) and other genes metabolizing iodide in the thyroid follicular cells
  • In thyroid nodules, the V600E BRAF mutation is limited to PTC, poorly differentiated and ATC arising from PTC:
    • Consequently, the identification of the BRAF V600E mutation in FNA cytology of thyroid nodules:
      • Practically confirms the diagnosis of PTC
    • Testing for the BRAF mutation is very useful diagnostically in thyroid FNA samples with indeterminate results:
      • As it can help to determine the diagnosis of PTC in a important portion of these biopsies
• Pathologically PTC is one disease and biologically at a minimum PTC has two significantly different groups:
  • Based on multiple type of analysis like gene expression alterations, microRNA alterations, DNA methylation, transcriptomics (Figure)
• The Cancer Genome Atlas (TCGA) study on PTC highlighted that PTC can be grouped into:
  • BRAFV600E-like and RAS-like tumors:
    • BRAFV600E-like tumors:
      • Also harbor RET fusions
    • RAS-like tumors:
      • Show RAS mutations, the BRAFK601E, and PPARG and THADA fusions
  • The V600E BRAF–like PTC:
    • Are usually classic PTC and tall cell subtype of PTC
  • Clinically when we look at the differentiation score:
    • Which is the expression of genes involved in iodine metabolism and synthesis:
      • BRAF tumors:
        • Loose expression of thyroid differentiation markers
      • RAS-like tumors retain them:
        • Almost at the level of a normal thyroid cell
        • This is important therapeutically because one of the most efficient management options in thyroid cancer is iodine therapy
      • RAS-like tumors:
        • Are usually follicular variant PTC
    • Usually all BRAF mutations are BRAF-like and all RAS mutations are RAS-like:
      • But all other type of molecular alterations can be hidden in either BRAF-like and RAS-like:
        • For example, BRAF K601E mutations are found in RAS-like tumors

• Most of the data that has been gathered is associated with somatic mutations:
  • Many of which occur early in the
    transformation process and are crucial for cancer development
• In thyroid cancer, vital genes are commonly mutated via two separate molecular mechanisms:
  • Point mutations
  • Chromosomal rearrangements
• Point mutations:
  • Are the result of a single nucleotide change within the DNA chain:
    • Which activates or inactivates a
      protein
• Chromosomal rearrangements:
  • Represent a large-scale genetic abnormality with breakage and fusion of parts of the same chromosome or different chromosomes
• The molecular pathogenesis of thyroid cancer:
  • Is relatively simple with two molecular pathways:
    • The mitogen‑activated protein kinase (MAPK) pathway
    • The phosphatidylinositol 3 – kinase – protein kinase B (PI3K-AKT) pathway (Figure)
• These pathways are activated in most thyroid cancers:
  • Via distinct molecular mechanisms mentioned previously, like:
    • Point mutations (single nucleotide variant):
      • Where a single nucleotide is
        changed:
        • Which activates or inactivates a protein
    • Gene fusions:
      • Were parts of two different genes located in the same or different chromosome are fused to each other:
        • That results in the generation of chimeric protein
    • Copy number alterations (CNA):
      • That have been recently accepted as a driver mutation for oncocytic cell tumors
• Activation of the MAPK pathway:
  • Is a critical step for tumor initiation
  • The mutated genes that impact
    these pathways encode:
    • The cell-membrane receptor tyrosine kinases:
      • RET and NTRK1
    • Intracellular signal transducers:
      • RAS and BRAF
  • These mutually exclusive mutations:
    • They do not overlap with each other because they activate the same pathway and only one event is sufficient to activate the process for cancer development:
      • Occur in roughly 70% to 75% of patients with PTC and are associated with specific clinical, pathologic, and biological tumor characteristics (Table)
  • In follicular thyroid cancer (FTC), in addition to mutations of RAS:
    • Another common event is PAX8 / PPARG rearrangement
• Thyroid cancer progression and dedifferentiation involves a number of additional mutations:
  • That affects the PI3K-AKT pathway and other cell signaling pathways

• The choice of biopsy technique:
  • Varies according to the anatomical site as well as the size and shape of the lesion
• Particular attention should be placed on the impact of the biopsy on definitive surgical treatment
• Either an excisional biopsy or an incisional biopsy using a scalpel or punch is acceptable
• Entire removal of the lesion is generally preferred to allow for accurate pathologic evaluation
• Punch biopsies:
  • Can be performed for most lesions:
    • Generally, they can be performed when lesions are located on areas where maximum preservation of surrounding skin is important, or can be completely excised with a punch
  • Punch biopsies:
    • Should be performed at the most raised or darkest area of the lesion to sample the most aggressive area of the potential melanoma
• Full-thickness biopsy:
  • Into the subcutaneous tissue should be performed to ensure accurate staging of the lesion
• An excisional biopsy:
  • Allows the pathologist to accurately determine the thickness of the lesion, since the entire lesion is available for evaluation
• Excisional biopsies:
  • Should be performed when the lesion is too large for a punch but still can be removed without excessive surgical intervention
• For excisional biopsies:
  • A narrow margin of normal-appearing skin (1 to 3 mm) is taken with the specimen
• An elliptical incision:
  • Is often used to facilitate closure
• The biopsy incision should be oriented to facilitate later wide excision (e.g., axially on extremities) and minimize the need for a skin graft to provide wound closure at the time of wide excision
• Shave biopsy:
  • Is generally discouraged if a diagnosis of melanoma is being considered since incomplete assessment of tumor thickness may result if the deep margin is not cleared
  • If a shave biopsy is performed:
    • A deep shave is preferable
• In general, I submit all pigmented lesions for permanent section examination and perform definitive surgery at a later time
• I generally prefer image-guided fine-needle aspiration biopsy as an initial diagnostic maneuver to document nodal or other melanoma metastases:
  • But not to diagnose primary melanomas

#Arrangoiz #CancerSurgeon #Teacher #HeadandNeckSurgeon #SurgicalOncologist #SkinCaner #Melanoma #PunchBiospy #MSMC #Mount SinaiMedicalCenter

• LIBRETTO‑531:
  • Design & Patient Population:
    • Phase III, global, multicenter, open-label, randomized (2:1) trial (NCT04211337):
      • Comparing selpercatinib (160 mg BID) to physician’s choice of cabozantinib or vandetanib:
        • In MKI-naïve, progressive advanced /metastatic RET-mutant MTC patients 
      • Stratified by RET M918T mutation status and intended control arm MKI
      • Crossover permitted from MKI arm to selpercatinib upon progression
  • Efficacy Results (Interim, ~ 12-months follow-up):
    • Primary endpoint (PFS, RECIST v1.1):
      • Selpercatinib:
        • Median not reached
      • MKI arm:
        • 16.8 months (95% CI, 12.2–25.1); HR 0.28; P<0.001 
      • 12‑month PFS:
        • 86.8% vs 65.7%
    • Secondary endpoint (Treatment Failure-Free Survival – TFFS):
      • Not reached vs 13.9 months in MKI arm; HR 0.25
    • Overall Response Rate (ORR):
      • 69.4% in selpercatinib group vs 38.8% in MKI group 
    • Safety-driven dose modifications:
      • 38.9% with selpercatinib vs 77.3% with MKIs
    • Discontinuations 4.7% vs 26.8% 
• Safety & Patient-Reported Outcomes:
• Common ≥ 25% AEs:
  • Hypertension, edema, dry mouth, fatigue, diarrhea
• Grade 3/4 laboratory abnormalities:
  • Lymphopenia, elevated ALT / AST, electrolyte disturbances
• Patient-reported tolerability (FACT-GP5):
  • Demonstrated robust reliability (ICC 0.80–0.85); high side-effect burden correlated with decreased functioning
• Mechanism of Action:
  • Selpercatinib is a highly selective RET inhibitor, effective against both:
    • RET point mutations (e.g., M918T in MTC)
    • RET fusions (common in papillary thyroid carcinoma and NSCLC)
  • High selectivity translates to less off-target toxicity compared to multikinase inhibitors (vandetanib/cabozantinib), which inhibit VEGFR, MET, etc.
• Guideline Endorsements:
  • NCCN (2024) now includes selpercatinib as a Category 1 first-line option:
    • For RET-mutant, progressive/unresectable MTC, alongside cabozantinib and vandetanib
  • ATA Guidelines:
    • Similarly endorse selective RET inhibitors as preferred agents for RET-driven MTC
  • ESMO / European Consensus:
    • Align with use in RET-mutant MTC post-MKI therapy
• Regulatory Perspective:
  • FDA granted traditional approval on September 27, 2024 for adults and pediatrics ≥ 2 years with advanced / metastatic RET-mutant MTC requirement systemic therapy
  • Earlier accelerated approval received in 2020 for patients ≥ 12 years; expanded to ≥ 2 years with pediatric dosing in May 2024
• Clinical Implications for Head and Neck Oncology Teams:
  • First-line therapy improvement:
    • LIBRETTO‑531 is the first randomized trial demonstrating selpercatinib superiority over MKIs in efficacy and tolerability
    • Reduced surgical urgency:
      • Durable responses may defer or potentially downstage extra-thyroidal or metastatic disease, assisting in surgical planning
    • Multidisciplinary coordination:
      • Shared decision-making essential for selecting candidates, managing MTC lesion status, and monitoring biochemical markers (calcitonin, CEA)
    • Monitoring & sequencing:
      • Be vigilant for long-term tolerability needs, dose adjustments, and resistance (e.g., RET solvent-front mutations); TKIs sequencing should involve endocrine-oncology collaboration
• Recommended References for Further Reading:
  • Primary LIBRETTO‑531 publication: NEJM (PubMed PMID: 37870969) 
  • Preceding phase I/II evidence: Wirth et al., N Engl J Med 2020 (LIBRETTO‑001)
  • NCCN Thyroid Carcinoma Guidelines, v2.2024  .
    FDA approval details for selpercatinib
  • Patient-reported outcomes analysis: Regnault et al., J Patient Rep Outcomes 2024
• Summary for Surgical Experts:
  • Selpercatinib sets a new standard first-line systemic therapy in RET-mutant MTC, delivering superior tumor and nodal responses while maintaining patient quality-of-life
  • Surgeons should integrate molecular profiling early, allowing neoadjuvant-like benefit of targeted therapy before considering resection or resection of metastatic deposits
  • Long-term surgical planning may be increasingly influenced by TKI response and durability

• Clinical Implications for Surgeons and Oncologists:
  • Preoperative:
    • Patients with borderline resectable MTC may benefit from downstaging with selpercatinib
    • Early molecular testing for RET mutations is essential
  • Postoperative:
    • Patients with biochemical persistence (calcitonin / CEA) or structural recurrence can receive selpercatinib earlier
    • More favorable AE profile allows longer-term outpatient management
• References:
  • Wirth LJ, et al. Selpercatinib vs Standard Therapy in RET-Mutant MTC. N Engl J Med. 2023;389(15):1344-1356. PMID: 37870969
    NCCN Guidelines: Thyroid Carcinoma v2.2024. https://www.nccn.org
  • ATA Guidelines Update (Thyroid, 2022): Use of targeted therapy in RET-mutant disease
    FDA Approval Summary: https://www.fda.gov/drugs
  • Drilon A, et al. Targeting RET-driven cancers with selpercatinib. Cancer Discov. 2020. PMID: 3221355

ESMO 2026 Head & Neck Cancer: 5 Trial Takeaways for Surgeons

KEYNOTE-412, OrigAMI-4, HexAgon-HN, TAISHAN-301, and iza-bren + pembro — with ORR, ctDNA, and surgical implications

1. KEYNOTE-412 – Pembrolizumab + CRT in Locally Advanced HNSCC

• ORR: Not primary endpoint. 5-yr data: no OS benefit in all-comers. In CPS ≥10 + HPV-negative: 12% EFS benefit, 10% OS benefit at 5 years.
• ctDNA data:[STRIPPED]strong> Presented by Jean-Pascal Machiels. 95% had detectable ctDNA at baseline. HPV-negative: High baseline ctDNA = worse EFS/OS. Early clearance at C3D1: 76.8% with pembro vs 66.3% placebo. 5-yr OS if cleared: 72.9% vs 38.9% if not cleared. HPV-positive: Baseline ctDNA not prognostic. Clearance only helped in placebo arm.
• Surgical takeaway: For HPV-negative, high-risk, unresectable LA-HNSCC, pembro+CRT isn’t approved yet. But baseline ctDNA high + failure to clear early = poor prognosis. Flag these for trials or closer post-CRT surveillance. Doesn’t change upfront surgery indications.

2. OrigAMI-4 – Amivantamab + Pembrolizumab + Carboplatin, 1L R/M HNSCC

• ORR: 77% confirmed ORR in HPV-unrelated disease, with 14% CR. HPV-positive OPSCC: 29% ORR.
• ctDNA data:[STRIPPED]strong> Not reported at ESMO 2026.
• Surgical takeaway: 77% ORR vs 36% historical pembro+chemo. If phase 3 confirms, more R/M pts may achieve deep responses and become candidates for surgical salvage. Less compelling for HPV-positive.

3. HexAgon-HN

• ORR/ctDNA: No data disclosed at ESMO 2026. Randomized test of OX40 agonism.
• Surgical takeaway: Watch for neoadjuvant IO data that could downstage borderline resectable cases.

4. TAISHAN-301

• ORR/ctDNA: No specifics released at ESMO 2026.
• Surgical takeaway: Details pending. Likely IO/chemo combo.

5. Iza-bren + Pembrolizumab – Izalontamab brengitecan ADC + pembro, 1L R/M HNSCC

• ORR: 57.9% ORR at 2.5 mg/kg dose, confirmed ORR 47.4%. Median PFS 8.5 mo.
• ctDNA data:[STRIPPED]strong> Not reported at ESMO 2026.
• Surgical takeaway: Strong 1L response vs KEYNOTE-048. EGFR/HER3 ADC toxicity: 95% anemia, 80% neutropenia. More PR/CRs may enable salvage surgery, but monitor marrow suppression perioperatively.

What Actually Changes for HNSCC Surgical Care Right Now?

1. Biomarker-driven decisions: KEYNOTE-412 supports ctDNA clearance as prognostic in HPV-negative LA-HNSCC. Consider baseline + week 6 plasma banking.
2. HPV status matters more: OrigAMI-4 and KEYNOTE-412 benefit driven by HPV-negative. HPV-positive needs different strategies.
3. R/M disease: 77% ORR amivantamab triplet and 58% iza-bren+pembro raise the bar. May convert more unresectable pts to surgical candidates.
4. Not practice-changing yet: Mostly phase 1b/2 or exploratory. Await phase 3 + mature OS. No new adjuvant/neoadjuvant surgical paradigms from ESMO 2026.

Caveat: KEYNOTE-412 was overall negative. OrigAMI-4 had n=29 efficacy-evaluable. CRT is immunosuppressive.

• Name: IoN – Is Ablative Radioiodine Necessary?
• Type:
  • Multicenter, open-label, non-inferiority RCT across 33 UK cancer centers 
• Enrollment Period:
  • June 2012 to March 2020
• Participants:
  • 504 patients post–total thyroidectomy:
    • R0 resection
• Pathology Stage:
  • pT1 to pT3 (TNM 7 edition):
    • Including pT3a (TNM 8 edition)
  • Nodes:
    • N0, Nx, or N1a
  • Exclusions:
    • pT1a unifocal
    • pN1b
    • M1
    • Aggressive variants 
• Intervention and Follow-Up:
  • Randomization (1:1):
    • RAI Arm:
      • 1.1 GBq (30 mCi) RAI post-surgery
    • No RAI Arm:
      • Surveillance only
  • Preparation:
    • rhTSH used where standard:
      • All received TSH suppression
  • Monitoring:
    • Neck US annually
    • Thyroglobulin (Tg) every 6 months
  • Primary Endpoint:
    • 5-year recurrence-free survival (RFS):
      • Absence of locoregional or distant structural disease or thyroid cancer related death 
  • Statistical Non-Inferiority Margin:
    • 5% absolute difference 
• Stratified Outcomes and Safety:
  • Subgroup analysis:
    • Recurrence was slightly higher for:
      • pT3 / pT3a tumors (9%) vs pT1 to pT2 (3%)
      • N1a nodes had 13% recurrence versus 2% in N0 / Nx 
    • Adverse events:
      • Similar between arms
      • Most common were:
        • Fatigue (~ 25%),
        • Lethargy (~ 14%)
        • Dry mouth (~ 10%)
        • No treatment-related deaths 
• Clinical Implications for Head and Neck Surgeons:
  • RAI omission is safe in patients meeting strict criteria (pT1 to pT2, N0 / Nx, complete thyroidectomy):
    • With no compromise in 5-year RFS
  • Non-inferiority achieved:
    • Difference lies well within prespecified 5% margin
  • Patient-centered benefits:
    • Avoids radiation isolation
    • Reduces side effects
    • Enhances QoL:
      • Especially important for younger patients
  • RAI may still be considered for pT3 / pT3a or N1a cases:
    • Due to higher recurrence observed:
      • Individual multidisciplinary tumor board (MDT) discussion is warranted
  • Supports 2025 Lancet recommendations:
    • Omission of adjuvant RAI is reasonable in selected low-risk DTC patients 
• Final Take-Home Points:
  • IoN validates RAI omission in strictly defined low-risk DTC post-total thyroidectomy:
    • 98% RFS at 5 years without RAI
  • Reinforces a move toward risk-adapted, de-escalated care in line with ATA risk guidelines and emerging global consensus
  • Tailor decision-making in MDT:
    • Offer RAI to > T2 or with nodal involvement:
      • Otherwise, provide informed reassurance and structured surveillance

👉The external branch of the superior laryngeal nerve (EBSLN) has been labelled ‘the neglected nerve’ of thyroid surgery.

👉Most surgeons have simply attempted to avoid this nerve on the assumption that so doing will prevent injury; however, it is now recognized that injury is relatively common and associated with the potential for significant impairment, espe- cially for those who use their voices professionally.

👉I was taught to always attempt to identify the nerve and recommend doing so.

👉Recently Aina and Hisham have shown that the nerve can be routinely identified in over 90% of cases, a level that sets a new benchmark for head and neck surgeons / endocrine surgeons.

👉The key to identifying the nerve is to develop the avascular plane between the cricothyroid muscle and the medial border of the upper pole of the thyroid lobe, a manoeuvre facilitated by lateral retraction of the lobe.

👉Awareness of the various positions of the EBSLN according to the Cernea classification is also essential if the nerve is to be both identified and preserved.

👉Type 1 EBSLN are located well clear of the thyroid, more than 1 cm above the upper pole of the lobe passing directly into the cricothyroid muscle.

👉Type 2a nerves pass in the vicinity of the superior thyroid vessels as they enter the gland substance.

👉Type 2b nerves cross over the anterior surface of the thyroid lobe.

👉Awareness of the anatomic variations, such as the nerve of Galen, a direct communication between the RLN and EBSLN, is important in avoiding injury to the nerve.

#Arrangoiz

#HeadandNeckSurgeon

#ThyroidSurgeon

#ParathyroidSurgeon

#CancerSurgeon

#SurgicalOncologist

#EndocrineSurgery

#Teacher

#MSMC

#MountSinaiMedicalCenter

• The regional state of lymph nodes:
  • Is one of the most important parameters determining prognosis in patients with head and neck squamous cell carcinoma (HNSCC)
• The presence of only one positive lymph node:
  • Can decrease survival by up to 50% in most HNSCC
• The risk of lymph node metastasis can be predicted in relation to:
  • Differentiation of tumor:
    • The more poorly differentiated the tumor:
      • The greater the risk
  • To the size and depth of the invasion (DOI)
  • The availability of capillary lymphatics
• The risk of lymphatic spread:
  • Increases with tumor recurrence
• Embryologically:
  • The lymphatic system is formed:
    • From its germination from the venous system:
      • Explaining the close anatomical relationship between these two systems
  • Blood capillaries have tight endothelial junctions:
    • That normally do not reabsorb larger molecules and cells
  • However, lymphatic capillaries have relatively open endothelial junctions:
    • That allow molecules and larger cells to be more easily reabsorbed:
      • Explaining the reason for easier lymphatic than vascular propensity
• The lymphatic system of the head and neck:
  • Is the region of the body composed by more lymphatic capillaries, lymphatic trunks and lymph nodes:
    • Epithelium, bone and cartilage:
      • Are devoid of lymphatic capillaries:
        • While a small minority is found in the periosteum and perichondrium
• Lymph node arrangement is archetypal and each group receives drainage (directly or indirectly) from specific areas:
  • In a deep cervical group (a terminal group for the head and region of the neck) before finally flowing into the lymphatic duct (right) / thoracic duct (left) in the jugular-subclavian junction
• Due to the absence of lymphatic vessels in the epithelium:
  • The tumor must penetrate the lamina propria before lymphatic invasion
• In the superficial layer:
  • The diameter of lymphatic capillaries is usually narrower than it is in the deeper layer
• The richness of the capillary network in each subsite can increase the relative incidence of lymph node metastases:
  • The nasopharynx, pyriform sinus (hypopharynx), supraglottic larynx and oropharynx:
    • Have the most profitable network of capillary lymphatic vessels:
      • Which is the clinical reflection of the potential presence of neoplastic lymph nodes
  • Paranasal sinuses, middle ear and vocal folds:
    • Have few or no capillary lymphatics:
      • Which is consistent with the low rate of lymph node metastases when the tumor is confined to these sites
• The involvement of lymph nodes usually follows an ordered progression and, rarely, skip nodal metastasis is revealed (exception lateral ventral tongue)
• Well lateralized lesions:
  • Determine ipsilateral lymph node metastases
• Lesions near the midline or lateral margin of tongue or nasopharyngeal lesions:
  • Can also spread contra-laterally or bilaterally:
    • But generally, tend to spread from the side of the lesion
• Patients with ipsilateral tumor nodal disease are at risk of contralateral disease:
  • Especially if the lymph node exceeds a certain size or if multiple lymph nodes are involved
• Obstruction of lymphatic pathways:
  • Caused by surgery or radiation therapy:
    • Can divert lymphatic flow on the opposite side of the neck:
      • Through anastomotic channels
• Finally, it should be remembered that metastases in cervical-cephalic regions:
  • Occur in approximately 10% of patients as neoplastic metastases from unknown primary sites
  • The histopathology of these metastases is generally referable to squamous cell carcinomas in various degrees of differentiation:
    • But metastases of adenocarcinomas, melanomas, or anaplastic tumors can also be found
  • The lymph node level is indicative of possible neoplastic origin
• Distant metastasis (DM):
  • In the absence of nodal metastasis is very rare in HNSCC
  • Untreated occult disease in the lymphatic venous system:
    • Can produce DM while the lymph node is growing
  • Patients with advanced disease have a high incidence of DM:
    • Particularly in the presence of jugular vein invasion or extensive soft tissue disease in the neck:
      • The rate of DM increases by:
        • Up to 25% to 30% for N3 disease compared to 18% to 20% for N2 disease

• The 10 signs of malignancy include:
  • Shadowing
  • Hypoechoic echotexture
  • Spiculation
  • Angular margins
  • Thick echogenic halo
  • Microlobulation
  • Taller than wide dimensions
  • Duct extension
  • Branching pattern
  • Calcifications
• Well-defined smooth border and posterior acoustic enhancement:
  • Are found in both malignant and nonmalignant lesions
• Layering / teacup mammographic microcalcifications:
  • Are usually associated with benign disease
• Sonographic mass with a benign mammographic imaging:
  • Is managed based on ultrasound features

• References
  • Evaluation and imaging features of malignant breast masses. In: Cardenosa G. Clinical Breast Imaging: The Essentials. Philadelphia, PA: Wolters Kluwer; 2015:234-282.
  • Stavros AT. Breast Ultrasound. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.