Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• 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.

• The basis and need for elective nodal treatment in head and neck cancer:
  • Have been based largely on surgical series evaluating pathologic nodal involvement found on elective neck dissection in patients with clinically negative necks
• In a consecutive series of 1,081 head and neck cancer patients undergoing radical neck dissection:
  • The incidence of pathologic node involvement:
    • Was 33% among those undergoing elective neck surgery
  • The pathologic findings identified the nodal stations at risk by tumor site:
    • To establish the rationale for selective neck dissection (SND) as the elective surgical procedure
• Several reports have summarized the risk for metastases and nodal stations at risk
• Some general observations from such data can be made:
  • Regarding larynx cancers:
    • Candela reported the Memorial Sloan Kettering Cancer Center (MSKCC) experience in determining the patterns of cervical nodal metastases in 247 larynx cancer patients undergoing radical neck dissections:
      • Seventy-eight underwent elective radical neck dissection whereas 118 underwent immediate radical dissection for clinically node-positive disease
      • The majority of patients (n = 189) were supraglottic larynx and 58 were glottic
      • Pathologic nodal involvement:
        • Was found in 37% undergoing elective neck dissection
      • It is noted that cervical nodes spread in a similar fashion whether the patients are clinically node negative or positive:
        • With predominant involvement of:
          • Level II and III jugular nodes
      • In clinically node-negative patients:
        • The incidence of involvement of level I and V:
          • Is less than 5% with less than 10% involvement of level IV
      • In node-positive patients:
        • The incidence of level IV node increases from 15% to 31% with greater involvement of levels II and III
      • In clinically node-positive patients:
        • Very rarely did patients present with isolated level I nodal metastases without involvement of the jugular nodes
• Shah and Candela reported that among oropharynx or hypopharynx cancers:
  • Treated with elective radical neck dissection:
    • Occult metastases are found in 26%
  • Level I and V were involved in only 1.4%:
    • Always in association with nodal disease at level II to IV
  • No skip metastases were reported
  • Among oropharynx patients:
    • Levels II to IV were predominantly involved
  • Among hypopharynx lesions:
    • The primary levels involved were levels II and III
  • In patients clinically node positive undergoing therapeutic neck dissection:
    • The incidence of level I and V involvement increased to about 10% to 15%:
      • However, levels II to IV were predominantly involved
    • Level V involvement:
      • Only occurred in association with nodal involvement at levels II to IV
    • Whereas the incidence isolated level I involvement without levels II to IV involvement (“skip metastasis”):
      • Occurred in 0.4%:
        • Thus, based on these studies, elective treatment of the neck in oropharynx or hypopharynx can be directed at levels II to IV
• Among oral cavity patients:
  • The incidence of nodal disease was 34% on elective evaluation
  • The majority of metastatic nodes involved:
    • Levels I to III:
      • With only 1.5% incidence of skip metastasis to level IV
  • Level V involvement:
    • Is found in only 0.5% with occult disease simultaneously involving other levels
  • Among those undergoing therapeutic neck dissections:
    • The incidence of level IV involvement increased to 20%
    • Level V was 4% always restricted to lower gum or floor of mouth primary sites
• The need for elective treatment not only relates to the estimated probability of nodal involvement and usually is implemented when the risk is 20% or greater but also relates to the morbidity of such treatment as well as the adequacy of coverage