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• Understanding the genetic mutations associated with thyroid cancer has become increasingly important. The most common genetic mutations found in thyroid cancer include BRAF, RAS, RET/PTC, and PAX8/PPARγ. These mutations can provide valuable information for diagnosis, prognosis, and targeted treatment approaches.
• Molecular testing, such as next-generation sequencing (NGS), has gained prominence in thyroid cancer diagnosis and management. It allows for the identification of specific genetic alterations and can guide treatment decisions. Testing for specific genetic mutations, such as BRAF V600E, may help determine the use of targeted therapies like BRAF inhibitors.
• Advances in understanding the molecular alterations in thyroid cancer have led to the development of targeted therapies. Tyrosine kinase inhibitors (TKIs) have shown promise in treating advanced or metastatic thyroid cancer, particularly those with RET rearrangements, BRAF mutations, or vascular endothelial growth factor receptor (VEGFR) mutations.
• Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, have shown effectiveness in a subset of patients with advanced or refractory thyroid cancer. These therapies work by unleashing the immune system to target cancer cells. However, response rates can vary, and not all patients will benefit from immunotherapy.
• Molecular testing can help refine risk stratification in thyroid cancer. Genetic profiling of the tumor can aid in distinguishing low-risk from high-risk thyroid cancers, allowing for tailored treatment plans and surveillance strategies.

How Skin Grafts Heal

Both split-thickness (STSG) and full-thickness (FTSG) skin grafts are avascular free tissue transfers that heal through the same three sequential phases. They differ in the speed/reliability of that process and in the trade-offs (contraction, durability, cosmesis, donor-site burden) that drive graft selection.

Shared Healing Sequence

1. Plasmatic imbibition (~first 24–48 hrs): The graft has no vascular connection to the bed and survives by passive diffusion of oxygen and metabolites from plasma exudate. Fibrin secures the graft. Close apposition and immobilization are critical; thinner grafts tolerate this ischemic period better.
2. Inosculation (~day 2–4 onward): A capillary network proliferates and anastomoses form between preexisting graft vessels and recipient-bed vessels, restoring continuity and giving the graft a pink color.
3. Revascularization/angiogenesis (~day 3–7, maturing through ~day 10–12): New vessels grow in from the wound bed while native graft vasculature regresses and is replaced. Ingrowth of recipient vasculature predominates. Afferent/efferent flow is generally restored by roughly days 8–12, though perfusion continues to evolve for weeks.

Why Thickness Affects Healing

• STSG (epidermis + partial dermis): Thinner, lower metabolic demand, revascularizes faster and more reliably — “takes” more readily on marginal or larger beds.
• FTSG (epidermis + full dermis): More tissue to perfuse across the same diffusion distance, higher metabolic demand — requires a well-vascularized bed and meticulous immobilization.

Indications: When to Use Each

Factor STSG FTSG Best for Large wounds, burns, marginal/less vascular beds, temporary coverage Small wounds needing durable, cosmetically superior coverage Graft take More reliable Less forgiving; needs excellent bed Secondary contraction Greater (more wound contraction) Minimal — preferred over joints, hands, face Cosmesis / color match Poorer, can be shiny/dyschromic Superior; better texture and pigment match Durability Less durable More durable, better sensation return Donor site Heals spontaneously; can re-harvest Must be closed primarily; limits size Typical sites Trunk, extremities, burns Face (nose, eyelids, ear), fingertips, palmar surfaces

Practical Selection Summary

• Choose STSG when the priority is reliable coverage of a large area or a suboptimal bed.
• Choose FTSG when the priority is cosmesis, durability, and minimizing contraction in a small wound at a functionally or cosmetically sensitive site with a well-vascularized bed.

• Tumor Histology
  • Numerous histologic variants of PTC have been described based on architectural or cellular features
  • Acknowledgement of the tumor subtype is important:
    • As it can contribute to the risk stratification of individual tumors
  • The classic subtype of PTC and the follicular subtype of PTC (FVPTC) are associated with very favorable outcomes
  • More concerning histologic subtypes include:
    • Tall cell, hobnail subtype, and, perhaps to a lesser extent, columnar cell:
      • These tumors tend to present at an older age and with more advanced disease than is seen in classic PTC
  • These more aggressive histologic subtypes:
    • Also are associated with worse recurrence-free and disease-specific survival rates
• Tumor Size
  • Primary tumor size is closely associated with the outcome of PTC, including both 10-year recurrence and cancer-specific mortality rates
  • Cancer-specific mortality rates increase incrementally from 2% for tumors 8 cm
  • Furthermore, larger tumors are associated with a higher rate of locoregional and distant metastases
• Multifocality
  • Patients with PTC have a 32% to 45% chance of cancer elsewhere in the ipsilateral or contralateral lobe
  • Tumor multifocality is also found frequently in papillary thyroid microcarcinomas (PMCs)
  • Multifocal disease increases the risk of recurrence, particularly in patients who have had a lobectomy
  • With the current trend to performing lobectomy for the majority of low-risk cancers, some have raised concerns about the potential for increased recurrence rates
  • Indeed, some patients may develop recurrence in the remaining contralateral lobe, necessitating completion thyroidectomy at a later date:
    • Fortunately, it is the minority (7% at 10 years of follow-up) of patients who will require such an intervention
  • A large, long-term follow-up study of patients undergoing lobectomy for PTC:
    • 14.6% of whom had multifocal disease, demonstrated a recurrence-free 20-year survival rate of 95% in the opposite lobe, 91% for lymph node (LN) recurrence, and a disease-specific survival rate of 97.8%
  • Predictors of recurrence or worse disease-specific survival were:
    • Age
    • Primary tumor > 4 cm
    • Clinically apparent LNs
      • Suggesting that properly selected patients will have an excellent prognosis after lobectomy of PTC
  • The implications of tumor multifocality on survival are controversial:
    • Some studies have determined that multifocal disease does not increase the risk of disease-specific mortality
    • However, when distinguishing unilateral multifocal from bilateral disease, other studies have demonstrated that survival was lower for bilateral tumors
• Extrathyroidal Extension
  • Extrathyroidal extension (ETE) of tumor beyond the thyroid capsule into the perithyroidal soft tissues and adjacent structures:
    • May be seen in up to 40% of surgical specimens and is an important prognostic factor in PTC
  • The specific extent of ETE should be described on the surgical pathology report
  • Minimal ETE is defined as:
    • Microscopic visualization of tumor into the immediate perithyroidal soft tissues
  • In contrast, extensive ETE is described as:
    • Gross tumor extension into subcutaneous soft tissues, larynx, trachea, esophagus, or the recurrent laryngeal nerve (RLN)
    • The prognostic implications of ETE in differentiated thyroid cancer is controversial, which may stem largely from a failure to distinguish between these distinct degrees of tumor spread
    • It is generally accepted that tumor extension into the surrounding tissues:
      • Which is visible intraoperatively or on preoperative imaging:
        • Is associated with a worse prognosis
    • The implications of minimal ETE on outcomes, however, is less clear:
      • Some retrospective studies have demonstrated that minimal ETE is associated with higher rates of LN metastases
      • Other studies found recurrence rates in those with minimal ETE were dependent on primary tumor size
      • In contrast others have found that minimal ETE is not associated with increased recurrence or decreased survival
      • A recent systematic review and meta-analysis of the effects of minimal ETE on survival and recurrence demonstrated:
        • No influence of minimal ETE on disease-related mortality but did indicate an increased risk of recurrence in patients with minimal ETE
      • The absolute recurrence risk increase for patients with lymph node negative disease was from 2.2% to 3.5% and for patients with lymph node positive disease the increase was from 6.2% to 7%:
        • Suggesting that the effects of minimal ETE on absolute risk for disease recurrence was small
        • Indeed, the 8th edition of The American Joint Committee on Cancer/The Tumor, Node, and Metastases (AJCC/TNM) cancer staging system removed the minimal ETE definition and its influence on overall tumor stage
        • This omission is an acknowledgment of the negligible effects of minimal ETE on tumor-associated mortality
• Lymph Node Metastases
  • The incidence rates of cervical LN metastases identified at the time of initial surgery in patients with PTC varies widely, depending on the mode of nodal detection
  • Prophylactic LN dissections yield high rates of LN micrometastases (up to 65%)
  • Whereas gross nodal involvement detected by preoperative US or during surgery occurs in a smaller, but still substantial, percentage (20%) of patients
  • The manner of discovery is important as it is related to the prognostic significance of nodal involvement:
    • Those nodes incidentally identified on surgical pathology with microscopic tumor deposits:
      • Do not significantly alter risk of recurrence
    • Prophylactic nodal dissection, therefore, is not recommended as it does not lower recurrence-free survival and risks upstaging patients:
    • Resulting in unnecessary additional treatment
  • In contrast, grossly abnormal nodes:
    • Are associated with a worse recurrence-free survival:
      • Removal of these nodes is thus considered therapeutic
• The number of involved nodes:
  • Is also related to the recurrence risk
• Even with microscopic nodal deposits:
  • More than five involved nodes:
    • Carries a higher risk of recurrence compared with lower numbers of diseased nodes:
      • 7% to 21% and 3% to 8%
• The effects of LN metastases on survival is less clear:
• There are conflicting reports regarding cancer-specific mortality in the presence of nodal involvement
• An analysis of the Surveillance, Epidemiology, and End Results (SEER) database:
  • Determined that nodal metastases were associated with increased mortality only in those patients over the age of 45 years:
    • However, a more recent study of patients from the SEER database and the National Cancer Database (NCDB) of patients under the age of 45 years:
      • Found that increasing numbers of nodal metastases were associated with decreasing overall survival up to six nodes, after which more metastatic nodes conferred no additional mortality risk
• Distant Metastases
  • Although distant metastases are uncommon in PTC:
    • They are present in approximately 5% of patients at the time of initial diagnosis:
      • Another 2.5% to 5% will develop distant metastases after initial therapy
  • The most common sites of involvement are:
    • Lung (50%) and bone (25%):
      • Followed by both lung and bone (20%) and other tumor sites (5%)
    • One study found a 50% survival rate of 3.5 years:
      • However, subsets of patients have better survival rates, especially postpubertal children, those with microscopic metastases, and patients with iodine-avid tumors
    • Additional prognostic information about distant metastases may be gained by performing 2-[18F]fluoro-2-deoxy-D- glucose-positron emission tomography (18FDG-PET) /computed tomography (CT) scanning:
      • One study found an inverse relationship between survival and degree of 18FDG-PET avidity of the most active lesion as well as the number of (18FDG-PET)–avid lesions
      • Patients with a positive 18FDG-PET scan had a 7.28-fold increased risk of dying from thyroid cancer compared with patients who had a negative scan
• Oncogenes
  • The MAPK (mitogen-activated protein kinase) pathway:
    • Is an intracellular signaling cascade that results in:
      • Cell growth
      • Proliferation
      • Apoptosis
    • A mutation in one of these signaling components in the MAPK pathway is responsible for the majority of PTCs:
      • These mutations are almost always mutually exclusive:
        • Suggesting that a single molecular alteration is sufficient to drive oncogenesis
      • Detection of these mutations may be used to:
        • Identify malignancy on fine-needle aspiration (FNA)
        • To prognosticate for patients with thyroid cancer
        • To guide the systemic agent used in radioiodine-refractory disease
• BRAF
  • BRAF is a serine / threonine kinase in the MAPK signaling pathway:
    • That regulates cellular differentiation, proliferation, and survival
  • The BRAF V600E pathogenic variant:
    • Is the most common oncogene in sporadic PTC:
      • With an incidence of 36% to 69%
    • The presence of BRAF V600E is associated with:
      • Higher risk clinic-pathologic features, including:
      • LN metastases
      • ETE
      • Recurrence
      • Age-associated mortality
• The independent prognostic utility of a BRAF mutation remains in question, however
• With such a high prevalence of this pathogenic variant and the excellent outcomes in the majority of thyroid cancer patients, the specificity of BRAF for prognostication is limited:
  • Further, because BRAF is often associated with high-risk clinical features, it is difficult to discern what component of the poor outcomes seen with this pathogenic variant are due to the mutation itself, independent of the pathologic elements
• Indeed several studies attempting to determine whether BRAF serves as an independent predictor of recurrence have produced mixed results
• The identification of a BRAF mutation instead may provide:
  • Direction for the management of radioiodine refractory tumors:
    • A recent clinical trial aimed at redifferentiating noniodine-avid tumors:
      • Used a BRAF-inhibitor, dabrafenib:
        • 60% of patients exhibited new iodine uptake on diagnostic whole-body scans
        • After treatment with 5GBq of 88I at 3 months of follow-up, two patients had partial responses and four had stable disease
        • An ongoing trial is examining the effect of dabrafenib alone or in combination with a MEK inhibitor, trametinib:
          • In progressive, iodine-refractory, BRAF-mutated tumors (clinicaltrials.gov, NCT01723202)
• TERT
  • Newly described in thyroid cancers, telomerase reverse transcriptase (TERT) promoter mutations:
    • Are found in low frequency in lower risk PTC (9%)
    • Increasing in frequency in more advanced PTC (51%):
      • PDTC (40%)
      • ATC (54% to 73%)
  • Telomerase is responsible for adding tandem repeats of the TTAAGGG sequence to the end of chromosomes:
    • To maintain genome stability
  • Whereas these enzymes are highly expressed in germline and stem cells, expression is reduced or even repressed in somatic cells
  • The loss of telomeres during somatic cell division:
    • Results in cells entering senescence
  • Reactivation of telomerase leads to immortalization:
    • By way of unrestricted proliferation and inactivation of replicative senescence
• Although there are conflicting reports regarding the effect of a TERT mutation on prognosis in PTC:
  • A recent meta-analysis demonstrated that the presence of coexisting BRAF and TERT mutations was associated with a more aggressive clinical course and another study demonstrated higher mortality rates
  • Further study is needed to determine the feasibility of pharmacologic therapy targeting TERT mutations
• Age at Diagnosis
  • Age at the time of tumor diagnosis is one of the most important contributing factors to prognosis:
  • There is a trend of worsening cause-specific survival for each decade starting at age 60 compared with younger patients (less than 20 years old)
  • An analysis of the NCDB revealed an incremental increase in 10-year mortality:
    • By 30% to 50% per 5 year increment beginning at age 35 years
  • A recent study determined that the age-associated increasing risk of mortality was associated with BRAF mutational status:
    • This multi-institutional study found that age is a strong, continuous, and independent mortality risk factor in patients with a BRAF V600E mutation but not in those with wild-type BRAF
  • Older patients are also more likely to harbor more aggressive histologic subtypes
  • In patients with distant metastases:
    • Those over the age of 40 years are less likely to demonstrate iodine avidity in their lung metastases
  • Children and adolescents:
    • Are more likely to have a more advanced tumor stage at the time of diagnosis
      • Up to 80% harbor nodal involvement and 15% to 20% develop pulmonary metastases rates that are nearly double those seen in adults
      • Despite the extent of disease at the time of diagnosis, children generally have excellent outcomes
      • In one systematic review of pediatric patients with pulmonary metastases, a complete response to radioactive iodine (RAI) therapy was seen in up to 50% and disease-specific mortality was 2.7%

• NCCN Guidelines, Head and Neck Cancers (v2.2026) still base clinical staging definitions on AJCC 8th edition (ST-4 for p16-negative, ST-7 for p16-positive):
  • Version 9 is not yet incorporated
• Version 9 changes apply only to:
  • HPV-positive (p16+) oropharyngeal carcinoma
• The p16-negative oropharynx / hypopharynx system:
  • Is unchanged in the current NCCN tables
• T – Tumor:
  • TX – Primary tumor cannot be assessed
  • Tis – Carcinoma in situ
  • T1 – Tumor 2 cm or smaller in greatest dimension
  • T2 – Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
  • T3 – Tumor larger than 4 cm in greatest dimensión or extensión to lingual surface of epiglottis
  • T4 – Moderately advanced or very advanced local disease
    • T4a – Moderately advanced local disease
      • Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid muscle, hard palate, or mandible
    • T4b – Very advanced local disease
      • Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

• Lymph node metastases:
  • At presentation are common in OPSCC:
    • With over half of patients:
      • Having clinical or radiological evidence of cervical metastasis
    • Around a third of patients diagnosed as cN0:
      • Having pathologic evidence of lymph node metastasis
  • The lymphatic drainage from the oropharynx:
    • Is mainly to:
      • Levels II, III and IV
    • It also drains into:
      • The retropharyngeal (RP) nodes:
        • Which need to be considered in the assessment of disease in this area
        • The risk of metastasis to RP lymph nodes depends on subsite:
          • A meta-analysis of papers suggests risk of RP lymphadenopathy being:
            • 19% for soft palate
            • 12% for tonsil
            • 6% for base of tongue and
            • 21% to 57% for posterior pharyngeal wall tumors:
              • Including hypopharynx
      • The prognostic impact of positive RP lymph node metastasis is disputed:
        • Some authors showing an adverse impact:
          • And others not
  • A particular feature of OPSCC:
    • Is the propensity to metastasis to the contralateral neck:
      • This occurring in up to 30% of patients overall in one series:
        • The subsites in which this is mostly likely to occur are the:
          • Soft palate
          • Base of tongue
          • Posterior pharyngeal wall:
            • However:
              • Even tonsil cancers have an approximate rate:
                • Of contralateral nodal spread of 10%

• Palpable thyroid nodules increase in frequency throughout life:
  • Reaching a prevalence of about 5% in the U.S. population for individuals ≥50 years having palpable thyroid nodules
• Nodules are even more prevalent when the thyroid gland is examined at autopsy or surgery, or when using ultrasonography:
  • 50% of the thyroids studied have nodules:
    • Which are almost always benign
• New nodules develop at a rate of about 0.1% per year:
  • Beginning in early life
• They develop at a much higher rate (approximately 2% per year):
  • After exposure to head and neck irradiation
• Thyroid nodules are approximately four times more common in individuals assigned female at birth (AFAB) than in individuals assigned male at birth (AMAB)
• By contrast, thyroid carcinoma is uncommon:
  • For the U.S. population:
    • The lifetime risk of being diagnosed with thyroid carcinoma is:
      • 1.2%
    • It is estimated that approximately 43,720 new cases of thyroid carcinoma will be diagnosed in the United States in 2023
    • As with thyroid nodules:
      • Thyroid carcinoma occurs two to three times more often in individuals AFAB than in individuals AMAB
    • Thyroid carcinoma is currently the seventh most common malignancy diagnosed in individuals AFAB
    • The disease is also diagnosed more often in white North Americans than in African Americans
  • The main histologic types of thyroid carcinoma are:
    • Differentiated (including papillary, follicular, and oncocytic)
    • Medullary
    • Anaplastic:
      • Which is an aggressive undifferentiated tumor
  • Of 63,324 patients diagnosed with thyroid carcinoma from 2011 to 2015:
    • 89.8% had papillary carcinoma
    • 4.5% had follicular carcinoma
    • 1.8% had oncocytic carcinoma
    • 1.6% had medullary carcinoma
    • 0.8% had anaplastic carcinoma
• A population-based study of data collected by the International Agency for Research on Cancer from 1998 to 2012:
• Showed that the global incidence of papillary thyroid carcinoma (PTC) increased during this time
• Mortality rates for thyroid carcinoma are, in general, very low
• Differentiated thyroid carcinomas usually have an excellent prognosis:
  • With 10-year survival rates exceeding 90% to 95%
• In contrast, anaplastic thyroid carcinoma (ATC) is almost uniformly lethal
• However, since differentiated thyroid carcinomas represent more than 95% of all cases:
  • Most thyroid carcinoma deaths are from:
    • Papillary, follicular, and oncocytic carcinomas
• In 2023, it is estimated that approximately 2120 cancer deaths will occur among persons with thyroid carcinoma in the United States
• Though thyroid carcinoma occurs more often in individuals AFAB:
  • Mortality rates are lower for younger individuals AFAB
• Although the estimated incidence of thyroid carcinoma previously increased by an average of ~5% annually between 2004 and 2013:
  • The incidence rate has more recently stabilized:
    • Likely due to more conservative indications for thyroid biopsy and the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)
  • Because overall mortality has not dramatically increased since 1975 (1150 vs. 2060 deaths):
    • The previous increase in incidence may reflect, at least in part, earlier detection of subclinical disease (ie, small papillary carcinomas):
      • However, data show the incidence has increased by varying degrees across all tumor sizes and age groups
        • The stable age- and gender-adjusted mortality rate for thyroid carcinoma contrasts distinctly with the declining rates for other solid tumors in adults
• A cohort study of 2000 to 2016 data from U.S. cancer registries:
  • Showed an increase in incidence of aggressive PTC
• In addition, an analysis of 1992 to 2018 SEER data showed that there is no evidence of an improvement in disease-specific survival (DSS) in patients with distantly metastatic differentiated thyroid cancer

• Gross extrathyroidal extension (ETE):
  • Is defined as direct tumor extension beyond the thyroid capsule into perithyroidal structures:
    • Identified clinically, on imaging, or on gross pathology:
      • This is the defining feature of locally advanced thyroid cancer
  • It must be distinguished from microscopic (minimal) ETE (mETE):
    • Which is detected only histologically and, because of poor interobserver reproducibility (kappa ≈ 0.14) and negligible independent prognostic weight:
      • Was removed from AJCC 8th edition T-staging in 2017
    • Only gross ETE (gETE) now drives T-category and stage
• Management is stratified by which structure is involved:
  • Strap muscles vs. recurrent laryngeal nerve (RLN), trachea, larynx, esophagus vs. prevertebral fascia / great vessels:
    • With the central principle that complete gross resection with acceptable morbidity, followed by risk-adapted RAI and / or EBRT:
      • Offers the best locoregional control
• Definitions and classification of ETE
  Microscopic (minimal / minor) ETE (mETE):
  • Tumor extension into immediate perithyroidal soft tissue or skeletal muscle:
    • Seen only on histology:
      • Not appreciated clinically or grossly
  • Associated with a 3% to 9% recurrence risk:
    • With no consistent independent effect on disease-specific (DSS) or overall survival (OS)
• Gross (extensive) ETE:
  • Macroscopic invasion evident at surgery, on preoperative imaging, or on gross specimen exam:
    • Into strap muscles (T3b) or into subcutaneous soft tissue, larynx, trachea, esophagus, RLN (T4a), or prevertebral fascia / carotid / mediastinal vessels (T4b)
  • Recurrence risk of 23% to 40%
  • Disease-specific mortality of 23% to 52%
  • The following Kaplan-Meier curves illustrate the sharp prognostic divergence:
    • Recurrence-free survival for mETE overlaps with no ETE (both near 100%), whereas gETE falls to roughly 35%

• Epidemiology:
  • ETE is present in roughly:
    • 10% to 15% of thyroid cancers at presentation:
      • Up to ~ 23.5% of papillary carcinomas in some pathologic series:
        • Most commonly involving the strap muscles
  • Frank aerodigestive-tract invasion is less common:
    • Tracheal invasion occurs in an estimated:
      • 1% to 8% of thyroid carcinomas
    • RLN is involved in:
      • 33% to 61% of the subset of tumors classified as “invasive”
    • Overall, roughly 10% to 15% of DTC patients have locoregionally advanced disease:
      • Carrying substantially higher recurrence and mortality risk
• Prognosis:
  • Gross ETE (gETE):
    • Is an independent predictor of reduced disease-specific survival (DSS), higher local recurrence, and greater risk of nodal and distant metastasis
  • In a SEER cohort of > 107,000 patients:
    • Cancer-specific mortality rates per 1,000 person-years rose stepwise:
      • 1.4 (thyroid-confined)
      • 5.1 (mETE)
      • 29.7 (gETE)
  • Among invaded structures, tracheal invasion carries particular weight:
    • In one T4 DTC series it was the only factor significantly associated with recurrence, and airway obstruction from local spread accounts for a substantial share of DTC deaths:
      • Coexisting macroscopic extranodal extension further worsens outcomes:
        • With unresectable macroscopic ENE dropping 5-year DSS to ~ 82%
• Staging (AJCC 8th edition):
  • The T-category is anchored to the depth of gross ETE, and staging is heavily age-dependent (cutoff 55 years):
    • Below is the NCCN reproduction of the AJCC 8th edition TNM definitions for differentiated (and anaplastic) carcinoma

• Management by structure involved:
  • Surgery is the mainstay:
    • The goal is complete gross tumor removal (R0 / R1) balanced against functional morbidity:
      • Followed by risk-adapted adjuvant therapy
  • A multidisciplinary team at a high-volume center:
    • Is recommended for bulky or viscerally invasive disease
  • The overall airway / aerodigestive management framework hinges on:
  • Whether invasion is:
    • Extraluminal:
      • Amenable to shave excision versus
    • Intraluminal:
      • Requiring formal resection

• Strap muscles (T3b):
  • En bloc resection of the involved strap muscle with the thyroid:
    • This is well tolerated and does not compromise function
• Recurrent laryngeal nerve (T4a):
  • Management is dictated by preoperative vocal cord function and the extent of invasion:
    • Functioning nerve with tumor adherent /encasing but mobile cords:
      • Attempt preservation:
        • Shave / partial-layer resection to remove all gross disease while keeping neural continuity, followed by adjuvant therapy
        • Preserving a functioning nerve, even at the cost of microscopic residual,, does not worsen survival
    • Nonfunctioning nerve (preoperative paralysis) and / or complete encasement:
      • Resection of the involved segment is appropriate:
        • Ideally with immediate reconstruction (direct / end-to-end anastomosis, ansa cervicalis–to–RLN anastomosis, or nerve grafting) to restore phonatory and swallowing function
        • Keep in mind contralateral nerve, want to avoid tracheostomy
      • Intraoperative nerve monitoring (NIM) and staged contralateral surgery help avoid bilateral paralysis:
        • If signal is lost on the first side during planned total thyroidectomy, defer the contralateral lobe
  • The following decision algorithm summarizes the RLN approach based on cord mobility and neural continuity:

• Trachea (T4a):
  • Extent of resection follows depth of invasion:
    • Shin classification
  • Superficial invasion not penetrating perichondrium / cartilage:
    • Tangential shave excision achieves local control up to ~ 95%:
      • Though positive-margin and recurrence rates are higher:
        • So adjuvant therapy is typically added
  • Intraluminal invasion or significant cartilage involvement:
    • Circumferential sleeve resection with end-to-end anastomosis:
      • Feasible for defects < ~ 5 cm / up to ~ half circumference)
    • Window resection with flap reconstruction is preferred for durable local control
    • Systematic review of 656 patients undergoing (crico)tracheal resection reported ~ 2% perioperative mortality, ~ 27% complications (mainly RLN palsy), 4% permanent tracheostomy, and 5-year DSS of 75.8% to 90%
• Larynx / esophagus (T4a):
  • Partial-thickness (“shave”) resection of the esophageal muscular wall or partial laryngeal / tracheal windowing is preferred when the lumen / mucosa is not breached
  • Transmural esophageal or full laryngeal involvement may require segmental esophageal resection with flap reconstruction, partial / total laryngectomy, or laryngopharyngectomy — reserved for highly selected cases
• Prevertebral fascia / carotid / mediastinal vessels (T4b):
  • Often unresectable or borderline resectable:
    • Options include cervical exenteration at expert centers in selected patients, or non-surgical management with EBRT ± systemic therapy when curative resection is not feasible or acceptable
• Adjuvant therapy (RAI and EBRT):
  • After surgery, the NCCN algorithm:
    • Branches on presence of gross residual disease, resectability, and RAI avidity
  • For locoregionally invasive disease or rapid progression:
    • EBRT or systemic therapy is considered

• RAI:
  • Indicated for iodine-avid residual / high-risk disease and is preferred when uptake is present:
    • Many invasive tumors, however, are relatively iodine-refractory
• EBRT:
  • The 2025 ATA guidelines state that adjuvant EBRT may be considered in select DTC patients with high-risk features for locoregional progression:
    • Aggressive histology
    • gETE
    • Positive margins
    • Visceral / soft-tissue invasion:
      • Especially when future progression would not be salvageable surgically:
        • Weighing improved locoregional relapse-free survival against toxicity and absence of a demonstrated overall survival benefit
  • EBRT ± concurrent chemotherapy:
    • Is also an option for gross residual or locally advanced unresectable disease
    • Retrospective and propensity-matched data show:
      • Improved locoregional control:
        • e.g., 10-year local failure-free survival 88% for EBRT+RAI vs. 72% RAI alone in pT4a PTC
        • LRR reduced from 51% to 8% after tracheal shave without consistent OS gain
  • Typical adjuvant EBRT doses for non-anaplastic thyroid cancer are:
    • 60 to 66 Gy to microscopic disease / thyroid bed
    • 50 to 56 Gy to elective nodal regions
    • 66 to 70 Gy for gross / unresectable disease:
      • Delivered by IMRT
  • For BRAF V600E–mutated anaplastic carcinoma:
    • Neoadjuvant dabrafenib / trametinib and multimodal EBRT / chemoradiation apply on separate ATC-specific algorithms
• References:
  • Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association Management Guidelines for Adult Patients With Differentiated Thyroid Cancer. Thyroid. 2025.
  • Sessa L, De Crea C, Voloudakis N, et al. Single Institution Experience in the Management of Locally Advanced (pT4) Differentiated Thyroid Carcinomas. Ann Surg Oncol. 2024.
  • Scognamiglio T. Aggressive follicular cell derived thyroid carcinoma: what do you need from the pathologist. Virchows Arch. 2026.
  • Xu B, Ghossein RA. Crucial parameters in thyroid carcinoma reporting – challenges, controversies and clinical implications. Histopathology. 2018.
  • Xu B, Ghossein RA. Crucial parameters in thyroid carcinoma reporting – challenges, controversies and clinical implications. Histopathology. 2018.
  • Shindo ML, Caruana SM, Kandil E, et al. Management of invasive well-differentiated thyroid cancer: An American Head and Neck Society consensus statement. Head Neck. 2014.
  • Li M, Tang Q, Yang X, et al. Application of modified spiral tracheoplasty in thyroid carcinoma with trachea invasion: a retrospective analysis of 15 cases. World J Surg Oncol. 2024.
  • Laskar SG, Mohanty S, Sinha S, et al. Adjuvant External Beam Radiotherapy in Differentiated Thyroid Cancers: An Audit of Clinical Practice, Adapting to New Evidence. Head Neck. 2025.
  • Yuan SS, Zhang XR, Yu XQ, et al. Prediction model for extrathyroidal extension in thyroid papillary carcinoma based on ultrasound radiomics. Sci Rep. 2025.
  • Liu Z, Huang Y, Chen S, et al. Minimal Extrathyroidal Extension Affects the Prognosis of Differentiated Thyroid Cancer: Is There a Need for Change in the AJCC Classification System? PLoS One. 2019. 12.
  • Liu Y, Zhang X, Liu J, et al. Prognostic significance of the extent of extranodal extension in patients with pN1b papillary thyroid carcinoma: a retrospective cohort study. Eur Arch Otorhinolaryngol. 2026.
  • National Comprehensive Cancer Network. Thyroid Carcinoma. NCCN Clinical Practice Guidelines in Oncology. 2026.
  • Perrier ND, Brierley JD, Tuttle RM. Differentiated and Anaplastic Thyroid Carcinoma: Major Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin. 2018.
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  • Rai S, Agarwal M, Bansal K, et al. Intraoperative management of recurrent laryngeal nerve invasion in thyroid carcinoma: Oncologic and functional outcomes with a surgical decision algorithm. Eur Arch Otorhinolaryngol. 2026.
  • Wang S, Li S, Yang X, et al. Surgical treatment for patients with papillary thyroid carcinoma invading the cervical trachea. Eur Arch Otorhinolaryngol. 2026.
  • Piazza C, Lancini D, Tomasoni M, et al. Tracheal and Cricotracheal Resection With End-to-End Anastomosis for Locally Advanced Thyroid Cancer: A Systematic Review of the Literature on 656 Patients. Front Endocrinol (Lausanne). 2021.
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• Before removal of thyroid cancer:
  • It is critical to perform a thorough evaluation:
    • To determine the extent of disease
• Preoperative imaging should include:
  • A comprehensive ultrasound (US) of the neck to examine the contralateral lobe of the thyroid, the central neck compartments, and the lateral neck lymph nodes (LN):
    • Such imaging may change the surgical approach in up to 40% of cases
• The anterior neck is divided into seven contiguous compartments in which thyroid cancer metastatic LN spread occurs
• The central neck compartment (level VI) contains the thyroid and poses the greatest challenge to clinicians when deciding the optimal surgery:
  • It is bordered laterally by the carotid arteries, inferiorly by the clavicles, and superiorly by the hyoid bone
  • Level VI is the compartment that is most frequently involved with LN metastases:
    • But sonographic identification of diseased nodes is hampered by poor preoperative sensitivity:
      • The intact thyroid gland obscures visualization of the majority of nodal metastases
• The lateral neck is further subdivided into four compartments lateral to the carotid:
  • Level IV is bordered laterally by the sternocleidomastoid (SCM), inferiorly by the clavicle, and superiorly by the cricoid cartilage
  • Level III, located immediately cephalad to level IV, extends superiorly to the carotid bifurcation
  • Level II is located below the mandible and extends to the hyoid bone
  • Level V nodes are located in the posterior triangle, lateral to the lateral edge of the SCM.
• The presence of malignancy in sonographically suspicious nodes:
  • Can be confirmed with FNA for cytologic analysis and measurement of thyroglobulin (Tg) in the needle washout
• If advanced, bulky nodal disease is identified on US, or the patient has clinical signs or symptoms of advanced disease (hoarseness, hemoptysis, a nonmobile thyroid mass):
  • CT or magnetic resonance imaging (MRI) of the neck may be considered to search for additional metastases in areas that cannot be visualized sonographically, including within the mediastinum, at the skull base, and posterior to the trachea

• Oropharyngeal tumor histological types:
  • Squamous cell carcinoma (SCC):
    • Is the most common malignancy of the oropharynx:
      • Making up 90% of the tumors in this region
  • Non-Hodgkin’s lymphomas:
    • Accounts for 8% of tumors in these region
  • Minor salivary gland tumors:
    • Account for 2% of tumors in these region
• With regard to squamous cell carcinoma:
  • The most frequent locations of affected sites is:
    • Tonsil / lateral wall:
      • 60% of the cases
    • Tongue base:
      • 25% of the cases
    • Soft palate:
      • 10% of the cases
    • Posterior pharyngeal wall:
      • 5% of the cases

• Two Distinct Disease Entities:
  • OPSCC is now classified as two biologically and prognostically distinct diseases:
    • Based on high-risk HPV status: 
      • HPV-associated (p16-positive) and HPV-independent (p16-negative) carcinoma:
        • A division formalized in the WHO classification and the AJCC 8th edition staging system
  • HPV-associated tumors:
    • Carry a markedly better prognosis:
      • With 8-year overall survival of 70.9% versus 30.2% for HPV-negative disease in RTOG 0129:
        • HR 0.30; 95% CI 0.21–0.42
• Histopathology:
  • HPV-Associated (
  • ) OPSCC:
    • These tumors arise from the specialized reticulated epithelium lining the tonsillar crypts rather than the surface mucosa
    • Characteristic features include:
      • Nonkeratinizing growth:
        • Lobules and sheets of immature basaloid cells with high nuclear-to-cytoplasmic ratios and hyperchromatic nuclei; absent or minimal keratinization
      • Basaloid cytology:
        • Resembling deep crypt epithelium, with lobular / endophytic growth and smooth pushing borders
      • Permeating tumor-infiltrating lymphocytes:
        • Within and around tumor nests
      • Absence of surface dysplasia:
        • Dysplasia is confined to crypts
      • Cystic nodal metastases:
        • Which can mimic branchial cleft cysts
    • In a 4-year prospective study of 435 OPSCCs:
      • Strictly defined nonkeratinizing morphology had a 99.1% positive predictive value for p16 positivity and 100% PPV for HR-HPV mRNA positivity
      • A “nonkeratinizing with maturation” (hybrid) intermediate pattern is p16-positive in ~92% of cases
  • HPV-Independent (Keratinizing) OPSCC:
    • These resemble conventional keratinizing SCC of the upper aerodigestive tract:
      • With keratin pearl formation
      • Individual cell keratinization
      • Intercellular bridges
      • Progressive squamous maturation
      • Origin from dysplastic surface epithelium
    • Molecularly they are characterized by high rates of:
      • TP53 mutation
      • CCND1 (cyclin D1) copy-number gains
      • 9p21 / CDKN2A loss
• A Note on Grading:
  • Although HPV-associated tumors appear “poorly differentiated” by conventional criteria:
    • They paradoxically carry the best prognosis:
      • Westra has argued they may be best viewed as well-differentiated given their resemblance to native crypt epithelium
  • Both the 2018 CAP guideline and its 2025 update recommend against providing traditional grade / differentiation status for HPV-associated OPSCC:
    • Instead recommend reporting the WHO histologic subtype
  • Conventional grading (G1 to G4) still applies to HPV-independent OPSCC
  • Certain morphologic features retain prognostic value even within p16-positive disease:
    • Tumor cell anaplasia (nuclei ≥ 5 lymphocyte diameters) and multinucleation:
      • Independently predicted worse disease-specific survival (HR 9.9 and 11.9, respectively), and “non-classic” HPV-positive morphology was associated with poorer 5-year survival (58.4% vs 83.9%)
    • Keratinization:
      • Independently predicts worse survival

• Histologic Variants:
  • Basaloid SCC:
    • Is a mixed entity resolvable by HPV status:
      • HPV-positive:
        • Younger patients
        • p16+ / p53−
        • Prognosis – favorable
      • HPV-negative:
        • Older patients
        • Tobacco / alcohol-related
        • p53 overexpression
        • Biology – aggressive
  • Lymphoepithelial-like carcinoma:
    • Requires mandatory dual HPV and EBV testing:
      • As it closely mimics metastatic nasopharyngeal carcinoma
• HPV / p16 Testing:
  • Who to Test:
    • All patients with newly diagnosed OPSCC should undergo HR-HPV testing, regardless of histologic subtype:
      • A strong CAP recommendation, endorsed by ASCO and listed as required in NCCN workup
    • Testing may be performed on the:
      • Primary tumor, a nodal metastasis, or FNA of a cervical node
    • Routine testing is not recommended for:
      • Nonsquamous oropharyngeal or non-oropharyngeal head and neck carcinomas (except sinonasal)
    • p16 IHC — the First-Line Test:
      • p16 immunohistochemistry is the recommended primary test:
        • Positivity requires:
          •  ≥ 70% nuclear AND cytoplasmic expression with at least moderate-to-strong intensity:
            • Typically in a confluent / block-like pattern
      • The E6H4 clone is most widely used and validated
      • With these criteria:
        • Sensitivity for transcriptionally active HR-HPV approaches 100% with specificity of ~ 85% to 95% in the oropharynx
      • Cases with 50% to 70% staining are equivocal and warrant HPV-specific testing
      • p16 and HPV may be used interchangeably only within the oropharynx
    • HPV-Specific (Direct) Testing:
      • The 2025 CAP update expanded indications for confirmatory HPV-specific testing beyond p16 IHC:

• HPV-specific testing should be performed in:
  • Low-prevalence geographic regions
  • Equivocal p16 staining
  • Discrepancy between p16 and morphology (e.g., p16+ but keratinizing)
  • Large multisite tumors
  • Non-tonsillar / non-base-of-tongue subsites
  • Clinical trials
  • SCC of unknown primary
• Discordant Results:
  • p16+ / HPV− discordance occurs in ~ 4% to 20% of cases:
    • In the multinational HNCIG-EPIC-OPC analysis (n=7,654):
      • Discordant patients had intermediate prognosis:
        • Significantly worse than double-positive and better than double-negative: 

• This has direct implications for de-escalation:
  • As p16+ / HPV− tumors may be misclassified and inappropriately de-escalated
• AJCC 8th Edition Staging:
  • The 8th edition established separate staging systems for p16-positive (HPV-mediated) and p16-negative OPSCC, based on the ICON-S validation study:
    • T Classification
      For p16+:
      • T0 is included, Tis is excluded, and T4 is a single category (no T4a / T4b:
        • Because T4a and T4b survival curves were indistinguishable
    • For p16−:
      • Tis is included, T0 is excluded, and T4 is subdivided into T4a (moderately advanced) and T4b (very advanced)
    • N Classification — The Most Divergent Element:
      • p16+ OPSCC uses separate clinical and pathological N criteria, and ENE is not part of either:
        • p16+ clinical N (laterality / size):
          • cN1 = ipsilateral node(s) ≤ 6 cm
          • cN2 = contralateral / bilateral ≤ 6 cm
          • cN3 = any node > 6 cm 
        • p16+ pathological N (node count):
          • pN1 = ≤ 4 positive nodes
          • pN2 = > 4 positive nodes 
      • p16− uses the traditional detailed system incorporating size, number, laterality, and ENE (N3b = clinically overt ENE)
  • Prognostic Stage Groups:
    • For p16+, only Stages I to IV exist, and Stage IV is reserved for M1 disease only: 
      • Clinical:
        • Stage I (T0 to T2 N0 to N1)
        • Stage II (T0 to T2 N2 or T3 N0 to N2)
        • Stage III (N3 or T4)
        • Stage IV (M1)
      • Pathological:
        • Stage I (T0 to T12 pN0 to N1)
        • Stage II (T0 to T2 pN2 or T3 to T4 pN0 to N1)
        • Stage III (T3 to T4 pN2)
        • Stage IV (M1)
    • For p16−, the traditional Stage 0 to IVC framework is retained
  • The complete AJCC 8th edition staging tables from the NCCN Guidelines for both p16+ and p16− disease are shown below:
    Table 4: American Joint Committee on Cancer (AJCC) TNM Staging System for HPV-Mediated (p16+) Oropharyngeal Cancer (8th ed., 2017) — NCCN Guidelines® — Head and Neck Cancers p. 135 (v2.2026)
    NCCNMay 11, 2026
    Table 3: TNM Staging System for the Oropharynx (p16-) and Hypopharynx (8th ed., 2017) — NCCN Guidelines® — Head and Neck Cancers p. 132 (v2.2026)
    NCCNMay 11, 2026
    TNM Staging System for the Oropharynx (p16-) and Hypopharynx (8th ed., 2017) — NCCN Guidelines® — Head and Neck Cancers p. 134 (v2.2026)
    NCCNMay 11, 2026
    Prognostic Impact
    The 8th edition downstages ~93% of HPV+ patients, with most Stage IVA (7th edition) patients reclassified as Stage I. [37]Prognostic discrimination improved substantially (concordance index 0.621→0.656 clinical; 0.640→0.663 pathological). [38]The validation Kaplan-Meier curves demonstrate that overlapping 7th-edition survival curves separate cleanly under the 8th edition:
    
    
    Figure 3. Observed 3‐year overall survival for patients with human papillomavirus (HPV)‐positive oropharyngeal cancer based on seventh and eighth edition staging manual.
    
    
    
  • Stages I and II in p16+ disease do not consistently separate on survival, and > 80% of pathologically staged cases fall into Stage I, creating wide within-group hazard variance
  • ENE — omitted from the formal p16+ classification — remains prognostically important (HR 3.40 for OS) and an NCCN adverse feature guiding adjuvant therapy
  • The proposed AJCC 9th edition (AJCC9V) reincorporates pathological ENE and refines node-count thresholds
  • p16+ non-tonsillar / non-base-of-tongue tumors may be inappropriately downstaged, as their favorable prognosis is less well established
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