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• 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.
  • Patel R. Thyroid. In: Essential Cases in Head and Neck Oncology. 2022.
  • Fundakowski CE, Hales NW, Agrawal N, et al. Surgical management of the recurrent laryngeal nerve in thyroidectomy: American Head and Neck Society Consensus Statement. Head Neck. 2018.
  • Perros P, Boelaert K, Colley S, et al. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf). 2014.
  • Masuoka H, Miyauchi A. Intraoperative Management of the Recurrent Laryngeal Nerve Transected or Invaded by Thyroid Cancer. Front Endocrinol (Lausanne). 2022.
  • 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.
  • Mercader-Cidoncha E, Zaraín-Obrador L, Lasso JM, Simón-Adiego C. Surgical Resources in Advanced Thyroid Cancer Treatment With Aerodigestive Tract Invasion. Surg Oncol. 2023.
  • Scharpf J, Tuttle M, Wong R, et al. Comprehensive management of recurrent thyroid cancer: An American Head and Neck Society consensus statement. Head Neck. 2016.
  • Piazza C, Lancini D, Paderno A. Cervical Exenteration and Its Variants for Locally Advanced Thyroid Cancer: When, Why, and How? Curr Opin Otolaryngol Head Neck Surg. 2023.
  • Kiess AP, Agrawal N, Brierley JD, et al. External-beam radiotherapy for differentiated thyroid cancer locoregional control: A statement of the American Head and Neck Society. Head Neck. 2016.
  • Kawamoto T, Shikama N, Fukumori T, Hoshi M, Yamada T. Propensity score matching analysis of adjuvant external-beam radiotherapy for the treatment of papillary thyroid carcinoma with other organ invasions. Endocrine. 2023.
  • 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.

• 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
• References:
  
  1.Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline Update.Archives of Pathology & Laboratory Medicine. 2025.Lewis JS, Beadle B, Bishop JA, et al.Guideline
  
  
  
  
  
  
  
  2.Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists.Archives of Pathology & Laboratory Medicine. 2018. Lewis JS, Beadle B, Bishop JA, et al.Guideline
  
  3.Head and Neck Cancer.The New England Journal of Medicine. 2020. Chow LQM.Review
  
  
  
  
  
  
  
  4.HPV-associated Head and Neck Cancer: A Virus-Related Cancer Epidemic.The Lancet. Oncology. 2010. Marur S, D’Souza G, Westra WH, Forastiere AA.Review
  
  
  
  
  
  
  
  5.Histologic Typing in Oropharyngeal Squamous Cell Carcinoma: A 4-Year Prospective Practice Study With P16 and High-Risk HPV mRNA Testing Correlation.The American Journal of Surgical Pathology. 2016. Gondim DD, Haynes W, Wang X, et al.
  
  6.HPV-related Squamous Cell Carcinoma of Oropharynx: A Review.Journal of Clinical Pathology. 2020. Rahimi S.Review
  
  7.Ciliated HPV-related Carcinoma: A Well-Differentiated Form of Head and Neck Carcinoma That Can Be Mistaken for a Benign Cyst.The American Journal of Surgical Pathology. 2015. Bishop JA, Westra WH.Case
  
  8.Comparison of Clinical, Radiological and Morphological Features Including the Distribution of HPV E6/­E7 Oncogenes in Resection Specimens of Oropharyngeal Squamous Cell Carcinoma.Oral Oncology. 2018. Channir HI, Kiss K, Rubek N, et al.
  
  9.Association of Cystic Neck Metastases and Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma.Archives of Pathology & Laboratory Medicine. 2009. McHugh JB.Case
  
  10.Human Papillomavirus-Related Head and Neck Squamous Cell Carcinoma Variants.Seminars in Diagnostic Pathology. 2015. El-Mofty SK.Review
  
  11.Histopathologic Risk Factors in Oral and Oropharyngeal Squamous Cell Carcinoma Variants: An Update With Special Reference to HPV-related Carcinomas.Medicina Oral, Patologia Oral Y Cirugia Bucal. 2014. El-Mofty SK.Review
  
  12.Detection of Human Papillomavirus DNA and Oncoprotein Overexpression Are Associated With Distinct Morphological Patterns of Tonsillar Squamous Cell Carcinoma.The American Journal of Pathology. 1998. Wilczynski SP, Lin BT, Xie Y, Paz IB.
  
  13.Stratification of HPV-associated and HPV-negative Oropharyngeal Squamous Cell Carcinomas Based on DNA Methylation Epigenotypes.International Journal of Cancer. 2020. Nakagawa T, Matsusaka K, Misawa K, et al.
  
  14.Identification of Prognostic Molecular Biomarkers in 157 HPV-positive and HPV-negative Squamous Cell Carcinomas of the Oropharynx.International Journal of Cancer. 2019. Dogan S, Xu B, Middha S, et al.
  
  15.Head and Neck Cancers.National Comprehensive Cancer Network. Updated 2026-05-12.Guideline
  
  16.Tumor Cell Anaplasia and Multinucleation Are Predictors of Disease Recurrence in Oropharyngeal Squamous Cell Carcinoma, Including Among Just the Human Papillomavirus-Related Cancers.The American Journal of Surgical Pathology. 2012. Lewis JS, Scantlebury JB, Luo J, Thorstad WL.
  
  17.Histological and Genetic Criteria Define a Clinically Relevant Subgroup of HPV-positive Oropharyngeal Carcinoma.Oral Oncology. 2025. Suchan M, Wuerdemann N, Wagner S, et al.
  
  18.Association of Keratinization With 5-Year Disease-Specific Survival in Oropharyngeal Squamous Cell Carcinoma.JAMA Otolaryngology– Head & Neck Surgery. 2015.Cooper T, Biron VL, Adam B, et al.Observational
  
  
  
  
  
  
  
  
  
  
  
  
  
  19.p16 overexpression and Rb loss correlate with high‐risk HPV infection in oropharyngeal squamous cell carcinoma.Histopathology. 2021. Jiromaru R, Yamamoto H, Yasumatsu R, et al.
  
  20.Utility of p16 and HPV testing in oropharyngeal squamous cell carcinoma: An institutional review.Diagnostic Cytopathology. 2021. Abdelhakam DA, Huenerberg KA, Nassar A.
  
  21.Keratinizing-Type Squamous Cell Carcinoma of the Oropharynx: P16 Overexpression Is Associated With Positive High-Risk HPV Status and Improved Survival.The American Journal of Surgical Pathology. 2014. Cai C, Chernock RD, Pittman ME, et al.
  
  22.Basaloid Squamous Cell Carcinoma of the Head and Neck Is a Mixed Variant That Can Be Further Resolved by HPV Status.The American Journal of Surgical Pathology. 2008. Begum S, Westra WH.
  
  23.Human Papillomavirus-Positive Basaloid Squamous Cell Carcinomas of the Upper Aerodigestive Tract: A Distinct Clinicopathologic and Molecular Subtype of Basaloid Squamous Cell Carcinoma.Human Pathology. 2010. Chernock RD, Lewis JS, Zhang Q, El-Mofty SK.
  
  24.Basaloid Squamous Cell Carcinoma of the Head and Neck: Role of HPV and Implication in Treatment and Prognosis.Journal of Clinical Pathology. 2010. Thariat J, Badoual C, Faure C, et al.Review
  
  25.Lymphoepithelial-Like Carcinoma of the Oropharynx: A Morphologic Variant of HPV-related Head and Neck Carcinoma.The American Journal of Surgical Pathology. 2010. Singhi AD, Stelow EB, Mills SE, Westra WH.
  
  26.Undifferentiated Carcinoma of the Oropharynx: A Human Papillomavirus-Associated Tumor With a Favorable Prognosis.Modern Pathology : An Official Journal of the United States and Canadian Academy of Pathology, Inc. 2011. Carpenter DH, El-Mofty SK, Lewis JS.
  
  27.Papillary Squamous Cell Carcinoma of the Head and Neck: Clinicopathologic and Molecular Features With Special Reference to Human Papillomavirus.The American Journal of Surgical Pathology. 2013. Mehrad M, Carpenter DH, Chernock RD, et al.
  
  28.Human Papillomavirus-Related Head and Neck Adenosquamous Carcinoma: A Systematic Review and Individual Patient Data Meta-Analysis.Oral Oncology. 2021. Fiacchini G, Benettini G, Tricò D, et al.SR
  
  29.Human Papillomavirus Testing in Head and Neck Carcinomas: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists Guideline.Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2018. Fakhry C, Lacchetti C, Rooper LM, et al.Guideline
  
  
  
  
  
  
  
  30.In Situ Hybridization for High-Risk HPV E6/­E7 mRNA Is a Superior Method for Detecting Transcriptionally Active HPV in Oropharyngeal Cancer.Human Pathology. 2019. Randén-Brady R, Carpén T, Jouhi L, et al.
  
  31.Evaluation of the Efficacy of the 4 Tests (P16 Immunochemistry, Polymerase Chain Reaction, DNA, and RNA in Situ Hybridization) to Evaluate a Human Papillomavirus Infection in Head and Neck Cancers: A Cohort of 348 French Squamous Cell Carcinomas.Human Pathology. 2018. Augustin J, Outh-Gauer S, Mandavit M, et al.
  
  32.Diagnostic Accuracy of P16INK4a Immunohistochemistry in Oropharyngeal Squamous Cell Carcinomas: A Systematic Review and Meta-Analysis.International Journal of Cancer. 2017. Prigge ES, Arbyn M, von Knebel Doeberitz M, Reuschenbach M.SR
  
  33.Prognostic Implications of P16 and HPV Discordance in Oropharyngeal Cancer (HNCIG-EPIC-OPC): A Multicentre, Multinational, Individual Patient Data Analysis.The Lancet. Oncology. 2023. Mehanna H, Taberna M, von Buchwald C, et al.Observational
  
  
  
  
  
  
  
  
  
  
  
  
  
  34.Head and Neck Cancers-Major Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual.CA: A Cancer Journal for Clinicians. 2017. Lydiatt WM, Patel SG, O’Sullivan B, et al.
  
  35.Development and Validation of a Staging System for HPV-related Oropharyngeal Cancer by the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S): A Multicentre Cohort Study.The Lancet. Oncology. 2016. O’Sullivan B, Huang SH, Su J, et al.Observational
  
  
  
  
  
  
  
  
  
  
  
  
  
  36.Derivation and Validation of the AJCC9V Pathological Stage Classification for HPV-positive Oropharyngeal Carcinoma: A Multicentre Registry Analysis.The Lancet. Oncology. 2025. Ho AS, Huang SH, O’Sullivan B, et al.Observational
  
  
  
  
  
  
  
  
  
  
  
  
  
  37.Utilizing the AJCC 8th Staging to Discriminate Survival Outcomes in HPV-associated Oropharyngeal Squamous Cell Carcinoma.Anticancer Research. 2024. Kim SI, Lee JW, Eun YG, Lee YC.
  
  38.Validation of the eighth edition American Joint Committee on Cancer staging system for human papillomavirus‐associated oropharyngeal cancer.Head & Neck. 2018. Cramer JD, Hicks KE, Rademaker AW, Patel UA, Samant S.Observational
  
  39.Comparison of the Seventh and Eighth Edition of American Joint Committee on Cancer (AJCC) Staging for Selected and Nonselected Oropharyngeal Squamous Cell Carcinomas.The Oncologist. 2022. Vijayvargiya P, Trivedi S, Rupji M, et al.
  
  40.Extracapsular Extension of Neck Nodes and Absence of Human Papillomavirus 16-Dna Are Predictors of Impaired Survival in P16-Positive Oropharyngeal Squamous Cell Carcinoma.Cancer. 2020. Freitag J, Wald T, Kuhnt T, et al.
  
  41.Survival of Patients With Oropharyngeal Squamous Cell Carcinomas (OPSCC) in Relation to TNM 8 – Risk of Incorrect Downstaging of HPV-mediated Non-Tonsillar, Non-Base of Tongue Carcinomas.European Journal of Cancer. 2020. Marklund L, Holzhauser S, de Flon C, et al.

• Surgery is the initial treatment for most thyroid cancers and is often curative for those with low-risk disease
• Historically, the majority of cancers measuring greater than 1 cm were recommended for total thyroidectomy:
  • To facilitate surveillance, allow for radioiodine therapy, and reduce the likelihood of recurrence
• Newer data, however, has cast doubt on the necessity of removal of the entire gland:
  • The recent trend to the use of less radioiodine therapy has obviated the need to perform total thyroidectomy in many patients with low-risk thyroid cancer
  • Further strengthening the argument for less extensive surgery is the recognition that the risk of complications with total thyroidectomy is double that seen in lobectomy, regardless of the surgeon’s experience level
  • Most importantly, multiple retrospective studies have revealed that outcomes are equivalent in patients with low-risk disease treated with lobectomy compared with total thyroidectomy when controlled for tumor size and extent of disease
• Those tumors measuring 4 cm or with preoperative evidence of nodal involvement or ETE, regardless of size:
  • Should proceed with total thyroidectomy

• There are three main indications for postoperative iodine-131 (131I) use:
  • To treat any known (or unknown) residual disease
  • To reduce the risk of recurrence
  • To destroy remaining noncancerous thyroid cells:
    • This last indication:
      • Called remnant ablation, improves the sensitivity of serum Tg and may also be used as a staging tool to identify previously undiagnosed tumors
• The use of RAI therapy is a contentious issue with conflicting findings regarding recurrence and survival benefit:
  • Largely stemming from the lack of prospective, randomized, and controlled trials
• The patients for whom RAI may be beneficial can be clarified based on the initial risk stratification of the individual tumor (Table) and the postoperative disease status

• Studies have consistently shown that patients with American Thyroid Association (ATA) low-risk tumors measuring 1 cm lacking nodal and distant metastases:
  • Do not benefit from RAI therapy, and its use is not recommended
• Additionally, low-risk tumors measuring 1 to 4 cm lacking local or distant metastases with complete tumor resection and no tumor invasion into the locoregional tissues or structures:
  • Do not derive mortality benefit from adjuvant RAI therapy:
    • As such, RAI therapy should not be routinely used in this group unless there is an aggressive histology or evidence of vascular invasion
• In contrast, RAI does appear to be beneficial in terms of mortality and disease-free survival for those patients with a high-risk tumor:
  • Its use is routinely recommended in the postoperative management of these patients
• For the remaining patients, including those with intermediate risk for recurrence:
  • There is conflicting data regarding the benefits of therapy:
    • Use of RAI in this cohort of patients should be considered on a case-by-case basis

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

• A postmastectomy chest wall recurrence:
  • Carries a high risk of concurrent or subsequent distant disease:
    • So the first steps are:
      • Tissue confirmation with receptor reassessment (ER / PR and HER2) and systemic staging to establish whether the recurrence is truly isolated:
        • Which determines whether curative-intent multimodality therapy versus palliative systemic therapy is appropriate
• High risk of concurrent systemic disease:
  • Staging First:
    • In the ACOSOG / Alliance AFT-01 study of stage II to III patients:
      • Synchronous distant metastases were present in 27% overall at the time of locoregional recurrence:
        • 30% specifically for postmastectomy chest wall recurrence
        • 35% for nodal
        • 15% for in-breast
    • A separate cohort found distant metastases in:
      • ~32% of patients at diagnosis of locoregional recurrence
  • This justifies obtaining systemic staging and receptor status before committing to local therapy
• NCCN staging modalities — confirmed with nuance:
  • NCCN workup for recurrent disease (BINV-18) includes:
    • History / physical
    • CBC, comprehensive metabolic panel with LFTs and alkaline phosphatase
    • Imaging:
      • Chest diagnostic CT ± contrast
      • Abdomen ± pelvis CT with contrast or MRI
      • Bone scan or sodium fluoride PET / CT (category 2B):
        • With FDG-PET/CT “useful in certain circumstances” (and FES-PET/CT considered for ER-positive / lobular disease)
      • Brain and spine MRI are reserved for relevant symptoms
      • So PET/CT is positioned as an option in select circumstances rather than fully interchangeable with CT + bone scan
    • Critically, NCCN also mandates biopsy of the recurrence with re-evaluation of ER / PR and HER2:
      • Because receptor status can discordantly change between primary and recurrence
• Surgical excision to negative margins + comprehensive chest wall / nodal RT — confirmed:
  • For an isolated chest wall recurrence after mastectomy, NCCN (BINV-19) recommends:
    • Consider appropriate systemic therapy to best response if indicated, then surgical resection if feasible + consider surgical axillary staging + post-mastectomy RT (radiation-naïve patients), or repeat RT if feasible and indicated in previously irradiated patients
  • Corroborating data:
    • The DEGRO guideline calls:
      • Complete (R0) resection followed by chest wall RT with strongly advised regional nodal irradiation the standard, using 50 to 50.4 Gy ± 10 Gy boost
  • A retrospective series of isolated chest wall recurrences found chest wall plus RNI significantly improved progression-free and overall survival versus chest wall RT alone:
    • Supporting comprehensive nodal coverage
• Multidisciplinary management — confirmed:
  • NCCN explicitly emphasizes that a multidisciplinary approach is especially important in recurrence to consider all treatment options
  • Involvement of a plastic / reconstructive surgeon is appropriate when full-thickness chest wall resection and reconstruction are needed
• CALOR trial — confirmed, with updated final numbers:
  • The final analysis (median 9-year follow-up, 162 patients):
    • Confirmed a significant chemotherapy benefit for ER-negative isolated locoregional recurrence (DFS HR 0.29, 95% CI 0.13–0.67; 10-year DFS 70% vs 34%) but no benefit for ER-positive recurrence (HR 1.07, 95% CI 0.57–2.00; 10-year DFS 50% vs 59%; P-interaction = 0.013)
    • The overall survival interaction was not significant (P = 0.53)
    • This refined the earlier 2014 Lancet Oncology report:
      • Which had shown an overall DFS benefit (HR 0.59) driven by the ER-negative subgroup
• Systemic therapy:
  • Is tailored to receptor status of the recurrence, not just chemotherapy
  • All hormone receptor-positive recurrences:
    • Should receive endocrine therapy:
      • Which is standard of care and improves disease-free survival:
        • SAKK 23/82 established tamoxifen’s role
    • HER2-positive recurrences:
      • Should receive HER2-targeted therapy
      • Chemotherapy is the component that CALOR showed benefits specifically ER-negative disease:
        • Emerging data qualify the “no chemo for ER-positive” message
  • A 2025 multi-institutional retrospective cohort of 958 patients with HR-positive / HER2-negative locoregional recurrence:
    • Found adjuvant chemotherapy associated with better invasive DFS (HR 0.70), particularly for non-IBTR recurrences and recurrences during adjuvant endocrine therapy:
      • Though with a worse trend in overall survival and the caveats of retrospective design
  • Genomic assays (e.g., Oncotype DX) are being explored to identify HR-positive patients who can safely omit chemotherapy
  • The POLAR trial is evaluating palbociclib in HR-positive recurrences
  • These do not overturn CALOR but reflect evolving practice
• Reirradiation is now a more established option for previously irradiated patients:
  • Modern techniques (IMRT, proton therapy, brachytherapy, hyperthermia, ± radiosensitizers):
    • Achieve local control of ~ 60% to 75% with acceptable toxicity, with the decision factoring in prior dose, interval since prior RT, and cumulative normal-tissue toxicity
• NCCN cautions the same:
  • Truly unresectable or widespread systemic disease shifts management to palliative systemic therapy per the metastatic algorithms (BINV-21 onward) rather than curative local therapy
• References:
  • NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, Version 6.2026