• The base of the adult breast extends:
  • Vertically:
    • From the 2nd to 6th ribs
  • Horizontally:
    • The breast extends from the lateral border of the sternum to the midaxillary line:
      • In some individuals, into the axilla itself
• The adult breast consists of:
  • Glandular and adipose tissue:
    • Together with a system of connecting ligaments

• 1. Nipple: 
  • This is located at the apex of the breast and projects up to 1 cm
  • Optimizing its positioning is of utmost importance in breast surgery
  • In the average adult female the nipples lie in the midclavicular line:
    • 19 cm to 21 cm from the sternal notch and 9 cm to 11 cm from the midline:
      • But their position varies widely according to shape, size and age
• 2. Areola: 
  • This is a circular area of skin that surrounds the nipple
  • Its color darkens during pregnancy due to the deposition of melanin
  • The areolar skin contains Montgomery glands:
    • Which secrete a protective oily lubricant

• 3. Glandular tissue: 
  • The glandular tissue is the functional component of the lactating breast and the site of milk production, which is passed to the nipple via a system of ducts:
    • Each breast, or mammary gland:
      • Contains 15 to 20 lobes and each lobe is comprised of 20 to 40 terminal ductal lobular units (TDLU):
        • The TDLU is the functional unit of the breast
  • The breast mound is roughly hemispherical
  • The bulk of the glandular tissue is found in the upper outer quadrant:
    • Which is the commonest site of malignancy.
• 4. Adipose tissue: 
  • This forms up to 70% of the breast mass:
    • It is the main determinant of breast size
• 5. Ligaments: 
  • The structure and shape of the breast is maintained by fascial and ligamentous supports:
    • As first described by Sir Astley Cooper in 1840
  • Superficial fascial system:
    • The breast is enveloped by the superficial and deep laminae of the superficial fascia:
      • The superficial lamina is separated from the dermis by a thin layer of fatty tissue:
        • But is often difficult to identify as a separate entity
  • Suspensory ligaments of Cooper:
    • These fibrous strands extend through the breast parenchyma between the layers of the superficial and deep (pre-pectoral) fascia:
      • They help to maintain a non-ptotic breast shape
• 6. Axillary tail (of Spence): 
  • There is a variable extension along the inferior edge of pectoralis major towards the axilla
  • This usually lies within the subcutaneous fat but may penetrate the axillary fascia to lie adjacent to the lymph nodes
  • Occasionally it is a separate entity with ducts that do not drain to the nipple.
• 7. Retromammary space: 
  • In reality this is not a space but a plane of loose connective tissue lying between the deep lamina of the superficial fascia and the deep pre-pectoral fascia
  • Chassaignac bursa (also known as the retromammary bursa, submammary serous bursa or occasionally Chassaignac bag):
    • Is the space behind the breast, lying between the pectoralis fascia posteriorly and deep layer of superficial fascia anteriorly
  • This is the plane of dissection in which a subglandular pocket can be created for insertion of a prosthesis for breast augmentation
• 8. Muscle: 
  • The medial two-thirds of the base of the breast lie over the pectoralis major muscle
  • The lateral one-third lies over serratus anterior and a small portion of the rectus abdominis and external oblique muscles
  • The muscles are separated from the breast by the deep fascia
• 9. Rib cage: 
  • Deformities of the ribs, including those that are secondary to a spinal deformity can lead to an apparent asymmetry of breast position and/or shape

• Vascular Supply of the breast:
  • The breast has a rich blood supply:
    • Which permits safe division and excision of breast tissue:
      • The viability of the nipple areolar complex is dependent on vessels that pass through the gland:
        • Which must therefore be preserved
• There are three main arterial systems:
  • Internal Thoracic (Mammary) Artery:
    • Is responsible for roughly 60% of the vascular supply to the breast
    • Arising directly from the subclavian artery, the internal thoracic artery passes posterior to the subclavian vein and runs along the edge of the sternum, deep to the costal cartilages
    • Perforating branches of the internal thoracic artery pass through the 2nd to 6th intercostal spaces to supply the medial half of the breast:
      • The 2nd and 3rd perforators are the predominant vessels and these are preferred for anastomosis when reconstructing the breast with a free tissue transfer
• Lateral Thoracic Artery:
  • A branch of the second portion of the axillary artery:
    • Supplies the upper outer quadrant of the breast
  • The lateral thoracic artery runs along the lower border of the pectoralis minor muscle and curls around the lateral border of pectoralis major to enter the breast
  • Other branches of the lateral thoracic artery perforate pectoralis major to supply the overlying breast tissue
• Posterior Intercostal Arteries:
  • The lateral branch of the posterior intercostal arteries divides into posterior and anterior branches
  • The anterior branches from the 3rd to 6th intercostal spaces supply the lateral portion of the breast and the overlying skin through their mammary branches
• Other Supply:
  • The axillary artery also provides other branches to the breast, including the:
    • Superior thoracic artery:
      • A branch from the first part of the axillary artery)
    • The pectoral branch of the thoracoacromial artery and the subscapular artery

• The venous drainage of the breast is via two venous systems:
  • Superficial system:
  • Which lies within the subdermal venous plexus:
    • The pattern of drainage is highly variable
  • Deep system:
    • The deep venous system parallels the arterial supply:
      • The medial half of the breast drains via veins that accompany the perforating branches of the internal mammary artery through the intercostal spaces, back to the internal mammary vein
    • The lateral thoracic veins drain into the axillary vein
    • The posterior intercostal veins drain into the azygous vein on the right and the hemiazygous vein on the left
• Innervation of the breast:
  • The nerve supply to the breast consists of sensory fibres from the skin and sympathetic efferent fibres to the blood vessels, glandular tissue and smooth muscle cells in the skin and nipple
  • The sensory nerve supply is derived from cutaneous branches of the intercostal nerves:
    • Medially:
      • Anterior branches of the 1st to 6th intercostal nerves
  • Laterally:
    • Lateral branches of the 2nd to 6th intercostal nerves
  • Nipple areola complex:
    • Supplied by the anterior branch of the 4th intercostal nerve
    • There is an extensive nerve plexus within the nipple
    • The skin of the nipple areola complex contains free nerve endings, Meissner’s corpuscles and Merkel disc endings

• Biochemical incomplete response (BIR) in thyroid cancer:
  • Is characterized by persistently abnormal thyroglobulin (Tg) levels or rising anti-Tg antibodies:
    • Without detectable structural disease
  • This response is seen in approximately 15% to 20% of patients with differentiated thyroid cancer (DTC)
• The American Thyroid Association (ATA) guidelines define BIR as:
  • Suppressed Tg ≥ 1 ng/mL
  • Stimulated Tg ≥ 10 ng/mL, or
  • Rising anti-Tg antibody levels:
    • In the absence of structural disease
• Clinical outcomes for patients with BIR are generally favorable:
  • With 56% to 68% eventually achieving no evidence of disease (NED) status
  • 19% to 27% maintaining persistently abnormal Tg levels without structural disease
  • 8% to 17% developing structural disease over 5 to 10 years
• Risk stratification for patients with BIR involves dynamic risk assessment:
  • Which considers initial risk estimates and modifies them based on response to therapy
• Factors predicting progression from BIR to structural disease include:
  • High post-ablation stimulated Tg levels
  • Presence of lymph node metastasis
  • Male gender
• The ATA and AJCC/TNM staging systems:
  • Are useful in predicting the shift from BIR to structural disease
• Management of BIR:
  • Typically involves continued observation with ongoing TSH suppression, especially if Tg levels are stable or declining
  • Rising Tg or anti-Tg antibody levels should prompt further investigations and potentially additional therapies
• In summary, biochemical incomplete response in thyroid cancer:
  • Is a dynamic condition requiring careful monitoring and individualized management based on risk stratification and response to therapy
• References
  2015 American Thyroid Association Management Guidelines for Adult Patients With Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Haugen BR, Alexander EK, Bible KC, et al. Thyroid : Official Journal of the American Thyroid Association. 2016;26(1):1-133. doi:10.1089/thy.2015.0020.
  Differentiated Thyroid Cancer With Biochemical Incomplete Response: Clinico-Pathological Characteristics and Long Term Disease Outcomes. Steinschneider M, Pitaro J, Koren S, et al. Cancers. 2021;13(21):5422. doi:10.3390/cancers13215422.
  Prognostic Value of Post-Ablation Stimulated Thyroglobulin in Differentiated Thyroid Cancer Patients With Biochemical Incomplete Response: A Bi-Center Observational Study. Wang Y, Wu J, Jiang L, Zhang X, Liu B. Endocrine. 2022;76(1):109-115. doi:10.1007/s12020-021-02976-8.
  Predicting Factors and Clinical Outcome of Biochemical Incomplete Response in Middle Eastern Differentiated Thyroid Carcinoma. Parvathareddy SK, Siraj AK, Ahmed SO, et al. Endocrine. 2024;86(1):268-275. doi:10.1007/s12020-024-03844-x.

• Structural incomplete response (SIR) in differentiated thyroid cancer (DTC):
  • Is defined as persistent or newly identified locoregional or distant metastases on imaging:
    • Usually in conjunction with elevated thyroglobulin (Tg) and / or anti-thyroglobulin antibody (TgAb) levels
  • It is one of four response-to-therapy categories in the ATA dynamic risk stratification system:
    • Alongside excellent, indeterminate, and biochemical incomplete responses
• Criteria by Treatment Context:
  • The definition of SIR is consistent regardless of surgical extent:
    • Structural evidence of disease confirmed by suspicious imaging or biopsy-proven local or distant metastatic disease
  • The TSH goal for patients with SIR:
    • Is maintained below the normal reference range
• Prevalence and Outcomes:
  • SIR occurs in approximately 2.8% to 10% of DTC patients after initial therapy
  • In a cohort of 501 patients treated with total thyroidectomy and RAI:
    • 2.8% had SIR at initial assessment:
      • By last follow-up, 10.2% had structurally incomplete responses
    • Key outcome data include:
      • Patients with an initial SIR:
        • Had an 83.9% rate of continued structural disease over long-term follow-up (mean 10.3 years)
      • All patients categorized as SIR after total thyroidectomy without RAI:
        • Experienced continued presence of disease
      • SIR requires multidisciplinary management tailored to disease status (regional vs. distant metastases, iodine-avid vs. non-iodine-avid disease)
• Management:
  • Management of SIR depends on:
    • Disease location, RAI avidity, resectability, and rate of progression
  • Locoregional disease:
    • Surgery is preferred for resectable locoregional recurrence:
      • With formal compartmental dissection for previously undissected basins
    • RAI therapy:
      • If radioiodine imaging is positive
    • Active surveillance:
      • Is appropriate for non-progressive disease that is stable and distant from critical structures:
        • Small-volume lymph node recurrences often show little progression over years
    • Local therapies (ethanol ablation, RFA, cryoablation):
      • May be considered for limited-burden nodal disease
    • RAI-refractory or progressive disease:
      • Somatic molecular testing for actionable mutations (BRAF, RET, NTRK, ALK fusions; dMMR/MSI/TMB) is recommended for advanced, progressive, or threatening disease
    • Systemic therapy for progressive and/or symptomatic disease:
      • Lenvatinib (preferred; PFS 18.3 vs. 3.6 months, ORR 65%)
      • Sorafenib (PFS 10.8 vs. 5.8 months)
      • Cabozantinib after prior VEGFR TKI (PFS 11.0 vs. 1.9 months)
      • Targeted therapies:
        • Dabrafenib / trametinib (BRAF V600E)
        • Selpercatinib / pralsetinib (RET fusion)
        • Larotrectinib / entrectinib (NTRK fusion)
        • Pembrolizumab (MSI-H/dMMR or TMB-H)
  • Disease monitoring is often appropriate for asymptomatic patients with indolent, non-progressive disease and no brain metastases:
    • TKI therapy may not be appropriate for stable or slowly progressive disease
  • TSH suppression should be maintained with TSH
• References:
  • 2025 American Thyroid Association Management Guidelines for Adult Patients With Differentiated Thyroid Cancer. Ringel MD, Sosa JA, Baloch Z, et al. Thyroid : Official Journal of the American Thyroid Association. 2025;35(8):841-985. doi:10.1177/10507256251363120.
  • SNMMI Procedure Standard/Eanm Practice Guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer: Abbreviated Version. Avram AM, Giovanella L, Greenspan B, et al. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2022;63(6):15N-35N.
  • Thyroid Carcinoma. National Comprehensive Cancer Network. Updated 2025-03-27.
    Thyroid Cancer. Chen DW, Lang BHH, McLeod DSA, Newbold K, Haymart MR. Lancet (London, England). 2023;401(10387):1531-1544. doi:10.1016/S0140-6736(23)00020-X.

• Type A:
  • Adherent to the posterior thyroid parenchyma:
    • Posterior to the upper pole of the thyroid:
      • But not intrathyroidal
  • Type A glands are in the accepted, expected location of a normal parathyroid gland
• Type B:
  • Behind the thyroid parenchyma
  • Type B glands are exophytic to the thyroid parenchyma and lie in the tracheoesophageal groove:
    • This category includes adenomas in:
      • Retroesophageal, retropharyngeal, high lateral pharyngeal, and carotid sheath locations
  • A ‘‘B+’’ subcategory can be used to document the location of adenomas above the level of the hyoid bone:
    • The ‘‘+’’ is meant to reflect cranial elevation
• Type C:
  • Caudal to the thyroid parenchyma:
    • In the tracheoesophageal groove
  • A type C gland is more inferior than a type B gland on lateral images:
    • Located inferior to the inferior pole of the thyroid:
      • Closer to the clavicle
• Type D:
  • Directly over the recurrent laryngeal nerve:
    • At the level of the inferior thyroid vessels
  • The dissection may be difficult:
    • Because a type D gland is dangerously close to the recurrent laryngeal nerve
• Type E:
  • Located in the external aspect of the inferior pole of the thyroid
  • A type E gland is in a location that is:
    • More superficial in an anterior–posterior plane than the recurrent laryngeal nerve:
      • It is the easiest to resect
• Type F:
  • ‘‘Fallen’’ into the thyrothymic ligament:
    • Below the inferior pole of the thyroid in a pretracheal plane
  • A type F gland is frequently referred to as an ectopic gland:
    • Its resection usually involves:
      • Transcervical delivery of the thyrothymic ligament or superior portion of the thymus
• Type G:
  • A gauge, true intrathyroidal gland location

• This nomenclature system has been designed that takes into account the pathologic position of the parathyroid glands (Figure):
  • Superior and inferior glands:
    • Are defined by the location of the gland’s pedicle and its relationship to the RLN:
      • Superior parathyroid glands:
        • Anatomically have a vascular pedicle superior and lateral to the RLN (type A through D glands)
      • Inferior parathyroid glands:
        • Anatomically have a vascular pedicle inferior and medial to the RLN (type D through F glands)
    • Type G glands:
      • Represent intrathyroidal parathyroid lesions
  • This information not only helps radiologists communicate potential parathyroid lesions of interest to surgeons:
    • But also helps surgeons direct their dissection in relation to the RLN

• A novel nomenclature to classify parathyroid adenomas:
  • World Journal of Surgery. 2009;33(3):412–416
• Background and Rationale:
  • Traditional descriptions of parathyroid adenomas (e.g., “left inferior,” “ectopic”):
    • Are inconsistent and often imprecise:
      • Particularly in reoperative surgery or when imaging is discordant
  • Problem:
    • Variable embryologic descent → unpredictable locations
    • Poor communication between surgeons, radiologists, and endocrinologists
    • Difficulty standardizing outcomes and reporting
  • Goal of Perrier et al:
    • Develop a standardized, anatomically reproducible nomenclature based on predictable embryologic migration patterns
• Embryologic Basis (Core Concept)

• During the fifth to sixth week of intrauterine development:
  • The embryonic pharynx is marked:
    • Externally by:
      • Four branchial clefts of ectoderm origin
    • Internally by:
      • Five branchial pouches of endoderm origin
  • The branchial apparatus is made up by:
    • The branchial clefts and branchial pouches:
      • Together with the branchial arches of mesoderm origin:
        • Found in between them
  • This apparatus undergoes normal involution:
    • Leaving behind some derivatives which include the:
      • Thyroid gland, parathyroid glands, thymus, ultimobranchial body, Eustachian tube, middle ear, and external auditory canal
• The parathyroid glands:
  • Develop as epithelial thickenings of the dorsal endoderm of the:
    • Third and fourth branchial pouches
  • The superior parathyroid glands:
    • Are derived from the fourth branchial pouch:
      • Which also gives rise to the ultimobranchial bodies:
        • The ventral aspect of these pouches is believed to fuse with the rudimentary fifth branchial pouches:
          • To from the ultimobranchial bodies
    • The superior parathyroid glands follow the migration of the ultimobranchial bodies:
      • Which descend a relative limited path toward the lateral thyroid region:
        • Ultimately giving rise to the parafollicular cells of the thyroid
      • The superior parathyroid glands separate from the ultimobranchial bodies:
        • As the median and lateral thyroid anlages fuse and incorporate the ultimobranchial bodies:
          • This separation event determines the final anatomic position of the superior parathyroid glands relative to the thyroid (Type A gland)
  • The inferior parathyroid glands:
    • Are derived from the third branchial pouch (dorsal aspect):
      • Along with the thymus (derived from the ventral aspect of the third branchial pouch)
• The parathyroid glands:
  • Remain intimately connected with their respective branchial pouch derivatives
• The normal anatomic location of the superior parathyroid glands:
  • Is more constant than the inferior parathyroid glands:
    • With 80% of the superior glands being found near the posterior aspect of the thyroid gland:
      • At the junction of the upper and middle portion of the thyroid lobes:
        • At the level of the cricoid cartilage:
          • Each gland with its own capsule of connective tissue:
            • Type A gland
  • Roughly one percent  (1%) of the superior parathyroid glands:
    • May be found in the paraesophageal or retroesophageal space, retrolaryngeal space, high lateral pharyngeal, and carotid shealth locations:
      • Type B glands:
        • Behind the thyroid parenchyma:
          • Type B glands are exophytic to the thyroid parenchyma:
            • Lie in the tracheoesophageal groove
      • Type C glands:
        • Caudal to the thyroid parenchyma:
          • In the tracheoesophageal groove
        • A type C gland is more inferior than a type B gland on lateral images and located inferior to the inferior pole of the thyroid (closer to the clavicle)
  • Enlarged superior parathyroid glands:
    • May descend in the tracheoesophageal groove and come to lie below the inferior parathyroid glands (Type C gland)
  • Truly ectopic superior parathyroid glands:
    • Are extremely rare:
      • But may be localized to the middle or posterior mediastinum or in the aortopulmonary window 
• During intrauterine development:
  • The thymus and the inferior parathyroid glands:
    • Migrate caudally in the neck
  • The most common location for the inferior parathyroid glands:
    • Is within 1 cm from a point centered where the inferior thyroid artery and the recurrent laryngeal nerve (RLN) cross
  • In roughly 50% of the cases:
    • The inferior parathyroid gland is located at the level of the inferior thyroid lobe:
      • Anterior of the posterolateral surface:
        • Type E:
          • Located in the external aspect of the inferior pole of the thyroid
          • A type E gland is in a location that is more superficial in an anterior-posterior plane than the recurrent laryngeal nerve
          • It is the easiest to resect
            
  • Approximately 15% to 50% of the inferior glands:
    • Are found in the thyrothymic ligament or the thymus
  • The inferior parathyroid gland is typically situated within a pocket of thymic derived fatty tissue:
    • But may be closely adherent to the thyroid capsule
  • The position of the inferior parathyroid glands:
    • However, tends to be more variable due to their longer migratory route:
      • Undescended inferior glands may be found near the:
        • Skull base, angle of the mandible, or above the superior parathyroid glands:
          • Along with an undescended thymus
  • The frequency of intrathyroidal glands:
    • Is approximately 2% 
• Superior parathyroid glands (4th branchial pouch):
  • Short migration
  • More constant location
  • Posterior to RLN, near cricothyroid joint
• Inferior glands (3rd branchial pouch):
  • Long migration with thymus
  • Highly variable
  • Can be anywhere from angle of mandible → mediastinum
• The classification is built on this predictable vs variable descent pattern

The Perrier Classification System

The authors propose categorizing adenomas based on their relationship to key anatomic landmarks, especially:

• Thyroid gland
• Recurrent laryngeal nerve (RLN)
• Thymus
• Carotid sheath

📍 Four Main Categories

Type A — Orthotopic (Normal Position)

• Located in expected anatomical position
• Adjacent to thyroid gland
• Most common

👉 Clinical relevance:

• Ideal for minimally invasive parathyroidectomy (MIP)
• High concordance with sestamibi + ultrasound

Type B — Ectopic but Cervical

Includes:

• Retroesophageal
• Carotid sheath
• Intrathyroidal
• High cervical (undescended)

👉 Key point: Still in the neck but outside usual location

👉 Surgical implication:

• May require focused but modified approach
• Intrathyroidal → partial thyroid resection

Type C — Thymic / Thyrothymic

• Along thymic descent pathway
• Thyrothymic ligament
• Within cervical thymus or upper mediastinum

👉 Most common ectopic site for inferior glands

👉 Surgical implication:

• Cervical thymectomy often required
• Important in failed initial exploration

Type D — Mediastinal

• Below thoracic inlet
• Aortopulmonary window, pericardium, deep thymus

👉 Rare but critical

👉 Surgical implication:

• May require:
  • VATS
  • Sternotomy
  • Interventional radiology localization

📊 Key Findings from Perrier et al.

• Majority of adenomas are Type A (orthotopic)
• Ectopic locations (Types B to D) account for:
  • ~15% to 20% of cases
• Inferior glands → disproportionately represented in ectopic group

👉 The classification correlates strongly with:

• Embryology
• Preoperative imaging success
• Surgical difficulty

🎯 Clinical Impact

1. Improves Communication

• Standard language across:
  • Surgeons
  • Radiologists
  • Endocrinologists

2. Enhances Preoperative Planning

• Predicts:
  • Likelihood of MIP vs BNE
  • Need for extended exploration

3. Reduces Failed Explorations

• Particularly valuable in:
  • Reoperative cases
  • Discordant imaging

4. Facilitates Research Standardization

• Enables:
  • Comparable outcome reporting
  • Better stratification in studies

🧠 Surgical Algorithm Integration

⚠️ Limitations of the Study

• Retrospective classification
• Single-institution experience (MD Anderson)
• No direct comparison with alternative systems
• Does not incorporate modern imaging (e.g., 4D-CT, PET)

📚 Key References

1. Perrier ND et al. World J Surg. 2009;33:412–416
2. Akerström G et al. Anatomy and embryology of parathyroid glands. World J Surg. 1984
3. Wang C. Parathyroid gland location study (645 cases). Ann Surg. 1976
4. Kunstman JW et al. Parathyroid localization techniques. J Surg Oncol. 2013
5. Cheung K et al. 4D-CT in parathyroid localization. Radiology. 2012

💡 Take-Home Messages (Chairman-Level)

• This classification is simple, reproducible, and embryology-driven
• Helps predict surgical complexity before incision
• Particularly powerful in:
  • Reoperative parathyroid surgery
  • Ectopic gland localization
• Should be integrated into:
  • Operative reports
  • Radiology reporting
  • Multidisciplinary discussions

• Mechanism of Action (CDK4/6 inhibition in HR+ disease):
  • Core biology (why surgeons should care):
    • Ribociclib is a selective CDK4/6 inhibitor:
      • Blocks Cyclin D + CDK4/6 → RB phosphorylation → G1→S transition
      • At baseline, a breast cancer cell moves from G1 → S phase (DNA replication) only if a key checkpoint is passed
      • The core engine – Cyclin D + CDK4/6 = active complex:
        • This complex’s job is to turn OFF the brake (RB protein)
      • The critical step:
        • RB (retinoblastoma protein) normally acts as a brake
        • When phosphorylated → RB becomes inactive
        • This releases E2F transcription factors
        • E2F turns on genes needed for DNA synthesis (S phase)
      • 👉 So – Active CDK4/6 = cell allowed to divide
      • CDK4/6 Inhibitors:
        • Results in cell-cycle arrest in luminal (ER+) tumor cells
    • Key downstream effects:
      • Prevents proliferation of ER-driven clones
      • Enhances endocrine therapy sensitivity (synergistic with AI)
      • May reduce micrometastatic outgrowth → recurrence prevention
  • Clinical interpretation:
    • Not cytotoxic → cytostatic disease control
    • Most impactful in:
      • Luminal A/B biology
      • Late recurrence–prone disease:
        • Rationale for long-duration adjuvant use (3 years)
• NATALEE Trial Design (context for surgeons):
  • Phase III randomized control trial:
    • ~ 5100 patients 
    • Population:
      • HR+ / HER2− early breast cancer
      • Stage II to III:
        • Including selected N0 high-risk
    • Treatment:
      • Ribociclib (400 mg, 3 yrs) + AI ≥ 5 yrs
        vs AI alone
    • Broad inclusion → more “real-world” than monarchE
• 5-Year Update (ESMO 2025 / latest analyses):
  • Efficacy (key numbers):
  • iDFS HR ~0.72 → ~ 28% relative risk reduction 
  • 5-year iDFS:
    • 85.5% (ribociclib) vs 81.0% (ET alone):
      • Absolute benefit ~ 4.5% 
    • Benefit persists after stopping drug (3-year exposure):
      • Indicates true disease-modifying effect 
  • Other endpoints:
    • ↓ Distant recurrence (DDFS HR ~0.71) 
    • ↓ DRFS / RFS consistently improved 
    • OS trend positive but immature 
  • Important nuance:
    • Absolute benefit increases over time (3 → 5 yrs):
      • Supports late recurrence suppression
• Indications (current clinical positioning):
  • Regulatory / guideline-aligned use:
  • Adjuvant therapy with AI for:
    • HR+ / HER2− early breast cancer
    • Stage II to III at high risk of recurrence 
    • “High-risk” (NATALEE definition):
      • Includes:
        • Stage IIB to III or
        • Stage IIA with N+ or
        • N0 + high-risk biology (e.g., Ki-67 ≥ 20%, grade 3, genomic risk) 
• Unique positioning vs abemaciclib:
  • Broader population:
    • Includes:
      • Node-negative high-risk
      • Lower tumor burden
      • Lower starting dose → better tolerability strategy
• Practical Implications for Breast Surgeons:
  • Expands “systemic adjuvant” discussion at MDT
  • You now need to identify patients who may benefit before finalizing adjuvant plan:
    • Candidates to flag early:
    • Stage II (even N0) with:
      • High grade
      • High Ki-67
      • Genomic high risk
    • Any Stage III HR+ disease
• Impacts surgical-pathologic reporting priorities:
  • Surgeons should ensure:
    • Accurate nodal staging
    • Grade
    • Ki-67
    • Genomic assay (if used) integrated early
      • These directly influence eligibility for CDK4/6 therapy
• Reinforces importance of recurrence biology:
  • Luminal cancers:
    • Long natural history
    • Late relapse risk
    • Ribociclib addresses micrometastatic dormancy
      → shifts mindset from:
      “Local control + endocrine therapy”
      → to
      “Extended systemic control strategy”
• Treatment duration considerations:
  • Ribociclib:
    • 3 years
  • Endocrine therapy:
    • ≥ 5 years
• Implication:
  • Long-term adherence planning begins at surgical consultation
• Safety Profile (surgeon-relevant highlights):
  • Common:
    • Neutropenia (non-febrile)
    • LFT elevation
    • QT prolongation
  • No new long-term safety signals at 5 years 
  • Clinical takeaway:
    • Manageable → supports use in early-stage curative setting
• Key Takeaways for Surgical Practice:
  • Ribociclib is now a standard adjuvant option in HR+/HER2− EBC:
    • Especially stage II to III and biologically high-risk disease
  • 5-year data confirms durability:
    • Benefit persists beyond treatment window:
      • Increasing absolute benefit over time
  • Expands eligible population:
    • Includes node-negative high-risk patients
  • Multidisciplinary coordination is critical:
    • Surgeons play a role in:
      • Early identification
      • Pathologic risk stratification
      • Timely referral to medical oncology
• Bottom line (surgeon-focused):
  • Ribociclib from NATALEE represents a shift toward proactive systemic prevention of recurrence in luminal breast cancer, with durable 5-year benefit and broader eligibility than prior CDK4/6 strategies—making early risk identification at the surgical stage increasingly important

The Phase III LEAP-10 trial represents a major collaborative effort between Merck & Co. and Eisai, addressing a persistent unmet need in recurrent /metastatic head and neck squamous cell carcinoma (R/M HNSCC).

In patients with PD-L1 CPS ≥1 disease, the combination of lenvatinib + pembrolizumab demonstrated:

• Improved objective response rate (ORR)
• Prolonged progression-free survival (PFS)

However, these gains did not translate into an overall survival (OS) benefit compared with pembrolizumab monotherapy, which remains the backbone of first-line treatment.

Clinical Context: Why OS Remains Elusive

Despite encouraging activity, the absence of OS improvement reinforces the durability of the current standard established by KEYNOTE-048 trial, where:

• Pembrolizumab ± chemotherapy continues as standard of care
• Survival benefit is tightly linked to PD-L1 expression and patient selection

The LEAP-10 findings highlight a recurring challenge in HNSCC:

Early efficacy signals (ORR, PFS) do not reliably predict survival benefit, particularly in an immunotherapy-sensitive disease where post-progression treatments and tumor biology heavily influence OS.

Biologic Interpretation

The addition of lenvatinib, a multi-kinase inhibitor targeting VEGFR, FGFR, and others, likely:

• Enhances tumor microenvironment modulation
• Improves initial tumor shrinkage and disease control

However, potential limitations include:

• Lack of deep, durable immune reprogramming
• Emergence of resistance mechanisms
• Possible toxicity-related treatment discontinuation

These factors may blunt long-term survival impact despite improved early endpoints.

Where the Field Is Heading: EGFR and Beyond

Attention is now shifting toward next-generation EGFR-targeted strategies, with the hypothesis that:

• More precise targeting of EGFR-driven signaling
• Coupled with immune engagement mechanisms

may yield more durable survival benefits.

Key players advancing this space include:

• Dana-Farber Cancer Institute
• Genmab
• Bicara Therapeutics
• Johnson & Johnson
• Merus N.V.
• Harvard Medical School

Emerging modalities include:

• Bispecific antibodies (EGFR × immune targets)
• Antibody-drug conjugates (ADCs)
• Combination immunotherapy strategies

These approaches aim to:

• Overcome primary and acquired resistance
• Deliver more sustained immune activation
• Ultimately shift the OS curve, not just early endpoints

Key Takeaway for Clinical Practice

While lenvatinib + pembrolizumab shows meaningful biologic and clinical activity, it does not currently challenge pembrolizumab-based regimens as standard of care in PD-L1–positive R/M HNSCC.

The central question remains:

What therapeutic strategy will meaningfully and reproducibly improve overall survival in first-line HNSCC?

The next wave of EGFR-targeted and immune-engaging therapies may be the most promising path forward.

Maxillary Artery

• The maxillary artery supplies deep structures of the face.

• It branches from the external carotid artery just deep to the neck of the mandible.

• Structure:

  • The maxillary artery, the larger of the two terminal branches of the external carotid artery:

    • Arises behind the neck of the mandible, and is at first imbedded in the substance of the parotid gland.

  • It passes forward between the ramus of the mandible and the sphenomandibular ligament, and then runs, either superficial or deep to the lateral pterygoid muscle, to the pterygopalatine fossa.

  • It supplies the deep structures of the face.

• May be divided into:

  • Mandibular portion (first part / bony part)

  • Pterygoid portion (second part / muscular part)

  • Pterygopalatine portions (third part).

• Mandibular portion (first part / bony part):

  • The first or mandibular portion (or bony portion) passes horizontally forward, between the neck of the mandible and the sphenomandibular ligament:

    • Where it lies parallel to and a little below the auriculotemporal nerve.

    • It crosses the inferior alveolar nerve, and runs along the lower border of the lateral pterygoid muscle.

    • Branches include:

      • Deep auricular artery

      • Anterior tympanic artery

      • Middle meningeal artery

      • Inferior alveolar artery:

        • Which gives off its mylohyoid branch just prior to entering the mandibular foramen

      • Accessory meningeal artery

• Pterygoid portion (second part / muscular part):

  • The second or pterygoid portion (or muscular portion) runs obliquely forward and upward under cover of the ramus of the mandible and insertion of the temporalis muscle:

    • On the superficial (very infrequently on the deep) surface of the lateral pterygoid muscle.

    • It then passes between the two heads of origin of this muscle and enters the fossa.

  • Branches include:

    • Masseteric artery

    • Pterygoid branches

    • Deep temporal arteries:

      • Anterior and posterior

    • Buccal (buccinator) artery

• Pterygopalatine portions (third part):

  • The third or pterygopalatine portion lies in the pterygopalatine fossa in relation with the pterygopalatine ganglion.

  • This is considered the terminal branch of the maxillary artery.

  • Branches include:

    • Sphenopalatine artery:

      • Nasopalatine artery is the terminal branch of the maxillary artery

    • Descending palatine artery:

      • Greater palatine artery

      • Lesser palatine artery

    • Infraorbital artery

    • Posterior superior alveolar artery

    • Artery of pterygoid canal

    • Pharyngeal artery

    • Middle superior alveolar artery (could be a branch of the infraorbital artery)

    • Anterior superior alveolar arteries (could be a branch of the infraorbital artery)

Rodrigo Arrangoiz MS, MD, FACS a head and neck surgeon at the Braman Comprehensive Cancer Center at Mount Sinai Medical Center in Miami, Florida.

He is first author on some publications on oral cavity cancer:

• Oral Tongue Cancer: Literature Review and Current Management 

  • https://www.oatext.com/pdf/CRR-2-153.pdf

• Understand Cancer: Research and Treatment Oral Cavity Cancer: Literature Review and Current Management. 

  • https://www.researchgate.net/publication/303366031_Understand_Cancer_Research_and_Treatment_Oral_Cavity_Cancer_Literature_Review_and_Current_Management

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

• The main trunk of the maxillary artery:
  • Is divided into three parts:
    • Which are named according to related structures along the artery’s course
  • These three parts are:
    • The mandibular division (1st part / bony part):
      • Named as such because it winds around deep to the neck of the mandible
    • The pterygoid division (2nd part / muscular part):
      • It has this name because it travels between the two heads of the lateral pterygoid muscle
    • The pterygopalatine division (3rd part):
      • This part derived its name from the pterygopalatine fossa, into which it enters
  • Conventionally, these three parts are described as the:
    • Part before-, part on-, and part beyond the lateral pterygoid muscle
    • This is also useful since out of the 15 branches of the maxillary artery:
      • The five branches from the second part (part on the lateral pterygoid muscle):
        • Are regarded as branches to soft tissues:
          • That do not course through foramina in bones
      • However, the remaining 10 branches:
        • From the first and third parts:
          • Go through foramina in bones
• Course:
  • The maxillary artery:
    • Continues as one of the terminal divisions of the external carotid artery:
      • At the level of the neck of the mandible:
        • Passing forward between the neck of the mandible and the sphenomandibular ligament
      • It continues its path by running deeply to the lower head and passes forward between the two heads of the lateral pterygoid muscle:
        • To break into its terminal branches at the pterygopalatine fossa

• Maxillary artery branches:
  • Branches of the first (mandibular) division:
    • The deep auricular artery:
      • Is the first branch of the mandibular part:
        • This branch runs upwards to enter the ear and courses superficially to the tympanic membrane, passing between the cartilage and bone
      • It supplies the external acoustic meatus of the ear and the deep surface of the tympanic membrane
      • The anterior tympanic artery:
        • Is the second branch that courses near the tympanic membrane
        • It passes deep to the membrane:
          • Through the petrotympanic fissure to the middle ear:
            • To join the circular anastomosis around the tympanic membrane
      • The middle meningeal artery:
        • Passes straight upwards through the foramen spinosum:
          • To join the two roots of the auriculotemporal nerve
        • It supplies bones of the skull (calvaria) and the dura mater
      • The inferior alveolar artery:
        • Runs inferiorly and anteriorly towards the inferior alveolar nerve:
          • To meet the nerve at the inferior alveolar (a.k.a. mandibular) foramen
        • The artery runs further anteriorly in the mandible:
          • Supplying the pulps of the mandibular teeth (with its dental branches) and the body of the mandible
        • Its other branch, the mental branch:
          • Emerges from the mental foramen and supplies the lower lip and skin of the chin 
      • The accessory meningeal artery:
        • Is the main source of blood supply to the trigeminal ganglion
        • It passes upwards through the foramen ovale to supply the dura mater of the floor of the middle fossa and of the trigeminal cave (Meckel’s cave)
  • Branches from the 2nd (pterygoid / muscular) segment:
    • All branches from the pterygoid part supply only soft tissues
    • The masseteric artery:
      • Accompanies the lingual nerve
      • It is small, and passes laterally through the mandibular notch to the deep surface of the masseter muscle
    • The pterygoid arteries:
      • Are small branches that vary in number
      • They supply the lateral pterygoid muscle and medial pterygoid muscle
    • The deep temporal arteries:
      • Course between the temporalis muscle and the pericranium
      • The main function of this branch is to:
        • Provide arterial supply to the temporalis muscle
    • The buccal (buccinator) artery:
      • Runs obliquely forward, between the medial pterygoid muscle and the insertion of the temporalis muscle, to the outer surface of the buccinator muscle
      • It mainly supplies the:
        • Buccinator muscle
      • Along its course, it forms anastomoses with branches of the facial and infraorbital arteries
  • Branches from the 3rd (pterygopalatine) segment:
    • The sphenopalatine artery:
      • Mainly supplies the nasal cavity:
        • Which is why it is also referred to as the nasopalatine artery
      • It passes through the sphenopalatine foramen and enters the nasal cavity
      • Here it gives off its posterior lateral nasal branches
      • Crossing the inferior surface of the sphenoid:
        • The sphenopalatine artery ends on the nasal septum giving off the posterior septal branches
    • The descending palatine artery:
      • Descends through the greater palatine canal:
        • With the greater and lesser palatine branches:
          • Of the pterygopalatine ganglion
        • It terminates by dividing into the greater and lesser palatine arteries:
          • That provide blood supply for the hard palate and soft palate, respectively
    • The infraorbital artery:
      • Passes forwards through the inferior orbital fissure:
        • Along the floor of the orbit and infraorbital canal:
          • To emerge with the infraorbital nerve on the face.
    • The posterior superior alveolar artery:
      • Supplies the maxillary teeth
      • It gives branches that accompany the corresponding nerves through foramina in the posterior wall of the maxilla
    • The middle superior alveolar artery:
      • Is most often a branch of the infraorbital artery
      • It arises within the infraorbital canal:
        • Where it descends to supply the maxillary sinus and plexus at the level of the canine tooth
    • The pharyngeal artery:
      • Supplies structures such as the pharynx and roof of the nose
    • The anterior superior alveolar artery:
      • Is branch of the infraorbital artery. 
    • The artery of the pterygoid canal:
      • Runs into the pterygoid canal:
        • It passes backwards along the pterygoid canal with the corresponding nerve
      • It supplies the upper part of the pharynx, and sends a small division into the tympanic cavity to anastomose with the tympanic arteries
        
        
        
        

The proximity or direct extension of a primary tumor of the oral cavity to the mandible requires appropriate radiological studies to establish the presence and extent of bone involvement:

• Although the absence of radiographic findings does not rule out bone invasion:

  • Bone destruction as seen on the radiograph confirms tumor invasion

• Radionuclide bone scans:
  • Often are positive before the radiographic appearance of bone destruction:
    • But they seldom provide accurate information regarding the extent of bone invasion
  • Bone scans also may be positive in non-neoplastic conditions:
    • Such as inflammatory lesions
• Plain radiographs of the mandible in the antero-posterior and oblique views:
  • Are not satisfactory as a routine screening test to establish or rule out bone destruction
• A panoramic view of the mandible (an orthopantomogram):
  • Is helpful to assess the general architecture of the mandible in relation to the dento-alveolar structures and invasion by the tumor (Figure)

• However, for technical reasons:

  • The midline of the mandible near the symphysis is not adequately evaluated by a panoramic view

  • In addition, early invasion of the lingual cortex of the mandible is not seen on a panoramic view

  • Occlusal films of the body of the mandible and intraoral dental films:

    • Often are most accurate in demonstrating early invasion by a tumor

      
      
• CT scans of the mandible:
  • Generally are not optimal for routine screening:
    • But may be considered in certain circumstances:
      • Such as primary tumors of the mandible and lesions where soft tissue extension from tumors involving the ascending ramus of the mandible is suspected (Figure)

Three-dimensional reconstructions of CT images provide an excellent overview of the mandible or maxilla from any desired angle

• A computerized tomogram of the oral cavity and neck:
  • Is the standard initial radiographic study for assessment of locoregional extent of the tumor
  • It allows comprehensive evaluation of neck nodes and also the relationship of the primary tumor to adjoining bone:
    • Especially in situations such as primary tumors of the mandible and lesions where soft-tissue extension from tumors involving the ascending ramus of the mandible is suspected

• Three-dimensional reconstructions of the mandible of a patient with an ossifying fibroma of the body of the mandible on the left-hand side causing expansion and involving the lingual cortex are shown in the Figures

  
  

• A three-dimensional CT scan and a one-to-one reproduction of the CT scan:

  • Are of great value to the surgeon for mandible reconstruction with a microvascular free flap