Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Management of the axilla continues to evolve in the setting of neoadjuvant therapy
• Sentinel lymph node biopsy (SLNB) in clinically node-negative patients after neoadjuvant chemotherapy;
  • Is feasible and accurate:
    • A recent systematic review reported a pooled identification rate of:
      • 96% and false negative rate of 6%
        • These data do not differ from studies evaluating SLNB in early breast cancer without neoadjuvant chemotherapy
• Neoadjuvant chemotherapy can result in:
  • Downstaging of the axilla
• Performing the SLNB after chemotherapy:
  • Decreases the rate of finding a positive sentinel lymph node and subsequent axillary dissection
• The ACOSOG / Alliance Z1071 trial involved patients with initially node-positive disease and sought to determine the false negative rate for sentinel lymph node surgery following neoadjuvant chemotherapy in this group of patients:
  • The false negative rate for the entire cohort was 12%:
    • But on additional analysis, retrieval of at least two sentinel nodes and the previously biopsied node:
      • Was associated with a false negative rate of 6.8%:
        • Therefore, marking the biopsied node with a clip and documenting excision at time of SLNB is recommended
• References:
  • Geng C, Chen X, Pan X, Li J. The feasibility and accuracy of sentinel lymph node biopsy in initially clinically node-negative breast cancer after neoadjuvant chemotherapy: a systematic review and meta-analysis. PLoS One.2016;11(9):e0162605.
  • Hunt KK, Yi M, Mittendorf EA et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg. 2009;250(4):558-566.
  • Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455-1461.
  • Boughey JC, Ballman KV, Le-Petross HT et al. identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with node-positive breast cancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 (Alliance). Ann Surg.2016;263(4):802-807.

• The sequence (seconds → minutes):
  • Vascular injury and vasoconstriction:
    • Neurogenic reflex + endothelin:
      • Transient narrowing:
        • Slows flow and exposes subendothelial collagen and vWF
  • Platelet adhesion (to the wound):
    • vWF anchored on exposed collagen binds GP Ib-IX-V on platelets (high-shear arterial beds):
      • Platelet membrane glycoprotein Ib–IX–V complex:
        • The major von Willebrand factor (vWF) receptor:
          • That mediates initial platelet adhesion:
            • At sites of vascular injury (especially high-shear arteries)
    • Direct collagen binding via GP Ia/IIa (α2β1) and GP VI:
      • Complements adhesion
  • Activation and shape change:
    • Cytoskeleton rearranges:
      • Discoid → spiky:
        • ↑ surface area:
          • Phosphatidylserine flips outward
    • Platelets synthesize / release mediators:
      • Dense granules: 
        • ADP, ATP, Ca²⁺, serotonin
      • Alpha granules: 
        • vWF, fibrinogen, factor V, fibronectin, P-selectin, PDGF, TGF-β
      • TxA₂ is generated via:
        • COX-1 (aspirin target)
  • Recruitment (amplification):
    • ADP → P2Y12/P2Y1, TxA₂ (TP receptor), thrombin (PAR-1 / PAR-4):
      • Amplify activation on nearby platelets
    • Ca²⁺ is essential for signaling and integrin activation
  • Aggregation (hemostatic plug formation):
    • Activated GP IIb/IIIa (αIIbβ3) undergoes conformational change:
      • Fibrinogen bridges adjacent platelets:
        • Primary hemostatic plug
    • Leukocytes tether via P-selectin:
      • Adding stability
    • Handoff to secondary hemostasis (minutes):
      • Tissue factor (injured cells) plus factor VII:
        • Activate factor X :
          • Factor X plus factor V:
            • Convert prothrombin (factor II) to thrombin:
              • Converts fibrinogen to fibrin polymer:
                • Factor XIII crosslinks fibrin:
                  • Stabilizing the platelet plug
• Why surgeons care (pattern recognition):
  • Primary (platelet) defects: 
    • Mucocutaneous bleeding, oozing from raw surfaces, petechiae, immediate post-incision bleeding
    • PT / PTT often normal
  • Secondary (coagulation) defects: 
    • Delayed re-bleeding, deep tissue / hematoma, hemarthrosis
• Drugs and diseases mapped to the steps:
  • Adhesion:
    • ↓ vWF (von Willebrand disease) → poor GP Ib-vWF “tether”:
      • DDAVP can ↑ endothelial vWF release (Type 1 vWD, some qualitative defects)
  • Activation:
    • Aspirin / NSAIDs → block COX-1 → TxA₂ (qualitative dysfunction)
    • Uremia, hypothermia, acidosis, hemodilution / CPB:
      • Global platelet dysfunction
      • DDAVP helps in uremia
  • Recruitment:
    • P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) blunt ADP signaling
  • Aggregation:
    • Gp IIb/IIIa antagonists (eptifibatide/tirofiban) block fibrinogen bridging
    • Glanzmann thrombasthenia (GP IIb/IIIa deficiency):
      • Severe aggregation defect
    • Bernard–Soulier (GP Ib deficiency):
      • Adhesion failure; giant platelets
• Practical peri-op numbers (rules of thumb):
  • Platelet count targets (institutional policies vary):
    • Most non-neurosurgical / non-ocular operations: 
      • ≥ 50k/µL
    • Neuraxial, intracranial, posterior eye:
      • ≥ 80 to 100k/µL
    • Ongoing microvascular free-flap or diffuse oozing often needs:
      •  > 75 to 100k/µL and intact function
  • Apheresis platelets: 
    • Typically ↑ count by ~ 30 to 50k/µL in a 70-kg adult
  • Coordinate any antiplatelet interruption with cardiology (especially recent stents):
    • If drugs cannot be stopped, plan local / topical strategies and consider point-of-care testing
• OR playbook for platelet-type bleeding:
  • Pre-op:
    • Focused history (mucosal bleeding, easy bruising), meds (aspirin, P2Y12), renal function
    • Consider PFA-100/VerifyNow/TEG-PlateletMapping if results will change management
  • Intra-op:
    • Local control: 
      • Meticulous pressure, bipolar, vessel loops; topical hemostats (thrombin, gelatin sponge, oxidized cellulose, collagen matrix, fibrin sealant)
    • Antifibrinolytics: 
      • Tranexamic acid (IV / topical) particularly helpful on mucosal fields (head and neck, oral cavity)
    • Maintain normothermia, ionized Ca²⁺, pH > 7.2; avoid hemodilution
    • If on aspirin / P2Y12 with urgent bleeding:
      • Platelet transfusion can overcome irreversible blockade (earlier works better for aspirin than ticagrelor); weigh thrombosis risk
    • DDAVP for vWD Type 1 or uremic dysfunction (watch Na⁺; tachyphylaxis after 1 to 2 doses)
  • Post-op:
    • Control blood pressure, avoid NSAIDs, continue local antifibrinolytics when helpful (e.g., pledgets / mouthwash in mucosal cases), and reassess platelet count / function if oozing persists
• Quick differentials when the field won’t dry:
  • Normal PT / PTT, low platelets or recent antiplatelet use → primary hemostasis problem
  • Prolonged PT / PTT, normal platelets → secondary hemostasis issue (think tissue factor pathway, anticoagulants)
  • Everything “normal,” but diffuse oozing → platelet dysfunction (uremia, hypothermia, CPB, meds) ± hyperfibrinolysis (consider TXA, fibrinogen / cryoprecipitate guided by TEG/ROTEM)

• Normal coagulation (hemostasis):
  • Three initial responses to vascular injury:
    • Vasoconstriction:
      • Neurohumoral + endothelin
    • Platelet adhesion / activation / aggregation:
      • Primary hemostasis
    • Thrombin generation:
      • That leads to fibrin clot formation:
        • Secondary hemostasis NCBI+1
• Primary hemostasis – what actually happens:
  • Adhesion: 
    • VWF bridges exposed subendothelial collagen to platelet GPIb-IX-V (high shear)
    • Collagen also signals via:
      • GPVI and α2β1 (GPIa/IIa) NCBI+1
  • Activation + secretion: 
    • Shape change
    • Dense granule:
      • ADP and TxA₂ amplify recruitment
    • Surface phosphatidylserine (PF3) flips out:
      • Creating a catalytic platform for coagulation enzymes NCBI
  • Aggregation: 
    • Inside-out signaling activates:
      • αIIbβ3 (GPIIb/IIIa)
    • Fibrinogen (and later fibrin) bridges adjacent platelets:
      • Platelet plug NCBI+1
  • Key receptors to remember: 
    • ADP → P2Y12 / P2Y1
    • TxA₂ → TP
    • Thrombin → PAR-1 / PAR-4(and also binds GPIbα) NCBI+2PubMed+2
  • Secondary hemostasis – complexes and convergence:
    • Tenase complexes:
      • Extrinsic:
        • Tissue factor (TF) from injured cells – factor VIIa:
          • Plus Ca²⁺, membrane:
            • Activates factor X
      • Intrinsic: 
        • Exposed collagen + prekallikrein + HMW Kininigen = Factor XII:
          • Activate Factor XI:
            • Activate factor IXa – then add factor VIIIa:
              • Plus Ca²⁺, membrane:
                • Powerfully activates factor X (major amplifier)
      • Factor X:
        • Is the common convergence point NCBI+1
      • Prothrombinase complex (correct name for what forms on platelets): 
        • Factor Xa + factor Va + Ca²⁺ + anionic phospholipid (PF3):
          • Converts prothrombin (factor II) to thrombin (factor IIa) NCBI
            • Thrombin – central protease (know these):
              • Converts fibrinogen → fibrin,
        • Activates factor V, factor VIII, factor XI, factor XIII
        • Strongly activates platelets via PAR-1 / PAR-4
        • When bound to thrombomodulin:
          • Activates protein C (anticoagulant pathway) NCBI+1
      • Factor XIII: 
        • A transglutaminase that crosslinks fibrin and incorporates α2-antiplasmin into the clot:
          • Producing stability and resistance to fibrinolysis NCBI
• Fibrin’s role with platelets:
  • Fibrin(ogen) binds αIIbβ3, linking platelets and stabilizing the plug as fibrin polymerizes and is cross-linked Haematologica
• Normal anticoagulation (checks and balances)
  • Antithrombin (AT-III):
    • Key serpin that neutralizes:
      • Thrombin (IIa), IXa, Xa, XIa, XIIa
  • Heparin / Heparan sulfate:
    • Accelerates AT-III activity dramatically (clinical basis of UFH /LMWH) NCBI+1
  • Protein C / Protein S (vitamin K–dependent):
    • Thrombin – thrombomodulin on endothelium:
      • Activates protein C:
        • Which (with protein S cofactor) proteolytically inactivates Va and VIIIa (not fibrinogen)
  • TFPI (tissue factor pathway inhibitor):
    • Endothelium-derived inhibitor:
      • That inactivates factor Xa and, in an factor Xa – dependent manner:
        • Shuts down TF – FVIIa:
          • The dominant brake on the initiation phase
    • Protein S enhances TFPIα’s factor Xa inhibition:
      • Nuance:
        • TFPI does not simply “inhibit factor X”; it inhibits factor Xa and the TF – FVIIa complex NCBI+2ASA Journals+2
  • Endothelial antithrombotic tone (nice to remember): 
    • PGI₂, NO, and CD39 (ecto-ADPase) limit platelet activation
    • Heparan sulfate potentiates AT
• Fibrinolysis (clot removal):
  • tPA / uPA (primarily from endothelium) convert plasminogen → plasmin:
    • Preferentially on fibrin-rich surfaces
  • Plasmin:
    • Degrades fibrin and fibrinogen → FDPs (D-dimer reflects cross-linked fibrin breakdown) NCBI+1
  • Major inhibitors / regulators:
    • PAI-1 (± PAI-2):
      • Inhibit tPA / uPA
    • α2-antiplasmin:
      • Neutralizes plasmin and is cross-linked to fibrin by factor XIII
    • TAFI (activated by thrombin – thrombomodulin) trims C-terminal lysines from fibrin, reducing plasminogen / tPA binding and slowing lysis NCBI+2PubMed+2
      
      

• The intergroup Radiation Therapy Oncology Group (RTOG 91–11) trial for advanced larynx cancer established:
  • Concurrent bolus cisplatin with radiation as a standard of care
• I mentioned that the study was open to patients with squamous cell carcinoma of the glottic or supraglottic larynx:
  • Patients with T1 disease or large-volume T4 disease were excluded
• Patients were randomly assigned to one of three larynx preservation strategies:
  • Induction cisplatin plus 5-FU followed by radiotherapy
  • Radiotherapy with concurrent cisplatin
  • Radiotherapy alone
• I mentioned that the dose of radiotherapy to the primary tumor and clinically positive nodes was:
  • 70 Gy in all treatment groups
• Severe or life-threatening mucositis in the radiation field was:
  • Almost twice as common in the concurrent treatment group compared with either the radiotherapy alone group or the sequential treatment group
• The primary endpoint of the study was:
  • Preservation of  the larynx
• The rate of laryngeal preservation was:
  • 84% for patients receiving radiotherapy with concurrent cisplatin versus 72% or patients receiving induction chemotherapy followed by radiation and 67% for patients receiving radiation therapy alone:
    • At a median follow-up of 3.8 years
• Distant metastases were reduced:
  • In patients who received either concurrent chemoradiotherapy or induction chemotherapy followed by radiotherapy compared with patients who received radiotherapy alone
• Overall survival:
  • Was not significantly different among the three treatment groups
• The lack of an overall survival difference between the three groups:
  • May be due to the contribution of salvage laryngectomy in all groups, as well as a 2% increase in the incidence of death that may have been related to treatment in the concurrent chemoradiotherapy group compared with the other two treatment groups:
    • It is important to recognize that the primary endpoint of the study was larynx preservation:
      • Not overall survival
• The current standard of care for larynx preservation remains:
  • Concurrent high-dose cisplatin and radiation for patients who fit the eligibility criteria that were used in RTOG 91–11

• Perhaps one of the most striking advances in breast cancer management and understanding:
  • Came with the molecular profiling of breast cancer:
    • Characterizing four distinct subtypes:
      • Based on the landmark paper by Perou et al., in 2000
• These define tumor biology and correlate with outcome and are broadly described as:
  • Luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and basal like:
    • According to the most common profiles for each subtype:
      • However, not all tumors within each subtype contain all features
• The estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor:
  • Are used as surrogates to approximate these subtypes and guide clinical care and management decisions
• Luminal A:
  • Most (80% to 85%) of breast cancers express the estrogen receptor (ER-positive) and / or the progesterone receptor (PR+) (75% to 80%) but not HER2:
    • These cancers tend to be more indolent than other subtypes
  • Luminal A tumors are associated with the most favorable prognosis:
    • Particularly in the short term:
      • In part because expression of hormone receptors:
        • Is predictive of a favorable response to hormonal therapy
• Luminal B:
  • These breast cancers are ER-positive and / or PR+:
    • They are further defined by either:
      • HER2 amplification, or high Ki-67 (an indicator of cellular proliferation)
  • They tend to have higher grade and more aggressive features than luminal A breast cancers
• HER2-enriched:
  • These breast cancers produce excess HER2 and do not express hormone receptors
  • These cancers tend to grow and spread more aggressively than other breast cancers and are associated with poorer short-term prognosis compared to ER-positive breast cancers:
    • However, the recent widespread use of targeted therapies for HER2-positive cancers:
      • Has reversed much of the adverse prognostic impact of HER2 overexpression:
        • With 40% to 70% of women achieving a pathologic complete response to combination chemotherapy and targeted anti-HER2 therapies
• Basal like:
  • These tumors are more biologically aggressive:
    • They are typically characterized by the lack of the ER, PR, and HER2 receptor
  • These cancers are often found in:
    • Premenopausal women
    • Those with a BRCA1 gene mutation
  • They are nearly two times more common:
    • In Black women than White women in US
  • The majority (> 70%) of triple negative breast cancers:
    • Fall into the basal-like subtype
  • Triple negative breast cancers:
    • Have a poorer short-term prognosis than other breast cancer types:
      • In part because there are currently no targeted therapies for these tumors:
        • However, a proportion of these tumors are very chemosensitive, exhibiting a pathologic complete response in up to a third of patients
    • Furthermore, several molecular subtypes of triple negative breast cancer have been described:
      • These may provide further insights into the varying biologic response and assist in development of therapeutic targets in addition to chemotherapy

• As reported by Veronesi in 1999:
  • 737 patients were randomized to either undergo Halsted mastectomy or extended mastectomy with IM node dissection
  • After 30 years of follow-up:
    • There was no difference in overall survival or disease-specific survival:
      • For the patients eligible with T1, T2, T3, N0, and N1 disease:
        • Who underwent IM node dissection vs. no IM dissection
• A 2019 retrospective review of 95 breast cancer patients with clinically detected IM nodes (IMNs) at diagnosis:
  • Were treated with surgery and radiation, with median follow-up of 43 months:
    • 77 received neoadjuvant chemotherapy:
      • With IMN normalization in 67.5%
      • Partial IMN response in 24.6%
  • The 5-year IMN failure-free survival, disease-free survival, and overall survival were:
  • 96%, 70%, and 84%, respectively
    • IMN failure-free survival:
      • Was significantly affected by:
        • Resection margin status
        • Size of IMN
        • Receipt of IMN boost radiation
• A recently published meta-analysis in the Annals of Surgery found that axillary staging following neoadjuvant chemotherapy:
  • Is best performed with a combination approach of sentinel lymph node biopsy (SLNB) with excision of the pre-chemotherapy-marked positive node:
    • With a false negative rate of 2% to 4%:
      • The identification rate was 100%
• ACOSOG Z1071:
  • Reported an overall false negative rate of 12.6% when SLNB was performed after neoadjuvant chemotherapy with documented node-positive disease prior to treatment:
    • The false-negative rate decreased to 6.8%:
    • When both sentinel node(s) and the clipped node were retrieved at the time of surgery
• References:
  • Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer. 1999;35(9):1320-1325.
  • Kim J, Chang JS, Choi SH, et.al. Radiotherapy for initial clinically positive internal mammary nodes in breast cancer. Radiat Oncol J. 2019;37(2):91-100.
  • Simons JM, van Nijnatten TJA, van der Pol CC, Luiten EJT, Koppert LB, Smidt ML. Diagnostic accuracy of different surgical procedures for axillary staging after neoadjuvant systemic therapy in node-positive breast cancer: a systematic review and meta-analysis. Ann Surg. 2019;269(3):432-442.
  • Boughey JC, Ballman KV, Le-Petross HT, et al. Identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with nodepositive breast cancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 (Alliance). Ann Surg. 2016;263(5):802-807.

• Design and Arms:
  • Population: 
    • 547 patients with stage III to IV (cT2 bulky to cT4) resectable squamous cell carcinoma of the larynx(supraglottic or glottic):
      • Who were candidates for total laryngectomy
• Randomization (3 arms):
  • Induction PF → RT (Control): 
    • Three cycles cisplatin 100 mg / m² day 1 + 5-FU 1 g/m²/day × 5, followed by definitive RT (66 to 76 Gy) for responders
  • Concurrent CRT: 
    • RT (70 Gy) + cisplatin 100 mg / m² q3wk ×3
  • RT Alone: 
    • 70 Gy definitive radiation
• Primary endpoint: 
  • Laryngectomy-free survival (LFS) and larynx preservation without loss of overall survival (OS)

• Interpretation:
  • Concurrent cisplatin-RT produced the highest larynx-preservation rate and superior laryngectomy-free survival compared with both RT alone and induction PF
  • No OS advantage for any arm:
    • Survival curves overlapped
• Long-Term and Late Toxicities (Forastiere et al., JCO 2013 update):
  • Non–cancer deaths:
    • Cardiopulmonary, treatment-related:
      • More frequent in the concurrent CRT arm after year 5
  • Late swallowing dysfunction and chronic aspiration:
    • Higher with CRT
  • Highlights need for lifelong surveillance and aggressive supportive care:
    • Speech / swallow therapy
    • Pulmonary monitoring
• Clinical Application:
  • Standard of care for organ preservation:
    • Definitive RT + high-dose cisplatin (100 mg / m² q3wk ×3):
      • For patients who are surgical candidates but wish to avoid total laryngectomy and are cisplatin-eligible
      • Requires baseline audiogram, renal function, and performance status assessment
  • Alternatives:
    • For cisplatin-ineligible patients:
      • Cetuximab-RT or carboplatin-based CRT:
        • With the understanding of lower organ-preservation rates

• Cisplatin-ineligible unresected disease:
  • Most guideline-concordant RT partner:
    • Cetuximab
• Anchor trials and what they show:
  • Proof that EGFR antibody + RT beats RT alone:
    • Establishes cetuximab as a curative RT partner
  • Bonner et al., NEJM 2006; 5-yr update 2010:
    • In locoregionally advanced, unresected HNSCC, adding cetuximab to definitive RT over RT alone improved:
      • Locoregional control:
        • Median 24.4 months vs 14.9 months:
          • HR 0.68, p=0.005 over RT alone
      • Overall survival:
        • Median 49.0 months vs 29.3 months:
          • HR 0.74, p=0.03 over RT alone
      • This occured without excess severe mucositis
    • This is the randomized dataset that legitimized cetuximab as a radiosensitizer when chemotherapy can’t be given:
      • New England Journal of Medicine+3PubMed+3New England Journal of Medicine+3
  • Proof that substituting cetuximab for cisplatin is harmful in HPV+ OPSCC:
    • So only use when truly ineligible
    • Trials:
      • RTOG-1016 (Lancet 2019): 
        • RT + cetuximab failed non-inferiority vs RT + cisplatin
        • It produced worse OS and PFS in HPV-positive OPSCC
        • Investigators conclude cisplatin remains the standard for eligible patients:
          • oralcancerfoundation.org+3PubMed+3The Lancet+3
      • De-ESCALaTE HPV (Lancet 2019): 
        • Similarly showed inferior OS and higher recurrence with cetuximab – RT vs cisplatin – RT:
          • Ending the practice of “de-escalation by substitution” 
            • The Lancet
  • Attempts to replace cetuximab in the cisplatin-ineligible setting haven’t beaten it:
    • NRG-HN004 (2024): 
      • In patients contraindicated for cisplatin, RT + durvalumab:
        • Did not improve outcomes over RT + cetuximab:
          • Cetuximab – RT remained the reference:
            • PubMed+2The Lancet+2
• Guideline through-line (how this translates to practice):
  • NCCN (2025): 
    • For definitive management when cisplatin is contraindicated:
      • For example:
        • Renal dysfunction, grade ≥ 2 SNHL, significant neuropathy
      • RT + cetuximab is a listed option:
        • Substitution for convenience or “de-escalation”;
          • Is not recommended given RTOG-1016 / De-ESCALaTE trials;
            • JNCCN
• Practical takeaways for your pathway:
  • Most guideline – concordant partner when cisplatin is off the table:
    • Cetuximab with RT:
      • Supported by the only randomized trial showing benefit over RT alone (Bonner) PubMed
  • Do not swap out cisplatin in HPV+ disease unless truly ineligible:
    • Expect worse survival with substitution PubMed+1
  • If cetuximab isn’t feasible:
    • Severe infusion reactions:
      • Some centers use carboplatin – based CRT (often AUC 1–2 weekly ± partner):
        • But high-level randomized evidence with RT is limited relative to cetuximab:
          • Data are mainly retrospective / phase II (Guideline nuances vary by site and risk) Cancer Treatment Reviews
• Bottom line: 
  • In cisplatin-ineligible, unresected HNSCC:
    • RT + cetuximab remains the most evidence-based, guideline-aligned radiosensitizer:
      • Chosen because it improves outcomes vs RT alone:
        • While trials show it must not replace cisplatin in eligible HPV+ patients

• Diffusely invasive carcinoma:
  • Has a mammographic appearance of diffuse architectural distortion:
    • Usually involving a large area, often larger than a lobe:
      • With no central tumor mass and no calcifications:
      • • It sometimes has the appearance of a “spider’s web” as shown in the Image

• The diffusely infiltrating cancer:
  • Forms concave contours with the surrounding fat in a manner similar to normal fibroglandular tissue (Images)

• The imaging findings of diffusely infiltrating breast cancer are strikingly different:
  • From the imaging findings of breast cancers originating either from the terminal ductal lobular units (TDLUs) or the lactiferous ducts:
  • • Suggesting that it may have a different site of origin

• It has been recently proposed that diffusely infiltrating breast cancers:
  • May originate from mesenchymal stem cells (progenitors):
    • Through a complex process of both:
      • Epithelial-mesenchymal transformation and more frequently, mesenchymal-epithelial transformation

• The clinical presentation:
  • Is typically a recently detected, extensive, firm lesion:
    • Often appearing as an interval cancer following a previous mammogram which was interpreted as normal

• On clinical breast examination:
  • The cancer does not have a distinct tumor mass or focal skin retraction seen in other cancers:
    • But rather an indistinct “thickening” and eventually a shrinkage of the breast.

• In order to make the diagnosis before the development of a palpable mass and a decrease in size of the breast:
  • The radiologist and breast surgeon must have a high level of suspicion and a thorough knowledge of the underlying pathophysiology

• The subgross (3D) histopathology images show how growth of the mesenchymal tissue:
  • Distorts the normal, harmonious connective tissue framework:
    • By causing nonuniform thickening of the fine sheets of connective tissue (Images):

• The predominance of mesenchyme in the diffusely infiltrating breast malignancy:
  • Allows it to be imaged with greater sensitivity by ultrasound than by mammography:

• • • The thin sheets or veils of tissue reflect the ultrasound waves:
      • But are relatively easily penetrated by x-rays

• • The structural / architectural distortion:
  • • While difficult to detect mammographically:
      • Is readily detectable on 2-mm thick coronal sections of automated breast ultrasound (Image)

• The 2-mm thick multi-slice series demonstrate the extensive architectural distortion, corresponding to the 3D histology:

• The hypoechoic changes can also usually be seen on hand held ultrasound, Image:

• The growth pattern and cell type of diffusely invasive breast cancer:
  • Is very similar to that of diffuse gastric carcinoma (linitis plastica), and both of these diseases can be associated with:
    • A deleterious mutation in the CDH1 gene:
      • Which is located on chromosome 16q22 and codes for e-cadherin protein (Image):

• CDH1 was initially known as a susceptibility gene for diffuse gastric cancer (linitis plastica)

• The histopathologic characteristics of diffuse gastric cancer:
  • Show similarities with e-cadherin negative:
    • Diffusely infiltrating breast cancer (infiltrating “lobular” carcinoma)
  • The neoplastic cells permeate the mucosa and wall as scattered individual signet-ring cells or small clusters of cells in an infiltrative growth pattern

• Since there are no TDLUs in the stomach:
  • If the similar cells in both conditions associated with CDH1 have a common origin, it could not be a TDLU:
  • • Raising the possibility that they could result from mesenchymal cell transformation in both organs

👉Rodrigo Arrangoiz MS, MD, FACS, FSSO cirujano oncology y cirujano de mamá de en Mount Sinai Medical Center:

• Es experto en el manejo del cáncer de mama

 👉Es miembro de la American Society of Breast Surgeons:

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

#Arrangoiz

#Surgeon

#Cirujano

#SurgicalOncologist

#CirujanoOncologo

#BreastSurgeon

#CirujanodeMama

#CancerSurgeon

#CirujanodeCancer

• When to perform sentinel lymph node mapping and biopsy?
  • cT1N0, 65 y, HR+/HER2–, tumor 1.5 cm, negative axillary US, breast-conserving surgery (BCS). SLNB or omit?
    • Omission of SLNB is reasonable per ASCO 2025 criteria:
      • Low-risk, ≥ 50 years, HR+ / HER2-, ≤ 2 cm, negative pre-op axillary imaging, BCS:
        • After shared decision-making
  • Same patient as #1 but undergoing mastectomy. SLNB?
    • Perform SLNB:
    • Even if cN0, mastectomy removes future SLNB opportunity:
      • Most guidelines advises SLNB at mastectomy in case invasive disease or nodal information will alter RT /systemic therapy
  • Define the standard indications for SLNB in invasive cT1 to T2, cN0 disease:
    • SLNB is standard for staging in clinically node-negative invasive cancers:
      • Exceptions include specific low-risk cohorts where omission is now endorsed
      • Omission is reasonable per ASCO 2025 criteria:
        • Low-risk, ≥ 50 y, HR+/HER2–, ≤ 2 cm, negative pre-op axillary imaging, BCS, after shared decision-making
  • Pure DCIS having lumpectomy – do you stage the axilla?
    • No:
      • Pure DCIS treated with BCS does not need SLNB
  • DCIS requiring mastectomy – do you add SLNB?
    • Yes:
      • Perform SLNB at mastectomy because later mapping is unreliable and occult invasion risk exists
  • Role of pre-op axillary ultrasound (US) before SLNB?
    • US triages patients:
      • If suspicious nodes, biopsy to confirm cN+:
        • If negative and tumor low-risk, supports SLNB omission in ASCO-defined cohorts
  • SOUND trial bottom line for small tumors with negative axillary US:
    • In cT1 ≤ 2 cm, cN0 with negative US, no axillary surgery was non-inferior to SLNB for 5-year distant DFS
  • INSEMA trial bottom line (NEJM 2025):
    • Among cT1 to cT2, cN0 undergoing BCS, omitting axillary surgery was non-inferior to SLNB for invasive DFS, with less morbidity
  • Does NCCN acknowledge de-escalation of axillary surgery in select early-stage cases?
    • Yes – NCCN endorses risk-adapted axillary management; details in current NCCN Breast Cancer Guideline
  • Key counseling points when considering SLNB omission
    • Ensure negative axillary imaging, small HR+ / HER2-tumor, BCS with adjuvant therapy, and that nodal information won’t change systemic / RT plans; use shared decision-making
• Omission of SLNB in Early Breast Cancer – ASCO 2025 / SOUND / INSEMA Trials;
  • ASCO 2025 Guideline Update (“Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer”) provides formal recommendations to omit routine SLNB in select patients:
    • The criteria include:
      • Age ≥ 50 and postmenopausal status 
      • HR positive
      • HER2 negative
      • Tumor grade 1 to 2
      • ≤ 2 cm size 
      • Clinically node negative (by exam)
      • Negative on preoperative axillary ultrasound (or a suspicious node that is benign on biopsy) 
      • Undergoing breast-conserving therapy with whole-breast irradiation (WBRT) ideally (for patients < 65; for older patients there is more flexibility) 
  • Trials supporting this omission:
    • SOUND trial – randomized patients with T1 (≤ 2 cm), cN0 breast cancer and negative axillary ultrasound to SLNB vs no axillary surgery:
      • At 5 years, distant disease-free survival was similar in both arms
    • INSEMA trial – included clinically node-negative invasive breast cancer ≤ 5 cm undergoing BCS:
      • This trial found omission of axillary surgery was non-inferior to SLNB in terms of invasive disease-free survival
  • Morbidity / Quality of life data:
    • In the INSEMA trial, omitting SLNB led to lower rates of persistent lymphedema:
      • ~ 1.8% in omission vs 5.7% in SLNB group
      • Other arm morbidity measures like restricted shoulder / arm movement and pain were significantly less in the omission group
      • These differences are clinically significant, especially considering the trade-off between morbidity and marginal gain in prognostic information in low-risk patients
  • Risks / caveats:
    • Even in SOUND and INSEMA trials, almost all patients still got radiotherapy (WBRT) which likely contributed to controlling any microscopic nodal disease
    • The longer follow-up is needed to ensure late recurrences in HR+ disease are not missed:
      • ASCO guidelines recognize that. 

• Positive sentinel nodes: who still needs ALND?
  • Z0011 scenario:
    • BCS + whole-breast RT, 1 to 2 positive SLNs (no gross ECE). ALND needed?
      • No. Omit ALND – no OS / DFS detriment at 10 years
  • IBCSG 23-01:
    • Micromets (≤ 2 mm) in SLN – ALND?
      • No:
        • Omit ALND; 10-year outcomes show safety
  • AMAROS take-home when SLN positive (mostly macromets):
    • Axillary RT provides comparable regional control to ALND with less lymphedema – a de-escalation option
  • Does Z0011 apply to mastectomy?
    • No:
      • Z0011 included lumpectomy + whole-breast RT only
      • If mastectomy and SLN+, decisions differ:
        • ALND or nodal radiation often considered
  • > 2 positive SLNs at upfront surgery – what’s recommended?
    • ALND or nodal RT (RNI) typically indicated
      • Z0011 criteria not met
  • Gross extranodal extension (ENE) in SLN on pathology – management?
    • Generally ALND (or comprehensive RNI) considered:
      • Most de-escalation trials excluded gross ENE
  • Under-coverage RT plans (no low-axilla tangents) but 1 to 2 SLN+ after BCS – omit ALND
    • Be cautious:
      • Z0011 assumed tangential fields. If axilla not covered, many favor ALND or add nodal RT
  • Inflammatory breast cancer – axillary staging approach?
    • ALND indicated:
      • SLNB is unreliable
  • cT3 / cT4 tumors but cN0, BCS planned – Z0011 applicable?
    • Z0011 enrolled T1 to T2:
      • Extrapolation to T3 / T4 is not evidence-based – individualize, often favor completion treatment
  • Do isolated tumor cells (ITCs) in SLN mandate ALND?
    • No; ITCs (pN0[i+]) do not require ALND
• ACOSOG Z0011 – ALND vs No ALND when SLNs positive
  • Population and design:
    • Women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, 1 to 2 sentinel lymph nodes positive by hematoxylin and eosin stain
    • All underwent lumpectomy + WBRT + adjuvant systemic therapy
    • Median follow-up ~ 9.3 years

• Hazard Ratios / Noninferiority:
  • The study had a prespecified noninferiority margin of HR = 1.3 for OS:
    • The observed HR was 0.85 (SLND alone vs ALND) for OS; P = .02 for noninferiority
  • DFS had HR 0.85 (95% CI 0.62-1.17), i.e. no statistically significant difference
• Applicability limits (i.e. external validity constraints):
  • Excluded patients with > 2 positive SLNs, gross extranodal extension, patients undergoing mastectomy without RT, or those not getting WBRT tangents as per protocol:
    • So results apply only to those meeting Z0011 criteria
• Additional / Supporting Data and Real-World Observations:
  • Risk of lymphedema:
    • ALND is associated with significantly higher rates of lymphedema, shoulder mobility limitations, and arm pain than SLNB alone
    • Studies show that lymphedema incidence after SLNB is much lower (e.g., single digits) compared to ALND (where rates may be 20% to 30+% depending on patient, RT, etc.)
    • The SOUND / INSEMA omission studies show ~ 5% to 6% lymphedema in SLNB arm vs ~1% to 2% when SLNB omitted
    • Ultrasound negative imaging correlate:
      • In ASCO guideline and supporting articles, it’s noted that when axillary US is negative preoperatively in low-risk patients, ~85% of the time the SLNB is also negative
      • So negative US is a strong predictor and helps avoid unnecessary SLNB in selected patients.
    • Long-term axillary recurrence rates:
      From Z0011:
      • Regional recurrence was < 1% over the 10 years in SLNB alone group
    • Real-world data (e.g. from NSABP, other cohorts) confirm similar low regional recurrence in patients meeting Z0011 criteria with SLNB alone
• Putting It All Together: Key Data-Driven Pearls:
  • For a patient meeting Z0011 criteria (T1 to T2, cN0, 1 to 2 SLNs positive, lumpectomy + WBRT + systemic therapy):
    • Omitting ALND results in noninferior OS and DFS at 10 years, with very low regional recurrence (< 1%)
  • In the ASCO 2025 SLNB omission group (SOUND, INSEMA), for low-risk patients (≤2 cm, HR+/HER2-, grade 1-2, ≥ 50 y, negative US):
    • Omission of SLNB is noninferior in invasive disease–free or distant disease-free survival at 5 years
    • Also, nodal positivity on SLNB in these patients is relatively uncommon
    • The trade-off:
      • Small absolute increase in risk of occult nodal disease vs measurable reduction of morbidity (lymphedema, pain, mobility)
      • For many patients, quality of life gains are meaningful