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Tubular Carcinoma of the Breast

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Tubular carcinoma:
    • Is a distinct histopathologic subtype of breast cancer:
      • Representing 1% to 2% of breast cancers diagnosed
    • It is a distinct entity from low-grade ductal carcinoma
  • The literature continues to suggest that it has an excellent prognosis:
    • With a very low likelihood of distant metastasis and excellent disease-free survival
  • In select patients, adjuvant therapies may be omitted:
    • However, there is a still a risk of axillary nodal metastasis:
      • Therefore sentinel lymph node biopsy is still recommended:
        • Due to a 10% to 20% risk of lymphatic spread:
          • Despite this finding, there is likely to be only one node involved and this histopathologic subtype still conveys an excellent prognosis
  • Tubular carcinoma:
    • Is more likely to be identified on screening mammography and is more common in Caucasians than blacks
    • Emerging data suggest that adjuvant systemic therapy can likely be safely omitted, although it should still be discussed with the multidisciplinary team
  • References:
    • Rakha EA, Lee AH, Evans AJ, et al: Tubular carcinoma of the breast: further evidence to support its excellent prognosis. J Clin Oncol. 2010;28(1):99-104.
    • Fedko MG, Scow JS, Shah SS, et al. Pure tubular carcinoma and axillary nodal metastases. Ann Surg Oncol. 2010;17(Suppl 3):338-342.
    • Anderson WF, Chu KC, Chang S, Sherman ME. Comparison of age-specific incidence rate patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev. 2004;13(7): 1128-1135.

Variant of Unknown Significance (VUS) in Hereditary Breast Cancer Tests

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • When patients are told they have a variant of unknown significance (VUS):
    • It can often lead to anxiety and overtreatment
  • It is important to counsel patients that a VUS:
    • Is not clinically actionable and the majority of VUS are reclassified as benign
  • Patients should be counseled to update their genetic counselors:
    • As their family history changes and keep contact information up to date as variantbreclassification does occur
  • The American College of Medical Genetics:
    • Has recommended that genetic testing classify genetic variants using the following classification schema:
      • Deleterious (pathogenic)
      • Suspected deleterious (likely pathogenic)
      • Variant of Uncertain Clinical Significance
      • Genetic variant:
        • Favor polymorphism:
          • Likely benign
      • Polymorphism:
        • Benign
  • While deleterious and suspected deleterious mutations BRCA mutations:
    • Are known to be associated with an increased risk of breast and ovarian cancer:
      • It is unknown whether a BRCA VUS mutation:
        • Is associated with an increased risk due to limited available data
  • As the use of genetic testing increases and as more of the population is tested:
    • The knowledge base regarding variant pathogenicity constantly grows
  • Given the amount of data available from many years of BRCA1 / BRCA 2 testing:
    • The prevalence of VUS among this population has declined to 2% to 5%:
      • However, among moderate and low penetrance genes:
        • The number of VUS continues to rise:
          • As the data expand and knowledge regarding a variant evolves, a variant may be reclassified.
  • In a study reported in the Journal of the American Medical Association:
    • 25.4% of patients initially diagnosed with a VUS were reclassified over a 12-year period:
      • Of these patients:
        • 97% were downgraded to benign or likely benign
      • Three percent of patients (3%):
        • Were upgraded to pathogenic or likely pathogenic variants
    • Given this low risk of reclassification to pathogenic mutation:
      • Risk-reducing mastectomy, salpingo-oophorectomy, or genetic testing of family members are not indicated for this patient
  • There is currently no established effective screening protocol for pancreatic cancer, even among patients with a deleterious BRCA 2 mutation
  • References
    • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
    • Hall MJ, Reid JE, Burbidge LA, Pruss D, Deffenbaugh AM, Frye C, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233.
    • Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.
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Lymphedema After Axillary Surgery in Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Following treatment for breast cancer:
    • The onset of lymphedema is insidious:
      • It is typically characterized by slowly progressive swelling of the upper extremity ipsilateral to the axillary node dissection or radiation treatments
  • The main risk factors for breast cancer-associated lymphedema include:
    • Dissection / disruption of axillary lymph nodes
    • Radiation therapy
    • Local infection
    • Obesity
    • Other factors may also contribute
  • There is no known link between smoking and lymphedema
  • The American College of Surgeons Oncology Group (ACOSOG) Z1071 study:
    • Demonstrated that 40% of women with proven involved axillary nodes who underwent neoadjuvant chemotherapy:
      • Obtain a pathologic complete response in the previously involved nodes
    • Although the study demonstrated an overall false-negative rate of sentinel lymph node biopsy (SLNB) in this setting to be 12%:
      • The authors stratified these results and found that if more than two sentinel lymph nodes (SLNs) were removed in patients with dual tracer mapping (blue dye and radioisotope):
        • The false-negative rate of SLNB then dropped below 10% (6.8%)
  • With these guidelines, if SLNB is negative after neoadjuvant chemotherapy:
    • Consideration can be given to SLNB alone
  • The risk of lymphedema is significantly reduced with SLNB than with a level I / II axillary node dissection:
    • Odds ratio (OR) 0.33 based on Cochrane Review of three studies comparing SLNB to axillary dissection
  • Manual lymphatic drainage:
    • May offer some additional benefit to help with swelling reduction in patients with mild to moderate lymphedema:
      • But not all studies have found a benefit for this technique
  • Data are conflicting with regard to the prophylactic use of compression sleeves, prophylactic manual lymphatic drainage, or timing of arm mobilization following surgery
  • References
    • Hayes SC, Janda M, Cornish B, Battistutta D, Newman B. Lymphedema after breast cancer: incidence, risk factors, and effect on upper body function. J Clin Oncol.2008;26(21):3536-3342.
    • 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.
    • Bromham N, Schmidt-Hansen M, Astin M, Hasler E, Reed MW. Axillary treatment for operable primary breast cancer. Cochrane Database Syst Rev. 2017;1:CD004561.
    • Patricolo GE, Armstrong K, Riutta J, Lanni T. Lymphedema care for the breast cancer patient: an integrative approach. Breast. 2015;24(1):82-85.
    • Stuiver MM, ten Tusscher MR, Agasi-Idenburg CS, Lucas C, Aaronson NK, Bossuyt PM. Conservative interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy. Cochrane Database Syst Rev. 2015;2:CD009765.
    • Brennan MJ, Miller LT. Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema. Cancer 1998; 83(12 Suppl American):2821-2827.
#Arrangoiz #CancerSurgeon #BreastSurgeon #SurgicalOncologist #MountSinaiMedicalCenter #MSMC #Miami #Mexico

First Generation Laryngeal Carcinoma Preservation Trials

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • The first generation of larynx preservation chemotherapy trials:
    • Appeared in the 1990s:
      • They randomized patients into surgery and radiotherapy or to induction chemotherapy cycles of cisplatin / 5FU:
        • Patients who responded to chemotherapy then received radiotherapy:
          • With possible salvage surgery
      • If they did not respond to the chemotherapy:
        • They received surgery and postoperative radiotherapy
    • Generally, the results of these studies showed:
      • No significant difference in survival:
        • Between the two treatment arms
    • The larynx was preserved in:
      • 56% of patients undergoing the experimental chemoradiotherapy arm
  • In 2000, Pignon et al:
    • Published a meta-analysis of the first generation of laryngeal preservation chemoradiotherapy trials:
      • They included T3 laryngeal and hypopharyngeal cancers
    • There was no statistically significant difference in overall survival:
      • However, it is important to note:
        • That there was a trend to benefit from surgery:
          • Hazard ratio 1.19 intervals (0.97–1.46)
        • Surgery ± radiotherapy:
          • Resulted in overall survival of 45%:
            • Compared to an overall survival from chemoradiotherapy of:
              • 39%
        • 56% of those who survived with chemoradiotherapy:
          • Managed to avoid laryngectomy:
            • Giving an overall laryngectomy survival rate of:
              • 23% at five years
        • Patients treated with chemoradiotherapy:
          • Had almost double the local recurrence rate:
            • But less distant metastases than the patients treated with surgery
        • Analysis of laryngeal cancer patients separately from hypopharyngeal cancer patients:
          • Showed that laryngeal cancer patients in the surgical arm:
            • Demonstrated a risk reduction of 32%:
            • This suggests that advanced laryngeal tumors would be better treated with surgery than chemoradiotherapy:
              • On the other hand, hypopharyngeal cancer patients showed no difference in survival between the two modalities of treatment
  • The meta-analysis showed that the overall survival benefit from chemotherapy in addition to radiotherapy:
    • Was 4% at five years
  • Concomitant chemotherapy:
    • Resulted in an 8% overall survival benefit:
      • Compared to a 4% overall survival benefit from neoadjuvant chemoradiotherapy
  • Adjuvant chemoradiotherapy:
    • Resulted in no overall survival benefit
  • These findings have resulted in the adoption of concomitant chemoradiotherapy as the standard regimen for delivery of chemotherapy when treating laryngeal and pharyngeal cancers:
    • Recently, an update of this meta-analysis confirmed an overall survival effect of 6.5% for concomitant chemoradiotherapy
  • References:
    • The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New England Journal of Medicine 1991; 324: 1685–90.
    • Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949–55.
    • Pignon JP, le Maítre A, Maillard E et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and Oncology 2009; 92: 4–14.
    • Forastiere AA, Goepfert H, Maor M et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. New England Journal of Medicine 2003; 349: 2091–8.
#Arrangoiz #CancerSurgeon #HeadandNeckSurgeon #SurgicalOncologist #Surgeon #Doctor #MD #MSCM #MountSinaiMedicalCenter #ThyroidSurgeon #EndocrineSurgery #ParathyroidSurgeon#Miami #Mexico #LaryngealCancer

Management of the Axilla in the Setting of Neoadjuvant Therapy for Breast Cancer

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.

Primary Hemostasis

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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)
Primary hemostasis is achieved initially with a platelet aggregation as illustrated. Note that platelet adhesion, shape change, granule release followed by recruitment, and the hemostatic plug at the area of subendothelial collagen and collagen exposure are the initial events for thrombus formation.

Normal Coagulation and Normal Anticoagulation

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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:
    • 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

Management of Locally Advanced Laryngeal Carcinoma

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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
Design and results of Radiation Therapy Oncology Group trial 91–11. (Adapted from Forastiere AA, Goepfert H, Maor M, et al. Concurrent
chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091–2098.)

Molecular Subtypes of Breast Cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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

Staging of the Axilla Following Neoadjuvant Chemotherapy

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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.