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• Significant increase in incidence after mammography screening:
  • 17-fold increase from 1970’s to 2004:
    • 1 in 1300 mammograms
  • Represents 20% of all screen-detected breast neoplasias diagnosed annually
• DCIS by it self:
  • Is not a risk to life
• DCIS may progress to invasion and compromise survival:
  • If left untreated:
    • 1 in 6 DCIS patients:
      • Progress to invasive breast cancer (IBC):
        • 70% estimated to remain indolent
• At this time we do not have any robust biomarkers:
  • That can quantify the risk of progression to IBC or
  • Help us separate indolent disease:
    • From the potentially dangerous lesions
• Risk of overtreament:
  • The increase incidence of DCIS in mammographically detected cases:
    • Has not lead to a decrease in the incidence of IBC or reduction of IBC morality
• Risk factors for progression / recurrence of DCIS:
  • The risk factors for IBC recurrence may be different from the risks factors for DCIS recurrence?
    • Risk of IBC recurrence:
      • African American race
      • Premenopausal status
      • Detection by palpation
      • Involved margins
      • High histologic grade
      • High p16 expression
    • Risk of IBC or DCIS recurrence:
      • DCIS size
      • Histology type
      • Comedo necrosis
      • Grade
      • Young age
      • Close margins or positive margins
  • Patients with DICIS that recur with an IBC:
    • Some patients with DCIS may develop:
      • Progression of there disease
      • Some will have a de novo invasive breast cancer
      • Some might have a missed invasive cancer?
  • Patient that have a DCIS recurrence:
    • Might be a true in situ recurrence
    • De novo DCIS
    • Residual disease?
  • Studies are describing observations of events:
    • Synchronous IBC
    • Subsequent ipsilateral or contralateral DCIS or IBC (often a mixture)
    • We have limited data on DCIS progression with paired molecular profiles
• The most consistent biological feature of DCIS:
  • Heterogeneity:
    • In clinical presentation
    • Morphology
    • Protein expression:
      • Including receptor status
    • Gene expression
    • Genetic alterations
    • Epigenetic alterations
  • The heterogeneity is:
    • Between patients – within the lesion – and within cells in a single duct
• Morphological features that help us predict progression is:
  • Histologic grading:
    • Combing the nuclear grade 1 to 3 and necrosis into a three tier system (the good, the bad, and the ugly):
      • Low / intermediate / high grade
      • Grade 1 to 3
      • Van Nuys Group 1 to 3
      • DIN 1 to 3
    • We all know that there is regression towards the mean and substantial interobserver variation

• Unclear prognostic value of the 3-tier system:
  • We suspect that:
    • Low to intermediate grade = low risk of progression
    • High grade system = high risk of progression or shorter time to progression
  • Maxwell, A.J. Eur.J.Surg.Oncol.,2018, Ryser, MD. J.Natl Cancer Inst., 2019:
    • Risk of ipsilateral recurrence (DCIS / IBC) at 10 years:
      • High grade 17.6% (95% CI=12.1-25.2%)
      • Non high grade 12.2 (95% CI=8.6-17.1%):
        • Including grade 2
    • There is overlap in the confidence intervals
  • Low grade DCIS are the lesions that might have:
    • Discontinuous growth and skip lesions that might lead to a:
      • Greater likelihood of residual disease and recurrence?
  • Heterogeneity of grade within a lesion
• Histology subtype as a prognostic factor:
  • Subtype:
    • Cribriform is more often a grade 1 lesion
    • Comedo type is more often a grade 3 lesion
  • Usually histology subtype correlates with grade but:
    • There is often a mixture of growth patterns:
      • Compromising the use for prognostication

• Tumor micro environment:
  • Could potentially be the most important morphologic feature suggestive of progression especially:
    • Circumferential periductal fibrosis and associated tumor infiltrating lymphocytes (TIL):
      • Indicating host reaction to the tumor cells
  • Tumor micro environment includes:
    • Myoepithelial cell layer
    • Tumor infiltrating lymphocytes (TIL)
    • Adipocytes
    • Fibroblasts
    • Matrix

• The myoepithelial layer acts as a gatekeeper:
  • Has tumor suppressive functions
  • The largest gene expression change from normal tissue to DCIS:
    • Occurs in the myoepithelial layer
  • DCIS associated myoepithelial loss:
    • That leads the decrease tumor suppressor functions
  • The myoepithelial layer is lost in IBC

• Disruption of the myoepithelial defense:

• Conflicting data on prognostic value of TIL:
  • Some studies have reported no prognostic value of stromal TIL for subsequent recurrences:
    • Does the spatial location of the immune cells matter?
      • The TIL in direct contact with the DCIS might be more important that the TIL that are further away
  • Other studies have shown a correlation between higher levels of TIL and increased risk of subsequent IBC and a shorter (ipsilateral) recurrence-free survival

When Do Thyroid Nodules Need a Biopsy?

Not every thyroid nodule needs a biopsy.

The decision is based on ultrasound findings and size—not symptoms alone.

🔍 What determines the need for biopsy?

Using high-resolution ultrasound and validated systems (ATA / ACR TI-RADS), we assess:

Ultrasound risk features (solid, hypoechoic, irregular margins, microcalcifications, taller-than-wide) Nodule size Patient-specific risk factors (e.g., prior radiation exposure)

➡️ Only nodules meeting specific risk and size criteria should undergo biopsy.

🧪 What type of biopsy is used?

The standard test is an ultrasound-guided fine-needle aspiration biopsy (FNAB):

✔️ Minimally invasive

✔️ Performed in the office

✔️ No general anesthesia

✔️ Very low complication rate

✔️ High diagnostic accuracy

📊 Key facts for patients

Most nodules do NOT require biopsy FNAB helps avoid unnecessary surgery Results guide observation vs surgery vs further testing

🦋 Why this matters

Performing biopsies only when indicated:

Reduces patient anxiety Prevents overtreatment Focuses care on clinically significant disease

👨‍⚕️ Dr. Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

The goal is not to biopsy every nodule —

it’s to biopsy the right nodule at the right time.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules. Thyroid Tessler FN et al. ACR TI-RADS. Radiology Gharib H et al. Fine-Needle Aspiration of Thyroid Nodules. Endocrine Practice

Not all thyroid nodules are the same. Ultrasound risk stratification helps determine which nodules need biopsy and which can be safely observed.

🔍 What are TI-RADS and ATA?

ACR TI-RADS and ATA ultrasound patterns are validated systems that estimate cancer risk based on ultrasound features—not symptoms. They standardize care and reduce unnecessary biopsies and surgeries.

📊 How do these systems work?

Ultrasound evaluates:

Composition (solid vs cystic) Echogenicity Margins Calcifications Shape (taller-than-wide)

Each feature contributes to a risk category, which guides:

✔️ Whether to biopsy

✔️ When to follow up

✔️ How closely to monitor

🧪 Key patient takeaway

Low-risk nodules → observation with periodic ultrasound Intermediate/high-risk nodules → biopsy at size thresholds ➡️ This approach is safe, evidence-based, and personalized.

🦋 Why this matters

Risk stratification:

Avoids overdiagnosis Focuses treatment on clinically meaningful disease Improves patient reassurance and outcomes

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

The goal is the right test for the right nodule at the right time.

📚 References

Tessler FN et al. ACR TI-RADS. Radiology Haugen BR et al. ATA Guidelines for Thyroid Nodules. Thyroid Russ G et al. EU-TI-RADS. Eur J Endocrinol

• Adjuvant endocrine therapy is evolving: 
  Oral SERD in early HR+ / HER2− disease:
  • lidERA (giredestrant vs standard endocrine therapy):
    • What it tested:
      • Adjuvant giredestrant (oral SERD) vs standard endocrine therapy after surgery in ER+ /HER2− early breast cancer
  • Headline result:
    • Significant iDFS improvement:
      • They reported ~30% relative risk reduction (HR ~0.70) vs standard ET
    • Why it matters:
      • First credible signal in a long time that “better endocrine backbone” (beyond AI / tamoxifen) could become standard for selected early HR+ patients:
        • Especially if subgroup and safety data remain favorable
    • Surgical implication:
      • Expect more conversations about systemic escalation / de-escalation:
        • For example who truly needs CDK4/6 inhibitors vs a more potent endocrine option
• Post-neoadjuvant HER2+ residual disease: 
  T-DXd moves earlier:
  • DESTINY-Breast05 (T-DXd vs T-DM1):
    • Population:
      • HER2+ early breast cancer with residual invasive disease after neoadjuvant therapy:
        • High-risk post-NAC setting
    • Key outcome:
      • T-DXd superior to T-DM1 for invasive disease-free outcomes
    • Reported data (NEJM / PubMed):
      • Events 6.4% vs 12.6%, HR 0.47:
        • With 3-year DFS 92.3% vs 83.5%
    • Why it matters:
      • This is a direct “KATHERINE-successor” story:
        • If adopted into guidelines / pathways, it could reset the post-neoadjuvant standard for residual HER2+ disease 
    • Surgical implication:
      • Reinforces the importance of accurate residual disease documentation (pathology, RCB, nodal status) because this is what triggers the post-NAC systemic pathway
• Axillary de-escalation: 
  Omitting SLNB in selected cN0 patients:
  • Dutch randomized trial (BOOG 2013-08):
    • Design:
      • Clinically node-negative (cT1 to cT2), treated with BCS + whole-breast RT, randomized to SLNB vs omission
    • Message:
      • Regional control / oncologic outcomes were not worse with omission in carefully selected patients, supporting a further step in axillary de-escalation
    • SABCS:
      • Also highlighted interpretation alongside RT fields (since RT contributes to axillary control)
  • Practical “surgeon filter”:
    • This is not “no axillary surgery for everyone,” but it strengthens the discussion for:
      • Older / low-risk, cN0, BCS+RT patients in centers that can replicate selection / imaging rigor
• Pre-op staging MRI:
  • Routine use questioned in specific early BC subsets:
    • Alliance A011104 / ACRIN 6694:
      • Population:
        • Stage I / II HR-negative early breast cancer
      • Result:
        • Routine pre-op MRI did not improve key oncologic outcomes
        • MD Anderson reported 5-yr locoregional recurrence 6.8% with MRI vs 4.3% without (not favoring MRI)
      • Message:
        • More evidence that routine MRI may not improve outcomes and can drive additional procedures
      • Surgical implication:
        • Helps justify a more selective MRI strategy, dense breasts, lobular carcinoma, occult primary, discordant imaging, suspected multicentric disease, rather than reflex MRI for all
• Immune priming concept: 
  • Preoperative RT + pembrolizumab
     in HR+ / HER2− (early signal):
    • TBCRC-053 (P-RAD):
      • Concept:
        • Short-course preoperative RT (e.g., 24 Gy / 3 fractions) added to pembrolizumab + chemotherapy
    • Signal:
      • Increased tumor T-cell infiltration and “immune activation” endpoints:
        • Hypothesis-generating but compelling
    • Clinical implication:
      • Not practice-changing yet, but it’s a blueprint for future trials aiming to convert HR+ tumors into more immunogenic disease
• DCIS de-escalation reality check: 
  Tamoxifen-only (no surgery) did not meet safety bar:
  • LORETTA (JCOG1505):
    • Design:
      • Single-arm tamoxifen without surgery for selected low-risk ER+ / HER2− DCIS
    • Outcome:
      • Reported 5-year ipsilateral invasive events exceeded prespecified safety threshold (widely summarized from SABCS)
    • Takeaway:
      • Supports continued caution:
        • Endocrine-only, surgery-free DCIS management should remain investigational / exceptional rather than broadly adopted
• What to say at tumor board (tight synthesis) HR+/HER2−:
  • LidERA:
    • Suggests a credible pathway toward next-generation endocrine therapy (oral SERD) in early disease
  • HER2+ residual disease post-NAC:
    • T-DXd > T-DM1 in DESTINY-Breast05 – likely a major sequencing shift as pathways update 
  • Surgery de-escalation:
    • Growing evidence that less axillary surgery and less routine MRI can be safe in well-defined populations
  • Translational front:
    • Preoperative RT + IO is an emerging strategy to watch, not a standard yet
  • DCIS:
    • Surgery-free endocrine-only strategies still struggle with invasive recurrence risk thresholds

• Is a randomized phase III trial:
  • That established trastuzumab deruxtecan (T-DXd) as the preferred therapy for patients with HER2-positive metastatic breast cancer:
    • Previously treated with trastuzumab emtansine (T-DM1)
• Population:
  • HER2-positive unresectable or metastatic breast cancer
  • Prior therapy:
    • Trastuzumab + taxane and T-DM1
  • Randomization: T
    • DXd vs Investigator’s choice (trastuzumab + capecitabine or lapatinib + capecitabine)
  • Primary endpoint:
    • Progression-free survival (PFS, BICR)
  • Key secondary endpoints:
    • Overall survival (OS), ORR, duration of response, safety
• Mechanism of Action (Why T-DXd Is Different):
  • Trastuzumab deruxtecan is a next-generation antibody–drug conjugate (ADC) with:
    • High drug-to-antibody ratio (≈8:1)
    • Cleavable linker membrane-permeable topoisomerase I payload bystander effect:
      • Enabling killing of adjacent tumor cells with heterogeneous HER2 expression:
        • This design explains its activity after T-DM1 failure, where resistance commonly develops.
• Efficacy Results:
  • Progression-Free Survival (Primary Endpoint):
    • Median PFS:
      • T-DXd:
        • ~17.8 months
      • Control:
        • ~6.9 months
      • Hazard ratio:
        • ~0.36
      • Risk reduction:
        • ~64% reduction in progression or death
    • Clinically transformative improvement in disease control
  • Overall Survival:
    • Median OS:
      • T-DXd:
        • ~39.2 months
      • Control:
        • ~26.5 months
      • Hazard ratio:
        • ~0.66
    • Statistically significant and clinically meaningful OS benefit, uncommon in heavily pretreated HER2-positive MBC trials
  • Objective Response Rate:
    • T-DXd:
      • ~69%
    • Control:
      • ~29%
    • Complete responses:
      • Observed with T-DXd
• Safety Profile:
  • Common Adverse Events (T-DXd):
    • Nausea
    • Fatigue
    • Alopecia
    • Vomiting
    • Neutropenia
    • Anemia
    • Interstitial Lung Disease (ILD) / Pneumonitis:
      • Any-grade ILD:
        • ~10%
      • Grade ≥3 ILD:
        • ~1–2%
      • Fatal events:
        • Rare but reported
• Key clinical takeaway:
  • Early recognition, prompt drug interruption, and steroid initiation are essential
  • Patient education and routine symptom monitoring are mandatory
• How DESTINY-Breast 02 Changed Practice:
  • Before DESTINY-Breast 02:
    • Post-T-DM1 options relied on capecitabine-based combinations:
      • Limited durability and modest survival benefit
  • After DESTINY-Breast 02:
    • T-DXd is the standard of care after T-DM1:
      • Supported by PFS + OS superiority:
        • Endorsed by NCCN, ASCO, ESMO
  • Represents a paradigm shift in the HER2-positive metastatic sequence
• Treatment Sequencing (Current Standard):
  • First line:
    • Trastuzumab + pertuzumab + taxane
  • Second line:
    • T-DXd
  • Later lines:
    • Tucatinib-based regimens
    • Clinical trials
    • Other HER2-targeted agents
• Surgical and Multidisciplinary Relevance:
  • Durable systemic control increases:
    • Consideration of local therapies for oligoprogression
    • Delayed need for palliative surgery
  • Highlights importance of:
    • Early referral to medical oncology
    • Coordinated surveillance for pulmonary toxicity
• Key Take-Home Messages:
  • DESTINY-Breast 02 firmly establishes T-DXd as best-in-class post-T-DM1 therapy:
    • Demonstrates both PFS and OS benefit in a refractory population
  • ILD monitoring is critical to safe delivery
  • Confirms the power of ADC engineering in overcoming resistance

When a thyroid nodule is suspected or discovered, high-resolution thyroid ultrasound is the single most important diagnostic study.

🔍 What does a thyroid ultrasound tell us?

Ultrasound allows us to evaluate:

Size and exact location of the nodule Composition (solid, cystic, or mixed) Margins (smooth vs irregular) Echogenicity and calcifications Vascularity (with Doppler imaging) Cervical lymph nodes

➡️ These features are far more predictive of cancer risk than symptoms or blood tests.

📊 Risk stratification matters

Using ultrasound findings, nodules are categorized with validated systems such as:

ATA risk patterns ACR TI-RADS

These systems help determine:

✔️ Which nodules need biopsy

✔️ Which nodules can be safely observed

✔️ Appropriate follow-up intervals

🧪 Important clarification

Blood tests do not diagnose thyroid cancer CT scans and MRIs are NOT first-line tests for thyroid nodules Ultrasound provides real-time, radiation-free, highly accurate evaluation

🦋 Why this matters for patients

Proper ultrasound evaluation:

Prevents unnecessary biopsies and surgeries Ensures early diagnosis of clinically significant thyroid cancer Guides personalized management

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Not all ultrasounds are equal.

Expert, high-resolution thyroid ultrasound makes all the difference.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules. Thyroid Tessler FN et al. ACR TI-RADS. Radiology Russ G et al. EU-TI-RADS. European Journal of Endocrinology

Thyroid Awareness Month – Day 3

Who Is at Risk for Thyroid Nodules?

Thyroid nodules can occur in anyone, but certain factors make them more likely.

👥 Common Risk Factors

Age: Nodules become more common as we get older Female sex: Women develop thyroid nodules 3–4 times more often than men Iodine imbalance: Both deficiency and excess can play a role Family history: Thyroid nodules or thyroid cancer in first-degree relatives Autoimmune thyroid disease: Hashimoto’s thyroiditis increases nodule prevalence

☢️ Higher-Risk Situations

Radiation exposure to the head and neck, especially during childhood Prior radiation therapy for acne, tonsils, or cancer (historical treatments) Certain genetic syndromes (rare, but important)

🧠 Important clarification

Having risk factors does not mean a thyroid nodule is cancer.

➡️ Even in higher-risk individuals, most nodules are benign.

🔍 What matters most?

Risk factors help guide how closely we evaluate, but ultrasound findings ultimately determine:

Cancer risk Need for biopsy Follow-up strategy

📌 Key point for patients:

A thyroid nodule should never be ignored — but it should also never cause unnecessary fear. Proper, evidence-based evaluation is the answer.

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Guth S et al. Very high prevalence of thyroid nodules. Thyroid Gharib H et al. Evaluation and Management of Thyroid Nodules. Endocrine Practice

Thyroid nodules can occur in anyone, but certain factors make them more likely.

👥 Common Risk Factors

Age: Nodules become more common as we get older Female sex: Women develop thyroid nodules 3–4 times more often than men Iodine imbalance: Both deficiency and excess can play a role Family history: Thyroid nodules or thyroid cancer in first-degree relatives Autoimmune thyroid disease: Hashimoto’s thyroiditis increases nodule prevalence

☢️ Higher-Risk Situations

Radiation exposure to the head and neck, especially during childhood Prior radiation therapy for acne, tonsils, or cancer (historical treatments) Certain genetic syndromes (rare, but important)

🧠 Important clarification

Having risk factors does not mean a thyroid nodule is cancer.

➡️ Even in higher-risk individuals, most nodules are benign.

🔍 What matters most?

Risk factors help guide how closely we evaluate, but ultrasound findings ultimately determine:

Cancer risk Need for biopsy Follow-up strategy

📌 Key point for patients:

A thyroid nodule should never be ignored — but it should also never cause unnecessary fear. Proper, evidence-based evaluation is the answer.

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Guth S et al. Very high prevalence of thyroid nodules. Thyroid Gharib H et al. Evaluation and Management of Thyroid Nodules. Endocrine Practice

Most thyroid nodules cause no symptoms at all and are found incidentally on imaging or routine exams.

🔹 Common scenario: You feel well — the nodule is discovered on ultrasound

🔹 Important fact: Lack of symptoms does NOT mean the nodule is dangerous (or benign)

👀 When can symptoms occur?

Symptoms are more likely when nodules are large or strategically located:

A visible or palpable lump in the neck Difficulty swallowing or a sensation of food “getting stuck” Hoarseness or voice changes (uncommon, but important) Neck pressure or fullness, especially when lying flat Rarely, shortness of breath

⚠️ Hormone-related symptoms (less common)

A small percentage of nodules produce excess thyroid hormone (“hot” nodules), which may cause:

Palpitations Weight loss Heat intolerance Tremors or anxiety

🚨 When should you seek evaluation?

You should be evaluated if you notice:

✔️ A new or growing neck lump

✔️ Persistent hoarseness

✔️ Difficulty swallowing or breathing

✔️ A personal history of radiation exposure or family history of thyroid cancer

🔍 Bottom line:

Symptoms alone cannot determine whether a nodule is benign or malignant.

➡️ High-resolution ultrasound is essential for proper evaluation.

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Most thyroid nodules are silent.

Don’t rely on symptoms — rely on proper imaging and expert evaluation.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules. Thyroid Gharib H et al. Evaluation and Management of Thyroid Nodules. Endocrine Practice Durante C et al. JAMA

What Are Thyroid Nodules?

Thyroid nodules are very common in the general population.

🔹 With modern high-resolution ultrasound, thyroid nodules are detected in up to 50–60% of adults

🔹 More than 90% are benign

🔹 Most people have no symptoms and feel completely well

👉 The key is not panic — it’s proper evaluation.

🔍 How should thyroid nodules be evaluated?

The most important first step is a high-resolution thyroid ultrasound, which allows us to:

Accurately measure and characterize nodules Assess features associated with cancer risk Use validated risk-stratification systems (ATA / TI-RADS) Decide whether a biopsy is actually necessary

🧪 A key fact for patients

Only 5–10% of thyroid nodules are cancer.

When thyroid cancer is detected early, cure rates are excellent.

👨‍⚕️ Rodrigo Arrangoiz, MD

Surgical Oncologist – Thyroid, Head & Neck, Breast

Mount Sinai Medical Center

📌 Take-home message:

Having a thyroid nodule is common.

Having it evaluated correctly by an experienced team makes all the difference.

📚 References

Haugen BR et al. ATA Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Durante C et al. Long-term surveillance of benign thyroid nodules. JAMA Gharib H et al. Fine-needle aspiration biopsy of thyroid nodules. Endocrine Practice