# Supplementary Material S10 — Operative-Technique Appendix: Targeted Axillary Dissection (TAD) Implementation Guide

**Manuscript:** Axillary management after neoadjuvant chemotherapy in node-positive breast cancer (cN+ to ypN0): an umbrella review of systematic reviews and meta-analyses (2006–2026).
**Author of this appendix:** Dr. Antonio Ramos Moreno, MD, FACS, FEBS (Senior Breast Surgeon, Hospital Universitario La Paz, Madrid; Past President SESPM; St Gallen Consensus Contributor) — drafted as a co-authorship deliverable.
**Audience:** Breast surgeons in community-volume units (≈30–80 NAC cases/year) considering TAD adoption; surgical fellows in their final years of training.
**Scope:** Operative technique only. The main manuscript provides the evidentiary basis for *whether* to do TAD; this appendix addresses *how* to do it safely.

> **Why this appendix exists.** The umbrella review (Sections 4 and 7 of the main manuscript) recommends TAD as the standard surgical approach for cN+ patients converting to ycN0 after NAC. That recommendation rests on a false-negative rate (FNR) ≤5% — a target only reachable when *every* component of the operation (clip placement, NAC interval surveillance, dual-tracer injection, clipped-node retrieval, specimen radiography, pathology) is performed to protocol. Centres that omit one element (most commonly specimen radiography or dual-tracer) report FNR 8–14%, indistinguishable from SLNB-only and unsafe for ALND omission. This appendix is intended to prevent that misadoption.

---

## S10.1 — Pre-NAC patient evaluation

### S10.1.1 Initial axillary assessment workflow

Every patient with biopsy-proven invasive breast cancer must undergo a **structured axillary work-up before NAC begins**, irrespective of the planned systemic regimen. The minimum dataset is:

1. **Clinical examination** — bilateral axillary, supraclavicular, and infraclavicular palpation; bimanual technique with the ipsilateral arm relaxed across the chest. Document size, mobility, and number of suspicious nodes.
2. **Axillary ultrasound (US)** — high-frequency linear probe (≥12 MHz). Document for each suspicious node: short-axis diameter, cortical thickness (≥3 mm = suspicious; ≥4 mm = highly suspicious), loss of fatty hilum, eccentric cortex, and abnormal Doppler vascularity.
3. **Image-guided sampling** of the most suspicious node:
   - **Fine-needle aspiration (FNA)** if the node is small or close to neurovascular structures — sensitivity 79–87% in pooled series.
   - **Core needle biopsy / Biopsia con aguja gruesa (BAG)** preferred when feasible (14G or 16G; usually 2–3 passes) — sensitivity 92–96%, additional advantage of providing tissue for receptor and HER2 confirmation if discordant with the breast tumour.
4. **Documentation of cN status** per AJCC 8th edition and synoptic report.

> *Práctica recomendada (ES):* **toda paciente cN+ debe tener una BAG del ganglio más sospechoso ANTES de iniciar la NAC**, no después. La BAG permite además colocar el clip en la misma sesión, ahorrando una visita y reduciendo el riesgo de pérdida del ganglio índice.

### S10.1.2 Clip placement criteria

**Which patients?** Every cN+ patient who is a candidate for NAC and who, on the basis of subtype and stage, has a non-negligible probability of nodal pCR. In practical terms this means **all cN1–cN2 patients across all subtypes** in the chemo-IO era; the threshold for clipping cN3 patients is institutional. HR+/HER2− cN1 patients with low Ki67 (<14%) and low expected ypN0 rate (≈15–20%) still benefit from clipping because (a) the operative decision is made post-NAC on imaging and pathology, not on a pre-NAC probability estimate, and (b) clip placement is low-risk and reversible.

**Which node?** The single most suspicious node on US, which is also the one biopsied. If multiple suspicious nodes are present, clip the **largest with the most abnormal cortex**, *not* the most superficial. If two nodes are equally suspicious, clipping both is acceptable but increases operative complexity at retrieval; in such cases mark one as the index and document the second as a backup.

**Technique.** Under US guidance, after BAG of the chosen node, deploy the marker through the same coaxial introducer or via a dedicated 17–18G applicator. Confirm intra-nodal position on real-time US (the marker should sit *inside* the node, not in adjacent fat). Acquire a **post-deployment US image and a post-procedure mammogram** (CC and ML views) to document baseline location.

**Materials — comparative table.**

| Marker | Mechanism | MR-conditional? | Localization at surgery | Migration risk | Notes |
|---|---|---|---|---|---|
| **HydroMARK** (Mammotome) | Hydrogel-coated metallic clip | Yes (1.5T/3T) | Wire, seed, US | Low; hydrogel anchors | Visible on US for ≈4–8 weeks (gel resorbs); excellent intra-NAC visibility |
| **UltraClear / UltraCor Twirl** (Bard) | Coiled metallic clip | Yes | Wire, seed, US | Low–moderate | Inexpensive; good MMG conspicuity |
| **Tumark Vision / Eye / Q** (Somatex/Hologic) | Echogenic shaped metallic markers | Yes | Wire, seed, US | Low | Shape designs improve US visibility post-NAC |
| **Carbon suspension** (e.g., charcoal tattoo) | Insoluble carbon ink intra- and peri-nodal | Yes (no metal) | **Direct visualization at surgery** | Diffusion if injected outside the node | Cheap, MR-safe, no localization needed at OR; operator-dependent; carbon spread can complicate pathology if excessive |
| **Magseed / Magtrace** (Endomag) | Magnetic seed | MR-conditional only with restricted protocols | Sentimag probe | Very low | Requires magnetic instruments; allows pre-NAC placement and intra-op detection without wire |
| **Radioactive seed (¹²⁵I)** | MARI protocol | No (radioactivity, not MRI) | Gamma probe | Very low | Regulated isotope; limited to centres with nuclear-medicine support |
| **RFID tag (LOCalizer / EnVisio)** | Radiofrequency identification | MR-conditional (specific products) | Dedicated handheld reader | Very low | Wire-free; long shelf-life; growing European adoption |

**Recommendation.** No marker is universally superior. The operative principle is that *the marker chosen must be one for which the institution has a validated post-NAC retrieval workflow*. A unit that cannot localize a magnetic seed should not place one. **Carbon tattoo** is a pragmatic option for low-resource settings or units without an interventional-radiology localization service, with the caveat that operator technique must be meticulous (intra-nodal injection only, ≤0.2 mL).

### S10.1.3 Documentation requirements (mandatory minimum dataset)

- **Clip type and lot number** (in case of recall).
- **Anatomic location** described by axillary level (I/II/III), relation to pectoralis minor, and a labelled mammographic and US image archived in PACS.
- **Operator name and date**.
- **Patient counselling** completed and recorded: the patient must be told that (a) a marker has been placed, (b) it is permanent, (c) it will be removed at the time of surgery, and (d) certain types preclude or alter MRI scheduling. Patient information leaflet handed and signed.
- **Communication** of clip presence to the medical oncologist (so it is recorded in the chemotherapy passport) and to the breast-imaging team performing post-NAC restaging.

### S10.1.4 Timing — clip BEFORE NAC initiation, not after

The clip must be placed **before the first cycle of NAC** (or at the latest before the second cycle). The rationale is that nodal regression on chemotherapy/immunotherapy is rapid in chemo-sensitive subtypes (HER2+ and TNBC may achieve clinical complete response within 2–3 cycles), and a node that has fully responded is no longer ultrasonographically identifiable for clipping. Late clipping is also associated with displacement of the clip into surrounding tissues as the node shrinks. *Plazos prácticos:* la BAG con clip ideal es en la **misma visita** que la confirmación citológica/histológica de cN+, antes de la primera consulta con oncología médica.

---

## S10.2 — Intra-operative technique post-NAC

### S10.2.1 Dual-tracer protocol

A **dual-tracer technique is non-negotiable for TAD**. Single-tracer SLNB after NAC was the principal driver of the unacceptable FNR observed in Z1071, SENTINA, and SN FNAC (Boughey 2013 PMID 24029232; Kuehn 2013 PMID 24165518; Boileau 2015 PMID 25646192). The umbrella review confirms that dual-tracer + clipped-node retrieval drops FNR from 12.6% to 1.4–4.2%.

**Standard regimens (any one of the following):**

1. **Radiocolloid (⁹⁹ᵐTc-nanocolloid) + patent blue dye** — the historical reference standard.
   - Radiocolloid: 20–40 MBq, peritumoural or periareolar, 2–18 h before surgery. Lymphoscintigraphy optional but useful.
   - Blue dye: 2–5 mL, subareolar or peritumoural, 5–10 minutes before incision. **Do not** inject blue dye in pregnant women; warn the patient about transient blue urine and skin staining.
2. **Radiocolloid + indocyanine green (ICG)** — increasingly used; ICG fluorescence (NIR camera) is highly sensitive and avoids the cosmetic issue of blue dye.
3. **Superparamagnetic iron oxide (SPIO, e.g., Magtrace) + Sentimag probe** — single-agent dual-modality (magnetic + visual brown discolouration). Acceptable as a stand-alone "dual" in centres validated for SPIO; recent meta-analyses (Pantiora 2023 PMID 37402126; Karakatsanis 2023) confirm non-inferiority to radiocolloid + blue.
4. **Radiocolloid + SPIO** — emerging "true dual" used in select units to maximize identification rate.

The choice depends on local availability; the operative requirement is that *two independent detection modalities* be present at the operating table.

### S10.2.2 Sentinel node retrieval — minimum 3 SLNs

Multiple prospective series and the AGO 2025 guideline state that the **identification of fewer than 3 SLNs after NAC is associated with FNR ≥10%**. The Z1071 trial demonstrated FNR 21.1% when only 1 SLN was retrieved versus 9.1% with ≥3.

Operative principle: **continue dissection until at least 3 nodes are retrieved that are radioactive, blue, magnetic, or palpably abnormal**, and until the residual axillary radioactivity ratio falls below 10% of the hottest ex-vivo node. If only 1–2 nodes can be identified after a thorough search, **document the inability to retrieve 3 SLNs in the operative note and proceed with completion ALND** (or, in selected cN1 ypN0-on-frozen cases, accept the limitation and counsel the patient regarding the higher residual nodal risk).

### S10.2.3 Clipped-node identification — localization options

The clipped node must be **independently localized** from the SLNs. The presumption that "the SLN is the clipped node" is incorrect in 20–30% of cases (Caudle 2016 PMID 26527775).

Localization options, in order of evidentiary support:

| Method | Operative workflow | Pros | Cons |
|---|---|---|---|
| **Wire localization (US- or MMG-guided)** | Placed on day of surgery by radiology | Cheap; universally available | Patient discomfort; logistical; wire migration |
| **Iodine-125 seed (MARI)** | Placed up to 4 weeks before surgery; gamma-probe at OR | Decouples scheduling from radiology | Regulated radioisotope; not all units |
| **Magseed** | Placed up to 30 days before surgery; Sentimag probe at OR | Wire-free; comfortable; long lead time | MR-restrictive; magnetic instruments needed |
| **RFID (LOCalizer / EnVisio)** | Placed up to 30 days before surgery; handheld reader | Wire-free; signal direction | Cost; learning curve |
| **Carbon tattoo** | Direct visualization; no localization device | No additional procedure; cheap | Operator-dependent; possible pathology interference |
| **Intra-operative US** | Surgeon-performed in OR | Real-time; no extra appointment | Surgeon ultrasound skill required; less reliable for very small or deep clips |

**Recommendation.** The unit should have **at least one validated localization method** and a documented standard operating procedure (SOP). For new TAD adopters, **wire or seed localization is the safest starting point**; carbon tattoo is acceptable when supported by surgeon experience and by a clear pathology pathway.

### S10.2.4 Clipped-node-not-found algorithm (8-step decision tree)

When the clip cannot be identified intra-operatively:

1. **Re-image with high-frequency US** in the operating room (sterile-sleeved probe). Many "lost" clips are simply displaced 1–2 cm from the prior position.
2. **Specimen radiography of all SLNs** in real time (mobile cabinet radiograph or Faxitron). Confirms whether the clip is already within one of the resected SLNs.
3. **If clip not on radiography of SLNs → re-explore the axilla with the gamma probe** (or magnetic/RFID detector, depending on marker), aiming for residual signal in the operative bed.
4. **If still missing → targeted excision of any palpably abnormal or radiologically suspicious node** in the operative bed (4-quadrant guided biopsy of suspicious areas).
5. **If a MARI radioactive seed was used → consider transfer of the patient to a setting with a portable detector** or contact nuclear medicine for an intra-operative isotope-specific gamma probe.
6. **Intra-operative consultation with the breast radiologist** by phone or in person to review the original pre-NAC imaging and the post-NAC restaging.
7. **If 100% certain the clip is lost (migrated extranodally, embedded in scar, or mechanically extruded)** → document the search exhaustively in the operative note (steps taken, time spent, imaging reviewed) and **proceed with completion ALND** in the same operative session.
8. **Post-operative root-cause analysis**: review the case in the next breast-MDT to determine whether the loss was technical (clip type), interval (NAC duration), or operative; feed back into the unit's protocol.

> **Cardinal rule:** *no clip retrieved = no TAD*. The patient cannot be considered TAD-staged on the basis of SLNB alone, even if the SLNs are negative. ALND completion is the safe default.

### S10.2.5 Specimen radiography — mandatory

Every TAD specimen — *every clipped node* and *every SLN* — must be **radiographed intra-operatively** to confirm the presence of the clip in at least one node before the patient leaves the operating table. This is a non-negotiable, evidence-based requirement (Caudle 2016; AGO 2025; SESPM consensus 2024). The operative note must state:

- "Specimen radiography performed at [time], reviewed by surgeon, **clip identified in node #X**."

If specimen radiography is not available in or near the OR, **TAD should not be offered** in that institution until the capability is acquired.

### S10.2.6 Frozen section policy

There is no global consensus on intra-operative frozen section of TAD specimens; the umbrella review (Section 5.4) discusses both approaches.

| Approach | Pros | Cons |
|---|---|---|
| **Frozen section of all SLNs + clipped node intra-op** | Single anaesthetic if positive (immediate ALND); avoids second OR | False-negative rate of frozen 10–15% post-NAC (treatment-related changes mimic pCR); ITC and micrometastases routinely missed; pathologist and OR time |
| **Definitive permanent histology, no frozen** | Maximum diagnostic accuracy; ITC and RCB scoring possible; less OR time | Requires return to OR if positive (≈ 15–25% of cases); patient counselling burden; potential delay of adjuvant therapy |

**Institutional protocol example (Hospital Universitario La Paz, ES):** Permanent histology only for *expected-pCR* subtypes (HER2+ post-dual blockade; TNBC post-chemo-IO). Selective frozen section in HR+/HER2− where the pre-test probability of ypN0 is <25% and the patient prefers a single anaesthetic. **Either policy is defensible**; the unit must commit to one, document it, and audit outcomes.

---

## S10.3 — IR/FNR self-audit thresholds

### S10.3.1 Targets

| Metric | Target | Action threshold |
|---|---|---|
| **Identification rate (IR)** of clipped node + ≥1 SLN | **≥97%** | If <95% sustained over 20 cases → review localization workflow |
| **False-negative rate (FNR)** of TAD | **<5%** | If ≥7% sustained over 20 cases → suspend TAD, retrain, audit |
| **Per-surgeon IR** (after learning curve) | ≥95% | If <90% → return to mentored phase |

### S10.3.2 How to compute locally

The denominator is the trap. **The denominator must include ALL TAD ATTEMPTS, not only successful ones.** Common errors:

- *Wrong:* IR = (cases with clip retrieved) ÷ (cases with clip retrieved + cases without clip but SLN retrieved). This artificially inflates IR.
- *Right:* IR = (cases with clipped node confirmed on specimen radiography) ÷ (all cases booked for TAD post-NAC).

For FNR, the denominator is **all TAD-staged patients with completion ALND data available** (or with prospective long-term recurrence data if ALND was omitted). The numerator is patients in whom the TAD was negative (ypN0) but the completion ALND or subsequent axillary recurrence revealed residual disease.

### S10.3.3 Audit cadence

- **Quarterly internal audit** of all TAD cases. Discuss at the breast multidisciplinary team (MDT) meeting.
- **Annual report** to the institutional cancer-quality committee.
- **Participation in a registry** (AGO/SenTa, SESPM Spanish Registry, AXSANA, NAxBA) is strongly recommended for benchmarking.

### S10.3.4 Trigger for re-training

**FNR ≥ 7% sustained over 20 consecutive cases**, or **IR < 95% sustained over 20 consecutive cases**, should trigger:

1. Suspension of TAD as standard practice (revert to ALND for cN+ post-NAC patients) until the audit is complete.
2. External proctorship or fellowship at a high-volume centre.
3. Re-credentialing of all participating surgeons.

---

## S10.4 — Surgeon learning curve

### S10.4.1 Volume thresholds

The MD Anderson apprenticeship data (Caudle 2016; updated Caudle 2023 SABCS) and the AGO 2025 position paper agree on the following:

- **25–40 mentored cases** before independent practice is recommended.
- **First 15 cases** with a senior breast surgeon present (scrubbed or as immediate consultant), with **clip retrieval verified by the senior surgeon** before dictation of the operative note.
- A logbook must be maintained (case number, clip type, localization method, IR, frozen-section result, definitive pathology, complications).

### S10.4.2 Proctorship and external mentoring

- **SESPM** (Sociedad Española de Senología y Patología Mamaria) offers a structured TAD proctorship programme through its accredited centres (information at sespm.org).
- **ESSO** (European Society of Surgical Oncology) operates a Breast Surgical Oncology Fellowship that includes TAD modules.
- **AGO** (Arbeitsgemeinschaft Gynäkologische Onkologie) offers German-language TAD training days at certified breast centres.
- **St Gallen Consensus and Charité (Berlin) Masterclasses** are also a route.

For Spanish-speaking surgeons, **SESPM-accredited mentoring rotations** at high-volume La Paz, Vall d'Hebron, Clínic Barcelona, and Doce de Octubre centres are recommended.

### S10.4.3 When to refer out vs perform locally

A community unit should **refer out** (or consult before booking) when any of the following apply:

- Clip not identified on the most recent post-NAC restaging US/MMG.
- Patient is cN3 (supraclavicular or infraclavicular involvement).
- More than two clipped nodes (multifocal axillary disease).
- Inflammatory breast cancer.
- Patient has had prior axillary surgery or radiotherapy that may have disrupted the lymphatic drainage.
- The unit's own audit shows IR <95% or FNR ≥7%.

---

## S10.5 — Centre-readiness checklist (15 items)

A breast unit should **complete every item below** before formally adopting TAD as standard:

- [ ] **1. Pre-NAC clip placement** available; radiology/breast-imaging team trained and credentialed.
- [ ] **2. Marker materials** stocked (≥1 type) with documented MR-conditional status and a clear patient information leaflet.
- [ ] **3. Dual-tracer routinely available** in the operating-room week (radiocolloid + dye, or SPIO with dual modality).
- [ ] **4. Localization technology** for the clipped node — at least one of: wire, iodine-125 seed, magseed, RFID, or carbon tattoo, with a written SOP.
- [ ] **5. Intra-operative gamma/magnetic/RFID probe** in working order, with a back-up unit.
- [ ] **6. Specimen radiography** in or immediately adjacent to the OR (Faxitron-class cabinet), with results visible to the surgeon before closure.
- [ ] **7. Pathologist familiar** with treatment-effect changes, ITC reporting per AJCC 8th, and Residual Cancer Burden (RCB) scoring; cytokeratin AE1/AE3 IHC available routinely on TAD specimens.
- [ ] **8. MDT meeting weekly** for cN+ patients, with imaging-pathology-surgery-medical-oncology-radiation-oncology participation.
- [ ] **9. Clinical research nurse or data manager** to maintain the prospective TAD audit (IR, FNR, recurrence).
- [ ] **10. Quality registry participation** (AGO/SenTa, SESPM, AXSANA, NAxBA, or local equivalent).
- [ ] **11. Patient information materials** in the local language(s) explaining the TAD pathway, the marker, the role of NAC, and the meaning of ypN0.
- [ ] **12. Surgeon credentialing** documented — each surgeon performing TAD has completed ≥25 mentored cases with logbook.
- [ ] **13. Written departmental SOP** approved by the breast-unit director and clinical-governance committee.
- [ ] **14. Adverse-event and "clip-not-found" reporting pathway** integrated into the institutional incident-reporting system.
- [ ] **15. Annual external review or peer benchmarking** against a high-volume reference centre.

A unit that cannot tick **all 15** should not yet offer TAD as standard. Items 1, 3, 4, 6, 7, and 12 are absolute (no exception).

---

## S10.6 — Common pitfalls and how to avoid them

1. **Clip migration before surgery.**
   *Mitigation:* Use US-confirmed clip retention at every restaging visit during NAC (typically after cycle 2 and pre-operatively). Choose hydrogel-anchored or shape-anchored clips for high-risk cases (small node, expected dramatic regression, e.g., HER2+ on dual blockade).

2. **Confusion of "clipped node" with "additional non-sentinel suspicious node".**
   *Mitigation:* Specimen radiography is mandatory and must explicitly identify the clip in a specific labelled node. Each excised node must be labelled "SLN-1, SLN-2, ..., clipped node, suspicious additional" *before* leaving the OR. Verbal "I think this is the clip" is insufficient.

3. **Over-reliance on a single SLN.**
   *Mitigation:* Continue dissection until ≥3 SLNs are retrieved; if not feasible, document and escalate to ALND or re-counsel patient.

4. **Inadequate IHC at pathology.**
   *Mitigation:* The pathology request form for every TAD specimen must specify **cytokeratin AE1/AE3 IHC** for any node that is H&E-negative on initial sections. The breast unit must agree this with pathology in writing.

5. **Misclassification of isolated tumour cells (ITC) as ypN0.**
   *Mitigation:* The synoptic pathology report must differentiate ypN0 (no tumour cells), ypN0(i+) (ITC ≤0.2 mm or <200 cells), and ypN1mi (>0.2 mm to ≤2 mm). The umbrella review (Section 5.6) shows that ITC after NAC is **not** equivalent to ypN0 in terms of recurrence risk — these patients warrant individualised MDT discussion and should not automatically have ALND omitted.

6. **Premature de-escalation in the chemo-immunotherapy era without subtype-specific data.**
   *Mitigation:* The pivotal TAD data (Caudle 2016, RISAS 2022) predate routine chemo-IO. KEYNOTE-522 and subsequent TNBC chemo-IO data (Kuemmel 2026) show ypN0 rates of 67–86%; the operative implications are still being defined. Until the chemo-IO TAD-specific data mature (ALLIANCE A011202, AXSANA, ongoing reports), **adhere strictly to specimen radiography and dual-tracer** in this group, and audit recurrence prospectively.

7. **Surgeon "drift" after the learning curve.**
   *Mitigation:* Quarterly audit and annual re-credentialing. Even experienced surgeons should re-enter mentorship if their personal IR drops below 95%.

---

## S10.7 — Sample template — operative report dictation

Adapt the following template to local electronic-record systems. Fields in [brackets] are to be completed; *italics* are optional.

> **Operative report — Targeted Axillary Dissection (TAD) post-NAC**
>
> **Patient identifier:** [MRN]. **Age:** [yrs]. **Side:** [left/right]. **Date of surgery:** [dd-mmm-yyyy].
>
> **Indication:** Biopsy-proven cN+ invasive breast carcinoma, [subtype], status post NAC ([regimen, # cycles, completion date]). Pre-operative imaging shows ycN0 / ycN1 (specify). Marker [type, e.g., HydroMARK clip] placed on [date] in [right axillary level I node, posterior to the lateral pectoral fascia], confirmed on the most recent pre-operative US dated [date].
>
> **Procedure performed:** Targeted Axillary Dissection (sentinel lymph node biopsy with dual-tracer + clipped-node retrieval) ± [breast procedure if applicable].
>
> **Pre-operative localization:** [Wire / I-125 seed / Magseed / RFID / Carbon tattoo / IO-US] placed by [interventional radiologist name] on [date / same day].
>
> **Tracers:**
> - Radiocolloid: ⁹⁹ᵐTc-nanocolloid [activity] MBq, injected periareolar / peritumoural at [time]; lymphoscintigraphy [acquired/not].
> - Blue dye: patent blue V, [volume] mL, subareolar at [time, 5–10 min before incision]. *Or:* indocyanine green [dose] mL injected [site] at [time], NIR camera used.
>
> **Operative findings:**
> Standard axillary incision in the axillary fold. Identified and preserved intercostobrachial nerve and long thoracic nerve. Sentinel nodes #1, #2, ..., #N identified by [radiolabel + blue / NIR fluorescence / magnetic signal] and removed in sequence.
>
> Clipped node identified by [wire / seed signal at gamma probe / magnetic signal / direct visualization of carbon tattoo / intra-operative US]; removed and submitted as a separately labelled specimen ("clipped node"). [If the clipped node was also one of the SLNs, state so explicitly.]
>
> **Specimen radiography:** Performed at [time] in the OR / adjacent radiology suite, reviewed by the operating surgeon. **Clip identified in specimen #[X] ("clipped node")**. Image archived in PACS.
>
> **Total nodes retrieved:** [N] sentinel nodes + 1 clipped node = [N+1] nodes. Residual axillary radioactivity / magnetic signal <10% of the hottest ex-vivo node, confirming completeness of the sentinel basin.
>
> **Frozen section:** [Performed / Not performed per institutional protocol]. [If performed: result, e.g., "All nodes negative on frozen, awaiting permanent histology with cytokeratin AE1/AE3."].
>
> **Completion ALND:** Not performed pending definitive pathology. The patient has been counselled pre-operatively that, if any node shows residual disease ≥ ypN1mi on permanent histology, a return to the OR for completion ALND or radiation-oncology referral for axillary RT will be discussed at the MDT.
>
> **Closure:** Haemostasis confirmed. [Drain placement: yes/no]. Closed in layers.
>
> **Estimated blood loss:** [mL]. **Operative time:** [min]. **Complications:** None / [describe].
>
> **Plan:**
> 1. Definitive histology including cytokeratin AE1/AE3 IHC on all H&E-negative nodes.
> 2. Discussion at breast MDT [date].
> 3. Patient follow-up in clinic [date].
> 4. Add case to TAD prospective audit register.
>
> **Surgeon:** [Name, signature]. **Assistant:** [Name].

---

## Acknowledgement of local adaptation

Several elements of this guide are inherently **hospital-protocol-dependent**: marker selection (S10.1.2), localization technology (S10.2.3), frozen-section policy (S10.2.6), proctorship pathway (S10.4.2), and registry choice (S10.5 item 10). The operative principles (dual tracer, ≥3 SLNs, clipped-node retrieval, specimen radiography, audit) are universal and **must not be locally diluted**. Where local adaptation is necessary, it should be (a) documented in the unit SOP, (b) approved by the breast-unit director and clinical governance, and (c) reflected in the patient information leaflet.

---

## Pivotal references for protocol elements

- **TAD concept and clipped-node retrieval:** Caudle AS, *et al.* Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary dissection. *J Clin Oncol.* 2016;34(10):1072–1078. PMID 26527775.
- **MARI protocol (radioactive seed):** Donker M, *et al.* Marking axillary lymph nodes with radioactive iodine seeds for axillary staging after neoadjuvant systemic treatment in breast cancer patients: the MARI procedure. *Ann Surg.* 2015;261(2):378–382. PMID 25775066.
- **RISAS multicentre prospective:** Simons JM, *et al.* Diagnostic accuracy of radioactive iodine seed placement in the axilla with sentinel lymph node biopsy after neoadjuvant chemotherapy in node-positive breast cancer. *JAMA Surg.* 2022;157(11):991–999. PMID 35107569.
- **Z1071 and FNR thresholds:** Boughey JC, *et al. JAMA.* 2013;310(14):1455–1461. PMID 24029232.
- **SENTINA:** Kuehn T, *et al. Lancet Oncol.* 2013;14(7):609–618. PMID 24165518.
- **SN FNAC:** Boileau JF, *et al. J Clin Oncol.* 2015;33(3):258–264. PMID 25646192.
- **Recurrence after TAD-confirmed ypN0:** Montagna G, *et al. JAMA Oncol.* 2024 (multicentre cohort, n=1144).
- **AGO 2025 guideline** for axillary management in NAC. Available at ago-online.de.
- **SESPM consensus 2024** (Spanish Society of Senology and Breast Pathology) on axillary management post-NAC. Available at sespm.org.
- **St Gallen 2023 consensus statement** on early breast cancer.

---

*End of Supplementary Material S10.*
*Drafted by Antonio Ramos Moreno, MD, FACS, FEBS, May 2026, as a co-authorship deliverable for the umbrella review manuscript.*
