HISMAR: Intraoperative Margin Assessment Using the Histolog® Scanner to Reduce Reoperation in Breast-Conserving Surgery

HISMAR: A Prospective Post-Market Performance Follow-up Study of the Histolog Scanner for Intraoperative Margin Assessment in Breast-Conserving Surgery for High-Risk Histological Subtypes (ILC, DCIS, NST+DCIS)

This study evaluates whether systematic intraoperative margin assessment using the Histolog® Scanner - a confocal fluorescence microscopy device - reduces the need for reoperation after breast-conserving surgery (lumpectomy) in women with lobular carcinoma (ILC), ductal carcinoma in situ (DCIS), or invasive carcinoma with a DCIS component (NST+DCIS).

After lumpectomy, the fresh specimen is imaged in real time by the surgeon using the Histolog® Scanner, which produces histological-quality images of the specimen surface without any tissue processing. This allows immediate assessment of surgical margins in the operating room, enabling the surgeon to perform additional tissue removal if needed before closing.

Based on institutional data from 266 cases at CHVR (2021-2024), the current reoperation rate in this population is 11.3%. The study tests whether systematic use of the Histolog® Scanner in addition to standard care reduces this rate by 50% or more (to ≤5.6%). A total of 228 patients will be enrolled prospectively at the Centre Hospitalier du Valais Romand (CHVR), Sion, Switzerland. The reoperation decision is made by the multidisciplinary tumour board based on final histopathology results, independently of the intraoperative findings.

BACKGROUND Breast cancer is the most common cancer in women in Switzerland, with approximately 6,500 new cases annually. Breast-conserving surgery (BCS, lumpectomy) is the preferred surgical approach for localised tumours and achieves equivalent survival outcomes to mastectomy when negative margins are obtained. However, re-excision rates of 20-30% have been reported in unselected BCS populations.

The risk of positive margins is particularly elevated in specific histological subtypes: published data indicate a relative risk of positive margins of 2.21 for ductal carcinoma in situ (DCIS) and 1.44 for invasive lobular carcinoma (ILC) compared to NST carcinoma without in situ component. A retrospective analysis of 266 consecutive eligible BCS cases at CHVR (2021-2024) identified a reoperation rate of 11.3% (30/266). A prospective study in the literature reported a reduction from 30% to 10% when intraoperative histological scanning was added to standard of care.

DEVICE The Histolog® Scanner (SamanTree Medical SA, Lausanne; CE IVD Class A, UDI 764017998003GV, software v3.4.0) enables real-time confocal fluorescence imaging of fresh lumpectomy specimen surfaces ex vivo, without tissue processing or staining, providing H&E-quality images intraoperatively. The device is already in routine clinical use at CHVR.

STUDY OBJECTIVE To evaluate whether systematic use of the Histolog® Scanner in addition to standard of care reduces the reoperation rate by 50% or more - from 11.3% to ≤5.6% - in patients with ILC, pure DCIS, or NST+DCIS undergoing BCS at CHVR.

STUDY DESIGN Prospective, single-arm, single-centre post-market performance follow-up (PMPF) study (IVDR 2017/746). Comparator: validated historical institutional control (CHVR 2021-2024, same surgical team, n=266, reoperation rate 11.3%). A randomised design was not ethically justifiable as the device is already in routine use at CHVR.

PROCEDURE Following lumpectomy, the fresh specimen undergoes standard palpation then systematic Histolog® Scanner imaging (ex vivo, on the specimen surface). At the surgeon's discretion, standard radiological assessment is also performed. Intraoperative recuts are decided based on combined standard of care and Histolog® Scanner findings. The specimen is sent to the institutional pathology laboratory (ICH-CHVR) for definitive histopathology. The primary endpoint (reoperation recommendation) is determined by the multidisciplinary tumour board based on final histopathology, independently of intraoperative findings.

OUTCOMES Primary: reoperation rate (proportion of patients for whom the tumour board recommends re-excision), assessed within 4 weeks of BCS.

Secondary: (1) subgroup reoperation rates (ILC, pure DCIS, NST+DCIS); (2) intraoperative recut rate and localisation; (3) cost analysis; (4) exploratory concordance between intraoperative and final pathological margin status.

ELIGIBILITY Inclusion: women ≥18 years; CNB/VAB confirming ILC, pure DCIS, or NST+DCIS; planned BCS at CHVR; signed eIC.

Exclusion: pregnancy; prior neo-adjuvant treatment; mastectomy indication; acriflavine hypersensitivity; incapacity to consent.

SAMPLE SIZE n=228 patients (205 evaluable minimum; 10% dropout). Calculated by one-sample z-test (Fleiss 1981): α=0.05 two-sided, power=80%, p₀=11.3%, p₁=5.6%. Estimated recruitment: 3-3.5 years.

STATISTICAL ANALYSIS Primary: one-sample z-test for a proportion (two-sided, α=0.05), per-protocol population, with exact 95% Clopper-Pearson CI. Pass criterion: p<0.05 and observed rate ≤5.6%. Sensitivity analysis on ITT population. No interim analysis planned.

ETHICAL / REGULATORY Category A1 (ClinO-MD Art. 6a). CEC: Commission cantonale d'éthique du Valais (CCVS). No Swissmedic approval required. Electronic informed consent (eIC). Declared conflict of interest: PI holds a consultancy arrangement with SamanTree Medical SA (institutional fee); mitigation: independent tumour board endpoint, independent biostatistician.

FUNDING Institutional budget of CHVR. No industry funding.

1. Female patient, aged 18 years or older at time of surgery.

2. Pre-operative core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) with histological diagnosis of one of the following:

   1. invasive lobular carcinoma (ILC/CLI),
   2. pure ductal carcinoma in situ (DCIS), or
   3. invasive carcinoma of non-special type (NST) with an associated DCIS component.

3. Planned breast-conserving surgery (BCS / lumpectomy) at CHVR.

4. Signed electronic informed consent (eIC) obtained prior to any study procedure.

Exclusion Criteria:

1. Pregnancy (confirmed or suspected) at time of surgery.
2. Prior neo-adjuvant treatment (hormonal therapy or chemotherapy) for the current breast cancer diagnosis.
3. Surgical indication for mastectomy rather than BCS.
4. Known hypersensitivity or allergy to acriflavine (fluorescent staining agent used with the Histolog Scanner).
5. Incapacity to provide informed consent.
6. Previous enrolment in this study.