Outcomes in patients with non‐invasive breast carcinoma

Abstract Background and Aim Non‐invasive breast carcinoma is considered to be localized disease and is distinguished from invasive ductal and lobular carcinomas. The local recurrence of non‐invasive carcinoma after surgery may lead to development of invasive carcinoma and promote distant metastasis, which worsens the prognosis for breast cancer mortality. The distant metastasis of non‐invasive carcinoma may involve the ductal microvasculature without invasion. The outcomes of non‐invasive breast carcinoma were examined in this retrospective cohort study. Methods and Results Of 872 primary breast cancers diagnosed at a single center between May 2008 and March 2022, 93 (10.6%) were found to be non‐invasive carcinomas and were examined in this study. The breast cancer recurrence and survival rates of patients with non‐invasive carcinoma were analyzed retrospectively. The median follow‐up period was 1891 (range, 5–4804) days. All patients underwent surgical treatment [mastectomy with sentinel lymph node biopsy (SLNB) and partial mastectomy with or without SLNB, tumorectomy, and microdochectomy]. Postoperatively, radiation therapy was administered to 73 (78.4%) of the patients and endocrine therapy was administered to 64 (81.0%) of 79 patients with hormone‐receptor positivity. Of 26 patients who underwent partial mastectomy with SLNB, 24 (92.3%) showed isolated tumor cells in the SLNs on one‐step nucleic acid amplification. Local recurrence was observed in three (0.3%) patients; no distant metastasis was observed. One patient died of a noncancerous disease. The overall survival rate was 98.0% and the breast cancer‐specific survival rate was 100.0%. Conclusions Non‐invasive breast carcinoma, like invasive breast carcinoma, causes local recurrence, but has a good prognosis without distant metastasis. The clinical significance of isolated tumor cells in the SLNs as a systemic component of non‐invasive breast carcinoma remains to be elucidated.


| INTRODUCTION
Breast cancer is classified histologically as invasive or non-invasive based on whether tumor cells in the ductal component pass through the epithelial basement membrane. 1 Invasive and non-invasive carcinomas are also classified as ductal or lobular based on the confinement of cells and sites of origin to the ducts or lobules. 1  Non-invasive carcinomas, such as DCIS and lobular carcinoma in situ (LCIS), are considered to be local diseases and do not develop distant metastasis unless they progress to invasive carcinoma with local recurrence after surgical treatment. 3 The sentinel lymph nodes (SLNs) in the axilla form the first immunological barrier to tumor metastasis; the evaluation of SLN metastasis is generally performed on frozen or permanent sections. One-step nucleic acid amplification (OSNA) [4][5][6] involves the amplification of cytokeratin (CK)19 mRNA from lysate for the determination of SLN status.
It is considered to be the most accurate method for the intraoperative diagnosis of lymph node metastasis. A recent study revealed no difference in disease-free survival or overall survival (OS) rates for patients with stages I and II breast cancer between those diagnosed using OSNA, frozen section analysis, and definitive histological analysis. 7 Sentinel lymph node biopsy (SLNB) is a standard procedure in breast cancer surgery. 8 It is used for the surgical treatment of DCIS with tumor formation or lesion extension due to the possibility of invasive carcinoma. The presence of tumor cells in the SLNs may be due to their iatrogenic dissemination into the lymphatic or vascular system via diagnostic biopsy [fine-needle aspiration (FNA), core needle, excisional, or incisional] [9][10][11] or to the microvascular invasion of DCIS, which may cause distant metastasis. 12  According to patients' preferences, outpatient surgery under local anesthesia (LA) and intravenous anesthesia (IVA) and/or sedation was performed at the clinic, 14 and inpatient surgery or total mastectomy (Bt) under general anesthesia (GA) was performed at an associated hospital. Breast-conserving surgery (BCS) was performed as an outpatient or inpatient procedure according to eligible patients' preferences, and was not mandatory. This cohort study was approved by the Ethics Committee of Hiroshima Mark Clinic (no. HMC-04), and all treatments were performed with patients' informed consent.

| Anesthesia
In outpatient surgeries performed during the study period, LA with lidocaine, benzodiazepines (e.g., diazepam and midazolam) as sedatives, IVA with propofol, and pentazocine (opioid receptor partial agonist) and pethidine (synthetic opioid) as analgesics were used.
Preoperatively, 10 ml 0.5% lidocaine was injected locally under ultrasound guidance into the retromammary tumor space when marking the tumor resection site; additional local injections were administered around the tumor before and during surgery. For the intraoperative monitoring of biological functions, each patient was fitted with a biometric monitor to measure the pulse rate, electrocardiographic data, blood pressure, respiratory rate, and oxygen saturation.
All patients received oxygen at a rate of 3-5 L/min delivered by oxygen mask during surgery, with preparation for emergency mask ventilation and tracheal intubation. In inpatient surgeries, GA was induced with total IVA using propofol and synthetic opioids such as remifentanil, or volatile anesthesia with sevoflurane using synthetic opioids.

| Surgical procedures
The patients underwent SLNB and BCS with partial (Bp) or quadrant (Bq) breast resection or Bt. BCS was defined as resection of the primary tumor and partial mastectomy with a 1-1.5-cm margin. In outpatient surgeries, axillary SLNB was performed using indigo carmine and indocyanine green dyes; in inpatient surgeries, it was performed using the radioisotope 99m Tc-phytate and indigo carmine dye. During outpatient surgeries, OSNA assays 4,5 (Sysmex, Kobe, Japan) were per-   Actual radiation doses were adjusted according to body surface areas. TAM, but no RT. The initial surgical margins were well over 2 mm (3 mm and 11 mm, respectively) in the first two cases; in the last case, the DCIS was exposed but the patient refused additional resection of the remaining breast.

| Immunohistochemical assays
No breast cancer-related deaths occurred, but one patient died following a stroke. The cumulative OS and BCSS rates for the entire cohort were 98.0% and 100%, respectively (Figure 1).

| DISCUSSION
In the present cohort of 93 patients, no distant metastasis of DCIS or LCIS occurred after surgical therapy. Local recurrence was seen in three patients; two cases were salvaged by total and repeat partial mastectomies, and the third case was managed with alternative therapy. The two surgically-treated cases were IDC and ILC with no distant metastasis at diagnosis. These findings suggest that local recurrence due to the transition from non-invasive to invasive carcinoma is not a cause of distant metastasis associated with an increase in breast cancer mortality. The results of the present study are consistent with previous reports that the local recurrence of DCIS after lumpectomy is reduced by postoperative RT, possibly in combination with adjuvant ET with TAM, relative to lumpectomy alone. [17][18][19] However, the presence of isolated tumor cells in the SLNs may suggest the possibility of metastasis without the invasive conversion of non-invasive carcinoma, although no distant metastasis was observed in this study. Whether such isolated cells are involved in the development of distant metastasis in non-invasive carcinoma cases remains to be determined.
The incidence of distant metastasis in patients with DCIS is low, but the reduction of local recurrence does not correlate with breast cancer mortality, 17,20,21 suggesting that tumor cells can invade the breast duct microvasculature as systemic disease in these patients. 12 Indeed, OSNA revealed isolated tumor cells in the SLNs in 24 of F I G U R E 1 Cumulative overall survival (OS, A) and breast cancer-specific survival (BCSS, B) for 93 patients with noninvasive carcinoma 26 patients in the present study. Thirteen of these 24 patients had undergone preoperative VAB. OSNA-detected micrometastasis has been suggested to be due to the mechanical disruption of the tubular component during CNB for the histological evaluation of DCIS. 22 Micrometastasis in DCIS has been proposed to be attributable to true metastasis due to occult invasion, and to iatrogenic dissemination by diagnostic CNB. 22,23 Repeat histopathological evaluation of surgical specimens has revealed occult invasion in some DCIS cases, but this does not account for about 40% of such cases. 23 In another study, DCIS cases showed SLN positivity despite the absence of occult invasion on comprehensive histological sectioning. 24  been reported to contribute to tumor progression and an increased risk of recurrence, 36 and was likely involved in the development of invasive lesions in these cases. However, the addition of HER-2 targeting therapy with trastuzumab to RT has been reported to have no significant effect on the local recurrence of HER-2-positive DCIS compared with RT alone. 37 Further studies of the effect of this additional therapy are needed.
The limitations of this study are that it was retrospective and conducted with a small sample. Thus, local recurrence was infrequent, and no distant metastasis was observed in this sample.