Navigating discrepancies: The assessment of residual lymphovascular invasion in breast carcinoma after neoadjuvant treatment

Abstract

The assessment of residual lymphovascular invasion (LVI) in breast cancer patients undergoing neoadjuvant therapy may be a critical factor influencing prognosis and treatment decisions. However, there is a notable discrepancy between the RCB, UICC/AJCC, and ICCR guidelines regarding how LVI should be evaluated and reported in this context. ICCR recommends including LVI in the invasive tumor size for neoadjuvant treated patients with only residual LVI affecting the Residual Cancer Burden (RCB) score. AJCC suggests that LVI should not be evaluated as invasive cancer. However, they do not recommend that such cases are considered as complete response. The RCB method does not address the LVI question at all. This editorial aims to explore the implications of these differing recommendations, highlighting the challenges in clinical practice. Even though there is limited evidence in the literature on this subject, leaving this discrepancy unaddressed leads to high variability in the staging of neoadjuvant-treated breast cancer patients among pathologists. This, in turn, may cause confusion in the clinical decision-making for these patients. The recommendation of the Swedish Breast Pathology Expert Group (KVAST breast) based on current evidence, is to report LVI as a separate prognostic biomarker in neoadjuvant setting and reporting it separately from the RCB treatment response criteria. For breast cancer patients with only LVI as residual disease in the breast without any lymph node metastasis after NACT, the Swedish Breast Pathology Expert Group recommends the following staging: RCB-0, pPR, ypT0, ypN0, L1.

Neoadjuvant chemotherapy (NACT) was initially introduced to manage inflammatory and locally advanced breast carcinomas; later, it was also applied to earlier stages of breast tumors. NACT may improve operability by reducing tumor volume/mass and at least as effective as adjuvant therapy [1]. Currently NACT is widely used and the number of breast cancer patients receiving neoadjuvant chemotherapy is increasing [2]. To make correct postoperative treatment decisions after NACT, it is necessary to evaluate the treatment response in the resection specimen (complete response – pCR, partial response – pPR or no response (pNR)) [2]. Pathologic examination of the residual breast carcinoma is the gold standard for determining response to treatment after NACT. When pCR has been achieved, there is no residual invasive cancer in the breast or the axillary lymph nodes (ypT0/is N0), indicating significantly better survival outcomes compared with patients with residual invasive breast carcinoma [1,3]. Lymphovascular invasion (LVI) is defined be the Rosen's criteria [4] as clusters of tumor cells within peritumoral vascular lumina (lymphatics and/or capillaries) lined by endothelial cells [4,5]. When assessing the residual tumor in post-NACT surgical specimens, the question arises whether the presence of LVI should be incorporated into the assessment of residual invasive tumor size affecting staging (ypTNM). It is important to note that assessing LVI in diagnostic core biopsies has no clinical value, and perineural invasion should not be confused with LVI.

LVI has proven to be an independent prognostic factor for both local recurrence and survival [4,[6], [7], [8], [9], [10]]. Moreover, LVI status for stage IIA and IIB breast cancer patients with axillary lymph node dissection may also influence the use of radiotherapy and LVI may also affect decision making for adjuvant chemotherapy in HER2-positive breast cancer [2]. Furthermore, residual carcinoma confined only to the lymphovascular spaces can persist in the tumor bed following NACT. LVI may occur in three forms.

• a)Residual pure intralymphatic breast carcinoma (PIC), without stromal invasion, although ductal carcinoma in situ (DCIS) may be present.
• b)Minimal residual invasive carcinoma accompanied by extensive intralymphatic component called predominantly pure intralymphatic carcinoma (PPIC). However, there is no consensus definition of extensive LVI.
• c)Residual invasive breast carcinoma, accompanied by intravascular tumor emboli.

Due to its rarity, LVI has received little attention in large scale clinical studies focusing on neoadjuvant setting, leading to debated clinical utility of PIC and PPIC after NACT. LVI in association with invasive carcinoma after NACT has been shown to be an independent predictor of survival [11]. Moreover, LVI – in rare cases - is the only residual disease in the breast after NACT with an incidence of PIC in 1.0–4.1 % [12,13]. MacColls’ study reported a better prognosis for patients with PIC in comparison with patients with PPIC [13]. In the study of Rabban et al., patients with residual PIC or PPIC had a 3-fold higher risk of death [14]. The increased risk existed regardless of whether the intralymphatic component was incorporated in the overall staging or as a separate biomarker [14]. These findings highlight the importance of evaluating LVI without residual invasive tumor (Table 1). In addition to these, the study by Hamy et al. demonstrated that the presence of LVI is an independent prognostic information to the Residual Cancer Burden (RCB) score investigating more than 600 neoadjuvant treated breast cancer patients [15].

Table 1.

Studies focusing on patients with LVI as the predominant residual disease (LVI groups as PIC and PPIC).

Author Year of publication	Number of patients	Age range	Breast carcinoma molecular subtype before NACT	Clinical outcome at the time of publication
Rabban [14] 2009	6 PIC 5 PPIC	33–51 35–64	1 ER+/HER2+ 2 ER-/HER2+ 3 TNBC 1 ER+/HER2- 1 ER+/HER2+ 1 ER-/HER2+ 2 TNBC	60 % alive and disease-free 1 died
Cheng [25] 2017	6 PIC	33–64	2 ER+/HER2+ 1 ER-/HER2+ 3 TNBC	2 died (one of pulmonary embolism)
Guilbert [12] 2018	18 PIC	38–69	3 ER+/HER2- 8 ER+/HER2+ 7 TNBC	3 died
MacColl [13] 2020	5 PIC 6 PPIC	41–57 41–72	4 ER-/HER2+ 1 ER+/HER2- 2 TNBC 4 ER+/HER2-	1 died 3 died
Hyunwoo Lee [24] 2024	4 PIC + DCIS 8 PIC	35–54	5 TNBC 2 ER+/HER2+ 4 ER-/HER2+ 1 ER+/HER2-	2 died with residual nodal disease

Not just the limited number of studies but also the challenging detection of LVI hampers its clinical utility. After NACT, gross pathology findings may be absent in the surgical specimen, warranting substantial sampling. Tissue processing artifacts (e.g: retraction artifact) can mimic LVI and needs to be excluded. In the neoadjuvant setting, recognition of LVI in the surgical specimen may be further complicated by treatment-induced changes in both the tumor cells and the tumor stroma [14]. Moreover, an extensive LVI can mimic invasive carcinoma with stromal retraction or DCIS [13]. Therefore, immunohistochemical staining (IHC) for displaying lymphatic vessels by D2-40 (podoplanin) and/or CD31 with p63 can aid pathologic diagnosis in difficult cases, but routine use of IHC is not recommended. Subcategorization of LVI as extensive or non-extensive is optional. Pathologists may report the number of tissue blocks with LVI as a measure of its extent—for example, focal LVI in one block, and extensive LVI in two or more blocks.

Due to the reasons above, LVI is undervalued and poorly represented in clinical guidelines. Furthermore, the available treatment response assessment guidelines (RCB, UICC/AJCC, and ICCR) interpret and incorporate LVI differently in their classifications, leading to confusion among pathologists in daily diagnostic practice. The UICC staging recommendations include LVI as an essential prognostic factor, but they don't detail how it should be reported after NACT [16]. According to the recommendations of the latest AJCC staging (8th edition) and the Breast International Group-North American Breast Cancer Group (BIG-NABCG), patients with only residual LVI after NACT should be designated as non-pCR [17,18]. On the other hand, LVI is currently not included in the RCB (Residual Cancer Burden) index by the MD Anderson Cancer Center [19]. Although the ICCR guidelines emphasize that patients with only residual LVI cannot be classified as pCR, they also recommend - in these cases – to include LVI in the invasive tumor size for the purpose of calculating RCB score [20].

With increasing clinical application of NACT for breast cancer patients, the staging issue of LVI in neoadjuvant setting should be properly addressed. The discrepancy between the different treatment response assessment guidelines (RCB, UICC/AJCC, and ICCR) can cause confusion in clinical decision-making for these patients. Leaving this discrepancy unaddressed might lead to high variability in the staging of neoadjuvant-treated breast cancer patients among pathologists. Of note, LVI may serve as a contraindication for certain surgical procedures and is also considered a marker of tumor aggressiveness according to the NCCN guidelines— in addition other clinicopathological features — in guiding adjuvant chemotherapy decisions in HER2-positive breast cancer [21]. Further harmonization and clarification are needed between the different guidelines to create a proper TNM staging and up-dated RCB adjusting for LVI in neoadjuvant setting. Individual discussion/evaluation of neoadjuvant treated patients with LVI (as appropriate TNM staging and RCB is lacking now) on the multidisciplinary meeting is necessary due to unfavorable prognosis. Some experts suggested that cases with LVI as the only residual disease should not be considered pCR and to be staged as ypTx [[22], [23], [24]]. The recommendation of the Swedish Breast Pathology Expert Group (KVAST breast) based on the current evidence, is to use LVI as a separate prognostic biomarker even in neoadjuvant setting and reporting it separately from the RCB treatment response criteria. Since the RCB scoring system is not adjusted for LVI, we do not recommend including LVI in the tumor size for calculating the RCB score. Furthermore, we do not believe that LVI should impact T staging even in neoadjuvant setting. For those breast cancer patients, when LVI is the only residual disease in the breast without any lymph node metastasis after NACT, the Swedish Breast Pathology Expert Group recommends the following staging: RCB-0, pPR, ypT0 ypN0, L1. Furthermore, we also propose collective awareness and revision of guidelines at the international level.

CRediT authorship contribution statement

Anikó Kovács: Writing – review & editing, Writing – original draft, Conceptualization. Åsa Rundgren-Sellei: Writing – review & editing, Conceptualization. Gunilla Rask: Writing – review & editing, Conceptualization. Annette Bauer: Writing – review & editing, Conceptualization. Anna Bodén: Writing – review & editing, Conceptualization. Johannes van Brakel: Writing – review & editing, Conceptualization. Eugenia Colón-Cervantes: Writing – review & editing, Conceptualization. Anna Ehinger: Writing – review & editing, Conceptualization. Johan Hartman: Writing – review & editing, Conceptualization. Balazs Acs: Writing – review & editing, Writing – original draft, Supervision.

Declaration of competing interest

JH has obtained speaker's honoraria or advisory board remunerations from Roche, Novartis, Pfizer, EliLilly, MSD, AstraZeneca, Sakura and has received institutional research support from Roche, MSD and Novartis. JH is co-founder and shareholder of Stratipath AB. Other authors have no conflict of interest.