Recent advances and updated highlights in breast cancer pathologic diagnosis: a narrative review

Introduction

Background

With the rapid development of breast cancer treatment, breast cancer pathologic diagnosis has faced many requirements and challenges. The study focused on searching the literature related to updated key points of invasive lobular carcinoma (ILC), phyllodes tumors, new advances in immunohistochemical (IHC) indexes, updated advances in neoadjuvant therapy, and advances in the study of human epidermal growth factor receptor 2 (HER2)-low breast cancer in the 2023 and 2024.

Rationale and knowledge gap

Among the hotspots studied in this paper, it is suggested that patients with ILC with papillary structures should be diagnosed with extra care to avoid misdiagnosis of some rare variant subtypes; it is suggested that the precise diagnosis of lobular tumours is also a challenge, and that more studies are needed to improve the classification and grading of lobular tumors. For the assessment of the efficacy of neoadjuvant therapy in breast cancer is also a topic of debate. Studies on the clinicopathological features and prognosis of HER2 low and ultra-low-expressing breast cancers are limited, and the limits of detection are currently unclear.

Objective

This article reviews and summarises the important results that will change the clinical practice of breast cancer. The aim is to accumulate more diagnostic experience for pathologists, thus bringing more accurate and long-lasting therapeutic benefits to patients. I present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-27/rc).

Methods

This paper explores the clinicopathological features of ILC and phyllodes tumors, new advances in IHC indexes, updated advances in neoadjuvant therapy for breast cancer, and advances in the study of HER2-low breast cancer. As of April 2024, a comprehensive literature search, compilation, and analysis were conducted across PubMed, Baidu Scholar, ClinicalTrials.gov, and relevant academic conferences (Table 1).

Progress in pathological diagnosis of ILC of breast

ILC of the breast is a group of invasive cancers characterized by the loss of cell adhesion and cytoskeletal regulation. It is the second most common histologic subtype of invasive breast cancer, accounting for 10% to 15% of cases. It exhibits unique clinicopathological features. Current studies have suggested a potential association with mutations in the cadherin gene (CDH1) (1).

With in depth studies of breast cancer pathology, it has been found that ILC has unique molecular distribution and clinical characteristics, distinguishing it from the traditional molecular classification and clinical features of invasive ductal carcinoma (IDC). Compared with IDC, it is more frequently manifested as multifocal and multicentric, and the simultaneous incidence rate of bilateral mammary glands is higher. 10–20% of clinical cases involve both sides. The clinical and imaging manifestations of ILC are often subtle and challenging to diagnose, posing a dual challenge for clinical management and pathological diagnosis. Based on the expression of estrogen receptors (ER⁺)/HER2⁻, ILCs are roughly classified as follows: 90% of ILCs are ER⁺/HER2⁻, comprising the vast majority of ILC patients; HER2⁺ ILCs account for 3% to 13%; and triple-negative ILCs account for 2% to 9%. In light of the increasing recognition of HER2-low status in breast cancer clinical treatment over the past two years, the proportion of HER2-low ER⁺/HER2⁻ ILC is about 53%. The metastasis pattern of ILC also differs from that of IDC. The main metastatic sites for ILC include the bone, gastrointestinal tract, uterus, ovaries, meningeal surfaces, and lungs (1).

Luminal type accounts for the highest proportion of breast cancer cases, and ILC and IDC also exhibit many pathological differences. Firstly, the immune microenvironment differs between these subtypes. A multicenter retrospective series published in the Journal of the National Cancer Institute in 2018 showed a mean tumor-infiltrating lymphocyte (TIL) level of 5% in ILCs compared with IDCs. High TIL levels were associated with younger age, lymph node involvement, and a high Ki-67 index. High TIL levels in ILC are associated with a poor prognosis. In the study cohorts of Luminal type ILCs and IDCs, the enrichment frequency of ERBB2 mutations in early IDCs was approximately 1.4% (18/1,301), compared to a more significant enrichment frequency of 5.7% (16/279) in ILCs, while the ERBB mutation rate was higher in metastatic ILCs, reaching 15%, and ERBB2-mutated ILC was associated with a poor prognosis. Targeted ERBB2 mutation status is an independent prognostic marker for 10-year overall survival (OS) in ILC patients (2).

The mutation rates of luminal-type metastatic ILC and IDC differ significantly. CDH1 mutations are particularly prominent, with a mutation rate of 76% in ILCs compared to only 6.8% in IDCs. The frequency of PIK3CA mutations is also higher in ILC (52.8%) than in IDC (39.8%). The characteristics of CDH1 and PIK3CA gene mutations in ILC suggest the potential for targeted therapy (3).

In terms of breast cancer immunotherapy, whether neoadjuvant or systemic, the focus has traditionally been on triple-negative breast cancer. However, in 2023, two clinical trials on HR⁺/HER2⁻ early breast cancer immunotherapy, KEYNOTE-756 and CA209, were announced at the San Antonio Breast Cancer Symposium. These studies investigated the use of pembrolizumab or nivolumab plus chemotherapy. Programmed death ligand 1 (PD-L1) expression was assessed using 22C3 combined positive score (CPS) ≥1 and SP142 immune cell (IC) ≥1%, respectively. Both trials significantly increased pathologic complete response (pCR) rates by more than 10%, as well as residual cancer burden (RCB) 0–1 rate (4,5). Therefore, for lobular cancer, identifying patients who may benefit from neoadjuvant immunotherapy combined with chemotherapy should also be a focus of future research.

The clinical diagnosis and treatment of ILC have initiated various clinical trials and studies. For pathologists, questions about the consistency and reproducibility of pathological diagnosis of ILC in the real world are crucial. To address some of these issues, Professor Christine Desmedt (6) of the University of Leuven, Belgium, and co-chair of the Lobular Cancer Consortium, launched a global online survey from December 14, 2020, to July 1, 2021. Approximately half of the pathologists (52%) reported that they often used IHC to assist in the diagnosis of ILC, 3% never used IHC for diagnosis, and 50% believed that IHC staining alone was adequate for diagnosing E-cadherin. Additionally, 23% thought that the combination of E-cadherin and p120 should be used to assist in the diagnosis of ILC. There is considerable variability in E-cadherin staining (e.g., antibody selection), which may lead to differences in staining and diagnostic results.

Prof. Calhoun (7) raised two important questions regarding the current status of pathological diagnosis of ILC as reported by Desmedt and colleagues (6): (I) does the initial diagnosis of ILC require IHC? (II) How should ILC be standardized for diagnosis? Subsequently, Prof. Christgen provided answers, suggesting that IHC should be used as an adjunct in the pathological diagnosis of ILC. He also emphasized that even in cases of loss of E-cadherin protein expression, typical histomorphology remains a key diagnostic criterion for ILC, including tumor cells exhibiting a pattern of complete loss of adhesion, presence of lobular carcinoma in situ, abnormal expression of p120 or β-catenin, and detection of CDH1 or CTNNA1 mutations through DNA sequencing (8).

In addition to ILCs with non-adhesive growth patterns, a special case of ILCs with papillary growth patterns has recently been discovered. Gessain et al. (9) retrospectively analyzed a case of ILC with papillary growth pattern, which exhibited lymph node metastasis. Histologically, tumor cells with loss of adhesion were scattered in fibrous stroma, arranged in a single-file pattern, with regions showing a papillary growth pattern. Tumor cells in these areas also demonstrated loss of adhesion, moderate nuclear pleomorphism, and lymph node metastatic cells also exhibited a papillary growth pattern.

Immunohistochemistry revealed positivity for ER and progesterone receptor (PR), negativity for HER2, abnormal expression of E-cadherin, and nuclear localization of β-catenin, confirming the diagnosis of ILC. Genetic analysis demonstrated CDH1 mutations in both primary and metastatic sites, further confirming the diagnosis of ILC. PIK3CA mutations were also identified, with similar quantitative chromosomal alterations observed in both primary and metastatic tumors. Given the distinct management of ILC compared to papillary carcinoma, special attention should be paid to the diagnosis of patients with infiltrating lobular carcinoma with papillary structures to avoid misdiagnosis of rare variant subtypes, which could impact subsequent treatment for patients.

Advances in pathological diagnosis of breast phyllode tumors (PTs)

PTs are relatively rare fibroepithelial tumors with prominent intraductal growth patterns, presenting a lobulated structure and abundant stromal cells. They are classified into benign, borderline, and malignant based on histopathological parameters. The fifth edition of the breast tumor classification recommendations from the World Health Organization (WHO) suggests that malignant phyllodes tumors (MPTs) should be diagnosed when all five morphological features are present: permeative borders, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 high power field (HPF), and stromal overgrowth. When only some of these criteria are met, the diagnosis is borderline phyllodes tumors (BPTs). MPTs can also be diagnosed based on the presence of a malignant heterologous component without the above characteristics, but well-differentiated liposarcomas are excluded from the criteria for malignant heterologous components in the latest WHO version. However, because of the correlation between grading criteria and clinical behavior, not all phyllodes tumors with metastatic potential can be captured when all five characteristics are met to diagnose MPT; some phyllodes tumors with metastatic potential may be classified as BPTs. For benign phyllodes tumors, the recurrence rate is approximately 10–17%, for borderline tumors approximately 14–25%, and for malignant tumors 23–30%, with metastasis occurring in approximately 16.7% of malignant cases. Metastasis occurs in 1.6% of borderline and 0.1% of benign phyllodes tumors. Therefore, the accurate classification and grading of phyllodes tumors are of great significance for the treatment and prognosis of patients.

Regarding the current status of phyllodes tumor diagnosis, Prof. Puay Hoon Tan (10) enrolled pathologists from 29 countries in an online survey. The results showed that 84% of the pathologists considered that interstitial cell density was the key to diagnosing phyllodes tumors, followed by interstitial overgrowth (76.6%) and interstitial mitosis (67.8%). Nearly half (49%) of pathologists said that not all histologic criteria need to be met for diagnosing MPTs. Marked overgrowth, atypia, and increased mitosis are the three most important histologic features for making a malignant diagnosis. Prof. Li et al. (11) conducted a multicenter study on grading criteria for MPTs, combining clinical pathology characteristics and prognosis with a Cox regression model. This study proposed revised criteria for MPT with distant metastases (meeting one of the following criteria for diagnosing MPTs): (I) stromal overgrowth combined with ≥1 feature(s) (marked cellularity, marked atypia, or ≥10 mitoses per 10 HPF); or (II) in the absence of stromal overgrowth, marked cellularity combined with ≥1 feature(s) (permeative borders, marked atypia, or ≥10 mitoses per 10 HPF). Subsequently, at the annual 2024 meeting of the United States and Canadian Academy of Pathology (USCAP), Prof. Li used the revised criteria and WHO diagnostic criteria for phyllodes tumor grading. The results showed that when the revised criteria were used, metastases occurred in 35.7% of the 140 MPT patients compared with none of the BPT patients, suggesting that the revised criteria are superior to the WHO criteria in predicting clinical outcomes.

Alterations in the immune microenvironment and genomics of MPTs are significant concerns for pathologists and clinicians. A study presented at the 2023 San Antonio Breast Cancer Symposium revealed heightened immune infiltration of B cells, M2 macrophages, and neutrophil cells within the tumor microenvironment of primary MPTs and lung metastases, compared to other metastatic sites. Additionally, specific gene mutations were identified in lung metastases, including TERT promoter, MED12, and RB1 alterations, holding crucial clinical implications for guiding subsequent treatment of MPTs. Prof. Puay Hoon Tan, presenting at the USCAP 2024, investigated genomic changes in phyllodes tumors, finding a lower incidence of recurrent metastatic PT mutations compared to primary PTs. Notably, alterations in the TERT gene were nearly ubiquitous among patients with recurrent/metastatic PTs. Other recurrent mutations included MED12, KMT2D, BCR, MUC16, EGFR, and Notch1.

In conclusion, the accurate diagnosis of phyllodes tumors remains a significant challenge for pathologists, necessitating further research to refine the classification and grading of these tumors. Understanding the accurate diagnosis, immune microenvironment, and genetic changes of phyllodes tumors holds pivotal importance in guiding clinical treatment.

Research progress on IHC diagnostic markers

P63

P63 is a transcription factor belonging to the P53 gene family, encoded by the TP63 gene located on chromosome 3q28. P63 can also be expressed in breast epithelial cells with specialized differentiation, such as squamous epithelium and spindle mesenchymal cells. Although P63 is typically not expressed in classic invasive carcinomas, it can be detected in breast tumors with myoepithelial differentiation, such as salivary adenoid cystic carcinomas, metaplastic carcinomas with squamous or spindle cell differentiation, lesions with skin appendage differentiation, and some papillary lesions. In certain invasive carcinomas, proliferating tumor cells may show P63 staining at the periphery of cell clusters, mimicking intrinsic myoepithelial cells at the epithelial-mesenchymal junction, particularly in low-grade adenosquamous carcinoma. This can complicate interpretation and pose a risk of missing an invasive carcinoma diagnosis (12).

Papillary lesions

The presence of myoepithelial cells at the epithelial-mesenchymal junction is critical for classifying papillary lesions. In classic intraductal papilloma, IHC staining for P63 is positive in the myoepithelial cells of the fibrovascular core and at the periphery of the lesion. In atypical intraductal papillomas or ductal carcinoma in situ (DCIS), P63 expression is absent in the affected area but remains present in the rest of the lesion and at the periphery.

A significant pitfall in using IHC P63 for evaluating papillary lesions is that some hyperplastic epithelial cells may also be P63-positive. This could represent focal myoepithelial cells or early squamous differentiation seen in some papillary tumors. In papillary lesions with overlapping morphological features with pleomorphic adenoma, squamous and myoepithelial differentiation are generally more prominent.

Metaplastic breast cancer

Metaplastic breast cancer encompasses a heterogeneous group of tumors characterized by varying differentiation directions and levels of P63 expression. P63 expression is more commonly observed in fibromatosis-like spindle cell metaplastic carcinoma, squamous cell metaplastic carcinoma, other low to intermediate-grade spindle cell metaplastic carcinomas, and low-grade adenosquamous carcinoma. However, the spindle cells in low-grade adenosquamous carcinoma are negative for P63. In contrast, the spindle cell component of fibromatosis-like metaplastic carcinoma and other low to intermediate-grade spindle cell metaplastic carcinomas is positive for P63, reflecting their epithelial origin. The positive rate and intensity of P63 expression in high-grade spindle cell metaplastic carcinoma gradually decrease, and P63 is not expressed in stromal metaplastic carcinoma.

Adenomyoepithelioma

The main cell type in adenomyoepithelioma may be ‘intermediate cells’, which exhibit myoepithelial cell morphology but have limited or abnormal expression of classical myoepithelial cell markers and other IHC features. When interpreting these cases, it is crucial to consider both the IHC results and the morphological features. Decreased P63 expression, or discrepancies between P63 expression and morphology, are more common in atypical adenomyoepithelioma than in benign adenomyoepithelioma, particularly in malignant forms. Therefore, IHC P63 may have limited utility in identifying cells with a myoepithelial phenotype in atypical and malignant adenomyoepithelioma.

IHC markers are also important in the diagnosis of breast cancer, e.g., TRPS1, FOXC1. TRPS1 has a positivity rate of 86% in triple-negative breast cancers and can help to differentiate primary secretory carcinomas of the breast from salivary glands, as well as some metastatic tumours (13-15). FOXC1, as an important member of the transcription factor superfamily, plays an important role in the process of tumour cell proliferation and differentiation, migration and invasion What is of concern is that FOXC1 is specifically elevated in breast cancer only in the basal-like breast cancer subtype, and correlates with the invasive biological behaviours of intermediate basal-like breast cancer (16).

Advances in pathologic diagnosis for neoadjuvant treatment of breast cancer

Neoadjuvant systemic therapy (NST) is a potential clinical trial design, with the Food and Drug Administration (FDA) assessing the efficacy of pCR as a surrogate endpoint for disease-free survival and OS to expedite the regulatory approval of neoadjuvant drugs in high-risk early-stage breast cancer. With the advancement of individualized therapy, various treatment regimens and responses have emerged for different molecular subtypes of breast cancer. In 2023, the American Society of Clinical Oncology (ASCO) and investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis (I-SPY) pathology working groups issued standardized evaluation guidelines for neoadjuvant efficacy endpoints (17) to guide pathologic evaluation in neoadjuvant trials.

First, the guidelines currently propose that ypT0/Tis ypN0 is the preferred definition of pCR after NST, and make recommendations for pathological examination of specimens after neoadjuvant chemotherapy (NCT): (I) primary tumor. If gross examination reveals a significantly larger tumor bed (>3 cm), it is recommended to take one section per centimeter for examination. If the residual tumor bed is small (≤3 cm), the entire fibrotic area should be examined. Care should be taken not to misinterpret the tumor bed as lymphovascular or vascular invasion when it is surrounded by obvious artifacts due to mesenchymal atrophy. In cases approaching pCR, AE1/AE3 staining can help delineate the distribution of tumor cells when residual individual tumor cells are difficult to distinguish from inflammatory cells in HE sections. (II) Lymphatic node. Identifying 10 or more lymph nodes from axillary lymph node dissection may be challenging due to chemotherapy-induced lymph node atrophy and fibrosis. Therefore, both axillary clearance and sentinel lymph node (SLN) biopsy should be conducted by meticulously searching for lymph nodes in the axillary fat and slicing and sampling all lymph nodes perpendicularly to the long axis at 2–3 mm intervals. For SLN biopsy, it is recommended to place biopsy clips in lymph nodes during fine-needle aspiration or image-guided core needle biopsy of clinically suspicious or positive lymph nodes (or before starting systemic therapy if not done during the core needle biopsy) to ensure that biopsy-positive or suspicious lymph nodes are excised during the final procedure. However, routine use of cytokeratin to detect metastasis in SLN is not recommended. (III) Tumor biomarkers. Current practice data indicate considerable differences in tumor biomarkers before and after neoadjuvant therapy. Therefore, biomarkers should be retested after NCT. (IV) Therapeutic efficacy assessment system. Since residual DCIS does not affect the final RCB classification or index, the pCR classification, or patient prognosis, the working group recommends simplifying the RCB algorithm to minimize errors. Conversely, the presence of isolated tumor cells (ITCs) after NCT may not hold the same clinical significance as in untreated tumors according to the American Joint Committee on Cancer evaluation system. To avoid understaging and undertreatment, lymph nodes with ITCs should not be categorized as ypN0 (i+), but rather as ypN1 (i+).

ASCO also suggests some specific circumstances that should be directly categorized as non-pCR: (I) cases where the treatment plan is adjusted due to a lack of pathological response in the preoperative monitoring of the neoadjuvant treatment regimen; (II) patients with insufficient postoperative pathological assessment after neoadjuvant therapy or those who do not undergo surgery; (III) patients with solitary tumor cells and micrometastases in axillary lymph nodes after neoadjuvant therapy; (IV) those who underwent SLN biopsy and/or lymph node dissection before neoadjuvant therapy. Additionally, the guidelines note that pCR rates for HR-positive breast cancers are generally low, making it inappropriate to use pCR as a primary endpoint for clinical trials.

Patients with inflammatory breast cancer, stage cN3 (especially synchronous bilateral) breast cancer may have inconsistent histologic types and molecular typing. It can be difficult to determine whether they are recurrent, metastatic, or bilateral primary tumors, and postoperative systemic therapy may involve different therapeutic regimens. Therefore, it is not recommended that these patients be enrolled in neoadjuvant clinical trials.

Progress in research on HER2 low

The DESTINY-Break06 (DB06) study was unveiled at the 2024 ASCO annual meeting for the first time, which confirmed that T-DXd showed clinically significant progression-free survival (PFS) benefit and OS benefit trends in patients with advanced breast cancer with low HER2 expression and ultra-low HER2 expression, further expanding the beneficiary population of anti-HER2 targeted therapy. The precise diagnosis of HER2 low remains a formidable challenge confronting pathologists. A study published in ESMO OPEN (18) re-evaluated 789 cases of breast cancer diagnosed as HER2-negative from 2014 to 2017, finding a moderate concordance between historical HER2 status and re-evaluated HER2 status, with a κ value of 0.583. The consistency for HER2-low (87.5%) was numerically higher than for HER2 IHC 0 (69.9%). Furthermore, Nielsen et al. (19) observed a significant increase in variability among HER2 low cases from 2011 to 2019 across eight departments using the same IHC testing process, with variability increasing from 52.5–64.9% to 46.5–81.6%. This suggests that the semi-quantitative nature of HER2 IHC may contribute to the subjectivity and variability in pathologists’ interpretations. Additionally, IHC results for HER2 low also exhibit variability and are influenced by various factors, indicating the challenges of using IHC for precise HER2 low diagnosis.

Addressing the limitations of semi-quantitative IHC, Wu et al. (20) explored the role of artificial intelligence (AI) in assisting HER2 IHC assessment to overcome the challenges of precise interpretation for HER2 low. Fifteen multi-center pathologists conducted two rounds of visual assessments and AI-assisted evaluations on 246 cases of HER2 0 and 1+ breast cancer. The results showed that AI-assisted interpretations improved the accuracy and consistency of pathologists’ readings for HER2 0 and 1+, particularly for HER2 1+ cases. Furthermore, AI-assisted in improving the accuracy of interpreting cases with HER2 heterogeneity, especially the dispersed type. This study provides initial evidence of AI’s role in assisting pathologists in distinguishing HER2 0 and 1+ cases and improving interpretations of cases with heterogeneity.

Moreover, Li et al. (21) measured HER2 expression in 526 breast cancer tissue microarray cores using FDA-approved pathway and HercepTest IHC methods, and assessed corresponding RNA levels via RNA scope. They also conducted RNA scope testing on 32 metastatic biopsy samples from 23 patients subsequently treated with T-DXd. The results demonstrated a close correlation between RNAscope-measured HER2 RNA levels and HER2 protein levels as well as HER2 IHC H scores. However, there were no significant differences in protein and RNA levels among cases scored as 0, ultra-low, and 1+ for HER2. Additionally, responders to T-DXd had significantly higher RNA levels compared to non-responders, suggesting that using RNAscope scoring may be superior to IHC scoring for predicting patient response to T-DXd.

Conclusions

Breast cancer treatment and pathology have made significant progress in 2023 and 2024. The diagnosis of ILC and breast phyllodes tumors continues to be updated. For the newly assisted post-neoadjuvant pathological evaluation of breast cancer, accumulating more interpretation experience is crucial. This will help ensure more accurate diagnoses and provide long-term treatment benefits for patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-27/rc

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-27/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-27/coif). Y.L. serves as an unpaid editorial board member of Translational Breast Cancer Research from May 2023 to April 2025. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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