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Brain metastases (BM) represent the most common intracranial tumors in adults and occur in up to 20–40% of patients with systemic cancer, frequently originating from lung, breast, skin, renal, or colorectal malignancies [1] Surgical resection remains a milestone of the management of large or symptomatic BM, particularl... |
Despite their traditionally circumscribed growth pattern, increasing histopathological evidence demonstrates that many BM exhibit tumor cell infiltration beyond the contrast-enhancing margins into the surrounding brain parenchyma, which may contribute to local recurrence after surgery [3,4]. The interface between metas... |
Frozen section histopathology can provide intraoperative diagnostic confirmation but requires tissue sampling and processing [8]. Confocal laser endomicroscopy (CLE) has emerged as a promising intraoperative imaging technique capable of providing real-time, high-resolution optical biopsies of brain tissue at the cellul... |
Prospective clinical studies have demonstrated that CLE using SF can achieve high diagnostic accuracy when compared with conventional histopathology for identifying tumor tissue during brain tumor surgery [8,10]. The potential role of CLE for assessing the metastasis–brain parenchyma interface (MBPI) and detecting tumo... |
Therefore, a systematic evaluation of the current clinical evidence is required to clarify the role of fluorescein-guided confocal laser endomicroscopy in metastasis surgery. The objective of this systematic review is to assess the available literature regarding the intraoperative use of confocal laser endomicroscopy w... |
## 2. Methods |
### 2.1. Search Strategy |
A comprehensive literature search was conducted to identify all studies evaluating the intraoperative use of CLE with SF for tumor detection and margin assessment during BM surgery. The following electronic databases were systematically searched: PubMed (n = 28), Ovid (n = 0), Scopus (n = 1), Embase (n = 183), Cochrane... |
The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to brain metastases, confocal laser endomicroscopy, and fluorescein. The following search query was used: |
(“Brain Neoplasms” OR “Neoplasm Metastasis” OR brain metastas* OR intracranial metastas* OR metastatic brain tumor*) AND (“Microscopy, Confocal” OR “confocal laser endomicroscopy” OR “confocal endomicroscopy” OR CLE OR CONVIVO®) AND (“Fluorescein” OR “fluorescein sodium” OR “SF” OR fluorescein). The review protocol was... |
Additional articles were identified through manual screening of reference lists from relevant publications. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. |
### 2.2. Eligibility Criteria |
Studies were considered eligible if they met the following criteria. |
### 2.3. Inclusion Criteria |
Adult patients (≥18 years) undergoing surgical treatment for BM;Studies reporting the intraoperative use of CLE with SF;Articles providing clinical outcomes, diagnostic accuracy, or intraoperative imaging findings related to tumor tissue or tumor margins;Original studies including prospective studies, retrospective coh... |
### 2.4. Exclusion Criteria |
Studies involving pediatric-only populations;Non-English publications without accessible full-text English translation;Review articles, editorials, letters, conference abstracts without full text, or expert opinions;Animal or preclinical studies;Studies using CLE without SF;Studies limited to ex vivo analysis without i... |
### 2.5. Study Selection |
All records identified through the database search were imported into a reference management software and duplicates were removed. After duplicate removal, 2676 articles remained for screening. Titles and abstracts were independently screened by two reviewers (SACM, NA). Studies that did not meet the eligibility criter... |
The PRISMA flow diagram summarizes the study selection process (Figure 1). The PRISMA Checklist was provided as a Supplementary document and submitted separately along with the manuscript (Supplementary Table S1). |
### 2.6. Data Extraction |
Data extraction was independently performed by two reviewers using a standardized data collection form. Extracted variables included: |
Study characteristics (author, year, country, study design);Sample size;Number of brain metastases included;CLE system used (e.g., CONVIVO® (Carl Zeiss Meditech, Oberkochen, Germany) or probe-based CLE);Fluorescein sodium usage;Imaging modality (in vivo or ex vivo intraoperative imaging);Location of imaging (tumor core... |
### 2.7. Quality Assessment |
The methodological quality and risk of bias of the included studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. The methodological quality of included studies is listed in Supplementary Table S2. |
This tool evaluates studies across four domains: |
Patient selection;Index test (confocal laser endomicroscopy);Reference standard (histopathological analysis);Flow and timing between the index test and reference standard. |
Each domain was assessed for risk of bias and concerns regarding applicability and categorized as low, high, or unclear risk of bias. |
## 3. Results |
### 3.1. Study Characteristics |
The characteristics of the included studies are summarized in Table 1. The 10 studies were published between 2011 and 2025 and included a mixture of prospective feasibility studies, prospective clinical trials, and cohort studies. Overall, the included studies investigated the intraoperative application of CLE using SF... |
[table] Table 1Characteristics of the studies included in the systematic review. Summary of study design, patient population, CLE system, fluorescein usage, imaging modality, and reference standards across the included studies evaluating intraoperative confocal laser endomicroscopy for brain tumor surgery with emphasis... |
The total number of patients across all included studies exceeded 650 patients, although the number of patients with BM specifically was substantially smaller, reflecting the heterogeneous tumor populations included in many CLE studies. Among the included studies, only two studies specifically focused on brain metastas... |
### 3.2. Intraoperative CLE Imaging and Tumor Margin Visualization |
Early feasibility work by Sanai et al. demonstrated the initial clinical applicability of intraoperative confocal microscopy in human brain tumors, establishing the foundation for subsequent CLE-based intraoperative imaging approaches [15]. Across the included studies, CLE imaging enabled visualization of tumor microar... |
Some studies have specifically described CLE imaging across different intraoperative zones, including the tumor core, tumor border, and peritumoral brain tissue. For example, Höhne et al. systematically evaluated CLE images obtained from the tumor center, tumor margin, and perilesional brain tissue, demonstrating disti... |
### 3.3. Diagnostic Accuracy of CLE |
All included studies evaluated the diagnostic performance of confocal laser endomicroscopy CLE using histopathological analysis as the reference standard. However, most of the available studies evaluated CLE for general tumor detection rather than specifically assessing the metastasis–brain interface. In addition, Abra... |
Early prospective work by Martirosyan et al. demonstrated that CLE using SF can achieve high diagnostic performance in brain tumor surgery, with reported sensitivity exceeding 90% for tumor detection [7]. Similarly, Abramov et al., in a prospective in vivo feasibility study using the CONVIVO® system, reported high conc... |
### 3.4. Risk of Bias Assessment |
Overall, most studies demonstrated, after using the QUADAS-2 tool, a low risk of bias in the index test and reference standard domains, reflecting consistent use of histopathological analysis as the diagnostic gold standard. Nevertheless, several studies showed unclear risk of bias in patient selection and flow and tim... |
## 4. Discussion |
Brain metastasis has traditionally been regarded as well-demarcated lesions amenable to resection along a clear surgical plane; however, accumulating evidence indicates that this concept is overly simplistic. The prospective MetInfilt trial by Proescholdt et al. demonstrated that metastatic cells frequently extend beyo... |
CLE has emerged as a promising intraoperative imaging adjunct to address this limitation. By combining SF with high-resolution optical imaging, CLE enables real-time visualization of tissue microarchitecture, effectively functioning as an intraoperative optical biopsy. Early feasibility studies by Sanai et al. and Mart... |
More recent studies using clinically integrated systems such as CONVIVO® have extended these findings into practical intraoperative applications. Restelli et al. demonstrated that CLE can accurately identify pathological tissue at infiltration margins, reporting high diagnostic accuracy across CNS tumors, including met... |
Several studies have specifically emphasized the ability of CLE to interrogate different intraoperative zones. Höhne et al. demonstrated distinct CLE patterns between tumor core, tumor border, and perilesional tissue, supporting its use for intraoperative assessment of the MBPI [13]. Likewise, Belykh et al. reported th... |
An additional metastasis-specific aspect is highlighted by Brielmaier et al., who demonstrated that metastatic tumors exhibit significantly higher intracellular SF accumulation compared with primary brain tumors [12]. This finding is particularly relevant for margin assessment, as it suggests that metastatic tumor cell... |
Taken together, the available evidence supports a consistent biological and technical interpretation. Brain metastases frequently exhibit infiltrative growth at the metastasis–brain interface, and CLE provides a feasible method for visualizing this interface intraoperatively. The ability to identify microscopic tumor i... |
Nevertheless, important limitations must be acknowledged. The current evidence base is characterized by relatively small cohorts, heterogeneous study designs, and frequent inclusion of mixed intracranial tumor populations, including gliomas, meningiomas, schwannomas, and metastatic lesions, with only a limited number o... |
At present, CLE should be considered an adjunctive modality that may assist intraoperative decision-making rather than a stand-alone determinant of surgical strategy. Future prospective studies focusing specifically on brain metastases, with standardized imaging protocols and outcome measures, are required to define it... |
## 5. Conclusions |
The current literature increasingly indicates that BM are often infiltrative beyond the radiological enhancing border. In this setting, CLE may provide additional microscopic information at the resection margin and could potentially support more biologically informed intraoperative decision-making; however, evidence de... |
## Acknowledgments |
The authors would like to thank the members of the Neurosurgery Team 2 at the Carlo Besta Neurological Institute for their valuable clinical support and contributions to patient care. We acknowledge Octavian Vatavu, Riccardo Ciocca, Erica Boccardi, Marco Paolo Schiariti, Marco Saini, and Alberto Cusin for their involve... |
## Supplementary Materials |
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm15124420/s1. Table S1: PRISMA 2020 Checklist; Table S2: Risk of bias assessment using the QUADAS-2 tool. |
## Author Contributions |
Conception of the idea was made by S.A.C.M. and F.R. A comprehensive literature search was conducted by S.A.C.M., P.F. and F.R. Initial screening of articles was performed by S.A.C.M. and N.A. The included studies were analyzed collaboratively by S.A.C.M., N.A. and F.R. Quality assessments were conducted independently ... |
## Institutional Review Board Statement |
Not applicable. |
## Informed Consent Statement |
Not applicable. |
## Data Availability Statement |
The raw data supporting the conclusions of this article will be made available by the authors on request. |
## Conflicts of Interest |
The authors declare no conflict of interest. |
## Funding Statement |
This research was partially supported by the Associazione Paolo Zorzi per le Neuroscienze ONLUS, and by the Italian Ministry of Health (RRC). |
## Footnotes |
## References |
## Associated Data |
### Supplementary Materials |
### Data Availability Statement |
The raw data supporting the conclusions of this article will be made available by the authors on request. |
235eafbe60ef287c674184d2951f2ac23571bcc08090fcfeb61c5224263856cb pmc13301885.txt |
PMCID: PMC13368955 |
TITLE: Lepidic and alveolar subepithelial squamous cell carcinoma: expansion of the concept of peripheral squamous cell carcinoma with proposal for revised terminology based on morphologic, immunophenotypic, and clinical analysis of 22 cases |
LICENSE: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Com... |
ABSTRACT: AbstractIn recent years, peripheral type SCC with alveolar filling growth pattern was described with an increasing prevalence in up to 55% of patients. We describe a series of rare growth pattern of SCC with subtotal or partial growth of tumor cells under reactive type II pneumocytes, termed subepithelial gro... |
## Introduction |
Squamous cell carcinoma (SCC) is a malignant epithelial tumour characterized by keratinization, intercellular bridges, or squamous differentiation at immunohistochemistry (IHC) [1]. |
SCC, the second most common subtype of lung cancer, account for 20% of all lung carcinomas [2] and 30% of non-small cell lung cancers [3]. |
At CT-scan, lung SCC usually appears as a nodule with sharply demarcated borders or a spiculated mass with distortion of adjacent lung parenchyma [4]. Based on anatomic location of the tumour, SCC can be central or peripheral. Traditionally, SCC has been reported to be mostly centrally located corresponding to two-thir... |
Both central and peripheral type are strongly associated with cigarette smoking [6], nevertheless they do not seem to be biologically related: central SCC are known to arise from bronchial epithelial cells with a multistep progression starting with dysplasia until carcinoma in situ [1], while this sequence has not been... |
Some studies have also found clinicopathological differences between the two SCC subtypes, where peripheral SCC has been associated with older patient age, lower rate of lymph nodes metastasis and lymphatic invasion, lower stage, higher rate of interstitial lung disease and cystic change in adjacent lung parenchyma, mo... |
In peripheral SCC four main histological pattern have been described: pushing, infiltrative, pseudoalveolar filling and alveolar filling (AF) pattern [10]. This latter is associated with excellent prognosis especially when comprising a major part (> 70%) of the tumor [11], and it has been proposed as the in situ compon... |
Moreover, few case-reports in English literature [12–22] describe an unusual growth pattern of peripheral SCC consisting of tumour squamous cells growing on the alveolar walls without their destruction, located under the reactive type II pneumocytes, called lepidic-pagetoid growth pattern of SCC or lepidic SCC. To prev... |
Here we describe a series of 22 peripheral lung SCC with partial subepithelial growth with radiologic and clinical correlation. |
## Material and methods |
### Patient collection |
Lung SCC with subepithelial growth were collected from consultation and regular diagnostic cases at the Amsterdam University Medical Center, Amsterdam, The Netherlands, and Maggiore Hospital of Bologna, Italy, between 1 st January 2018 and 31 st December 2024. Clinical information, overall survival (OS), recurrence fre... |
### Histology |
All cases and previous biopsy when present were reviewed and pathological information with special attention on subepithelial growth were recorded. A representative block with subepithelial growth was selected and 4 µm sections were cut from formalin-fixed paraffin embedded (FFPE) block and stained with Hematoxylin and... |
Subepithelial growth was defined as layers or nests of tumour cells growing along the alveolar septa which are immunoreactive for p40 IHC and covered by normal/reactive pneumocytes type II TTF1 positive. This pattern has been subdivided in lepidic-subepithelial and alveolar-subepithelial [19]: the lepidic-subepithelial... |
The CT scan for each case was reviewed and images correlated with histologic sections; the presence of ground glass component of the nodule was recorded. The tumor was defined as peripheral if located in the outer third of the lung at CT-scan [5]. |
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