INTRODUCTION
Gastric cancer (GC) is the fifth most frequent tumor worldwide and represents the fourth-leading cause of death from cancer[1]. GC is a complex disease, where both genetic and environmental features can affect its incidence and progression. The vast majority of GC are adenocarcinomas and arise sporadically with no demonstrable inherited component. Hereditary cancer syndromes are linked to less than 3% of GC cases[2].
Traditionally, GC is divided into two main subtypes, intestinal and diffuse GC, on the basis of Lauren’s classification[3]. These subtypes of GC have diverse molecular characteristics and show distinctive growth pathways. Intestinal-type GC commonly develops from a premalignant gastric alteration, such as chronic atrophic gastritis (CAG), intestinal metaplasia (GIM), and dysplasia, whereas diffuse GC does not seem to develop from this step-wise tumor progression but arises from normal gastric mucosa with no eventual premalignant stage.
The incidence of GC increases progressively with age; the median age of the patients with GC at diagnosis is 70 years (conventional GC), although around 10% of GCs are diagnosed at the age of 45 or younger (early-onset GC). Approximately 990000 people are diagnosed with GC in the world each year, of whom around 738000 eventually die[4]. GC is more frequent in males and is supposed to develop from a number of premalignant lesions through a series of stages from CAG, by way of GIM, through low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia (HGIN), to cancer[5].
The detection of GC at an early stage is crucial since early GC (EGC), which is an invasive stomach malignancy limited to the mucosal or submucosal regions, may be treatable, with a 5-year survival rate of more than 90%[6]. Advanced GC generally shows a poor prognosis, although current treatment standards (neoadjuvant/adjuvant chemotherapy, radical oncologic surgery with D2 lymph node dissection, targeted treatments) have led to significant improvements in survival[6]. Symptoms of GC tend to emerge late in the development of the disease, leading to a poor prognosis and a lack of curative therapeutic options; thus, prevention strategies are necessary to reduce the occurrence of GC and for its early detection.
The two main primary prevention strategies for GC at a population level include changes in dietary habits and a decreasing occurrence of Helicobacter pylori infection. The secondary prevention strategy is the early detection of GC using available resources, mainly esophagogastroduodenoscopy (EGD), which has been established as the gold standard for the diagnosis of GC. EGD with biopsies plays a crucial role in the diagnosis and follow-up of patients with precancerous lesions of the stomach, showing high sensitivity and specificity in the diagnosis of GC; furthermore, it is carried out for the minimally invasive treatment of early GC by endoscopic submucosal dissection and mucosal resection. However, despite increasing experience in the field of endoscopy, traditional white light endoscopy (WLE) showed a number of limitations in the observation of microscopic lesions and a remarkable rate of gastric tumors are actually undiagnosed.
A meta-analysis reported that 11.3% of upper gastrointestinal tract tumors were ignored at EGD up to 3 years before the diagnosis[7]. Immediate histological assessment of fresh tissue is fundamental for successful cancer diagnosis and therapy to allow the detection of tumor cells and to guarantee curative resection. Nonetheless, the conventional frozen section technique shows intrinsic limitations, such as suboptimal slide quality due to preparation artifacts, and a long processing time. So far, despite many attempts to overcome these limitations, alternative techniques have not been diffusely adopted in clinical practice. As the most valuable tools for GC screening, modern endoscopy techniques, such as confocal laser endomicroscopy (CLE), narrow-band imaging, and magnifying endoscopy, have been developed to improve the diagnostic process.
PRINCIPLES AND APPLICATIONS OF CLE
CLE shows benefits in identifying EGC and premalignant conditions, as it can offer a clear histological examination of the cells and subcellular areas in vivo[8-11] as well as reveal alterations in the mucosa that cannot be identified by WLE[12]. CLE can be used to study luminal structures, such as the esophagus, stomach, large bowel, and ductal structures, such as bile and the pancreatic ducts. CLE can magnify the structure of the mucosa by a factor of 1000, making it possible to view in real-time at the cellular or subcellular level[13]. CLE showed a sensitivity of 81.8%-92.6%, a specificity of 97.6%-100%, and an accuracy of 94.2%-96.3% in differentiating gastric cancerous mucosa from normal mucosa as compared with histology findings[14,15]. CLE is generally not applied for the follow-up of large regions but is used for the characterization of lesions within a small field of view[16]. CLE utilizes a confocal laser microscope miniaturized to contain a flexible endoscope and can be used for the histological assessment of tissue during endoscopy, also known as virtual or optical biopsy[17].
The physical principle of CLE consists of light illumination of the gastric mucosal surface using a confocal laser and identifying the fluorescence returning back from the same area. The light source is focused at a definite depth, and the light from a single point on the focal plane can be selectively monitored and refocused through a pinhole confocal hole. Two types of CLE platforms are generally used: A scope-embedded type, which integrates a small confocal scanner into the tip of a flexible endoscope; and a miniature probe-type CLE, which can be passed through an accessory channel of a standard diagnostic scope[14,15]. CLE requires the use of a topical or intravenous fluorescent agent. Intravenous fluorescein sodium is most commonly used as it highlights cellular and subcellular details but does not stain the nuclei. The advantages of CLE are that it enhances the contrast and resolution of optical imaging and at the same time achieves the “in vivo” imaging of living tissues to avoid artifacts caused by tissue processing.
Zhang et al[18] examined the characteristics of gastric pits in various pathologies by means of eCLE and separated the gastric tips into different types: Normal gastric mucosa was classified as type A; CAG as type F; GIM as type E; signet-ring cell carcinoma and poorly differentiated tubular adenocarcinoma as type G1; and differentiated tubular adenocarcinoma as type G2. The type G pattern could predict GC with a high sensitivity (90.0%) and specificity (99.4%). The Miami classification system was suggested in order to standardize imaging acquisition and criteria for diagnosis of gastrointestinal mucosal alterations using CLE[19]. Four CLE diagnoses were obtained by evaluating the architecture of glands, cells, and microvessels (normal mucosa or benign inflammatory lesions, CAG and/or GIM, low-grade intraepithelial neoplasia and HGIN, cancer). In the Miami classification, EGC is described as a completely disorganized epithelium, fluorescein leakage, and dark irregular epithelium.
Li et al[20] suggested to add an index of blood vessel changes according to the Miami classification system for a more inclusive evaluation of gastric mucosa; this novel probe-type CLE classification includes three types of gastric pit patterns with seven subtypes and three types of vessel architecture. This classification also reports the blood vessel modifications in the pathological development of gastric mucosa and specifies the different pathological types, which may be more useful in clinical practice.
A number of studies have demonstrated the diagnostic importance of CLE for precancerous gastric alterations and GC[21-23]. In studies on GC, CLE has been found to reveal the final histopathology of the resection sample more accurately than traditional biopsies[16]. Furthermore, CLE permits the visualization of Helicobacter pylori in combination with acriflavine staining with 93% sensitivity and 86% specificity for the diagnosis of Helicobacter pylori-related gastritis[24,25].
ADVANTAGES AND LIMITATIONS OF CLE
As a novel imaging technique, CLE has different advantages: (1) It can minimize the amount of biopsies, allowing a high diagnostic sensitivity rate, decreasing the risk of mucosal injury, infection, loss of blood, and other complications due to multiple specimen collections; (2) It is more suitable for the long-term surveillance and follow-up of EGC; (3) It can assist doctors in making fast clinical assessments during endoscopy and decrease the waiting times for clinical decisions due to the time-consuming features of histology tests; (4) It shows advantages in the tumor margin evaluation of EGC, which will facilitate the effective endoscopic treatment of early tumors; and (5) It can evaluate the resection margins of gastrectomy, representing a noninvasive, real-time tool to help in the identification of tumor cells. In a large-scale prospective study with 1572 patients eCLE showed higher sensitivity (88.9%), specificity (99.3%), and accuracy (98.9%) than WLE in the diagnosis of superficial GC or HGIN[6].
Although these results highlighted the promising role of CLE, the technique has significant limitations that require improvement: (1) CLE cannot examine the whole gastric lumen because of the restricted field of vision and microscopic inspection within the stomach is unsteady and mobile due to respiratory excursions; (2) The use of a fluorescent dye is needed during CLE to visualize intestinal tissues (fluorescein cannot stain nuclei, so fluorescein-assisted CLE diagnoses is based exclusively on structural atypia); (3) Its low depth of tissue penetration limits the capability of CLE to visualize deeper tissues; and (4) The high cost of equipment and probes and the special training needed for image interpretation have delayed its extensive use. As a result of these disadvantages, it is impossible to use this method alone for early GC screening, so CLE will not be a viable alternative to forceps biopsy. However, despite these limitations, CLE is a promising imaging technique for the detection of upper digestive tract malignancies.
CONCLUSION
To date, CLE has not replaced histopathology; however, it may represent an advanced endoscopic imaging technology that permits the clear diagnosis of gastric lesions and achieves the early detection of malignancies in patients with a high risk of the development of cancer. The extensive use of CLE is limited by its high costs, low availability, and need for trained experts. Future technological advancements and joined applications with other new diagnostic techniques will help to overcome its intrinsic flaws and further support the accurate diagnosis of early gastrointestinal cancer.
ACKNOWLEDGEMENTS
We are grateful for the invitation to address this important issue in a reasoned editorial article.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Italy
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Liu TF, China S-Editor: Bai Y L-Editor: Filipodia P-Editor: Zhao YQ
