Pancreatic cancer (PC) is a common and highly malignant tumor of the digestive system with a 5-year survival rate of only 3% and a median survival time of less than 6 months [1]. It has become one of the leading fatal diseases in Europe [2]. The overall surgical resection rate and 5-year survival rate of pancreatic cancer have not changed significantly in the past 20 years [3]. Therefore, early diagnosis and comprehensive treatment have become the key to improve the outcome of pancreatic cancer treatment. Precancerous lesions are the beginning stage of malignant tumor development and are the best time to give treatment and interrupt malignant transformation. Precancerous lesions of pancreatic cancer include pancreatic intraepithelial neoplasia, chronic pancreatitis, intraductal papillary mucinous tumors and mucinous cystic tumors. Recent advances in epidemiological investigations and pathological histological studies have provided some new concepts for the above lesions. This article provides a brief review on how to recognize and manage precancerous lesions of pancreatic cancer. Pancreatic intraepithelial neoplasia (Pan IN) is a new term proposed in recent years, which is a continuous process of evolution of precancerous lesions from atypical proliferation of small ductal epithelial cells to carcinoma in situ in the pancreas. In 2000, Hruban et al [4] described the different genetic changes involved in the progression of normal pancreatic ductal epithelium through intraepithelial neoplasia to pancreatic cancer by detecting genetic alterations in normal pancreatic ducts, all levels of Pan IN and pancreatic cancer, and linked the histological changes of pancreatic cancer with molecular genetic changes. The histological changes in pancreatic cancer are linked to molecular genetic alterations. Pancreatic intraepithelial neoplasia can be classified into 3 grades, of which grade 1 can be subdivided into two grades A and B. The normal ductal epithelium is a single layer of cuboidal or hypocolumnar epithelium without mucinous cytoplasm and crowded and heterogeneous nuclei. pan IN-lA epithelium consists of highly columnar cells with nuclei located at the base and abundant mucinous cytoplasm. pan IN-1B epithelial lesions appear papillary, micropapillary or essentially pseudostructured compared to pan IN-lA. pan IN-2 epithelial lesions are mostly papillary in structure with abnormal nuclear changes. Pan IN-3 epithelial lesions are usually papillary or micropapillary, with loss of nuclear polarity, dystrophic cup cells, and occasionally abnormal nuclear divisions. The nuclear morphology of such cells resembles that of carcinoma, but without invasion of the basement membrane [5]. Several studies have confirmed Pan IN as an important stage in the development of pancreatic cancer. The incidence of Pan IN increases gradually from normal pancreas to chronic pancreatitis and pancreatic ductal adenocarcinoma, especially in high-grade Pan IN, while high-grade Pan IN lesions are only found in pancreatic adenocarcinoma and chronic pancreatitis tissues [6].Swartz et al [7] found that infiltrating carcinoma expressed mucin 24 at a constant level, and that the expression of mucin 24 increased with increasing grade of Pan IN. The results of several recent studies showed that the expression of COX-2 and p53 was significantly stronger in high-grade Pan IN tissues and pancreatic cancer tissues than in low-grade Pan IN tissues and normal pancreatic tissues, with statistical differences between them [8-10]. Morphological changes in the progression of Pan IN to pancreatic cancer have been observed dynamically in a rat pancreatic cancer model using dimethylbenzanthracene (DMBA) [11]. Since Pan IN is a morphological change of pancreatic epithelial tissue, non-mass-forming stage, with no specific clinical symptoms such as abdominal pain, jaundice and wasting, it poses great difficulties for early diagnosis. To date, no one has isolated and established Pan IN cell lines, and the previously obtained knowledge about the cellular characteristics of Pan IN is mainly derived from the analysis of mixed tissues of Pan IN and pancreatic cancer, so currently medical doctors lack a systematic and comprehensive understanding of the biological characteristics of Pan IN. How to identify and diagnose pancreatic intraepithelial neoplasia has become one of the keys to improve the early diagnosis and prognosis of pancreatic cancer. With the further development of genetic biochemical analysis, we have reasons to believe that Pan IN will become an ideal target for early interruption of pancreatic cancer development in the future. 1. Chronic pancreatitis Chronic pancreatitis (CP) has been recognized as one of the etiological factors of pancreatic cancer. Several epidemiological surveys and evidence-based medical treatises support the close association between chronic pancreatitis and pancreatic cancer. A joint survey of more than 2000 patients diagnosed with CP in 6 countries over 2 years showed a 16-fold increase in the relative risk of developing PC in patients with CP [12]. Another large-scale epidemiological survey found that the development of pancreatic cancer was positively correlated with the course of chronic pancreatitis, with 2% and 4% of patients with chronic pancreatitis developing pancreatic cancer after 10 and 20 years of follow-up, respectively [13]. It is now believed that recurrent chronic inflammation gradually destroys and damages the normal biological barrier of the pancreas and induces pancreatic cancer by long-term stimulation. The high incidence age of pancreatic cancer is 10 to 20 years later than the age of onset of chronic pancreatitis, which is consistent with the timing of inflammatory cancer. Both chronic pancreatitis and pancreatic cancer preferentially develop in the head of the pancreas, and focal carcinomas are often seen in pathological specimens from patients with pancreatic head mass-type pancreatitis. In recent years, it has been confirmed that some CP and PC share some of the same gene mutation profiles, such as K-ras gene 12 codon point mutations in about 40% of CP, p16, BRCA1, PRSS1, CFTR and other mutations in about 30% of CP, and p53 mutations in about 20% of CP, suggesting that there is a close relationship between CP and PC genetic variants [14-15 ]. Mass-type chronic pancreatitis and pancreatic head cancer are sometimes clinically indistinguishable. Both usually have obstructive jaundice and pancreatic head masses as the first presentation. The main features of jaundice and abdominal pain in mass-type chronic pancreatitis are mild, fluctuating and intermittent, while jaundice and abdominal pain in pancreatic head cancer are often characterized by progressive worsening. To some extent, the medical history is helpful in differentiating the two. Tumor markers CA19-9, CA242, and CEA have reference value for differential diagnosis, and it has been reported that the specificity of CA19-9 for the diagnosis of pancreatic cancer is 90%, while CA19-9 in mass-type chronic pancreatitis is usually less than 100 U/dl [13]. In terms of imaging, CT can detect the typical changes of chronic pancreatitis such as pancreatic calcification, pancreatic duct dilatation and pancreatic duct stones, while pancreatic head cancer shows pancreatic head mass, pancreatic duct dilatation and pancreatic atrophy, etc. ERCP can clearly show the location of pancreaticobiliary duct lesions, the nature of obstruction, the presence of stenosis and dilatation, stones, etc., and brush the pancreatic duct wall cells, extract pancreatic fluid for cytological examination and K-ras mutation gene detection. At the same time, pancreatic duct and bile duct stents can be placed for internal drainage treatment. In the early stages of most chronic pancreatitis, standardized conservative medical treatment is essential. Early medical treatment not only relieves clinical symptoms, but also has a significant effect on slowing down the natural course of the disease. However, with the prolongation of time, chronic pancreatitis can progress to pancreatic cancer, especially mass-type chronic pancreatitis and pancreatic cancer are often not easily distinguished clinically, which brings great confusion to patients and clinicians. In our opinion, for patients with a clear preoperative diagnosis of chronic pancreatitis, biliary-intestinal anastomosis and pancreatic duct-jejunostomy are feasible to resolve clinical symptoms such as jaundice and abdominal pain. In recent years, with the continuous improvement of endoscopic technology and corresponding instruments, endoscopic pancreatic bile duct lithotomy and internal drainage of pancreatic duct and bile duct stent placement have been feasible for chronic pancreatitis with masses located around the jugular abdomen, successfully replacing open surgery and effectively reducing the huge risks associated with open surgery. For those who are highly suspected of pancreatic head cancer or cannot be excluded, radical resection of the mass including pancreaticoduodenectomy should be actively used due to the great harm caused by pancreatic head cancer to avoid missing patients with pancreatic cancer and missing the best time for treatment. Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are defined by the WHO as mucus-producing tumors of the ducts with tall columnar mucus-rich epithelial cells with or without papillary protrusions, involving the main pancreatic duct and/or major lateral pancreatic ducts and lacking the nested stroma characteristic of mucinous adenomas [16]. -7.5% of pancreatic tumors and 21%-33% of pancreatic cystic tumors [17]. Their biological behavior is diverse, and they can be subdivided into main pancreatic ductal, branching pancreatic ductal, and mixed types according to the site of intraductal tumorigenesis. According to the degree of epithelial atypical proliferation, they can be classified as intraductal papillary mucinous adenoma, junctional intraductal papillary mucinous adenoma and intraductal papillary mucinous carcinoma. In recent years, Japanese scholars believe that intraductal papillary mucinous carcinoma should be subdivided into non-invasive carcinoma, microinvasive carcinoma and invasive carcinoma, and through this stratified analysis, it was found that non-invasive carcinoma has the same long-term survival rate as microinvasive carcinoma, while invasive carcinoma has a poor prognosis and is similar to advanced pancreatic ductal adenocarcinoma after the appearance of lymph node metastasis or distant metastasis [18-20]. It is now well established that IPMT can progressively progress to malignancy in a manner similar to the carcinogenesis of colon polyps (hyperplasia-adenoma-carcinoma) [21-22]. IPMT is often suggestive of malignancy if it has the following features: ① jaundice: more common in patients with invasive IPMNs, jaundice may be due to gelatinous mucus occluding the duodenal jug abdomen, malignant IPMNs compressing the common bile duct or wall nodules involving the The jaundice may be caused by the common bile duct and duodenal jugular abdomen. (ii) Main pancreatic duct type and mixed IPMNs: Kawamoto et al [23] reported that invasive IPMNs accounted for 40% and 60% of the main pancreatic duct type and mixed pancreatic duct type IPMNs, respectively, while only 9% of the branching pancreatic duct type IPMNs. (iii) The diameter of the main pancreatic duct: in both main pancreatic duct type and mixed type IPMNs, significantly dilated main pancreatic ducts were closely associated with malignant or invasive IPMNs. However, there is no definite cut-off value for the diameter of the main pancreatic duct to distinguish benign from malignant. ④Size of the lesion: some studies have reported that a cystic mass with a maximum diameter of more than 2.8 cm often suggests a high likelihood of malignancy [24]. ⑤ Site of the tumor: IPMNs occurring in the head or leptomeninges of the pancreas usually suggest malignancy or invasiveness, while those occurring in the caudal part of the pancreatic body usually suggest benign [25]. (vi) The presence of wall nodules and intraductal papillae, dilated duodenal papillae and soft tissue masses are suggestive of malignant or invasive IPMNs. The prognosis of IPMN is reported to be variable. The 5-year survival rate after surgical resection of benign IPMNs has been reported to range from 77% to 100%, whereas the 5-year survival rate of intraductal papillary mucinous carcinoma has been reported to vary from 24% to 60%, a phenomenon that Japanese scholars believe is related to the failure to subdivide malignant IPMNs into invasive and non-invasive carcinomas [18].The treatment of IPMNs is still controversial, with some literature suggesting that for IPMNs less than 3 cm in diameter, without attached wall nodules It has been suggested that for branching pancreatic duct type IPMN with a diameter of less than 3 cm, no attached nodules or papillary protrusions, and asymptomatic, observation and follow-up is feasible [26]. Some scholars have questioned the above concept, arguing that because of the potential malignancy of IPMN, long-term follow-up increases the economic and mental burden of patients, and almost all patients with preoperative diagnosis of branching IPMN have postoperative pathology confirmed as mixed IPMN, and therefore advocate surgical treatment for all patients with IPMN [27]. In our opinion, patients with no absolute contraindication to surgery, long life expectancy, and difficulty in adhering to long-term follow-up should, in principle, be actively treated surgically. For patients with high suspicion of malignancy, the site of tumor invasion, potential extra-ductal or extra-pancreatic invasion, the patient’s age, and the scope of surgical proposed resection and clearance should be fully evaluated preoperatively to achieve complete radical resection. Mucinous cystic neoplasms (MCN) are cystic pancreatic tumors formed by mucus-producing epithelial cells, which can be divided into mucinous cystadenoma, junctional mucinous cystadenoma and mucinous cystic adenocarcinoma. It is most commonly seen in middle-aged women and is found in the tail of the pancreatic body, accounting for 1% of pancreatic tumors and 10% to 45% of cystic lesions of the pancreas [28]. Mucinous cystadenoma has a potential malignant tendency, and its malignancy rate is reported to be 17.5% in foreign literature [29]. The following aspects can help identify cystadenoma from cystadenocarcinoma: (i) age: the age of onset of cystadenocarcinoma is higher than that of cystadenoma, with an average of 5.5 years beyond, while the age of onset of invasive cystadenocarcinoma is 11 years later than that of non-invasive cystadenocarcinoma [29]. (ii) Jaundice: the incidence of jaundice was significantly higher in cystic adenoma than in cystic adenocarcinoma, 28% and 6%, respectively. ③Tumor markers: elevated CEA and CA19-9 values in blood and cystic fluid suggest the diagnosis of cystadenoma carcinoma or cystic adenocarcinoma. ④Imaging examination: B-ultrasound or CT examinations that reveal signs such as varying thickness of cyst wall, papillary protrusions, adhesions with surrounding areas or enlarged lymph nodes suggest a high possibility of malignancy. ⑤ Diameter of the mass: malignancy is highly suspected if it exceeds 6 cm. ⑥Intraoperative freezing: the determination of benign and malignant tumors mainly relies on intraoperative multi-point frozen section examination. warshaw et al [30] reported that cystic tumors of the pancreas can be seen in the same capsule with pathological manifestations of cystadenoma, cystic adenocarcinoma and cystic adenoma malignancy, so biopsy should be taken multiple times at multiple points, which can improve the diagnostic rate. The 5-year survival rate of non-invasive MCN is 100%, while that of mucinous cystadenocarcinoma is only 57%. There are several evidences that mucinous cystadenoma can progress to cystic adenocarcinoma, therefore, in principle, complete surgical resection of the tumor should be performed for MCN. Mucinous cystadenoma should be resected together with the surrounding normal pancreatic tissue, while patients with a clear diagnosis of mucinous cystadenoma should undergo radical resection, including pancreaticoduodenectomy or even total pancreatectomy. Simple resection or partial resection and internal drainage of any tumor is inappropriate. Only elderly patients with tumor diameter less than 3 cm, no signs of lymph node metastasis and presence of severe comorbidities can be treated under observation [31]. Pancreatic malignancy has been one of the hot issues of concern and discussion among clinicians in recent years, but at present, there is no breakthrough in either surgical treatment or adjuvant radiotherapy for progressive pancreatic cancer, and the comprehensive treatment effect is unsatisfactory. The key to improve the treatment effect of malignant tumors still lies in early diagnosis and early treatment, therefore, the correct identification of benign and malignant pancreatic tumors, strengthening the understanding of precancerous lesions of pancreatic cancer, standardizing the treatment of precancerous lesions of pancreatic cancer, and creating a new path for the treatment of pancreatic malignant tumors will improve the therapeutic effect of pancreatic cancer.