Early Detection of Sporadic Pancreatic Cancer Free

Currently, surveillance is recommended for those with a strong family history of pancreatic cancer (PC) or those with germline mutations in PC susceptibility genes, such as ATM, BRCA1, BRCA2, CDKN2A, PALB2, or STK11. In the future, with the availability of accurate early detection tests, additional high-risk individuals may be included in surveillance programs, such as those with new-onset diabetes >50 years, those with early symptoms suggestive of PC, or those with premalignant cystic lesions.

Globally, we agreed on the recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium [1] whom to include into surveillance programs: individuals with ≥2 first-degree relatives with PC or one first-degree relative and another relative who developed PDAC younger than 40 years. There is consensus that individuals with a greater than 5% lifetime risk of PC, or a 5-fold increased relative risk, depending on the germline mutation [2], are considered high-risk individuals (HRIs) [1]. Furthermore, intraductal papillary mucinous neoplasias (IPMNs) represent a group with a definite malignant potential. They are included in screening according to pertinent guidelines [3]. Since IPMNs are common, many HRIs also have a branched-duct IPMN. For the time being it is unclear whether those two risk factors act synergistically, however, IPMNs in HRIs seem to grow faster [4]. There is no evidence whatsoever to offer surveillance to the general population [5]. Besides IPMN, both chronic pancreatitis [6] and autoimmune pancreatitis [7] carry a risk for developing PC. While the guidelines recommend follow-up of these patients for endocrine and exocrine insufficiency and related secondary condition such as osteoporosis, no recommendation for follow-up regarding the cancer risk has been given.

Biochemical tests (e.g., CA 19-9, CEA), cytology, or genetic/mutational analysis should be performed on pancreatic specimens obtained from EUS-guided puncture in IPMN patients at risk.

For patients with IPMN at risk, EUS-guided fine-needle aspiration (FNA) or fine-needle biopsy (FNB) with additional molecular studies can provide valuable diagnostic and prognostic information, guide management, and improve early detection. Biochemical markers, such as CEA, amylase/lipase, and glucose levels, are more helpful for diagnostic purposes (i.e., distinction of mucin-producing tumors from serous neoplasms or from non-neoplastic cysts) than for risk assessment [8]. Conventional cyto-/histopathology is the gold standard for the identification of high-grade dysplasia and cancer. Immunocytochemistry (e.g., after cell block preparation) and immunohistochemistry can be added for the assessment of the IPMN subtype using the MUCs expression profile (MUC1, MUC2, MUC5AC, and MUC6) since distinct subtypes have a distinct biology and a different risk of being associated with invasive cancer [9]. In addition, an overexpression or a complete loss of p53 and a loss of expression of Smad4 are usually associated with high-grade changes and/or cancer. Molecular tests, usually based on NGS panels, are helpful to identify mutations that are more commonly associated with high-grade dysplasia and/or malignant transformation, such as mutations in CDKN2A, PIK3CA, SMAD4, and TP53genes [10].

EUS is performed according to the recommendations from the CAPS Consortium [1], in any case if a suspicion arises from the cross-sectional imaging (CT, MRI). From suspicious areas/lesions, samples should be taken. EUS-guided FNB is preferred over FNA for obtaining core tissue samples, which retain architecture necessary for detailed histological analysis [11]. In case of FNA, bedside cytological examination should be done, which is not always possible for logistic reasons. While cytology from EUS-FNA is commonly used, its sensitivity is limited. It is often supplemented with molecular profiling for better diagnostic accuracy [11]. For both FNA and even more FNB, hematoxylin and eosin staining is the basis. The most determinating factor is an experienced pathologist specialized in pancreatic pathology and cytology. Carcinoembryonic antigen (CEA) levels in cyst fluid are routinely measured, although their utility is limited without additional molecular data [12].

Analysis of KRAS and GNAS mutations is crucial as they are common in IPMNs and help differentiate them from other cystic lesions [12]. DNA methylation and microRNA profiling can provide insights into the malignant potential of IPMNs [12].

While these studies provide a robust framework for evaluating IPMN lesions, challenges remain in accurately predicting which lesions will progress to malignancy. The multifocal and multiclonal nature of IPMNs complicates risk stratification, necessitating ongoing research into more precise molecular markers and improved imaging techniques [13].

Pre-emptive resection of all types of IPMN is not recommended. Two-thirds of specimens from pre-emptive IPMN resections are LGD and do not have increased survival compared to in situ or early cancer. Because of the high complication rate, pancreatic resection should be avoided when LGD is probable [14]. On the other hand, pancreatic resection is recommended for all patients with IPMN with HGD or invasive cancer, as well as patients with conventional PC.

The surgical strategies for intraductal papillary mucinous neoplasms (IPMNs) and PC differ significantly due to the distinct nature and progression of these conditions. While IPMNs are precursors to PC, their management focuses on preventing malignant transformation, which influences surgical decisions. Small IPMN can be enucleated [15]. However, any suspicion for a malignant lesion in the pancreas should lead to an oncological resection. Due to the biology of IPMN, even if malignant, they are caught in earlier stages and hence lead to better survival on a national level [16]. In case of main duct involvement, intraoperative pancreaticoscopy (SpyGlass) may help to determine the extent of the resection [17].

CA 19-9 may be used in conjunction with imaging (MRI, EUS), but no investigational biomarker has yet been translated into the clinic.

For the time being, no approved or certified biomarker or panel exist. The marker used according to the CAPS criteria [1] is CA 19-9, being well aware of the limitations. Since new-onset diabetes mellitus has been identified as a sign for developing PC [18], HbA1c has been included in the screening. Obviously, a better biomarker/panel is urgently needed. The PANFAM study using a panel of immunological markers [19, 20] unfortunately was not successful. Currently, the Pancreatic Cancer Early Detection (PRECEDE) Consortium [21] in the USA represents one initiative. In Europe, several projects are ongoing. Within the PANCAID consortium, we are specifically aiming for HRIs and early PC [22]. For those with IPMN, a promising panel has been proposed [23], currently evaluated within the said PANCAID project [24].

If biomarkers include genetic predispositions such as BRCA2, CDKN2A [2], then the presence of a germline mutation in one of the acknowledged target genes determines the outcome of the surveillance [25]. As a consequence, every effort ought to be made to identify such genetic alterations in HRIs.

CT has limited resolution to detect small or otherwise isoattenuating pancreatic tumors. MRI and EUS have better resolution for recognizing early pancreatic tumors. In the future, there may be a place for molecular imaging, which may help identify differences between tumor and normal tissue on a molecular level, instead of only relying on morphological differences.

Depending on the quality of the technique, such small lesions could remain undetected to the ordinary radiologist. As a result, only a minority (10–15%) of the resected carcinomas are T1 tumors. Furthermore, there is evidence that such very small lesions in few individuals may grow toward PC during a surveillance interval. Within the European project PANCAIM, we develop AI tools to improve the detection of such small lesions [26]. Notwithstanding the surveillance, pancreatic lesions are detected by chance. In patients with such pancreatic incidentalomas [27], a thorough family history ought to be taken. In case of IPMN, patients will be included in surveillance according to the guidelines [3].

R. Andersson and D. Ansari: both Roland Andersson and Daniel Ansari are share holders in the start-up company Reccan AB developing a blood test for early diagnosis of pancreatic ductal adenocarcinoma. I. Esposito: Falk Foundation: scientific lecture and BMS: advisory board, Amgen: lecture. T. Hackert and M. Löhr: no conflict of interest to declare. H. Scherübl: Novartis: lecture.

R. Andersson and D. Ansari: the study was funded by the Swedish Research Council, the Swedish Cancer Society, the Crafoord Foundation, and Region Skåne (ALF). The funders had no role in the design, data collection, data analysis, and reporting of this study. I. Esposito, T. Hackert, and H. Scherübl: no funding for this study. M. Löhr: the study was funded by the European Union, PANCAIM (101016851) on the early detection of pancreatic cancer, and PANCAID (101096309) on the use of liquid biopsy. Views and opinions expressed are however those of the author only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.

Prof. Dr. med. Hans Scherübl

Klinik für Innere Medizin II, Gastroenterologie, GI Onkologie, Diabetologie und Infektiologie Vivantes-Klinikum Am Urban

Akademisches Lehrkrankenhaus der Charité

Dieffenbachstrasse 1, 10967 Berlin, Germany

[email protected]

Prof. Dr. med. Thilo Hackert, MBA

Klinik & Poliklinik für Allgemein-, Viszeral-und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf

Martinistraße 52, Gebäude Ost 10, 20246 Hamburg, Germany

[email protected]

Prof. Roland Andersson

Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital

Lund, Sweden

[email protected]

Prof. Daniel Ansari

Department of Surgery, Clinical Sciences Lund

Lund University, Skåne University Hospital, Lund, Sweden

[email protected]

Prof. Dr. med. Irene Esposito

Institut für Pathologie

Heinrich-Heine-Universität und Universitätsklinikum Duesseldorf

Moorenstr. 5, 40225 Düsseldorf, Germany

[email protected]

Prof. Dr. med. J.-Matthias Löhr

Div. of Surgery & Oncology, Karolinska Comprehensive Cancer Center

Karolinska Institutet, CLINTEC, Karolinska Universitetssjukhuset

Hälsovägen 11, SE-141 86 Stockholm, Sweden

[email protected]