Preface

Despite the progress in pancreatic cancer (PC) chemo/radiotherapies, immunotherapies, and novel targeted therapies, as well as the improvement in its perioperative management policies, it is still a deadly and challenging catastrophic tumor with a high mortality rate, even after radical resection. It has a notable bad prognosis in comparison to other malignant tumors due to its high degree of malignancy, gradual onset, typical symptoms defect, delayed discovery, difficult anatomical location, early neural and vascular invasions, early micro-metastatic spread, tumor heterogeneities, unique desmoplastic stroma and tumor microenvironment (TME), high rate of chemo/radiotherapy resistance, lower rate of curative resection, and its tendency to recur after resection. Globally, PC is the seventh leading cause of cancer-related mortality.

The most common cancer of the pancreas is pancreatic duct adenocarcinoma (PDAC), which accounts for more than 90% of all cancers. Both the occurrence and progression of PDAC come from changes in some genes (i.e., KRAS oncogene mutational activation, inactivation of tumor suppressor genes (CDKN2A, TP53 and SMAD4), and/or mutations in other genes involved in the cell cycle and apoptosis). Other risk factors include lifestyle factors (i.e., tobacco use, alcohol, obesity, diabetes, chronic pancreatitis, etc.) as well as some precancerous lesions (i.e., pancreatic intraepithelial neoplasia (PanIN), intra-ductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasms (MCN), etc.)

Besides PDAC, there are other pathological types of pancreatic cancers, such as acinar cell carcinoma, small cell carcinoma, cystadenocarcinoma, pancreatoblastoma, pancreatic neuroendocrine tumor (PNET), and others.

PC can be diagnosed clinically (i.e., jaundice, dark urine, clay stool, abdominal pain, unexplained weight loss, etc.), by laboratory measures (i.e., carbohydrate antigen (CA19-9), etc.), by imaging (endoscopic ultrasonography (EUS), abdominal magnetic resonance imaging (MRI) and/or multi-detector computed tomography (MDCT) with pancreatic protocols, etc.), and by pathological detection (pancreatic biopsy).

Understanding tumor pathogenesis at the detailed genetic/epigenetic/metabolic/ molecular levels as well as studying the tumor risk factors and its known precancerous lesions is required for successful treatment. In addition, early diagnosis and treatment by a multidisciplinary team of surgeons, gastroenterologists/interventional upper endoscopists, medical/radiation oncologists, diagnostic/intervention radiologists, and pathologists at high-volume centers is important for better outcomes. Moreover, surgical resection with a negative margin (R0) is the only cure for PC.

According to tumor stage; resectable cancers are treated by surgical resection followed by adjuvant therapy. On the other hand; borderline resectable tumors are

treated by neoadjuvant therapy followed by surgical resection. However, for patients with locally advanced or distant metastatic pancreatic cancers, FOLFIRINOX (fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin) and/or gemcitabine (a nucleotide analogue) plus albumin-bound paclitaxel (nab-paclitaxel) have been approved for use with high success. Lastly, future targeted therapies depending upon molecular pathways, tumor gene mutations, and modulation of the tumor microenvironment (TME) are currently being studied in clinical trials.

This book discusses PC, focusing on its pathogenesis, risk factors, pathology, diagnosis, and treatment. It is organized into four sections. The first section includes an introductory chapter about PC prevention, screening, and detection. The second section examines the pathogenesis and risk factors of PC. The third section discusses cancer pathogenesis, pathology, and management. Finally, the fourth section presents pancreatitis in children.

Overall, the book provides updated knowledge about the pathogenesis, prevention, screening, detection, and treatment of this catastrophic cancer.

> **Emad Hamdy Gad, MBChB, MD, MSc, Doctor, Professor, Surgeon** Professor of Hepatobiliary Surgery, National Liver Institute, Menoufia University, Menoufia, Egypt

Section 1

Introduction

Section 1 Introduction

#### **Chapter 1**

## Introductory Chapter: Pancreatic Cancer – How to Prevent, Screen, and Detect?

*Emad Hamdy Gad*

#### **1. Introduction**

Pancreatic cancer is a very rapidly invasive/metastatic tumor having a poor response to the standard therapies. It has a very poor prognosis; moreover, pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive type of pancreatic cancer (PC), has the lowest 5-year survival rate among all known cancers globally. This poor prognosis comes from cancer late presentation due to non-specific symptoms (i.e., weight loss, abdominal pain, nausea, fatigue) leading to its discovery at late advanced/metastatic stages (i.e., around 80% of patients have distant metastases when diagnosed) precluding its effective curative surgical resection resulting in its catastrophic bad outcome [1]. So, it is fundamental to have new tools for prevention, screening, and proper early detection of this challenging cancer for improving its outcome.

PC is classified pathologically into adenocarcinomas (>90%), cystadenocarcinomas, mucinous tumors, and lastly, the neuroendocrine tumors (NET) that have the best prognosis [1]. It can be diagnosed clinically (i.e., jaundice, dark urine, clay stool, abdominal pain, unexplained weight loss), by laboratory measures (i.e., carbohydrate antigen (CA19–9)), imaging (endoscopic ultrasonography (EUS), abdominal magnetic resonance imaging (MRI), and/or multi-detector computed tomography (MDCT) with pancreatic protocols), and pathological detection (pancreatic biopsy) [2].

Our book discusses some recent issues related to pancreatic cancer with stress on its pathogenesis, risk factors, pathology, diagnosis, and treatment, where we sorted it into four sectors; the first sector includes an introductory chapter about pancreatic cancer prevention, screening, and detection, the second sector contains pathogenesis and risk factors of cancer, while the third sector includes cancer pathogenesis, pathology, and management, and finally, the fourth sector is about miscellaneous pancreatic topics.

This introductory chapter gives some recent hints about the updated data on the prevention, screening, and detection of this catastrophic cancer.

#### **2. Prevention**

PC can be prevented by lifestyle modification and by acting on and modulating its modifiable risk factors (i.e., smoking, obesity, physical inactivity, diabetes

mellitus (DM), alcohol abuse) [3, 4]; moreover, it can be prevented by high vegetables/fruits/nuts/whole grain diets as well as by low fat/calory diets [5]. Regarding chemoprevention of PC, metformin is a good example as it acts on different organs/ tissues in diabetic and/or obese patients (i.e., liver, gut, skeletal muscle, fat) leading to decreased levels of blood glucose, insulin and insulin growth factor (IGF), reduced food intake, weight loss, as well as changes in the gut microbiome (microbiota having a role in PC pathogenesis), as a sequence, leading to prevention of PDAC development. Furthermore, phytochemicals like curcumin may have a role in its prevention [6].

#### **3. Screening and surveillance**

Selective screening of the non-symptomatic persons at high risk for cancer pancreas is required for early discovery of the high-grade precancerous lesions (e.g., pancreatic intraepithelial neoplasia (PanIN-3) or cystic lesions (intra-ductal papillary mucinous neoplasm (IPMN)/mucinous cystic neoplasm (MCN) with high-grade dysplasia) or the early stage cancer that can be resected with a high survival rate. Moreover, screening is associated with better cures/survivals and lower unnecessary/ overtreatments if performed using better diagnostic tools, and through multidisciplinary teams qualified in pancreatic surgery, radiology, endoscopy, pathology, as well as genetics. Also, it has a positive effect on personal quality of life (QOL), cancer worry, and psychological distress [2, 7, 8].

The high-risk PC patients that should undergo screening are first-degree relatives (FDRs) of familial pancreatic cancer(FPC)patients, patients with Peutz-Jeghers syndrome (PJS) or Familial atypical multiple-mole melanoma syndrome (FAMMM) irrespective of family history of PC, carriers of breast cancer susceptibility (BRCA2, BRCA1), partner and localizer of BRCA2(PALB2), and ataxia telangiectasia mutated (ATM) gene mutation with ≥1 affected FDR, carriers of mismatch repair(MMR) gene mutation with ≥1 affected FDR, as well as incidentally discovered pancreatic cystic lesions [2, 7, 8].

The screening should start at 35–40 years of age in PJS and FAMMM cases, at 45 years in other detected mutations of hereditary pancreatic cancer (HPC) syndromes(i.e., mutations of BRCA2, BRCA1, PALB2, ATM genes) and at 50 years of age or 10 years younger than the earliest age of PC in FPC cases. Moreover, it should be performed twice a year. EUS ± fine needle aspiration cytology/biopsy (FNAC/B) and MRI/magnetic resonance cholangiopancreatography (MRCP) are the recently advised initial screening tools. However, other non-common screening tools are MDCT, positron emission tomography (PET)/CT, and endoscopic retrograde cholangiopancreatography (ERCP) ± brush cytology. Nevertheless, the previous screening tools have remarkable false-positive or false-negative results leading to unnecessary or delayed management, respectively [2, 4, 7].

In addition to the previously mentioned screening tools, there are other promising tools under investigation (e.g., contrast-enhanced EUS, EUS elastography (tissue stiffness measurement), CA19–9 + thrombospondin-2(multifunctional family of glycoproteins that regulates tumor migration and invasion), circulating tumor DNA, radiomics (extraction of information from certain medical images by advanced feature analysis)) [9].

#### **4. Diagnosis, staging, and early detection of PC**

The earlier the diagnosis of PC, the more possibility of well-differentiated, nodal free, smaller tumors with non-vascular non-neural invasions leading to better outcomes; so, multiple recent efforts have been made in different directions for getting early diagnostic PC tools; they include serological tests, genetic mutation marker analysis, DNA/RNA/protein markers, imaging (EUS/CT/MRI/ERCP) tools, diagnostic laparoscopy, as well as histopathological tools [10].

Clinically and according to PC location, it can be manifested by abdominal pain, back pain, shoulder pain, nausea, vomiting, weight loss, bloating, dyspepsia, dysphagia, bowel habit changes, pruritus, jaundice, steatorrhea, lethargy, new-onset diabetes, and depression. However, cancer patients may be asymptomatic and patients with pancreatic body/tail cancers may have late presentation [1, 11].

Serologically, a complete blood count and complete metabolic panel (i.e., liver function tests (LFT), coagulation profile, serum markers, pancreatic juice markers) are required for serological detection of PC.

CA19-9 is a carbohydrate antigen widely used as a serum biomarker for PC and it is still the current standard serum tumor marker; however, it has some limitations (i.e., low sensitivity and specificity, expressed only in individuals with Lewis a+/b- or Lewis a+/b + genotypes, elevated also in some non-cancerous conditions as pancreatitis and in many non-pancreatic malignancies, poor in the screening of symptomatic patients). Nevertheless, its combination with other serum markers like cell migrationinducing protein (CEMIP), CA125, carcinoembryonic antigen (CEA), and K-RAS gene mutation markers may improve its accuracy in diagnosing PC [12, 13].

CA-242 is a sialylated carbohydrate antigen elevated in some tumors like pancreatic cancers and its combination with CA19–9 leads to higher sensitivities and specificities in diagnosing PC. Similarly, other serum markers like hematopoietic growth factors (HGFs), alcohol dehydrogenase (ADH), tissue polypeptide-specific antigen (TPS), pancreatic cancer-specific antigen (PAA), D-dimer (DD), fibrinogen (FIB), and beta 2-microglobulin (beta 2-MG) may be elevated in PC. In addition to the previous markers, pancreatic juice CEA elevation can detect pancreatic cancer with acceptable accuracy [11, 12, 14].

Recently, new agents like DNA biomarkers (i.e., mutant TP53/SMAD4(tumor suppressor genes)) in pancreatic juice, and circulating-tumor DNA (cell-free DNA(cfDNA)) in serum), RNA biomarkers(e.g., microRNAs (miRNAs); noncoding RNA molecules regulating gene expression at mRNA levels either by their degradation or by translational inhibition), protein markers (osteopontin (OPN)), circulating tumor cells, exosomes (extracellular vesicle containing cellular constituents such as DNA, RNA, protein, and lipids secreted by all cell types into the circulation to transport biological components to other cells regulating intercellular communication), as well as microbiota (living microorganisms that normally inhabit human bodies mainly gastrointestinal tracts (GITs)) have been developed for the early detection of PC; however, their sensitivities and specificities remain under investigations [2].

Cell-free DNAs (cfDNAs) are double-stranded DNA molecules circulating in the blood. They are released during normal cellular metabolism, apoptosis, or necrosis. PC patients have a significant level of cfDNA in their blood. The detection of cfDNA tumor-specific mutations (e.g., KRAS mutation) and/or epigenetic alteration by

methods such as digital PCR, peptide-nucleic acid clamp PCR, and panel sequencing in the serum of PC patients is a promising diagnostic tool [15].

Recent rapid diagnostic technologies (e.g., *in situ* hybridization, oligonucleotide microarrays, northern blotting with radiolabelled probes, deep/parallel sequencing, TaqMan assays (qPCR-based detection of miRNAs)) have been used to perform miRNA expression profiling for early detection of PC through samples taken from PC tissues, serum/plasma, and pancreatic juice with high accuracy rate. Moreover, the increased serum levels of certain miRNAs like miR-16 and miR-196a in combination with elevated serum CA19-9 have higher accuracy in detecting early PC. On the other hand; some other miRNAs like miR-1290 have a better diagnostic accuracy of early PC than CA19-9 [16, 17].

Osteopontin (OPN) is an extracellular matrix protein (ECM) having a role in cell adhesion, migration, and apoptosis. It is upregulated in PC and linked to cancer invasiveness and metastasis. Its serum level is elevated in PC with acceptable accuracy [15].

Circulating tumor cells (CTCs) are tumor cells that originated from a primary tumor into circulation. They are involved in the distant metastatic character of the tumor. They can be used as potential serum biomarkers for PDAC [18].

Exosomes are perfect promising future PC diagnostic tool due to the following: 1—They are produced frequently by PC cells, 2—they can be non-invasively collected from different body fluids, 3—they can be re-collected over time for monitoring, 4—they are stable, and their contents of proteins and nucleic acids are protected from destruction by external nucleases and proteases, and 5—they can be detected easily by sensitive modern technologies. The exosomal glypican-1 (GPC1), zinc transporter protein (ZIP4), miR-196a, miR-1246, mutant KRAS, and Mutant TP53 are examples of those exosomal diagnostic biomarkers [19, 20].

The microbiota that normally inhabits human mouth and colon undergo changes in PDAC; analysis of those microbiotal changes (dysbiosis) as well as their metabolites through salivary and fecal samples can be used as a non-invasive tools for early detection of PDAC [21].

Abdominal ultrasound (US) can be a tool for the diagnosis of PC patients despite the difficulty due to the retroperitoneal pancreatic location. Being cost-effective and non-invasive, US can be used as a screening method for early detection of pancreatic cancer where the tumor appears as a hypoechoic mass. Moreover, US-guided fine needle aspiration cytology/biopsy (FNAC/B) and DNA analysis of the lesion can also be performed [11].

EUS is more accurate in detecting pancreatic tumor shape, morphology, internal echo, LNs, vascular relations and bile duct changes. Along with MDCT, EUS is considered excellent tool in preoperative staging of PC. Moreover, EUS-guided FNAC/B can be done safely, effectively, and easily with higher accuracy in distinguishing benign from malignant lesions. Furthermore, novel techniques of EUS-FNAC/B, such as fanning and slow-pull techniques with or without liquid-based cytology, have many advantages (i.e., higher detection accuracy, getting more material for histological diagnosis, better detection of KRAS mutation, microRNA profiling) [11, 14, 22].

Accurate tumor diagnosis and staging can be done through angiographic MDCT with pancreatic protocol with advanced volumetric techniques to detect small lesions, and to reach the relationship between the tumor and the neighboring vessels (i.e., celiac axis and superior mesenteric vessels) [11, 14]. Moreover, in MDCT pancreatic protocol, the reconstructed slice thickness should be 3 mm without gap with 3D volumetric images for vascular assessment. It is done in dual phase pattern: the pancreatic

#### *Introductory Chapter: Pancreatic Cancer – How to Prevent, Screen, and Detect? DOI: http://dx.doi.org/10.5772/intechopen.111726*

parenchymal phase (40 to 50 sec) and the portal venous phase (65 to 70 sec). Maximal pancreatic parenchyma enhancement and adequate arterial opacification are obtained in the first phase, while porto-mesentric venous and liver opacifications are achieved in the other phase [23].

PET is accurate in localizing primary and metastatic lesions depending upon increased FDG uptake by tumor in comparison with normal tissue. If combined with CT (PET/CT), the diagnostic accuracy increases. It is recommended in screening of high-risk patients of pancreatic cancer for detecting extra pancreatic metastases after the standard screening tools [11, 14].

MRI either gadolinium-enhanced MRI or diffusion-weighted imaging (DWI)-MRI are similar to helical CT regarding sensitivities and specificities, and in determining tumor resectability; moreover, the non-invasive MRCP is an excellent delineator of the pancreatic and biliary ducts [11, 14, 22]. In addition to the previous MRI tools, PET-MRI is a newer technique providing more information regarding cancer spread to the main pancreatic duct, collateral veins, superior mesenteric artery, celiac artery, and the liver [24].

ERCP-guided brushing cytology and aspiration cytology are good diagnostic tools of PC; furthermore, ERCP-probe-based confocal laser endomicroscopy and ERCP-guided serial pancreatic juice aspiration cytologic examination (SPACE) have high sensitivities in detecting malignant pancreaticobiliary strictures and pancreatic carcinoma *in situ* (PCIS), respectively [22, 25].

Staging laparoscopy may be needed through a case-by-case basis, especially in patients with a high suspicious of occult metastatic disease (i.e., body/tail tumors, large tumors (>3 cm), suspected LN involvement in the image, and a very high CA 19–9 [24]).

Lastly, the pathological diagnosis is required for non-operative non-resectable cases to draw a suitable treatment plan of chemo/radio/immune therapies. In addition, it may be required preoperatively to give the proper neo-adjuvant therapies. The pathological samples may be US, EUS, CT, or laparoscopic guided biopsies (FNAC/B, true cut biopsy, etc.) taken from the primary lesion, the regional/metastatic LNs, the metastatic lesion or from ascites [13, 26].

Finally, I think our book will give the readers important knowledge about pancreatic cancer.

#### **Author details**

Emad Hamdy Gad Hepatobiliary and Liver Transplantation Surgery Department, National Liver Institute, Menoufia University, Menoufia, Egypt

\*Address all correspondence to: emadgadsalemaa@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## Section 2
