Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening

Abstract

Pancreatic cancer (PC) is a highly fatal malignancy with a unique tumor microenvironment that limits the effectiveness of chemotherapeutics. PC develops from genetic mutations, cellular injury, and environmental exposure, progressing from precursor lesions to malignant neoplasms. This silent disease presents non-specific symptoms, including abdominal pain and painless jaundice. Serological and imaging evaluation aids in the diagnosis, with imaging modality selection dependent on cholestasis presence. The meticulous evaluation of vascular involvement and distant metastasis determines the tumor’s resectability. Neoadjuvant therapy improves patient selection and limits micrometastases, while chemotherapy is the preferred treatment for unresectable cases. Early detection and personalized treatment are essential in improving PC’s clinical outcomes.

1. Introduction

Pancreatic cancer (PC) is used interchangeably to describe pancreatic ductal adenocarcinoma, the most common pancreatic malignancy and one of the most fatal cancers worldwide [1, 2]. To gain a better understanding of PC pathogenesis, it is crucial to comprehend the pancreatic tumor microenvironment (TME). The TME is uniquely characterized by a dense desmoplastic fibrotic stroma in which extracellular matrix proteins (e.g., collagens), along with tumor-derived immune cells (e.g., neutrophils, macrophages), host immune cells (e.g., T-cells), fibroblasts, and activated pancreatic stellate cells (PSCs), form a dense barrier that limits the efficacy of different chemotherapeutics. This renders PC a difficult-to-treat illness [3, 4, 5, 6]. Indeed, the tumorigenesis of PC involves genetic mutations, cellular injury, and environmental exposure that permit the transition into precursor lesions, which further progress into malignant neoplasms [7]. For instance, a constitutively active KRAS allows persistent downstream signaling with substantial cellular proliferation, resulting in ductal metaplasia [8, 9]. However, this process requires the acquisition of further genetic mutations, such as Angiopoietin-like 4, that permit the progression into pancreatic intraepithelial neoplasia (PanINs) [10, 11]. Additionally, mutated TP53, CDKN2A, and SMAD4 accelerate PC growth and progression [12, 13, 14, 15]. Moreover, various environmental factors are believed to contribute to PC tumorigenesis. Smoking has been shown to potentiate desmoplastic reactions by activating PSCs and the associated free radical injury [16]. Other contributing factors include obesity, primarily linked to its associated inflammatory status, which potentiates tumor progression [17, 18]. Furthermore, diabetes mellitus has been shown to over-activate PSCs, potentiating PC development [18]. Non-modifiable risk factors are also involved in PC development. Indeed, a higher incidence of PC was reported in patients of African American descent and patients with a family history of PC [19, 20]. Moreover, specific loci and familial cancer syndromes (e.g., hereditary non-polyposis colon cancer, familial atypical multiple mole melanoma syndromes) have been implicated in PC development [21]. Nonetheless, PC development is a multifactorial process, with various genetic and environmental factors contributing to its pathogenesis.

2. Clinical features of pancreatic cancer

The presentation of PC may vary based on the tumor location and stage. It is generally a silent disease, and if symptoms do occur, they tend to be non-specific, often leading to alternative diagnoses [22, 23]. Although “silent jaundice” is a classical symptom, abdominal pain is more frequently reported in 60–80% of cases [24, 25]. Tumors located in the head of the pancreas (70% of cases) tend to present with jaundice earlier in the course of the illness, while those in the body or tail present with jaundice later, indicating hepatic metastasis instead of biliary obstruction [26]. Other historical findings may include recent-onset diabetes, nausea or vomiting, anorexia, back pain, and weight loss.

In more advanced cases, pancreatic duct obstruction can result in symptoms of pancreatic failure, reported as post-prandial abdominal pain and steatorrhea. Fat malabsorption with associated vitamin deficiencies may also occur [24, 27, 28, 29]. Jaundice, hepatomegaly, and rarely epigastric mass may be noticed on examination [27]. Additionally, patients may experience recurrent venous stasis, resulting in splenomegaly with portal or splenic vein compression, ascites with inferior vena cava obstruction, and/or superficial thrombophlebitis (Trousseau’s syndrome), palpable gallbladder (Courvoisier’s sign), enlargement of the supraclavicular (Troisier’s sign), or periumbilical (Sister Mary Joseph’s node) lymph nodes may be observed [30, 31, 32]. Unfortunately, these findings are identified later in the course of the illness, indicating more advanced cases with poorer outcomes.

Clinicians should look for specific features of syndromes associated with PC, such as numerous atypical nevi in familial atypical multiple mole melanoma syndromes, mucocutaneous pigmentation in Peutz-Jeghers syndrome, and sebaceous tumors and cutaneous keratoacanthomas in patients with Lynch syndrome [33, 34, 35]. Syndromes associated with PC and their clinical features are summarized in Table 1.

Syndrome	Associated features	Increased risk of PC	References
Hereditary non-polyposis colon cancer	Increase risk for endometrial, ovarian, gastric, colorectal, renal, gliomas, keratoacanthomas, and other malignancies	8.6-fold	[36]
Hereditary breast and ovarian cancer syndrome	Increased risk for breast (in males and females), ovarian, prostate, and skin (e.g., melanoma) malignancies	3–7%	[37]
Familial atypical multiple mole melanoma syndrome	Numerous atypical nevi resembling early melanoma, and a family history of melanoma; Increase risk for lung, skin, larynx, and breast malignancies	13–22 folds	[38]
Familial adenomatous polyposis	Increased risk for desmoid tumors, gastric/duodenal, hepatoblastoma, and thyroid malignancies	4 folds	[39]
Peutz-Jeghers syndrome	Increased risk for colorectal, gastric, breast, ovarian, cervical, and testicular malignancies	15 folds	[40]
Li-Fraumeni syndrome	Increased risk for bone and soft tissue sarcomas and breast, brain, and adrenocortical malignancies	7 folds	[41]

Table 1.

Brief summary of familial cancer syndromes associated with pancreatic cancer (PC).

3. Diagnosis of pancreatic cancer

The clinical presentation of PC is neither specific nor sensitive for establishing a diagnosis; therefore, suspected cases typically require serological and imaging testing. Liver function tests, including serum aminotransferase, bilirubin, and alkaline phosphatase, should be performed in all patients. The selection of subsequent testing primarily depends on the presence of jaundice or obstructive laboratory features (e.g., elevated direct bilirubin). In such cases, transabdominal ultrasound (TAUS) provides excellent sensitivity in detecting masses in the head of the pancreas and visualizing biliary tract patency or dilatation (Figure 1) [42, 43].

Figure 1.

Simplified algorithm for pancreatic cancer diagnosis. * Pancreatic protocol to assess the resectability of the tumor.

For anicteric patients who present with epigastric pain or other worrisome symptoms, such as weight loss, anorexia, or post-prandial flatulence, an abdominal computed tomography (CT) scan should be performed, which provides higher sensitivity in detecting lesions in the body and tail of the pancreas. In addition, a CT scan can be used initially, rather than TAUS, in cases of acute pancreatitis, as bowel gases may obscure the visualization of the biliary tract and the pancreas [44, 45]. If initial imaging is positive, further evaluation using a multi-phase contrast-enhanced, helical abdominal CT scan (i.e., pancreatic protocol) is the preferred option, accurate characterization of the pancreatic mass and resectability evaluation [46, 47, 48].

In cases where initial imaging (i.e., TAUS or CT scan) is negative, no further testing is required unless there is a strong suspicion that pancreatic cancer is the culprit of patient symptoms. In such cases, patients may undergo endoscopic retrograde cholangiopancreatography (ERCP), which allows for direct visualization of the biliary tract and pancreatic duct, tissue sampling for histopathological examination, and therapeutic decompression through stent insertion in selected cases. Alternatively, magnetic resonance cholangiopancreatography (MRCP) can be used in patients who are not qualified to undergo ERCP due to bowel obstruction or cases when ERCP fails to provide an informative visualization of the biliary tract [49, 50, 51]. When these modalities are negative, no further testing is required unless pancreatic cancer is strongly suspected. In such cases, endoscopic ultrasound (EUS) may be sought to to assess further the presence of any pathologies, which should be sampled through fine needle aspiration (FNA). More recently, contrast-enhances EUS appeared to be a more feasible approach for tissue sampling in such cases [43, 52, 53, 54].

Tumor, node, metastasis (TNM) system by the American Joint Committee on Cancer manual is a widely-accepted staging system that aids in the assignment of patients based on the resectability of PC. Additionally, it provides prognostic information based on the stage; for instance, patients in stage Ia had an overall 5-years survival of 39% compared to 11% in stage III [48, 49]. Nevertheless, a four-grouped classification system is used by many clinicians, which classifies PC based on resectability into; resectable, borderline resectability, locally advanced, and metastatic PC [50]. Regardless of the system used, the ultimate goal is to determine the suitable patient for curative resection.

4. Screening of pancreatic cancer

Early diagnosis of PC has been shown to improve overall survival. Nevertheless, the low incidence of PC discourages the implementation of nationwide screening modalities due to the high risk of false positive cases that may undergo unnecessary invasive testing. Furthermore, there are currently no guidelines regarding the optimal screening for PC [55, 56, 57, 58]. Therefore, patients should be selected cautiously and counseled regarding their risks, the benefits and harms of the test, and the probable outcomes of their testing.

Given the rarity of PC, a targeted screening approach may be the most suitable option. Initially, the identification of high-risk patients based on National Comprehensive Cancer Network (NCCN) recommendations [59] is primarily made on the basis of specific associated genetic mutations or syndromes to select the most appropriate age for screening initiation, as summarized in Table 2.

Patient group	Age of initiation
High-risk genetic mutation, any of the: ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2 or TP53 With a first-degree relative diagnosed with PC	Whichever earlier: At 50 years old or 10 years prior to the first PDAC in the family
Peutz-Jeghers syndrome	At 30–35 years old
Hereditary pancreatitis	40-years old or 20 years following the onset of pancreatitis
CDKN2A mutation	40-years old or Within 10 years of the first PDAC in the family

Table 2.

Screening age recommendations for high-risk patient groups.

Various serological markers and liquid biopsies have been extensively studied; however, only Carbohydrate Antigen 19-9 (CA19-9) has gained approval from the Food and Drug Administration (FDA). Carcinoembryonic antigen (CEA), which is classically elevated in colorectal cancer, appears to have some diagnostic utility for detecting cancer but has lower specificity compared to CA19-9. The use of multiple biomarkers together provides higher cumulative sensitivity and specificity. For instance, CA19-9, CEA, CA125, and CA242 together had 90.4% and 93.8% sensitivity and specificity, respectively, substantially higher than any single marker [60, 61, 62]. More recently, liquid biopsies have gained tremendous interest as an alternative non-invasive method to detect PC. Mainly, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are among the most promising. However, they are not readily available in many healthcare settings and have variable diagnostic accuracy [63, 64, 65]. Table 3 summarizes different screening methods, their usefulness, and limitations.

Test	Sensitivity	Specificity	Advantage	Limitations
Serology
CA19–9	80% [60]	75% [60]	Readily-available, FDA-approved	Low specificity, elevated in benign and non-PC cases, can be negative in up to 10% of Caucasians [66, 67]
CEA	45% [68]	89% [68]		Low sensitivity, elevated in benign and non-PC cases [68]
CA125	59% [69]	78% [69]	Not influenced by bilirubin levels, hence, its positive is the same in jaundiced and non-jaundiced individuals with PC [70]	Elevated in benign and non-PC cases [71]
CA242	66.2% [61]	80.14% [72]	May provide prognostic indications [73]	Ineffective early screening as a high level indicates a huge tumor burden [73]
IgG4	72% [74]	89% [74]		Limited usefulness to differentiate hereditary pancreatitis from PC [75]
Glycoproteomics	~90% [76]	90% [77]	Very high sensitivity and specificity can detect PC in its early stages
Lipodomic profiling	>90% [78]	>90% [78]	Very high sensitivity and specificity may provide a prognostic indicator [78]
Liquid biopsy
CTCs and ctDNA	25–100% [63, 64]	95.4% [79]	May serve as recurrence, invasion, and metastasis predictors [63]	Variable sensitivity, and no standardized methodology to detect their recurrence [80]
cfDNA	76% [81]	59% [81]	Can detect genetic mutations (e.g., KRAS), and may serve as a recurrence, predictor [82, 83]	Low diagnostic accuracy, cannot detect the cancer cells origin [84]
Circulating miRNAs	92.5% [85]	90% [85]		The detection rate is tumor-burden dependent [86]
Circulating exosomes	75.4–100% [87]	92.6–100% [87]	High specificity can detect cancer DNA in its early stages [88]

Table 3.

Different pancreatic cancer screening methods, their usefulness, and limitations.

Little is known regarding the best approach to screening for PC. Nevertheless, a comprehensive evaluation with cautious patient selection and integrative serological and imaging testing may be the most appropriate approach.

5. Management of pancreatic cancer

The management of PC is multidisciplinary. The tumor resectability should be evaluated initially with a multi-phase contrast-enhanced, helical chest and abdominopelvic CT scans. The tumor is considered resectable when confined to the pancreas with no metastasis or vascular encasement, such as the superior mesenteric artery/vein, celiac trunk, or common hepatic artery. Conversely, the presence of hepatic, peritoneal, or extra-abdominal metastasis renders the tumor unresectable [89, 90]. Nevertheless, in selective cases, the NCCN considers PC to be borderline unresectable. Examples of such cases include head of pancreas cancer that directly contacts the inferior vena cava, hepatic artery with no extension to the bifurcation, or tail/body PC with a celiac axis of 180 degrees or less [59]. For resectable PC that involves the head of the pancreas, the Whipple procedure is performed, including pancreatic head, duodenum, proximal jejunum, common bile duct, gall bladder, and a portion of the stomach resection (i.e., pancreaticoduodenectomy) [91, 92]. In contrast, distal pancreatectomy is typically performed in PC of the body/tail, which occasionally may include splenectomy [93]. Biliary drainage has been classically performed pre-operatively in patients with obstructive jaundice. However, the clinical benefits of this approach are controversial; therefore, it should be reserved for patients with severe hyperbilirubinemia, protracted itching, or cholangitis [94, 95, 96].

Neoadjuvant therapy has been found to outperform initial surgical resection for PC in providing a more precise patient selection and possibly limiting micrometastases linked to PC recurrence even after surgical resection. In addition, lower margin-positive resections were observed with the use of neoadjuvant therapy [97, 98, 99]. However, there are currently no established guidelines regarding optimal chemotherapy. The FOLFIRINOX protocol and a combination of gemcitabine plus nab-paclitaxel have been used, but there is no sufficient evidence to support the superiority of each approach [100]. Thus, we recommend a multidisciplinary team evaluation that takes into account the patient’s preferences, institutional experience, and cost-effectiveness when selecting the chemotherapeutic agents.

Metastatic and locally advanced PC are generally considered unresectable, and chemotherapy is the preferred approach for such cases. Although there is no consensus available for the preferred regimen, FOLFIRINOX or Gemcitabine-based protocols may be used. Different clinical trials have demonstrated the efficacy of each approach. However, FOLFIRINOX has shown a longer overall survival compared to Gemcitabine [101, 102, 103, 104, 105]. Patients who fail one protocol may be considered for the other after assessing their performance status. Additionally, patients should be re-evaluated for possible resection following chemotherapy, as tumor downstaging may permit resection.

List of abbreviation

CA19-9	carbohydrate antigen 19-9
CA125	cancer antigen 125
CA242	carbohydrate antigen 242
CEA	carcinoembryonic antigen
cfDNA	cell-free DNA
CT	computed tomography
ctDNA	circulating tumor DNA
CTCs	circulating tumor cells
ERCP	endoscopic retrograde cholangiopancreatography
EUS	endoscopic ultrasound
FDA	Food and Drug Administration
IgG4	immunoglobulin G4
MRCP	magnetic resonance cholangiopancreatography
NCCN	National Comprehensive Cancer Network
PanINs	pancreatic intraepithelial neoplasia
PC	pancreatic cancer
PSCs	pancreatic stellate cells
TAUS	transabdominal ultrasound
TME	tumor microenvironment
TNM	tumor, node, metastasis