**6. Diagnosis of sporadic pancreatic cancer**

Failure to diagnose SPC at an early stage is the main impediment to improving the prognosis of patients with this malignant disease. Currently, more than 80% of cases are diagnosed in advanced stages (T3 and T4), which generally excludes radical surgery, the only possibly curative treatment. The prerequisite for early diagnosis of SPC is the timely use of high-resolution imaging methods (HRIMs), which will lead to the identification of patients with early stage, effectively curable disease. The specificity and sensitivity of the classical tumor biomarkers currently used in the clinical practice is low. Therefore, novel biomarkers are critically needed to identify patients in whom HRIMs should be used. Recently, we have proposed a structured diagnostic strategy for individuals with newly diagnosed diabetes, who represent a significant risk group for SPC, involving primary care physicians (both general practitioners and diabetologists) [2].

#### **6.1. Biomarkers**

T3cDM with weight loss are alarming signs of a paraneoplastic origin and patients presenting with these signs require further examination. Recent reviews have summarized the present knowledge of biomarkers for the diagnosis of SPC [54–56]. A widely used biomarker, **carbohydrate antigen CA 19–9,** is neither sufficiently specific (68–91%) nor sensitive (70–90%) in patients with SPC and, as such, it is not a reliable marker for screening and early detection [57]. While a more sensitive assay for CA 19–9 has been developed, which also demonstrated higher specificity [58], a combination of different markers in multiplex detection appears to be more promising. A biomarker panel consisting of three proteins: (1) plasma tissue factor pathway inhibitor (TFPI), (2) Tenascin-C (TNC-FN III-C), and (3) CA 19–9, was better than CA 19–9 alone in early-stage cohorts (stage I and IIA/IIB), including the ability to discriminate stage IA/IB/IIA from healthy controls [59]. This panel had the predictive power to detect early-stage pancreatic cancer and may have clinical utility for early detection of surgically resectable pancreatic ductal adenocarcinoma. In another study, a surface enhanced Raman spectroscopy (SERS) based immunoassay of CA 19–9 in combination with matrix metalloproteinase (MMP7) and mucin (MUC4) in serum had significantly enhanced sensitivity and could be a promising tool for liquid biopsy diagnostics [60].

**MicroRNAs**, small non-coding molecules circulating in blood, have been tested in patients with pancreatic cancer and healthy controls. They play roles in regulation of cell physiology, tumorigenesis, apoptosis, proliferation, invasion, metastasis, and chemoresistance. Many miRNAs found in serum have been suggested as reliable biomarkers of early SPC detection [61]. Combining several miRNAs with CA19–9 in a composite panel could improve diagnosis compared to a single biomarker. This was documented with six miRNAs (including miR-20a, miR-21, miR-25, miR-155, miR-196a, and miR-210), and CA19–9 [62]. The panels had a high specificity for pancreatic cancer compared to other gastrointestinal cancers and they showed better sensitivity and specificity than CA19–9 alone. A panel of miRNAs could be used to differentiate patients with new-onset diabetes with SPC, healthy controls, and new-onset Type 2 diabetes without SPC [63, 64]. MiRNAs were also analyzed using weighted gene co-expression network analysis (WGCNA). This method better discriminates between healthy and cancer patients and demonstrates that miRNAs can serve as prognostic biomarkers [65]. On the other hand, a set of 15 selected miRNAs was able to discriminate SPC patients from controls at the time of diagnosis but could not be used in earlier stages because their alterations only appeared in the later stages of the disease [66].

**6. Diagnosis of sporadic pancreatic cancer**

PP, pancreatic polypeptide; GIP, glucose-dependent insulinotropic peptide.

**Indicator Type 2 DM Type 3c DM** Body weight Increase Decrease

Family history of DM Positive Frequently negative

 Insulin High or normal Low or normal PP High or normal Low or normal GIP Normal Low or normal

 Insulin High or normal Low PP High or normal Low GIP Normal Low

eral practitioners and diabetologists) [2].

**6.1. Biomarkers**

Fasting plasma concentration

60 Advances in Pancreatic Cancer

Poststimulation levels

with SPC.

Failure to diagnose SPC at an early stage is the main impediment to improving the prognosis of patients with this malignant disease. Currently, more than 80% of cases are diagnosed in advanced stages (T3 and T4), which generally excludes radical surgery, the only possibly curative treatment. The prerequisite for early diagnosis of SPC is the timely use of high-resolution imaging methods (HRIMs), which will lead to the identification of patients with early stage, effectively curable disease. The specificity and sensitivity of the classical tumor biomarkers currently used in the clinical practice is low. Therefore, novel biomarkers are critically needed to identify patients in whom HRIMs should be used. Recently, we have proposed a structured diagnostic strategy for individuals with newly diagnosed diabetes, who represent a significant risk group for SPC, involving primary care physicians (both gen-

**Table 2.** Clinical and laboratory characteristics differentiating new-onset Type 2 from Type 3c diabetes associated

T3cDM with weight loss are alarming signs of a paraneoplastic origin and patients presenting with these signs require further examination. Recent reviews have summarized the present knowledge of biomarkers for the diagnosis of SPC [54–56]. A widely used biomarker, **carbohydrate antigen CA 19–9,** is neither sufficiently specific (68–91%) nor sensitive (70–90%) in patients with SPC and, as such, it is not a reliable marker for screening and early detection [57]. While a more sensitive assay for CA 19–9 has been developed, which also demonstrated higher specificity [58], a combination of different markers in multiplex detection appears to be more promising. A biomarker panel consisting of three proteins: (1) plasma tissue factor pathway inhibitor (TFPI), (2) Tenascin-C (TNC-FN III-C), and (3) CA 19–9, was better than CA 19–9 alone in early-stage cohorts (stage I and IIA/IIB), including the ability to discriminate Another area of investigation provides new data from **metabolomic** studies that are based on metabolic differences between new-onset diabetes with and without pancreatic cancer as well as in comparison with Type 2 diabetes [67]. Sixty-two metabolites, from several hundred, were analyzed using liquid chromatography/mass spectrometry. The results were able to discriminate between the three abovementioned groups, although the procedure is not yet suitable for routine use. In another study, using a metabolomic profile of 206 metabolites, most significant changes were found in oleanolic acid, palmitic acid, taurochenodeoxycholate, and d-sphingosine, discriminating between healthy controls and pancreatic cancer patients [68].

T3cDM caused by pancreatic cancer is characterized by **abnormal concentrations of several hormones** which participate in glucose homeostasis. In cases where basal plasma concentrations of the hormone are within normal limits, the impairment may be disclosed after mixed-nutrient stimulation [52]. The determination of insulin, pancreatic polypeptide (PP), or glucose-dependent insulinotropic peptide (GIP) during the "meal test" may confirm their decreased levels, which would demonstrate their altered dynamics [19].

**Exosomes** bring new possibilities to the detection of SPC [69]. The proteins, miRNAs, and mRNAs transferred by these vesicles originating in cancer cells can be used as biomarkers. Several body fluids like serum, urine, and saliva were demonstrated to contain pancreatic cancer-derived exosomes [70]. Exosomes may improve early diagnosis of pancreatic cancer in stage I and IIA when the tumor is still localized [71]. Two miRNAs, miR-196a and miR-1246, were found to be highly enriched in pancreatic cancer exosomes and elevated in plasma exosomes of patients with localized pancreatic cancer. Exosomes can be examined in pancreatic juice when new-onset diabetes is suspected as a paraneoplastic symptom of SPC [72]. Exosomes trafficking within pancreatic juice may facilitate the development of a pre-metastatic niche well before any symptomology that might support an early diagnosis of pancreatic cancer [72].

Sometimes the fluctuations of blood glucose confirm unstable diabetes regardless of intensified insulin treatment. The findings of (1) worsening diabetes control and (2) failure of antidiabetic drug treatment indicate the need for SPC screening. Patients in both risk groups (i.e., new-onset and long-term diabetes) should be examined according to the structured protocol

Sporadic Pancreatic Cancer: Glucose Homeostasis and Pancreatogenic Type 3 Diabetes

http://dx.doi.org/10.5772/intechopen.75740

63

**a.** A clinical suspicion of SPC in the risk groups evaluated by general practitioners (GPs) or

**b.** A determination of biomarkers (oncomarkers, microRNAs, etc.) and hormones (GIP, PP,

**c.** An endoscopic examination of the patient and use of high-resolution imaging methods (HRIMs) as prescribed by an endoscopist/radiologist in collaboration with a pathologist.

A multidisciplinary team approach should improve the prognosis of this malignant disease. The early symptoms (new-onset T3cDM and weight loss), the effect of the initial antidiabetic drug therapy, as well as the failure of antidiabetic therapy in long-term diabetes control, with newly developing weight loss, should be properly evaluated by a GP or a diabetologist.

We suggested an algorithm for the examination of patients with new-onset diabetes (**Figure 1**) [2]. Regular screening of blood glucose in the general population above 50 years of age may disclose abnormalities in glucose homeostasis. Additionally, the evaluation of body weight and any changes during the months prior to the visit is critical. A decrease in body weight > 2 kg in a patient with newly confirmed prediabetes or diabetes should arouse suspicion of its para-

A patient with new-onset diabetes should be treated with the first line antidiabetic drug according to the guidelines for Type 2 diabetes. If the diabetes control is not satisfactory during the first 3 months and body weight remains stable or increases, then a second antidiabetic drug should be added. An inadequate response to intensified treatment or unintentional weight loss should lead to a suspicion of T3cDM. In this situation, the collaboration with a gastroenterologist, preferably in a tertiary center, is necessary. The patient should be tested for PP and GIP secretion after nutritional stimulation. A response by PP and GIP that is diminished or absent confirms the pancreatogenic origin of the diabetes (T3cDM). A gastroenterologist should arrange the next steps involving an endoscopic examination and HRIMs. A patient with long-term diabetes with failing antidiabetic drug treatment combined with decreasing body weight should be included in the same multistep screening program as

GLP-1) after nutritional stimulation as prescribed by a gastroenterologist,

neoplastic origin. In this case, a gastroenterologist should be consulted.

**8. Protocol for early sporadic pancreatic cancer detection**

The program of early SPC detection has three steps [2]:

we described earlier [2].

diabetologists,

described for T3cDM patients.

It appears that an early diagnosis is increasingly dependent on a combination of biomarkers with sufficient sensitivity to disclose localized tumors or, better still, their precursors.

#### **6.2. Imaging methods**

Diagnosis based on visualization of the tumor and classification of its stage is necessary for clinical decisions regarding treatment and the use of high-resolution imaging methods (HRIMs) is therefore immediately recommended in patients suspected of having SPC. The results of different methods were compared using a large database [73]. Effective screening procedures for early detection of pancreatic cancer were described by Hanada et al. [74, 75]. A review of the advances in various imaging methods, as well as their proper selection is beyond the scope of this review.
