Keywords

1 Definition and Classification [1]

  • Malignant tumors.

    Origin:

    • Ductal cells.

      • Ductal adenocarcinoma—75–90%.

      • Giant-cell carcinoma—5%.

      • Cystadenocarcinoma—rare.

      • Mucinous carcinoma—rare.

      • Small-cell carcinoma—rare.

      • Anaplastic carcinoma—rare.

    • Acinar cells:

      • Acinar cell carcinoma.

      • Acinar cell cystadenocarcinoma.

    • Conjunctive tissue.

      • Sarcoma—rare.

      • Lymphoma—rare.

    • Pancreatic metastasis (more frequently from breast carcinoma, lung carcinoma, melanoma, or non-Hodgkin lymphoma).

  • Tumors with malignant potential.

    • Solid pseudopapillary tumors.

    • Intraductal papillary mucinous neoplasia (IPMN).

  • Benign tumors.

    • Serous cystadenoma.

    • Mucinous cystadenoma.

    • Solid serous adenoma.

    • Lymphoepithelial cyst.

    • Hamartoma.

2 Pancreatic Ductal Adenocarcinoma

2.1 Epidemiology [2]

  • Aggressive, 5-year survival rate < 10%,

  • Rare before the age of 45, incidence rises sharply thereafter,

  • Men > women,

  • Risk factors [2, 3]:

    • Cigarette smoking,

    • Obesity,

    • Diabetes mellitus, metabolic syndrome,

    • Family history (>2 first-degree relatives),

    • Familial pancreatitis (PRSS1),

    • Peutz–Jeghers syndrome (STK11).

    • familial atypical multiple mole melanoma syndrome FAMMM (P16),

    • Lynch syndrome (MLH1, MSH2, MSH6, or PMS2).

    • Ataxia-telangiectasia (ATM),

    • Hereditary ovarian and breast cancer (BRCA1, BRCA2),

    • PALB2, CHECK2 mutations.

2.2 Pathogenesis [4]

  • Precursor lesions: pancreatic intraepithelial neoplasia (PanIN).

    • PanIN-1: flat/papillary without atypia.

    • PanIN-2: papillary with atypia.

    • PanIN-3: severe architectural and cytonuclear abnormalities, but invasion through the basement membrane is absent.

  • The most frequent genetic abnormalities in invasive pancreatic adenocarcinoma:

    • Mutational activation of Kras oncogene,

    • Inactivation of tumor suppressor genes: CDKN2A/p16, TP53 si SMAD4.

2.3 Diagnostic [4, 5]

  • Clinical signs.

    • Asthenia.

    • Weight loss.

    • Abdominal/epigastric/back pain.

    • Nausea, vomiting.

    • Steatorrhea.

  • Physical exam.

    • Hepatomegaly or epigastric mass.

    • Jaundice,

    • Courvoisier’s sign (nontender but palpable distended gallbladder at the right costal margin).

    • Cachexia.

    • Ascites.

  • Laboratory tests:

    • Increased total and conjugated (direct) bilirubin, alkaline phosphatase (AP), GGT (obstructive jaundice—pancreatic head tumors),

    • CA 19–9 usually elevated.

    • Mild normochromic anemia, thrombocytosis,

    • Increased liver enzymes and AP (liver metastasis).

  • Imaging tests:

    • Transabdominal ultrasound: indicates presence and level of obstruction, rarely the tumor (lesions smaller than 3 cm are usually missed).

    • CT with pancreatic protocol: preferred imaging tool for staging and resectability status [3].

    • MRCP: provides supplementary information; noninvasive method for imaging the biliary tree and pancreatic duct [3].

    • PET-CT: in high-risk patients to detect metastasis.

2.4 Role of Endoscopy

  • EUS significantly improved PDAC diagnosis, especially for small-size tumors [3, 6,7,8].

    • Identifies dilated biliary ducts (Fig. 41.1) and the level of obstruction (Fig. 41.2).

    • Allows for the characterization of pancreatic lesions (using EUS-elastography and contrast-enhanced EUS) (Fig. 41.2).

    • EUS can be used for staging as it allows for the identification of liver metastasis (Fig. 41.3).

  • EUS-FNA/FNB is preferable to a CT-guided FNA in patients with resectable disease because of better diagnostic yield, safety, and lower risk of peritoneal seeding (Fig. 41.4) [3, 6].

  • EUS-FNA can be used for interventional procedures such as celiac plexus neurolysis, fiducial markers placement for guidance of radiotherapy (Fig. 41.5), or biliary drainage with metallic stents [9].

  • A pathologic diagnosis is not required for resectable tumors before surgery [3].

  • ERCP is used for confirmation of diagnosis (by brush cytology/direct biopsies) and for drainage with plastic stents or SEMS.

Fig. 41.1
Two E U S images reveal an enlarged left lobe of the liver in the first image and sludge in the gallbladder in the second image.

EUS showing dilated intrahepatic biliary ducts in the left liver lobe (a) and a distended gallbladder with sludge (b) in a patient with pancreatic ductal adenocarcinoma

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Fig. 41.2
Four sets of E U S images with Doppler of the pancreas. Dark-shaded and dense areas within the pancreas indicate the presence of a tumor.

EUS showing a hypoechogenic, irregular pancreatic tumor (a) with a “hard” appearance on EUS-elastography (b) with a poor Doppler signal and collateral circulation (c), hypoenhanced in the arterial and venous phase on contrast-enhanced EUS (d)

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Fig. 41.3
4 sets of E U S images of the liver. The presence of dark-shaded, dense, and opaque regions in the liver indicates the tumor.

EUS elastography showing liver metastasis (lesions with “hard” appearance on elastography) in left liver lobe in patient with pancreatic ductal adenocarcinoma (a, b); contrast-enhanced EUS showing liver metastasis with hypoenhancement in the arterial phase (c) and allows for guidance of EUS-FNA (d)

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Fig. 41.4
A. An E U S image of the pancreas. A dense, hypoechoic, and dark-shaded structure indicates the presence of a tumor. B. In the microscopic image, the tumor-affected region appears densely stained.

EUS-guided fine-needle biopsy of a pancreatic tumor (a) with a histopathology examination showing pancreatic ductal adenocarcinoma (b)

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Fig. 41.5
2 E U S images of the pancreas. The tumors in the pancreas are indicared by dense, dark-shaded areas surrounded by highlighted regions with varying shades.

EUS-guided fiducial marker placement (b) inside a pancreatic tumor (a) for guidance of radiotherapy

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2.5 Staging [3]

2.5.1 TNM Staging

  • Tumor (T).

    • TX—Primary tumor cannot be assessed.

    • T0—No evidence of primary tumor.

    • Tis—Carcinoma in situ.

    • T1—Tumor limited to the pancreas, 2 cm or smaller in greatest dimension.

    • T2—Tumor limited to the pancreas, larger than 2 cm in greatest dimension.

    • T3—Tumor extension beyond the pancreas (duodenum, bile duct, portal or superior mesenteric vein) but not involving the celiac axis or superior mesenteric artery.

    • T4—Tumor involves the celiac axis or superior mesenteric arteries.

  • Regional lymph nodes (N).

    • NX—Regional lymph nodes cannot be assessed.

    • N0—No regional lymph node metastasis.

    • N1—Regional lymph node metastasis.

  • Distant metastasis (M).

    • MX—Distant metastasis cannot be assessed.

    • M0—No distant metastasis.

    • M1—Distant metastasis.

2.6 Criteria Defining Resectability Status at Diagnosis [3]

  1. 1.

    Resectable.

    1. (a)

      No arterial tumor contact with celiac axis (CA), superior mesenteric artery (SMA), common hepatic artery (CHA).

    2. (b)

      No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or ≤ 180 vein contact.

  2. 2.

    Borderline resectable.

    1. (a)

      Tumor contact with CHA without extension with CA allowing for safe and complete resection and reconstruction.

    2. (b)

      Tumor contact with the CA or SMA ≤ 180°.

    3. (c)

      Tumor contact with the SMV or PV > 180°, allowing for safe and complete resection and reconstruction (Fig. 41.6).

  3. 3.

    Locally advanced, unresectable.

    1. (a)

      Tumor contact with CA or SMA > 180° (Fig. 41.7).

    2. (b)

      Unreconstructible SMV/PV due to tumor involvement or occlusion.

Fig. 41.6
An E U S image and elastogram of the pancreas. The tumor on the pancreatic tissue is present in dark-shaded regions. In the elastogram, the hardness of the tissue is indicated as a brightly shaded region.

EUS showing a ductal pancreatic adenocarcinoma with 180° tumor contact with SMV (a) with a hard appearance of the tumor on EUS elastography (b)

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Fig. 41.7
An E U S image and a 3-D reconstruction of the pancreas. The tumor-affected region is present as dense and dark-shaded structures surrounded by brightly-shaded waves. In the 3-D structure, the tumor is visualized as a dense and solid structure with a lighter shade.

Contrast-enhanced EUS showing a pancreatic ductal adenocarcinoma with circumferential invasion of the celiac axis and the hepatic artery visible on Doppler (a), with 3D reconstruction in harmonic mood with low mechanical index (b)

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2.7 Treatment [3, 10, 11]

  • Resectable disease (<20%).

  • Complete resection with negative margins (R0) is the only curative treatment.

  • Surgical procedures:

    • Pancreatoduodenectomy Whipple (or modified Whipple with pylorus preservation)—for tumors of the pancreatic head and uncinate.

    • Distal pancreatectomy with en-bloc splenectomy—for tumors of the pancreatic body and tail.

  • Adjuvant therapy: mFOLFIRINOX* (fit patients, good performance status, and no important comorbidities); capecitabine + gemcitabine; fluorouracil/folinic acid.

  • Borderline disease.

  • Neoadjuvant chemotherapy (FOLFIRINOX or gemcitabine), followed by chemoradiation (with capecitabine).

  • Locally advanced disease.

  • Obstructive jaundice: stent placement (ERCP) or bypass surgical interventions (cholecystic-jejunostomy/choledochal-jejunostomy).

  • Palliative chemotherapy: gemcitabine, 6 months.

  • Chemoradiation improves local control.

  • Metastatic/recurrent disease.

    • First line.

      • FOLFIRINOX (European standard)/gemcitabine + nab-paclitaxel (American standard)—for patients with performance status 0–1.

      • Gemcitabine monotherapy—for patients with performance status 2.

      • BRCA1/BRCA 2 mutations: maintenance therapy with Olaparib after minimum 16 weeks of platinum-based chemotherapy.

  • Second line.

    • Performance status 0–1: fluoropyrimidine in combination with oxaliplatin, irinotecan, or nanoliposomal irinotecan (after gemcitabine +/− nab-paclitaxel in first line); gemcitabine +/− nab-paclitaxel (after FOLFIRINOX in first line).

    • Performance status 2: monotherapy with a fluoropyrimidine (after gemcitabine in first line) or gemcitabine (after FOLFIRINOX in first line).

*FOLFIRINOX:5-fluorouracil + folinic acid + irinotecan + oxaliplatin.

3 Pancreatic Cystic Neoplasms

3.1 Classification [1, 12]

  • Benign.

    • Serous cystadenoma,

    • Lymphangioma/hemangioma/teratoma.

  • Premalignant/malignant.

    • Mucinous cystadenoma,

    • Intraductal papillary mucinous neoplasms (IPMN),

    • Mucinous cystadenocarcinoma,

    • Cystic neuroendocrine tumors.

3.2 Epidemiology [12]

  • Detected in approximately 10–15% of general population,

    • Without history of pancreatitis,

    • Discovered incidentally on IRM/CT scans.

  • Represent 1–2% of malignant pancreatic tumors,

    • Better prognosis than pancreatic ductal adenocarcinoma.

3.3 Serous Cystadenoma [13]

  • Almost always benign and occur more commonly in women,

  • Classified into serous microcystic adenomas and serous macrocystic adenomas,

  • Unifocal, round, well-demarcated, and often honeycombed,

  • Contain serous fluid that is mucin-free,

  • Characteristic aspect on EUS as described in Fig. 41.8.

Fig. 41.8
4 E U S images of the pancreas. The regions affected by tumors are present as dense, dark-shaded, and opaque regions. The presence of septa is visualized as hypoechoic regions.

Serous microcystic adenoma with pseudo- “hard” appearance on EUS elastography due to artifacts induced by microcysts and blood vessels located on the septations (a), with hypoenhanced septations on contrast-enhanced EUS (b)

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3.4 Mucinous Cystadenoma [12]

  • Premalignant lesions.

    • Frequent in women, incidentally discovered, commonly located in the pancreatic head/body.

    • Survival >60% for resected mucinous cystadenoma.

    • Survival <5% pentru resected mucinous cystadenocarcinoma.

  • EUS aspect in described in Fig. 41.9.

    • EUS-FNA with fluid aspiration (amylase, CEA, CA 19–9) + cytological examination.

    • Risk factors for malignancy.

      • Mural nodules and thick wall.

      • Size >3 cm.

Fig. 41.9
2 E U S images of the pancreas. The presence of cysts are present as dark-shaded and dense patches, and nodules on the tissue are present as dark-shaded spots.

Mucinous macrocystic adenoma with thick wall (a) and mural nodules (b) that requires EUS-FNA for diagnosis confirmation

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3.5 Mucinous Cystadenocarcinoma [12]

  • Arises from mucinous cystadenoma.

  • Characteristic EUS aspect as described in Fig. 41.10.

    • Irregular cystic lesions with solid areas and thick wall.

    • requires aspiration of the cystic lesions and EUS-FNA from the solid component.

Fig. 41.10
A. An E U S image of the pancreas. A dark-shaded patch present at the center indicates the presence of a tumor. B. In the corresponding histopathological slide, multiple oval and dark-shaded patches are present, indicating the presence of tumors.

Mucinous cystadenocarcinoma with hypoechogenic solid component (a), with EUS-FNA and cytological examination showing hyperchromatic nuclei, with decreased nuclei-cytoplasm ratio (b)

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3.6 Intraductal Papillary Mucinous Neoplasms (IPMN) [12]

  • Premalignant lesions,

  • EUS/EUS-FNA superior to CT and IRM.

    • Allows for the detection of mural nodules and differential diagnosis with mucus plugs using contrast enhanced EUS,

    • Identifies the communication with the pancreatic duct,

    • EUS-FNA enables the aspiration of the cystic fluid (positive “string sign”).

    • Depicts concomitant pancreatitis changes.

  • Types of IPMN:

    • Branch duct (Fig. 41.11), incidentally discovered, incidence increases with age,

    • Main duct, frequently located in the pancreatic head, symptomatic (weight loss, abdominal pain, jaundice).

Fig. 41.11
2 pancreatic E U S images indicate a tumor in the pancreatic isthmus.

Side branch IPMN located in the pancreatic isthmus, closed to the spleno-mesenteric confluent (a) without enhancement in the arterial and venous phase on contrast-enhanced EUS (b)

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