• Clinical science

Pancreatic cancer

Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the US and typically affects older individuals in the sixth to eighth decades of life. Underlying risk factors include smoking, obesity, alcohol consumption, and chronic pancreatitis. Pancreatic carcinomas are mostly ductal adenocarcinomas and frequently located in the pancreatic head. The disease is commonly diagnosed at an advanced stage because of the late onset of clinical features (e.g., epigastric pain, painless jaundice, and weight loss). In many cases, the tumor has already spread to other organs (mainly the liver) when it is diagnosed. Treatment is often palliative as surgical resection is only possible in approx. 15% of cases. The most commonly used surgical technique is the pancreaticoduodenectomy (“Whipple procedure”). Five-year survival rates range from 1–20% depending on the extent, spread, and resectability of the tumor.

Epidemiology

  • Sex: >
  • Age of onset: 60–80 years
  • More common in African Americans
  • Accounts for ∼ 3% of all cancers in the US and ∼ 7% of cancer deaths
  • The average lifetime risk: ∼ 1.5%

References:[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[5][6][7][8][2]

Classification

TNM classification for pancreatic cancer

TNM Ausdehnung
T1 Tumor limited to the pancreas: extent of tumor ≤ 2 cm
T2 Tumor limited to the pancreas: extent of tumor > 2 cm
T3 Tumor extends beyond the pancreas but not into major blood vessels or nerves
T4 Tumor grows into nearby large blood vessels or nerves
N1 The cancer has spread to nearby lymph nodes
M1 The cancer has spread to distant lymph nodes or to distant organs

Clinical features

References: [4][3][9][10]

Stages

UICC staging for pancreatic cancer (Union for International Cancer Control)

UICC-Stages TNM
Stage 0 Tis (Carcinoma in situ)
Stage I T1 (IA) or T2 (IB)
Stage II T3 (IIA) or N1 (IIB)
Stage III T4
Stage IV M1

Diagnostics

Blood

Imaging

  • First test: usually either contrast-enhanced abdominal CT or ultrasound → if ultrasound reveals a pancreatic mass → subsequent CT
    • Poorly defined, hypodense/hypoechoic and hypovascular mass
    • Double-duct sign; : With increasing size, tumors of the pancreatic head may block bile drainage in both the common bile duct and the pancreatic duct, leading to dilatation of both structures.
  • Endoscopic or magnetic retrograde cholangiopancreatography (ERCP/MRCP): to rule out choledocholithiasis and/or if biliary decompression is indicated; , e.g., in case of palliative treatment to alleviate jaundice
  • Endoscopic ultrasound (EUS)
    • Used when other diagnostic tests are inconclusive or to perform fine needle aspiration
    • Findings similar to transcutaneous ultrasound
    • A negative EUS is nearly 100% specific at ruling out pancreatic cancer.
    • More sensitive than CT for detecting venous and lymph node involvement
  • Fine needle aspiration
    • Not routinely performed
    • Can help differentiate pancreatic cancer from pancreatitis (e.g., chronic or autoimmune)
    • Can be done via EUS (preferred) or percutaneously (US or CT-guided)

Staging

  • Clarify before tumor conference
  • Mandatory examinations
    • Abdominal ultrasound
    • CT abdomen
    • Chest x-ray
  • Optional examinations
    • CT thorax
    • Laparoscopy
      • Alternative approach: surgical exploration with laparotomy in tumors classified as potentially resectable

References:[9][4]

Pathology

  • Location
  • Pancreatic exocrine tumors (95%)
    • Mostly ductal adenocarcinoma with altered ductal structures with uneven multilayered epithelium
    • Less common: acinar adenocarcinoma (acinar cells produce digestive enzymes) and others
  • Pancreatic endocrine tumors (neuroendocrine tumors/NET, < 5% of tumors)
  • R classification system of resected pancreatic tissue
    • The guidelines request that the surgeon marks the resection margins in a way that the pathologist can correctly assess them.
    • Analogous to rectal carcinoma the distance from the tumor cell to the surgical resection margin is defined ("circumferential resection margin")
      • Margin > 1 mm - "true R0"
      • Margin < 1 mm - "narrow R0"

References:[11][4]

Differential diagnoses

  • Pancreatitis
  • Metastasis (e.g., breast carcinoma, bronchial carcinoma)
  • Pancreatic pseudocyst
  • Pancreatic cyst: Epithelium-lined cyst, filled with serous or mucous liquid, often associated with the rare von-Hippel-Lindau syndrome; can be benign, precancerous or cancerous.
    • Clinical features: abdominal pain, back pain, jaundice, and in case of infection, fever and sepsis
    • CT scan: cyst appears as a well-circumscribed hyperdense mass in comparison to the surrounding tissue. Pancreatic cancer, on the other hand, is hypodense.
    • ERCP: cyst shows contrast-enhancement
    • Treatment
      • Asymptomatic cyst: no surgical treatment
      • Symptomatic cyst: CT-guided, endoscopic, or surgical drainage
  • Intraductal papillary mucinous neoplasms (IPMNs)
    • Brief description: most frequent pancreatic lesion (about 20–30%); commonly located in the head of the pancreas. Histologically, intraductal papillary proliferations present with atypical columnar epithelium and variable mucinous content.
    • Classification: "main duct type" and "branch duct type"
    • Clinical features: One-third of all patients are asymptomatic. If symptoms occur, they resemble those of chronic pancreatitis.
    • Diagnostics: : Initially, cross‑sectional imaging is performed (MRI with Magnetic resonance cholangiopancreatography (MRCP) or abdominal CT). Ultrasound or CT-guided fine-needle aspiration may help to confirm a diagnosis (particularly in branch duct type) or to assess malignancy.
      • Malignancy criteria of cystic lesions in IPMNs: peripheral wall nodes, main pancreatic duct dilation, detection of malignant cells in cytopathology
    • Treatment:
      • Main duct type: surgical resection
      • Branch duct type: Surgical resection is only performed when IPMN meets malignancy criteria.
      • If necessary, watchful-waiting in small branch-duct type in multimorbid older patients with high operative risk
  • Serous cystic neoplasms (SCNs)
    • Brief description: SCNs account for approx. 10–20% of all cystic lesions. They typically occur in elderly women and are most frequently located in the body or the tail of the pancreas. Malignant transformation is extremely rare.
    • Treatment: surgical resection only if symptoms like passage disorder or pain occur, or if lesion is > 4 cm in size
  • Mucinous cystic neoplasms (MCNs)
    • Brief description:MCNs account for approx. 10% of all cystic lesions and only occur in women. Their most common localization is the tail of the pancreas. Imaging in MCN patients shows multilobular space-occupying lesions with a thick cyst wall. MCN typically show ovarian-like stroma. There is a 30–50% risk of malignancy in this type of cystic neoplasm. Therefore, surgical resection is generally recommended.
  • Solid-pseudopapillary neoplasms (SPNs)
    • Brief description: SPNs are rare and are only responsible for approx. 5% of cystic lesions. There is a slight tendency for malignancy and in 5% of all diagnosed SPNs liver metastasis is present. Surgical resection is the goal even if metastasis is present. If complete surgical resection is successful, the overall prognosis is good.
  • Lipomas of the pancreas (pancreatic lipomas)
    • Brief description: Pancreatic lipomas are very rare benign lesions of the pancreas. MRI typically shows a tissue which is isointense to fat. Malignant transformation of pancreatic lipomas into pancreatic liposarcomas is even rarer than the pancreatic lipomas themselves. Specific treatment is not necessary unless the lipoma causes complications; e.g., compression of neighboring organs can lead to organ dysfunction, pain, and other symptoms, which may require treatment (e.g., surgical resection).

The differential diagnoses listed here are not exhaustive.

Treatment

As the only curative treatment option for pancreatic cancer is surgical resection, patients with operable tumors; (∼ 20%) are always recommended for surgery. If surgical tumor resection is not possible or distant metastasis is present, a palliative approach is chosen.

Basic principles

  • Curative versus palliative treatment
    • The only curative treatment option is surgical resection that aims for R0 resection. Therefore, patients with operable tumors are always recommended to undergo surgery.
    • If surgical tumor resection is not possible or distant metastasis is present, the cancer is incurable (palliative situation).
  • Criteria for resectability
    • Infiltration of neighboring organs: R0 resection is still possible. Surgical resection should be considered if the operation technique allows it.
    • Infiltration of arteries: If the celiac artery is infiltrated, surgical resection of the pancreatic carcinoma should not be performed.
      • According to the NCCN (National Comprehensive Cancer Network) Guidelines, surgical resection is contraindicated in the case of celiac artery encasement greater than 180 degrees.
    • Infiltration of veins: R0 resection is still possible when the portal vein, splenic vein, and superior mesenteric vein are infiltrated by the tumor; the determining factor for surgery is the possibility of reconstruction and the technical limits to it.
    • Borderline resectable tumors (NCNN guidelines)
      • Infiltration of the superior mesenteric artery or the portal vein - Imaging shows that the tumor reaches the vessels but doesn't narrow them by compressing the veins and arteries.
      • Encasement of the superior mesenteric vein and/or the portal vein by the tumor, but neighboring vessels are not completely encased by it
      • Short-segment occlusion or stenosis of a vein caused by a thrombus or tumor encasement if there is enough vessel material for reconstruction at the proximal and distal end of the occlusion
      • Short-segment encasement or tumor reaches the gastroduodenal artery or the proper hepatic artery but the celiac artery is not encased by the tumor
      • Celiac encasement less than half of its circumference
      • If the responsible surgeon has doubts about the resectability or does not have enough surgical experience, a second opinion should be obtained from a pancreas specialist.

Curative approach

Surgery

Neoadjuvant or adjuvant chemoradiotherapy

Palliative approach

The significantly limited prognosis in pancreatic cancer patients should always be taken into consideration when thinking about palliative chemotherapy. If side-effects are remarkable and the patient's quality of life is significantly impaired, withdrawal from therapy should be openly discussed with the patient!

  • Analgesia according to the WHO step-by-step plan
    • Early consultation with a pain therapist for optimizing the need of coanalgesics and adjuvants may be indicated.
    • When administering opioids: consistent treatment of paralytic constipation caused by these drugs (e.g., with macrogol )
    • Prescription of on-demand medication: especially for pain which sets in with food intake
    • Psycho-oncological service: medicinal and interventional pain management may be complemented by psycho-oncological treatment. The benefits of this complementary treatment must be assessed on an individual basis.
  • Radiotherapy: used in patients with symptomatic metastasis, especially to the brain and bones (rare)
  • Celiac ganglion block (Celiac plexus block)
  • Cholestasis : ERCP with stent implantation
    • Implantation of a wire mesh-like configured and self-unfolding metal stent in the common bile duct or in the affected area of the biliary tree. In patients with a life expectancy of less than 3 months, a plastic stent can be used.
    • If the tumor progresses and infiltrates the implanted metal stent it can be ablated using argon plasma coagulation (APC)
    • Percutaneous transhepatic bile duct drainage (PTCD)
      • Indication: if endoscopic access path is complicated (e.g., in duodenal stenosis, duodenal resection, and inaccessibility of the biliodigestive anastomosis)
      • Technique: initially, external drainage in a collection bag
    • Biliodigestive anastomosis
      • Indication: if endoscopic approaches fail or are not possible
      • Technique: especially as a combinatorial procedure with gastroenterostomy (see “Gastroenterostomy” below) and usually additional choledochojejunostomy
  • In tumor-induced passage disorders of the gastrointestinal tract
    • Drug treatment attempt
      • Indication: subtotal stenoses and functional passage disorders of the stomach and duodenum
      • Technique: attempt with prokinetic drugs, e.g., the combination of metoclopramide and erythromycin for 3–5 days (off-label-use, common and approved medical practice)
    • Percutaneous Endoscopic Jejunostomy (PEJ) tube
      • Indication: best supportive care in patients with passage disorder of the stomach and/or the duodenum
  • Gastroenterostomy: best supportive care in patients with gastric outlet stenosis. The stomach is anastomosed with the small intestine bypassing the duodenum.
  • Technique: anastomosis of the stomach and the duodenum (jejunum; short-circuit surgery)
  • Percutaneous endoscopic gastrostomy (PEG) tube as a relief tube: indicated for severe palliative patients with chronic ileus and subileus that are inoperable
    • Technique: a PEG tube with a great lumen (20 Fr.) is set up as an outflow tube
  • Nutrition counseling
    • Easily digestible foods (carbohydrates, little dietary fiber); small, frequent meals
    • Pancreatic enzyme supplements

References:[4][3][12][10][13]

Complications

References:[4][10][12]

We list the most important complications. The selection is not exhaustive.

Prognosis

  • The overall 5-year survival rate is 7%, but mainly depends on the stage of disease.
  • Median survival for patients who undergo successful resection: ∼ 12–19 months, with a 5-year survival rate of 15–20%
  • A metastatic pancreatic cancer has a 5-year survival rate of ∼ 2%.

References:[14][1][15][4]