Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma is the most common type of pancreatic cancer, typically of the ductal epithelium and associated with KRAS mutation, and presents as an obstructing head of pancreas mass in older adults.

Description

Pancreatic adenocarcinoma (PAC), also referred to as pancreatic ductal adenocarcinoma, is the most common type of pancreatic cancer, accounting for about 90% of all pancreatic neoplasms. It typically originates from the ductal epithelium of the pancreas and is notorious for its aggressive nature and poor prognosis.

Pathogenesis

The pathogenesis of PAC is a multistep process that involves the progression from pre-neoplastic lesions, known as PanINs (Pancreatic Intraepithelial Neoplasia), to invasive carcinoma. This process is associated with various genetic alterations, the most common of which is a mutation in the KRAS gene, occurring in up to 95% of cases.

Epidemiology, Risk Factors & Associations

• PAC predominantly affects adults over 50 years, with the median age at diagnosis being 71 years.
• Slightly more common in men than in women.

Risk factors include:

• Lifestyle factors: Tobacco smoking (most important risk factor), obesity, high alcohol consumption
• Chronic or hereditary pancreatitis
• Diabetes type 1 and 2
• Family history (first-degree relative)
• Certain genetic syndromes (BRCA2 mutation, Peutz-Jeghers syndrome, multiple endocrine neoplasia, hereditary nonpolyposis rectal cancer (HNPCC), familial adenomatous
  polyposis (FAP), Gardner syndrome, familial atypical multiple mole melanoma (FAMMM) syndromes).

Clinical Features

• May be clinically silent
• Patients can present with clinical jaundice (suggests pancreatic head tumour) and palpable gallbladder (Courvoisier sign).
• Migratory thrombophlebitis (Trousseau syndrome) – inflammatory reaction of the vein accompanied by a thrombus.
• Tumours of the body present with mid-epigastric pain with radiation to the back due to invasion of the nerves around the pancreas. Physical examination can show hepatomegaly and ascites.
• Non-specific: Weight loss, anorexia, nausea and fatigue
• New-onset diabetes

Complications

PAC can give rise to several complications, including biliary obstruction, pancreatic duct obstruction leading to pancreatitis, duodenal obstruction, and liver metastases. Mortality rate is high with median survival of 4-6 months.

Subtypes

PAC is classified histologically into several subtypes, the most common of which is conventional (pancreatobiliary) type, accounting for approximately 90% of cases. Other, rarer subtypes include adenosquamous carcinoma, colloid (mucinous non-cystic) carcinoma, medullary carcinoma, signet ring cell carcinoma, and undifferentiated (anaplastic) carcinoma.

Pathological Features

Histopathology

• Head of pancreas is the most common site of pancreatic adenocarcinoma
• Characterised by invasive glands that are surrounded by a dense desmoplastic stroma.
• Glands are lined by cuboidal to columnar cells with eosinophilic cytoplasm and large, hyperchromatic nuclei.

Biochemistry

• Elevated bilirubin, dark urine, and pale stools.

Serology

• CA19–9 antigen (tumour marker) and CEA raised (not sensitive)

Genetics

• In addition to the KRAS mutation, other common genetic alterations include inactivation of the TP53, CDKN2A, and SMAD4 genes.

Radiological Features

General Features

• Most frequently arises in the head of the pancreas (60-70% of cases).
  • The remaining 30-40% of cases are roughly evenly distributed between the body and tail of the organ.
• Mass may cause dilation of the pancreatic and bile ducts, loss of the normal fat plane between the pancreas and adjacent vessels, and atrophy of the distal pancreatic parenchyma.
• Distal pancreatic atrophy and dilatation of the pancreatic duct upstream of the tumour (double duct sign when common bile duct is also dilated).
• Poorly defined soft-tissue mass with extensive surrounding desmoplastic reaction and invasion into the surrounding tissue.
• Typically a hypovascular lesion.
• Very rarely calcified.
• May encase nearby blood vessels, such as the superior mesenteric artery and vein.
  • Arterial involvement is quantified as < 180° or ≥ 180° tumoral involvement of vessel circumference, while venous involvement may involve abutment, encasement, narrowing, or occlusion
• Distant metastases commonly to the liver and peritoneum.

Terminology used to describe vascular involvement:

• No contact: Clear fat plane between tumour and vessel.
• Abutment: ≤180° tumour contact with vessel circumference.
• Encasement: >180° tumour contact—suggests likely vessel wall invasion.
• Contact: Generic term, includes both abutment and encasement.
• Deformity/narrowing: Suggests invasion, especially for venous structures.
• Occlusion: Vessel is completely obstructed by tumour.
• Reconstructable: Vessel involvement is surgically bypassable or replaceable.
• Unreconstructable: Involvement precludes safe surgical bypass or reconstruction.

CT

• Typically hypoattenuating compared to the normal pancreas on all phases of contrast-enhanced CT.
• Duct dilation: Both the pancreatic duct and common bile duct may be dilated due to obstruction by the tumour.
• Atrophy: There may be atrophy of the pancreatic parenchyma distal to the tumour.

MRI

• T1: Usually hypointense compared to the normal pancreas.
• T2: Variable; usually iso- to slightly hyperintense. Signal primarily depends on desmoplastic response associated with the tumour.
• T1:
  • Pre-contrast: Typically hypointense compared to normal pancreatic parenchyma.
  • Post-contrast (Gadolinium): Hypovascular mass with delayed enhancement. This delayed enhancement pattern is due to the dense fibrotic stroma of the tumour, which contrasts with the relatively well-vascularised normal pancreatic tissue.
• T2:
  • The tumour generally appears slightly hyperintense or isointense relative to the normal pancreatic tissue. The margins of the tumour may be poorly defined.
  • There may be associated findings such as dilatation of the pancreatic duct (double duct sign when both the pancreatic and common bile ducts are dilated).
• DWI/ADC: The tumour often shows restricted diffusion, appearing hyperintense on DWI due to the high cellularity of the adenocarcinoma. Correspondingly, the lesion will show low ADC values, reflecting restricted diffusion.
• T1 Gad+:
  • Arterial Phase: The tumour appears hypovascular and hypointense compared to the surrounding pancreatic tissue.
  • Venous Phase: The tumour continues to appear hypointense with a lack of significant enhancement.
  • Delayed Phase: Shows some enhancement but still remains relatively hypointense compared to normal pancreatic parenchyma due to its fibrotic content.
• MPGRE: Tumour appears markedly low in signal
• MRCP: Often included in the pancreatic protocol, MRCP can help visualise the pancreatic ductal system. Pancreatic adenocarcinoma may cause strictures or dilatation of the pancreatic duct. May exert mass effect upon the common bile duct.

Additional Findings

• Pancreatic Ductal Dilatation: Often present and seen as the double duct sign (simultaneous dilatation of the pancreatic and common bile ducts).
• Vascular Involvement: MRI can assess involvement of adjacent vessels, such as the superior mesenteric artery (SMA) or vein (SMV), portal vein, and celiac axis.
• Metastatic Disease: MRI can also be used to evaluate liver metastases, which may show hyperintensity on T2 and restricted diffusion on DWI/ADC.
• Pitfalls
• Small tumours can be missed if they do not cause significant ductal obstruction or are isoattenuating on some sequences.
• Differentiating pancreatic adenocarcinoma from mass-forming pancreatitis can be challenging; both can present as hypointense on T1 and hyperintense on T2 images with delayed enhancement patterns. Biopsy or further imaging may be required for definitive diagnosis.

US

• Pancreatic duct cut-off sign – Abrupt tapering of a dilated pancreatic duct

Grading and Staging

Grading of PAC is based on glandular differentiation and mitotic activity. The TNM (Tumour, Node, Metastasis) system is used for staging, with T describing the size and extent of the main tumour, N describing the extent of spread to nearby lymph nodes, and M describing metastasis.

Differential Diagnosis

• Chronic or Focal Pancreatitis: May mimic pancreatic ductal adenocarcinoma, especially when a mass is present. However, in chronic pancreatitis, clinical features like a long-standing history of alcohol abuse and repeated episodes of pancreatitis, coupled with imaging findings of calcification and ductal dilation are characteristic and differentiate it from pancreatic cancer.
• Pancreatic Neuroendocrine Tumour (pNET): These are typically hypervascular on contrast-enhanced imaging and may secrete hormones leading to specific clinical syndromes, unlike PAC. In addition, the use of specific stains such as chromogranin and synaptophysin can help differentiate pNETs from PDAC. Insulinomas are usually smaller (< 1 cm) compared with gastrinomas (~ 3 cm). Calcification seen in 15% (vs. rare in adenocarcinoma).
• Pancreatic Serous Cystadenoma: These are benign tumours which often present as a multicystic mass in the pancreas. They lack the solid component usually seen in PDAC on imaging and have a honeycomb appearance.
• Pancreatic Mucinous Cystadenoma: Differentiation from PAC can be challenging if these tumours manifest as cystic lesions with a solid component. Typically presents as a single large cyst with a clear, thick, mucinous fluid.
• Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN): Often presents with a dilated main pancreatic duct or side branches filled with mucin, a feature not seen in PAC. However, these can also coexist with PAC or progress to invasive carcinoma, and thus differentiation may be challenging.
• Autoimmune Pancreatitis (AIP): Whilst characteristically appears as diffuse sausage-like enlargement of the pancreas with delayed enhancement, AIP can also appear mass-like mimicking adenocarcinoma. The pancreatic duct however penetrates the mass causing duct narrowing without abrupt cut-off and does not cause distal duct dilatation, unlike adenocarcinoma. It responds dramatically to steroids, which is not seen in PAC.
• Metastases to the Pancreas: Metastatic disease to the pancreas most commonly originates from renal cell carcinoma, lung cancer, breast cancer, melanoma and colon cancer. The patient’s known history of a primary malignancy, multiple lesions in the pancreas, and the presence of lesions elsewhere in the body can suggest this diagnosis.

Management

Pancreatic cancer resectability (imaging criteria):

• Resectable: No contact with SMA, CA, CHA, SMV/PV; or ≤180° contact with SMV/PV without narrowing.
• Borderline: ≤180° contact with SMA/CA; short CHA contact (reconstructable); >180° SMV/PV contact or short occlusion (reconstructable).
• Unresectable: >180° contact with SMA/CA; unreconstructable CHA involvement; unreconstructable SMV/PV occlusion.

Treatment

• The mainstay of treatment for PAC is surgical resection (Whipples procedure, pancreaticoduodenecotmy), if the tumour is deemed resectable based on its extent and the patient’s overall health status.
• Adjuvant chemotherapy is typically given following surgery.
• For unresectable tumours, treatment options include palliative chemotherapy and radiation therapy.
• Invasion of the hepatic artery is widely recognised as an absolute contraindication to curative surgical resection.
• Other features which may be unsuitable for curative resection are distant metastases, ascites, distant organ invasion, SMA/coeliac/aortic invasion and involved lymph nodes outside the boundaries of the resection
• Invasion of the splenic and portal veins with partial occlusion are relative contraindications. Invasion of the second part of the duodenum is not a contraindication as it is resected at surgery.