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Pancreatic carcinoma

Cancer of the pancreas.

Cancer of the pancreas.

Pancreatic carcinoma refers to cancerous cells forming in the pancreas. Most often cancer forms in the exocrine pancreas, particularly in the ductal epithelial cells, which case it’s referred to as pancreatic adenocarcinoma.


Epidemiology

Incidence:

  • 14th M/C cancer worldwide
  • 7th highest cause of cancer mortality worldwide
Global mortality and incidence rates of pancreatic cancer
Global mortality and incidence rates of pancreatic cancer. Estimated age-standardized rates (ASRs) of mortality (part a) and incidence (part b) for both sexes (per 100,000 persons) in 2012 | Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 29February 2016.

Survival rates:

  • Average survival: 1-2 years
  • 5-year survival rate ~ 6%
    • Only 20% of patients with pancreatic cancer have surgically resectable disease at time of presentation
    • After successful resection 27%
Pancreatic cancer, age-standardized 1-year and 5-year net survival
Pancreatic cancer, age-standardized 1-year and 5-year net survival, adults (age: 15 – 99 years), England and Wales 1971 – 2011 | Cancer Research UK, https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/survival#ref-2

Etiology

Non-modifiable risk factors:

  • Male (♂ 5.5 : ♀ 4.0)
  • Age (> 65 years in 90% cases)
  • African-American race (↑ 50-90% risk)
  • Non-O blood group

Modifiable risk factors:

  • Smoking (↑ 74% risk in current smokers & ↑ 20% risk in former smokers): Smoking cessation remains the only recommended measure for the prevention of pancreatic cancer.
  • High-fat/low-fibre diet + ↑ red-meat
  • Obesity
  • Occupational exposure (industrial/toxic metals)
  • Alcohol (indirect link: linked to chronic pancreatitis which is linked to pancreatic cancer)

Assocaited conditions:

  • Diabetes (↑ 2x risk)
  • Chronic pancreatitis (5% develop to cancer)
  • Liver cirrhosis

Syndromic associations:

  • Peutz–Jeghers syndrome (STK11/LKB1 gene)
  • Hereditary pancreatitis (PRSS1 gene)
  • Familial atypical multiple mole melanoma (CDKN2A gene)
  • Lynch syndrome (MSH2, MLH1, MSH6, PMS and PMS2 genes)
  • Familial pancreatic cancer
  • Cystic fibrosis (CFTR gene)
  • Breast and ovarian cancer syndrome (BRCA1, BRCA2 and PALB2 genes)
  • Ataxia telangiectasia (ATM gene)
  • Li–Fraumeni syndrome (TP53 gene)

Familial pancreatic cancer (7–10% cases have family history):

Families in which a pair of first-degree relatives have been diagnosed with pancreatic tumours (they have an 80% increased risk of developing pancreatic adenocarcinoma compared with individuals with no reported family history)
Gene alterations in pancreatic cancer
Gene alterations in pancreatic cancer: a) Commonly altered genes in pancreatic cancer include KRAS, CDKN2A, TP53 and SMAD4. Activating (KRAS) and inactivating (CDKN2A, TP53 and SMAD4) mutations as well as homozygous deletions and other mechanisms of gene inactivation, such as promoter hypermethylation, are taken into account. b) Less commonly mutated genes in pancreatic cancer determined using MutSig analysis. c) Pancreatic cancer subtypes have been proposed based on the number and location of structural rearrangements. Stable genome tumours have few (200 structural genome variants. Locally rearranged tumours are defined by a large number of events localized to 1–3 chromosomes. | Kleeff, J., Korc, M., Apte, M. et al. Pancreatic cancer. Nat Rev Dis Primers 2, 16022 (2016). https://doi.org/10.1038/nrdp.2016.22

Pathophysiology

Premalignant lesions:

  • Pancreatic intraepithelial neoplasia (PanIN) (M/C precursor): Arise from small (<0.5 cm) pancreatic ducts
  • Intraductal papillary mucinous neoplasm (IPMN): Arise from main pancreatic duct or one of the side branches
  • Mucinous cyst neoplasms
PanIN progression model, showing genetic alterations
PanIN progression model, showing genetic alterations | Vincent, A., Herman, J., Schulick, R., Hruban, R. H., & Goggins, M. (2011). Pancreatic cancer. Lancet (London, England), 378(9791), 607–620. https://doi.org/10.1016/S0140-6736(10)62307-0
Precursor lesions of pancreatic cancer: pancreatic intraepithelial neoplasia (PanINs)
Precursor lesions of pancreatic cancer: pancreatic intraepithelial neoplasia (PanINs). PanINs represent progressive stages of neoplastic growth that precede the onset of the invasive carcinoma. The progression from low-grade lesions to carcinoma (from the left to the right) is associated with an increasing number of genetic alterations. Lines represent the stage of onsent of these alterations; the thickness of the line indicates the frequency of the alteration; whereas the colour corresponds to the type of alteration (green, activation; red, loss of function). | Corbo, V., Tortora, G., & Scarpa, A. (2012). Molecular pathology of pancreatic cancer: from bench-to-bedside translation. Current drug targets, 13(6), 744–752. https://doi.org/10.2174/138945012800564103

Histopathology:

More than 90% of adenocarcinoma of the pancreas are duct cell adenocarcinomas with other types being cystadenocarcinoma and acinar cell carcinoma. Two-thirds arise in the pancreatic head; one-third arise in the rest (body and tail of pancreas).
Common types of pancreatic cancer
Common types of pancreatic cancer. Adenocarcinomas comprise the majority of pancreatic neoplasms (75–80% of tumours surgically resected at the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, over three decades). Adenocarcinomas are characterized by atypical neoplastic glands in a dense stroma (part a). The next most frequently occurring pancreatic neoplasms are neuroendocrine tumours (15–20%; characterized by a nested growth pattern, ‘salt and pepper’ nuclei and expressing the neuroendocrine markers synaptophysin and chromogranin) (part b); colloid carcinomas (2%; characterized by the formation of pools of mucin in the stroma) (part c); solid-pseudopapillary tumours (2%; characterized by poorly cohesive cells) (part d); acinar cell carcinomas (1%; characterized by cells with granular cytoplasm and a single prominent nucleoli) (part e); and pancreatoblastomas (0.5%; characterized by neoplastic cells with acinar differentiation and squamoid nests) (part f). The remaining tumours include variants such as adenosquamous, hepatoid, medullary, signet ring cell and undifferentiated carcinomas. | Kleeff, J., Korc, M., Apte, M. et al. Pancreatic cancer. Nat Rev Dis Primers 2, 16022 (2016). https://doi.org/10.1038/nrdp.2016.22
  • Adenocarcinomas (M/C. 75–80%): Characterized by atypical neoplastic glands in a dense stroma
    • Adenocarcinoma variants (rare): Adenosquamous, hepatoid, medullary, signet ring cell and undifferentiated carcinomas
  • Neuroendocrine tumours (15–20%): Characterized by a nested growth pattern, ‘salt and pepper’ nuclei and expressing the neuroendocrine markers synaptophysin and chromogranin
  • Colloid carcinomas (2%): Characterized by formation of pools of mucin in the stroma
  • Solid-pseudopapillary tumours (2%): Characterized by poorly cohesive cells
  • Acinar cell carcinomas (1%): Characterized by cells with granular cytoplasm and a single prominent nucleoli
  • Pancreatoblastomas (0.5%): Characterized by neoplastic cells with acinar differentiation and squamoid nests

Clinical features

Early-stage pancreatic cancer is usually clinically silent, and disease only becomes apparent after the tumour invades surrounding tissues or metastasises to distant organs. Most people who present with symptoms attributable to pancreatic cancer have advanced disease

  • Painless jaundice (70% cases) (due to obstruction of the common bile duct from the pancreatic head tumor)
  • Weight loss (90% cases) (arise from anorexia, maldigestion from pancreatic ductal obstruction, and cachexia)
  • Abdominal pain (75% cases)
Pancreatic cancer: Signs Symptoms
Dóra, I. (2017). Pancreatic cancer – the silent killer – Tétékás Nyúz. [online] Nyuz.elte.hu. Available at: http://nyuz.elte.hu/pancreatic-cancer-the-silent-killer/ [Accessed 26 May 2017]

Tumour at the head of the pancreas:

  • Gastric-outlet obstruction: Nausea and vomiting
  • Biliary obstruction:
  • Pancreatic-duct obstruction: Recurrent pancreatitis

Endocrine tumours:

  • New-onset diabetes (25% case) (most people with new-onset diabetes, however, do not have pancreatic cancer)
  • Impaired glucose tolerance (40% cases)

Specific signs:

  • Mid-epigastric pain
    • Radiates to lower back 
    • Worse when lying flat
  • Trousseau sign of malignancy: Migratory clots felt as small lumps under skin
  • Courvoisier sign: Gallbladder enlarged & palpable (non-tender)
    • D/D gallstones (tender enlargement)
  • Recurrent deep vein thrombosis (DVT) (due to hypercoagulability, indicative of malignant disease)

Diagnosis

The majority of cases present late, with either locally advanced or metastatic disease

Diagnostic algorithm for pancreatic cancer
Diagnostic algorithm for pancreatic cancer. Laboratory investigations include a complete blood count (CBC), liver enzyme tests for biliary obstruction, and fasting glucose and glycated hemoglobin (HbA1C) tests to monitor for new onset or worsening diabetes. A transabdominal ultrasound can be performed for patients presenting with jaundice or nonspecific abdominal pain, followed by computed tomography (CT) if suspicious for pancreatic cancer. Patients with contraindications to CT, intolerance to contrast or in whom resectability is questioned can undergo magnetic resonance imagining (MRI). Endoscopic retrograde cholangiopancreatography (ERCP) is not routinely used, but cytologic brushings for diagnosis can be taken in those with cholangitis and an unknown pancreatic mass, or with jaundice who are unfit for immediate surgery. Endoscopic ultrasound- or CT-guided biopsies are used when diagnosis is unclear after imaging, in unresectable cases before palliative treatment or before neoadjuvant treatment. *Painless jaundice, pain in the right–upper quadrant or epigastric pain, indigestion, early satiety, steatorrhea, weight loss, abdominal mass. Dashed lines indicate imaging modalities that can be contained but are not routinely necessary. | Kanji, Z. S., & Gallinger, S. (2013). Diagnosis and management of pancreatic cancer. CMAJ : Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne, 185(14), 1219–1226. https://doi.org/10.1503/cmaj.121368

Serum markers:

Non-specific, as similar in smokers.
  • ↑ Serum amylase
  • ↑ Serum lipase
  • ↑ CA 19-9 Antigen (immune surveillance)
  • ↑ CEA (glycoprotein involved in cell adhesion)
  • Obstructive jaundice:
    • ↑ Bilirubin
    • ↑ Alkaline phosphatase (ALP)
    • ↑ Transaminase

Barium studies:

  • Frostberg reverse/inverted 3 sign: Broadening of the duodenal loop with a ‘puckering’ around the ampulla of Vater, classically associated with pancreatic adenocarcinoma at the head of the pancreas
Frostberg reverse/inverted 3 sign
Frostberg reverse/inverted 3 sign: Broadening of the duodenal loop with a ‘puckering’ around the ampulla of Vater, classically associated with pancreatic adenocarcinoma at the head of the pancreas

Multidetector CT (MDCT):

Best imaging modality to diagnose and evaluate the extent of disease including perivascular extension and distant metastasis. Not preferred as multiple imaging studies required during treatment which will expose patient to unnecessary amounts of radiation
Axial CT image with i.v. contrast and added color. Cross lines towards top left surround a macrocystic adenocarcinoma of the pancreatic head.
Axial CT image with i.v. contrast and added color. Cross lines towards top left surround a macrocystic adenocarcinoma of the pancreatic head. | By MBq at German Wikipedia – Transferred from de.wikipedia to Commons.(Original text: selbst erstellt), Public Domain, https://commons.wikimedia.org/w/index.php?curid=2163329

Secretin-enhanced MRI/MRCP:

Preoperative evaluation of pancreatic cancer and the assessment of vascular invasion.
  • Double duct sign
MR cholangiopancreatography shows a distended gallbladder, dilatation of the common bile duct (long arrow) and main pancreatic duct (short arrows) consistent with a double duct sign
MR cholangiopancreatography shows a distended gallbladder, dilatation of the common bile duct (long arrow) and main pancreatic duct (short arrows) consistent with a double duct sign. A mass is noted in the region of the ampulla of Vater (arrowhead) and a periampullary tumor (black arrow) is confirmed on upper gastrointestinal endoscopy (inset). | Agrawal, S., & Vohra, S. (2017). Simultaneous Courvoisier’s and double duct signs. World Journal of Gastrointestinal Endoscopy, 9, 425 – 427.

ERCP + EUS ± biopsy:

Level of biliary or pancreatic obstruction can be delineated. In some case, placement of a biliary stent can help relieve symptoms of jaundice.
  • Endoscopic retrograde cholangiopancreatography (ERCP): Contrast dye is injected into the biliary ducts and pancreatic duct with an endoscope
  • Endoscopic ultrasound (EUS): Delineate the pancreatic mass and can be used to biopsy the mass under ultrasound guidance.
  • Fine needle aspiration biopsies can be done of suspicious lesions for the pathologic specimen
EUS-guided fine-needle aspiration with a 22-gauge needle (yellow arrow points to the needle) of the same pancreatic head tumor via transduodenal approach
EUS-guided fine-needle aspiration with a 22-gauge needle (yellow arrow points to the needle) of the same pancreatic head tumor via transduodenal approach. The tip of the needle is seen inside the mass. | Vareedayah, A. A., Alkaade, S., & Taylor, J. R. (2018). Pancreatic Adenocarcinoma. Missouri medicine, 115(3), 230–235.

Fine needle aspiration biopsy:

Cellular components of Pancreatic Cancer
Cellular components of Pancreatic Cancer. H&E and immunohistochemical-stained sections of pancreatic cancer tissues: (A) Ductal adenocarcinoma composed of epithelial neoplastic cells (arrow) embedded in a fibrous stroma (asterisk); (B) Immunostaining of Pancreatic stellate cells with SMA antibody (alpha-smooth muscle actin). | Corbo, V., Tortora, G., & Scarpa, A. (2012). Molecular pathology of pancreatic cancer: from bench-to-bedside translation. Current drug targets, 13(6), 744–752. https://doi.org/10.2174/138945012800564103

Differential diagnosis:

  • Acute/chronic pancreatitis
  • Cholangitis
  • Cholecystitis
  • Choledochal cyst
  • Peptic ulcer disease
  • Cholangiocarcinoma
  • Gastric cancer

TNM staging:

Radiologic staging:

MD Anderson Cancer Center Clinical/ Radiologic Staging of Pancreatic Cancer
MD Anderson Cancer Center Clinical/ Radiologic Staging of Pancreatic Cancer

Management

Close proximity to major blood vessels results in readily invadsion by tumour. This means that 80%-85% of tumours are not resectable at the time of presentation.

Treatment algorithm for pancreatic cancer
Treatment algorithm for pancreatic cancer. | Kanji, Z. S., & Gallinger, S. (2013). Diagnosis and management of pancreatic cancer. CMAJ : Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne, 185(14), 1219–1226. https://doi.org/10.1503/cmaj.121368

Surgical resection:

Only potential cure for pancreatic cancer, although rates of recurrence are high with inevitably dismal rates of long-term survival. Treatment depends on location of the primary tumour: the pancreatic head, neck or uncinate process (70%); the body or tail (20%); or multifocal disease (10%)
  • Pancreatico-duodenectomy (Whipple’s procedure): Lesions of head, neck and uncinate process
  • Distal pancreatectomy: Lesions of the body or tail
  • Total pancreatectomy: Multifocal disease

Summary:

Pancreatic cancer
Kleeff, J., Korc, M., Apte, M., La Vecchia, C., Johnson, C. D., Biankin, A. V, … Neoptolemos, J. P. (2016). Pancreatic cancer. Nature Reviews Disease Primers, 2(1), 16022. https://doi.org/10.1038/nrdp.2016.22

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