Pancreatic Cancer

Approximately 57,600 people develop exocrine pancreatic cancer each year in the United States.[GLOBOCAN database] Almost all are expected to ultimately die from the disease. The majority of exocrine pancreatic tumours (85%) are adenocarcinomas arising from the ductal epithelium.

Surgical resection offers the only chance of cure for exocrine pancreatic cancer, but only 15-20% of patients have potentially resectable disease at presentation. Local unresectability is usually—though not always—due to vascular invasion.

Prognosis remains poor, even for those undergoing microscopically complete (R0) resection. With high rates of both systemic (> 80%) and local (> 20%) recurrence after surgery alone, surgical treatment is often supplemented with systemic chemotherapy, radiation therapy (RT), or combined chemoradiotherapy, either prior to (neo-adjuvant) or following (adjuvant) surgical resection, in an effort to improve rates of cure (Ryan, 2019).

Traditionally, the characteristic combination of epigastric and back pain, jaundice, and weight loss suggested cancer of the pancreas. The patient who presents early, however, may only volunteer one of these symptoms, and then only more vaguely; instead presenting with a general and gradual deterioration in well being.

Conversely, not all painless jaundice is from pancreatic cancer; whether accompanied by weight loss or not. This leaves a clinician wandering whether a patient with vague upper abdominal pain and perhaps early satiety—one who might have gastritis, for instance—could indeed have a neoplasm of the pancreas. But you can not (and should not) request an upper abdominal CT scan in everyone with upper abdominal pain.

But things do not, for the most part, happen out of the blue. Nothing occurs in a vacuum. Take a good history. Do not ask questions randomly, as part of a system review (although that may help towards the end of the interview); as if going through the motions. Use directed questions to actively probe  a diagnostic possibility. In that way. most primary-care practitioners will say, the diagnosis in most cases should be clear after taking of the history alone. Generally speaking, patients will have one or more clues  in the history to alert to the possibility of their condition. If you listen carefully, the patient will “reveal” their diagnosis in the words they say. A clinician remains ever alert to this probability, keeping an open mind while surveying the patient for clues. Remaining alert requires also great sensitivity,  combined with a process of diagnostic elimination that refines the specificity. At all times, remain also sensitive to how  this is actuated; at all times remain sensitive to the patient as person.

Historically, medicine has established precedents to guide the approach to relatively common conditions, such as pancreatic cancer, to inform the pre-test probability.  In pancreatic cancer, for instance, four patients out of five will be over 60 years old. Without using that information alone to foreclose on any diagnosis, that information alone does, however, serve in distinguishing the person in front of you from, say, the one that was seen just before. In everyday practice, it pays to use an odds “logic.” The odds logic looks at odds and utilised odds ratios. Every decision making process is informed by some sort of odds equation, whether scientifically-quantified or one qualitatively obtained from personal observation (anecdotal, empiric observation).

Consider some of the information which may present a “clue” during the consultation.

Who is at risk of Pancreatic Cancer?

Non-randomised controlled-trial data show people exposed to various petrochemicals, including benzidine, gasoline derivatives, or 2-naphtalamine (manufacturing plants) carry a five-fold increase in risk of pancreatic cancer; those with chronic pancreatitis a four-fold increase in risk; while the risk for someone who smokes is about 1.5 x that of a non-smoker.¹ It takes a decade, perhaps two, of smoking abstinence to return risk to normal levels.

• petrochemicals: 5 x  ± nickel, insecticides, radiation, heavy metal exposure
• chronic (and hereditary) pancreatitis: 4 x; patients are younger, often < 30 years old
• smokers 1.5 x: the heavier the higher the risk

Apart from such environmental exposure, there can be a hereditary predisposition to pancreatic cancer. Two or more first-degree relatives who develop pancreatic cancer before the age of 50 confers an increased risk of pancreatic cancer. The risk of pancreatic cancer increases if there is a history of familial breast (BRCA), ovarian or colon cancer (FAP, HNPCC), or familial melanoma (FAMMM). African-Americans and Ashkenazi Jews also show a higher incidence of pancreatic cancer. Obesity is also a risk factor.²

How might the patient with pancreatic cancer present?

Because ductal adenocarcinoma arises predominantly from the head of the pancreas, they are more likely to produce problems like acute pancreatitis or biliary tract obstruction—such patients generally present with jaundice or pain (> 50%) or both; hence the triad of symptoms first noted above. I guess that means they are also more likely to present early. Nonetheless, most pancreatic cancers have extended beyond the organ at the time of diagnosis, often perineurally and lymphatically (even distant, e.g. the so-called Virchow’s node of the left supraclavicular fossa, via the thoracic duct).

Painless jaundice is, however, a concerning sign, particularly with a palpable, non-tender gall-bladder (Courvoisier’s Law), in which case pancreatic cancer suddenly becomes probable rather than possible—more than half of those with cancer of the head of the pancreas have an enlarged, non-tender gall bladder. In the examination, the patient’s liver, their abdominal peritoneum, and their lungs may disclose distant metastatic disease.¹ Otherwise, new-onset  diabetes may provide a clue to  the presence of an expanding pancreatic lesion. Recall also that malignancy confers in the patient a hypercoagulable state. In this respect, pancreatic cancer has traditionally associated with a migrating superficial thrombophlebitis (Trousseau’s syndrome). A patient with migrating superficial thrombophlebitis must be investigated, looking for what may be predisposing them to this thrombotic tendency–malignancy remains a distinct possibility.

Start investigation with an Upper-Abdominal Ultrasound Scan (USS). But high-resolution (helical) CT or Magnetic Resonance Imaging will make the presumptive diagnosis to help plan surgery.  Endoscopic Retrograde Cholangiopancreatography (ERCP) can help stage disease and can be useful therapeutically–e.g. pancreatic or biliary stenting. Serological markers are also highly corroborative, with a sensitivity and specificity of up to 90%. Test for:

• Carbohydrate antigen (CA) 19-9: useful for monitoring treatment success
• CAM 17-1: 86% sensitivity, 91% specificity; although the ranges are wide [Yiannakou (1997); Lee (2013); Xing (2018)]
• Carcinoembryonic Antigen (CEA): prognostic; sensitivity and specificity too low to be used diagnostically on its own, rather used to corroborate CA19-9 [Meng (2017); Lee (2013)]

Disease Stageing

Apart from tumour size, the Union for International Cancer Control (UICC) system considers lymph node metastases as the most important prognostic factor. There is also a more comprehensive Japanese Pancreas Society (1996) stageing system [(Isaji (2004)].

Late presentation of most pancreatic cancers affords a poor prognosis (5-year survival is under 5%) and means surgery offers the only potential cure through partial pancreaticoduodenectomy, a Whipple’s procedure. More extensive procedures still, can also be performed where there is lymphatic spread. Parodically, cancers in the body or tail of the pancreas are more problematic to remove, requiring left subtotal pancreatic resection with a 2-cm margin. Such surgery comes with significant risk of morbidity and mortality. Adjuvant and neo-adjuvant therapies offer hope to those with unresectable lesions.³

References

1. Pancreatic Cancer, Dieter Birk and Hans G Beger. In Surgical Treatment: Evidence-Based and Problem-Oriented.
2. Genetic Mutations, Risk factors, About Pancreatic Cancer – pancreatic Cancer Action Network
3. Adjuvant therapy for pancreas cancer in an era of value based cancer care, Ahn et al. Cancer Treatment Reviews 42, January 2016, Pages 10-17.
4. Treatment for potentially resectable exocrine pancreatic cancer, UpToDate
5. Gentile and Greenlund. 66-Year-Old Woman With Painless Jaundice. Mayo Clin Proc. 2012 Oct; 87(10): 1021–1024. doi:  10.1016/j.mayocp.2012.03.018.
6. Staging systems for pancreatic cancer: Differences between the Japanese and UICC systems, Kobari and Matsuno – J Hep Bil Pancr Surg (1998) 5:121–127
7. Oxford Handbook of General Practice, 3rd Edition, Simon, Everitt, van Dorp – Oxford University Press, 2010
8. Murtagh’s General Practice, 4th Ed. McGraw-Hill, 2007
9. Isaji, Shuji; Kawarada, Yoshifumi; Uemoto, Shinji. Classification of pancreatic cancer: comparison of Japanese and UICC classifications. Pancreas 2004 Apr; 28(3):231-4. doi: 10.1097/00006676-200404000-00003.
10. Ryan, David P. and Mamon, Harvey. “Treatment for potentially resectable exocrine pancreatic cancer.” Version 80.0. UpToDate. Aug 23, 2019. https://www.uptodate.com/contents/treatment-for-potentially-resectable-exocrine-pancreatic-cancer/print.

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