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Pancreatic cancer: Clinical presentation, pitfalls and early clues

Article  in  Annals of Oncology · February 1999

DOI: 10.1093/annonc/10.suppl_4.S140 · Source: PubMed

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Pancreatic cancer: Clinical presentation, pitfalls and early clues
E. P. DiMagno
Division of Castroenterology and Gastroenterology Research Unit, Mayo Clinic, Mayo Medical School, and Mayo Foundation, Rochester, MN USA
Summary
The diagnosis of pancreatic cancer usually depends upon
symptoms; consequently it is late when there is no chance for cure.
At this point, pain, anorexia, early satiety, sleep problems and
weight loss are present. Back pain also may be prominent, which
predicts unresectability and shortened survival after resection.
However, earlier recognition of symptoms of pancreatic cancer
might improve early detection of the cancer. For example, 25% of
patients have symptoms compatible with upper abdominal disease
up to 6 months prior to diagnosis and 15% of patients may seek
medical attention more than 6 months prior to diagnosis. These
symptoms erroneously may be attributed to problems such as
irritable syndrome. Symptoms, however, may be less common. For
example a quarter of patients with pancreatic cancer may have no
pain at diagnosis, and half, particularly those with pancreatic head
tumors, may have little pain compared with patients with body-tail
tumors. However, if the tumor is suspected because of predisposing
conditions, earlier diagnosis may be possible. These conditions
include diseases such as chronic pancreatitis, intraductal papillary
mutinous tumor (BPMT), and recent onset of diabetes mellitus,
particularly if the diabetes occurs during or beyond the sixth
decade. In addition inherited syndromes also are associated with an
Introduction
Pancreatic cancer is a relatively common and deadly tumor.
In a community-based population, the age adjusted incidence
is 8 and 13 per 100,000 person years in women and men,
respectively [1]. It is the fifth and fourth most common
tumor in women and men, respectively, and has the lowest
5-year survival of all tumors in the USA [2]. The overall 5-
year survival in the USA has increased over the past decade,
but is still only 1-3% in whites and 3-5% in blacks [2].
Late diagnosis, resulting in low resection rates (10-20%)
[3], is a major reason for poor survival. Patients who
undergo resection of the tumor have a 10% chance of
surviving 5 years [3]. Five-year survival is related to size of
the resected tumor. In our experience, 5-year survival is -20-
30% if the tumor is <2 cm [4], but 5-year survival is nil if the
tumor is >3 cm [4].
These data give hope that detection of early tumors defined
as ~2 cm or less may increase 5-year survival appreciably. A
major problem is that there is no proven strategy to detect
small, early tumors. Furthermore, even if we had such a
strategy, we don't know if it would improve survival.
Symptoms and signs as clues to pancreatic cancer
Nearly a quarter of a century ago we performed a
prospective clinical trial of diagnostic tests in patients
Annals of Oncology 10 Suppl. 4: S140-S142,1999.
© 1999 Kluwer Academic Publishers. Printed in the Netherlands.
increased risk of pancreatic cancer including familial pancreatic
cancer, hereditary pancreatitis, familial adenomatous polyposis
syndrome (FAP) and familial atypical multiple mole melanoma
(FAMMM) syndrome (hereditary dysplastic nevus syndrome). Of
these conditions, recent onset of diabetes may be the best clue and
should be included in a clinical profile of patients prior to the onset
of symptoms to identify a high-risk group to apply screening
strategies for detection of early disease. Contrary to a clinical
aphorism that pancreatic cancer patients are elderly, lean and
recently may have developed diabetes, we found that patients who
develop pancreatic cancer are overweight prior to onset of
symptoms compared to controls (body mass index, 28 vs 25). Forty
percent had the diagnosis of diabetes made at the time of diagnosis
of pancreatic cancer and more patients with a resectable tumor had
diabetes (58%) compared to patients with locally unresectable or
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metastatic disease (37%). Perhaps, screening overweight persons
who have new-onset diabetes may lead to a diagnosis of
asymptomatic, early, resectable pancreatic cancer.
Key words: CA19-9, diabetes, IAPP (amylin), IPMT, K-ras,
pancreatic cancer, pancreatitis, signs, symptoms
suspected of having pancreatic cancer on the bases of
clinical symptoms and signs [5]. For this study, we selected
patients if they were >35 years old and had two or more of
the following problems for 18 months or less: pain in the
upper abdomen; pain extending to the back or night
awakening; loss of more than 10% of ideal body weight;
obstructive jaundice; or unexplained pancreatitis in patients
beyond 50 years of age. All patients had a gold standard
diagnosis proven at surgery. Of the 70 patients entered into
the study, 30 had pancreatic cancer, and of these only 4 had
a resectable cancer (13%).
These symptoms likely identified patients with advanced
disease. For example, more recently, Krech and Walsh
reported that 82, 64, 62, 54, and 5 1 % of patients who had
unresectable disease had pain, anorexia, early satiety, sleep
problems and weight loss, respectively [6]. In addition, back
pain predicts unresectability and shortened survival after
resection [7].
However, earlier diagnosis might be possible if the onset of
symptoms would give rise to suspicion of pancreatic cancer.
There is support for this hypothesis because symptoms
compatible with upper abdominal disease may be present in
25% of patients up to 6 months prior to diagnosis. Further,
5% of patients may seek medical attention more than 6
months prior to diagnosis [8], but the symptoms may be
attributed erroneously to problems such as irritable syndrome
[9].
Symptoms, however, may be less common. Grahm and

Andren-Sandberg [10] reported that 27% of 46 consecutive
patients with pancreatic cancer had no pain at diagnosis,
53% had little pain, and patients with pancreatic head tumors
had less pain compared with patients with body-tail tumors.
Also, The clinical profile of patients prior to the onset of
symptoms may help to identify a high-risk group to apply
screening strategies for detection of early disease.
Pitfalls
Most patients with symptoms highly suggestive and sensitive
for pancreatic cancer have other problems to explain their
symptoms. In our experience, 57% of patients with these
symptoms have other problems [5]. Thirteen percent had
non-pancreatic, intraabdominal cancers (lymphomas, small
bowel carcinomas, ovarian cancer or uterine cancer) and
44% had non-pancreatic, non-neoplastic disease including
negative laparotomy in 23% (irritable syndrome),
pancreatitis in 13%, and other miscellaneous problems in
11%.
Early clues
Finding early cancers is uncommon because clues for early
cancer have been lacking. Several diseases and inherited
syndromes, however, recently have been identified as having
an increased risk for developing pancreatic cancer. Diseases
include chronic pancreatitis, intraductal papillary mucinous
tumor (EPMT), recent onset of diabetes mellitus, particularly
if the diabetes occurs during or beyond the sixth decade.
Inherited syndromes include familial pancreatic cancer,
hereditary pancreatitis, familial adenomatous polyposis
syndrome (FAP) and familial atypical multiple mole
melanoma (FAMMM) syndrome (hereditary dysplastic
nevus syndrome)
The strongest evidence for the development of pancreatic
cancer in chronic pancreatitis is in hereditary pancreatitis
where the estimated cumulative risk of pancreatic cancer to
age 70 is 40% [11]. Diagnosis of pancreatic cancer in
hereditary pancreatitis is usually after 35. One of the two
specific gene mutations that have been identified for
hereditary pancreatitis [12,13] occur in about 60% of
patients with the disease. Thus, it is possible to screen
families for affected persons and to plan a rational screening
program for detecting pancreatic cancer. The cumulative risk
for pancreatic cancer in patients with chronic pancreatitis is
2% per decade [14]. The relative risk (ratio of observed to
expected cases) ranges from 4 to 16. However, only -1-2%
of pancreatic cancer is due to chronic pancreatitis [14-16].
Intraductal papillary mucinous tumor (IPMT) [17],
commonly confused with chronic pancreatitis [18], is
characterized by dilation of the main pancreatic duct or
branch ducts associated with mucin overproduction. There
may be peripheral lesions consisting of ectatic branch ducts
connected to the main duct or cysts that do not connect with
the main duct [18], which mimic mucinous cystic neoplasm
(MCN). Typical changes evident on CT and ERCP
distinguish IPMT from chronic pancreatitis. At ERCP or CT
there may be characteristic intraductal filling defects mucus
may be seen exuding from the papilla at ERCP [20]. Invasive
141
cancer is present in 25-50% of surgical specimens [18,20],
but even if invasive cancer is not present the lesion is
premalignant, and benign lesions contain several genetic
mutations associated with pancreatic cancer [19,21].
Diabetes mellitus may herald pancreatic cancer, particularly
if the diagnosis of diabetes is made during or beyond the
sixth decade and there is no family history of diabetes [22].
Diabetes is present in 60 [23] to 81% [24] of patients with
pancreatic cancer and most patients are diagnosed within 2
years of recognizing pancreatic cancer. In a recent study
[23], 56% had diabetes diagnosed concomitantly with the
tumor and 16% had the diagnosis of diabetes made 2 years
prior to the diagnosis of the cancer. With a meta-analysis, the
risk of developing pancreatic cancer in patients with diabetes
of more than 1 year's duration was 2.1 (95% CI: 1.6-2.8)
[25]. Sixty-six percent of patients with pancreatic cancer and
diabetes have no family history of diabetes [22].
Some pancreatic cancers are inherited. Seven to 8% of
patients with pancreatic cancer have a family history of
pancreatic cancer, which is an -13-fold increase compared
to 0.6% of controls [26,27]. In a recent prospective.survey of
our pancreatic cancer patients attending a pancreatic clinic,
10% of them had one or more first degree relatives who died
of pancreatic cancer [28]. In familial adenomatous polyposis
syndrome (FAP), there is 4.46 relative risk (95% CI: 1.2-
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11.4) for developing pancreatic cancer in polyposis patients
and in family members at risk, but the absolute risk is
low—21/100,000 person years [29]. Pancreatic cancer risk
is increased in familial atypical multiple mole melanoma
(FAMMM) syndrome (hereditary dysplastic nevus
syndrome) [30] but only in some kindreds [31]. In this
disorder, a gene on chromosome 9p, pl6INK4 has been
implicated in the pathogenesis of the melanoma. However,
risk of pancreatic cancer (13-fold) is only in kindreds with
an impaired function of the p 16INK4 protein (p 16M alleles);
without impaired function of pl6INK4 protein (pl6W
alleles), there is no increased risk for pancreatic cancer.
Many environmental factors are associated with an
increased risk for pancreatic cancer but they are so
ubiquitous that it is impossible to use them as clues for
diagnosis. The interpretation of most data suggests that
environmental risks associated with pancreatic cancer may
be related to exposure to aromatic amines. For example the
most prominent risk factor is cigarette smoking, and about 30
aromatic amines are in cigarette smoke [32]. Similarly,
carcinogenic and mutagenic heterocyclic aromatic amines
present in cooked meat and fish (formed during cooking as
pyrolysis products of amino acids and proteins) [33-35] may
be the basis for the association between meat and fish
consumption and risk of pancreatic cancer [36-38].
Occupations (chemists, petrochemical workers, hairdressers
and rubber workers) with an increased exposure to aromatic
amines have a greater risk of pancreatic cancer [39,40].
Conversely, some plant components (dithiolthiones and
limonene) may induce glutathione transferase and increase
levels of glutathione, which may inhibit mutageneic
activation of heterocyclic amines [41,42], and explain why
eating fruits and vegetables may protect against development
of pancreatic cancer.
The clinical profile of patients prior to the onset of
symptoms may help to identify a high-risk group to apply
screening strategies for detection of early disease. A clinical
 142
aphorism is that pancreatic cancer patients are elderly, lean
and recently may have developed diabetes. Contrary to this
aphorism, in an ongoing study [43] we found that patients
who develop pancreatic cancer are overweight prior to onset
of symptoms compared to controls (body mass index, 28 vs
25). Forty percent had the diagnosis of diabetes made at the
time of diagnosis of pancreatic cancer and more patients
with a resectable tumor had diabetes (58%) compared to
patients with locally unresectable or metastatic disease
(37%). Perhaps, screening overweight persons who have
new-onset diabetes may lead to a diagnosis of asymptomatic,
early, and resectable pancreatic cancer.
Ideally, all patients at risk for pancreatic cancer should be
investigated and followed closely for development of
pancreatic cancer. However, it is unknown when to begin
screening and current tumor markers are too insensitive and
to detect early pancreatic cancer. However, combination of
tumor markers may increase sensitivity for detection of small
tumors. Recent studies in our unit have demonstrated that
IAPP (amylin) in blood and K-ras measured in DNA
extracted from pancreatic secretions obtained at endoscopy
are approximately 50% sensitive for detection of pancreatic
cancer, but in comparison to CA 19-9 sensitivity is
independent of stage of tumor [44]. Thus, a battery of
markers may increase sensitivity for detecting small tumors,
particularly in patients who are obese and have recent onset
of diabetes [43].
Currently, specific recommendations cannot be given. It
seems prudent, however, to initiate screening 10 years before
the age that pancreatic cancer was first diagnosed in familial
pancreatic cancer and in the various syndromes, and at age
35 in hereditary pancreatitis. Spiral CT and EUS have the
best sensitivity for detecting pancreatic cancer, and are the
imaging tests that should be considered for screening.
However, the differentiation between inflammatory and
neoplastic masses with imaging tests is problematic. This
topic, however, is beyond the scope of this review.
References
1. Riela A, Zinsmeister AR, Melton LJ et al. Increasing incidence of pancreatic
cancer among women in Olmsted County, Minnesota, 1940 through 1988.
Mayo Clin Proc 1992; 67: 839-645.
2. Parker SL, Tong T, Bolden S et aL Cancer statistics 1996. CA A Cancer Journal
for Clinicians 1996; 46: 5-27.
3. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base
report on pancreatic cancer. Cancer 1995; 76: 1671-7.
4. Nitecki SS, Sar MG, Colby TV et al. Long-term survival after resection for
ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 1995;
221:59-66.
5. DiMagno EP, Malagelada J-R, Taylor WP et al. A prospective comparison of
current diagnostic tests in pancreatic cancer. N Engl J Med 1977; 97:737-42.
6. Krech RL, Walsh D. Symptoms of pancreatic cancer. J Pain Symptom
Management 1991; 6: 360-7.
7. Ridder GJ, Klempnauer J. Back pain in patients with ductal pancreatic cancer.
Its impact on resectabilit and prognosis after resection. Scared J Gastroenterol
1995; 30: 1216-1220.
8. Tarpila E, Borch K, Kullman E et al. Pancreatic cancer. Ann Chir Gynaecol
1986; 75:146-50.
9. Svendsen JH, Munck LK, Andersen JR. Irritable bowel syndrome—prognosis
and diagnostic safety. A 5-year follow-up study. Scand J Gastroenterol 1985; 20:
415-8.
10. Grahm AL, Andren-Sandberg A. Prospective evaluation of pain in exocrine
pancreatic cancer. Digestion 1997; 58:542-9.
11. Lowenfels AB, Maisonneuve P, DiMagno EP et al. International Hereditary
Pancreatitis Study Group: Hereditary pancreatitis and the risk of pancreatic
cancer. J Nad Cancer Inst 1997;89:442-6.
12. Whitcomb DC, Gorry MC, Preston RA et al. Hereditary pancreatitis is caused
by a mutation in the canonic trypsinogen gene. Nature Genetics 1996; 14:141-
5.
View publication stats
13. Gorry MC, Gabbaizedeh D, Furey W et al. Mutations in the cationic trypsinogen
gene are associated with recurrent acute and chronic pancreatitis.
Gastroenterology 1997; 113: 1063-8.
14. Lowenfels AB, Maisonneuve P, Cavallini G et aL International Pancreatitis
Study Group. Pancreatitis and the risk of pancreatic cancer. New Engl J Med
1993; 328:1433-7.
15. Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer.
Gastroenterology 1995; 109: 247-51.
16. Karlson BM, Ekbom A, Josefsson S et al. The risk of pancreatic cancer
following pancreatitis: an association due to confounding? Gastroenterology
1997; 113:587-92.
17. Ohashi K, Takagi K. ERCP and imaging diagnosis of pancreatic cancer.
Gastrointestinal Endosc 1997; 77:1493-5 (in Japanese with English abstract).
18. Loftus EV Jr, Olivares-Pakzad BA, Bans KP et al. Intraductal
papillary-mucinous tumors of the pancrtas-clinicopathologic features, outcome,
and nomenclature. Gastroenterology 1996; 110:1909-18.
19. Rivera JA, Femandez-del Castillo C, Pins M et al.. Pancreatic mucinous ductal
ectasia and intraductal papillary neoplasms. A single malignant
clinicopathologic entity. Ann Surg 1997; 225:637-44.
20. McDowell RK, Gazelle GS, Murphy BL et al. Mucinous ductal ectasia of the
pancreas. J Computer Assisted Tomography 1997; 21: 383-8.
21. Sessa F, Solcia E, Capella C et al. Intraductal papillary-mucinous tumours
represent a distinct group of pancreatic neoplasms: an investigation of tumour
cell differentiation and K-ras. p53 and c-erbB-2 abnormalities in 26 patients.
Virchows Arch 1994; 425:357-67.
22. Gullo L, Pezzilli R, Morselli-Labate AM, Italian Pancreatic Cancer Study Group.
Diabetes and the risk of pancreatic cancer. New Engl J Med 1994; 331 :81-4.
23. Permert J, Larsson J, Westermark GTet al. Islet amyloid polypeptide in patients
with pancreatic cancer and diabetes. New Engl J Med 1994; 330: 313-8.
24. Schwarts SS, Zeidler A, Moossa AR et al. A prospective study of glucose
intolerance, insulin, C-peptide, and glucagon in patients with pancreatic
carcinoma. Am J Dig Dis 1978; 23: 1107-14.
25. Everhan J and Wright D. Diabetes mellitus as ariskfactor for pancreatic cancer.
J Am Med Assoc 1995; 273: 1605-9.
26. Ghadiri&n P, Boyle P, Simard A et al. Reported family aggregation of pancreatic
Downloaded from annonc.oxfordjournals.org by guest on July 12, 2011
cancer within a population-based case-control study in the Francophone
community in Montreal, Canada. Intematl J Pancreatol 1991; 10: 183-96.
27. Lynch HT, Rtzsimmons ML, Smyrk TC et al. Familial pancreatic cancer
clinicopathologic study of 18 nuclear families. Am J Gastroenterol 1990; 85:54-
60.
28. Norton ID, Petersen BT, Miller LJ et al.Frequency of a family history of
pancreatic malignancy in patients with pancreatic malignancy. Pancreas 1998;
17:451.
29. Giardiello FM, Offerhaus GJ, Lee DH et al. Increased risk of thyroid and
pancreatic carcinoma in familial adenomatous polyposis. Gut 1993; 34:1394-6.
30. Lynch HT, Fusaro RM. Pancreatic cancer and the familial atypical multiple mole
melanoma. Pancreas 1991; 6: 127-31.
31. Goldstein AM, Fraser MC, Struewing JP et al. Increased risk of pancreatic
cancer in melanoma-prone kindreds with pl6INK4 mutations. N Engl J Med
1995; 333:970-4.
32. Patrianakos C, Hoffman D. Chemical studies on tobacco smoke LXTV. On the
analysis of aromatic amines in cigarette smoke. J Anal Toxicol 1979; 3:150-9.
33. Norell SE, Ahlbom A, Erwald R et al. Diet and pancreatic cancer a case-control
study. Am J Epidemiol 1986; 124: 894-902.
34. Sugimura T. Carcinogenicity of mutagenic heterocyclic amines formed during
the cooking process. Mutat Res 1985; 150: 33-41.
35. Sugimura T, Sato S. Mutagens-carcinogens in foods. Cancer Res 1983; 43:
2415s-21s.
36. Mack TM, Yu MC, Hanisch R et al. Pancreas cancer and smoking, beverage
consumption and past medical history. J Natl Cancer Inst 1986; 76:49-60.
37. Falk RT, Pickle LW, Fbntham ET et al. Life-style risk factors for pancreatic
cancer in Louisiana: a case-control study. Am J Epidemiol 1988; 128:324-36.
38. Mills PK, Beeson L, Abbey DE et al. Dietary habits and past medical history as
related to fatal pancreas cancer risk among Adventists. Cancer 1988; 61:2578-
85.
39. Mack TM. Pancreas. IN: Schottenenfeld D, Fraumeni JF Jr (eds). Cancer
epidemiology and prevention. WB Saunders Co, Philadelphia, 1982.
40. Falk RT, Pickle LW, Fontham ET et al. Occupation and pancreatic cancer risk
in Louisiana. Am J Int Med 1990; 18: 565-76.
41. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. L Epidemiology.
Cancer Causes and Control 1991; 2: 325-7.
42. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer
Causes and Control 1991; 2:427-42.
43. Chari ST, Miller LJ, DiMagno EP. Elderly, overweight subjects with recent
onset diabetes-a highriskgroup for pancreatic cancer (PC)? Gastroenterology,
in press.
44. Chari S, Klee GG, Miller LJ et al. Sensitivity and specificity of CA19-9 and
islet amyloid polypeptide (IAPP) for symptomatic pancreatic cancer (PC).
Pancreas 1998; 17: 429.
Correspondence to:
E.P. DiMagno
Div. Gastroenterology and Gastroenterology Reserach Unit
Mayo Clinic, Mayo Medical School, and Mayo Foundation
Rochester, MN USA