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Carcinoma of the pancreas refers to
carcinomas of the exocrine pancreas, almost always arising from ductal
epithelial cells.
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Pancreatic Pathology Online
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Exocrine Pancreatic Tumours.
Ductal
adenocarcinoma accounts for almost 90% of all pancreatic cancers; only
about 1% derive from acinar cells.
The remaining
tumours are for the most part of uncertain origin, although rare
connective tissue sarcomas and even rare mixed-cell carcinomas are
reported.
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Rare histologic variants include:
1. Adenosquamous carcinoma
2. Anaplastic carcinoma with giant
cell formation
3. Acinar cell carcinoma (arising
from acinar cells with abundant eosinophilic cytoplasm).
Periampullary
carcinomas
refer to pancreatic carcinomas in the immediate vicinity of the
ampulla of Vater as well as tumours of the most distal common bile duct
and ampulla itself.
Incidence:
Its geographic
distribution is worldwide, with the highest incidence
among male Maoris, Polynesian aborigines of New Zealand, and female
natives of Hawaii.
Its lowest
incidence is in women of India.
Carcinoma of the pancreas accounts
for 5% of all cancer deaths.
Incidence rates are higher in smokers
than nonsmokers.
Alcohol consumption imposes a
modestly increased risk.
Pancreatic
carcinoma is a disease of late life, with the greatest incidence
between 60 to 80 years of age, although its appearance as early as the third
decade is not rare.
Five-year survival is less than 4%.
Pathological Lesions:
Distribution is as follows:
1. Head, 60% ; 2. Body, 15% ; 3. Tail, 5% ; 4. Diffuse or widely spread, 20%.
Tumours may be small and ill defined
or large (8 to10 cm), with extensive local invasion and regional
metastasis.
Microscopically, more or less differentiated glandular
patterns (adenocarcinoma)arise from ductal epithelium, mucus
or non-mucus secreting.
Clinical
features:
Insidious growth occurs over years.
85% are unresectable at
presentation, with a dismal outlook.
First-year mortality exceeds 80%.
Weight loss and pain are typical
presenting symptoms.
Obstructive jaundice develops with tumours in the
head or pariampullary region.
Massive metastasis to the liver occurs
via splenic vein invasion.
Migratory thrombophlebitis (Trousseau sign)
may occur with pancreatic and pulmonary neoplasms or other visceral
cancers.
Carcinomas of
the exocrine pancreas arise from duct cells and, more rarely, acinar
cells.
Prognosis:
The prognosis of
pancreatic carcinoma is so dismal because of the anatomic location
deep in the retroperitoneum, an area in which abundant lymphatic and
venous drainage offers an ample opportunity for early and massive
dissemination of tumor.
Adenocarcinoma
arises anywhere in the anatomic segements of the pancreas, with the
most frequent focus in the head (60%), followed by the body (13%) and
the tail (5%).
In the remaining
22% the pancreas is diffusely involved, a finding that suggests either
late diagnosis or a multicentric origin, or both.
Carcinomas of the
head of the pancreas tend to be smaller and show a more limited spread
to regional lymph nodes and more distant sites than those of the body
and tail.
In 13% of cases
of carcinoma localized in the head, no metastases had occurred at the
time of diagnosis.
 In large
part, this is due to the fact that tumours in the head cause
obstruction by compressing the ampulla of Vater, common bile duct, and
duodenum early in their development.
The classic
Courvoisier’s sign, consisting of an acute painless dilatation of the
gallbladder accompanied by jaundice, is due to obstruction of the
common bile duct and is often the first evidence of cancer of the
pancreas.
Because tumours
in the head give early clinical symptoms, they tend to be discovered
sooner than those in the more clinically silent body and tail, and
thus carry a somewhat better survival.
The bleak overall
outlook for patients with pancreatic carcinoma is emphasized by the
statistic that one-half are dead within a few months of the onset of
symptoms.
Extensive
metastases involve the regional lymph nodes, followed in descending
order by liver, lungs, peritoneum, duodenum, adrenals, and stomach.
Patients with
carcinoma of the pancreas present with symptoms of anorexia, weight
loss, and gnawing pain in the epigastrium that often radiates to the
back.
Jaundice is
present in about half of all patients with cancer localized in the
head, and is less than 10% of those in whom the body or tail of the
pancreas is the focus of disease.
The clinical
course of pancreatic cancer is one of progressive deterioration with
intractable pain, cachexia, and death.
10% of patients develop
a migratory thrombophlebitis, especially when the cancer involves the
body and tail of the pancreas.
In this condition, also known as
Trousseau’s syndrome, thrombi develop in multiple veins, including the
subclavian, saphenous, iliacs, inferior vena cava, portal, and
inferior and superior mesenteric.
Although the mechanisms responsible
for the hypercoagulable state that leads to migratory thrombophlebitis
are not completely understood, the following facts are known :
- a serine
protease synthesized and released by malignant tumour cells directly
activates plasma factor X;
- tumour cells spontaneously shed plasma
membrane vesicles that exhibit procoagulant activity;
-
intracellular tissue thromboplastin is released from necrotic tumour.
Gross:
Pancreatic carcinoma is a firm, gray, poorly demarcated multinodular
mass, often embedded in a dense connective tissue stroma.
The tumours
may invade the common duct and the duodenal wall.
If they penetrate
the wall, they may compress or invade the ampulla of Vater.
Carcinoma
is localized in the head, if extensive, it may cause atrophy of the body and
tail.
In the body and tail, the tumours are larger and extend more
widely than do those localized in the head.
They permeate the
retroperitoneal space and may invade the adjacent spleen and the splenic vein, showering the liver with metastases.
Intraperitoneal
metastases appear as small, grayish, firm nodules in the mesentery and
on the surface of intraperitoneal organs.
More than 75%
of ductal adenocarcinomas of the pancreas are well differentiated,
secrete mucin, and stimulate a florid synthesis and deposition of
collagen by the host, a process referred to as a desmoplastic
reaction.
Histologically, such carcinomas resemble mucinous
adenocarcinoma of the lung, stomach, gallbladder, colon, ovary, and
other organs.
Thus, in the absence of symptoms referable to the
pancreas, the identification of distant foci of metastatic cancer as
pancreatic in origin is difficult.
The remaining 25% of carcinomas
that originate from pancreatic ducts and ductules include giant cell
carcinoma, adenosquamous carcinoma, microadenocarcinoma, and a few
other rare types.
Etiology and
Pathogenesis:
The factors
involved in the causation of pancreatic cancer are obscure.
Epidemiologic studies have implicated both host and environmental
factors as of possible etiologic significance.
Notable among the host
factors is chronic gallbladder disease, particularly that associated
with cholesterol gallstones, dibetes mellitus, chronic hereditary
pancreatitis.
Environmental factors that have been implicated include:
-
cigarette smoking ;
- diet high in meat and fat and occupational exposure
to chemicals, namely, beta-naphthylamine, benzidine, and coal tar
derivatives.
- The association
of obstructive gallbladder disease with pancreatic cancer is of
special interest because it may serve to explain how carcinogenic
chemicals, if they are indeed involved in pancreatic carcinogenesis,
may reach the pancreas.
The liver is one
of the major organs involved in the oxidative metabolism of foreign
compounds, including carcinogens and other potentially toxic
chemicals.
Metabolites of
such reactive intermediates are released into the bile and the blood
and could gain direct access to the pancreas either by the reflux of
bile into the pancreatic duct or from the blood.
Diabetes
mellitus, especially in women, is an important risk factor for the
development of carcinoma of the pancreas, the incidence being two
times higher in diabetics than in the rest of the population. In fact,
it is the most frequent cancer encountered in diabetics. It may be
significant that those ethnic groups that appear to be particularly
susceptible to diabetes mellitus - namely, American Indians, blacks,
Jews, Hawaiians, and Maoris - also have a high incidence of pancreatic
cancer.
Furthermore, proliferative lesions of the pancreatic ducts,
such as papillary hyperplasia and metaplasia, are frequently
encountered in diabetics.
Epidemiologic
studies have shown a significant increase in the risk of pancreatic
cancer in cigarette smokers.
A causal relationship is further implied
by an apparent dose response related to the number of cigarettes
smoked per day, and the demonstration of hyperplastic pancreatic ducts
in autopsy studies of smokers.
Experimental
studies lend support to a role for chemical carcinogenesis in
pancreatic cancer. 7,12-dimethylbenz[a]anthracene, a polycyclic
hydrocarbon carcinogen, and a number of beta-oxidized dipropylnitrosamines, among other carcinogens, are pancreatic
carcinogens in rodent species. The nitrosamines are of particular
interest because they induce adenocarcinoma of the pancreatic ducts,
the predominant type of pancreatic cancer in man.
Epidemiological
studies also suggest that dietary factors are involved in the
development of pancreatic cancer.
Although a
positive correlation has been shown to exist between the consumption
of a variety of foodstuffs and mortality from pancreatic cancer, a
high intake of meat and fat appears to be of particular significance,
especially the latter.
In Japan, for
example, where pancreatic cancer was a rare disease, its incidence has
increased steadily over past 25 years.
This coincides
with the period of westernization of Japanese dietary practices, in
which consumption of meat and fat has increased.
Similar
relationships between the consumption of meat and fat and pancreatic
cancer have also been identified in other countries. Experimental dose
- effect relationships between the level of fat consumption and
carcinogenesis support the etiologic role of dietary factors.
K-ras mutations are observed in
greater than 90% of pancreatic cancers, and 60 to 80% exhibit
mutations in p53. The reasons for this striking
pattern of genetic alteration are not yet known.
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