Pancreatic Pathology Online
Carcinoma of the Pancreas
Dr Sampurna Roy MD July 2016
Carcinoma of the pancreas refers to carcinomas of the exocrine pancreas, almost always arising from ductal epithelial cells.
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.
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.
Prognosis: Five-year survival is less than 4%.
Clinical presentation, and Pathology of Pancreatic Carcinoma:
Distribution of the tumour 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.
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.
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 Courvoisierís 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, intractable 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.
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 Trousseauís 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 features of Pancreatic Carcinoma :
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.
Microscopic features of the Pancreatic Carcinoma
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.
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.
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.
Pancreatic carcinoma has a poor prognosis. This is 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 the tumour.
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