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           Atypical Fibroxanthoma

                Dr Sampurna Roy MD

 
 

                

Carcinoma of the pancreas refers to carcinomas of the exocrine pancreas, almost always arising from ductal epithelial cells.

Visit: Pancreatic Pathology Online  ; 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.  Image Link

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 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 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 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:  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.

                  

Distribution of Intraductal Lesions in Small Invasive Ductal Carcinoma of the Pancreas. Pancreatology. 2007 Aug 15;7(4):341-346

Aims: To investigate the distribution of intraductal lesions in small invasive ductal carcinoma (IDC) of the pancreas. Methods: In 21 cases with IDCs microscopically </=20 mm in diameter, the intraductal lesions around a mass were studied histologically and mapped according to the pancreatic intraepithelial neoplasia (PanIN) classification. Results: PanIN-3, PanIN-2, PanIN-1B and PanIN-1A were found in 17, 10, 20 and 21 of 21 cases, respectively, and were divided into lesions in adjacent and distal areas, respectively defined as within and beyond 10 mm from the mass as follows: 100% (17/17), 100% (10/10), 95.0% (19/20) and 90.5% (19/21) in the former, while 23.5% (4/17), 50.0% (5/10), 90.0% (18/20) and 95.2% (20/21) in the latter. PanIN-3 lesions were predominantly found in the area adjacent to the mass. In some cases, significant PanIN-3 appeared to show a consecutive geographic extension around the mass via the main pancreatic duct (MPD). The distance of PanIN-3 spread was within 25 (mean 10.5) mm from the mass edge. PanIN-2 lesions were found in the area adjacent to the mass and discontinuous with the mass or PanIN-3 lesions. PanIN-1B and PanIN-1A tended mainly to exist sporadically throughout the entire pancreas. In the MPD, PanIN-3 was found in 14 (82.4%) of 17 cases and in 36 (32.1%) of 112 lesions, which was most frequent in intraductal lesions. Conclusions: PanIN-3 lesions might be an intraductal extension of the main tumor. The resection margin of 25 mm, at least longer than 11 mm, from the mass edge will be necessary.

Utility of pancreatic duct brushing for diagnosis of pancreatic carcinoma.
J Gastroenterol. 2007 Aug;42(8):657-62.

BACKGROUND: The aim of this study was to evaluate the usefulness of pancreatic duct brushing for diagnosis of pancreatic carcinoma. METHODS: Brush cytology was attempted in 58 patients suspected of having pancreatic malignancy because of stricture of the main pancreatic duct, confirmed by endoscopic retrograde cholangiopancreatography. Thirty-eight patients were finally diagnosed by an operation or the clinical course as having pancreatic carcinoma, and the remaining 20 patients as having chronic pancreatitis. The usefulness of brush cytology for diagnosis of pancreatic carcinoma was estimated. We interpreted failures of pancreatic duct brushing to be false negatives when the lesion was malignant. RESULTS: In 48 of 58 patients (82.8%), brushing was successfully performed and satisfactory specimens were obtained. Brush cytology was positive in 25 of 38 patients with pancreatic carcinoma (sensitivity 65.8%) and negative in all patients without malignancy (specificity 100%). Overall accuracy was 76.4%. During 2001-2005, the number of back-and-forth motions of the brush was increased to more than 30 times. The sensitivity significantly improved from 43.8% in 1997-2000 to 81.8% in 2001-2005 (P < 0.05). The increased success rate of brushing by improvement of skill in manipulating the guidewire and increased number of cells smeared on glass slides by increased back-and-forth motion of the brush may account for this improvement over time. Moreover, the sensitivity in 2001-2005 was 85.7% if failures of brushing with pancreatic carcinoma are excluded. No major complications occurred, except for two patients with a moderate grade of acute pancreatitis. CONCLUSIONS: Although further studies with a large number of patients are needed, our results suggest that with recent improvements of the brushing technique, pancreatic duct brushing is a useful and safe method for the differential diagnosis of malignancy from benign diseases of the pancreas.

The early state of invasive pancreatic ductal adenocarcinomas: characteristics of the low papillary type and flat type intraductal carcinoma.Pancreas. 2006 Aug;33(2):135-41.

OBJECTIVE: To analyze the early state and the mode of advancement of IPDACs. METHODS: Eighty-two cases of IPDAC were resected, and the noninvasive cancer parts were identified pathohistologically. According to the pancreatic intraepithelial neoplasia (PanIN) classification, noninvasive cancer parts were equivalent to PanIN-3; the noninvasive cancer parts in the invasive area and noninvasive intraductal spread (NIIDS) area were histologically examined. Noninvasive intraductal spread means a diffuse PanIN-3 change that extended continuously outward from the invasive area. In cases with NIIDS, the length of NIIDS was measured. RESULTS: Histologically, the noninvasive cancer parts were categorized into 3 types: flat (F), low papillary (LP), and mixed (flat and low papillary [FLP]) types; each type comprised 18.3%, 34.1%, and 47.6%, respectively. Cases with NIIDS of 2 mm or more were found in 56.1% of all the patients, and the F, FLP, and LP types comprised 13.3%, 59.0%, and 75.0%, respectively. The maximal NIIDS lengths were 10, 40, and 80 mm with averages of 1.5, 5.7, and 12.5 mm in the F, FLP, and LP types, respectively. The cases with the LP component revealed positive NIIDS and longer NIIDS lengths more frequently than those without the component (F type) (P < 0.001). The survival rates of the F, FLP, and LP types showed no statistical difference. The prognosis was better in cases of less advanced stages. CONCLUSIONS: The noninvasive cancer parts (PanIN-3 lesions) of IPDACs were divided into 3 types: F, LP, and mixed types; the LP type had a greater tendency than the F type to spread intraductally. The LP type seemed to change to invasive cancer after or while spreading intraductally to some extent, whereas the F type seemed to invade with little intraductal spread.

Morphological behavior of carcinoma of the pancreas. 1. Histological classification and electron microscopical observation.Acta Pathol Jpn. 1983 May;33(3):467-81.

A total of 84 autopsied and 10 operative pancreatic carcinoma cases were studied to investigate their morphological behavior, by light and electron microscopies. The autopsied materials were classified into 70 duct cell carcinomas, 11 undifferentiated carcinomas including 2 giant cell carcinomas simulating giant cell tumor of bone, and 3 endocrine cell carcinomas which might be called carcinoid or oat cell carcinoma. No acinar cell carcinoma was found. Duct cell carcinomas were further subclassified into 37 large and 24 small duct-forming adenocarcinomas, 8 adenosquamous carcinomas, and 1 cystadenocarcinoma. The majority of undifferentiated carcinomas were considered to be of ductal or ductular cell origin. Rare tumors, such as cystadenocarcinoma, giant cell carcinoma, and endocrine cell carcinoma, were shown as case presentations. Electron microscopic features of duct cell carcinoma and its related findings were also presented. These studies should be pursued, because it may be important clinically and disclose, in the future, possible differences in etiology or effective therapeutic agents among the categories, although the classification, made from a viewpoint of histogenesis, did not reflect prognostic differences at the present.

The pathological features of carcinoma of the pancreas.Can J Surg. 1981 Mar;24(2):168-70, 175.

The frequency of cancer of the pancreas is increasing and has surpassed that of cancer of the stomach. Lesions are more common in the head of the gland than in the body and tail. Smaller tumours tend to be localized and are associated with a better prognosis. The majority of tumours are hard and demonstrate a prominent desmoplastic reaction. They present as ill-defined masses which makes their differentiation from chronic pancreatitis difficult. Duct cell adenocarcinomas constitute 75% of all cancers of the pancreas. Some of the uncommon types include giant cell carcinoma, adenosquamous carcinoma, mucinous cystadenocarcinoma and acinar cell carcinoma. The role of open biopsy in diagnosing cancer of the pancreas remains controversial. Percutaneous fine-needle aspiration cytology appears promising. The technique is safe and inexpensive but needs an experienced cytopathologist to interpret the results accurately.

 
November  2009

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Clinicopathological aspects of pancreatic cancer.Gan To Kagaku Ryoho. 2005 May;32(5):605-11.

Using the nationwide database of the Japan Pancreas Society (JPS), the clinicopathological features of 23,284 cases (1981-2000) and 2,298 cases (2001-2002) with pancreatic neoplasms were compared. Intraductal papillary mucinous neoplasms and mucinous cystic neoplasms were increased in the registry. More detailed histological repertoires of endocrine tumors, intraductal tubular tumors and solid-pseudopapillary tumors were registered in the last two years. The numbers of serous cystadenocarcinomas and carcinomas in situ were decreased. The proportion of less differentiated adenocarcinoma was increased in the more advanced stages of the disease. In Stage IVa, the survival of the patients with papillary adenocarcinoma was not statistically different from that of patients with well or moderate tubular adenocarcinoma, though the difference was significant in earlier stages. The survival of the patients with poorly differentiated adenocarcinoma, adenosquamous carcinoma and undifferentiated carcinoma was miserable. Histological confirmation is critically important to prospect the outcome and to determine the treatment modality. Integration of the nationwide registry and pathological information will give new insights for the treatment of pancreatic cancer.

Pathologic characteristics and evaluation of the pancreatic cancer.Gan To Kagaku Ryoho. 2005 May;32(5):599-604.

Ductal adenocarcinoma is the most common tumor type of cancer of the pancreas. It is generally a poorly demarcated, white to grey-solid tumor located in the pancreatic head. Histologically, it is often well-to moderately-differentiated tubular adenocarcinoma along with marked desmoplastic change. There are three well-defined precursors to invasive cancer; mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic intraepithelial neoplasia PanINs. PanIN is now considered to be a precursor of pancreatic ductal adenocarcinoma based on molecular studies. However, it is difficult to distinguish between small IPMNs and PanINs pathologically because both of them often show similar epithelium with cytoplasmic mucin. IPMNs and MCNs can form similar invasive carcinomas such as tubular adenocarcinoma and/or mucinous carcinoma. Another focus of this review is the issue of pathologic evaluation of the surgically resected specimens. Histologic grading and pathologic staging of each case are important especially in terms of the clinical aspects. Careful attention should be paid to the processes and/or criteria of pathologic diagnosis.

Morphological patterns of primary nonendocrine human pancreas carcinoma.Cancer Res. 1975 Aug;35(8):2234-48.

The study of histological sections of 406 cases of nonendocrine pancreas carcinoma at Memorial Hospital indicated that morphological patterns of pancreas carcinoma could be delineated as follows: duct cell adenocarcinoma (76%), giant-cell carcinoma (5%), microadenocarcinoma (4%), adenosquamous cancinoma (4%), mucinous adenocarcinoma (2%), anaplastic carcinoma (2%), cystadenocarcinoma (1%), acinar cell carcinoma (1%), carcinoma in childhood (under 1%), unclassified (7%). In 195 cases of patients with pancreas carcinoma, search was made for changes in the pancreas duct epithelium and these were compared to duct epithelium in a control group of 100 pancreases from autopsies of patients with nonpancreatic cancer. The following incidences were found for pancreas cancer and nonpancreatic cancer, respectively: mucous cell hypertrophy, 39 versus 28%; pyloric gland metaplasia, 28 and 17%; epidermoid metaplasia, 6 and 12%; papillary hyperplasia, 42 and 12%; atypical duct hyperplasia, 14% and none; cancinoma in situ in 19% and none in the control group. Mucin in the majority of pancreas cancers suggested that the cell type of origin of the common pancreas cancer is the mucin-producing duct epithelium. The association of atypias and carcinomas in situ in the patients with pancreas carcinoma implies, by analogy to other organs, that there may be a significant latent period between the appearance of carcinoma in situ and the grossly recognizable pancreas cancer.


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