Histopathology

Ovarian Cyst Miracle

Ovarian Cyst Miracle Handbook

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Most ductal adenocarcinomas are well to moderately differentiated. They are characterized by well-developed glandular structures, which more or less imitate normal pancreatic ducts, embedded in desmoplastic stroma. The large amount of fibrous stroma accounts for their firm consistency. Variations in the degree of differentiation within the same neoplasm are frequent, but well differentiated carcinomas with foci of poor differentiation are uncommon.

Well differentiated carcinomas consist of large duct-like structures, combined with medium-sized neoplastic glands. Tubular or cribriform patterns are typical; there may also be small irregular papillary projections without a distinct fibrovascular stalk, particularly in large duct-like structures. Mitotic activity is low. In between the neoplastic glands there may be a few non-neoplastic ducts as well as remnants of acini and individual islets. Sometimes, the neoplastic duct-like glands are so well differentiated that they are difficult to distinguish from nonneoplastic ducts. However, the mucin-con-taining neoplastic glands may be ruptured or incompletely formed, a feature that is not seen in normal ducts. The mucin-producing neoplastic cells tend to be columnar, have eosinophilic and occasionally pale or even clear cytoplasm, and are usually larger than those of non-neoplastic ducts. They contain large round to ovoid nuclei which may vary in size, with sharp nuclear membranes and distinct nucleoli that are not found in normal duct cells. Moreover, although the neoplastic cell nuclei tend to be situated at the base of the cell, they always show some loss of polarity. Moderately differentiated carcinomas predominantly show a mixture of medium-sized duct-like and tubular structures of variable shape, embedded in desmo-plastic stroma. Incompletely formed glands are common. Compared with the well differentiated carcinoma, there is a greater variation in nuclear size, chro-matin structure and prominence of nucleoli. Mitotic figures are rather frequent. The cytoplasm is usually slightly eosinophilic, but clear cells are occasionally abundant. Mucin production appears to be decreased and intraductal in situ components are somewhat less frequent than in well differentiated carcinomas. Foci of poor and irregular glandular differentiation are often found at the leading edge of the neoplasm, particularly where it invades the peripancreatic tissue. Poorly differentiated ductal carcinomas are infrequent. They are composed of a mixture of densely packed, small irregular glands as well as solid tumour cell sheets and nests, which entirely replace the acinar tissue. While typical large, duct-like structures and intraductal tumour components are absent, there may be small squamoid, spindle cell, or anaplastic foci (comprising by definition less than 20% of the tumour tissue). There may be some scattered inflammatory cells. Foci of necrosis and haemorrhage occur. The neoplastic cells show marked pleomor-phism, little or no mucin production, and brisk mitotic activity. At the advancing edge of the carcinoma, the gland and the peripancreatic tissue are infiltrated by small clusters of neoplastic cells.

Changes in non-neoplastic pancreas

All ductal adenocarcinomas are associated with more or less developed fibrosclerotic and inflammatory changes

Fig. 10.05 Undifferentiated carcinoma exhibiting extreme pleomorphism with giant cells.

in the adjoining non-neoplastic pancreas, due to carcinomatous duct obstructions (obstructive chronic pancreatitis). In cases of complete occlusion of the main duct, there is marked upstream dilatation of the duct and almost complete fibrotic atrophy of the parenchyma. In contrast to chronic pancreatitis due to alcoholism, intraductal calcifications are generally absent. Poorly differentiated carcinomas usually destroy the islets. In the well and moderately differentiated neoplasms, however islets may be found entrapped in neo-plastic tissue. In addition, scattered endocrine cells occur attached to or intermingled between neoplastic columnar cells. Only in exceptional cases do the endocrine cells constitute a second cell component of the ductal carcinoma (see mixed ductal-endocrine carcinoma).

Histochemistry and immunohistochem-istry

Although no histochemical or immuno-histochemical marker is able to unequivocally distinguish pancreatic from extra-

pancreatic adenocarcinoma, some markers are useful in separating ductal adenocarcinoma of the pancreas from non duct-type tumours or other gastrointestinal carcinomas.

Mucin. Ductal adenocarcinomas mainly stain for sulphated acid mucins but focal-ly also for neutral mucins {1714}. Immunohistochemically, most ductal adenocarcinomas express MUC1, MUC3 and MUC5/6 (but not MUC2) {1918, 2179}, CA 19-9, Du-Pan 2, Span-1, CA 125 and TAG72 {1714, 1884}. The expression patterns of CA 19-9, Du-Pan 2, Span-1, CA 125 and TAG 72 are largely comparable in their immunoreactivity and specificity. These markers also label the epithelium of normal pancreatic ducts to some extent, particularly in chronic pancreatitis, and the tumour cells of some serous cystadenomas and acinar cell carcinomas {1282}. Carcinoembryonic antigen (CEA). Monospecific antibodies against CEA that do not recognise other members of the CEA family are capable of discriminating between non-neoplastic duct changes, such as ductal papillary hyperplasia, and a variety of neoplasms {119}. CEA is negative in serous cystadenoma. Cytokeratins, vimentin, endocrine markers and enzymes. Normal pancreatic and biliary ductal cells and pancreatic centroacinar cells express the cytoker-atins (CK) 7, 8, 18, 19 and occasionally also 4 {1696}. Acinar cells contain only CK 8 and 18, and islet cells 8, 18 and occasionally also 19. Ductal adenocarci-nomas express the same set of cytoker-atins as the normal duct epithelium, i.e. CK 7, 8, 18 and 19. More than 50% of the carcinomas also express CK 4 {1696}, but are usually negative for CK 20 {1259}. As the usual keratin patterns of non-duct-type pancreatic neoplasms (i.e. acinar carcinomas and endocrine tumours, CK 8, 18 and 19) and gut carcinomas (i.e. CK 8, 18, 19 and 20) differ from that of ductal carcinoma, it is possible to distinguish these tumours on the basis of their CK profile. Ductal adenocarcinomas are usually negative for vimentin {1696}. With rare exceptions (see mixed ductal-endocrine carcinoma), they also fail to label with endocrine markers such as synapto-physin and the chromogranins, but may contain, particularly if well differentiated, some scattered (possibly non-neoplas-tic) endocrine cells in close association with the neoplastic cells {167}. They are generally negative for pancreatic enzymes such as trypsin, chymotrypsin and lipase {739, 1282}. Growth factors and adhesion molecules. Pancreatic carcinomas overexpress epidermal growth factor and its receptor, c-erbB-2, transforming growth factor alpha {380, 1676, 2163}, metallothionein {1409}, CD44v6 {259, 1880} and membranous E-cadherin {1519}.

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