Histological variants

Adenosquamous carcinoma and undif-ferentiated (anaplastic) carcinoma (including osteoclast-like giant cell tumours), mucinous noncystic adenocarcinoma and signet-ring cell carcinoma are considered variants of ductal adeno-carcinoma because most of these carcinomas, even if poorly differentiated, contain some foci showing neoplastic glands with ductal differentiation {288, 359, 941, 947, 1781}.

Adenosquamous carcinoma

This rare neoplasm, relative frequency 3-4% {941, 359, 813, 1415}, is characterized by the presence of variable proportions of mucin-producing glandular elements and squamous components. The squamous component should account for at least 30% of the tumour tissue. In addition, there may be anaplastic and spindle cell foci. Pure squamous carcinomas are very rare.

Undifferentiated (anaplastic) carcinoma

Also called giant cell carcinoma, pleo-morphic large cell carcinoma, and sarco-matoid carcinoma, these tumours have a relative frequency of 2-7%. They are composed of large eosinophilic pleomor-phic cells and/or ovoid to spindle-shaped cells that grow in poorly cohesive formations supported by scanty fibrous stroma. Commonly the carcinomas contain small foci of atypical glandular elements {359, 941, 1786, 1962}. Carcinomas consisting predominantly of spindle cells may also contain areas of squamoid differentiation. High mitotic activity as well as perineural, lymphatic, and blood vessel invasion is found in almost all cases. Immunohistochemical-ly, some or most tumour cells express cytokeratins and usually also vimentin {740}. Electron microscopy reveals microvilli and mucin granules in some cases {359}. Undifferentiated carcinomas with a neoplastic mesenchymal component (carcinosarcoma) have so far not been described.

Undifferentiated carcinoma with osteo-clast-like giant cells

This rare neoplasm is composed of pleo-morphic to spindle-shaped cells and scattered non-neoplastic osteoclast-like giant cells with usually more than 20 uniformly small nuclei. In many cases there is an associated in situ or invasive ade-nocarcinoma {359}. The osteoclast-like giant cells are often concentrated near areas of haemorrhage and may contain haemosiderin and, occasionally, phago-cytosed mononuclear cells. Osteoid formation may also be found. Immunohistochemically, at least some of the neoplastic cells express cytokeratin, vimentin and p53 {740, 2095}. The osteo-clast-like giant cells, in contrast, are negative for cytokeratin and p53, but positive for vimentin, leukocyte common antigen (CD56) and macrophage markers such as KP1 {740, 1258, 2095}. The mean age of patients with osteo-clast-like giant cell tumours is 60 years but there is a wide age range from 32 to 82 years {1370}. Some tumours are found in association with mucinous cystic neoplasms {1258, 2095, 2198}. In the early reports on this tumour it was suggested that they may have a more favourable prognosis than the usual duc-tal adenocarcinoma {359}. More recently a mean survival of 12 months has been reported.

Mucinous noncystic carcinoma

This uncommon carcinoma (relative frequency: 1-3%) {941} has also been called 'colloid' or gelatinous carcinoma. Mucin accounts for > 50% of the tumour. The large pools of mucin are partially lined by well-differentiated cuboidal cells and contain clumps or strands of tumour cells. Some floating cells may be of the signet-ring cell type.

Sex and age distribution are similar to those of ductal adenocarcinoma. The tumours may be very large and are usually well demarcated. The development of pseudomyxoma peritonei has been described {285}. It is of interest that the invasive component of some of the intra-ductal papillary-mucinous tumours resembles mucinous noncystic carcinoma. Mucinous noncystic carcinoma should not be confused with mucinous cystic tumour because of the much better prognosis of the latter (see chapter on muci-nous cystic neoplasms).

Signet-ring cell carcinoma

The extremely rare signet-ring cell carcinoma is an adenocarcinoma composed almost exclusively of cells filled with mucin {1781, 1951}. The prognosis is extremely poor; a gastric primary should always be excluded before making this diagnosis.

Mixed ductal-endocrine carcinoma

Mixed ductal-endocrine carcinoma {947} has also been referred to as mixed carci-noid-adenocarcinoma, mucinous carcinoid tumour {359}, or simply mixed exocrine-endocrine tumour. This neoplasm is characterized by an intimate admixture of ductal and endocrine cells in the primary tumour as well as in its metastases. By definition, the endocrine cells should comprise at least one third to one half of the tumour tissue. The duc-tal differentiation is defined by mucin production and the presence of a duct type marker such as CEA. The endocrine cells are characterized by the presence of neuroendocrine markers and/or hormonal products; immunoexpression of all four islet hormones, amylin (IAPP), serotonin, pancreatic polypeptide (PP), and occasionally gastrin have been described {167}.

Mixed ductal-endocrine carcinomas, as defined above, seem to be exceptionally rare in the pancreas {1714, 1781}. Biologically, the mixed carcinoma behaves like the usual ductal adenocar-cinoma.

Acinar cell carcinomas {739, 1694, 1985} and pancreatoblastomas {741} with some endocrine and ductal elements, and endocrine tumours with ductal components {1372, 1941} are not discussed here, because their behaviour is dictated by their acinar and endocrine elements. Mixed ductal-endocrine carcinomas should also be distinguished from ductal adenocarcinomas with scattered endocrine cells, since scattered endocrine cells are found in 40-80% of ductal adenocarcinomas {167, 289} and seem to be particularly frequent in the well differentiated tumours, where they are either lined up along the base of the neoplastic ductal structures or lie between the neoplastic columnar cells. 'Collision tumours' composed of two topographically separate components are not included in the mixed ductal-endocrine category.

Other rare carcinomas

Other very rare carcinomas of probable ductal phenotype include clear cell carcinoma {359, 882, 1908, 1121} and ciliated cell carcinoma (see chapter on miscellaneous carcinomas) {1276, 1786}. Carcinomas with 'medullary' histology have recently been described {590}; these lesions are associated with wildtype KRAS status and microsatellite instability.

The so-called microglandular carcino-mas{359} or microadenocarcinomas are distinguished by a microglandular to solid-cribriform pattern. They most likely do not form an entity of their own but belong to either the ductal, endocrine, or acinar carcinomas.

Grading

A few formal grading systems have been described. Miller et al. graded pancreatic tumours using the system of Broder, which distinguishes four grades of cellular atypia. High-grade carcinomas (Broder grades 3 and 4) were larger and the frequency of venous thrombosis and metastasis higher than in low-grade tumours.

A more recent grading system is based on combined assessment of histological and cytological features and mitotic activity {944, 1119}. If there is intratumour heterogeneity, i.e. a variation in the degree of differentiation and mitotic activity, the higher grade and mitotic activity is assigned. This rule also applies if only a minor component (less than half of the tumour) was of lower grade. Using this system, there is a correlation between grade and survival and grade is an independent prognostic variable {944, 1119}.

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