Morphological Patterns of Primary Nonendocrine Human Pancreas Carcinoma'

[CANCER RESEARCH 35, 2234-2248, August 1975] Morphological Patterns of Primary Nonendocrine Human Pancreas Carcinoma'

Antonio L Cubifla and Patrick J. Fitzgerald2 Department of Pathology, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York UX@21

Summary the parenchymal cells. In the subsequent 5 decades terms such as mucous adenocarcinoma, colloid carcinoma, duct The study of histological sectionsof 406 casesof nonen adenocarcinoma, pleomorphic cancer, papillary adenocar docrine pancreas carcinoma at Memorial Hospital mdi cinoma, cystadenocarcinoma, and other variants, such as cated that morphological patterns of pancreas carcinoma epidermoid carcinoma, mucoepidermoid cancer, giant-cell could be delineated as follows: duct cell adenocarcinoma carcinoma, adenoacanthoma, and acinar cell carcinoma, (76%), giant-cell carcinoma (5%), microadenocarcinoma have appeared (7, 18, 23, 47, 62). Subtypes of islet-cell (4%), adenosquamous carcinoma (4%), mucinous adeno tumors have been defined (27). As pointed out by Baylor carcinoma (2%), anaplastic carcinoma (2%), cystadenocar and Berg (5) in discussing the limitations of their study of cinoma ( 1%), acinar cell carcinoma (1 %), carcinoma in 5000 patients with pancreas cancer from 8 cancer registries, childhood (under 1%), unclassified (7%). few pathologists precisely characterize the microscopic In 195 cases of patients with pancreas carcinoma, search features of their cases. was made for changes in the pancreas duct epithelium and We have reviewed cases of cancer of the pancreas at these were compared to duct epithelium in a control group Memorial Hospital to determine whether there are defina of 100 pancreases from autopsies of patients with nonpan ble morphological subgroups and to indicate their relative creatic cancer. The following incidences were found for distribution in our material. The delineation of morphologi pancreas cancer and nonpancreatic cancer, respectively: cal patterns of pancreas cancer may eventually permit a mucous cell hypertrophy, 39 versus 28%; pyloric gland correlation with some genetic, biochemical, endocrinologi metaplasia, 28 and 17%; epidermoid metaplasia, 6 and 12%; cal, clinical, epidemiological, prognostic, or other parame papillary hyperplasia, 42 and 12%; atypical duct hyper ter of significance and thereby further an understanding of plasia, 14% and none; carcinoma in situ in 19% and none in this neoplasm that appears to be increasing and has such a the control group. poor prognosis for the patient at the present time. 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 Materials and Methods atypias and carcinomas in situ in the patients with pancreas carcinoma implies, by analogy to other organs, that there From a survey of 757 cases listed as cancer of the may be a significant latent period between the appearance of pancreas in the Cancer Registry, Clinical Information carcinoma in situ and the grossly recognizable pancreas Center, Memorial Hospital, during the years 1949 through cancer. 1972, we have been able to examine histological sections of tissue from 503 cases. Sixty-seven were eliminated from the study for the following reasons: in 42 cases biopsy material Introduction did not show any cancer; 3 cases were reclassified as periampullary carcinoma; 7 cases were reclassified as The morphological classification of primary pancreas metastatic cancer (2 casesof oat-cell carcinoma of lung; 1 carcinomas of the nonendocrine variety would seem to pose case each of adenocarcinoma of the lung, breast, and colon; no problem to the pathologist because most of these cancers I malignant lymphoma; and 1 embryonal rhabdomyo@ar are adenocarcinomas and they span the spectrum com coma of the retroperitoneum); in 13 cases aspiration biop monly found with adenocarcinomas of other organs. Origi sies did not furnish enough tissue for classification; 1 de nally, Ewing ( 18), from this laboratory, described only 2 batable case w@sof either gastric or pancreas origin; and 1 types of pancreascancers,cylindrical cell adenocarcinoma tumor was believed to be of common bile duct origin rather arising from the ducts and carcinoma simplex arising from than of pancreatic duct. Thirty cases of malignant islet-cell tumor, recently reported from this laboratory (14), were 1 Presented at the Symposium â€œCurrent Progress in Pancreatic Car also excluded. cinogenesis Research,â€• February 4, 1975, Orlando, Fla., as part of the Cases coded as ampullary or periampullary cancer, Third Annual Carcinogenesis Conference. Aided by Contract NOl CP-43232 from the National Cancer Institute, NIH, Bethesda, Md. duodenal cancer, islet-cell tumors, or retroperitoneal tu 2 Presenter. mors involving the pancreas were not examined, and

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1975 American Association for Cancer Research. Patterns of Pancreatic Carcinoma possibly a few pancreas cancers were thereby lost to our interpretation made on the small sampling of a tumor, study. which was sometimes restricted to only a few slides. There In 406 cases there was an operative biopsy ofa pancreatic were some cases (7%) where admixtures oftypes occurred so tumor; a confirmation of a pancreas cancer in the surgically that they were listed as unclassified. A much larger resected pancreas, or autopsy specimen; or, in association sampling might change the subtyping of cancers or the with a lesion clearly defined in the operative notes as a incidence of changes in duct epithelium. pancreatic tumor, there was a biopsy taken of a regional lymph node, or of a metastatic lesion, which revealed a neoplasm consistent with pancreas cancer. In 29 1 cases Results tissue diagnostic of pancreas cancer was obtained at opera tion, and in 115 casesthe tissue was obtained at autopsy. In Nonendocrine Pancreas Neoplasms 99 cases surgically resected (partial or total) pancreas tissue was studied. Histological slides of the primary tumor varied Benign Epithelial Nonendocrine Neoplasms. We were able from 4 to 9, but often only 1 or a few, slides of the to examine histological material from only 7 cases of benign metastasis were available. Additional slides, particularly epithelial nonendocrine neoplasms (3 serous and 4 mucinous for the demonstration of mucin, were cut from the paraffin cystadenomas) and from I case containing a microscopic embedded block in 53 cases. focus of adenomatous hyperplasia of acinar cells found Recently, we have obtained for electron microscopy incidentally at autopsy. ultrastructural studies pancreas cancer tissue removed at Malignant Epithelial Neoplasms. We have classified pri operation in 28 cases and from autopsy in 3 cases (not mary malignant lesions of the nonendocrine pancreas under included in the morphological classification study). the general headings of carcinomas (Table 1), sarcomas, In 214 cases (99 cases of partial or total pancreatectomy primary malignant lymphomas, a miscellaneous group, and and 115 autopsies), additional study of the pancreas cancer metastatic cancer. We estimate that over 95% of the material for associated hyperplasia, metaplasia, atypias, or malignant lesions of the nonendocrine pancreas are adeno carcinoma in situ changes in the duct epithelium was carcinomas and the following appear to be distinctive types. attempted. Nineteen cases were rejected because of autol Duct Cell A denocarcinoma [Adenocarcinoma, Cylindri ysis ofduct epithelium or insufficient ductal tissue present in cal-Cell Adenocarcinoma (18), Papillary Adenocarcinoma the histological slides, leaving 195 cases with adequate (23), Pancreas Cancer (5)]. In the normal duct system of the material. Pancreases from 100 consecutive autopsies (per human pancreas there is variation from the flat to cuboidal formed in 1973) of patients with nonpancreatic cancers, epithelium of the smallest ductules to the high columnar similar in age and sex to the pancreascancer cases,were mucouscell ofthe epithelium in the headofthe pancreas(9, used as controls. Patients were subjected to different 24). There is absence of mucin in the smallest ductules, as regimensof chemotherapy or radiotherapy in the 2 groups, indicated by the negative mucin stains, and the presence of and no corrections were made for these factors. Four to 9 mucin, indicated by a positive mucin stain, in the apical histological sections from each pancreas of the 2 groups region of the columnar cell of the duct epithelium, particu were examined. larly in the larger ducts (24, 46). By electron microscopy it Standard fixation in 10% formalin solution and staining can be demonstrated that droplets of mucigen are present in with hematoxylin and eosin were used for all tissues. Meyer's the duct epithelium (9) (Fig. 7) and not in the smallest mucicarmine stain (45) wasusedto demonstratemucin, and epithelial cells of the ductules. the periodic acid-Schiff (43) and Alcian blue stains (44) Our cases of duct adenocarcinomas were similar to the were used to indicate pyloric gland metaplasia (57, 58, 68). adenocarcinomas seen elsewhere in the biliary tract, gas The tissue for electron microscopy was fixed overnight in trointestinal tract, lung, and other organs (Figs. I and 2). Karnovsky fixative, rinsed in buffer (s-collidine), and post There was a mixture of large and small glands, often with I fixed for 1 hr in 1% osmium tetroxide. The specimens were embedded in epoxy resin (Maraglas) and stained with Table I uranyl acetate followed by lead citrate, and examined in a Classification of nonendocrine pancreas carcinomas Siemens-Elmiskop 101 electron microscope (17). Material from one of our acinar cell carcinomas was taken from No.ofcases%Duct autopsy â€œwetâ€•tissuekept in 10% aqueous formalin solution celladenocarcinoma30876Giant-cell for 8 months. Autopsy had been performed 12 hr postmortem. carcinoma195Microadenocarcinoma154Adenosquamous In the attempt to subclassify the cases it was required that for a case to fall into one of the groups a predominant, carcinoma144Mucinous consistent pattern must have beenpresentthroughout most adenocarcinoma72Anaplastic of the tissue. In the cases where both a primary and carcinoma62Cystadenocarcinoma31Acinar-cell metastatic lesion were available, the same morphological carcinoma3ICarcinoma features had to be present in both lesions, with few childhood10.3Unclassified307Total406102in exceptions. It was fully realized that the quest for a consistent morphological structure, or for changes associ ated with cancer, was a difficult one involving subjective

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1975 American Association for Cancer Research. A. L. Cubilla and P. J. Fitzgerald size predominating, but because of much overlapping we were recognizable, with either the solid or glandular compo lumped all cases altogether (23). Areas of well-differen nent predominating. In most areas the microadenocar tiated adenocarcinoma to foci of poorly differentiated cinoma was predominant and large foci of necrosis were glandular configurations were present. The glands were present. Sometimes the adenocarcinoma resembled the lined by tall columnar or cuboidal cells. The nucleus was biliary-pancreas duct epithelium; in other cases it resembled usually round to oval and was located in the base of the cell. more the gastrointestinal types. The pattern is also seen in The cytoplasm varied from a watery clear to darker pink, colon cancer and adenocarcinomas of other organs. We most often resembling the cytoplasm of the cells of the large debated whether this should be called solid microadenocar pancreatic ducts or the biliary tract epithelium. Mucicar cinoma becauseof the frequent presenceof areas of solid mine, periodic acid-Schiff or Alcian blue stained the masses of small cells, but becaase the microadenocarcinoma cytoplasm usually at the apical portion, or luminal border. predominated in many of our cases we decided to name the Occasionally, goblet cells were present. Desmoplastic re type by its predominant component. Both componentswere sponse was usually considerable (Fig. 2), and often sclerotic malignant in all of our 15 carcinomas. areas revealed only a few glands separated by dense bands A denosquamous Carcinomas [A denoacanthoma (12), of collagen. Mucoepidermoid Carcinoma (23), Squamous Carcinoma Focally, mucinous cells, â€œsignet-ringâ€•cells, papillary (41)]. A characteristic pattern of the adenosquamous car carcinoma, and small tubular patterns of adenocarcinoma cinoma was the presence of 2 components, an adenocarci were observed. Some glands were so well differentiated that noma and a squamous cell carcinoma (Fig. 9). The glandular when they were present in the periampullary region it was areas varied in their differentiation from well to poorly dif difficult to distinguish the tumor from the normal glands ferentiated. In the 3 cases tested where there was a question found in this area (40). Pancreatic duct adenocarcinoma asto whether mucin waspresent,all gavea positive stain for when metastatic to the lung occasionally simulated primary mucin, either in glands or in the individual adenocarcinoma adenocarcinoma of the lung (37, 38). cells. The squamous pattern was characterized by epithe Electron microscopic study of 28 duct adenocarcinomas hum with whorls, keratohyalin, or â€œpearls.â€•Occasionally, showed in many cases globules of mucigen usually in the intercellular bridges were present. By electron microscopy apical cytoplasm (Fig. 8), but in some cases none was one could demonstrate tonofibrils (Fig. 10). In 1 case only present. In cases with duct obstruction and no pancreas squamous carcinoma was present in the metastatic lesion. cancer, there appeared to be mucous cell hypertrophy with The metastatic lesions had the same pattern as the primary more than the usual amount of mucigen in the cytoplasm tumor in all other cases. Both the glandular and the (Fig. 7). Zymogen granules were not present in any case. squamous components were malignant in all ofour 14 cases. Giant-Cell Carcinoma [Pleomorphic (28, 35), Medullary Mucinous A denocarcinoma [Colloid (23, 50), Gelatinous (62), Sarcomatoid (47), or Carcinosarcoma (23, 32)]. The (34), or Mucoid Carcinoma (69)]. Mucinous adenocar giant-cell carcinoma appeared to be a distinctive type (Fig. cinoma was a distinctive type, characterized by the presence 3), although it was not specific for the pancreas. It was of huge multiloculated pools of mucus (Fig. 11), some characterized by the presence of huge cells with very large, times with very few cells being present. The cells were often pleomorphic, often vacuolated nuclei, containing prominent flattened or compressed in the periphery against a c@llagen nucleoli and abundant coarse nuclear chromatin. The stroma, so that one found in both primary and metastatic cytoplasm was abundant, dense, and stained heavily with areas large pools of mucus in a relatively acehular field eosin. Phagocytosis was seen occasionally. The tumor cell separated by strands of collagen. Usually, there were small resembled similar cells seen in melanoma, hepatocellular foci or individual cells of adenocarcinoma discernible (Fig. carcinoma, choriocarcinoma, rhabdomyosarcoma, and the 12). In I case there were diffuse, isolated foci of â€œsignet giant- and spindle-cell carcinomas of the thyroid and lung. ringâ€•carcinoma cells in the mucus pool. A similar pattern is Areas of spindle malignant cells were usually present and seen occasionally in the breast, gastrointestinal tract, and sometimes made up a large part ofthe tumor. With multiple other organs. sections of these tumors, one could find in most of the cases Cystadenocarcinoma [Papillary Cystadenocarcinoma (3, areas ofadenocarcinoma contiguous to the giant tumor cells 6, 55, 67)]. This appears to be a malignant variation of the (Fig. 4) (conversely, in some duct adenocarcinomas of the benign cystadenoma with cysts of varying size and contents, pancreas, or in adenocarcinomas of other organs, small foci separated by collagen strands and lined at the periphery of giant cells can be demonstrated). Only when the predomi with epithelium (Fig. 13). In the cystadenocarcinoma, the nant mass of tissue was composed of giant cells was the case epithelium ran a gamut from flat cells to papillae of assigned to the giant-cell category. No case of carcinoma of malignant epithelium projected into and filling the cyst (Fig. the pancreas simulating the giant cell tumor of the bone, 14). Generally, the malignant epithelium showed loss of believed to be of acinar cell origin by Rosai (59), was polarity, hyperchromicity, and bizarre nuclei with very present. heavy nuclear chromatin. Mitotic figures were present. Microadenocarcinoma. This neoplasm usually consisted Some cysts were empty, or more often they had serous or of an intimate combination of 2 types of tissue: nests of small mucinous contents. Cystadenocarcinoma has to be distin to intermediate-sized cells without glands or intervening guished from a duct adenocarcinoma with focal papillary stroma, or intercellular substance, and small glands (Figs. 5 features, or cystic degeneration, or one with duct carcinoma and 6). The mucicarmine stain was positive in many such producing obstruction and dilation of the ducts. Our 3 cases glands. Usually, within a microscopic field both elements showed mucin in the cyst contents.

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A cinar Cell Carcinoma [Parenchymatous Adenocar in age and sex to our pancreas cases, 16 showed metastasis cinoma (18, 64)]. The structure of the normal acinar cell to the pancreas. The most common primary sites were lung, with its basal nucleus and prominent nucleolus surrounded melanoma of the skin, and diffuse malignant lymphoma, 3 by extensiveergastoplasmand the apical zymogengranules cases ofeach. The primary cancers in the other 7 cases were is well known (9). 1 each from a variety of organs. Our few cases showed gland formation, tubular arrange ment, and somewhat random mixtures ofvarious configura Miscellaneous tions of acini (Figs. 15 and I6). Usually, in the cell there was considerable deeply staining cytoplasm, a basal nucleus, and, as in many carcinomas, nests of malignant cells that Although in this study no ciliated (23, 42, 62), carcinoid did not retain the characteristic configuration of the normal (52)(69),or oncocytictumor(31)wasincluded,thesecells gland but appeared as sheets of smaller malignant cells. In are normal, although rare, constituents of duct epithelium some cells zymogen granules could be discerned, but in most and, presumably, tumors of these cell types will appear, of the slides there was only a diffuse, nonparticulate pink to rarely. From this hospital there has been reported (15) a red cytoplasm. A few foci resembled islet cells. No enzyme case of carcinoid syndrome the cell type of which was studies were done to confirm the presence or absence of the uncertain, being either of islet-cell or of carcinoid origin. usual pancreas exocrine enzymes. In I case we were able to We have not included the case in this report. obtain formalin-fixed â€œwetâ€•tissue and examine it by electron microscopy. There was much nuclear and cytoplas Associated Duct Cell Changes mic autolysis, but typical zymogen granules, fewer in number than in normal acinar cells and somewhat autolyzed Hypertrophy of mucous cells (Fig. 7) was more prevalent but still recognizable (Fig. 17), were present in many cells. in the pancreas cancer cases than in the control group (39 None of the 3 casesgaveany evidenceof the production of versus 28%, respectively). Pyloric gland metaplasia (57, 58, excessive amounts of enzyme activity. 68) (Fig. 20) was slightly greater in the pancreas cancer A naplastic Carcinoma [Indeterminate Carcinoma (47)1. group (28 versus 17%). Epidermoid (squamous) metaplasia There were 6 cases in which differentiation of a small, of duct epithelium was less frequent in pancreas cancer diffusely infiltrating cell was so limited that it was not patients (6%) than in the patients with cancer of other possible to place the cell type, or pattern ofgrowth, in any of organs ( I2%). Papillary hyperplasia (63) was seen in 42% of the above groups. Because the cells grew in nests or chords pancreas cancer cases (Fig. 20) and in 12% of the patients of cells they were placed in the general category of with nonpancreatic cancer. Marked atypia of duct epithe carcinomas (Fig. 18). However, in view of the absence of hum (Fig. 21) was found in 14% of our pancreas cancer electron microscopy and other studies, this assignment was cases, but none was noted in the pancreases of 100 autopsies provisional. The mucin stain wasnegativein 3 ofthe 3 cases of patients with nonpancreatic cancer. In l9%.ofcases with tested. pancreas cancer, there were associated carcinoma in situ Cancer of the Pancreas in Childhood [Infantile Type changes of the duct epithelium. In none of the control (22)]. One tumor was found in a 3-year-old child. There nonpancreatic cancer cases did we find in situ lesions. were areas of small-cell adenocarcinoma, squamous-cell Usually, the in situ changes (Figs. 22 to 25) were associated elements, malignant spindle cells, and benign areas of with areas of papillary hyperplasia and/or marked atypia mesenchymal tissue, including bone, found in a tumor of the and most often were found adjacent to the primary tumor. head of the pancreas (Fig. 19). A similar case has been However, in 2 cases of cancer of the head of the pancreas, in described by Frable et a!. (22). Another case in a child, not situ changes were present in the body, and/or tail of the included in this study, was seen in consultation by Dr. Frank pancreas (Fig. 25). W. Foote, Jr., who noted that the structure was that of a papillary cystadenoma resembling a case described by Frantz (Ref. 23, Fig. 13). An apparently similar case has Prevalence of Subtypes been recorded (3 1). Other cases in children have been reported (49, 66). The categories of carcinomas, their incidence, and the Unclassified Cancer. There was a significant percentage relative percentages of metastasis to the pancreas from of tumors (7%) of cases that were difficult to classify. Most other organs represent findings in patients of a cancer showed poor, or partial, formation of glands or ducts. hospital and may not be representative of the general Mucin was demonstrated in some cases. In other cases the population. pattern was solid, or trabecular, without mucin. Some cases presented with small glands, or gland-like structures. Discussion

Histological Types. One may legitimately question the Metastatic Cancer (23) value of subclassification of pancreas cancer at the present time because most patients die within I year from the onset In 100 consecutive autopsies of adults from this hospital of symptoms. In addition, there is the possibility that 1 with a primary cancer other than pancreas, roughly similar category might merely represent a minor variation of

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another group, e.g., the giant-cell carcinoma might repre carcinoma cases would have been classified as cystadeno sent an accelerated growth rate of the duct adenocarcinoma. carcinomas by us. However, there were 19 cases of the giant-cell variety with a The microadenocarcinoma pattern, although present in distinctive, fairly uniform structure and it might be instruc foci of tumors from many organs, particularly the colon, tive from a conceptual viewpoint to know why this differ has not. to our knowledge, been set aside previously as a ence occurred even if the 2 types represented essentially the type of pancreas cancer. It may represent a variant of the same tumor. One subgroup, widely recognized as having duct adenocarcinoma, or possibly carcinoid, but enough a characteristic appearance, the cystadenocarcinoma, seems cases showed this consistent appearance to warrant the sug to have a better prognosis than the other types and is, gestion that this might be a distinct entity. thereby, different in both morphological structure and The anaplastic group of tumors also appears to be a biological behavior (5, 6, 67). The acinar cell carcinoma is recognizable cell type, but until electron microscopy, histo morphologically recognizable, particularly if electron mi chemical, or biochemical studies are performed its cell of croscopy is used, and occasionally it continues to synthesize origin is uncertain. This tumor type is present in many other the enzymes characteristic of the cell type (2, 11, 13, 5 1, 64). organs. It is possible that chemotherapeutic compounds will be The acinar cell carcinoma has been widely recognized. In found that have differential effects on the cancer subtypes, 3 reports the incidence of this lesion has differed from our just as ethionine has been shown to affect the normal acinar figures [15% in 1 group (37), 13% in a 2nd (47), and 11% in cell more than it does the normal duct, or islet, cell the 3rd (62)], higher than the 1% found in our patients. Only epithelium (19, 21, 25), or as streptozotocin has been if very-well-differentiated acini, or acinar cells, were pres demonstrated to cause more damage to the a-islet cell than ent in some foci would we include the cases in this category it does to other pancreas cell types (10). and possibly we have thereby excluded poorly differentiated Occasionally, as in tumors of other organs, a specific acinar cell tumors. Frantz (23) and others (30, 48) remarked histological type will be the characteristic expression of an that the type was rare. environmental factor, e.g., mesothelioma of the lung in The extreme rarity of acinar cell adenomas of the pan asbestos workers (60) and the recently reported angiosar creas in humans is surprising because adenomas and ade coma of the liver in polyvinyl chloride workers (53). A cell nomatous lesions have been produced experimentally in type may give rise to a specific hormonal response, such as animals by azaserine (39), nitrosoamines (54), and 4-hy the medullary carcinoma of the thyroid C-cell and its droxyaminoquinoline 1-oxide (33, 61). Our only case of be production of the calcitonin hormone (65). Usually, there is nign acinar cell lesion was a microscopic focus of adenoma not a clean-cut relationship between morphology and an tous hyperplasia. Cystadenomas were more frequent in our etiological agent. material. Our 7 cases were fairly representative of these One of our adenosquamous cancer patients had 2 other lesions. Glenner and Mallory (24) collected 36 such cases cancers, as well as the adenosquamous cancer, develop in from 6 Boston hospitals. a radiated field, the latter 30 years after the radiotherapy. Whether these histological subtypes represent a spectrum This is somewhat reminiscent of the thyroid cancers devel of random morphological expressions of a single process or oping subsequent to â€œthymicâ€•radiation in infancy (16, 56). whether they are the result of multiple different carcino One of 4 adenosquamous cancers in the population of genic factors, each giving rise to a characteristic type, is Hiroshima appeared in a person exposed to the atomic unknown. It is assumed that morphological aspects of a bomb radiation (12). tumor have an underlying macromolecular basis for their The subtypes that we have listed have been noted in anatomical distinctiveness,evenif thesepatterns cannot be, many cancers by many investigators, most of whom have in at the present time, correlated with an unique phenotypic dicated that the commonest cancer of the pancreas is an biochemical process. There probably are severe limitations adenocarcinoma (1, 5, 7, 18, 23, 26, 30, 47, 48, 62). In con to the variety of morphological patterns that a cell can trast to our designation of duct adenocarcinoma as the manifest in reacting to carcinogenic factors. Nevertheless, principal type is the report of Baylor and Berg (5), who col the search for possible correlations should be pursued. lected the diagnoses from 8 cancer registries. Only 4.4% of Cell of Origin of Adenocarcinomas. Conceivably, the duct their cases were listed as â€œductaladenocarcinoma. â€œHow (or ductule) cell, the islet cell, or the acinar cell could give ever, 63% of the cancers were called â€œadenocarcinomaâ€• rise to the commonest type of adenocarcinoma since it is and another 23% were labeled as â€œcancerNOSâ€•(not other believed by most embryologists that the duct cell gives rise wise specified). Essentially similar results were reported to both the acinar and islet cells. By â€œdedifferentiation,â€•the from the Connecticut Cancer Registry (48). latter 2 might revert to an embryonic duct cell type and then We have not recognized the category of â€œpapillary be transformed to the carcinoma, or be transformed di adenocarcinoma,â€•reportedby Baylor and Berg (5) to occur rectly to a carcinoma. in 1.3% of their cases. In many duct cell adenocarcinomas The distinctive acinar cell with its abundant ergasto there are areas of papillary carcinoma, carcinomas of the plasm, a basal nucleus,and zymogen granules in the apical periampullary area tend to be papillary, and cystadenocar cytoplasm doesnot produce mucin. It would therefore have cinomas characteristically have considerable papillary car to lose its ability to synthesize zymogen granules and cinomatous foci. Our incidence of 1% and theirs ofO.2% for acquire a mucin-producing facility to give origin to the cystadenocarcinoma and the significantly better 3-year adenocarcinoma. The absence of zymogen granules by light survival figures for both groups suggest that their papillary or electron microscopic examinations in 28 consecutive

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1975 American Association for Cancer Research. Patterns of Pancreatic Carcinoma cases of duct adenocarcinoma does not suggest that transi papillary hyperplasia, usually more prevalent in the vicinity tion between the 2 cell types occurred. of the cancer and the larger ducts. Similar papillary (or The islet cells have distinctive tinctorial and morphologi adenomatous) hyperplasia occurred in about 9% of nonneo cal characteristics that permit one to identify by light plastic autopsies and in 28% of autopsies of diabetic microscopy a group of tumors that fit into that category. patients. Our higher incidence of papillary hyperplasia in The islet cell contains no mucigen and has no zymogen the pancreas cancer cases (42%) is consistent with these granules. Further separation into different islet cell groups findings. However, there was obstruction to the pancreas through the use of histochemical staining and electron duct in most of our cases, a complicating factor in the as microscopy examination and hormone production by the sessment of this ch: n@e. Birnstingl (8), in cases with a van tumor is possible (27). In none of the 28 cases diagnosed as ety of acute and c.ironic nonpancreatic diseases and no adenocarcinomas by light microscopy was there noted by cancer of the pancreas, reported an incidence of 29% having electron microscopy the distinctive granules of any type of hyperplastic columnar epithelium. islet cell. The greater percentage of mucous cell hypertrophy in the There appears to be no significant evidence supporting pancreas cancer cases is also complicated by the presence of the possibility that either the acinar cell or the islet cell duct obstruction and the lack of a more appropriate control â€œdedifferentiatesâ€•and gives rise to the commonest adeno group, one with duct obstruction without pancreas cancer. carcinoma. In situ carcinoma lesions were recognized in It was somewhat surprising to find less epidermoid duct epithelium adjacent to the primary lesion, further metaplasia in the pancreas cancer cases (6%) than in the supporting the claim of the duct cell as the cell or origin. nonpancreatic cases (12%) and such a low incidence of Ductule epithelium also could give rise to the duct cell changes in both groups. Sommers et al. (63) also noted that adenocarcinoma but the absence of mucin makes this cell a epidermoid metaplasia was not pronounced in pancreas less likely candidate for the cell of origin. cancer cases. Birnstingl (8) found an incidence of 8% in The duct cell would also be the favorite contender as the patients with acute and chronic disease but without pancreas cell type of origin for the mucin-producing microadenocar cancer. KorpÃ¡ssy (36) found epidermoid metaplasia of the cinoma, the adenosquamous carcinoma, the mucinous ade pancreas in 12% of 500 unselected, carefully studied autop nocarcinoma, the cystadenocarcinoma, and the giant-cell sies.This increasedto 29% in patients over 70 years old. adenocarcinom a. In 2 cases of cancer of the head of the pancreas, the in situ Whether an islet cell or an acinar cell gives rise to the carcinoma areas were in the body and tail of the pancreas other subgroups is not clear. Either would have to be some distance away from the primary tumor (Fig. 25). considered, as would the ductule cell, as a potential cell type Multicentnic origin of papillary carcinoma in the ducts of of origin in the non-mucus-producing anaplastic carcinomas the pancreas was noted by HabÃ¡n (29), a finding consistent and some unclassified tumors. with the multicentnicity of other human carcinomas. Duct Epithelium Changes Associated with Pancreas Cancer. Our figure of 19% ofthe cases showing a carcinoma in situ adjacent to the primary cancer is higher than the 3% References reported by Sommers et al. (63) in 141 autopsies of pancreas cancer cases collected from 3 hospitals. Whether this rep I. Arkin, A., and Weisberg, S. W. Carcinoma of the Pancreas, a Clinical resents differences in the amount of duct epithelium avail and Pathologic Study of Seventy-Five Cases. Am. J. Pathol., 13. able for study (we concentrated on 195 cases in which 118â€”126,1949. considerable duct epithelium was present) or because of 2. Auger, C. Acinous Cell Carcinoma ofthe Pancreas with Extensive Fat different criteria usedfor diagnosisis unknown. The results Necrosis. Arch. Pathol., 43: 400â€”405,1947. of both groups nevertheless suggest the possibility that there 3. Ayella, A. S., Jr., Howard, J. M., and Grotzinger, P. J. Cystadenoma may be a significant latent period between the appearance of and Cystadenocarcinoma ofthe Pancreas. Am. J. Surg., 103: 242â€”246, cancer in situ in duct epithelium and the grossly recogniza 1962. 4. Barron, B. A., and Richart, R. M. A Statistical Model ofthe Natural ble pancreas cancer, analogous to the long interval between History of Cervical Carcinoma Based on a Prospective Study of 557 carcinoma in situ of the human uterine cervix and invasive Cases. J. Nail. Cancer Inst., 4!: 1343â€”1353, 1968. cervical cancer (4, 20). Tempering the findings is the fact 5. Baylor, S. M., and Berg, J. W. Cross-Classification and Survival that in Bell's (7) 609 autopsies of cancer of the pancreas. Characteristics of 5,000 Cases of Cancer of the Pancreas. J. Surg. collected from many hospitals, only 2 were found inciden Oncol.,5.335â€”358,1973. tally at autopsy; the rest were diagnosed clinically. How 6. Becker, W. F. Cystadenoma and Cystadenocarcinoma of the Pan ever, it would not appear from this report that an intensive creas. Ann. Surg., 161: 845â€”860, 1965. search for in situ lesions was made. 7. Bell, E. T. Carcinoma of the Pancreas. I. A Clinical and Pathologic The incidence of 14% of cases showing marked atypia in Study of609 Necropsied Cases. II. The Relation ofCarcinoma of the the pancreas cancer group and none in the control group Pancreas to Diabetes Mellitus. Am. J. Pathol., 33: 499â€”523, 1957. 8. Birnstingl, M. A Study of Pancreatography. Brit. J. Surg., 47. would appear to be significant. It is consistent with the 128â€”139,1959. general finding in human cancer that, with primary cancers, 9. Bloom, W., and Fawcett, D. W. A Textbook of Histology, Ed. 9, pp. one frequently finds associated atypical hyperplasias, 101â€”104.Philadelphia: W. B. Saunders Co., 1968. marked atypia, and carcinoma in situ, the yield increasing 10. Broder, 1., and Carter, S. K. Pancreatic Islet Cell Carcinoma. I. with the amount of tissue studied. Clinical Features of 52 Patients. Ann. Intern. Med., 79: 101â€”118, Sommers et al. (63) found that 4 1% of their cases showed 1973.

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II. Burns, W. A., Matthews, M. J., Hamosh, M., Vander Weide, G., 351â€”356,1936. Blum, T., and Johnson, F. B. Lipase-Secreting Acinar Cell Carci 35. Kay, S., and Harrison, J. M. Unusual Pleomorphic Carcinoma of the noma of the Pancreas with Polyarthropathy. Cancer, 33: 1002- 1009, Pancreas Featuring Production of Osteoid. Cancer, 23: I I58â€”II62, 1974. 1969. 12. Cihak, R. W., Kawashima, T., and Steer, A. Adenocanthoma 36. KorpÃ¡ssy, B. Die Basalzellenmetaplasie der Ausfuhrungsgange des (Adenosquamous Carcinoma) ofthe Pancreas. Cancer, 29: I 133- I 140, Pankreas. Arch. Pathol. Anat. Physiol., 303: 359-373, 1939. 1972. 37. Leach, W. B. Carcinoma of the Pancreas. A Clinical and Pathologic 13. Comfort, M. W., Batt, H. R., Baggenstoss, A. H., Osterberg, A. E., Analysis ofThirty-nine Autopsied Cases. Am. J. Pathol., 26: 333â€”347, and Priestley, J. T. Acinar Cell Carcinoma of Pancreas: Report of 1950. Case in Which Function ofCarcinomatous Cells Was Suspected. Ann. 38. Lisa, J. R., Trinidad, S., and Rosenblatt, M. B. Pulmonary Manifesta Intern. Med., 19: 808â€”816, 1943. tions of Carcinoma of the Pancreas. Cancer, 17: 395â€”401,1964. 14. Cubilla, A. L., and Hajdu, S. H. Islet Cell Carcinoma ofthe Pancreas. 39. Longnecker, D., and Crawford, B. Hyperplastic Nodules and Adeno Arch. Pathol., 99. 204-207, 1975. mas of Exocrine Pancreas in Azaserine-Treated Rats. J. NatI. Cancer 15. Dollinger, M. R., Ratner, L. H., Shamoian, C. A., and Blackbourne, Inst., 53: 573â€”577, 1974. B. D. Carcinoid Syndrome Associated with PancreaticTumors. Arch. 40. Loquvam, G. S., and Russell, W. 0. Accessory Pancreatic Ducts of the Intern. Med., 120: 575â€”580, 1967. Major Duodenal Papilla. Normal Structures to Be Differentiated from 16. Duffy, B. J., Jr., and Fitzgerald, P. J. Cancer of the Thyroid in Cancer. Am. J. Clin. Pathol., 20: 305â€”313,1950. Children: A Report of Twenty-Eight Cases. J. Clin. Endocrinol. 41 . Lowry, C. C., Whitaker, H. W., Jr., and Greiner, D. J. Squamous Cell Metab.,10.1296-1308,1950. Carcinoma of the Pancreas. Southern Med. J., 42: 753â€”757, 1949. 17. Erlandson, R. A. A New Maraglas, D. E. R. 732, Embedment for 42. Mallory, F. B. Principles of Pathologic Histology, p. 391. Philadel Electron Microscopy. J. Cell Biol., 22: 704â€”709,1964. phia: W. B. Saunders Co., 1914. 18. Ewing, J. Neoplastic Diseases: A Treatise of Tumors, Ed. 1, p. 683. 43. McManus, J. F. A., and Mowry, R. W. Staining Methods, Histologic Philadelphia: W. B. Saunders Co., 1919. and Histochemical, pp. 126â€”128.NewYork: Paul B. Hoeber, Inc., 19. Farber, E., and Popper, H. Production of Acute Pancreatitis with 1960. Ethionine and Its Prevention by Methionine. Proc. Soc. Exptl. Biol. 44. McManus, J. F. A., and Mowry, R. W. Staining Methods, Histologic Med., 74: 838â€”840,1950. and Histochemical, pp. 136â€”138.New York: Paul B. Hoeber, Inc., 20. Fidler, H. K.. Boyes, D. A., and Worth, A. J. Cervical Cancer 1960. Detection in British Columbia. J. Obstet. Gynaecol. Brit. Common 45. McManus, J. F. A., and Mowry, R. W. Staining Methods, Histologic wealth, 75: 392â€”404, 1968. and Histochemical, pp. 138â€”139. New York: Paul B. Hoeber, Inc. 21. Fitzgerald, P. J., Herman, L., Carol, B., Roque, A., Marsh, W. H., 1960. Rosenstock, L., Richards, C., and Perl, D. Pancreas Acinar Cell 46. McMinn, R. M. H., and Kugler, J. H. The Glands of the Bile and Regeneration. I. Cytologic, Cytochemical and Pancreatic Weight Pancreatic Ducts: Autoradiographic and Histochemical Studies. J. Changes. Am. J. Pathol., 52: 983â€”1012,1968. Anat., 95. lll, 1961. 22. Frable, W. J., Still, W. J. S., and Kay, S. Carcinoma ofthe Pancreas, 47. Miller, J. R., Baggenstoss, A. H., and Comfort, M. W. Carcinoma of Infantile Type. A Light and Electron Microscopic Study. Cancer, 27: the Pancreas. Effect of Histological Type and Grade of Malignancy on 667-673, 1971. Its Behavior. Cancer, 4: 233â€”241, 1951. 23. Frantz, V. K. Tumors ofthe Pancreas. In: Atlas ofTumor Pathology, 48. Moldow, R. E., and Connelly, R. R. Epidemiology of Pancreatic Section VII, Fascicles 27 and 28, American Registry of Pathology. Cancer in Connecticut. Gastroenterology, 55. 677â€”686, 1968. Washington, D.C.: Armed Forces Institute of Pathology, 1959. 49. Moynan, R. W., Neerhout, R. C., and Johnson, T. S. Pancreatic 24. Glenner, G. G., and Mallory, G. K. The Cystadenoma and Related Carcinoma in Childhood. J. Pediat., 65: 71 1â€”720,1964. Nonfunctional Tumors of the Pancreas. Cancer, 9: 980â€”996, 1956. 50. Muir, E. G. â€œColloidâ€•Carcinoma of the Pancreas. Brit. J. Surg., 40: 25. Goldberg, R. C., Chaikoff, I. L., and Dodge, A. H. Destruction of 177,1952. Pancreatic Acinar Tissue by D-L-ethionine. Proc. Soc. Exptl. Biol. S1. Osborne, R. R. Functioning Acinous Cell Carcinoma of the Pancreas Med.,74:869â€”872,1950. Accompanied with Widespread Focal Fat Necrosis. Arch. Intern. 26. Gray, 1. W., Jr., Crook, J. N.,and Cohn, I., Jr. Carcinoma of the Med., 85: 933â€”943, 1950. Pancreas. NatI. Cancer Conf. Proc., 7: 503â€”510,1973. 52. Persaud, V., and Walrond, E. R. Carcinoid Tumor and Cystadenoma 27. Greider, M. H., Rosai, J., and McGuigan, J. E. The Human of the Pancreas.Arch. Pathol., 92: 28â€”30,1971. Pancreatic Islet Cells and Their Tumors. II. Ulcerogenic and Diar 53. Popper, H. The Heuristic Importance of Environmental Pathology. rheogenic Tumors. Cancer 33: 1423- 1443, 1974. Arch. Pathol., 99: 69â€”71,1975. 28. Guillan, R. A. Pleomorphic Adenocarcinoma of the Pancreas. An 54. Pour, P., Kruger, F. W., Althoff, J., Cardesa, A., and Mohr, U. Analysis of Five Cases. Cancer, 21: 1072â€”1079,1968. Cancer ofthe Pancreas Induced in the Syrian Golden Hamster. Am. J. 29. HabÃ¡n, G. Papillomatose und Carcinom des Gangsystems der Pathol., 76: 349â€”358, 1974. Bauchspeicheldruse. Arch. Pathol. Anat. Physiol., 279: 207â€”220,1936. 55. Probstein, J. G., and Blumenthal, H. T. Progressive Malignant 30. Halpert, B., Mark, L., and Jordan, 0. 1. A Retrospective Study of 120 Degeneration of a Cystadenoma of the Pancreas. Arch. Surg., 81: Patients with Carcinoma of the Pancreas. Surg. Gynecol. Obstet., 683â€”689, 1960. 121: 91-96, 1965. 56. Refetoff, S., Harrison, J., Karanfilski, B. T., Kaplan, E. L., DeGroot, 31. Hamoudi, A. B., Misugi, K., Grosfeld, J. L., and Reiner, C. B. 1. J., and Bekerman, C. Continuing Occurrence of Thyroid Card Papillary Epithelial Neoplasm of Pancreas in a Child. Report of a noma after Irradiation to the Neck in Infancy and Childhood. New Case with Electron Microscopy. Cancer, 26: I 126â€”1134,1970. Engl.J.Med.,292:171â€”175,1975. 32. Hartz, P. H., and van der Sar, A. Cancerous Cyst of Tail of Pancreas 57. Roberts, P. F. Pyloric Gland Metaplasia of the Human Pancreas. Simulating Carcinosarcoma. Am. J. Clin. Pathol., 16: 219â€”224,1946. Arch. Pathol., 97: 92â€”95,1974. 33. Hayashi, Y., and Hasegawa, T. Expcrmential pancreatic Tumor in 58. Roberts, P. F., and Burns, J. A Histochemical Study of Mucins in Rats after Intravenous Injection of 4-Hydroxyaminoquinoline-1- Normal and Neoplastic Human Pancreatic Tissue. J. Pathol., oxide. Gann, 62: 329â€”330, 1971. 107:87â€”94,1972. 34. Hemken, L. Gelatinous Carcinoma of Pancreas. Arch. Pathol., 2!: 59. Rosai, J. Carcinoma of Pancreas Simulating Giant Cell Tumor of

2240 CANCER RESEARCH VOL. 35

Bone: Electron-Microscopic Evidence of Its Acinar Cell Origin. 65. Tashjian, A. H., Jr., Howland, B. G., Melvin, K. E. W., and Hill, C. Cancer, 22: 333â€”344, 1968. S., Jr. Immunoassay of Human Calcitonin. Clinical Measurement, 60. Selikoff, I. J., Churg, J., and Hammond, E. C. Asbestos Exposure and p elation to Serum Calcium, and Studies in Patients with Medullary Neoplasia. J. Am. Med. Assoc., 188: 22â€”26,1964. Carcinoma. New Engl. J. Med., 283: 890â€”895, 1970. 61. Shinozuka, H., and Konishi, Y. Degenerative and Hyperplastic 66. Tsukimoto, I., Watanbe, K., Lin, J. B., and Nakajima, T. Pancreatic Changes in Rat Pancreatic Acinar Cells Induced by 4-Hydroxy Carcinoma in Children in Japan. Cancer, 2!: 1203â€”1207,1973. aminoquinoline-l-oxide. Am. J. Pathol., 74: 59a, 1974. 67. Warren, K. W., and Hardy, K. J. Cystadenocarcinoma of the 62. Sommers, S. C., and Meissner, W. A. Unusual Carcinomas of the Pancreas. Surg. Gynecol. Obstet., 127: 734â€”736, 1968. Pancreas. Arch. Pathol., 58.101â€”111, 1954. 68. Whitehead, R. Normal Appearances in Gastric Biopsy Specimens. In: 63. Sommers, S. C., Murphy, S. A., and Warren, S. Pancreatic Duct Mucosal Biopsy of the Gastrointestinal Tract, Vol. 3 in the series, Hyperplasia and Cancer. Gastroenterology, 27: 629-640, 1954. Major Problems in Pathology, J. 1. Bennington (ed), pp 7â€”15. 64. Sugiura, K., Pack, G. T., and Stewart, F. W. A Study ofthe Enzyme Philadelphia: W. B. Saunders Co., 1973. Content of a Parenchymatous Adenocarcinoma of Pancreas and a 69. Willis, R. A. Epithelial Tumours of the Pancreas. In: Pathology of Comparison with the Normal Human Pancreas. Am. J. Cancer, 26: Tumours, Ed. 4, pp. 445-455. London: Butterworth & Co. (Publish 351â€”357,1936. ers), Ltd., 1967.

Fig. 1. Duct adenocarcinoma. Fairly-well-differentiated adenocarcinoma resembling pancreatic ductal epithelium. There is desmoplastic reaction. H & E,x 136. Fig. 2. Duct adenocarcinoma. Fairly-well-differentiated adenocarcinoma showing a variety of large and small glands and desmoplastic reaction. H & E, x 136. Fig. 3. Giant-cell carcinoma. Bizarre tumor giant cells with huge, often irregular, sharply defined, dark nuclei and abundant deeply staining cytoplasm are present. H & E, x 250. Fig. 4. Giant-cell carcinoma. Peritoneal implant showing a focal area of fairly-well-differentiated glands (left) in the presence of many tumor giant cells. H & E, x 148. Fig. 5. Microadenocarcinoma. Solid configuration ofcancer cells intermixed with small glands. H & E, x 54. Fig. 6. Microadenocarcinoma. Predominantly microglandular cancer with intervening small cells. H & E, x 136. Fig. 7. Electromicrogram of benign pancreatic duct epithelium in head of the pancreas. Cancer of ampulla giving pancreas duct obstruction was present. Hypertrophy ofmucous cell with apical mucigen globules. x 16,000. Fig. 8. Electromicrogram of well-differentiated adenocarcinoma of head of pancreas. Mucigen globules are present in apical cytoplasm of 2 cells. No zymogen granules present. x 17,600. Fig. 9. Adenosquamous carcinoma. Fairly-well-differentiated adenocarcinoma with a squamous cell carcinoma component. H & E, x 136. Fig. 10. Adenosquamous carcinoma. Electromicrogram of an adenosquamous carcinoma cell showing tonofibrils (black wavy lines). H & E, x 6,720. Fig. I I . Mucinous adenocarcinoma. Pools of mucus subdivided by collagenous septae. Only a few carcinoma cellular elements are present. H & E, x 35. Fig. 12. Mucinous adenocarcinoma. Similar to Fig. 11 except that carcinoma cells are present (lower center and upper right cysts). H & E, x 56. Fig. I3. Cystadenocarcinoma. Cystic areas with cyst wall lined by papillae of mostly columnar mucinous epithelium with small foci of cells running a gamut fromhyperplasia to marked atypia to carcinoma. H & E, x 62. Fig. 14. Cystadenocarcinoma. Papillary variety of cystadenocarcinoma illustrating the complex arborizing labyrinthine structure. H & E, x 54. Fig. I 5. Acinar-cell carcinoma. Metastatic nodule of mostly fairly-well-differentiated acini and acinar cells. Undifferentiated or poorly differentiated cells, left upper and left lower regions. H & E, x 54. Fig. 16. Acinar cell carcinoma. Same as in Fig. 15, different field, showing many acini with basal nuclei and abundant apical dense cytoplasm. As is usual with formalin fixation and hemotoxylin and eosin staining, zymogen granules are not distinct. H & E, x 136. Fig. 17. Acinar-cell carcinoma. Electromicrogram of the same case as Figs. 15 and 16. Marked postmortem autolysis. However, characteristic zymogen granules are present, although somewhat autolyzed. Specimen fixed 12 hr postmortem. x 15,600. Fig. I8. Anaplastic carcinoma. Diffuse infiltration of varying sized cells with large nuclei and relatively little cytoplasm. There are nests of tumor cells surrounded by thin fibrous septae. H & E, x 350. Fig. 19. Carcinoma of childhood. Tumor of the head of the pancreas in a 3-year-old boy. There are areas of anaplastic small cells, small gland formations, foci of squamous elements. H & E, x 56. Fig. 20. Papillary hyperplasia of pancreatic duct. Tissue from area adjacent to cancer of head of the pancreas. Papillae of orderly hyperplastic epithelium showing periodic acid-Schiff-positive material (black) in apex of cell (left). Stained areas at base of papillae (black, right represent pyloric gland metaplasia. H & E, x 62. Fig. 21. Atypical papillary hyperplasia and carcinoma in situ. A pancreatic duct showing atypical papillary hyperplasia with a focal area of carcinoma in situ. Tissue taken from area close to carcinoma of head of pancreas. Periductal fibrosis present. H & E, x 52. Fig. 22. Carcinoma in situ. A large pancreatic duct showing intraductal carcinoma. Note the cribriform pattern, loss of polarity, and nuclear and other cytological abnormalities. Tissue adjacent to invasive duct adenocarcinoma. H & E, x 140. Fig. 23. Carcinoma in situ. Enlargement of lower left zone of Fig. 21 showing focus in in situ carcinoma. Variation in size and shape of nuclei, loss of nuclear and cell polarity, and increased condensation and abnormal distribution of nuclear chromatin. H & E, x 340. Fig. 24. Carcinoma in situ. Small duct near carcinoma of head of pancreas. Lower area, cells and nuclei with marked variation in size, shape, staining, and polarity of nuclei. H & E, x 340. Fig. 25. Carcinoma in situ. Large duct in body of pancreas in case with cancer at head of pancreas. Carcinoma in situ with papillary features. H & E, x 340.

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