[CANCER RESEARCH 35, 2234-2248, August 1975]

Summary

The study of histological sectionsof 406 casesof nonendocrine pancreas carcinoma at Memorial Hospital mdicated that morphological patterns of pancreas carcinomacould be delineated as follows: duct cell adenocarcinoma(76%), giant-cell carcinoma (5%), microadenocarcinoma(4%), adenosquamous carcinoma (4%), mucinous adenocarcinoma (2%), anaplastic carcinoma (2%), cystadenocarcinoma ( 1%), acinar cell carcinoma (1 %), carcinoma inchildhood (under 1%), unclassified (7%).

In 195 cases of patients with pancreas carcinoma, searchwas made for changes in the pancreas duct epithelium andthese were compared to duct epithelium in a control groupof 100 pancreases from autopsies of patients with nonpancreatic cancer. The following incidences were found forpancreas cancer and nonpancreatic cancer, respectively:mucous cell hypertrophy, 39 versus 28%; pyloric glandmetaplasia, 28 and 17%; epidermoid metaplasia, 6 and 12%;papillary hyperplasia, 42 and 12%; atypical duct hyperplasia, 14% and none; carcinoma in situ in 19% and none inthe control group.

Mucin in the majority of pancreas cancers suggested thatthe cell type of origin of the common pancreas cancer is themucin-producing duct epithelium. The association ofatypias and carcinomas in situ in the patients with pancreascarcinoma implies, by analogy to other organs, that theremay be a significant latent period between the appearance ofcarcinoma in situ and the grossly recognizable pancreascancer.

Introduction

The morphological classification of primary pancreascarcinomas of the nonendocrine variety would seem to poseno problem to the pathologist because most of these cancersare adenocarcinomas and they span the spectrum commonly found with adenocarcinomas of other organs. Originally, Ewing ( 18), from this laboratory, described only 2types of pancreascancers,cylindrical cell adenocarcinomaarising from the ducts and carcinoma simplex arising from

1 Presented at the Symposium “Current Progress in Pancreatic Car

cinogenesis Research,― February 4, 1975, Orlando, Fla., as part of theThird Annual Carcinogenesis Conference. Aided by Contract NOlCP-43232 from the National Cancer Institute, NIH, Bethesda, Md.

2 Presenter.

the parenchymal cells. In the subsequent 5 decades termssuch as mucous adenocarcinoma, colloid carcinoma, ductadenocarcinoma, pleomorphic cancer, papillary adenocarcinoma, cystadenocarcinoma, and other variants, such asepidermoid carcinoma, mucoepidermoid cancer, giant-cellcarcinoma, adenoacanthoma, and acinar cell carcinoma,have appeared (7, 18, 23, 47, 62). Subtypes of islet-celltumors have been defined (27). As pointed out by Baylorand Berg (5) in discussing the limitations of their study of5000 patients with pancreas cancer from 8 cancer registries,few pathologists precisely characterize the microscopicfeatures of their cases.

We have reviewed cases of cancer of the pancreas atMemorial Hospital to determine whether there are definable morphological subgroups and to indicate their relativedistribution in our material. The delineation of morphological patterns of pancreas cancer may eventually permit acorrelation with some genetic, biochemical, endocrinological, clinical, epidemiological, prognostic, or other parameter of significance and thereby further an understanding ofthis neoplasm that appears to be increasing and has such apoor prognosis for the patient at the present time.

Materials and Methods

From a survey of 757 cases listed as cancer of thepancreas in the Cancer Registry, Clinical InformationCenter, Memorial Hospital, during the years 1949 through1972, we have been able to examine histological sections oftissue from 503 cases. Sixty-seven were eliminated from thestudy for the following reasons: in 42 cases biopsy materialdid not show any cancer; 3 cases were reclassified asperiampullary carcinoma; 7 cases were reclassified asmetastatic cancer (2 casesof oat-cell carcinoma of lung; 1case each of adenocarcinoma of the lung, breast, and colon;I malignant lymphoma; and 1 embryonal rhabdomyo@arcoma of the retroperitoneum); in 13 cases aspiration biopsies did not furnish enough tissue for classification; 1 debatable case w@sof either gastric or pancreas origin; and 1tumor was believed to be of common bile duct origin ratherthan of pancreatic duct. Thirty cases of malignant islet-celltumor, recently reported from this laboratory (14), werealso excluded.

Cases coded as ampullary or periampullary cancer,duodenal cancer, islet-cell tumors, or retroperitoneal tumors involving the pancreas were not examined, and

CANCER RESEARCH VOL. 352234

Morphological Patterns of Primary Nonendocrine Human PancreasCarcinoma'

Antonio L Cubifla and Patrick J. Fitzgerald2Department of Pathology, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York UX@21

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No.ofcases%Duct

celladenocarcinoma30876Giant-cellcarcinoma195Microadenocarcinoma154Adenosquamous

carcinoma144Mucinousadenocarcinoma72Anaplasticcarcinoma62Cystadenocarcinoma31Acinar-cell

carcinoma3ICarcinomainchildhood10.3Unclassified307Total406102

Patterns of Pancreatic Carcinoma

interpretation made on the small sampling of a tumor,which was sometimes restricted to only a few slides. Therewere some cases (7%) where admixtures oftypes occurred sothat they were listed as unclassified. A much largersampling might change the subtyping of cancers or theincidence of changes in duct epithelium.

Results

Nonendocrine Pancreas Neoplasms

Benign Epithelial Nonendocrine Neoplasms. We were ableto examine histological material from only 7 cases of benignepithelial nonendocrine neoplasms (3 serous and 4 mucinouscystadenomas) and from I case containing a microscopicfocus of adenomatous hyperplasia of acinar cells foundincidentally at autopsy.

Malignant Epithelial Neoplasms. We have classified primary malignant lesions of the nonendocrine pancreas underthe general headings of carcinomas (Table 1), sarcomas,primary malignant lymphomas, a miscellaneous group, andmetastatic cancer. We estimate that over 95% of themalignant lesions of the nonendocrine pancreas are adenocarcinomas and the following appear to be distinctive types.

Duct Cell A denocarcinoma [Adenocarcinoma, Cylindrical-Cell Adenocarcinoma (18), Papillary Adenocarcinoma(23), Pancreas Cancer (5)]. In the normal duct system of thehuman pancreas there is variation from the flat to cuboidalepithelium of the smallest ductules to the high columnarmucouscell ofthe epithelium in the headofthe pancreas(9,24). There is absence of mucin in the smallest ductules, asindicated by the negative mucin stains, and the presence ofmucin, indicated by a positive mucin stain, in the apicalregion of the columnar cell of the duct epithelium, particularly in the larger ducts (24, 46). By electron microscopy itcan be demonstrated that droplets of mucigen are present inthe duct epithelium (9) (Fig. 7) and not in the smallestepithelial cells of the ductules.

Our cases of duct adenocarcinomas were similar to theadenocarcinomas seen elsewhere in the biliary tract, gastrointestinal tract, lung, and other organs (Figs. I and 2).There was a mixture of large and small glands, often with I

Table I

Classification of nonendocrine pancreas carcinomas

possibly a few pancreas cancers were thereby lost to ourstudy.

In 406 cases there was an operative biopsy ofa pancreatictumor; a confirmation of a pancreas cancer in the surgicallyresected pancreas, or autopsy specimen; or, in associationwith a lesion clearly defined in the operative notes as apancreatic tumor, there was a biopsy taken of a regionallymph node, or of a metastatic lesion, which revealed aneoplasm consistent with pancreas cancer. In 29 1 casestissue diagnostic of pancreas cancer was obtained at operation, and in 115 casesthe tissue was obtained at autopsy. In99 cases surgically resected (partial or total) pancreas tissue

was studied. Histological slides of the primary tumor variedfrom 4 to 9, but often only 1 or a few, slides of themetastasis were available. Additional slides, particularlyfor the demonstration of mucin, were cut from the paraffinembedded block in 53 cases.

Recently, we have obtained for electron microscopyultrastructural studies pancreas cancer tissue removed atoperation in 28 cases and from autopsy in 3 cases (notincluded in the morphological classification study).

In 214 cases (99 cases of partial or total pancreatectomyand 115 autopsies), additional study of the pancreas cancermaterial for associated hyperplasia, metaplasia, atypias, orcarcinoma in situ changes in the duct epithelium wasattempted. Nineteen cases were rejected because of autolysis ofduct epithelium or insufficient ductal tissue present inthe histological slides, leaving 195 cases with adequatematerial. Pancreases from 100 consecutive autopsies (performed in 1973) of patients with nonpancreatic cancers,similar in age and sex to the pancreascancer cases,wereused as controls. Patients were subjected to differentregimensof chemotherapy or radiotherapy in the 2 groups,and no corrections were made for these factors. Four to 9histological sections from each pancreas of the 2 groupswere examined.

Standard fixation in 10% formalin solution and stainingwith hematoxylin and eosin were used for all tissues. Meyer'smucicarmine stain (45) wasusedto demonstratemucin, andthe periodic acid-Schiff (43) and Alcian blue stains (44)were used to indicate pyloric gland metaplasia (57, 58, 68).

The tissue for electron microscopy was fixed overnight inKarnovsky fixative, rinsed in buffer (s-collidine), and postfixed for 1 hr in 1% osmium tetroxide. The specimens wereembedded in epoxy resin (Maraglas) and stained withuranyl acetate followed by lead citrate, and examined in aSiemens-Elmiskop 101 electron microscope (17). Materialfrom one of our acinar cell carcinomas was taken fromautopsy “wet―tissue kept in 10% aqueous formalin solutionfor 8 months. Autopsy had been performed 12 hr postmortem.

In the attempt to subclassify the cases it was required thatfor a case to fall into one of the groups a predominant,consistent pattern must have beenpresentthroughout mostof the tissue. In the cases where both a primary andmetastatic lesion were available, the same morphologicalfeatures had to be present in both lesions, with fewexceptions. It was fully realized that the quest for aconsistent morphological structure, or for changes associated with cancer, was a difficult one involving subjective

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A. L. Cubilla and P. J. Fitzgerald

size predominating, but because of much overlapping welumped all cases altogether (23). Areas of well-differentiated adenocarcinoma to foci of poorly differentiatedglandular configurations were present. The glands werelined by tall columnar or cuboidal cells. The nucleus wasusually round to oval and was located in the base of the cell.The cytoplasm varied from a watery clear to darker pink,most often resembling the cytoplasm of the cells of the largepancreatic ducts or the biliary tract epithelium. Mucicarmine, periodic acid-Schiff or Alcian blue stained thecytoplasm usually at the apical portion, or luminal border.Occasionally, goblet cells were present. Desmoplastic response was usually considerable (Fig. 2), and often scleroticareas revealed only a few glands separated by dense bandsof collagen.

Focally, mucinous cells, “signet-ring―cells, papillarycarcinoma, and small tubular patterns of adenocarcinomawere observed. Some glands were so well differentiated thatwhen they were present in the periampullary region it wasdifficult to distinguish the tumor from the normal glandsfound in this area (40). Pancreatic duct adenocarcinomawhen metastatic to the lung occasionally simulated primaryadenocarcinoma of the lung (37, 38).

Electron microscopic study of 28 duct adenocarcinomasshowed in many cases globules of mucigen usually in theapical cytoplasm (Fig. 8), but in some cases none waspresent. In cases with duct obstruction and no pancreascancer, there appeared to be mucous cell hypertrophy withmore than the usual amount of mucigen in the cytoplasm(Fig. 7). Zymogen granules were not present in any case.

Giant-Cell Carcinoma [Pleomorphic (28, 35), Medullary(62), Sarcomatoid (47), or Carcinosarcoma (23, 32)]. Thegiant-cell carcinoma appeared to be a distinctive type (Fig.3), although it was not specific for the pancreas. It wascharacterized by the presence of huge cells with very large,pleomorphic, often vacuolated nuclei, containing prominentnucleoli and abundant coarse nuclear chromatin. Thecytoplasm was abundant, dense, and stained heavily witheosin. Phagocytosis was seen occasionally. The tumor cellresembled similar cells seen in melanoma, hepatocellularcarcinoma, choriocarcinoma, rhabdomyosarcoma, and thegiant- and spindle-cell carcinomas of the thyroid and lung.Areas of spindle malignant cells were usually present andsometimes made up a large part ofthe tumor. With multiplesections of these tumors, one could find in most of the casesareas ofadenocarcinoma contiguous to the giant tumor cells(Fig. 4) (conversely, in some duct adenocarcinomas of thepancreas, or in adenocarcinomas of other organs, small fociof giant cells can be demonstrated). Only when the predominant mass of tissue was composed of giant cells was the caseassigned to the giant-cell category. No case of carcinoma ofthe pancreas simulating the giant cell tumor of the bone,believed to be of acinar cell origin by Rosai (59), waspresent.

Microadenocarcinoma. This neoplasm usually consistedof an intimate combination of 2 types of tissue: nests of smallto intermediate-sized cells without glands or interveningstroma, or intercellular substance, and small glands (Figs. 5and 6). The mucicarmine stain was positive in many suchglands. Usually, within a microscopic field both elements

were recognizable, with either the solid or glandular component predominating. In most areas the microadenocarcinoma was predominant and large foci of necrosis werepresent. Sometimes the adenocarcinoma resembled thebiliary-pancreas duct epithelium; in other cases it resembledmore the gastrointestinal types. The pattern is also seen incolon cancer and adenocarcinomas of other organs. Wedebated whether this should be called solid microadenocarcinoma becauseof the frequent presenceof areas of solidmasses of small cells, but becaase the microadenocarcinomapredominated in many of our cases we decided to name thetype by its predominant component. Both componentsweremalignant in all of our 15 carcinomas.

A denosquamous Carcinomas [A denoacanthoma (12),Mucoepidermoid Carcinoma (23), Squamous Carcinoma(41)]. A characteristic pattern of the adenosquamous carcinoma was the presence of 2 components, an adenocarcinoma and a squamous cell carcinoma (Fig. 9). The glandularareas varied in their differentiation from well to poorly differentiated. In the 3 cases tested where there was a questionasto whether mucin waspresent,all gavea positive stain formucin, either in glandsor in the individual adenocarcinomacells. The squamous pattern was characterized by epithehum with whorls, keratohyalin, or “pearls.―Occasionally,intercellular bridges were present. By electron microscopyone could demonstrate tonofibrils (Fig. 10). In 1 case onlysquamous carcinoma was present in the metastatic lesion.The metastatic lesions had the same pattern as the primarytumor in all other cases. Both the glandular and thesquamous components were malignant in all ofour 14 cases.

Mucinous A denocarcinoma [Colloid (23, 50), Gelatinous(34), or Mucoid Carcinoma (69)]. Mucinous adenocarcinoma was a distinctive type, characterized by the presenceof huge multiloculated pools of mucus (Fig. 11), sometimes with very few cells being present. The cells were oftenflattened or compressed in the periphery against a c@llagenstroma, so that one found in both primary and metastaticareas large pools of mucus in a relatively acehular fieldseparated by strands of collagen. Usually, there were smallfoci or individual cells of adenocarcinoma discernible (Fig.12). In I case there were diffuse, isolated foci of “signetring―carcinoma cells in the mucus pool. A similar pattern isseen occasionally in the breast, gastrointestinal tract, andother organs.

Cystadenocarcinoma [Papillary Cystadenocarcinoma (3,6, 55, 67)]. This appears to be a malignant variation of the

benign cystadenoma with cysts of varying size and contents,separated by collagen strands and lined at the peripherywith epithelium (Fig. 13). In the cystadenocarcinoma, theepithelium ran a gamut from flat cells to papillae ofmalignant epithelium projected into and filling the cyst (Fig.14). Generally, the malignant epithelium showed loss ofpolarity, hyperchromicity, and bizarre nuclei with veryheavy nuclear chromatin. Mitotic figures were present.Some cysts were empty, or more often they had serous ormucinous contents. Cystadenocarcinoma has to be distinguished from a duct adenocarcinoma with focal papillaryfeatures, or cystic degeneration, or one with duct carcinomaproducing obstruction and dilation of the ducts. Our 3 casesshowed mucin in the cyst contents.

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Patterns of Pancreatic Carcinoma

A cinar Cell Carcinoma [Parenchymatous Adenocarcinoma (18, 64)]. The structure of the normal acinar cellwith its basal nucleus and prominent nucleolus surroundedby extensiveergastoplasmand the apical zymogengranulesis well known (9).

Our few cases showed gland formation, tubular arrangement, and somewhat random mixtures ofvarious configurations of acini (Figs. 15 and I6). Usually, in the cell there wasconsiderable deeply staining cytoplasm, a basal nucleus,and, as in many carcinomas, nests of malignant cells thatdid not retain the characteristic configuration of the normalgland but appeared as sheets of smaller malignant cells. Insome cells zymogen granules could be discerned, but in mostof the slides there was only a diffuse, nonparticulate pink tored cytoplasm. A few foci resembled islet cells. No enzymestudies were done to confirm the presence or absence of theusual pancreas exocrine enzymes. In I case we were able toobtain formalin-fixed “wet―tissue and examine it byelectron microscopy. There was much nuclear and cytoplasmic autolysis, but typical zymogen granules, fewer innumber than in normal acinar cells and somewhat autolyzedbut still recognizable (Fig. 17), were present in many cells.None of the 3 casesgaveany evidenceof the production ofexcessive amounts of enzyme activity.

A naplastic Carcinoma [Indeterminate Carcinoma (47)1.There were 6 cases in which differentiation of a small,diffusely infiltrating cell was so limited that it was notpossible to place the cell type, or pattern ofgrowth, in any ofthe above groups. Because the cells grew in nests or chordsof cells they were placed in the general category ofcarcinomas (Fig. 18). However, in view of the absence ofelectron microscopy and other studies, this assignment wasprovisional. The mucin stain wasnegativein 3 ofthe 3 casestested.

Cancer of the Pancreas in Childhood [Infantile Type(22)]. One tumor was found in a 3-year-old child. Therewere areas of small-cell adenocarcinoma, squamous-cellelements, malignant spindle cells, and benign areas ofmesenchymal tissue, including bone, found in a tumor of thehead of the pancreas (Fig. 19). A similar case has beendescribed by Frable et a!. (22). Another case in a child, notincluded in this study, was seen in consultation by Dr. FrankW. Foote, Jr., who noted that the structure was that of apapillary cystadenoma resembling a case described byFrantz (Ref. 23, Fig. 13). An apparently similar case hasbeen recorded (3 1). Other cases in children have beenreported (49, 66).

Unclassified Cancer. There was a significant percentageof tumors (7%) of cases that were difficult to classify. Mostshowed poor, or partial, formation of glands or ducts.Mucin was demonstrated in some cases. In other cases thepattern was solid, or trabecular, without mucin. Some casespresented with small glands, or gland-like structures.

Metastatic Cancer (23)

In 100 consecutive autopsies of adults from this hospitalwith a primary cancer other than pancreas, roughly similar

in age and sex to our pancreas cases, 16 showed metastasisto the pancreas. The most common primary sites were lung,melanoma of the skin, and diffuse malignant lymphoma, 3cases ofeach. The primary cancers in the other 7 cases were1 each from a variety of organs.

Miscellaneous

Although in this study no ciliated (23, 42, 62), carcinoid(52)(69),or oncocytictumor(31)wasincluded,thesecellsare normal, although rare, constituents of duct epitheliumand, presumably, tumors of these cell types will appear,rarely. From this hospital there has been reported (15) acase of carcinoid syndrome the cell type of which wasuncertain, being either of islet-cell or of carcinoid origin.We have not included the case in this report.

Associated Duct Cell Changes

Hypertrophy of mucous cells (Fig. 7) was more prevalentin the pancreas cancer cases than in the control group (39versus 28%, respectively). Pyloric gland metaplasia (57, 58,68) (Fig. 20) was slightly greater in the pancreas cancergroup (28 versus 17%). Epidermoid (squamous) metaplasiaof duct epithelium was less frequent in pancreas cancerpatients (6%) than in the patients with cancer of otherorgans ( I2%). Papillary hyperplasia (63) was seen in 42% ofpancreas cancer cases (Fig. 20) and in 12% of the patientswith nonpancreatic cancer. Marked atypia of duct epithehum (Fig. 21) was found in 14% of our pancreas cancercases, but none was noted in the pancreases of 100 autopsiesof patients with nonpancreatic cancer. In l9%.ofcases withpancreas cancer, there were associated carcinoma in situchanges of the duct epithelium. In none of the controlnonpancreatic cancer cases did we find in situ lesions.Usually, the in situ changes (Figs. 22 to 25) were associatedwith areas of papillary hyperplasia and/or marked atypiaand most often were found adjacent to the primary tumor.However, in 2 cases of cancer of the head of the pancreas, insitu changes were present in the body, and/or tail of thepancreas (Fig. 25).

Prevalence of Subtypes

The categories of carcinomas, their incidence, and therelative percentages of metastasis to the pancreas fromother organs represent findings in patients of a cancerhospital and may not be representative of the generalpopulation.

Discussion

Histological Types. One may legitimately question thevalue of subclassification of pancreas cancer at the presenttime because most patients die within I year from the onsetof symptoms. In addition, there is the possibility that 1category might merely represent a minor variation of

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another group, e.g., the giant-cell carcinoma might represent an accelerated growth rate of the duct adenocarcinoma.However, there were 19 cases of the giant-cell variety with adistinctive, fairly uniform structure and it might be instructive from a conceptual viewpoint to know why this difference occurred even if the 2 types represented essentially thesame tumor. One subgroup, widely recognized as havinga characteristic appearance, the cystadenocarcinoma, seemsto have a better prognosis than the other types and is,thereby, different in both morphological structure andbiological behavior (5, 6, 67). The acinar cell carcinoma ismorphologically recognizable, particularly if electron microscopy is used, and occasionally it continues to synthesizethe enzymes characteristic of the cell type (2, 11, 13, 5 1, 64).

It is possible that chemotherapeutic compounds will befound that have differential effects on the cancer subtypes,just as ethionine has been shown to affect the normal acinarcell more than it does the normal duct, or islet, cellepithelium (19, 21, 25), or as streptozotocin has beendemonstrated to cause more damage to the a-islet cell thanit does to other pancreas cell types (10).

Occasionally, as in tumors of other organs, a specifichistological type will be the characteristic expression of anenvironmental factor, e.g., mesothelioma of the lung inasbestos workers (60) and the recently reported angiosarcoma of the liver in polyvinyl chloride workers (53). A celltype may give rise to a specific hormonal response, such asthe medullary carcinoma of the thyroid C-cell and itsproduction of the calcitonin hormone (65). Usually, there isnot a clean-cut relationship between morphology and anetiological agent.

One of our adenosquamous cancer patients had 2 othercancers, as well as the adenosquamous cancer, develop ina radiated field, the latter 30 years after the radiotherapy.This is somewhat reminiscent of the thyroid cancers developing subsequent to “thymic―radiation in infancy (16, 56).One of 4 adenosquamous cancers in the population ofHiroshima appeared in a person exposed to the atomicbomb radiation (12).

The subtypes that we have listed have been noted inmany cancers by many investigators, most of whom have indicated that the commonest cancer of the pancreas is anadenocarcinoma (1, 5, 7, 18, 23, 26, 30, 47, 48, 62). In contrast to our designation of duct adenocarcinoma as theprincipal type is the report of Baylor and Berg (5), who collected the diagnoses from 8 cancer registries. Only 4.4% oftheir cases were listed as “ductaladenocarcinoma. “However, 63% of the cancers were called “adenocarcinoma―and another 23% were labeled as “cancerNOS― (not otherwise specified). Essentially similar results were reportedfrom the Connecticut Cancer Registry (48).

We have not recognized the category of “papillaryadenocarcinoma,―reported by Baylor and Berg (5) to occurin 1.3% of their cases. In many duct cell adenocarcinomasthere are areas of papillary carcinoma, carcinomas of theperiampullary area tend to be papillary, and cystadenocarcinomas characteristically have considerable papillary carcinomatous foci. Our incidence of 1% and theirs ofO.2% forcystadenocarcinoma and the significantly better 3-yearsurvival figures for both groups suggest that their papillary

carcinoma cases would have been classified as cystadenocarcinomas by us.

The microadenocarcinoma pattern, although present infoci of tumors from many organs, particularly the colon,has not. to our knowledge, been set aside previously as atype of pancreas cancer. It may represent a variant of theduct adenocarcinoma, or possibly carcinoid, but enoughcases showed this consistent appearance to warrant the suggestion that this might be a distinct entity.

The anaplastic group of tumors also appears to be arecognizable cell type, but until electron microscopy, histochemical, or biochemical studies are performed its cell oforigin is uncertain. This tumor type is present in many otherorgans.

The acinar cell carcinoma has been widely recognized. In3 reports the incidence of this lesion has differed from ourfigures [15% in 1 group (37), 13% in a 2nd (47), and 11% inthe 3rd (62)], higher than the 1% found in our patients. Onlyif very-well-differentiated acini, or acinar cells, were present in some foci would we include the cases in this categoryand possibly we have thereby excluded poorly differentiatedacinar cell tumors. Frantz (23) and others (30, 48) remarkedthat the type was rare.

The extreme rarity of acinar cell adenomas of the pancreas in humans is surprising because adenomas and adenomatous lesions have been produced experimentally inanimals by azaserine (39), nitrosoamines (54), and 4-hydroxyaminoquinoline 1-oxide (33, 61). Our only case of benign acinar cell lesion was a microscopic focus of adenomatous hyperplasia. Cystadenomas were more frequent in ourmaterial. Our 7 cases were fairly representative of theselesions. Glenner and Mallory (24) collected 36 such casesfrom 6 Boston hospitals.

Whether these histological subtypes represent a spectrumof random morphological expressions of a single process orwhether they are the result of multiple different carcinogenic factors, each giving rise to a characteristic type, isunknown. It is assumed that morphological aspects of atumor have an underlying macromolecular basis for theiranatomical distinctiveness,evenif thesepatterns cannot be,at the present time, correlated with an unique phenotypicbiochemical process. There probably are severe limitationsto the variety of morphological patterns that a cell canmanifest in reacting to carcinogenic factors. Nevertheless,the search for possible correlations should be pursued.

Cell of Origin of Adenocarcinomas. Conceivably, the duct(or ductule) cell, the islet cell, or the acinar cell could giverise to the commonest type of adenocarcinoma since it isbelieved by most embryologists that the duct cell gives riseto both the acinar and islet cells. By “dedifferentiation,―thelatter 2 might revert to an embryonic duct cell type and thenbe transformed to the carcinoma, or be transformed directly to a carcinoma.

The distinctive acinar cell with its abundant ergastoplasm, a basal nucleus,and zymogen granules in the apicalcytoplasm doesnot produce mucin. It would therefore haveto lose its ability to synthesize zymogen granules andacquire a mucin-producing facility to give origin to theadenocarcinoma. The absence of zymogen granules by lightor electron microscopic examinations in 28 consecutive

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Patterns of Pancreatic Carcinoma

cases of duct adenocarcinoma does not suggest that transition between the 2 cell types occurred.

The islet cells have distinctive tinctorial and morphological characteristics that permit one to identify by lightmicroscopy a group of tumors that fit into that category.The islet cell contains no mucigen and has no zymogengranules. Further separation into different islet cell groupsthrough the use of histochemical staining and electronmicroscopy examination and hormone production by thetumor is possible (27). In none of the 28 cases diagnosed asadenocarcinomas by light microscopy was there noted byelectron microscopy the distinctive granules of any type ofislet cell.

There appears to be no significant evidence supportingthe possibility that either the acinar cell or the islet cell“dedifferentiates―and gives rise to the commonest adenocarcinoma. In situ carcinoma lesions were recognized induct epithelium adjacent to the primary lesion, furthersupporting the claim of the duct cell as the cell or origin.Ductule epithelium also could give rise to the duct celladenocarcinoma but the absence of mucin makes this cell aless likely candidate for the cell of origin.

The duct cell would also be the favorite contender as thecell type of origin for the mucin-producing microadenocarcinoma, the adenosquamous carcinoma, the mucinous adenocarcinoma, the cystadenocarcinoma, and the giant-celladenocarcinom a.

Whether an islet cell or an acinar cell gives rise to theother subgroups is not clear. Either would have to beconsidered, as would the ductule cell, as a potential cell typeof origin in the non-mucus-producing anaplastic carcinomasand some unclassified tumors.

Duct Epithelium Changes Associated with PancreasCancer. Our figure of 19% ofthe cases showing a carcinomain situ adjacent to the primary cancer is higher than the 3%reported by Sommers et al. (63) in 141 autopsies of pancreascancer cases collected from 3 hospitals. Whether this represents differences in the amount of duct epithelium available for study (we concentrated on 195 cases in whichconsiderable duct epithelium was present) or because ofdifferent criteria usedfor diagnosisis unknown. The resultsof both groups nevertheless suggest the possibility that theremay be a significant latent period between the appearance ofcancer in situ in duct epithelium and the grossly recognizable pancreas cancer, analogous to the long interval betweencarcinoma in situ of the human uterine cervix and invasivecervical cancer (4, 20). Tempering the findings is the factthat in Bell's (7) 609 autopsies of cancer of the pancreas.collected from many hospitals, only 2 were found incidentally at autopsy; the rest were diagnosed clinically. However, it would not appear from this report that an intensivesearch for in situ lesionswas made.

The incidence of 14% of cases showing marked atypia inthe pancreas cancer group and none in the control groupwould appear to be significant. It is consistent with thegeneral finding in human cancer that, with primary cancers,one frequently finds associated atypical hyperplasias,marked atypia, and carcinoma in situ, the yield increasingwith the amount of tissue studied.

Sommers et al. (63) found that 4 1% of their cases showed

papillary hyperplasia, usually more prevalent in the vicinityof the cancer and the larger ducts. Similar papillary (oradenomatous) hyperplasia occurred in about 9% of nonneoplastic autopsies and in 28% of autopsies of diabeticpatients. Our higher incidence of papillary hyperplasia inthe pancreas cancer cases (42%) is consistent with thesefindings. However, there was obstruction to the pancreasduct in most of our cases, a complicating factor in the assessment of this ch: n@e. Birnstingl (8), in cases with a vanety of acute and c.ironic nonpancreatic diseases and nocancer of the pancreas, reported an incidence of 29% havinghyperplastic columnar epithelium.

The greater percentage of mucous cell hypertrophy in thepancreas cancer cases is also complicated by the presence ofduct obstruction and the lack of a more appropriate controlgroup, one with duct obstruction without pancreas cancer.

It was somewhat surprising to find less epidermoidmetaplasia in the pancreas cancer cases (6%) than in thenonpancreatic cases (12%) and such a low incidence ofchanges in both groups. Sommers et al. (63) also noted thatepidermoid metaplasia was not pronounced in pancreascancer cases. Birnstingl (8) found an incidence of 8% inpatients with acute and chronic disease but without pancreascancer. Korpássy (36) found epidermoid metaplasia of thepancreas in 12% of 500 unselected, carefully studied autopsies.This increasedto 29% in patients over 70 years old.

In 2 cases of cancer of the head of the pancreas, the in situcarcinoma areas were in the body and tail of the pancreassome distance away from the primary tumor (Fig. 25).Multicentnic origin of papillary carcinoma in the ducts ofthe pancreas was noted by Habán (29), a finding consistentwith the multicentnicity of other human carcinomas.

References

I. Arkin, A., and Weisberg, S. W. Carcinoma of the Pancreas, a Clinicaland Pathologic Study of Seventy-Five Cases. Am. J. Pathol., 13.118—126,1949.

2. Auger, C. Acinous Cell Carcinoma ofthe Pancreas with Extensive FatNecrosis. Arch. Pathol., 43: 400—405,1947.

3. Ayella, A. S., Jr., Howard, J. M., and Grotzinger, P. J. Cystadenomaand Cystadenocarcinoma ofthe Pancreas. Am. J. Surg., 103: 242—246,1962.

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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 cytoplasmare 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, x35.

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 isusual 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, characteristiczymogen 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 cellssurrounded 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 glandformations, 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 hyperplasticepithelium showing periodic acid-Schiff-positive material (black) in apex of cell (left). Stained areas at base of papillae (black, right represent pyloricgland 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 carcinomain 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 othercytological 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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1975;35:2234-2246. Cancer Res   Antonio L. Cubilla and Patrick J. Fitzgerald  Pancreas CarcinomaMorphological Patterns of Primary Nonendocrine Human

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