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Difficult Diagnostic Problems in Pancreatobiliary Neoplasia. (Special Section--HSCP 2014 Spring Symposium, Part II).

Pancreatic cancer is the fourth most-common cause of cancer-related death in the United States, with an estimated 46 420 new cases and 39 590 deaths in 2014. (1) Cancers of the extrahepatic biliary tract and gallbladder are relatively less common, with an estimated 10 650 new cases in 2014. (1) Pancreatobiliary carcinomas have a notoriously poor prognosis with an overall 5-year survival rate of less than 5% for pancreatic ductal adenocarcinoma (PDAC), (2-4) and few of these tumors are resectable at presentation because of the concomitant presence of metastasis or involvement of regional vital structures, such as the superior mesenteric or portal vasculature. In those pancreatic tumors that are resectable, the clinical and radiologic presentation demonstrates a high degree of overlap with a number of other neoplastic and pseudoneoplastic processes that can confound the clinical diagnosis. Furthermore, the histologic differentiation of pancreatic neoplasms from each other, from extrapancreatic tumors involving the pancreas, and even from benign processes, can be a challenge for the pathologist, especially on small biopsies or frozen sections. Nevertheless, careful correlation of clinical presentation, gross pathology, and histopathologic findings allows distinction in most cases.

Arguably, the most-common diagnostic problem encountered in the pancreas by the practicing pathologist is distinguishing PDAC from chronic pancreatitis and from extrapancreatic carcinomas involving the pancreas, such as distal common bile duct or ampullary carcinomas. A less-common diagnostic dilemma in the pancreas, but one that is potentially underrecognized, is the differentiation among nonclassic intraductal pancreatic neoplasms, specifically intraductal tubulopapillary neoplasms (iTPNs), intraductal oncocytic papillary neoplasms (IOPNs), and acinar cell carcinoma with intraductal growth. Outside the pancreas, difficult diagnostic predicaments are often encountered with intrahepatic biliary proliferations, such as the distinction of intrahepatic cholangiocarcinoma from metastases to the liver.

This review presents a brief discussion of these common diagnostic dilemmas with an overview of each entity and tools that may be useful to avoid some of the diagnostic pitfalls encountered in the course of routine surgical pathology sign out.

PANCREATIC DUCTAL ADENOCARCINOMA VERSUS CHRONIC PANCREATITIS

Nonmalignant pathologies, such as chronic pancreatitis, including special variants thereof (eg, autoimmune pancreatitis and groove pancreatitis), may show overlapping features with pancreatic carcinoma both clinically and radiologically and, occasionally, may be indistinguishable from PDAC. (5,6) Because only a small proportion of radiologically detected masses in the pancreas are benign, preoperative pathologic sampling is occasionally omitted and surgery performed without a tissue diagnosis. Therefore, pathologists may encounter pancreatic resection specimens that fail to harbor malignancy, much to the surprise of the surgeon. The histologic overlap between PDAC and chronic pancreatitis often further complicates the issue.

By gross examination, ductal adenocarcinomas are typically poorly circumscribed, solid, firm masses that are difficult to distinguish from surrounding fibrotic tissue. Although usually located in the head of the pancreas, approximately 15% arise from the body or tail, and a similar proportion diffusely involve the pancreas. (7) The cut surface is typically white-tan and fibrotic appearing and, occasionally, contains areas of necrosis. Rarely, the tumors undergo cystic degeneration or are associated with cystic dilation of the ducts and may, therefore, mimic primary cystic neoplasms of the pancreas. The tumors often involve the distal common bile duct and main pancreatic duct, classically resulting in abrupt stenosis with upstream duct dilation. Similarly, involvement of the ampulla or wall of the duodenum occurs not infrequently and may suggest an extrapancreatic carcinoma invading the pancreas (discussed below). A thoughtful dissection of the specimen will generally locate the epicenter of the tumor in the head of the pancreas, a finding that argues for a primary pancreatic carcinoma. In contrast, chronic pancreatitis is grossly characterized by uneven and poorly circumscribed fibrosis of the parenchyma, which usually involves the pancreas more diffusely than it does in PDAC and is often associated with calculi in the ducts and pseudocyst formations. Other forms of pancreatitis, such as autoimmune pancreatitis and paraduodenal pancreatitis, may be associated with a discrete mass. Stenosis of the common bile duct and pancreatic duct may occur in chronic pancreatitis but is typically tapering rather than abrupt. (8)

Useful histologic features for establishing the malignant nature of pancreatic lesions are well documented (Table 1) (9) and include poorly circumscribed, irregular, or angulated malignant glands associated with abundant desmoplastic stroma and ducts outside of their normal lobular distribution (Figure 1, A and B). The presence of ducts at an aberrant location constitutes an important diagnostic parameter--normally only a few medium-to-large caliber ducts should be found in the interlobular septa. Thus, the presence of ducts adjacent to an artery (unlike in the liver where ducts accompany arteries) or at a perineural location is highly suggestive of malignancy (Figure 1, C and D). (9,10) Other helpful parameters for a diagnosis of malignancy include incomplete duct lumina, the presence of intraluminal mucin or necrotic glandular debris, and single-cell infiltration (Figure 1, E). (9,11) The architectural features are often emphasized at the expense of cytologic parameters, primarily because, in many cases, the cells have a rather banal appearance. Cytologically, the 2 most-reliable nuclear features in PDAC are markedly irregular nuclear outlines and anisonucleosis (>4:1 variation in nuclear size within a single gland). (11)

Biomarkers of Pancreatic Ductal Adenocarcinoma

There are a host of markers that may be of assistance in distinguishing benign from malignant pancreatic glands. Some of these, such as mucins, including Muc4 and Muc16, mesothelin, and clusterin-[beta], are either not widely available or have not been rigorously validated. (12,13) A number of markers, for example mucin-1 (MUC1) and mesothelin, among many others, may be useful for prognostication in PDAC, but their utility for diagnosis is not well studied. (14,15) Arguably, the most robust immunohistochemical marker of PDAC is SMAD4. The protein is lost in approximately onehalf of all PDACs, (16) whereas nuclear reactivity is preserved in reactive and inflammatory diseases of the pancreas, such as chronic pancreatitis. Total loss of protein expression in PDAC results from biallelic mutations or mutation in one copy of the gene followed by either deletion or epigenetic silencing of the second copy. There is a strong correlation between SMAD4 mutations and loss of immunoreactivity, and thus, immunohistochemistry serves as a robust surrogate marker for the mutation (Figure 1, F). When evaluating this stain, adjacent benign tissue, such as stroma and inflammatory cells, should be regarded as an internal control. Interestingly, the SMAD4 wild-type tumor has been shown to have a better prognosis when compared to tumors with SMAD4 mutations. (17) Finally, a number of genetic mutations are also observed in pancreatic carcinomas, which distinguish them from benign processes (Table 2) but not necessarily from noninvasive pancreatic neoplasia, such as pancreatic intraepithelial neoplasia. (18) The most frequent among those genetic mutations are KRAS, TP53, SMAD4 and CDKN2A/p16. (19,20) Virtually all pancreatic carcinomas will have one or more of these mutations.

Chronic Pancreatitis

In benign conditions such as chronic pancreatitis, other than an occasional large duct, few glands should be seen in the interlobular septae (Figure 2, A). Glands located within lobules, regardless of the degree of atypia, would suggest a "benign" interpretation. It should be remembered that a high percentage of pancreata, particularly those in elderly individuals, can show intrapancreatic fat, and thus, the presence of atypical ducts within fat is not diagnostic for carcinoma and does not constitute extrapancreatic invasion--a detail that is relevant in the staging of pancreatic carcinoma, specifically the distinction of pT2 from pT3 tumors. In chronic pancreatitis, reactive nuclear atypia is seen, but variation in nuclear size should be minimal. Benign and reactive ducts typically show dense eosinophilic cytoplasm (Figure 2, B). In contrast, many adenocarcinomas, especially well-differentiated carcinomas, show abundant, pale, apical cytoplasm (Figure 1, E), which gives the cells a low nuclear to cytoplasmic ratio, a common finding in PDAC and one that can create a deceptively bland appearance.

Islets can be especially problematic mimics of carcinoma in chronic pancreatitis. Typically, islets are relatively unaffected by the inflammatory process and appear as small, benign-appearing nests of cells embedded in fibrotic stroma. However, in pancreatitis islets may become hyperplastic or diffuse and can be closely associated with nerves and muscular vessels, mimicking endocrine neoplasia or poorly differentiated carcinoma, particularly on frozen section.

The distinction of autoimmune and paraduodenal pancreatitis from PDAC may be especially difficult clinically and radiologically but is usually straight forward histologically. Details of these entities have been previously described in depth. (21,22) The presence of storiform-type fibrosis and obliterative phlebitis would indicate type 1 autoimmune pancreatitis, whereas a periductal infiltrate accompanied by neutrophilic abscesses would support type 2 autoimmune pancreatitis. The key ancillary test for the diagnosis of type 1 autoimmune pancreatitis is an immunohistochemical assay for immunoglobulin G4 (IgG4). Notably, approximately 10% of pancreatic adenocarcinomas are associated with increased IgG4+ plasma cells, (23) so correlation with histomorphology is required. In paraduodenal, or groove, pancreatitis, the mass lesion is located in the groove between the duodenum, the common bile duct, and the pancreatic head, adjacent to the minor papilla. Fibrosis involves both the duodenal wall and the adjacent pancreas. (22) Embedded within the lesion are cystic spaces lined by granulation tissue, prompting the designation cystic dystrophy of heterotopic pancreas, or paraduodenal wall cyst, (24) and exuberant Brunner gland hyperplasia is invariably seen. (25) Although this form of pancreatitis may mimic pancreatic carcinoma clinically, the histologic features are generally unequivocally benign and the few "atypical" pancreatic ducts embedded within the lesion do not raise a concern for malignancy. However, similar to other mass-forming variants of chronic pancreatitis, the strong clinical suspicion for malignancy may bias the pathologist into suspecting a well-differentiated adenocarcinoma.

PANCREATIC DUCTAL ADENOCARCINOMA VERSUS DISTAL BILE DUCT AND AMPULLARY CARCINOMA

The ampullary region is anatomically and histologically complex because it serves as the confluence of the common bile duct, pancreatic duct, duodenum, and pancreas. Therefore, adenocarcinomas arising from these extrapancreatic structures and invading the pancreas may be difficult to distinguish from PDAC, although the latter is encountered considerably more often. Although the distinction is not easily made on a biopsy sample, the distinction is obligatory on a Whipple resection because each site has a specific TNM staging system, and the site of origin may affect the choice of adjuvant therapy and entry into clinical trials. An accurate diagnosis is contingent upon identification of the primary site of tumor involvement, which is accomplished through a proper gross dissection in which sections are taken that demonstrate the relationship between tumor, ampulla, periampullary duodenum, distal common bile duct, and pancreas. We find that is best accomplished through probing and opening anteriorly along both the common bile duct and pancreatic duct.

Ampullary Carcinoma Versus Pancreatic Ductal Adenocarcinoma

Grossly, identification of the epicenter of the tumor in an extrapancreatic location such as the ampulla strongly suggests a nonpancreatic malignancy (Figure 3, A). Most pathologists refer to tumors arising from the ampullary papilla, the distal-most common bile duct and the pancreatic duct, and the common channel as ampullary carcinomas. Identification of the pattern of ampullary involvement is often possible and prognostically relevant categorization of ampullary carcinomas has recently been established. (26) These 4 categories of ampullary carcinoma include (1) intra-ampullary papillary-tubular neoplasm with invasion, in which a predominant preinvasive component is present in the common channel of the ampulla; (2) ampullary-ductal type carcinoma, which is usually a pancreatobiliary type and shows invasion associated with fibrous thickening of the ampullary duct; (3) periampullary-duodenal carcinoma, which shows prominent exophytic growth on the duodenal surface of the papilla with involvement of the ampullary orifice but a relatively small intra-ampullary component; and (4) ampullary-not otherwise specified (papilla of Vater), in which the carcinoma is localized at the tip of the ampullary papilla, often with ulceration. (26) Among these groups, the ampullary-ductal type was associated with the poorest overall survival, but all subtypes had a better prognosis than PDAC, therefore, necessitating accurate diagnosis. (26) Besides prognostication, use of this classification scheme may decrease confusion about the spectrum of tumors that should be designated ampullary carcinoma.

Similar to nonampullary duodenal carcinomas, ampullary adenocarcinomas most commonly have an intestinal-type morphology characterized by atypical, pseudostratified, columnar epithelium with elongated nuclei forming glands reminiscent of colorectal carcinoma (Figure 3, B). In contrast, pancreatobiliary-type tumors form small, infiltrative glands with 1 to 2 cuboidal cell layers (Figure 3, C). Ampullary carcinoma with a pancreatobiliary or combined intestinal/biliary phenotype can be troublesome to differentiate from PDAC because of morphologic overlap. Histologically, the most helpful clue pointing to an ampullary origin is the presence of a preinvasive component within the most distal portion of the bile duct or ampulla; such lesions frequently have a tubulopapillary appearance. (27)

Intestinal-type ampullary and nonampullary duodenal adenocarcinomas usually express keratin 20, CDX2, and MUC2 but are negative for MUC1, MUC5AC, and keratin 7 in most cases. (28,29) Pancreatobiliary-type carcinomas of the ampulla usually have the opposite staining pattern, which is shared with PDAC. (29) Among these markers, CDX2, MUC1, and MUC2 are particularly reliable, and the keratin stains are relatively unreliable. (30) However, these markers may be less effective in distinguishing among phenotypes in ampullary neoplasia than in pancreatic intraductal papillary mucinous neoplasms (IPMNs) given the mix of cell types normally found at the ampulla. (27) Notably, cancerization of the ampullary, bile ductular, and duodenal epithelium by PDAC may occur and can be difficult to distinguish from primary carcinoma in situ. The aforementioned immunostains may be of use in distinguishing such colonization from a primary dysplastic process of these sites. (29,31) Like PDAC, loss of DPC4 (SMAD4) expression has been documented in ampullary carcinomas, and expression of CEA and CA 19-9 is often seen and cannot be used to differentiate these tumors. (32)

Given the prominent fibrotic response and poor circumscription that can be seen in tumors arising at or near the ampulla, gross and histopathologic distinction of the primary site is not always possible in large tumors. At a minimum, documentation of differentiation (intestinal, pancreatobiliary, or mixed) should be reported because studies have shown that intestinal-type ampullary carcinomas carry a better prognosis than do pancreatobiliary-type tumors. (30,33-35) However, the optimal method of distinguishing the intestinal from the pancreatobiliary phenotypes remains to be determined--through morphology alone or through a combination of morphology and immunohistochemistry. A recent analysis (36) used a combination of CDX2, MUC1, and morphology to separate pancreatobiliary ([MUC1.sup.+] [CDX2.sup.-]) from intestinal ([MUC1.sup.-] [CDX2.sup.+]) tumors and showed that the phenotype, particularly when combined with lymph node status, was highly predictive of prognosis. Although pure forms of intestinal and pancreatobiliary phenotypes exist, many cases show elements of both. Finally, it may be difficult or impossible to determine the phenotype of non-tubule forming variants, such as medullary or signet ring cell carcinomas.

Distal Bile Duct Carcinoma Versus Pancreatic Ductal Adenocarcinoma

Distinction of PDAC from distal bile duct carcinoma involving the pancreas may be even more problematic than distinguishing ampullary tumors because of their intrapancreatic location and identical pancreatobiliary-type morphology and immunophenotype. The distinction between these entities may be important for stratification of patients into clinical trials or treatment groups and has prognostic significance. (33) Distal bile duct carcinomas are frequently misclassified as either PDAC or ampullary carcinoma, and survival in cases reclassified from PDAC is better than it is in true PDAC. (37) The distinction may also have therapeutic implications; in one study, (38) treatment of patients who have bile duct carcinoma (including advanced or metastatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer) with cisplatin plus gemcitabine (the latter being a key agent used to treat PDAC) was associated with a significant survival advantage as compared with use of gemcitabine alone, without the addition of substantial toxicity.

Helpful features that point to a distal bile duct origin include the finding of an in situ component, such as prominent biliary intraepithelial neoplasia or a biliary intraductal papillary neoplasm, as well as circumferential involvement of the bile duct by invasive carcinoma (Figure 3, D). In tumors situated near the bile duct, circumferential and symmetric involvement was found to be associated with bile duct dysplasia, whereas tumors with their epicenter away from the common bile duct were more likely associated with pancreatic intraepithelial neoplasia, suggesting a pancreatic origin. (39) Therefore, when a tumor is centered in the bile duct, we are inclined to favor the diagnosis of bile duct carcinoma. Otherwise, we are hesitant to make a diagnosis of distal bile duct carcinoma, regardless of the extent of bile duct involvement. Currently, other than careful gross and histologic examination, reliable markers that can distinguish distal bile duct carcinoma from PDAC are lacking.

UNCOMMON PANCREATIC INTRADUCTAL PAPILLARY LESIONS

Intraductal papillary mucinous neoplasms are often seen in clinical practice, and although they may cause some diagnostic dilemmas, such as the differential with mucinous cystic neoplasms, the characteristic features of classic gastric-type, intestinal-type, and pancreatobiliary-type IPMNs are generally widely known and have been reviewed previously. (40,41) In contrast, the diagnosis of oncocytic-type IPMNs, such as IOPNs and other infrequently encountered intraductal papillary lesions, such as intraductal tubulopapillary neoplasms and acinar cell carcinoma with intraductal growth, may cause more of a diagnostic dilemma given their degree of morphologic overlap and most pathologists' lack of familiarity with these entities. Knowledge of the typical histology and characteristic immunohistochemical profiles of these lesions (Table 3) is helpful.

Intraductal Oncocytic Papillary Neoplasm

Intraductal oncocytic papillary neoplasms, like the other types of IPMNs, are often grossly cystic with mucin production and duct dilation. Histologically, they are characterized by a multilayered proliferation of atypical oncocytic cells with large nuclei, prominent nucleoli, and distinctive eosinophilic cytoplasm (Figure 4, A and B). Intraductal oncocytic papillary neoplasms show complex arborizing papillae, cribriform formations, and solid nests within the lumen of a dilated duct. Mucin-containing intraepithelial and intracellular lumina, as well as scattered goblet cells, maybe seen (Figure 4, B). (42,43) These neoplasms show diffuse high-grade dysplasia and may evolve into invasive carcinoma with similar oncocytic features. Intraductal oncocytic papillary neoplasms are typically positive for MUC6 (Figure 4, C) and MUC1, may be focally positive for MUC5AC, and are usually negative for MUC2 and CDX2, except in interspersed goblet cells. (43,44) Intraductal oncocytic papillary neoplasms characteristically lack the KRAS mutations that are found in PDAC and many nononcocytic IPMNs. (45,46)

Intraductal Tubulopapillary Neoplasm

Intraductal tubulopapillary neoplasms are relatively rare, making up approximately 3% of the intraductal neoplasms of the pancreas, and they are clinically and histopathologically distinct from IPMNs. (27) Radiologically and grossly, they form solid masses with no mucin production. Histologically, the intraductal nodules are predominantly made up of closely apposed, tubule-forming glands and cribriform structures with uniform high-grade dysplasia (Figure 4, D and E). (47) There is morphologic overlap with the pancreatobiliary type of IPMNs, but the latter do not show complex tubulopapillary proliferations expanding and clogging the pancreatic duct, which are characteristic of ITPNs. The cuboidal cells show a modest amount of eosinophilic to amphophilic cytoplasm (Figure 4, E). Mitoses are frequently seen, and necrosis is more commonly seen than is seen in IPMNs. (48) In contrast to IPMNs, mucin is absent, and the broad range of atypia is typically not seen. An associated invasive tubular carcinoma is often present. (48) Stains for mucins, such as MUC1 and MUC6, can be positive but are more often negative than they are in IPMNs, including IOPN, and trypsin and chymotrypsin staining should be absent (Figure 4, F). Unlike IPMNs, these tumors are negative for KRAS mutations and, instead, show mutations in the PI3K pathway. (48,49)

Intraductal Acinar Cell Carcinoma

Acinar cell carcinomas occasionally have a component of intraductal polypoid growth, (50) and when predominantly intraductal, they can mimic other intraductal neoplasms, such as ITPNs and IOPNs. (51,52) Grossly, such tumors show a nodular or polypoid intraductal growth pattern accompanied by duct dilation and surrounding parenchymal sclerosis. Like ITPNs, acinar cell carcinomas are typically composed of sheets of back-to-back acinar structures (Figure 4, G and H). True tumor-lining papillary structures may be seen. (53) The nuclei are round, relatively uniform, and typically contain a single prominent central nucleolus (Figure 4, H). The presence of PAS+, diastase-resistant, apical, eosinophilic zymogen granules and intraluminal concretions are helpful features in distinguishing acinar cell carcinomas from other intraductal lesions but are not always present. (53) Immunohistochemistry for trypsin (Figure 4, I) and chymotrypsin, both of which are positive in acinar cell carcinoma, may be invaluable for distinguishing intraductal acinar cell carcinoma from other intraductal lesions, such as ITPNs, which can appear quite similar on hematoxylin-eosin. The absence of keratin 19 (positive in virtually all ductal neoplasms) may be the first clue to an acinar cell proliferation.

Other neoplasms that may show a prominent intraductal pattern of growth include pancreatic endocrine neoplasms (54) and invasive pancreatic adenocarcinomas, which may show a cystic papillary pattern of growth, mimicking an IPMN. (55,56)

INTRAHEPATIC CHOLANGIOCARCINOMA VERSUS CARCINOMA METASTATIC TO THE LIVER

The differentiation of an intrahepatic cholangiocarcinoma (IHCC) from a metastatic tumor of unknown primary constitutes a major unsolved problem in diagnostic surgical pathology. The morphologic appearance is of some value in this distinction. Most IHCCs are composed of well-formed, round to oval glands lined by low cuboidal epithelium that is devoid of mucin. The tumor frequently displays a "neverending" glandular pattern in which the glands appear to merge into each other without intervening stroma (Figure 5, A). A substantial proportion of IHCC cases have a bland morphology and thus often bear a superficial resemblance to bile duct adenomas. Other common patterns of growth include solid nests and glands with cribriform structures. Focal areas of clear cell change are commonly observed (Figure 5, B). The glands are present in the abundant stroma, which is often hyalinized. The IHCC cases tend to differ morphologically from perihilar and distal bile duct carcinomas, which instead resemble PDACs. Despite these characteristics, the poorly differentiated variant of IHCC cannot be distinguished with confidence from a metastatic carcinoma by histology or immunohistochemistry. That conundrum can result in an extensive clinical workup to exclude a potential tumor of nonhepatic origin.

Although immunohistochemical confirmation is required for a definitive diagnosis of IHCC, there are no markers unique to cholangiocarcinoma, and the foremost role of an immunohistochemical panel is to exclude a metastatic adenocarcinoma. However, the keratin profile is identical to a host of other tumors: keratin [7.sup.+] and [19.sup.+], and keratin [20.sup.-]. Access to a definitive marker for IHCC would allow the oncologist to forego the obligatory, and often extensive, immunohistochemical workup. The introduction of 2 markers may change the current diagnostic algorithm in IHCC: albumin and IDH1/2. Recent data from our group suggest that the presence of albumin in IHCC, detected using branch chain chromogenic in situ hybridization technology (ViewRNA, Affymetrix, Santa Clara, California), can distinguish this neoplasm from metastatic adenocarcinoma (Figure 5, C and D). (57) Thus, detecting albumin in a gland-forming tumor that lacks histologic evidence of hepatocytic differentiation is evidence of IHCC. (57) Similarly the presence of IDH1/2 mutations in a gland-forming tumor in the liver is highly suggestive of IHCC, although such mutations are present in only one-third of these neoplasms. (58) IDH1/2 mutations are identified in a variety of other tumor types, such as glioma, chondrosarcoma, and acute myeloid leukemia; however, none of those tumors are likely to be confused with IHCC.

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Jacob R. Bledsoe, MD; Shweta A. Shinagare, MD; Vikram Deshpande, MD

Accepted for publication July 10, 2014.

From the Department of Pathology, Massachusetts General Hospital, Boston (Drs Bledsoe and Deshpande); and the Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston (Dr Shinagare).

Dr Deshpande is a coprimary investigator in a sponsored research agreement between Affymetrix, Inc, and Massachusetts General Hospital. The other authors have no relevant financial interest in the products or companies described in this article.

Reprints: Vikram Deshpande, MD, Department of Pathology, Massachusetts General Hospital, Warren Bldg 2-256, 55 Fruit St, Boston, MA 02114 (e-mail: vdeshpande@partners.org).

Caption: Figure 1. Pancreatic ductal adenocarcinoma. A, Atypical angulated ducts with abundant surrounding desmoplastic stroma. B, Haphazardly organized glands outside of the normal ductal distribution, within fat and fibrous tissue adjacent to a large muscular vessel. C, The presence of isolated glands adjacent to a medium-sized artery on frozen section is highly suggestive of an invasive carcinoma. D, Perineural invasion is a useful diagnostic feature of pancreatic ductal adenocarcinoma, particularly in cases with deceptively benign-appearing malignant glands. E, Conventional features of pancreatic ductal carcinoma include angulated glands with incomplete lumina, pale cytoplasm, intraluminal necrotic debris, and surrounding desmoplastic stroma. F, Loss of SMAD4/DPC4 expression in atypical glands is the most useful biomarker for pancreatic ductal adenocarcinoma. Note that the islets provide a robust positive internal control (hematoxylin-eosin, original magnifications X100 [A and B], X200 [C], X400 [C inset, D, and E]; SMAD4, original magnification X400 [F]).

Caption: Figure 2. Chronic pancreatitis. A, Although atypical glands can be seen in chronic pancreatitis, they are limited to a normal lobular distribution and do not extend into interlobular fibrous septae. B, High-power view of the A inset. In comparison to pancreatic ductal adenocarcinoma, reactive ducts show complete lumina, more uniformity in nuclear size, open chromatin, and relatively dense eosinophilic cytoplasm (hematoxylin-eosin, original magnifications X100 [A] and X400 [B]).

Caption: Figure 3. Ampullary and distal bile duct carcinomas. A, Gross photo of an ampullary carcinoma (arrow). The relative location of the tumor is apparent after opening the duodenum, common bile duct (CBD), and the pancreatic duct. B, Intestinal-type ampullary carcinoma with large glands lined by atypical, pseudostratified columnar cells reminiscent of colorectal carcinoma. C, Ampullary carcinoma with a pancreatobiliary phenotype has an identical appearance to pancreatic ductal adenocarcinoma and distal bile duct carcinoma. D, Concentric involvement of the bile duct is a useful diagnostic feature of distal bile duct carcinoma, which otherwise looks identical to pancreatic ductal carcinoma (hematoxylin-eosin, original magnifications X400 [B and C], X40 [D], and X200 [D inset]).

Caption: Figure 4. Uncommon intraductal neoplasms. A through C, Intraductal oncocytic papillary neoplasm consisting of papillae lined by oncocytic cells with prominent nucleoli projecting into the lumen of the duct. Characteristic intraepithelial and intracellular lumen formation is sometimes seen (B). Immunostains for MUC6 (C) and MUC1 are typically positive. D through F, Intraductal tubulopapillary neoplasm. Complex tubular and cribriform growth filling the duct lumen. Distinction from intraductal oncocytic papillary neoplasm and acinar cell carcinoma can be made based on hematoxylin-eosin morphology and immunohistochemistry. Intraductal tubulopapillary neoplasms should be negative for trypsin (F) and chymotrypsin. G through I, Acinar cell carcinoma with prominent intraductal growth. Acinar morphology is almost always apparent, but a papillary growth pattern may be seen (G). Apical eosinophilic granularity may be appreciable on high power. Immunostains for exocrine proteases trypsin (I) and chymotrypsin are positive (hematoxylin-eosin, original magnifications X200 [A, D, and G] and X400 [B, E, and H]; original magnification X400 [C, F, and I]).

Caption: Figure 5. Intrahepatic cholangiocarcinoma. A, Intrahepatic cholangiocarcinoma is typically composed of infiltrating tubular glands with a "never-ending" pattern, in which one gland merges imperceptibly with another in the setting of background fibrosis. B, Solid nests with cytoplasmic clearing are frequently seen in intrahepatic cholangiocarcinoma. C and D, Chromogenic in situ hybridization for albumin is diffusely positive in the tumors depicted in A and B (hematoxylin-eosin, original magnification X200 [A and B]; original magnification X200 [C and D]; original magnification X400 [D inset]).

Please Note: Illustration(s) are not available due to copyright restrictions.
Table 1. Helpful Diagnostic Features of Chronic
Pancreatitis and Pancreatic Ductal Adenocarcinoma

Feature                   Chronic          Pancreatic
                          Pancreatitis     Ductal
                                           Adenocarcinoma

Desmoplastic stroma       No               Yes
Irregular ducts with      No               Yes
  incomplete lumina
Nuclear variation of      No               Yes
>4:1 within a gland
Cytoplasm                 Dense            Pale
                            eosinophilic
Lobular architecture      Yes              No
  maintained
Nonlobular distribution   No               Yes
  of glands
Association of ducts      No               Yes
  with arteries
Perineural invasion       No               Yes

Table 2. Genetic Markers that Distinguish Benign and
Malignant Pancreatic Lesions

                             Pancreatic Cancers
               Role in           Showing
Gene        Tumorigenesis     Alteration, %

KRAS        Oncogene               >90

TP53        Tumor suppressor        50
            gene

SMAD4       Tumor suppressor        50
            gene

CDKN2A/p16  Tumor suppressor        95
            gene

            Mechanisms of Activation/
Gene              Inactivation                 Diagnostic Value

KRAS        Activating mutation in     May provide supportive evidence
            codons 12, 13, or 61       for pancreatic adenocarcinoma
                                       and intraductal papillary
                                       mucinous neoplasms

                                       Caveat: Virtually all pancreatic
                                       intraepithelial neoplasia lesions
                                       also harbor KRAS mutation

TP53        Mutation in one allele     Strong reactivity for p53 is
            and loss of other allele   seen in 50% of PDACs

                                       Caveat: Immunoreactivity for p53
                                       does not always correlate with
                                       p53 mutation, ie, p53 reactivity
                                       may be seen in reactive lesions

SMAD4       Homozygous deletion or     On immunohistochemistry, loss of
            mutation in one allele     SMAD4 is diagnostic for PDAC
            and loss of other allele   Caveat: Technically difficult
                                       stain, ensure positive control
                                       on tissue before reporting

CDKN2A/     Homozygous deletion or     Not helpful diagnostically
  p16       mutation in one allele
            and loss of other allele or
            promoter methylation

Abbreviation: PDAC, pancreatic ductal adenocarcinoma.

Table 3. Comparative Immunohistochemistry of Intraductal Oncocytic
Papillary Neoplasms, Intraductal Tubulopapillary Neoplasms, and
Intraductal Acinar Cell Carcinoma Immunohistochemistry

                         Immunohistochemistry (a)

Tumor   Acinar   CK7   CK19     MUC1      MUC2     MUC5AC     MUC6
        Growth

IOPN      -       +     +        +       focal/-   focal       +

ITPN      +       +     +     [+ or -]      -        -      [+ or -]
IACC              -     -        -          -        -         -
          +

                          Immunohistochemistry (a)

Tumor   CDX2   Trypsin   Chymotrypsin   DPC4/ SMAD4         Other

IOPN     -        -           -         Retained (b)   Mitochondrial
                                                       stains:
                                                       phosphotungstic
                                                       acid
                                                       hematoxylin,
                                                       antibody (42)
ITPN     -        -           -         Retained (b)   Novelli stain,
IACC     -        +           +         Retained (b)   Other exocrine
                                                       markers 111.3

Abbreviations: IACC, intraductal acinar cell carcinoma; IOPN,
intraductal oncocytic papillary neoplasm;ITPN, intraductal
tubulopapillary neoplasm.

(a) Typical staining patterns based on the authors' experience.
Staining defined as typically positive (+), typically negative (-),
variable ([+ or -]), typically focally positive (focal), or typically
negative or only focally positive (focal/-).

(b) Loss of DPC/SMAD4 expression can be seen in a corresponding
invasive component.
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Author:Bledsoe, Jacob R.; Shinagare, Shweta A.; Deshpande, Vikram
Publication:Archives of Pathology & Laboratory Medicine
Date:Jul 1, 2015
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