Martha Bishop Pitman

Indications

An unexplained pancreatic mass and a bile duct stricture are the major indications for cytologic evaluation of the pancreas and bile ducts. Imaging studies contribute useful information on the location, distribution (solitary, multiple, or diffuse), and nature (cystic versus solid) of a lesion, but a cell sample is usually necessary for definitive diagnosis. In the case of a potentially resectable mass that is malignant by imaging, however, the value of preoperative aspiration or brushings is still debated. The increased cost, potential delay in diagnosis, and imperfect negative predictive value attributed to aspiration and brushings are cited as arguments to proceed with surgical resection without preoperative cytology in this scenario.¹ Still, many clinicians request a tissue diagnosis even in this circumstance, because radiologic accuracy is not 100%.^2–5 Despite improvements in surgical technique, the morbidity of pancreatic surgery is significant,⁶ and not all malignancies are surgically managed (e.g., lymphoma). Moreover, nonsurgical management of patients with a benign neoplasm or premalignant disease is increasingly common.^3,7–10

Sampling Techniques

A fine-needle aspiration (FNA) of the pancreas can be performed percutaneously (by a radiologist) or endoscopically (by a gastroenterologist). A percutaneous pancreatic FNA is performed using computed tomography (CT). Percutaneous needle placement techniques vary depending on the location of the lesion and the trajectory of the needle. The tandem technique involves placing a guide needle to serve as a reference point for the second, biopsy needle and is most useful in CT-guided FNA when real-time visualization of needle insertion is impossible. The coaxial technique involves inserting a larger caliber needle to localize the lesion. A smaller caliber needle is then inserted through the larger needle to sample the lesion. This method permits multiple sampling attempts without the increased risk to local structures created by repeated needle passes.¹¹

Percutaneous FNA has been largely replaced by endoscopic ultrasound (EUS)-guided FNA because it provides real-time visualization of the needle tip, better visualization of small lesions than with CT, and the ability to identify local metastases or invasion of local structures, thus permitting simultaneous diagnosis and staging.5,12,13 EUS equipment consists of an image guidance system and an echoendoscope that is placed into the stomach or duodenum. A high-frequency ultrasound transducer on the tip of the echoendoscope guides a 19 to 25 gauge needle through the gut wall into the pancreatic mass or cyst. Pancreatic head masses benefit from a transduodenal approach, and body and tail masses from a transgastric approach. The pathologist should be aware of the approach so that contaminating normal gastric or duodenal mucosa is recognized and not misinterpreted as lesional. Once in the lesion, the stylet is removed and the needle oscillated under suction to dislodge cells and pull them into the needle.

With cystic lesions, as much fluid is drained as possible. Depending on volume, cyst fluid can be submitted for routine cytology and biochemical and molecular analysis. Any visible mural nodule or solid component should be separately sampled.

Suspicious pancreatic and extra pancreatic biliary lesions can be sampled by brushing the pancreatic and common bile ducts, which is particularly useful when there is a duct stricture without a discernible mass. Brushings are obtained endoscopically, sometimes in conjunction with endoscopic retrograde cholangiopancreatography (ERCP); they can also be obtained during percutaneous transhepatic cholangiography (PTC). Because pancreatic ductal adenocarcinoma tends to invade the main pancreatic or common bile ducts, this sampling method is highly effective. Brushings can also diagnose accessible cholangiocarcinomas and hepatocellular carcinomas (HCCs).¹³

Complications

The most common major complication of FNA is acute pancreatitis, with an incidence of 1% to 3%; mortality is less common.14–19 Other, rare major complications include pancreatic duct leaks, massive hemorrhage, and septic shock.²⁰ Perforation associated with a malignant luminal stenosis is a specific complication of EUS-guided FNA.²⁰ Post aspiration needle tract seeding by tumor cells or mucin is exceedingly rare.^21–23 Complications of bile duct brushing are minor and include cholangitis and mild pancreatitis.

Rapid On-Site Evaluation

Rapid on-site evaluation of the specimen by a cytologist provides feedback to the operator on the adequacy of individual passes, allowing the operator to obtain additional passes until the sample is judged adequate. It has potential utility with solid masses, where some have found that on-site evaluation reduces the rate of nondiagnostic results;24–28 others have questioned its value when experienced operators perform the procedure, finding no difference in nondiagnostic rates with and without on-site evaluation.²⁹ On-site evaluation offers little benefit with cysts, because smearing a small drop of cyst fluid results in a paucicellular sample poorly suited for rapid examination.

Sample Preparation and Cyst Fluid Analysis

Aspirates and brushings can be prepared as smears, a liquid-based preparation (e.g., ThinPrep, SurePath), a CytoSpin, a cell block, or some combination. If smears are employed, proper smear technique is vitally important; even the most cellular sample is useless if the cells cannot be evaluated due to a preparation-related artifact. Clotted tissue in needle casts (“worms”) should be gently lifted from the glass slides and placed into formalin for a cell block. (Small formalin vials like those used for bone marrow cores are recommended.) Smears can be air-dried and Romanowsky-stained or alcohol-fixed and Papanicolaou-stained, depending on the preference of the laboratory.

Bile duct brushings are best prepared by a liquid-based method (e.g., ThinPrep, SurePath), cytocentrifugation (i.e., CytoSpin), and/or cell block, because a liquid collection method, used by all these methods, allows for less mechanical artifact when dislodging the cells from the brush.

A cell block from the sedimented fluid can be invaluable for immunohistochemical and molecular studies. An aliquot for microbiologic cultures or flow cytometry might be considered based on the on-site evaluation findings.

Biochemical and molecular analysis can help in classifying cyst fluids. Table 14.1 shows the usual (expected) results for the 4 most useful tests. Fresh, unfixed cyst fluid is, therefore, often apportioned among cytology, biochemistry, and molecular studies to establish if the cyst is mucinous, and if so, if it is malignant. Grossly viscous white fluid, cytologic evidence of colloidlike extracellular mucin, and an elevated carcinoembryonic antigen (CEA) level support a mucinous cyst.³⁰ Cytomorphologic assessment, however, is required to establish malignancy.^31–34 The two most useful biochemical tests are CEA and amylase. If CEA is low, KRAS molecular testing is helpful for the identification of a mucinous cyst but adds no value if CEA is elevated, which by itself supports a mucinous cyst.³⁵ GNAS may add value by distinguishing an intraductal papillary mucinous neoplasm (IPMN) from a mucinous cystic neoplasm (MCN), given that the latter is resected irrespective of grade.³⁶ KRAS and GNAS do not help in distinguishing benign from malignant lesions.

Accuracy and Limitations

To best guide patient management, the cytologic diagnosis should be correlated with clinical findings and radiologic and ancillary laboratory test results.37,38 Given the technical challenges in obtaining an adequate sample and the cytomorphologic interpretive challenges, the sensitivity of EUS-FNA of the pancreas is variable, averaging 80%. Specificity ranges from 60% to 100%.^39–55 Sensitivity improves with increasing technical expertise.^{56, 57} Diagnostic accuracy for solid pancreatic masses is greater than 90%, lower for cystic lesions.^32,55,58

Brush cytology has almost 100% specificity but only about 50% sensitivity because of false-negatives due to sampling and interpretation.¹³ Indeterminate (i.e., atypical or suspicious) interpretations result not only from preparation artifact but also from the high threshold needed for an unequivocal malignant interpretation, given that marked atypia on brush cytology is often associated with an inflamed and/or stented duct.59,60

Reporting Terminology

There is no universal standard for reporting pancreatic cytology results, but the following modification of conventional cytologic nomenclature offers a useful framework:

A negative sample is one that contains adequate cellular and/or extracellular tissue to evaluate or define a non-neoplastic lesion identified on imaging. An atypical diagnosis reflects a mild degree of cytologic atypia, often in the setting of inflammation, previous duct instrumentation, or sparse cellularity. This interpretation implies a low suspicion of malignancy. A suspicious interpretation implies a strong concern for malignancy, usually for ductal adenocarcinoma, but a definitive interpretation is not possible, usually because the cytologic features are quantitatively or qualitatively insufficient. A second opinion can be helpful before issuing a report in such cases; without a definitive diagnosis, an additional procedure might be needed. A positive interpretation indicates that the cytologic features meet the criteria for the diagnosis of a malignancy of some type, most commonly ductal adenocarcinoma. A nondiagnostic specimen is one that provides no useful information about the lesion sampled. Any cellular atypia precludes a nondiagnostic report.

The neoplastic category is for cases that clearly represent a neoplasm. These include premalignant neoplasms (e.g., IPMN; MCN with low-, intermediate-, or high-grade dysplasia) and neoplasms whose risk for metastasis cannot be predicted from cytologic parameters (e.g., pancreatic neuroendocrine tumor (PanNET) and solid-pseudopapillary neoplasm [SPN]). The same is true for a biliary tract counterpart, now called intraductal papillary neoplasm of the bile ducts (previously, intraductal papillary mucinous neoplasm or papillomatosis or papillary cholangiocarcinoma).

Normal Pancreas and Bile Duct

The pancreas is rich in parenchyma and poor in stroma. Exocrine acinar tissue is arranged in lobules around a ductal system that increases in caliber as it progresses toward the ampulla. Acinar cells secrete digestive enzymes into this excretory ductal system, which is lined by epithelium that progressively increases in size from cuboidal (in the smaller intralobular ducts) to tall columnar cells (in the larger interlobular ducts). The epithelial cells lining the pancreatic ductal system are generally nonmucinous, although goblet cells are occasionally noted in the main pancreatic duct. Mucinous differentiation, therefore, is evidence of pancreatic intraepithelial neoplasia. Loose connective tissue separates the lobules, and a zone of connective tissue surrounds the ducts and islets.⁶¹

Acinar cells are normally arranged in small rounded (“grapelike”) groups (acini) with a small lumen. They are polygonal, with ample dense, blue-green cytoplasm with a Papanicolaou stain (Fig. 14.1A) and punctate and purple with a Romanowsky stain. Nuclei are round, with finely textured, evenly distributed chromatin and small nucleoli that enlarge markedly with reactive changes. Nucleoli help to distinguish naked acinar cell nuclei from lymphocytes.

Aspirates of benign acinar tissue are often very cellular, which can result in a mistaken impression of a neoplasm. Isolated acini (“grapes”) and clusters of acini attached to fibrovascular tissue (“grapes on a vine”) (Fig. 14.1B) are characteristic of benign pancreatic acinar tissue. Single cells are also present, but are less prominent than in acinar cell carcinoma.

An FNA specimen of normal pancreas displays fewer ductal cells than acinar cells, whereas pancreatic and bile duct brushings consist mostly of ductal cells, and acinar cells are absent. Ductal cells are cuboidal or columnar and usually arranged as monolayer sheets or strips of cells with a luminal edge of nonmucinous cytoplasm. Monolayer sheets have a uniform, latticelike (“honeycomb”) appearance, with evenly spaced, round, regular nuclei and well-defined cytoplasmic borders (Fig. 14.2). Nuclei have evenly distributed, finely granular chromatin and inconspicuous nucleoli that enlarge significantly in reactive conditions. The cytoplasm varies in amount, from scant to moderate, and is dense and nonmucinous with routine stains. Any visible cytoplasmic mucin is pathologic; overtly mucinous ductal cells warrant careful examination to exclude pancreatic intraepithelial neoplasia and well-differentiated adenocarcinoma. With liquid-based preparations, nuclei may appear crenated, a common artifact that is easily recognized with experience.

Normal islet cells are rarely identified owing to their relative paucity and fragility.

The pancreas is nestled in the retroperitoneum, with its head surrounded by the second portion of the duodenum. It is close to the liver, transverse colon, stomach, spleen, and kidneys; thus it is not unusual for a CT-guided needle to procure normal tissue elements from adjacent organs on its way to the pancreas. Mesothelial cells, hepatocytes, and renal tubular cells are occasionally encountered. Mesothelial cells resemble benign ductal cells: They have a similar flat, monolayer sheetlike arrangement. Because they are relatively large cells that vary in size, they are prone to misinterpretation as adenocarcinoma. Recognizing the characteristic slitlike spaces (“windows”) between adjacent mesothelial cells helps identify them as such.

With EUS-FNA, cells from the stomach and duodenum are ever-present contaminants.62,63 Both duodenal and gastric epithelial cells appear as flat, monolayer sheets with a honeycomb pattern. Duodenal enterocytes are nonmucinous epithelial cells in large sheets studded with goblet cells, which have the appearance of a fried egg on alcohol-fixed preparations, because the centrally placed goblet cell nucleus is surrounded by a clear halo (Fig. 14.3). Intraepithelial lymphocytes (“sesame seeds”) are sprinkled among the enterocytes. Because most branch-duct IPMNs are lined by gastric-foveolar type cells, the absence of visible mucin and the presence of intraepithelial lymphocytes and a brush border help identify the fragment as duodenal in origin.

Gastric surface foveolar cells appear as sheets of cells with mucinous cytoplasm; larger groups contain intact crypts (Fig. 14.4). Stripped naked nuclei with grooves are also seen. The distinction from low-grade neoplastic mucinous epithelium, particularly that seen in branch-duct cysts that are typically lined by gastric-foveolar type cells, is virtually impossible. Gastrointestinal (GI) epithelium is readily distinguished from a high-grade adenocarcinoma and a high-grade dysplasia of mucinous cysts, however. Reactive epithelium with atypia can resemble adenocarcinoma, leading to a false-positive interpretation. Conversely, a specimen consisting exclusively of epithelial contaminants should be interpreted as nondiagnostic; misinterpreting epithelial contaminants as benign ductal cells, for example, can result in a false-negative interpretation.

Pancreatitis and Reactive Changes

Acute pancreatitis results from the enzymatic auto-destruction of pancreatic parenchyma. In the United States, it is most often caused by alcohol abuse. Other causes include biliary stones, trauma, and surgery. The diagnosis of acute pancreatitis is based on clinical findings coupled with laboratory evidence, including an elevated white blood cell count and elevated plasma amylase and lipase levels. The radiologic appearance is seldom suggestive of a mass lesion. For these reasons, acute pancreatitis is rarely aspirated. Aspirates demonstrate a background of necrotic debris composed of degenerating cells, foamy histiocytes, fat necrosis, calcifications, and acute inflammation (Fig. 14.5).

In contrast, late stage chronic pancreatitis with mass-forming fibrosis is often indistinguishable radiologically from a neoplastic process. Fibrosis is particularly prominent in autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), a duct-centric inflammatory process dominated by lymphocytes and plasma cells. Autoimmune pancreatitis is important to recognize, as it responds to corticosteroid therapy and does not require surgery.⁶⁴

Because its features are not very distinctive, autoimmune pancreatitis is a difficult diagnosis to make by FNA, and the results are rarely definitive. Clues include hypocellularity, cellular stromal fragments with crush artifact, and chronic inflammation with plasma cells (Fig. 14.6).⁶⁵ Some forms of autoimmune pancreatitis are associated with a predominantly neutrophilic infiltrate.⁶⁶ There can be marked reactive ductal cell atypia, with nuclear crowding and cytoplasmic mucin from an associated pancreatic intraepithelial neoplasia.^65,67

The reactive ductal epithelium with atypia (Fig. 14.7) that is associated with pancreatitis and cholangitis should be distinguished from ductal adenocarcinoma. A high threshold for malignancy is especially needed for brushings from patients with primary sclerosing cholangitis, primary biliary cirrhosis, stones, or an indwelling stent.^13,68,69 Mitoses, prominent nucleoli, and nuclear enlargement are common to both reactive and malignant epithelium. Characteristic malignant features include irregularly distributed chromatin with parachromatin clearing, nuclear membrane irregularity, loss of polarity, nuclear crowding, and significant anisonucleosis: Variation in nuclear diameter more than 3- or 4-fold within a group of cells favors a malignant interpretation.^70,71 Because morphologic features of reactive and malignant cells overlap, in borderline cases the most appropriate diagnosis is either “atypical cells present” or “suspicious for malignancy,” the choice depending on the quality and quantity of atypia. Immunohistochemical analysis for SMAD4 (DPC4) and p53 is helpful in selected cases, inasmuch as half of pancreatic adenocarcinomas show loss of SMAD4, and most demonstrate an accumulation of p53, features not seen in chronic pancreatitis.^72,73

Pancreatic Intraepithelial Neoplasia

Pancreatic intraepithelial neoplasia (PanIN) is a premalignant mucinous change of pancreatic ducts that includes low-grade atypia (PanIN-1), moderate atypia with stratification and tufting of the epithelium but maintained polarity (PanIN-2), and severe atypia, with malignant-appearing cells confined to the duct (PanIN-3).⁷⁴ These changes are subclinical and do not create a mass that can be targeted by FNA. But, as a common finding in the setting of chronic pancreatitis and other conditions, PanIN can “contaminate” aspirates and cause false-positive interpretations.^74,75

Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma is the most common tumor of the pancreas, accounting for 85% to 90% of all pancreatic neoplasms.⁷⁶ Smoking is a well-established risk factor. Ductal adenocarcinoma is a highly aggressive tumor occurring predominantly in individuals aged 60 to 80 years. Presenting symptoms include abdominal pain, jaundice, pruritus, and unexplained weight loss. Radiologically, most ductal adenocarcinomas appear as poorly defined, hypodense (on CT) or hypoechoic (on EUS) masses that distort the normal lobular architecture of the pancreas.⁷⁷ Because most (60% to 70%) are located in the pancreatic head, they are commonly associated with pancreatic and bile duct stricture, with downstream dual dilatation of both ducts (“double-duct” sign).⁷⁷ Secondary cystic change occurs sometimes, obscuring the solid appearance and causing confusion with cystic tumors, primarily IPMN.

Histologically, most ductal adenocarcinomas are well to moderately differentiated, consisting of large, medium-sized, or small malignant ducts that infiltrate a desmoplastic stroma. Infiltrating tubular architecture is most common, and reactive myxoid or desmoplastic stroma is a key to correct interpretation.

The cells of a well-differentiated ductal adenocarcinoma are large and columnar, often with abundant pale, mucinous cytoplasm. Cells in sheets lose the evenly spaced, latticelike distribution of benign ductal cells, becoming disarranged (dubbed a “drunken honeycomb”).⁷⁸ Marked anisonucleosis (4:1 or higher variation in diameter among nuclei within a group or sheet) and visible cytoplasmic mucin are very helpful features^70,79 (Fig. 14.8A). Some well-differentiated carcinomas have abundant, “foamy” cytoplasm, yielding a deceptively low nuclear-to-cytoplasmic ratio (“foamy gland adenocarcinoma”) ^80,81 (Fig. 14.8B). Cell blocks from sedimented fluid and/or core biopsy specimens help by highlighting cribriform architecture (Fig. 14.8C) and invasion of desmoplastic stroma (Fig. 14.8D).

High-grade ductal adenocarcinoma (Fig. 14.9) shows more overt features of malignancy and is more easily distinguished from reactive ductal epithelium and GI contamination. Slides reveal marked variation in cell size, loss of polarity, large nucleoli, numerous isolated cells, necrosis, and mitoses.

Cholangiocarcinomas are morphologically indistinguishable from pancreatic ductal adenocarcinomas.

Several benign conditions cause ductal cell atypia that mimics ductal adenocarcinoma. Chronic pancreatitis, especially autoimmune and radiation-induced, often results in ductal atypia, including nuclear enlargement and prominent nucleoli. Background elements like fat necrosis and calcific, inflammatory debris, should raise the possibility of pancreatitis.

Biliary and pancreatic duct stents cause irritation and reactive/reparative ductal cell changes, with enlarged nuclei and nucleoli (see Fig. 14.7). A high threshold for malignancy is required in the evaluation of specimens from patients with a current or recent stent and those with primary sclerosing cholangitis and primary biliary cirrhosis. Nuclear membrane irregularity, an increased nuclear-to-cytoplasmic ratio, isolated atypical cells, and marked anisonucleosis (4-fold or greater differences in nuclear size) are the more reliable indicators of malignancy. A definite distinction between reactive atypia and ductal adenocarcinoma is not possible in all cases. For cases with equivocal findings, an atypical or suspicious interpretation is appropriate.

Immunohistochemistry for p53 and SMAD4 can help establish a malignant interpretation, because half of pancreatic adenocarcinomas show loss of SMAD4, and most demonstrate an accumulation of p53, features not seen in normal cells or chronic pancreatitis (Fig. 14.10A and B).^82,83 Loss of nuclear expression of SMAD4 can also distinguish pancreatic adenocarcinoma from other adenocarcinomas, because SMAD4 is rarely lost in adenocarcinomas of the ovary, colon, endometrium, and lung.⁷³ The evaluation of these markers can be difficult, however, in limited samples. Fluorescence in situ hybridization (FISH) is also useful but not commonly available.^71,84–86 To date, molecular tests have not found wide application to diagnosis. KRAS mutations, however, are found in just under half of low-grade PanIN cases, and their frequency increases with increasing degrees of dysplasia.⁸⁷

Variants of Ductal Adenocarcinoma

The two most common variants of pancreatic ductal adenocarcinoma are adenosquamous carcinoma (Fig. 14.11A), accounting for 3% to 4% of all pancreatic malignancies, and undifferentiated (anaplastic) carcinoma (Fig. 14.11B), accounting for 0.3% to 10%.⁷² The proportions of the glandular and squamous components of an adenosquamous carcinoma vary widely from one tumor to another, and a metastasis from a primary elsewhere needs to be considered.⁸⁸ Undifferentiated carcinomas lack glandular differentiation. FNAs yield highly cellular specimens with pleomorphic epithelioid and spindled cells and bizarre multinucleated tumor giant cells.⁸⁹ The giant cell nuclei resemble those of the mononuclear tumor cells. In contrast, undifferentiated carcinoma with osteoclast-like giant cells is characterized by benign osteoclast-type giant cells admixed with usually pleomorphic mononuclear cells. In some cases, the mononuclear malignant component of the tumor appears very bland. The mononuclear tumor cells generally express vimentin, but they can also express cytokeratin. KRAS mutations, however, are found in about 90% of the mononuclear component of the tumors, and TP53 mutations in about half, whereas these mutations are not found in the giant cell component.^72,90 The cytologic features of the other variants (colloid carcinoma, hepatoid carcinoma, medullary carcinoma, and signet ring cell carcinoma) demonstrate features that recapitulate their histopathology.

Pancreatic Neuroendocrine Tumor

Also known as islet cell tumor, pancreatic endocrine neoplasm (PEN), and pancreatic endocrine tumor, this tumor is called pancreatic neuroendocrine tumor (PanNET) in the WHO 2010 Classification of Neoplasms of the Digestive System, to be consistent with similar tumors elsewhere in the GI tract.⁹¹ Uncommon tumors, they represent only 1% to 2% of all pancreatic neoplasms. They are histologically separated into well-differentiated (low- and intermediate-grade) tumors and poorly differentiated (high-grade) neuroendocrine carcinomas. By histopathologic definition, a carcinoma has greater than 20 mitoses per 10 high-power fields (hpf) and is subclassified into small cell and large cell types.

PanNETs can be functional or nonfunctional. A majority of functional tumors secrete one of the following hormones: insulin, glucagon, somatostatin, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, serotonin, adrenocorticotropic hormone (ACTH), or calcitonin. Owing to excess hormone secretion, patients with a functional tumor can develop life-threatening signs and symptoms such as hypoglycemia, GI ulcers, and diarrhea with dehydration. Functional tumors are typically detected earlier than nonfunctional ones and are smaller at resection. Insulinomas are often less than 1 cm in size and usually follow a benign course. Most PanNETs, however, are biologically aggressive, 65% to 80% demonstrating unequivocal features of malignancy.⁹¹

Although PanNETs occur at any age, they are most common in adults (mean age around 40 years). They tend to be small, usually around 1 to 3 cm in diameter, but biologic behavior is not correlated with tumor size. Like acinar cell carcinoma and solid pseudopapillary neoplasm (and unlike ductal adenocarcinomas), PanNETS tend to be circumscribed masses. They can be partially cystic but are completely cystic in only 4% of cases, which can lead to misclassification as a primary pancreatic cyst by imaging studies.⁹²

Most PanNETs are well differentiated, and the unqualified term PanNET is assumed to mean a well-differentiated tumor. Although certain histologic features predict malignant behavior (e.g., invasion of adjacent structures and vessels), no features are capable of predicting benign behavior. Of note, cytologic atypia does not correlate with malignant behavior, with the exception of high-grade small and large cell neuroendocrine carcinomas.

Although all neuroendocrine tumors of the pancreas larger than 0.5 cm in diameter are potentially malignant,⁹³ it is common cytologic practice to use “neoplasm” or “neoplastic cells present” in reporting these tumors, for consistency with the histologic classification. The most reliable indicator of malignancy in the case of a well-differentiated PanNET is the presence of metastasis or invasion of adjacent structures.^72,91

Histologically, tumor cells show a variety of growth patterns: solid, trabecular, and gland-forming. Cells are usually monomorphic, with a round or oval nucleus. Nucleoli are usually indistinct, but they can be prominent. The cytoplasm is typically granular, but rare cases have predominantly clear and vacuolated or dense and oncocytic cytoplasm. Amyloid is seen in some cases, more commonly with insulinomas. Somatostatinomas, particularly those that arise in the duodenum, often show gland formation with psammoma bodies.

Cytomorphology of pancreatic neuroendocrine tumor

• highly cellular aspirate with solid-cellular smear pattern

• predominantly isolated cells, bare nuclei

• pseudorosettes and small clusters

• uniform, round/oval nuclei

• eccentric nuclei (plasmacytoid appearance)

• finely stippled (“salt and pepper”) chromatin

• moderate to abundant cytoplasm, typically granular but may be vacuolated or oncocytic

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