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Fine Needle Aspiration Biopsy Cytology of Pancreas: A Diagnostic Approach Based on Pattern Recognition
The number of pancreatic fine needle aspiration biopsies (FNAB) has increased substantially over the past decade due to (1) the development of new imaging and guidance mechanisms, specifically endoscopic ultrasound scopes with the ability to perform an ultrasound directed FNAB; (2) the increased sensitivity of detection of incidentally discovered masses; and (3) the improved recognition and classification of cystic neoplasms. Still today, pancreatic FNAB represent one of the most challenging sample types for pathologists because of the innate difficulty in distinguishing reactive ductal changes from adenocarcinoma in a background contaminated with gastrointestinal tract (GIT) mimics of adenocarcinoma. Recent challenges include distinguishing cystic neoplasms from contaminants, benign inflammatory processes from invasion, and identifying high-risk features of intraductal papillary mucinous neoplasms (IPMN) or mucinous cystic neoplasms (MCN) once these lesions have been identified.
Integrative Approach to Pancreatic FNAB
Assessment of the pancreatic FNAB sample needs to begin before viewing the slides, and it involves the integration of information, including review of the clinical history, radiologic findings, previous cytologic studies and associated ancillary tests, and the site of the mass sampled by the FNAB, as this will determine the types of contaminants obtained. FNAB performed under endoscopic ultrasound guidance (EUS) almost invariably obtains gastric or duodenal contaminants, but percutaneous FNAB is less likely to do so. Finally, the clinical and imaging findings are correlated with the cytologic and ancillary testing findings to arrive at a final diagnosis.
Indications for Pancreatic FNAB
The indications include the presence of a mass lesion, whether solid and/or cystic, although occasionally diffuse processes or vague abnormalities in the pancreas may be sampled. The differential diagnosis (DD) and therefore the cytologic algorithmic approach depend on the imaging characteristics of the mass ( Table 7-1 ). Solid masses that undergo FNAB include acute and chronic pancreatitis, pancreatic ductal adenocarcinoma (PDAC), nonductal neoplasms, and metastases. Solid and cystic masses include solid neoplasms that have undergone cystic degeneration such as cystic pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN). Cystic masses include neoplastic lesions, as well as non-neoplastic cystic lesions and pseudocysts. Finally, non–organ-specific masses include lymphomas, metastases, and mesenchymal neoplasms, which may present as either solid, cystic masses or as primarily cystic masses. This chapter focuses on primary pancreatic neoplastic and non-neoplastic processes and the most significant metastatic malignancies, while the reader is referred to other chapters for discussion of lymphomas and mesenchymal processes.
Table 7-1
Differential Diagnosis Based on Imaging
| Solid Masses | Solid and Cystic | Cystic Masses |
|---|---|---|
Benign
Malignant
|
|
Benign/Non-neoplastic
Neoplastic
|
Specimen Preparation
The FNAB material requires triage using a set protocol for cytomorphologic preparations, cell block, and additional studies including carcinoembryonic antigen (CEA) and/or amylase (cyst fluids), culture, immunohistochemistry (IHC), and molecular studies. The cytologic preparations can be direct smears or cytospins (Thermo-Shandon Instruments) or liquid-based preparations such as ThinPrep (Cytyc Corporation, Marlborough, Mass.) or SurePath Prep (TriPath, Inc., Burlington, N.C.) and cell blocks can be prepared from separate passes or needle rinses. IHC can be performed on cell blocks or direct smears, and local expertise will determine which method is used.
Decisions on the best use of the FNAB material for cytology and ancillary tests are greatly facilitated by rapid on-site evaluation (ROSE) by a cytopathologist or experienced cytotechnologist, and many units regard this as mandatory to effectively handle the material and report the FNAB.
There is no standardized method for processing cyst fluids. It is preferable that cyst fluids be submitted fresh and undiluted to the pathology laboratory for processing and triaging for cytologic, biochemical, and mutational analysis (e.g., KRAS , GNAS ). A 0.3-mL aliquot of the neat fluid after the sample has been vortexed is usually sufficient for the mutational studies. The CEA and amylase may be run on the neat fluid or the supernatant. The samples may be diluted with saline if they are too scant for CEA and amylase analysis. In this case, the CEA value needs to be corrected by the dilution volume. Usually, a 0.5-mL volume is needed for each of the CEA and amylase analyses. The cell button should be used for cytologic and cell block processing.
New devices have been developed and U.S. Food and Drug Administration approved to attempt to improve the cellular sampling of pancreatic masses. First is the EchoBrush, (Cook Medical, Bloomington, Illinois, USA) which is used to sample the interior wall of cystic masses to then make direct smears, or the brush is simply cut off and submitted in saline for cytospins and cell blocks. Second is the ProCore needle, (Cook Medical, Bloomington, Illinois, USA) which is a reverse bevel needle in 25 gauge (ga), 22 ga, and 19 ga that obtains fragmented material similar to core biopsy specimens that can be handled as cell blocks. Touch imprints may be made from the core biopsy fragments for on-site evaluation.
Cytologic Approach to Assessing Pancreatic FNAB
A stepwise analysis of the FNAB material begins with an evaluation of the gross sample, and it is particularly important to assess pancreatic cyst fluid and its volume, which should be recorded when received in the laboratory.
At low power (×5 or ×10 magnification), cellularity and smear pattern are assessed. The smear pattern is a product of the background and the number, size, and architecture of tissue fragments. At intermediate power, architectural details in tissue fragments can be assessed in greater detail, while at high power, the individual cellular details and mitoses are appreciated. The final diagnosis is reached after integration of the features found at all the magnifications.
Low- to Intermediate-Power Assessment
At low power the overall cellularity is assessed with a quick initial scan of the slides. The cellularity of the specimen is determined by the size and nature of the lesion, number of passes, and experience of the operator. Unlike FNAB for other organs, at present there are no established criteria for adequacy, and an FNAB lacking epithelial cells may still be adequate and representative of the targeted mass, especially for cystic lesions (e.g., FNAB of a pseudocyst). FNAB of solid masses should in general be cellular, but extensive desmoplasia and hemorrhagic degeneration in the mass may lead to a scantier cellular yield. While it is generally true that pancreatic neoplasms are more cellular than benign processes, some benign processes may lead to cellular smears, particularly GIT contamination and benign pancreas, which consists mostly of acini. FNAB of cystic lesions typically yields a scant number of diagnostic cells, which accounts for the low sensitivity of cytology for the detection of cystic neoplasms.
The first step is to assess the background, which can yield important information ( Table 7-2 ). It is important to note that more than one background pattern may be present in a smear, particularly since a mucinous background can be due to GIT contamination caused by the FNAB traversing the gastric or duodenal wall, as well as noninvasive cystic neoplasms (MCN and IPMN) and invasive adenocarcinomas. Other patterns include clean, bloody, mostly inflammatory, or dirty and necrotic backgrounds. A clean background occurs in normal pancreas, well-differentiated adenocarcinoma, and some other neoplasms including metastases. Blood is a nonspecific finding because it is present almost invariably, but some lesions have a vascular stroma and therefore may be especially bloody, such as serous cyst adenomas, pancreatic neuroendocrine tumors, and metastatic renal cell carcinoma. A predominantly inflammatory background is associated with various forms of pancreatitis, pseudocyst, and abscess but may also obscure adenocarcinoma. Dirty and necrotic backgrounds occur with pancreatitis and pseudocysts, as well as adenocarcinomas with necrosis or other neoplasms with degeneration or necrosis.
Table 7-2
Background Appearances of Pancreatic FNAB
| Background | Cytomorphology | Associated with: |
|---|---|---|
| Clean | Lacks any of the other background elements except for contaminant mucin | Normal pancreas PDAC, well differentiated ACC Metastases |
| Blood | Abundant | PanNET, metastatic RCC, SCA, SPN, any neoplasm |
| Inflammatory | Abundant neutrophils, eosinophils, lymphocytes, plasma cells, histiocytes, in various combinations | Pseudocyst Abscess Acute and chronic pancreatitis Autoimmune pancreatitis Dermoid cyst Ectopic spleen PDAC with inflammation Lymphomas |
| Dirty and necrotic | Granular debris Degenerated cellular elements Coagulative necrosis |
Pseudocyst Acute and chronic pancreatitis Infections (e.g., TB) Dermoid cyst Epidermoid cyst in ectopic spleen LECP PDAC Metastatic malignancies |
| Mucin | Thin, watery Thick, colloidy, diffuse ∗ Thick and pink on Papanicolaou ∗ Thick aggregates or clumps ∗ Thick and fanlike ∗ Ferning ∗ Oncotic cells with histiocytes in the mucin ∗ |
GI contaminant Retention cyst Ciliated foregut cyst SCOPD MCN IPMN Mucinous noncystic carcinoma |
ACC, acinar cell carcinoma; GI, gastrointestinal; IPMN, intraductal papillary mucinous neoplasm; LECP, lymphoepithelial cyst of the pancreas; MCN, mucinous cystic neoplasm; PanNET, pancreatic neuroendocrine tumor; PDAC, pancreatic ductal adenocarcinoma; RCC, renal cell carcinoma; SCOPD, squamous cyst of pancreatic ducts; SPN, solid pseudopapillary neoplasm; TB, tuberculosis.
∗ Associated with mucin derived from true cystic masses or neoplasms, not from contaminant.
The second step is to determine what types of parenchymal epithelial or epithelioid and stromal elements are present, if any. Epithelial cellular elements may be either glandular or ductal, or nonglandular or nonductal in type, the latter including acinar, neuroendocrine, or squamous cells. Ductal, acinar, and neuroendocrine cells are all normal components of the pancreas, and the phenotype of most primary pancreatic neoplasms can be related to one of these cells ( Table 7-3 ). Understanding the morphologic features of the normal components of the pancreas and how neoplastic transformation impacts them is critical to understanding the pattern-based approach to the pancreas.
Table 7-3
Histogenesis of Neoplasms of the Pancreas
Ductal phenotype
Interlobular and intralobular ducts
Centroacinar
Acinar phenotype
Neuroendocrine phenotype
Unknown
|
The characteristic architecture of ductal epithelium in cytology is honeycombing, rather than the cross-sectional cuboidal, low columnar, or tall columnar architecture seen in sections in histology ( Fig. 7-1A ). The honeycomb pattern may be uniform, like a “marching band” in benign ductal cells, or it may show varying levels of disarray with or without crowding, termed “drunken honeycombing” in neoplastic ductal cells ( Fig. 7-1B ). The tissue fragments can become three-dimensional with a multilayering of cells or “cells on top of cells” reflecting early tufting that progresses to micropapillary formation, cribriforming, and syncytial, papillary, and solid fragments. After identifying the honeycombing pattern in the center of a tissue fragment, the focus needs to move to the edge of the tissue fragment, which has a tendency to fold. The apical-to-basal orientation of ductal cells is best revealed at the edges of the sheet where the columnar or cuboidal cytoplasm of the cells can be recognized ( Fig. 7-1C ). Normal ductal structures in FNAB smears yield few single intact cells and few naked nuclei from disrupted cells.
Acinar cells are clearly distinguished from ductal epithelium by their lack of honeycombing. Unlike ductal cells, acinar cells have a much more delicate cytoplasm, with occasional vacuolization and pyramidal, triangular, or polygonal shapes ( Fig. 7-2A ). They form characteristic acinar structures with the acinar cells radiating like a flower’s petals from the center of the acinus and the luminal apex of the cell to the base of the cell apposed to the circumferential basement membrane. Acinar cells are distinctive in that they contain abundant, granular cytoplasm with numerous intracytoplasmic zymogen granules. The cytoplasm is dense blue-green on Papanicolaou (Pap) smears and contains coarse purple granules in the Giemsa stain or negative images of the granules in the cytoplasm ( Fig. 7-2B ). Acinar cells have eccentric round nuclei, a granular chromatin pattern, and prominent nucleoli. The cytoplasm is fragile, and smearing produces naked nuclei from ruptured cells.
Islet cells are only rarely detected in FNAB of the normal pancreas but are seen more often in chronic pancreatitis with islet cell hyperplasia. When present, they occur as discohesive tissue fragments of cells that have wispy, ill-defined amphophilic cytoplasm and oval nuclei with a stippled chromatin pattern ( Fig. 7-3 ). The cytoplasm of neoplasms with neuroendocrine differentiation may be variable, but the nuclear features remain the same.
Stromal elements that may occur in a pancreatic FNAB include fibrous stromal fragments, fibrovascular cores, and spindle cells from stromal or mesenchymal processes. Fibrous stromal elements are associated with pancreatitis or pancreatic ductal adenocarcinoma. Vascular stromal fragments are associated with solid and cellular neoplasms of the pancreas, serous cystic neoplasm, papillary neoplasms, metastatic renal cell carcinoma, and hepatocellular carcinoma.
The architecture of tissue fragments can be identified at low power and confirmed at intermediate power. At low power, it is possible to determine whether the sample consists of predominantly cohesive or discohesive tissue fragments, or single cells. Large, syncytial tissue fragments or honeycomb sheets or “picket fence–like” parallel arrays of cells can be seen, as can stripped nuclei and vascular structures forming papillary fronds. At intermediate power, glandular or squamous or acinar differentiation can be determined, glandular sheets and tissue fragments can be assessed for whether they retain or lose their honeycomb appearance, nonductal groups can be assessed for three-dimensionality and overlapping, and the cellularity of stromal fragments can be assessed.
High-Power Assessment
At this power, the focus is on the nucleus including nuclear size, nuclear to cytoplasmic (N:C) ratio, nuclear membrane contour, distribution of chromatin, presence of nucleoli, and mitoses. Nuclear enlargement, increased N:C ratio, nuclear membrane irregularities, and chromatin abnormalities are features of pancreatic ductal adenocarcinoma. The nuclei of pancreatic neuroendocrine tumors and acinar cell carcinoma have rounded contours but are differentiated by the chromatin pattern and presence of nucleoli, respectively.
Patterns in Pancreatic FNAB Smears
The low- and high-power features discussed earlier can be integrated into eight smear patterns. One specific lesion can be associated with more than one smear pattern. All of the patterns can be associated with benign and malignant entities.
1
Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments ( Plate 7-1 )
This pattern shows a predominance of inflammatory cells, which may consist predominantly of lymphocytes or neutrophils, or may show a mixed pattern consisting of a combination of inflammatory cells including neutrophils, lymphocytes, histiocytes including multinucleated forms, and granulomatous components. The inflammatory cells may be admixed with fragments of granulation tissue, fibrous tissue fragments, or pancreatic epithelial cells. These lesions are typically the results of an inflammatory process in the pancreas but may also occur adjacent to a neoplasm that has been undersampled or obtained from a cyst. Medullary carcinoma may be associated with a dense lymphocytic infiltrate and is included in this pattern. Included in the DD are peripancreatic benign lymph nodes and lymphoproliferative processes. Discussions of benign reactive lymphoid proliferations and lymphomas are covered in the lymph node chapter.
Plate 7-1
Pattern 1 Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments
Plate 7-1 Table
Pattern 1: Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments
Entities in the Differential Diagnosis
|
2
Mucinous Background ( Plate 7-2 )
This pattern has a mucinous background and epithelial cellular components varying from scant or even absent to highly cellular. The entities with a mucinous background include normal components and contaminants, non-neoplastic and neoplastic lesions, and malignant entities. The most common benign entity associated with this pattern is GIT contamination, while the most common neoplastic entity is intraductal papillary mucinous neoplasm. The nature of the mucin can differentiate between contaminant mucin and true lesional mucin.
Plate 7-2
Pattern 2 Mucinous Background
Plate 7-2 Table
Pattern 2: Mucinous Background
Entities in the Differential Diagnosis
|
3
Dirty or Necrotic Background Predominating ( Plate 7-3 )
There is a spectrum of frank granular or cellular necrosis with apoptosis and chromatinic smearing to fragmented degenerate cellular material and acellular necrosis. Lesions in this entity include benign processes, such as acute pancreatitis, and some moderately or poorly differentiated adenocarcinomas, as well as anaplastic or undifferentiated carcinoma with or without multinucleated giant cells.
4
Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments ( Plate 7-4 )
This pattern of predominantly ductal or other epithelial large tissue fragments is seen in benign and malignant glandular proliferations. The cells are arranged in cohesive, tight tissue fragments. The cells will be recognized as ductal depending on the degree of differentiation of the neoplasm or carcinoma. In carcinomas with glandular differentiation, the morphology is that of large, glandular, sheetlike tissue fragments or cells seen on edge with a “picket fence arrangement.” The DD includes mesothelial cells, benign ducts and acinar cells, gastric or duodenal epithelium, reactive ducts, pancreatic intraepithelial neoplasia, well-differentiated pancreatic ductal adenocarcinoma, undifferentiated carcinoma, medullary carcinoma, pancreatoblastoma, and metastatic adenocarcinomas.
Plate 7-4
Pattern 4 Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments
Plate 7-4 Table
Pattern 4: Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments
Entities in the Differential Diagnosis
|
5
Loosely Cohesive Tissue Fragments With Predominantly Dispersed Single Cells ( Plate 7-5 )
This pattern consists of predominantly dispersed single cells with some smaller tissue fragments. This includes pancreatic neuroendocrine tumor, acinar cell carcinoma, pancreatoblastoma, poorly differentiated neuroendocrine carcinoma, moderately and poorly differentiated adenocarcinomas, oncocytic carcinoma, signet ring cell carcinoma, and metastatic melanoma. Hepatocytes may show a similar pattern.
Plate 7-5
Pattern 5 Loosely Cohesive Tissue Fragments With Predominantly Dispersed Single Cells
6
Epithelial Proliferations With Fibrovascular Stroma or Cores Within Epithelial Tissue Fragments ( Plate 7-6 )
This pattern has epithelial tissue fragments containing stroma with fibrovascular strands or cores, which may vary in quantity and size. Entities include solid pseudo-papillary neoplasms, intraductal papillary mucinous neoplasm, and intraductal papillary oncocytic neoplasms. Pancreatic neuroendocrine tumors and acinar cell carcinomas may also have prominent fibrovascular strands with epithelial elements attached. Benign hepatocytes and metastatic hepatocellular carcinoma and renal cell carcinoma may show this pattern.
Plate 7-6
Pattern 6 Epithelial Proliferations With Fibrovascular Stroma or Cores Within Epithelial Tissue Fragments
Plate 7-6 Table
Pattern 6: Epithelial Proliferations With Fibrovascular Stroma or Cores Within Epithelial Tissue Fragments
Entities in the Differential Diagnosis
|
7
Squamous Cells Predominating ( Plate 7-7 )
This pattern is characterized by the presence of cells with squamous differentiation. The DD includes benign and malignant entities, including squamous metaplasia of ducts, squamous cyst of pancreatic ducts, lymphoepithelial cyst of the pancreas, squamous cysts in ectopic spleen, dermoid cysts, pancreatoblastoma, adenosquamous carcinoma, and metastatic squamous cell carcinoma.
Plate 7-7
Pattern 7 Squamous Cells Predominating
Plate 7-7 Table
Pattern 7: Squamous Cells Predominating
Entities in the Differential Diagnosis
|
8
Stromal Fragments With or Without Epithelial Tissue Fragments ( Plate 7-8 )
Angulated stromal fragments are a significant component of some processes, and the cellularity varies depending on the nature of the process. Stromal fragments are components of chronic pancreatitis and autoimmune pancreatitis. In autoimmune pancreatitis, the characteristic fragment is cellular, due to a lymphoplasmacytic infiltrate, but because the distribution of the inflammatory cells within autoimmune pancreatitis is variable, the fragments from autoimmune pancreatitis may also be hyalinized and paucicellular. Pancreatoblastoma may have a mesenchymal component. Finally, mesenchymal neoplasms metastasizing to or secondarily involving the pancreas have this pattern, as for example, gastrointestinal stromal tumor arising in the stomach.
Plate 7-8
Pattern 8 Stromal Fragments With or Without Epithelial Tissue Fragments
Normal Pancreas
Smear Pattern: Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments
FNAB of normal pancreas is composed predominantly of acinar cells with few ductal cells ( Fig. 7-4 ). The features of benign ductal and acinar cells have been described at the beginning of this chapter. Acinar cells present in “grapelike clusters” of acini, or sometimes larger fragments, where they are embedded in the pancreatic stroma. The appearance of the ductal cells will depend on whether they are derived from the larger, interlobular ducts or the smaller intralobular ducts. The epithelial lining of the large pancreatic ducts is composed of columnar epithelium arranged in flat, honeycombed, two-dimensional, monolayered sheets of cells with centrally located nuclei. These ductal cells may also be observed in a palisaded “picket fence” arrangement, in which nuclei are basally located in the cells at the edges of the sheets. In contrast to the epithelium of the large ducts, intercalated or intralobular duct epithelium is composed of cuboidal-shaped cells with scant basophilic cytoplasm typically presenting as flat sheets, small tissue fragments, or tubular fragments.
Contaminants From Percutaneous FNAB
Mesothelial Cells
Smear Pattern: Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments
Mesothelial cells are found in percutaneous FNAB and are polygonal cells arranged in flat sheets, with round to oval nuclei and intercytoplasmic “windows” ( Fig. 7-5 ). They may be mistaken for benign ductal cells or possibly squamous cells.
Hepatocytes
Smear Pattern: Loosely Cohesive Aggregates With Dispersed Single Cells OR Epithelial Proliferations With Fibrovascular Stroma or Cores Within Epithelial Tissue Fragments
Normal hepatocytes found in percutaneous FNAB are large polygonal cells with dense, sharply defined, finely granular cytoplasm and round, central or eccentric nuclei with prominent single nucleoli. Nuclear pseudoinclusions, as seen in histopathology, are also seen in cytopathology. They may occur in small sheets, small numbers of dispersed cells, or large fragments with fibrovascular cores when reactive. Stripped nuclei may be seen ( Figs. 7-6A and B ).
Gastrointestinal Tract Contaminants From Endoscopic Ultrasound-Guided FNAB
Smear Pattern: Mucinous Background
GIT contaminants present as background thin and watery mucin with glandular mucinous cells and usually abundant degenerate or crushed material. In some cases, an associated lamina propria may resemble a stromal neoplasm but has attached epithelium ( Fig. 7-7 ). The mucin with the GIT contaminants may sometimes appear thick on the smear, but it lacks the epithelial cells and histiocytes seen with mucin aspirated from a true mucinous cystic lesion. The GIT honeycomb epithelial tissue fragments are embedded or localized in spotty or splotchy mucinous regions ( Fig. 7-8 ).
Gastric epithelium includes surface foveolar cells, mucous neck cells, and the chief and parietal cells of the glands. The foveolar and mucous neck cells show a uniform honeycomb pattern in large sheets or may be seen on edge, with basal nuclei and columnar cytoplasm containing abundant mucin characteristically forming an apical cup only in the upper third of the foveolar cell ( Fig. 7-9A ). The gastric epithelium may also appear as stripped, bland, slightly elongated nuclei within a background of mucin ( Fig. 7-9B ). Chief and parietal cells may be seen if the FNAB traverses the fundic or body region of the stomach. The chief cells will have abundant bluish granules in the cytoplasm while the parietal cells have abundant, well-defined dense cytoplasm ( Fig. 7-10 ).
Small intestinal epithelium, obtained when the FNAB traverses the duodenum to sample the head or the uncinate process of the pancreas, is composed of absorptive enterocytes with a microvillus border, sporadically placed goblet cells, and characteristic intraepithelial lymphocytes, which are darker and smaller than the epithelial cells ( Figs. 7-11A and B ). Paneth cells are identified by the presence of coarse, eosinophilic granules in their apical cytoplasm on the Pap stain.
Inflammatory Processes
Abscess
Smear Pattern: Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments
Clinical Features
Pancreatic abscess occurs as a secondary infection of pancreatic necrosis following a bout of acute pancreatitis or as a secondary infection of an existing pseudocyst. Clinical features include prolonged course, hemodynamic instability, fever, or failure of medical therapy. Imaging studies include the presence of fluid collections in the pancreas on computed tomography (CT) scan. Leukocytosis with a left shift and positive blood cultures are suggestive of this diagnosis. FNAB is performed for diagnosis and to collect a specimen for microbiological studies.
Cytopathology
The smears are composed predominantly of neutrophils, with some histiocytes. Normal parenchymal elements are scarce, if seen at all.
Cytologic diagnostic criteria ( Fig. 7-12 )
Differential Diagnosis
Acute pancreatitis, pseudocyst, and poorly differentiated adenocarcinoma obscured by inflammation are the three leading DD, and the clinical history will provide significant help. Acute pancreatitis is accompanied by degenerate cellular debris and fat necrosis, faintly birefringent fatty acid crystals, debris, and histiocytes. Pseudocysts have pigment including hemosiderin and often bile, a proteinaceous background with debris and a mixed inflammatory infiltrate. A careful search of a pancreatic FNAB smear with abundant acute inflammation is mandatory to exclude adenocarcinoma obscured by the inflammation.
Acute Pancreatitis
Smear Pattern: Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments OR Dirty or Necrotic Background Predominating
Clinical Features
Acute pancreatitis is an inflammatory process of the pancreas that occurs suddenly. The most common causes of acute pancreatitis are alcohol abuse and gallstones. Other causes include trauma, metabolic disorders such as hereditary pancreatitis, endoscopic retrograde cholangiopancreatography, ulcers, carcinomas that obstruct the pancreatic ductal system, drugs, infections, and structural abnormalities such as pancreas divisum. Common presenting symptoms and signs include abdominal pain that radiates to the back, nausea, vomiting, diarrhea, fever, tachycardia, and chills. Grey-Turner sign, which is hemorrhagic discoloration of the flank, and Cullen sign, which is hemorrhagic discoloration of the umbilicus, are less common signs associated with severe disease. Severe abdominal pain with elevated lipase and amylase will trigger the initial diagnosis. CT scan may be used to assess the extent of disease and complications of acute pancreatitis such as pseudocyst, abscesses, necrosis, ascites, and pleural effusions. Magnetic resonance imaging (MRI) provides an alternative imaging method for patients with allergies to contrast. Magnetic resonance cholangiopancreatography (MRCP) may identify stones obstructing the ductal system. FNAB is usually not indicated, but occasionally a residual mass lesion may be aspirated. FNAB may also be used to assess whether the necrosis is sterile or infected or to drain fluid collections.
Cytopathology
Smears are typically cellular and composed of a mixed inflammatory population of neutrophils and histiocytes in a dirty, granular background resulting from necrosis of pancreatic parenchyma and inflammatory cells.
Cytologic diagnostic criteria ( Fig. 7-13 )
Differential Diagnosis
The primary entities in the DD include abscess and pseudocyst, both of which are associated with necrosis. Usually, these are suspected before FNAB. An abscess consists of a pure population of neutrophils with degeneration, without the other features of acute pancreatitis. FNAB of a pseudocyst obtains an abundant amount of turbid fluid, and smears demonstrate abundant histiocytes, neutrophils, degenerated debris, and bile pigment. Because acute pancreatitis may surround an obstructing neoplasm, an underlying neoplasm needs to be excluded.
Diagnostic Ancillary Tests
Generally, ancillary studies are not applicable in this setting.
Chronic Pancreatitis
Smear Pattern: Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments OR Stromal Fragments With or Without Epithelial Tissue Fragments
Clinical Features
Chronic pancreatitis is an inflammatory disease of the pancreas that results in permanent loss of the structure and function of the pancreas. Presenting signs and symptoms include pain or malabsorption and sometimes the new onset of diabetes. The most common cause in the United States is chronic alcohol abuse while smoking, malnutrition, hereditary diseases, trypsinogen and inhibitory protein defects, cystic fibrosis, trauma, hypercalcemia, and stones are other causes. Some cases are idiopathic.
Most cases of chronic pancreatitis are associated with nonfocal lesions and irregular ductal dilatation that is often associated with stricture formation, obstruction, and calcifications on CT imaging studies. MRCP will show the characteristic beaded appearance of the pancreatic duct. Endoscopic ultrasound criteria for the diagnosis of chronic pancreatitis include visible side branches, cysts, lobularity, an irregular main pancreatic duct, hyperechoic foci and strands, dilation of the main pancreatic duct, and hyperechoic margins of the main pancreatic duct. However, the presence of stones is reportedly the most predictive endosonographic feature. Pseudocyst formation, focal involvement, and dense expanses of fibrosis can create masslike lesions mimicking carcinoma and are indications for FNAB.
Cytopathology
FNAB smears of chronic pancreatitis are typically paucicellular, consisting of varying numbers of inflammatory cells, ductal cells, acinar cells, calcifications, fibrous tissue fragments, and debris. Islet cells are scant if present.
Cytologic diagnostic criteria ( Fig. 7-14 )
-
Cellularity: usually paucicellular.
-
Pattern: inflammatory cells predominating with or without epithelial tissue fragments.
-
Few ductal cells showing reactive changes.
-
Acinar cells scant and may be involved by lymphocytic infiltrates.
-
Background inflammatory component, mostly histiocytes and lymphocytes.
-
Microcalcifications.
-
Fibrous, stromal fragments.
-
Islet cells may be present but are scarce.
Differential Diagnosis
The DD includes mainly autoimmune pancreatitis and poorly differentiated adenocarcinoma. Autoimmune pancreatitis will show cellular stromal fragments with both eosinophils and a lymphoplasmacytic infiltrate and lack calcifications. Reactive ductal groups may mimic moderately or poorly differentiated adenocarcinoma, and this DD is discussed in the carcinoma section.
Autoimmune Pancreatitis
Smear Pattern: Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments OR Stromal Fragments With or Without Epithelial Tissue Fragments
Clinical Features
There are two types of autoimmune pancreatitis: Type I is a multiorgan, IgG 4–related disease associated with serum IgG4 elevations and an IgG4 positive plasma cell infiltration, while type II is organ specific. Type I patients are on average 16 years older and present more often with obstructive jaundice, whereas type II patients present with acute pancreatitis and abdominal pain.
Both respond to therapy with steroids or immunosuppressant agents, but type I is prone to relapse, whereas type II is not. Type I is more likely to show pancreatic swelling and elevated serum IgG 4 levels, with classic imaging showing a diffusely swollen “sausagelike” pancreas with a halo effect around its periphery. Occasionally, patients may present with a solitary, ill-defined mass lesion in which case the DD is adenocarcinoma.
Cytopathology
FNAB smears are typically scantly cellular, composed of a small number of ductal epithelium tissue fragments, with mixed inflammatory cells and stromal fragments. The key feature that helps distinguish this process from others is the presence of cellular stromal fragments with embedded lymphocytes.
Cytologic diagnostic criteria ( Fig. 7-15 )
-
Cellularity: scant.
-
Pattern: inflammatory cells predominating with or without epithelial tissue fragments OR stromal fragments with or without epithelial tissue fragments.
-
Cellular fibrous stromal fragments with embedded lymphocytes.
-
Lymphoplasmacytic infiltrate with eosinophils.
-
Ductal cells with reactive or regenerative changes.
-
Lymphocytes infiltrating ductal cell tissue fragments.
Differential Diagnosis
FNAB is typically performed to rule out adenocarcinoma in clinically and imaging indeterminate cases. Pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm may coexist with autoimmune pancreatitis. The cytomorphology of these entities overlaps significantly with that of well-differentiated pancreatic ductal adenocarcinoma. Chronic pancreatitis will lack the cellular stromal fragments, and autoimmune pancreatitis will not produce calcifications as seen in chronic pancreatitis.
Diagnostic Ancillary Studies
If the pancreatitis is IgG4 related, IHC for both IgG4 and IgG may be beneficial. A cutoff of 30 IgG4-positive cells per high-power field (HPF) has been proposed for tissue specimens, and a lower cutoff of 10 IgG4-positive cells per HPF has been proposed for biopsy specimens. This lower cutoff for biopsies was established to account for tissue heterogeneity. Sclerotic areas may lack IgG4-positive cells. The IgG-to-IgG4 ratio is beneficial in helping to differentiate diseases with an increased number of plasma cells overall from IgG4-related disease. A ratio of greater than 40% is reportedly sensitive for IgG4-related disease.
Benign Non-Neoplastic Lesions
Ectopic Spleen
Smear Pattern: Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments
Clinical Features
These lesions are usually found during workup for abdominal symptoms or incidentally on CT or ultrasound. On imaging, ectopic spleen is located within or immediately adjacent to the pancreas and appears similar to a pancreatic neuroendocrine tumor. CT imaging will show an ovoid, well-enhanced nodule with a density greater than that of normal pancreas but similar to the spleen. Sonography will show a homogenous and isoechoic nodule with echogenicity similar to the spleen.
Cytopathology
The smears show a heterogeneous lymphoid pattern with small lymphocytes predominating, fragments of germinal centers, and often prominent histiocytes, along with occasional tissue fragments of white pulp or rarely red pulp including branching sinusoidal vessels and capillaries.
Cytologic diagnostic criteria ( Fig. 7-16 )
Differential Diagnosis
The cytomorphology excludes pancreatic neuroendocrine tumor. The DD includes lymphoma or plasma cell neoplasm, which usually shows a more monomorphic small or large cell population, or a benign lymph node, which has a similar heterogeneous lymphoid population with small lymphocytes predominating to the splenic white pulp. Red pulp can be diagnostic. Correlation with imaging is required.
Ancillary Diagnostic Studies
Flow cytometry is often required to exclude monoclonal B-cell lymphomas and plasma cell neoplasms, which are CD138 positive. IHC for CD8 will confirm that the vessels are of splenic origin.
Reactive Ductal Atypia
Pattern: Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments
Clinical Features
Reactive ductal atypia may be induced by pancreatitis or other inflammatory processes. Since these occur secondarily to another underlying process, such as pancreatitis, they are not associated with specific clinical or imaging features.
Cytopathology
Features of reactive atypia include monolayered ductal tissue fragments showing nuclear enlargement, some loss of polarity, large nucleoli, and a relatively low N:C ratio. Neutrophils may be seen within the atypical ductal sheets.
Cytologic diagnostic criteria ( Fig. 7-17 )
Differential Diagnosis
The main DD is ductal adenocarcinoma and is discussed in the section on ductal adenocarcinoma .
Neoplastic Lesions
Pancreatic Intraepithelial Neoplasia
Smear Pattern: Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments
Clinical Features
Pancreatic intraepithelial neoplasia (PanIN) is the precursor to invasive pancreatic ductal adenocarcinoma and occurs in intermediate-sized ducts. PanIN does not form a mass visible on imaging studies, but it may be a component of a pancreatic mass formed by another process, such as pancreatitis, and it may be adjacent to a nonductal neoplasm.
Cytopathology
FNAB of PanIN shows varying numbers of cohesive ductal tissue fragments with nuclear crowding and loss of polarity. If the mass is due to pancreatitis, the background may show features of the cause of the pancreatitis, such as a lymphoplasmacytic infiltrate in autoimmune pancreatitis.
Cytologic diagnostic criteria ( Fig. 7-18 )
The nuclei are subtly enlarged, and the cells have an increased N:C ratio. The nuclear features resemble those of papillary thyroid carcinoma, with the pale chromatin, occasional grooves, and small, peripherally placed nucleoli. The nuclear membranes may remain smooth or show subtle angulations and irregularities.
Differential Diagnosis
The key DD is well-differentiated pancreatic ductal adenocarcinoma. Experience with PanIN in preoperative biopsies is limited. It has been shown that PanIN may be a source of atypical FNAB or false-positive diagnoses of adenocarcinoma. The only clue may be that the tissue fragments are tightly cohesive and the cells show nuclear features resembling those of papillary thyroid carcinoma. Intraductal papillary mucinous neoplasms, which are discussed in the section on cystic masses, show similar nuclear features.
Ancillary Diagnostic Studies
There are no ancillary studies currently used to differentiate PanIN from adenocarcinoma in routine practice.
Ductal Adenocarcinoma
Smear Pattern: Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments OR Dirty or Necrotic Background Predominating OR Loosely Cohesive Tissue Fragments with Predominantly Dispersed Single Cells
Pancreatic ductal adenocarcinoma (PDAC) shows a range from well-differentiated carcinoma when the smear pattern is one of cohesive ductal-type tissue fragments in a clean or mucinous background to the more common, moderately to poorly differentiated carcinoma with a predominant dirty or necrotic background with limited epithelial material. The histopathology of PDAC is characterized by a tubular carcinoma within a dense, desmoplastic stroma with variable necrosis.
Well-differentiated PDAC will be referred to as low-grade carcinoma and moderately and poorly differentiated PDAC as high-grade carcinoma for the remainder of this chapter.
Clinical Features
The clinical presentation is similar for all PDAC. Patients present with nonspecific symptoms including malaise, nausea, fatigue, and midepigastric or back pain, and in addition, cancers arising in the pancreatic head have signs and symptoms related to obstruction of the common bile duct and the resultant hyperbilirubinemia including jaundice, pruritus, dark urine, and pale-colored stools. A subset of patients may present with migratory thrombophlebitis (Trousseau syndrome). The gallbladder may be palpable (Courvoisier sign). A metastatic node in the cervical region may be palpable (Virchow sign). CA19-9 is a serum marker that is associated with pancreatic ductal adenocarcinoma, and a level above 100 U/mL in the absence of bile duct obstruction, benign pancreatic disease, or intrinsic liver disease is indicative of pancreatic cancer.
The classic imaging findings are that of the “double duct sign” or a mass with invasion beyond the pancreas. Desmoplasia and necrosis may make the tumor gritty and difficult to sample.
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