Fine-needle aspiration cytology of pancreatic lymphoepithelial cysts




Lymphoepithelial cysts (LECs) of the pancreas are extremely rare, benign, nonneoplastic cysts that can mimic pseudocysts or cystic neoplasms clinically and radiographically. The cytologic features of LECs have been described only in a handful of case reports and may overlap with both benign and malignant pancreatic tumors.


The authors conducted a 5-year, retrospective, computerized review of the cytopathology files of 2 institutions for all diagnoses of pancreatic LECs. Clinical, radiographic, cytologic, and chemical findings were reviewed.


Four patients were identified. The study group consisted of 3 men and 1 woman who ranged in age from 33 years to 63 years. The masses were located throughout the pancreas. Tumor sizes ranged from 1.8 cm to 5.7 cm in greatest dimension. Smears from all patients revealed numerous anucleated squamous cells, rare benign nucleated cells, amorphous debris, and an absence of lymphocytes. Mildly atypical mucinous glandular and parakeratotic epithelium were identified in 2 patients, leading to diagnoses of atypical and suspicious for malignancy. Subsequent surgical follow-up of 3 patients revealed pancreatic LECs.


Pancreatic LECs are extremely rare, and certain cytologic pitfalls may hinder a correct prospective diagnosis. Familiarity with the lesion's clinical and cytologic features may help clinicians arrive at the appropriate prospective diagnosis and, thus, permit conservative management. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

The increased use of diagnostic imaging and better imaging modalities, in general, have led to the increased detection of cystic lesions of the pancreas. However, distinguishing between types of pancreatic cysts by radiologic findings alone often is not possible. Fine-needle aspiration (FNA) of pancreatic lesions has been used and accepted widely, because it allows for a definitive diagnosis of most pancreatic lesions and, thus, proper triaging. FNA is used increasingly with pancreatic cystic lesions to distinguish lesions that must be resected from lesions that can be managed more conservatively.

Lymphoepithelial cysts (LECs) of the pancreas are extremely rare. The largest series in the surgical pathology literature was reported by Adsay et al. and included a total of 12 patients.1 Because of their rarity, the cytologic features of LECs have been described only in a handful of case reports, and it has been reported that LECs overlap with both benign pancreatic lesions (dermoid cyst and accessory-splenic epidermoid cyst) and malignant pancreatic lesions (metastatic well differentiated squamous cell carcinoma and pancreatic adenosquamous carcinoma).2–8 In the current study, the clinical, radiologic, and cytologic features of 4 patients who had LECs of the pancreas sampled by endoscopic ultrasound (EUS)-guided FNA are analyzed and compared with the previously published literature. The differential diagnosis and methods for distinguishing the various pancreatic cystic lesions are discussed.


Retrospective, computerized searches of the cytopathology files at 2 institutions (University of Virginia and Hennepin County Medical Center) were reviewed for all patients who underwent sampling of pancreatic LECs between January 1, 2001 and April 1, 2006. Histologic and cytologic materials, chemical analyses of pancreatic fluids, and clinical, computed tomography, and ultrasound findings also were reviewed. All aspirates were performed by EUS-guided FNA. Both 22-gauge and 25-gauge biopsy needles were used. In total, 2 passes were performed for each patient. A portion of the cyst fluid from 1 patient was sent for chemical analysis (carcinoembryonic antigen [CEA], amylase, and lipase). Aspirates from the remaining 3 patients showed extremely thick material, which precluded the procurement of additional material for chemical analysis. Smears were either air-dried or fixed in alcohol and stained with Diff-Quik or Papanicolaou stain, at the discretion of the pathologist who performed the rapid assessment. All specimens were assessed for adequacy and were given preliminary diagnoses.


Four patients with LECs who had undergone FNA were identified, and 3 of those patients underwent surgical follow-up (2 patients underwent distal pancreatectomy, and 1 patient underwent pancreatoduodenectomy). One patient had cytologic findings consistent with LEC on 2 separate occasions but has not undergone resection. There were 3 men and 1 woman ages 63 years, 58 years, 48 years, and 33 years. Three patients presented with abdominal pain, and one patient presented with shortness of breath. Tumor sizes were 1.8 cm, 2.7 cm, 4 cm, and 5.7 cm in greatest dimension (3 tumors were measured at resection, and 1 tumor was measured by sonography). Two lesions were located in the pancreatic body, 1 lesion was located in the pancreatic head, and 1 lesion was located in the tail of the pancreas.

Sonographically, all lesions were hypoechoic and were either unilocular or multicystic. Chemical analysis was performed with the aspirated material from a single patient and showed a markedly increased CEA level (35,028 ng/mL), an increased amylase level (480 U/L), and a normal lipase level (20 U/L). Preliminary interpretations were as follows: 1) acellular material; 2) rare groups of atypical glandular cells, no cells diagnostic of malignancy; 3) large amount of debris consistent with resolving pancreatitis; and 4) acellular debris and crystals. The final FNA diagnoses were l) mucoid material and rare atypical epithelial cells; 2) scattered, atypical cells suspicious for malignancy; 3) squamous cyst showing no evidence of malignancy, differential diagnosis includes dermoid cyst and lymphoepithelial cyst; and 4) squamous cyst consistent with lymphoepithelial cyst.

Most of the smears showed abundant, anucleated, keratinous debris and rare nucleated squamous epithelial cells (Figs. 1, 2). The keratinous debris showed varying degrees of degeneration, and 1 smear showed a predominance of definite anucleated squamous cells. Two smears (Patients 1 and 2) showed a somewhat mucoid, metachromatic (Diff-Quik)-appearing substance (Fig. 3), which we believe was keratinous debris with only occasional intact anucleated squamous cells. Cholesterol crystals were seen in 2 smears. There was a paucity of lymphocytes in all smears. Two smears showed rare atypical epithelial cells, which, in retrospect, may have been gastric contaminants (1 patient) and clusters of parakeratotic squamous cells (1 patient) and which led to FNA diagnoses of atypical and suspicious for malignancy. For Patient 1, adequate material was available for cell block preparation, which revealed abundant keratinous debris and a small fragment of stromal tissue with mucinous epithelium (in retrospect, we believed this was gastric epithelium). Three patients underwent subsequent surgical follow-up, which revealed pancreatic LECs (Fig. 4). One patient did not undergo surgical follow-up but had a repeat FNA, which revealed similar cytologic finding consistent with LEC. The repeat FNA procedure was complicated by superinfection of the pancreatic cyst; however, the patient was doing well at his most recent clinical follow-up. Radiologic follow-up after 5 months revealed that the lesion has remained stable in size, and no other new lesions were identified in the pancreas or in his other organs. Although we cannot rule out a benign squamous cyst (epidermoid cyst) or an under-sampled dermoid cyst entirely for this patient, the management is similar to that for LEC. The findings in all 4 patients are summarized in Table 1 together with the findings in previously reported LECs from the literature.

Figure 1.

Keratinous debris with varying degrees of degeneration (Papanicolaou stain, original magnification ×200).

Figure 2.

Rare nucleated squamous epithelial cells (Diff-Quik stain, original magnification ×400).

Figure 3.

Abundant mucoid metachromatic material with plate-like cholesterol crystals (Diff-Quik stain, original magnification ×200).

Figure 4.

Cyst wall lined by keratinized squamous epithelium with an underlying lymphoid cuff (hematoxylin and eosin stain, original magnification ×200).

Table 1. Findings of Pancreatic Lymphoepithelial Cysts
InvestigatorsAge, YearsGenderSymptomsSize, cmLocationImagingChemistryFNA findingsCell blockFinal
  1. FNA indicates fine-needle aspiration; CT, computed tomography; LEC, lymphoepithelial cyst; CEA, carcinoembryonic antigen; US, ultrasound.

Mitchell,  1990242MaleAbdominal  pain6HeadLow-density  mass on CTNoneAnucleated squamous cells and benign  nucleated cellsNoneLEC
Cappellari,  1993344MaleAbdominal  pain6HeadCystic mass  on CTAmylase, 120 U/LNumerous anucleated squamous cells,  few superficial squamous cells,  histiocytes, rare lymphocytes, and  plate-like cholesterol crystalsNoneLEC
Rino et al.,  1995458MaleAsymptomatic6.1HeadCystic mass on CTNoneAnucleated and nucleated squamous  cellsNoneLEC
Bolis et al.,  1998564MaleAbdominal  pain5.5Head and  bodyHomogenous  mass on CTNoneNoneStratified squamous epithelium with subepithelial lymphocytic infiltrates and keratinous materialNone
Mandavilli  et al., 1999649FemaleAbdominal  pain6Neck and  bodyCystic mass  on CTNoneAnucleated squamous cells, lymphocytes,  benign squamous epithelial cells,  abundant keratinous debris, focal  mucinous material, and  multinucleated giant cellsBenign squamous epithelium, lymphoid tissue, foreign-body type giant cells, cholesterol clefts, and gastric-type glandular epitheliumLEC
Centeno  et al., 1999747MaleAbdominal  pain2TailUnilocular cyst on CTCEA, 26,880 ng/mL;  CA 125, 11U/L;  CA 19-9,  >5 × 106U/mL;  amylase, 256 U/LNoneKeratinous debris, mature keratinized squamous epithelium, and wall with dense lymphoid infiltrateLEC
Liu et al.,  1999856MaleAbdominal  pain5TailCyst on CTNonePredominantly anucleated squamous cells,  rare benign nucleated cells, background  of keratinous and amorphous debris,  and plate-like cholesterol crystalsKeratinized squamous epithelium with  distinct granular  cell layer and lymphoid aggregatesLEC
Liu et al.,  1999849MaleAbdominal  pain6TailFluid-filled mass on CTNonePredominantly anucleated squamous cells,  rare benign nucleated cells, background  of keratinous and amorphous debris,  and plate-like cholesterol crystalsNoneLEC
Current study  (Patient 1)63MaleAbdominal  pain5.7Neck and  bodyMulticystic on CT;  hypoechoic on USCEA, 35,028 ng/mL;  amylase,  480 U/L;  lipase, 20 U/LNumerous anucleated squamous cells with  keratinous mucoid-appearing debris, rare  benign nucleated squamous cells,  mucinous epithelium (contaminant), and  plate-like cholesterol crystalsAnucleated keratinous debris, cholesterol  crystals, stromal tissue  with mucinous epitheliumLEC
Current study  (Patient 2)33MaleAbdominal  pain2.7HeadMultilocular on CT;  hypoechoic on USNoneNumerous anucleated squamous cells and  amorphous keratinous debris, few benign  parakeratotic squamous cells, and fragments  of squamous epitheliumNoneLEC
Current study  (Patient 3)58FemaleAbdominal  pain1.8TailUnilocular on CT;  hypoechoic on USNoneNumerous anucleated squamous cells,  foreign body giant cells, and amorphous  keratinous debrisNoneLEC
Current study  (Patient 4)48MaleShortness  of breath4BodyUnilocular on CT;  hypoechoic on USNoneNumerous anucleated squamous cells,  amorphous keratinous debris,  rare benign nucleated squamous cells,  and plate-like cholesterol crystalsNoneNone


LECs of the pancreas are extremely rare, and there have been very few patients reported in the English literature. The morphologic findings are distinctive and were described first in 1985 by Luchtrath and Schriefers, who noted the histologic similarity to the branchial cleft cysts of the lateral neck.9 In 1987, Truong et al. proposed the term “LEC of the pancreas” and speculated regarding its histogenesis.10

Macroscopically, the lesions may appear either intrapancreatic or peripancreatic, they may be either unilocular or multilocular, and they may contain keratinous debris of varying consistency. Microscopically, the cysts are lined by a maturing, stratified squamous epithelium that is devoid of cytologic atypia. Rare mucinous or sebaceous differentiation may be observed.11, 12 Surrounding the squamous epithelium is a dense, lymphoid infiltrate that may contain occasional germinal centers and occasional lymphoepithelial islands.

LECs occur in both genders at any age, but they are identified more commonly in middle-aged men. The lesions are not believed to be neoplastic; and, to date, no metastatic behavior has been recorded. However, the etiopathogenesis of LEC of the pancreas remains unclear. In contrast to lymphoepithelial lesions of the head and neck, which frequently are associated with viral or systemic illness, there has been no recorded evidence of such diseases with pancreatic LECs. An in situ hybridization study failed to show increased numbers of Epstein–Barr virus-positive cells in pancreatic LECs.13

To our knowledge, there are a few hypotheses concerning the histogenesis of pancreatic LECs.9–10, 14–16 One theory suggests an origin from misplaced branchial cleft tissue, because the 2 lesions histologically resemble one another.9 Another theory suggests squamous metaplasia of an obstructed pancreatic duct, which subsequently protrudes into a peripancreatic lymph node.10, 16 Although this is a possibility, squamous metaplasia in the uninvolved pancreatic tissue is a relatively uncommon finding in these pancreata.1 Finally, some investigators have suggested that cysts develop from ectopic pancreatic tissue in peripancreatic lymph nodes.10 This theory would explain the often extrinsic location of the lesions and the fact that pancreatic tissue can be found throughout these entire lesions.17 Furthermore, benign ectopic pancreatic tissue has been reported in peripancreatic lymph nodes.18

The first description of the cytologic findings of LECs was published by Mitchell in 1990.2 To our knowledge, there have only been 8 reported patients with LEC who were diagnosed by FNA, including the original report (Table 1).2–8 These lesions occurred in middle-aged patients (mean age, 46 years; range 33–64 years) with a male predilection (male:female ratio, 10:2). Nearly all of those patients presented with abdominal pain except for 1 patient who presented with shortness of breath. It was noted that a single patient was asymptomatic. The lesions ranged in size from 1.8 cm to 6.1 cm and occurred throughout the pancreas. Imaging studies showed both multilocular and unilocular cysts.

Cyst fluid, which was available from only 1 patient in our series, had markedly high concentrations of CEA (35,028 ng/mL) and amylase (480 U/L) and had a fluid lipase concentration within normal limits (20 U/L). There have been very few other patients reported in the literature who had chemical analysis of pancreatic LEC fluid. Of those, 2 patients had amylase levels that were either within normal limits or slightly increased.3, 7 High CEA and CA19-9 concentrations repeatedly have been reported.19, 20 In 1 report, the authors speculated that these levels suggested that the cyst contents most likely were produced by cells derived from the exocrine pancreas.20 These results demonstrate that, although high CEA concentrations are associated most often with mucinous neoplasms, the finding is not specific and may be misleading.

The FNA samples typically showed abundant, anucleated squamous cells with few benign-appearing, nucleated squamous cells; debris (keratinous and amorphous); occasional multinucleated giant cells; and cholesterol crystals. In contrast to LECs of the head and neck region, most aspirates from pancreatic LECs showed a paucity of lymphocytes. This may be because pancreatic LECs are deep-seated masses and usually attain a significant size at the time of diagnosis.3, 8 Because of the increased size of LECs, more of cyst content is aspirated, and less of the compressed lymphoid element is obtained. In addition, endoscopists and radiologists may be less aggressive in their sampling of pancreatic LECs, because secondary acute pancreatitis can lead to severe morbidity and even mortality. The occasional presence of mucinous epithelium suggests contamination with gastric or duodenal epithelium, although rare mucinous cells have been identified in surgical specimens.

The differential diagnosis should include other squamous lesions that may be found in the pancreas, such as dermoid cysts, splenic epidermoid cysts, adenosquamous carcinoma, and metastatic squamous cell carcinoma. Dermoid cysts have a squamous lining with skin appendages and respiratory, gastrointestinal, and mesodermal tissues, all of which may be sampled by FNA; and they usually are observed in younger patients and show no gender predominance.16 Accessory splenic epidermoid cysts are extremely rare; although they have the same lining epithelium as pancreatic LECs, they also have normal splenic pulp present within the cyst wall, and they usually develop in the tail of the pancreas and are filled with serum.21–25 It is doubtful that FNA findings will allow for the distinction of these lesions, especially when only keratinous debris is seen.

The treatments for dermoid cyst, epidermoid cyst of the accessory spleen, and pancreatic LEC do not differ.21–28 If the patient is asymptomatic, then he or she may be followed with serial cross-sectional imaging of the upper abdomen.29 If the patient is symptomatic, then several types of surgical treatment options are available, including simple enucleation or pancreatectomy (distal or pancreatoduodenectomy).30–33

Distinguishing LECs from primary adenosquamous carcinoma and metastatic squamous cell carcinoma of the pancreas should not be difficult, because those lesions will show cytologic features of malignancy, such as nuclear atypia, mitotic figures, and necrotic background. This may not always be true, however, and some cytologic overlap may be reported, as it has in the head and neck.

The differential diagnosis of LEC also may include other pancreatic cysts. Pseudocysts contain abundant necrotic debris, cholesterol crystals, and inflammatory cells. However, squamous epithelium should not be seen, and amylase levels usually are elevated markedly, whereas CEA levels usually are lower.7 Aspirates from mucinous cysts (mucinous cystic neoplasms and intraductal papillary mucinous neoplasms) usually show background extracellular mucus with or without mucinous epithelium. However, the degenerated squamous material of an LEC may be misinterpreted as mucoid material (Mandavilli et al.6) (Patient 1 in the current study). With high CEA and CA 19-9 concentrations, a mucinous neoplasm could be diagnosed erroneously, especially because EUS-guided FNA samples may show both squamous contaminant (likely derived from the esophagus or upper aerodigestive tract) and glandular contaminant (from either the stomach or the duodenum). The presence of abundant anucleated squamous epithelium, however, should favor a diagnosis of pancreatic LEC.

In conclusion, pancreatic LECs are extremely rare, nonneoplastic lesions of the pancreas. Because of their rarity, certain pitfalls may hinder a correct prospective diagnosis. Nonetheless, familiarity with this lesion's clinical and cytologic features may allow the correct diagnosis of these lesions and thereby permit conservative management.