Pancreatic cyst endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA): Benign or malignant. Clues to cytological diagnosis with major consequences

QUESTION # 1

What is your interpretation?

1. Mucinous cystic lesion (mucinous cystic neoplasm [MCN]/intraductal papillary mucinous neoplasm [IPMN])

2. Pseudocyst

3. Carcinoma with cystic and necrotic changes

4. Cystic neuroendocrine tumor.

ANSWER

b. Pseudocyst.

The differential diagnosis of pancreatic cyst includes neoplastic and non-neoplastic categories. Although the majority of pancreatic cysts are benign, the survival after invasive carcinomas in potentially malignant mucinous cystic lesions either MCN or IPMN is often dismal. Distinction between a true cyst versus a pseudocyst can be challenging. The crucial role of cytology is to properly triage such patients.

EUS-FNA in the current case was relatively hypocellular with abundant thick myxoid material in the background without unequivocal epithelial cells (cyst lining cells). The polyhedral cells showed vacuolated/foamy cytoplasm with small, occasional folded nuclei consistent with reactive foamy histiocytes. Many spindle cells with repair-like pattern were also noted [Figure 2]. Cyst debris with occasional non-specific crystalline yellow pigment was noted in the background. The yellow pigment retained its yellow crystalline feature in Diff-Quik smear also. The cell-block (CB) showed stroma with reactive pancreatic ducts with mild chronic inflammation without pancreatic acini and malignancy [Figure 3]. The findings were consistent with pseudocyst in the background of chronic pancreatitis.

Close

Figure 2:

Cell-block of transgastric EUS-FNA cytology of cystic lesion in tail of pancreas. The sections showed reactive pancreatic ducts in ill-defined lobular architecture with sclerotic stroma without pancreatic acini. (H and E stained cell-block sections; (a) ×10, (b) ×20, (c) ×40, (d) magnification of cropped area).

Export to PPT

Close

Figure 3:

Transgastric EUS-FNA cytology of cystic lesion in the tail of pancreas. Focal collection of polyhedral stromal histiocytes should not be confused with epithelial cells with myxoid debris in the background. This may lead to misinterpretation as mucinous cystic lesion (MCN or IPMN). (Diff-Quik stained direct smear, ×40).

Export to PPT

The patient had medical history of alcohol abuse, pancreatitis, and ovarian borderline mucinous neoplasm status post-resection presented with upper abdominal pain. Based on the history of borderline mucinous neoplasm of the ovary, the differential interpretation included MCN and IPMN.^[1,2] However, the absence of epithelial lining and lack of thick viscid mucin ruled out MCN or IPMN.

Cystic neuroendocrine tumor would have shown singly scattered plasmacytoid neuroendocrine cells with focal cohesive pattern without significant proportion of myxoid material which was not seen in this case.

QUESTION # 2

Which are the diagnostic features of pancreatic pseudocyst?

1. Chemical analysis of cyst fluid with high amylase

2. Absence of epithelial cells with repair-like stromal cells

3. Foam cells and cyst debris with myxoid background

4. Presence of yellow crystalline pigment

5. All of the above.

The proper diagnosis of a pancreatic cyst should be based on the combination of pre-procedural findings (clinical and imaging) in conjunction with post-procedural findings (chemical analysis of cyst fluid and cytologic evaluation). The ultimate goal of such diagnostic tests is to distinguish benign cyst with malignant potential (IPMN and MCN) and to evaluate the morphological features of malignancy. The helpful features include the presence or absence of yellow pigment, the proportion and nature of background myxoid contents, and the presence or lack of epithelial lining. The cytologic findings that distinguish pseudocyst from neoplastic cyst with malignant potential are summarized in Table 1. In addition to the cytologic features, cyst fluid analysis along with the clinical presentation and imaging is critical to make correct interpretation. Cytopathology of mucinous cystic lesions also allows evaluation and follow-up for neoplastic progression towards high grade dysplasia and invasive carcinoma.

Myxoid background in pancreatic pseudocysts may be difficult to distinguish from viscid mucin in mucinous cystic lesions [Figure 4]. In our case, it showed focal myxoid areas admixed with spindle cells and stromal fragments with refractile yellow pigment. However, the aspirates lacked atypical epithelial cells. There were many histiocytes including foam cells with neutrophils.

Close

Figure 4:

Transgastric endoscopic EUS-FNA cytology of cystic lesion in the tail of pancreas. The direct smears showed spindle cells (a and b) and some polyhedral cells (c) with foam cells (d) in the background with myxoid debris (Diff-Quik stain; (a and b) ×20; (c and d) ×40).

Export to PPT

QUESTION # 3

What clinical/imaging scenario is typical for pseudocyst compared to neoplastic cyst?

1. New, non-specific GI complaints with multilocular complex cyst in pancreatic head

2. New, non-specific GI complaints with cystically dilated pancreatic duct

3. History of recurrent pancreatitis with unilocular simple cyst

4. History of pancreatic neuroendocrine tumor with a newly identified partially cystic mass.

Pancreatic pseudocyst results from reparative changes secondary to the pancreatic parenchymal injury. Typically, pseudocysts are the result of multiple episodes of acute and chronic pancreatitis. The pseudocyst contents are rich in amylase and/or lipase and lack epithelial lining. History of recurrent pancreatitis with unilocular simple cyst is the classic clinical scenario to trigger the clinical suspicion of a pancreatic pseudocyst. MCN and IPMN, on the other hand, usually present with a multilocular cystic lesion. IPMN communicates with pancreatic ductal system and usually causes pancreatic duct obstruction with dilated duct on imaging (endoscopic retrograde cholangiopancreatography [ERCP] or magnetic resonance cholangiopancreatography [MRCP]). Thus, obstructive jaundice is the usual initial presentation of IPMN.

Serous cystic neoplasm composed numerous small cysts in a honeycomb-like formation of locules ranging from 1 to 20 mm size are typically seen on CT scan as a multicystic, lobulated lesion described as “bunch of grapes” with tendency for central scar and calcification. There is usually lack of the history of pancreatitis. Some pancreatic primary neoplasms can be associated with cystic degeneration, including neuroendocrine tumors of the pancreas. However, the presence of a previous neoplasm makes the possibility of a pseudocyst less likely.

QUESTION # 4

What chemical markers are most helpful in distinguishing pseudocyst from neoplastic mucinous cyst?

1. CEA and amylase

2. Amylase and lipase

3. CA 19-9 and CA-125

4. Glucose.

Chemical analysis can be an useful ancillary test to support cytopathologic evaluation, The panel of chemical tests to be performed on cyst fluid should be directed based on the clinical suspicion and the amount of fluid aspirated. In general, the most useful markers to distinguish pseudocyst versus neoplastic mucinous cyst are CEA and Amylase. A pseudocyst is, by definition, a collection of amylase-rich fluid. CEA, on the other hand, is a marker of glandular epithelial cells. As a result, a typical pseudocyst would show increased amylase and low level of CEA. A reversed result is expected in neoplastic mucinous cysts. The combination of amylase and lipase is not helpful as both markers are expected to be elevated in most pseudocysts but can also be elevated in neoplastic a number of neoplastic cysts as well. Tumor markers CA 19-9 and CA-125 are typically elevated in neoplastic cysts while they are not elevated in most pseudocysts thus are not helpful in distinguishing between the two.

BRIEF REVIEW OF THE TOPIC

SUMMARY

The primary role of cytology is the exclusion of cyst with malignant potential (IPMN and MCN) or malignant cystic lesion. Pseudocysts usually show cytologic features which are frequently nonspecific and are primarily interpreted in correlation with clinical (alcoholism and pancreatitis) and imaging (gland atrophy with calcification and a unilocular cyst without a mural nodule) features with chemical analysis of cyst fluid.

Yellow pigment which continues to be yellow crystalline in Diff-Quik stained smears is important clue as surrogate marker of a pseudocyst. Myxoid background focally should not be confused for viscid and abundant mucin in cysts with malignant potential (IPMN and MCN).

Answers for Question 2 through 4:

2. e

3. c

4. a.