Post-brushing and fine-needle aspiration biopsy follow-up and treatment options for patients with pancreatobiliary lesions: The Papanicolaou Society of Cytopathology Guidelines

Non-diagnostic

A non-diagnostic cytology sample is defined as a sample that is inadequate for interpretation due to whatever cause; there is not enough cytological material to make any diagnostic comment. For pancreatic lesions, a simple cell count to determine sample adequacy as is done in thyroid FNA is not enough. Obtaining pancreatic cytology samples is much more involved and often has more serious implications than FNA of superficial sites. The cytologic diagnosis must explain and be consistent with the clinical and radiologic findings no matter the number of cells or cellular groups in the cytology sample. It is suggested that only up to four passes be attempted, after which the FNA procedure's opportunity to obtain diagnostic material decreases. This has demonstrated in the pancreas and in other sites.[10111213]

With an inadequate FNA or brushing, clinical management becomes solely dependent on the clinical and imaging findings and is more insecure. If diagnostic confidence in the imaging and clinical findings is high, the team may elect to proceed directly to laparotomy to obtain diagnostic material through tru-cut needle, incisional or excisional biopsy.

If the first attempt at cytological diagnosis is by bile DBs, then second bile brushing attempt or EUS-FNA of any mass lesion of the distal hepatic, mid/proximal bile duct or intra-pancreatic common bile duct should be attempted. If the first attempt was by percutaneous FNA then it may be most reasonable to use EUS-FNA, even if this means moving the patient to an institution better suited at performing EUS-FNA. If the first attempt was EUS-FNA, reassessment of the EUS findings and other imaging should be undertaken, followed by a review of the FNA line of approach. Although repeat EUS-FNA is a costly procedure, it is still a less expensive and less invasive option than biopsy through laparoscopy or laparotomy.[1014]

Repeat EUS-FNA of cystic lesions of the pancreas should be considered carefully as it has been recommended that only one draining pass be made due to risks as high as 14% of infection even if there is no cellular cytological material. Correlation with imaging is mandatory.[15] This infection risk can be reduced to under 3% by using intra-procedural intravenous antibiotics, such as fluoroquinolone and then oral antibiotics for 3-5 days.[16171819]

Negative

A negative cytology sample is defined as a cytological interpretation that is negative for malignancy and any cellular atypia; preferably a diagnosis is made that is specific for a benign non-neoplastic condition. A descriptive negative interpretation implies that the sample is adequately cellular and that no cytological atypia is identified in the evaluated cytology sample. This includes the presence of normal pancreatic tissue in the appropriate clinical setting such a vague fullness on imaging and no distinct mass lesion. A negative cytology interpretation that is descriptive without a diagnosis of a specific condition such as chronic pancreatitis or pseudocyst is not synonymous with a benign lesion.

Entities that fall under this category include acute, chronic and autoimmune pancreatitis (AIP), pseudocyst, ectopic or intrapancreatic splenule and lymphoepithelial cyst.

The multidisciplinary team or individual in charge of the patient's care must perform the “triple test”, i.e., an assessment that includes the clinical presentation, radiologic findings and cytopathology. If any one of the elements of the “triple test” is discrepant it is mandatory to reassess that component and if found on review to be sound, then the overall diagnosis and other elements have to be reassessed.[6891315] For example, if EUS demonstrates biliary or pancreatic duct dilation, or radiology finds regional lymphadenopathy, it is more likely that there is a malignancy despite a non-diagnostic or negative cytology report. In such cases the interventionalist might be more aggressive in their attempts at obtaining material through FNA or proceed to laparoscopy or laparotomy.[61520212223] Pancreatic EUS-FNA has a very high specificity with very few false positive interpretations, however, false negative interpretations are not uncommon due to sampling and interpretive errors, which impact the sensitivity of the test.

Post-procedural management of specific benign diagnoses includes the following:

Acute pancreatitis is usually managed by an institutional specific protocol which commonly consists of cessation of oral intake, intravenous fluid hydration and narcotic analgesia. Patient recovery is largely monitored by the patient's symptoms and the physician's examination. The etiology of the pancreatitis is sought to prevent future episodes. Significant complications of pancreatitis including pseudocyst, hemorrhage, obstruction and pancreatic necrosis may occur. Pseudocysts commonly occur in a background of pancreatitis and EUS-FNA may have a significant risk of post-procedure infection. Life support may be necessary in severe cases of acute pancreatitis and surgical intervention with resection and debridement is reserved for cases where medical management fails. Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis may complicate up to 5% of ERCP procedures. Most cases are mild but rare fatalities are reported.[24] Bile DBs have been associated with potential exacerbation of acute pancreatitis. EUS-FNA is an excellent alternative to ERCP/brushings for evaluation of extra-hepatic bile duct and peri-ductal lesions that appear to arise in the intra-pancreatic ducts and gallbladder.[12162526]

Chronic pancreatitis is characterized by chronic abdominal pain due to progressive inflammation, destruction of pancreatic tissue, parenchymal replacement by fibrous tissue and resultant impairment of pancreatic exocrine and endocrine function. Therapy is aimed at identification and removal of the cause of the pancreatitis, treating the patient's pain and managing pancreatic failure (e.g., enzyme digestive replacement for exocrine failure and oral hypoglycemic or exogenous insulin for endocrine failure).[25]

AIP is a rare disease. The radiologic pattern of AIP can be distinctive with a diffusely enlarged pancreas, but may also mimic pancreatic cancer. Elevated serum IgG ₄, the clinical context and response to steroids may help confirm the diagnosis. Steroids are the main treatment.[162627] There are no known specific complications of EUS-FNA of AIP.[27]

Pseudocysts usually occur in a background of chronic pancreatitis or a history of acute pancreatitis related to trauma. Once diagnosed their management is dependent on their size and symptomatology and presence/absence of ductal communication. Treatment may involve endoscopic stenting, internal drainage (endoscopic or operative) or external drainage (percutaneous).[2528] EUS-FNA may have a significant risk of post-procedural infection.[161824]

Lymphoepithelial cysts are relatively rare lesions that can be managed conservatively if the patient is asymptomatic and the diagnosis can be securely established by imaging and EUS-FNA. They need to be distinguished from mucinous cystic lesions of the pancreas. EUS-FNA can establish the diagnosis based on the presence of benign squamous cells, keratotic debris and the lack of mucin. There are no specific complications of FNA of lymphoepithelial cysts.[1329]

Accessory spleen or splenules (splenucules) can occur in the pancreas or in the splenic hilum adjacent to the pancreas. They are commonly found incidentally on CT radiologic examination and even with EUS may raise a differential diagnosis that includes neoplasms. FNA can be diagnostic. No complications (hemorrhage) have been reported with FNA. If a clinical question remains after identification or the diagnosis is uncertain, resection is curative.

Hydatid cysts have been reported in the pancreas or impinging on the pancreas. FNA poses a potential risk of an anaphylactic reaction following leakage of cyst contents and activation of type 1 hypersensitivity. FNA where the diagnosis was suspected prior to the procedure based on imaging findings has not been reported and the actual risk with FNA is not known. Therapy is careful surgical resection.[18]

Atypical

An atypical interpretation is defined as cytoplasmic, nuclear, or architectural features that are not consistent with normal or reactive cellular components of the pancreas or bile ducts, but features are not sufficient to indicate a neoplasm or overt malignancy. This interpretation calls for additional diagnostic testing.

In other organ systems the usual response to an atypical cytologic interpretation is a repeat procedure. For uterine cervical cytology or thyroid FNA the performance of a repeat procedure is relatively easy with the major problem being rescheduling of the patient back into the clinic. The logistics of repeat EUS, ERCP or percutaneous FNA are much more involved and require the services of a number of individuals and utilization of expensive equipment. The resource utilization and costs of operative biopsy are even greater. The resource problem causes immediate repeat diagnostic procedure to be a non-trivial issue. The appropriate course of action is dependent on a multidisciplinary review, the functional status of the patient and the wishes of the patient after clinical consultation.

Ancillary testing in some cases may assist determination of the management of the patient after an atypical cytological diagnosis. Just as positivity for high-risk human papilloma virus increases the likelihood of disease in an indeterminate “atypical” cervical smear, atypical pancreatic cytology in combination with a number of biochemical tests may be helpful in clinical management and follow-up. Although not routinely performed, Dpc4/SMAD4 suppressor gene is lost in 55% of pancreatic ductal adenocarcinomas (PDAC) and this finding may add support to the indeterminate “atypical” interpretation when imaging is suspicious for adenocarcinoma. Although not specific for malignancy, detection of mutant KRAS, which is seen in over 90% of malignancies may contribution to management decisions in the appropriate clinical setting.[303132]

Neoplastic

Neoplastic: Benign

The major entity in this category, serous cystic neoplasm (SCN), can be observed or treated by resection. SCN may or may not have a diagnostic imaging presentation. When it does, FNA is not performed. When there is uncertainty about the diagnosis, FNA is performed in an attempt to make a specific diagnosis on one hand, but to at least make a diagnosis of a non-mucinous cyst. If imaging, cytology and cyst fluid biochemistry (carcinoembryonic antigen [CEA] and amylase) support an interpretation of a SCN, the patient can be conservatively managed with observation, with the proviso that the patient is asymptomatic and that there is no evidence of significant growth, which raises the risk of hemorrhage and rupture.[17183334]

Neoplastic: Other

Pancreatic neuroendocrine tumor (PanNET)

PanNET presents two problems: Tumor growth, spread and hormonal activity. Whether to perform surgery and the type of surgery is dependent on patient age, fitness and symptoms as well as lesion location, size, grade and stage. With the increasing use of cross-sectional imaging, very small (~1 cm) tumors are being discovered incidentally in a large number of patients, many of whom are elderly and with co-morbid conditions increasing surgical risk. PanNETs may grow very slowly for prolonged periods and although the majority (50-60%) eventually exhibit malignant behavior, surgical intervention may not be the best option for all patients. As such, placing PanNETs in this more generic category of neoplastic: Other rather than in the positive or malignant category increases management options significantly. Convincing a patient that conservative management of their incidental 1 cm PanNET is the best option for them would be virtually impossible, when diagnosed by cytology as malignant.

Genetic testing for germline mutations should be performed if the family or personal history is suggestive of multiple endocrine neoplasia or Von Hippel Lindau disease. Symptoms usually cause functioning PanNETs to be discovered at a smaller size than with non-functioning PanNETs. The initial treatment of functioning PaNET is aimed at controlling the symptoms. For example, proton pump inhibitors or high dose histamine H2-receptor antagonists can oppose hypersecretion of gastrin in Zollinger-Ellison syndrome. Secretion of other hormones may be controlled with somatostatin analogs (octreotide). Where resection has failed or is impossible, a number of molecularly based modern treatments are available including sunitinib (tyrosine kinase inhibitor [TKI]), rapamycyin (mTOR inhibitor) and peptide receptor radionuclide therapy.[635] Functioning PanNET may have elevated serum pancreatic polypeptide (PP), insulin, C-peptide, pro-insulin, gastrin, vasoactive intestinal peptide, glucagon, calcitonin, or somatostatin. Levels for these hormones should be drawn and monitored during the therapeutic process. For patients with non-functioning PanNET, serum chromogranin A is useful for following treatment response. PP may also be elevated in apparently non-functional PanNET and can serve as a useful post-treatment marker.[36] Local and or hepatic resection is done for functioning and non-functioning tumors with the aim of curative resection or debulking/palliation dependent upon size and location. The National Comprehensive Cancer Network^® (NCCN^®) provides guidelines and algorithms for management of functioning and non-functioning PanNETs that are available online.[3738394041]

For patients with metastatic disease, if the metastatic disease is restricted to the liver, resection (including the possibility of hepatectomy and transplantation) is warranted for both functioning and non-functioning tumors with the aim of curative resection or debulking/palliation dependent on the size and location of the tumor. Embolization or radiofrequency ablation may be considered with or without chemotherapy for liver metastases to decrease symptoms from hormonally active tumors. Somatostatin analog infusion may be indicated in resection of primary tumors, metastatic lesions, anesthetic procedures or embolization to avoid hormonal crises. The NCCN^® management algorithm for metastatic disease that provides detail is also accessible through the web link http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#neuroendocrine.[4142]

Intraductal papillary mucinous neoplasms

Surgical intervention versus observation depends on the type of IPMN: IPMN may involve the main duct alone or in combination with branch-duct cysts (M-IPMN) or branch duct (BD-IPMN) only cysts.[454849]

M-IPMNs are treated by resection. Observation of mucous extruding from a patulous (“fish-mouth”) ampulla of Vater is diagnostic of M-IPMN. Main-duct dilatation >10 mm is considered as a high-risk imaging feature and surgery is typically performed without pre-operative tissue diagnosis. M-IPMN's are most commonly lined by intestinal-type epithelial cells and invasive carcinoma is found in 40-45%, with high-grade dysplasia identified in another 20%[43] M-IPMN's usually occur in the pancreatic head requiring a pancreatoduodenectomy.

Management options for patients with BD-IPMN are more controversial. BD-IPMNs are most often benign and asymptomatic. Increased use of cross-sectional imaging has greatly increased the detection of these incidentalomas identified in nearly 8% of elderly patients.

Since, the time to malignant transformation is estimated to be about 10 years, many patients, especially those with co-morbid conditions, benefit more by conservative observation than surgery. The decision to operate is determined by the risk of malignancy, which in many centers is solely based on imaging features such as the presence of an enhancing mural nodule. Worrisome imaging features such as large cyst size (>3 cm) or non-enhancing mural nodule warrant evaluation with FNA.[45] The cytologic identification of high-grade epithelial atypia (e.g., high-grade dysplasia or invasive carcinoma) is a high-risk feature as well warranting surgical resection.[46] Although, the typical BD-IPMN is lined by low-grade dysplastic gastric type epithelium, when invasive carcinoma occurs, it is of the tubular type with the same dismal prognosis as conventional ductal adenocarcinoma.[47] As such, the patient has the best prognosis when premalignant (e.g., pre-invasive) carcinoma is identified, preferably at the level of high-grade dysplasia. Demographics (age/gender), family history of pancreatic cancer, social history of tobacco usage, obesity and serum tumor markers (carbohydrate antigen [CA] 19-9, Ha1c) may also influence the patient's risk of pancreatic cancer and thus, the decision to operate.

A flowchart illustrating the Fukuoka revised guidelines for management of mucinous cystic neoplasms and IPMN is shown with permission in Figure 1.[45]

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Figure 1

The Fukuoka revised guidelines for management of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms[4548]

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Suspicious

These lesions show severe cellular atypia, suspicious for invasive ductal carcinoma or other high-grade malignant neoplasm, for example, an aspirate with a solid-cellular smear pattern without diagnostic cytological features or tissue available for confirmatory molecular or immunohistochemical findings supportive of a specific neoplasm such as PanNET or SPN, which would then allow for the classification as “Neoplastic: Other”.

As with the benign and atypical interpretations, when there are discrepant imaging findings suggesting malignancy and an atypical interpretation, management of the patient with a “suspicious” cytological interpretation requires a stringent multidisciplinary review of the clinical and imaging findings. Biochemical and molecular analytical markers may increase the sensitivity and specificity of the interpretation.

If the cytological findings are unexpected and do not correlate with imaging predictions of a benign lesion, then repeat brushings or EUS-FNA should be considered, with the goal of obtaining sufficient tissue for cellblock preparation and ancillary testing.

If the cytological findings of suspicious for malignancy do correlate with the imaging findings suggestive of malignancy, then the patient can be worked-up and staged. This could include laparoscopy with biopsy, further EUS-FNA of lymph nodes and positron emission tomography and CT scans to exclude distant metastases. The exact work-up is dependent on the availability of these modalities, personnel and local established protocols.

Positive/Malignant

The malignant category is definitive for a high-grade malignancy and should be accompanied by a specific diagnosis whenever possible.[5052]

Management relates to the specific type of malignancy present. Since, conventional ductal adenocarcinoma PDAC or a variant represents 9 of 10 pancreatic malignancies, this interpretation category, more likely than not, represents PDAC. In some cases, it may not be possible to define the particular malignancy on cytology alone. In these cases ancillary tests on cell block or other fluid based preparations should be done, when available. For example, it is important to distinguish acinar cell carcinoma, a high-grade aggressive malignancy, from mimickers such as PanNET. Metastatic malignancy to the pancreas should always be considered especially when the imaging or EUS findings are not typical of a pancreatic primary or the cytological findings are not characteristic.