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CytoJournal 2014,  11, Suppl S1:5

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


1 Departments of Pathology, University of Wisconsin
2 Saint Vincent's Hospital, Sydney, Australia
3 Department of Surgery, UCSF
4 Department of Surgery,Case Western Reserve University
5 Department of Surgery, Albert Einstein College of Medicine, Philadelphia, PA
6 Department of Surgery, Indiana University
7 Department of Surgery, UCLA
8 Division of Gastroenterology, University of Wisconsin
9 University of Michigan, Departments of Medicine
10 Division of Surgical Oncology, Vanderbilt University, USA
11 Massachusetts General Hospital, Harvard Medical School, USA

Date of Submission06-Feb-2014
Date of Acceptance06-Feb-2014
Date of Web Publication02-Jun-2014

Correspondence Address:
Daniel F. I. Kurtycz
Departments of Pathology, University of Wisconsin

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1742-6413.133356

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 » Abstract 

The Papanicolaou Society of Cytopathology (PSC) has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature for pancreatobiliary cytology, ancillary testing and post-procedure management. All documents are based on the expertise of the authors, a review of the literature and discussions of the draft document at several national and international meetings over an 18 month period and synthesis of online comments of the draft document on the PSC web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on the follow-up and treatment options for patients after procedures performed for obtaining cytology samples for the evaluation of biliary strictures and solid and cystic masses in the pancreas. These recommendations follow the six-tiered terminology and nomenclature scheme proposed by committee III.


Keywords: Cytology, guidelines, management, pancreas, Papanicolaou Society of Cytopathology, treatment


How to cite this article:
Kurtycz DF, Field A, Tabatabai L, Michaels C, Young N, Schmidt CM, Farrell J, Gopal D, Simeone D, Merchant NB, Pitman MB. Post-brushing and fine-needle aspiration biopsy follow-up and treatment options for patients with pancreatobiliary lesions: The Papanicolaou Society of Cytopathology Guidelines. CytoJournal 2014;11, Suppl S1:5

How to cite this URL:
Kurtycz DF, Field A, Tabatabai L, Michaels C, Young N, Schmidt CM, Farrell J, Gopal D, Simeone D, Merchant NB, Pitman MB. Post-brushing and fine-needle aspiration biopsy follow-up and treatment options for patients with pancreatobiliary lesions: The Papanicolaou Society of Cytopathology Guidelines. CytoJournal [serial online] 2014 [cited 2017 May 27];11, Suppl S1:5. Available from: http://www.cytojournal.com/text.asp?2014/11/2/5/133356



 » Introduction Top


The successful performance of any medical procedure is operator dependent. In the case of bile duct brushings (DB) and/or endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) of pancreatic lesions; a successful outcome depends on the performance of multiple operators acting as a dedicated team. The interventionalist must accurately identify and biopsy the target tissue as well as obtain sufficient cellular material for interpretation. The cytologist must make a good quality, interpretable smear or other satisfactory preparation, be it a liquid based cytology, cell-block or sample for genetic analysis. Finally, the cytopathologist who analyzes the sample must be well-trained and experienced in interpretation of rapid on site evaluations (ROSE) and final slides, or at least have adequate training and the backup of senior more experienced colleagues. In addition, the diagnosis of pancreatic lesions is helped by a multidisciplinary approach involving radiologic and clinical input. This multidisciplinary component is often not recognized or investigated in the various studies published in the literature regarding the sensitivity, specificity and predictive values of pancreatic/biliary DBs and EUS-FNA. [1],[2],[3],[4]

The clinician managing the patient needs to have confidence in the cytologic diagnosis. To this end, the cytopathology team should regularly demonstrate their findings at multidisciplinary case conferences and where appropriate, during ROSE. A double-headed microscope can quickly acquaint the interventionalist with the yield of their brushings or FNA. The interventionalist can make this a two-way learning experience by sharing the radiographic images of the pancreatic lesion being biopsied. Imaging will inevitably give valuable clues to the existence, diagnosis and extent of the pancreatic lesion. This information will narrow the diagnostic possibilities and help optimize the cytologic interpretation. Dual phase, contrast enhanced spiral computed tomography (CT) can establish the solid, cystic, confined or infiltrative nature of a lesion, as well as provide information about potential metastatic sites in nearby organs or regional lymph nodes. [5] In cases where actual tissue sampling is necessary, core needle biopsy may need to be performed. ROSE of a cytologic touch preparation from the core biopsy may prove to be very valuable. The results can be communicated directly at the same procedure, just as in an FNA, ROSE of a touch preparation can confirm whether the interventionalist has obtained a significant sample, provide direction to obtain additional material if the original biopsy was not successful, or if material is needed for ancillary stains or procedures.

Cytologic sampling can be achieved by endoscopic retrograde DB, percutaneous FNA or EUS guided FNA (EUS-FNA). For cystic pancreatic lesions greater than 2 cm, a cytobrush passed down a 19-gauge needle may be added to routine FNA. In certain instances, core biopsy to obtain adequate tissue can be performed with a 22-25 gauge FNA needle, although, it is more usual to gain core biopsy type samples with needles 19 gauge and larger. [6],[7],[8],[9]

The purpose of this workgroup effort is to discuss the options regarding and management of patients following cytologic diagnoses made by biliary brushing or FNA cytology, using the terminology developed by the Pancreatic/Biliary Guideline Committee III.


 » Follow-Up In Relation To The Proposed Diagnostic Terminology Top


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. [10],[11],[12],[13]

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. [10],[14]

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. [16],[17],[18],[19]

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. [6],[8],[9],[13],[15] 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. [6],[15],[20],[21],[22],[23] 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. [12],[16],[25],[26]

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. [16],[26],[27] 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). [25],[28] EUS-FNA may have a significant risk of post-procedural infection. [16],[18],[24]

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. [13],[29]

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. [30],[31],[32]

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. [17],[18],[33],[34]

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. [6],[35] 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. [37-41]

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. [41],[42]

Solid-pseudopapillary neoplasm

Surgical resection is the treatment for SPN. Approximately 15-20% are malignant with local recurrence and distant spread most commonly to the liver. Most patients are cured by resection with 95% or better survival at 5 years. Even with hepatic and lymph node metastases, the tumor shows low aggressiveness. [18],[43],[44]

Mucinous cystic neoplasm

Surgical resection is the treatment of choice for all MCN regardless of grade due to the expense and anxiety associated with lifelong surveillance of the usual middle-aged female affected by this neoplasm. Although most are benign, nearly 18% will undergo malignant transformation. Mural nodularity and cyst diameter greater than 4 cm are imaging features associated with malignant risk. Patients considered surgical risks with small cysts without high-risk imaging features may be managed with observation, but must be subjected to lifelong clinical and radiologic scrutiny to evaluate for features suggestive of malignant transformation. [43],[28],[45]

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. [45],[48],[49]

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]
Figure 1: The Fukuoka revised guidelines for management of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms[45,48]

Click here to view


Gastrointestinal stromal tumor

For localized GIST, surgical resection with an aim of achieving negative margins is indicated. For advanced or metastatic c-Kit + GIST, the c-Kit TKI, imatinib, has shown improved clinical response over what was previously a dismal outlook. Unfortunately, TKI therapy is not a cure and resistance tends to develop. Thus, few patients with advanced disease are cured by chemotherapy and remission or stabilization is the current expectation until new generations of therapeutic agents are created and tested.

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. [50],[52]

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.

Adenocarcinoma of the pancreatobiliary ducts and variants

The current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for the management of patients with PDAC are outlined in Tempero et al. [52],[54] Currently, approximately 15% of patients are candidates for surgical resection based upon pre-operative staging. Using all available diagnostic modalities including high resolution, dual phase CT scanning and EUS, the accuracy of determining resectability is approximately 85%, but this still leaves one in five laparotomies that will find a non-resectable tumor. Initial laparoscopy may be of further help for detection of occult metastases reducing the number of unnecessary laparotomies to 10% for body/tail lesions, which tend to be more advanced at presentation than head/uncinate lesions.

Prior to attempted resection, liver "function tests" including coagulation tests are necessary to determine the patient's functional liver reserve. If liver function tests fail to return to normal following endoscopic stenting in patients with biliary obstruction, this may indicate liver failure from prolonged biliary obstruction or unsuspected pre-existing liver disease.

Tumors in the head or uncinate process of the pancreas are treated with pylorus preserving pancreaticoduodenectomy (Whipple's procedure). Tumors of the body/tail are treated with distal pancreatectomy and splenectomy. With surgical resection and adjuvant chemotherapy patients have a median survival of 18-24 months and a 15-20% chance of 5 year survival in this limited form of disease.

Serum CA19-9 is elevated in 70-80% of cases of PDAC. While not an optimal screening tool, it is useful to monitor for recurrence and disease progression in patients demonstrating pre-operatively elevated serum CA19-9.

In cases of non-resectable disease, common complications include pain, jaundice, pancreatic exocrine insufficiency and gastric outlet obstruction. Oral narcotic analgesics and celiac nerve blocks may address the pain when it is due to invasion of the pancreatic nerves and celiac plexus.

Endoscopic stents are optimal palliation for biliary obstruction. Stents obstructed by tumor ingrowth can be re-stented. Operative biliary bypass may be considered in cases where patients are explored for cure and found to be locally unresectable.

Pancreatic exocrine insufficiency may be managed with exogenous pancreatic enzyme supplementation. Gastric outlet obstruction is optimally managed with newer generation endoscopic duodenal stents. If not amenable to endoscopic stenting, operative gastrojejunal bypass may be considered in fit patients and a gastrostomy tube may be placed for palliation in unfit patients.

Less than 10% of tumors resected are Stage I or II. Overall 5 year survival for all patients with pancreatic adenocarcinoma is approximately 5% (SEER data 1996-2003). [45] Chemotherapeutic agents gemcitabine, 5-flourouracil and paclitaxel have each been shown to improve survival alone or in combination. Adjuvant gemcitabine on average increases patient survival 4-6 weeks. GemcitabinFe treatment for unresectable disease also improves survival several weeks. A recent study indicates this effect may be enhanced by combination treatment with paclitaxel. Neoadjuvant trials have shown slight benefit. [53]

Approximately 10% of patients who develop pancreatic cancer have a hereditary component. Another 10% of patients who develop pancreatic cancer may be predisposed by a precancerous (mucinous) pancreatic cystic lesion. Patients with mucinous pancreatic cysts or a familial predisposition to pancreatic cancer may benefit from screening. Early detection may prevent pancreatic cancer or detect its presence early enough to optimize the chance of curative treatment. At present, prevention in these select groups is the most promising treatment.

Acinar cell carcinoma

These tumors are managed surgically and medically in a similar fashion to PDAC.

High-grade neuroendocrine carcinoma (small and large cell type)

These tumors are associated with a rapid clinical course with the majority of patients having liver metastases at the time of diagnosis. Treatment is with chemotherapy regimens similar to small cell lung carcinoma guidelines. [56]

Pancreatoblastoma

The optimum management of this malignant tumor of childhood is complete surgical resection. Approximately half do well with surgical resection. In cases of resectable disease, adjuvant chemotherapy is recommended with regimens including cisplatin and doxorubicin. Even following what appears to be curative resection, there is a high recurrence rate and patients must be followed closely. In cases of unresectable tumor at initial diagnosis, neoadjuvant chemotherapy may downstage the tumor enough to reconsider surgery. [55]

Lymphoma

Lymphomas are included in this category although not all lymphomas are "high-grade" per se specific treatment will be subject to medical management directed by the hematologic work-up including histologyic morphology, flow cytometry and cytogenetic analysis.

Metastases

The presence of metastatic disease usually indicates widespread dissemination of the primary malignancy and the management will be dependent on the specific primary tumor and its histologic grade.


 » Summary Top


These guidelines provide a brief overview for patient treatment and management following the cytological interpretation of diseases as categorized by the six-tiered terminology and nomenclature classification system proposed by committee III (refer to document from committee III in this issue). More detailed treatment strategies are provided by surgical and gastrointestinal specialty organizations (British society of Gastroenterology, Pancreatic Society of Great Britain, Royal College of Pathology, Japan Pancreas Society, International Association of Pancreatology) as well as NCCN.


 » Competing interests statement by all authors Top


There are no disclaimers or conflicts of interest to report.


 » Authorship statement by all authors Top


All authors of this article declare that we qualify for authorship as defined by ICMJE http://www.icmje.org/#author. Each author has participated sufficiently in the work and take public responsibility for appropriate portions of the content of this article. Each author acknowledges that this final version was read and approved.

 
 » References Top

1.Elek G, Gyökeres T, Schäfer E, Burai M, Pintér F, Pap A. Early diagnosis of pancreatobiliary duct malignancies by brush cytology and biopsy. Pathol Oncol Res 2005;11:145-55.  Back to cited text no. 1
    
2.Eloubeidi MA, Jhala D, Chhieng DC, Chen VK, Eltoum I, Vickers S, et al. Yield of endoscopic ultrasound-guided fine-needle aspiration biopsy in patients with suspected pancreatic carcinoma. Cancer 2003;99:285-92.  Back to cited text no. 2
    
3.Stewart CJ, Mills PR, Carter R, O'Donohue J, Fullarton G, Imrie CW, et al. Brush cytology in the assessment of pancreatico-biliary strictures: A review of 406 cases. J Clin Pathol 2001;54:449-55.  Back to cited text no. 3
    
4.Kocjan G, Rode J, Lees WR. Percutaneous fine needle aspiration cytology of the pancreas: Advantages and pitfalls. J Clin Pathol 1989;42:341-7.  Back to cited text no. 4
    
5.Chong I, Cunningham O. Pancreatic Cancer. In: Longo O, editor. Harrison's Principles of Internal Medicine. 19 th ed. New York, NY: McGraw Hill; 2012.p. 786-9.  Back to cited text no. 5
    
6.Spier BJ, Johnson EA, Gopal DV, Frick T, Einstein MM, Byrne S, et al. Predictors of malignancy and recommended follow-up in patients with negative endoscopic ultrasound-guided fine-needle aspiration of suspected pancreatic lesions. Can J Gastroenterol 2009;23:279-86.  Back to cited text no. 6
    
7.Wani S, Gupta N, Gaddam S, Singh V, Ulusarac O, Romanas M, et al. A comparative study of endoscopic ultrasound guided fine needle aspiration with and without a stylet. Dig Dis Sci 2011;56:2409-14.  Back to cited text no. 7
    
8.Gimeno-García AZ, Elwassief A. How to improve the success of endoscopic ultrasound guided fine needle aspiration cytology in the diagnosis of pancreatic lesions. J Interv Gastroenterol 2012;2:31-6.  Back to cited text no. 8
    
9.Noh KW, Wallace MB. Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic adenocarcinoma. MedGenMed 2005;7:15.  Back to cited text no. 9
    
10.Suzuki R, Lee JH, Krishna SG, Ramireddy S, Qiao W, Weston B, et al. Repeat endoscopic ultrasound-guided fine needle aspiration for solid pancreatic lesions at a tertiary referral center will alter the initial inconclusive result. J Gastrointestin Liver Dis 2013;22:183-7.  Back to cited text no. 10
    
11.Gagovic V, Spier BJ, DeLee RJ, Barancin C, Lindstrom M, Einstein M, et al. Endoscopic ultrasound fine-needle aspiration characteristics of primary adenocarcinoma versus other malignant neoplasms of the pancreas. Can J Gastroenterol 2012;26:691-6.  Back to cited text no. 11
    
12.Xie HB, Cornwell R, Grossman JE, Hoerl HD, Kurtycz DF. Bronchoscopy-guided transtracheal and transbronchial fine-needle aspiration biopsy: A 5-year institutional review of 111 cases. Diagn Cytopathol 2002;27:276-81.  Back to cited text no. 12
    
13.Karim Z, Walker B, Lam E. Lymphoepithelial cysts of the pancreas: The use of endoscopic ultrasound-guided fine-needle aspiration in diagnosis. Can J Gastroenterol 2010;24:348-50.  Back to cited text no. 13
    
14.Rösch T, Hofrichter K, Frimberger E, Meining A, Born P, Weigert N, et al. ERCP or EUS for tissue diagnosis of biliary strictures? A prospective comparative study. Gastrointest Endosc 2004;60:390-6.  Back to cited text no. 14
    
15.Wiersema MJ, Vilmann P. EUS-guided FNAB. Gastrointest Endosc 1997;45:243-50.  Back to cited text no. 15
    
16.Reddy N, Wilcox CM, Tamhane A, Eloubeidi MA, Varadarajulu S. Protocol-based medical management of post-ERCP pancreatitis. J Gastroenterol Hepatol 2008;23:385-92.  Back to cited text no. 16
    
17.Del Chiaro M, Verbeke C, Salvia R, Klöppel G, Werner J, McKay C, et al. European experts consensus statement on cystic tumours of the pancreas. Dig Liver Dis 2013;45:703-11.  Back to cited text no. 17
    
18.Farrell JJ, Fernández-del Castillo C. Pancreatic cystic neoplasms: Management and unanswered questions. Gastroenterology 2013;144:1303-15.  Back to cited text no. 18
    
19.Lee LS, Saltzman JR, Bounds BC, Poneros JM, Brugge WR, Thompson CC. EUS-guided fine needle aspiration of pancreatic cysts: A retrospective analysis of complications and their predictors. Clin Gastroenterol Hepatol 2005;3:231-6.  Back to cited text no. 19
    
20.Eloubeidi MA, Tamhane A. EUS-guided FNA of solid pancreatic masses: A learning curve with 300 consecutive procedures. Gastrointest Endosc 2005;61:700-8.  Back to cited text no. 20
    
21.Eloubeidi MA, Chen VK, Jhala NC, Eltoum IE, Jhala D, Chhieng DC, et al. Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol 2004;2:209-13.  Back to cited text no. 21
    
22.Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. Am J Gastroenterol 2003;98:1289-94.  Back to cited text no. 22
    
23.Moparty B, Logroño R, Nealon WH, Waxman I, Raju GS, Pasricha PJ, et al. The role of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in distinguishing pancreatic cystic lesions. Diagn Cytopathol 2007;35:18-25.  Back to cited text no. 23
    
24.Eloubeidi MA, Tamhane A, Varadarajulu S, Wilcox CM. Frequency of major complications after EUS-guided FNA of solid pancreatic masses: A prospective evaluation. Gastrointest Endosc 2006;63:622-9.  Back to cited text no. 24
    
25.Trikudanathan G, Navaneethan U, Vege SS. Modern treatment of patients with chronic pancreatitis. Gastroenterol Clin North Am 2012;41:63-76.  Back to cited text no. 25
    
26.Erickson RA, Garza AA. EUS with EUS-guided fine-needle aspiration as the first endoscopic test for the evaluation of obstructive jaundice. Gastrointest Endosc 2001;53:475-84.  Back to cited text no. 26
    
27.Sugumar A. Diagnosis and management of autoimmune pancreatitis. Gastroenterol Clin North Am 2012;41:9-22.  Back to cited text no. 27
    
28.Basturk O, Coban I, Adsay NV. Pancreatic cysts: Pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med 2009;133:423-38.  Back to cited text no. 28
    
29.Nasr J, Sanders M, Fasanella K, Khalid A, McGrath K. Lymphoepithelial cysts of the pancreas: An EUS case series. Gastrointest Endosc 2008;68:170-3.  Back to cited text no. 29
    
30.Maitra A, Kern SE, Hruban RH. Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20:211-26.  Back to cited text no. 30
    
31.Hruban RH, Adsay NV. Molecular classification of neoplasms of the pancreas. Hum Pathol 2009;40:612-23.  Back to cited text no. 31
    
32.Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60:2002-6.  Back to cited text no. 32
    
33.Tseng JF, Warshaw AL, Sahani DV, Lauwers GY, Rattner DW, Fernandez-del Castillo C. Serous cystadenoma of the pancreas: Tumor growth rates and recommendations for treatment. Ann Surg 2005;242:413-9.  Back to cited text no. 33
    
34.Brandwein SL, Farrell JJ, Centeno BA, Brugge WR. Detection and tumor staging of malignancy in cystic, intraductal, and solid tumors of the pancreas by EUS. Gastrointest Endosc 2001;53:722-7.  Back to cited text no. 34
    
35.Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): Recent insights and advances. J Gastroenterol 2012;47:941-60.  Back to cited text no. 35
    
36.Syversen U, Ramstad H, Gamme K, Qvigstad G, Falkmer S, Waldum HL. Clinical significance of elevated serum chromogranin a levels. Scand J Gastroenterol 2004;39:969-73.  Back to cited text no. 36
    
37.Klimstra DS. Pathology reporting of neuroendocrine tumors: Essential elements for accurate diagnosis, classification, and staging. Semin Oncol 2013;40:23-36.  Back to cited text no. 37
    
38.Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: A review of nomenclature, grading, and staging systems. Pancreas 2010;39:707-12.  Back to cited text no. 38
    
39.Couvelard A, Deschamps L, Ravaud P, Baron G, Sauvanet A, Hentic O, et al. Heterogeneity of tumor prognostic markers: A reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 2009;22:273-81.  Back to cited text no. 39
    
40.Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: Implications for prognostic stratification. Am J Surg Pathol 2011;35:853-60.  Back to cited text no. 40
    
41. Kulke MH, Benson AB 3r d, Bergsland E, Berlin JD, Blaszkowsky LS, Choti MA, et al. Neuroendocrine tumors. J Natl Compr Canc Netw 2012;10:724-64. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Neuroendocrine Tumors V.2.2014. © National Comprehensive Cancer Network, Inc.; 2013. All rights reserved. [Last accessed on 2013 Dec 20]. To view the most recent and complete version of the guideline, go online to www.nccn.org.http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#neuroendocrine.  Back to cited text no. 41
    
42.Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 2004;80:394-424.  Back to cited text no. 42
    
43.Fisher W, Andersen D, Bell R, Saluja A. Pancreas. In: Brunicardi C, editor. Schwartz's Principles of Surgery. 9 th ed. New York: McGraw-Hill; 2010. p. 1217-37.  Back to cited text no. 43
    
44.Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol 2002;160:1361-9.  Back to cited text no. 44
    
45.Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183-97.  Back to cited text no. 45
    
46.Pitman MB, Genevay M, Yaeger K, Chebib I, Turner BG, Mino-Kenudson M, et al. High-grade atypical epithelial cells in pancreatic mucinous cysts are a more accurate predictor of malignancy than "positive" cytology. Cancer Cytopathol 2010;118:434-40.  Back to cited text no. 46
    
47.Mino-Kenudson M, Fernández-del Castillo C, Baba Y, Valsangkar NP, Liss AS, Hsu M, et al. Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes. Gut 2011;60:1712-20.  Back to cited text no. 47
    
48.Pitman MB. Revised international consensus guidelines for the management of patients with mucinous cysts. Cancer Cytopathol 2012;120:361-5.  Back to cited text no. 48
    
49.Pitman MB, Lewandrowski K, Shen J, Sahani D, Brugge W, Fernandez-del Castillo C. Pancreatic cysts: Preoperative diagnosis and clinical management. Cancer Cytopathol 2010;118:1-13.  Back to cited text no. 49
    
50.Eltoum IA, Eloubeidi MA, Chhieng DC, Tamhane A, Crowe R, Jhala D, et al. Cytologic grade independently predicts survival of patients with pancreatic adenocarcinoma. Am J Clin Pathol 2005;124:697-707.  Back to cited text no. 50
    
51.Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: A systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7:e1000267.  Back to cited text no. 51
    
52.Tempero MA, Arnoletti JP, Behrman SW, Ben-Josef E, Benson AB 3 rd , Casper ES, et al. Pancreatic Adenocarcinoma, version 2.2012. J Natl Compr Canc Netw 2012; 10:703-713.  Back to cited text no. 52
    
53.Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol 2012;36:173-84.  Back to cited text no. 53
    
54.Roland CL, Bian A, Mansour JC, Yopp AC, Balch GC, Sharma R, et al. Survival impact of malignant pancreatic neuroendocrine and islet cell neoplasm phenotypes. J Surg Oncol 2012;105:595-600.  Back to cited text no. 54
    
55.Pancreatric Section, British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, Royal College of Pathologists, Special Interest Group for Gastro-Intestinal Radiology. Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut 2005;54 Suppl 5:v1-16.  Back to cited text no. 55
    
56.Yamaguchi K, Tanaka M. Committee for Revision of Clinical Guidelines for Pancreatic Cancer of Japan Pancreas Society. EBM-based Clinical Guidelines for Pancreatic Cancer 2009 from the Japan Pancreas Society: A synopsis. Jpn J Clin Oncol 2011;41:836-40.  Back to cited text no. 56
    


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