to 1 cm), incidentally discovered PanNETs in elderly patients with multiple comorbid conditions may be managed conservatively. PanNETs may grow very slowly for prolonged periods. Although the majority (50–60%) exhibit malignant behavior, surgical intervention may not be the best option, especially for elderly patients with multiple comorbidities. Hence, PSC has placed PanNETs in the “neoplastic: other” rather than in the “malignant” category so that patients can have more conservative management options as well. Genetic testing for germline mutations may be performed in cases where family or personal history is suggestive of MEN1 or VHL disease. Medical management of functioning PanNETs is available with multiple drugs, especially in non-resectable cases. For patients with metastatic disease, if the 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/palliative treatment depending on the size and location of the tumor [30]. Radiofrequency ablation or embolization may be considered with or without chemotherapy for liver metastases.
Solid-Pseudopapillary Neoplasm. Surgical resection is the treatment of choice for SPN.
Mucinous Cystic Neoplasm. MCNs are mostly benign, with 18% of cases undergoing malignant transformation. Hence, due to the expense and anxiety associated with life-long surveillance, these neoplasms are removed surgically regardless of their grade. However, patients with small cysts and without high-risk imaging features can be managed with observation.
Intraductal Papillary Mucinous Neoplasms. IPMNs are treated with either surgical resection or observation depending upon the location. IPMNs that involve the main pancreatic duct are treated with resection. IPMNs that involve only branch ducts can be treated by either of the two options. The decision to operate depends upon the presence of worrisome imaging features such as a large cyst size (>3 cm) or a non-enhancing mural nodule. IPMNs with cytological presence of high-grade dysplasia and adenocarcinoma are surgically resected. Figure 1 shows the Fukuoka revised guidelines for the management of MCNs and IPMNs.
Gastrointestinal Stromal Tumor. Surgical resection is the treatment of choice for localized gastrointestinal stromal tumors (GISTs). For advanced or metastatic c-Kit-positive GISTs, tyrosine kinase inhibitor (TKI) imatinib is used. Patients who develop resistance to TKI are treated with chemotherapy.
Suspicious
Suspicious findings on cytology are generally correlated with the clinical and imaging findings, and if radiology favors a malignant neoplasm the patient may be worked up and staged. Biochemical and molecular analytical markers may increase the sensitivity and specificity of the interpretation [26]. If the cytological findings are suspicious whereas imaging findings are benign, then a repeat sampling of the lesion should be considered.
Positive/Malignant
Adenocarcinoma of the Pancreas. For adenocarcinomas of the pancreas, if resectable, surgery is the initial option (Whipple’s procedure for tumors in the head or uncinate process and distal pancreatectomy and splenectomy for tumors in the body and tail) with adjuvant chemotherapy. In cases of non-resectable disease or metastatic disease patients are treated with chemotherapy.
Acinar Cell Carcinoma. Treatment of ACC is similar to that of PDAC.
High-Grade Neuroendocrine Carcinoma (Small Cell and Large Cell Type). These tumors are treated with chemotherapy regimens that are similar to small cell carcinomas of the lung [44].
Pancreatoblastoma. Surgical resection with adjuvant or neoadjuvant chemotherapy is the preferred treatment for pancreatoblastomas.
Lymphoma. Lymphomas are medically managed depending upon the specific type, including histologic morphology, flow cytometry, and cytogenetic findings.
Metastases. Diagnosis of metastasis generally indicates a widespread malignancy that is managed according to its specific subtype.
For further details, strategies provided by surgical and gastrointestinal specialty organizations, including the British Society of Gastroenterology, the Pancreatic Society of Great Britain, the Royal College of Pathology, the Japan Pancreas Society, the International Association of Pancreatology [45, 46], and the National Comprehensive Cancer Network (NCCN) [47], can be referred to.
Utilization of Ancillary Studies in the Cytologic Diagnosis of Pancreatic Lesions
Ancillary techniques that help in refining the cytological diagnosis are invaluable. A good cell block containing ample material is required. Ancillary tests include biochemical and molecular tests and immunohistochemical and special stains. These tests have diagnostic and prognostic implications. The PSC made recommendations on the utilization of ancillary studies [29]. These are further expanded upon in subsequent chapters of this monograph. Indications for ancillary testing in the pancreas include the following scenarios: differentiation of benign from malignant ductal lesions, diagnosis of primary and metastatic neoplasms, work-up of suspected hematopoietic lesions, and preoperative work-up of pancreatic cysts.
Several studies have found KRAS mutations in the premalignant dysplastic lesions and invasive carcinomas of the pancreas [48–53]. Although KRAS mutation analysis is a sensitive test for pancreatic adenocarcinoma, it can also test positive in benign cases such as chronic pancreatitis [50, 51]. Current data do not support KRAS testing in solid pancreatic masses. The PSC recommends the use of commercially available UroVysion FISH testing (Abbott Molecular, Abbott Park, IL, USA) on brushings from pancreatobiliary strictures with cytological diagnosis of indeterminate atypia. This test analyzes individual cells for DNA abnormality to determine if the sample is positive or negative. FISH analysis outperforms routine cytology with very high specificity and much higher sensitivity for the identification of carcinoma [54–56].
For the assessment of pancreatic cystic lesions, ancillary tests that aid in the diagnosis are CA19-9, CEA, and amylase levels in the cyst fluid, and some special stains. Special stains such as periodic acid-Schiff (PAS) and PAS with diastase (dPAS) detect the presence of glycogen. Glycogen is present in the clear cytoplasm of the cuboidal cells of serous cystadenoma and in the zymogen granules of the acinar cell lesions. PAS, mucicarmine (for neutral mucin), and Alcian blue (acid mucin) are used to detect the presence of intracellular and extracellular mucin. The cyst fluid CEA level is a very good test to diagnose if the cyst is mucinous, in which case the level usually exceeds 192 ng/mL [57]. Cyst fluid amylase levels help to diagnose pseudocyst where the levels are typically elevated into thousands. This test, however, does not distinguish IPMN from MCN as both can show slightly elevated levels.
Immunostaining for Smad4 is a good surrogate for SMAD4 genetic alterations and is useful in establishing a diagnosis of adenocarcinoma as it is retained in benign pancreatic ducts and is lost in more than half of PDACs [58]. Overexpression of mesothelin favors a diagnosis of adenocarcinoma. Trypsin and chymotrypsin positivity helps to diagnose ACC.