The diagnosis of a PanNET can be made on morphology alone when the cytological features are classically endocrine as described above. Confirmatory immunohistochemical stains include endocrine markers, most commonly synaptophysin and chromogranin A [7]. Synaptophysin is more sensitive and generally produces strong diffuse staining whereas chromogranin A is more specific but is more likely to give patchy, focal staining [8]. If a fine-needle aspiration (FNA) is only suggestive of a PanNET, and a specific diagnosis is not possible, then the appropriate category is “Atypical” rather than “Suspicious (for Malignancy).”

Grading PanNETs on FNA specimens is controversial. Accurate grading is dependent on analyzing the mitotic count and/or Ki-67 labeling of tumor cells in the most active area (hot spots) of the resected specimen covering 50 high-powered fields [7, 9]. Studies have shown a strong correlation between grading on cellblocks and histology [6]; however, if a PanNET is to be resected, preoperative grading on a cellblock does not affect management and is a waste of resources since accuracy in grading would likely need to be established on histology. Grading on a cellblock is justified, however, when conservative management is desired. Although the accuracy in the distinction between G1 and G2 tumors is debatable, the detection of, or more importantly, the absence of diffuse nuclear staining of the tumor cells for Ki-67 indicating a G3 tumor is valuable information [6].

Conservative management is becoming an increasingly common option for patients with small PanNETs (<  2 cm), especially in patients with advanced age and comorbid conditions [10, 11]. In addition, observation is common for patients with MEN 1 syndrome who often have small (< 2.5 cm) and not uncommonly multiple PanNETs [11]. Classifying a PanNET as “Positive for Malignancy” makes conservative patient management unnecessarily complicated and challenging. With patient access to their medical records, notes, and pathology reports, convincing a patient not to have surgery with the diagnosis of a malignant tumor is virtually impossible [12].

Discovery of the molecular mechanisms of PanNETs leading to progression and malignancy has offered management options for patients with unresectable disease [7]. Elaboration on these mechanisms is beyond the scope of this atlas, but FNA will likely play a significant role in obtaining tissue for such molecular studies in the future.

Solid-pseudopapillary neoplasm (SPN) is a solid, secondarily cystic low-grade malignant epithelial neoplasm with potential for regional recurrence and metastasis. Although called a “neoplasm,” it is classified as a malignant tumor in the 2010 WHO classification [13]. The tumors occur in young females with rare exception. Imaging demonstrates a complex cyst with a solid and cystic appearance, which is variable in proportion due to the secondary nature of the cystic change. This neoplasm is included in the category “Neoplastic: Other” because, like PanNET, it has unpredictable malignant behavior with only ~ 15 % recurrence or metastasis rate, and it is not an aggressive malignancy like the malignancies in the “Positive” category [13, 14]. Classification as “Positive (for Malignancy)” is certainly an accurate category however .

Although the cytomorphology can be diagnostic, samples without the characteristic papillary architecture may lead to a differential diagnosis with the other parenchymal-rich, stromal-poor tumors of the pancreas. PanNETs may also occur in relatively young women and have round, occasionally solid, and cystic imaging features [4]. To confirm the diagnosis of SPN, immunohistochemical staining for beta-catenin is usually sufficient to highlight the strong nuclear positivity seen in virtually 100 % of tumors [17]. If the FNA is suggestive but not diagnostic of SPN, the preferred category is “Atypical” rather than “Suspicious (for Malignancy)”; however, “Suspicious (for Malignancy)” is not inaccurate.

Surgical resection is the treatment of choice.

The two primary neoplastic mucinous cysts of the pancreas, IPMN and MCN, are premalignant cysts until invasive carcinoma occurs. Once invasion occurs, prognosis declines by up to almost 50 %, so the ideal time to resect these neoplasms is prior to invasion [3]. Surgical intervention is determined by the specific tumor type and the risk of malignancy, which is primarily based on cross-sectional imaging characteristics [18].

Both MCN and IPMNs are mucin-producing epithelial cystic neoplasms stratified by the degree of cytological and architectural atypia into low-grade, intermediate-grade, and high-grade dysplastic, premalignant (noninvasive neoplasms) and invasive carcinomas (tubular or colloid type in most cases) [3]. If the epithelial component of the cyst aspirate demonstrates the cytological criteria of malignancy, then the appropriate interpretation category is “Positive (for Malignancy).” If, however, the interpretation of a mucinous cyst is established by cytology and/or ancillary testing such as with carcinoembryonic antigen (CEA) [19, 20] or KRAS and GNAS mutational analysis [21–23], and the epithelial component is not cytologically malignant, then the appropriate category is “Neoplastic: Other” rather than “Atypical” or “Suspicious for Malignancy.” The “Neoplastic: Other” category establishes that a neoplasm exists and provides a broad categorization of the cyst that provides maximum flexibility for patient management.

Accurate grading of premalignant, dysplastic cyst lining epithelium is challenging. Confounding factors include degeneration, gastrointestinal contamination, and cyst lining heterogeneity. Simplifying the grading of the epithelial component using a two-tiered system of low-grade atypia (low-grade and intermediate-grade dysplasia) and high-grade atypia (high-grade dysplasia and adenocarcinoma) has been proposed [24]. This approach attempts to separate cysts that can be monitored conservatively (low-grade atypia) from those that should be resected (high-grade atypia). Intermediate-grade dysplasia is a challenge as the cytological features overlap with those of high-grade atypia significantly. The criteria for high-grade atypia (HGA) in the more common IPMN include small cell size (< 12 micron duodenal enterocyte) and thus elevated nuclear to cytoplasmic ratio, abnormal chromatin (hypo or hyperchromatic), and background cellular necrosis [25].

Mucin production established: