Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic cysts by combined cytopathology and cystic content analysis

Table 1 Pancreatic cytology terminology (modified from pitman et al[34], 2014)

Terminology category	Definition	Example interpretations
Category I:	No diagnostic or useful information about the solid or cystic lesion sampled	Gastrointestinal contamination only;
Non-diagnostic		Non-specific cyst contents with insufficient cyst fluid volume for ancillary testing;
		Evaluation limited by scant cellularity
Category II:	Adequate cellular and/or extracellular tissue to evaluate	Benign pancreatobiliary tissue in the setting of vague fullness and no discrete mass
Negative (for malignancy)		Acute pancreatitis
		Chronic pancreatitis
		Autoimmune pancreatitis
		Pseudocysts
		Lymph epithelial cyst
		Spleenful/accessory spleen
Category III:	Cells present with cytoplasmic, nuclear, or architectural features that are not consistent with normal or reactive cellular changes of the pancreas or bile ducts and are insufficient to classify them as a neoplasm or suspicious for a high-grade malignancy	Atypical ductal cells obscured by crush artifact
Atypical		Scant population of small monomorphic polygonal cells of unclear origin: Normal cigar cells vs endocrine proliferation
		Atypical bile duct epithelium with nuclear features suggestive of repair in a background of acute inflammation
		Atypical bile duct epithelium with mucinous metaplasia and mild nuclear atypia
Category IVA:	The presence of a cytological specimen sufficiently cellular and representative, with or without the context of clinical, imaging and ancillary studies, to be diagnostic of a benign neoplasm	Scant non-mucinous cuboidal epithelium and scant hemosiderin-laden macrophages in a non-mucinous cyst fluid consistent with the clinical impression of a serous cystadenoma
Neoplastic: Benign
Category IVB1:	Premalignant such as intraductal papillary neoplasm of the bile ducts (IPN-B), IPMN or MCN with low, intermediate or high-grade dysplasia by cytological criteria	MCN: Typically a multiloculated, mucin-producing epithelial neoplasm with sub epithelial ovarian-type stroma that in almost all cases does not communicate with the pancreatic ductal system and in almost all cases occurs in women; located in the body or tail; easily removed comparing life-long surveillance
Neoplastic:		IPMN: Primarily intraductal proliferations of ductal epithelium creating a macroscopic lesion resulting in ductal dilatation, cyst formation and/or a mass lesion
Mucinous neoplasm		1 Main-duct IPMN: Associated with diffuse dilatation of any portion of the main pancreatic duct or the entire pancreas
		2 BD-IPMN: Cysts adjacent to a non-dilated main pancreatic duct
		IPN-B: A papillary proliferation of mucin containing neoplastic cells that may occur anywhere in the ductal system; similar to IPMN
Category IVB2:	A low-grade malignant neoplasm such as well-differentiated PanNET, SPN or rare GIST	PanNET (pancreatic endocrine tumor and pancreatic endocrine neoplasm): A well-differentiated proliferation of the pancreatic endocrine cells creating a mass lesion greater than 0.5 cm that may or may not be functional by producing inappropriate levels of various hormones and that may or may not demonstrate aggressive features on histological examination
Neoplastic:		SPN: A solid, secondarily cystic low-grade epithelial neoplasm with established clonal mutations in cancer-associated genes and an ability to metastasize
Non-mucinous neoplasm		GIST: Spindle cell and/or epithelioid mesenchymal neoplasms with differentiation along the lines of the interstitial cell of Cajal that usually expression c-kit protein (CD117), DOG1 and CD34 by immunohistochemistry; located in a peripanreatic location
Category V:	when some, but an insufficient number of the typical features of a specific malignant neoplasm are present, mainly pancreatic adenocarcinoma	Rare markedly atypical epithelial cells suspicious for adenocarcinoma
Suspicious (for malignancy)		Mucinous cyst with high-grade epithelial atypia and abundant coagulate necrosis suspicious for invasive carcinoma
		Solid cellular neoplasm with features suspicious for acinar cell carcinoma. Tissue for confirmatory ancillary studies is not available
Category VIA:	A group of neoplasms that unequivocally display malignant cytological characteristics and include PDAC and its variants, cholangiocarcinoma, acinar cell carcinoma, high-grade neuroendocrine carcinoma (small cell and large cell), pancreatoblastoma, lymphomas, sarcomas and metastases to the pancreas	PDAC: A malignant invasive gland (duct) forming epithelial neoplasm typically composed of classic tubular glands; 85%-90% of all pancreatic malignancies
PDAC and variants		Colloid carcinoma (mucinous, non-cystic): Abundant extracellular mucin production, with at least 80% of the tumor on histology demonstrating large pools of extracellular mucin and cuboidal epithelial cells "floating" in the mucin
		Medullary carcinoma: Poor histologic differentiation, syncytial growth pattern, pushing borders and an intense lymphoplasmacytic response
		Undifferentiated carcinoma with osteoclast-like giant cells: Distinctive type of sarcomatoid carcinoma with the striking and unique cytohistologic features characterized by a prominent component of reactive osteoclast-like giant cells in a background of spindle cells.
		Undifferentiated carcinoma: A high-grade carcinoma composed of large, undifferentiated, markedly pleomorphic cells; 2%-7% of PDAC
Category VIA:	A group of neoplasms that unequivocally display malignant cytologic characteristics excluding PDAC and its variants; including acinar cell carcinoma, high-grade neuroendocrine carcinoma (small cell and large cell), cholangiocarcinoma, pancreatoblastoma, lymphomas, sarcomas and metastases to the pancreas	Cholangiocarcinoma: The diagnostic criteria for invasive cholangiocarcinoma are the same as for ductal adenocarcinoma; usually diagnosis by bile duct brushings with high false negative rate due to overlying benign epithelium, insufficient sampling, reactive change with stent; degeneration due to bile
Malignancy:		Acinar cell carcinoma: A rare malignant epithelial neoplasm with exocrine acinar differentiation
Others		Poorly-differentiated neuroendocrine carcinoma (small cell carcinoma or large cell neuroendocrine carcinoma): Rare high-grade neuroendocrine tumor with < 1% of pancreatic tumor and 2%-3% of PanNETs
		Pancreatoblastoma: A rare neoplasm, primarily of childhood, characterized by acinar differentiation, endocrine differentiation and distinctive squamoid nests
		Non-Hodgkin lymphoma: Rare and usually involve the pancreas secondarily
		Metastatic tumors: Secondary neoplasms involving the pancreas are rare; most common: Renal cell carcinoma

MCN: Mucinous cystic neoplasms; IPN-B: Intraductal papillary neoplasm of the bile ducts; IPMN: Intraductal papillary mucinous neoplasm; cPanNET: Pancreatic neuroendocrine tumor; SPN: Solid pseudopapillary neoplasms; PDAC: Pancreatic ductal adenocarcinomas.

Table 2 Criteria for integrated molecular pathology diagnostic categories

Diagnostic category	Molecular criteria1	Co-existing concerning clinical features2
Benign	DNA lacks molecular criteria	Not considered for this diagnosis
Statistically indolent	DNA meets 1 molecular criterion	None
SHR	DNA meets 1 molecular criterion	1 or more
Aggressive	DNA meets at least 2 molecular criteria	Not considered for this diagnosis

¹Four molecular criteria that have been independently correlated with pancreatic malignancy or high-grade dysplasia are used to make an integrated molecular pathology diagnosis: (1) a single high-clonality mutation; (2) elevated level of high-quality DNA; (3) multiple low-clonality mutations; and (4) a single low-clonality oncogene mutation;

²Include any of the following: cyst size  >  3  cm, growth rate  >  3  mm/year, duct dilation  >  1  cm, carcinoembryonic antigen level  >  1000  ng/mL, cytologic evidence of high-grade dysplasia. (Table 2 from Al-Haddad et al[75] 2015 was permitted by publisher). SHR: Statistically higher risk.