Inside the WHO Reporting System for Pancreaticobiliary Cytopathology

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The low-grade pancreatic mucinous neoplastic cysts—i.e. IPMNs and MCNs with low- to intermediate-grade dysplasia—mostly reveal low cellularity. The background may show colloid-like thick mucin, which aids in interpreting a neoplastic mucinous cyst. The epithelium itself is composed of columnar cells, with size similar to that of a duodenal enterocyte, that are arranged in evenly spaced, mildly crowded, or pseudostratified groups. They have moderate to abundant mucinous cytoplasm, smooth to mildly irregular nuclear membranes, even chromatin, and they may harbor intranuclear inclusions. The main differential diagnosis includes gastrointestinal tract contaminant epithelium. Ancillary tests including a carcinoembryonic antigen level of greater than 192 ng/mL and presence of KRAS/GNAS/RNF43 mutations can aid significantly in the diagnosis of a neoplastic mucinous cyst.

High-grade neoplastic mucinous cysts of the pancreas mostly include IPMNs and MCNs with high-grade dysplasia or even an associated invasive carcinoma. High-grade atypia is typically seen as clusters of or singly lying cells smaller than a duodenal enterocyte (< 12 µm) with variably mucinous cytoplasm, high nuclear-cytoplasmic ratio, hyperchromasia or hypochromasia, and irregular nuclear membranes. The background may reveal necrosis. Ancillary studies can be employed to assess the grade of the cyst. Mutations in TP53, SMAD4, CDKN2A, PTEN, or PIK3CA can be associated with high-grade cysts. Immunohistochemical staining on cell block sections with p53 (strong and diffuse or null pattern) or SMAD4 (loss of staining) can aid in the diagnosis as well.

The ROM for the PaN-Low category has been reported to be five to 20 percent (with no data yet for bile duct brushings). Management may involve clinical correlation with repeat sampling in conjunction with ancillary studies (i.e. FISH/NGS). For the PaN-High category, the ROM ranges from 60 to 95 percent. Surgical resection is appropriate in surgically fit patients; however, conservative follow-up may be considered if there are increased risks involved with surgery or the imaging is not high risk.

Suspicious for malignancy. Suspicious for malignancy is used when a specimen demonstrates cytologic features worrisome for malignancy but insufficient in quantity or quality to make a definitive diagnosis of malignancy. This category accounts for about five to 16 percent of the pancreaticobiliary tract cytologic diagnoses reported in the literature. Reasons for using this category include sparse cellularity, poor preservation or staining quality, or concurrent pancreatitis, stents, stones, and inflammatory conditions. The ROM for suspicious for malignancy in pancreatic FNA and bile duct brushing ranges from 80 to 100 percent and 74 to 100 percent, respectively, reflecting the degree of interobserver variability.

When using the suspicious category, a detailed note should be included in the report to convey the worrisome cytologic features in the sample and why a definitive “malignant” diagnosis is not made. The results of ancillary testing (if available) with correlation to clinical and radiologic features should be emphasized when managing these patients. Suspicious for malignancy should not be treated the same as malignant diagnosis. It is best to discuss these patients in multidisciplinary conference where all the relevant information can be gathered. However, if clinical information and imaging strongly support a malignancy, definitive therapy can proceed without additional tissue confirmation.

Positive for malignancy. A malignant diagnosis is provided when there are unequivocal cytologic features of malignancy. The malignant cytologic features for pancreatic ductal adenocarcinoma include hypercellular sample, loss of the normal honeycomb architecture, enlarged nuclei, vesicular chromatin, irregular nuclear contours, size variation of 4:1 in a given fragment, and atypical mitoses. The malignant category includes primary and metastatic diseases. In contrast to the PSC system, well-differentiated pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN) are included in the new WHO classification as malignant to align with the WHO Classification of Tumours of the Digestive System. The ROM for malignant category in pancreatic FNA and bile duct brushing ranges from 99 to 100 percent and 96 to 100 percent, respectively. Other entities in this category include acinar cell carcinoma, cholangiocarcinoma, and pancreatoblastoma.

Malignant diagnosis typically will be managed with surgical excision for primary pancreaticobiliary tract diseases. However, patients with PanNET smaller than 2 cm and Ki-67 less than three percent may be managed with surveillance. More advanced diseases may be treated with chemotherapy and radiation therapy.

Comparison between WHO and PSC systems (Table 2). One major change in the WHO system, as compared with the PSC system, is the classification of neoplasia. In the PSC system, there is a single category for neoplasms including “benign” (serous cystadenoma and lymphangioma) and “other” (IPMNs of any grade, MCNs of any grade, PanNETs, and SPNs). In the WHO system, these neoplasms are classified into four categories: benign/negative for malignancy (serous cystadenoma and lymphangioma), PaN-Low (IPMN/MCN with low- to intermediate-grade dysplasia), PaN-High (IPMN/MCN with high-grade dysplasia), and positive for malignancy (PanNETs and SPNs). Additionally, pancreatic FNAs with findings suspicious for a well-differentiated PanNET or SPN that are categorized as atypical in the PSC system are now reclassified as suspicious for malignancy per the WHO system recommendation.

Summary. The WHO Reporting System for Pancreaticobiliary Cytopathology mirrors the WHO Classification of Tumors series and provides an evidence-based terminology system with associated ROMs to assist the clinical care team in managing the patient. The performance indicators (ROM) for each category of the WHO system were derived from literature based on the previous system, and therefore future studies focusing on the current WHO system are warranted.

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Dr. Li is an associate professor of pathology at Ohio State University Wexner Medical Center, Dr. Goyal is an associate professor of clinical pathology and laboratory medicine at Weill Cornell Medicine, and Dr. Huang is an associate professor of laboratory medicine and pathology at the University of Washington. Drs. Goyal and Huang are members of the CAP Cytopathology Committee and Dr. Li is a former member of the committee.