We report on the value of cytological analysis in predicting malignancy in the preoperative evaluation of patients with small (< 3 cm) branch-duct IPMNs. Cytology was almost twice as sensitive, specific, and accurate as symptoms in predicting malignancy in small cysts, without imaging risk factors. The absence of HGA on cytology yielded a NPV of 96%, contributing to a powerful triple negative test for malignancy — no dilated MPD (< 6 mm), no MN, and no HGA on cytology — providing a much more accurate assessment of no malignancy for conservative clinical management.
The Sendai guidelines for the management of mucinous cysts are mainly based on the radiological features. Resection is recommended for symptomatic cysts, cysts greater than 30 mm, or 10 – 30 mm cysts with high-risk stigmata, which include dilated MPD (> 6 mm), a MN on radiological studies or positive cytology.[1
] Although, overall highly sensitive in the appropriate surgical triage (sensitivity 97.3 to 100%), in specificity (21.7 to 29.8%) it suffers.[11
] This high sensitivity arises from a surgical triage for any of the features in the algorithm.
The use of symptoms as a predictor of malignancy contributed to the low specificity of the guidelines, especially in small branch-duct IPMNs.[22
] Even as patients who were symptomatic were significantly more likely to have a malignant cyst, in the recent study by Mimura,[22
] an asymptomatic patient was equally likely to have a malignant cyst. Our data shows similar findings in small branch-duct IPMNs. Three patients with malignant cysts were symptomatic, but two were not. In another study, Weisenaur et al
] found that new onset diabetes and jaundice were significant predictors of malignancy, but a variety of symptoms were present in patients with non-malignant cysts, especially abdominal pain. Patients with small cysts were not likely to present with such dramatic symptoms, as was true of the 31 patients in our study. Additionally, a recent multivariate analysis by Shin et al
., revealed that a history of pancreatitis was predictive of invasive IPMN.[26
] In our cohort, the two patients with invasive carcinoma did present with pancreatitis; however, the remaining five patients with pancreatitis had only low-grade dysplasia on histology. Of the patients with HGD / carcinoma in-situ
, two were asymptomatic and one presented with abdominal pain.
Large tertiary referral centers like the MGH, with a symptomatic patient population, may bias the data to some degree as was the case in a large series by Schmidt,[23
] where over 90% of the 150 patients in the study were symptomatic. Symptoms are clearly important in patient evaluation, and the presence of symptoms is a valid indication for resection, if for no other reason than to alleviate the symptom. The significance and association of the symptoms with the cyst may be quite difficult to assess in the clinical setting of an elderly patient with comorbid conditions, however.
Even as the risk of malignancy was low in a small cyst, it was not zero. The rate of malignancy in this study was 16%, falling within the previously reported range of 0 – 20% in cysts < 3 cm.[1
] Furthermore, Sawhney showed that although cyst size was a predictor of malignancy in pancreatic cysts, nearly half (9 / 21) of the malignant cysts were < 3 cm.[28
Tissue confirmation of malignancy is a strong motivator for surgical intervention. To achieve a cytological diagnosis of ‘positive,’ indicating > 90% PPV of malignancy, is a high standard in cyst specimens, where cellularity and cellular preservation often limit optimal interpretation. Aspirating cyst contents may underestimate the highest histological grade of the cyst.[16
] Experience with these relatively rare specimen types and specialty training in cytology are also often lacking in many settings, leading to a conservative interpretation of the cells that may be present in the fluid.
We have recommended that cells that meet the criteria for high-grade atypia[20
]  trigger resection, as these cells have an ~70% sensitivity and 85% specificity for predicting malignancy, very likely preinvasive disease. Given that invasion greatly decreases the prognosis of patients with IPMN,[30
] resection prior to invasion is optimal, especially in young patients who have many years for potential progression of the dysplasia to invasive carcinoma. Knowing that some patients may indeed have only moderate or low-grade dysplasia on histology warrants careful consideration of morbidity related to surgical intervention. High-risk surgical candidates and very elderly patients require assessment of the greatest risk to survival: surgery or the possibility of progression to invasive carcinoma. Importantly, however, the absence of HGA on cytology yielded a NPV of 96%, contributing to a powerful triple negative test for malignancy - no dilated MPD (< 6 mm), no MN, and no HGA on cytology — providing a much more accurate assessment of no malignancy for conservative clinical management.