Abstract
Introduction
Using Kaplan–Meier curves, a 2006 study illustrated a shorter time interval between development of symptoms and detection of malignant IPMN in the main pancreatic duct versus a side-branch duct location. Of 93 cases, only 62 were confirmed histologically. To support these interesting findings, we examined a larger cohort of cases where the diagnosis was confirmed histologically and asked if symptoms by themselves, as well as main duct location, were associated with malignant detection.
Methods
Between 1989 and 2009, 210 IPMN cases meeting international criteria were resected and histologically examined. Actuarial rates of malignant detection over time were calculated from the first clinical symptom to malignant detection (resection). These rates of malignant detection over time were compared for main vs. side-branch duct location and symptomatic vs. asymptomatic cases.
Results
The most common indications for resection were symptoms (88%) and main pancreatic duct location (65%). The actuarial malignant detection rates were significantly shorter for main duct location and also for symptomatic cases, regardless of duct location.
Conclusions
Presence of symptoms followed by main pancreatic duct location had a significantly shorter elapsed time to malignant detection. The visual depiction of these actuarial rates highlights the importance of the clinical history. To determine malignant risk, the primary determinants for resection were either symptoms or main duct location (but not cyst size), confirming the 2006 study with a larger cohort of histologically confirmed cases.
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Discussion
DR. SHARON M. WEBER (Madison, WI): I want to start by thanking your group for this and many prior important studies evaluating pancreatic cystic neoplasms. What I take away from this presentation as the most important message is that one should resect symptomatic lesions. Interestingly, if you look back at the original Sendai criteria, they basically concluded the same thing. But I believe those recommendations were probably made based more on the fact that we could palliate symptoms, rather than because there was an increased cancer risk. As you much more eloquently point out, this increased risk of malignancy has not been well recognized until your very important paper.
The questions I have for you really center around this issue of symptoms——particularly to look more closely at the group that had symptoms. I was surprised at the high percentage of patients that were symptomatic. To put this in context, of all the patients that you evaluate for cystic neoplasms, what percentage did this represent? What was the denominator? From a national perspective, other authors have reported that only about 25% of all the cystic neoplasms we evaluate in the clinic are symptomatic. So that was a very high percentage to me, particularly for the side branch lesions.
And a second question, can you be more specific about how you define symptoms? For instance, a very common patient we might be referred would be someone who had some vague epigastric pain, then gets a CT scan where they are found to have a pancreatic cyst, but when they see us, are really doing fairly well, having no symptoms whatsoever. How would you classify that patient? Did that patient count as symptomatic?
Lastly, from a pathological perspective, IPMN has not been well recognized until the mid '90s or so, but yet you included patients who underwent resection dating back to 1989. Did your study include pathological re-review of the slides to assure that there was a homogeneous patient population?
Closing Discussant
DR. TOSHIYUKI MORIYA: The first symptom is—our data revealed 88% of the patient had symptoms. But this is not uncommon, I think, because Johns Hopkins data or another paper revealed 20% patients don't have any symptoms. Our data is not uncommon, I think.
The second question, I reviewed only clinical records. We have not standardized our manual before resection. That is a really weak point of our study.
I reviewed only the pathological report; it depends on our pathologists. Sorry, I don't know the pathological details.
DR. JENNIFER TSENG (Worcester, MA): The Kaplan–Meier curves are not truly Kaplan–Meiers, in the sense that they all start at 0, so you're assuming that the IPMNs are uniformly not malignant when they're diagnosed. And that if you took them to the OR, whether it was 17 months or plus or minus that, and had pathology return as malignant IPMN, suddenly they turned malignant at that exact time—when really you finally just had the gold standard pathology (and you were perhaps wrong assuming it was benign at time 0). I would argue that you are not perhaps actually looking at the time course to malignancy but the time course to resection. And then, at resection, it's either malignant or not. And I think your conclusions are still very valid, but perhaps a chi-square as to whether it's malignant or not, as opposed to a Kaplan–Meier type of presentation.
DR. WILLIAM TRAVERSO: The French study by Levy gave us the idea to do the study this way. They only had 66 patients that actually had histologically confirmed malignancy for IPMN. So we wanted to see if what they found was supported by our 210 cases. And I had the same difficulty you did when I first read their paper.
But what the Kaplan–Meier curve measures is not the time course to malignancy but simply just what you said: the time course from the first time it was symptomatically detected to the time when they came to resection. And then at that time, the percentage of those cases that were malignant.
So over time, if 50% were malignant at the time of resection, it would suggest that they were on a faster time course to what the surgeon would know to predict whether they would have a malignancy, yes or no.
If the patients are not symptomatic, then we only know they're there because they are incidentally found at the time of some imaging study, like for kidney stones.
These patients have a much slower need for surgery. But when we did fortuitously operate on them for the other Sendai criteria, none of them had malignant disease. And so what the study brought out was if a person has symptoms, or the main pancreatic duct involvement, within 2 years of the detection of that entity, half of these patients, will have malignancy. But in the patients that have IPMN appearing on an just imaging study, those patients were not progressing and just had to be followed with caution. And the ones that we took out because they had exceeded the criteria from the Sendai group of greater than 3 cm, all of those were not malignant, which were a very small minority of the group.
The Indiana study that was published recently in Annals of Surgery shows that 93% of their cases were symptomatic. In ours, 88% were symptomatic. In this group of symptomatic people, you don't really need to do extra tests, don't need do EUS.
One just has to have a good clinical history to decide the chance for detecting malignancy at the time of the resection. And if the chance is over 50%, the doctor can show the patient the Kaplan–Meier curve, the patient can grasp this easily, and get behind the operation as a good thing to do.
DR. MICHAEL G. SARR (Rochester, MN): You are assuming that people with carcinoma-in-situ are going to go on and develop invasive disease. You call it cancer, as does the WHO. Is that an appropriate assumption?
DR. WILLIAM TRAVERSO: In the manuscript—we didn't present it here because we didn't have time—there's a second set of Kaplan–Meier curves for just invasive IPMN. And it established a similar trend.
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Moriya, T., Hashimoto, Y. & Traverso, L.W. The Duration of Symptoms Predicts the Presence of Malignancy in 210 Resected Cases of Pancreatic Intraductal Papillary Mucinous Neoplasms. J Gastrointest Surg 15, 762–771 (2011). https://doi.org/10.1007/s11605-011-1437-6
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DOI: https://doi.org/10.1007/s11605-011-1437-6