LETTER TO THE EDITOR Questions About Branch-Duct IPMNs With Sendai Negative Criteria To the Editor: e read with interest the article by Fritz et al,1 which evaluates the feasibility of a nonoperative management for asymptomatic patients with branch-duct intraductal papillary mucinous neoplsms (IPMNs) less than 3 cm in size without mural nodules and other worrisome features (Sendai negative criteria).2 In the updated version of these guidelines, surgical resection is recommended only for branch-duct IPMNs with symptoms, solid components/mural nodules, main-duct involvement, and positive cytology for malignancy.3 Several retrospective studies encompassing more than 400 resected patients and other prospective, observational studies have validated the safety of this nonoperative approach for patients with Sendai negative criteria.2–5 Fritz and colleagues report a rate of malignancy—including invasive carcinoma and high-grade dysplasia—of 24.6% in 69 patients with “Sendai negative criteria.” It is not known if some others Sendai negative branchduct IPMNs are under follow-up evaluation at Heidelberg University. If so, did these 69 patients undergo resection because they were simply offered surgery, or did authors identify in this subgroup any “worrisome feature”? For example, it is remarkable that high levels of serum carbohydrate antigen 19.9 and/or carcinoembryonic antigen were found in 17/69 (24.6%) patients and 8/17 patients (47%) had invasive carcinoma. All patients included in the study had preoperative high-resolution imaging based on computed tomography and/or magnetic resonance imaging with or without cholangiopancreatography (MRCP). However, no specific imaging protocols are described. It would be interesting to know if radiological examinations were carried out at Heidelberg University or elsewhere. Pancreas-protocol imaging at high-volume centers can improve significantly preoperative staging of pancreatic tumors and can change management in patients undergoing prereferral imaging.6 This is also true in our experience with IPMNs, especially for magnetic resonance imaging and/or MRCP. Moreover, preoperative endoscopic ultrasound (EUS) “was considered for
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Disclosure: All authors report no potential conflict of interest. There are no sources of funding for this article. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/25903-e0042 DOI: 10.1097/SLA.0000000000000208
e42 | www.annalsofsurgery.com
analysis,” but unfortunately no detailed data regarding EUS in these 69 patients is reported. The 2006 International Association of Pancreatology (IAP) guidelines clearly recommend EUS for all branch-duct IPMNs ranging between 1 and 3 cm in size.2 Although we fully agree with the Heidelberg group that cyst fluid carcinoembryonic antigen level is not useful in differentiating malignant from benign disease, cytological analysis after EUS with fine-needle aspiration (FNA) can improve the diagnostic yield of high-resolution imaging techniques.3 In a recent study, cytology detected 30% more cancers in small branch-duct IPMNs than radiological “worrisome features” alone.7 In this light, the lack of a systematic application of EUS with FNA to all patients does not allow Fritz and coworkers to define these 69 patients with “Sendai negative criteria.” One could argue that EUS with FNA for cytology could be of help in identifying some of these 17/69 (24.6%) malignant branch-duct IPMNs without radiologic worrisome features. Despite being an operator-dependent technique, EUS proved to be useful in discriminating epithelial mural nodules from mucous clots with higher sensitivity compared to computed tomographic scan.8 The clear identification of mural nodules in the preoperative setting is of paramount importance in the workup of branch-duct IPMNs. The likelihood of malignancy increased significantly with the presence of nodules in a cohort of 145 resected branch-duct IPMNs,4 because the rate of nodules was 0% in lowgrade dysplasia and 75% in invasive cancer. Fritz et al do not give any data on the presence of mural nodules at pathological examination of the surgical specimens. It would be of interest to know if mural nodules were finally detected at pathology in some of the 69 patients with Sendai negative criteria to evaluate sensitivity and specificity of their imaging techniques in identifying solid components. The authors of the article identified 17 malignant tumors (24.6%) in the so-called Sendai negative group. Interestingly, 8 of these 17 tumors (47%) were reclassified at histology as mixed IPMNs because they had “at least focal involvement of the main pancreatic duct.” In this study, branch-duct IPMN was defined as a “cyst lesion with communication to the main pancreatic duct (MPD) of less than 6 mm.” Of note, recent guidelines suggest that a dilatation of MPD 5 mm or more can increase the sensitivity for radiologic diagnosis of mixed or main-duct IPMNs without losing specificity.3 Mixed IPMNs show close similarities with mainduct IPMNs in regard to clinicopathologic characteristics, with higher rates of malignancy compared with branch-duct IPMNs.9 Therefore, the malignancy rate of 24.6%
in presumed branch-duct IPMNs without worrisome features should be reconsidered, as half of these patients had mixed IPMNs. A different cutoff for MPD dilatation and the combination of MRCP with EUS could be useful to reliably discriminate between branch-duct and mixed or main-duct IPMNs in the preoperative setting. As well pointed out by Fritz et al, the decision to follow rather than to resect a branch-duct IPMN should be individualized “on the basis of patient’s age, comorbidities, willingness to undergo follow-up studies, and the availability of safe and high-quality pancreatic surgery.” Above all that, a dedicated, high-quality preoperative workup with MRCP and EUS is mandatory for the proper diagnosis of IPMN type and of risk factors for malignancy according to IAP guidelines. In our experience, a nonoperative approach can be safely proposed to patients with real “Sendai negative criteria.” Stefano Crippa, MD Stefano Partelli, MD Massimo Falconi, MD Division of Pancreatic Surgery Universit`a Politecnica delle Marche Academic Hospital “Ospedali Riuniti” Ancona, Italy
REFERENCES 1. Fritz S, Klauss M, Bergmann F, et al. Small (Sendai negative) branch-duct IPMNs: not harmless. Ann Surg. 2012;256:313–320 2. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32. 3. Tanaka M, Fern´andez-Del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183–197 4. Rodriguez JR, Salvia R, Crippa S, et al. Branchduct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection. Gastroenterology. 2007;133:72–79 5. Tanno S, Nakano Y, Nishikawa T, et al. Natural history of branch-duct intraductal papillary mucinous cystic neoplasms of the pancreas without mural nodules: long-term follow-up results. Gut. 2008;57:339–343 6. Walters DM, Lapar DJ, de Lange EE, et al. Pancreas-protocol imaging at a high-volume center leads to improved preoperative staging of pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2011; 18:2764–2771 7. Genevay M, Mino-Kenudson M, Yaeger K, et al. Cytology adds value to imaging studies for risk assessment of malignancy in pancreatic mucinous cysts. Ann Surg. 2011;254:977–983 8. Zhong N, Zhang L, Takahashi N, et al. Histologic and imaging features of mural nodules in mucinous pancreatic cysts. Clin Gastroenterol Hepatol. 2012;10:192–198 9. Crippa S, Fernandez-del Castillo C, Salvia R, et al. Mucin-producing neoplasms of the pancreas: an analysis of distinguishing clinical and epidemiologic characteristics. Clin Gastroenterol Hepatol. 2010;8:213–219.
Annals of Surgery r Volume 259, Number 3, March 2014
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Disclosure: All authors report no potential conflict of interest. There are no sources of funding for this article. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/25903-e0042 DOI: 10.1097/SLA.0000000000000208
e42 | www.annalsofsurgery.com
analysis,” but unfortunately no detailed data regarding EUS in these 69 patients is reported. The 2006 International Association of Pancreatology (IAP) guidelines clearly recommend EUS for all branch-duct IPMNs ranging between 1 and 3 cm in size.2 Although we fully agree with the Heidelberg group that cyst fluid carcinoembryonic antigen level is not useful in differentiating malignant from benign disease, cytological analysis after EUS with fine-needle aspiration (FNA) can improve the diagnostic yield of high-resolution imaging techniques.3 In a recent study, cytology detected 30% more cancers in small branch-duct IPMNs than radiological “worrisome features” alone.7 In this light, the lack of a systematic application of EUS with FNA to all patients does not allow Fritz and coworkers to define these 69 patients with “Sendai negative criteria.” One could argue that EUS with FNA for cytology could be of help in identifying some of these 17/69 (24.6%) malignant branch-duct IPMNs without radiologic worrisome features. Despite being an operator-dependent technique, EUS proved to be useful in discriminating epithelial mural nodules from mucous clots with higher sensitivity compared to computed tomographic scan.8 The clear identification of mural nodules in the preoperative setting is of paramount importance in the workup of branch-duct IPMNs. The likelihood of malignancy increased significantly with the presence of nodules in a cohort of 145 resected branch-duct IPMNs,4 because the rate of nodules was 0% in lowgrade dysplasia and 75% in invasive cancer. Fritz et al do not give any data on the presence of mural nodules at pathological examination of the surgical specimens. It would be of interest to know if mural nodules were finally detected at pathology in some of the 69 patients with Sendai negative criteria to evaluate sensitivity and specificity of their imaging techniques in identifying solid components. The authors of the article identified 17 malignant tumors (24.6%) in the so-called Sendai negative group. Interestingly, 8 of these 17 tumors (47%) were reclassified at histology as mixed IPMNs because they had “at least focal involvement of the main pancreatic duct.” In this study, branch-duct IPMN was defined as a “cyst lesion with communication to the main pancreatic duct (MPD) of less than 6 mm.” Of note, recent guidelines suggest that a dilatation of MPD 5 mm or more can increase the sensitivity for radiologic diagnosis of mixed or main-duct IPMNs without losing specificity.3 Mixed IPMNs show close similarities with mainduct IPMNs in regard to clinicopathologic characteristics, with higher rates of malignancy compared with branch-duct IPMNs.9 Therefore, the malignancy rate of 24.6%
in presumed branch-duct IPMNs without worrisome features should be reconsidered, as half of these patients had mixed IPMNs. A different cutoff for MPD dilatation and the combination of MRCP with EUS could be useful to reliably discriminate between branch-duct and mixed or main-duct IPMNs in the preoperative setting. As well pointed out by Fritz et al, the decision to follow rather than to resect a branch-duct IPMN should be individualized “on the basis of patient’s age, comorbidities, willingness to undergo follow-up studies, and the availability of safe and high-quality pancreatic surgery.” Above all that, a dedicated, high-quality preoperative workup with MRCP and EUS is mandatory for the proper diagnosis of IPMN type and of risk factors for malignancy according to IAP guidelines. In our experience, a nonoperative approach can be safely proposed to patients with real “Sendai negative criteria.” Stefano Crippa, MD Stefano Partelli, MD Massimo Falconi, MD Division of Pancreatic Surgery Universit`a Politecnica delle Marche Academic Hospital “Ospedali Riuniti” Ancona, Italy
REFERENCES 1. Fritz S, Klauss M, Bergmann F, et al. Small (Sendai negative) branch-duct IPMNs: not harmless. Ann Surg. 2012;256:313–320 2. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32. 3. Tanaka M, Fern´andez-Del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183–197 4. Rodriguez JR, Salvia R, Crippa S, et al. Branchduct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection. Gastroenterology. 2007;133:72–79 5. Tanno S, Nakano Y, Nishikawa T, et al. Natural history of branch-duct intraductal papillary mucinous cystic neoplasms of the pancreas without mural nodules: long-term follow-up results. Gut. 2008;57:339–343 6. Walters DM, Lapar DJ, de Lange EE, et al. Pancreas-protocol imaging at a high-volume center leads to improved preoperative staging of pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2011; 18:2764–2771 7. Genevay M, Mino-Kenudson M, Yaeger K, et al. Cytology adds value to imaging studies for risk assessment of malignancy in pancreatic mucinous cysts. Ann Surg. 2011;254:977–983 8. Zhong N, Zhang L, Takahashi N, et al. Histologic and imaging features of mural nodules in mucinous pancreatic cysts. Clin Gastroenterol Hepatol. 2012;10:192–198 9. Crippa S, Fernandez-del Castillo C, Salvia R, et al. Mucin-producing neoplasms of the pancreas: an analysis of distinguishing clinical and epidemiologic characteristics. Clin Gastroenterol Hepatol. 2010;8:213–219.
Annals of Surgery r Volume 259, Number 3, March 2014
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
