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Original article Clinical endoscopy: Editorial| Volume 90, ISSUE 6, P944-946, December 2019

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Pancreatic cyst through-the-needle biopsy: two’s the charm

      Abbreviations:

      CEA (carcinoembryonic antigen), IPMN (intraductal papillary mucinous neoplasm), MCN (mucinous cystic neoplasm), PCL (pancreatic cystic lesion), TTNB (through-the-needle biopsy)
      Pancreatic cystic lesions (PCLs) are commonly encountered, with a prevalence of over 40% in patients undergoing cross-sectional imaging; the incidence increases with age.
      • Moris M.
      • Bridges M.D.
      • Pooley R.A.
      • et al.
      Association between advances in high-resolution cross-section imaging technologies and increase in prevalence of pancreatic cysts from 2005 to 2014.
      The vast majority are discovered incidentally, are branch duct intraductal papillary mucinous neoplasms (IPMNs), and will never progress to cancer. Despite this, and because the guidelines are controversial and based on little evidence, the management of PCLs continues to create anxiety and frustration for both the patient and the gastroenterologist.
      EUS with or without FNA is generally used for further evaluation, especially when worrisome features (cyst size >3 cm, thickened enhanced cyst walls, mural nodules, main pancreatic duct size 5 to 9 mm, abrupt change in the caliber of the main pancreatic duct with distal gland atrophy, lymphadenopathy, elevated CA19-9, rapid cyst growth >5 mm/2 years)
      • Tanaka M.
      • Fernández-del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      • Tanaka M.
      • Fernández-del Castillo C.
      • Kamisawa T.
      • et al.
      Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
      are present, for both diagnostic and risk stratification purposes. Unfortunately, cytology has poor sensitivity, cyst fluid carcinoembryonic antigen (CEA) cutoff values can vary across institutions, and molecular analysis is not widely available. Thus, even after an expensive and invasive evaluation, the definitive diagnosis and future risk may remain obscure.
      For selected cases, it is becoming clear that through-the-needle biopsy (TTNB) with use of the Moray microforceps (U.S. Endoscopy, Mentor, Ohio, USA) is superior to FNA for the diagnosis of PCLs.
      • Basar O.
      • Yuksel O.
      • Yang D.
      • et al.
      Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts.
      • Barresi L.
      • Crino S.F.
      • Fabbri C.
      • et al.
      Endoscopic ultrasound-through-the-needle biopsy in pancreatic cystic lesions: a multicenter study.
      • Mittal C.
      • Obuch J.C.
      • Hammad H.
      • et al.
      Technical feasibility, diagnostic yield, and safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video).
      • Yang D.
      • Samarasena J.B.
      • Jamil L.H.
      • et al.
      Endoscopic ultrasound-guided through-the-needle microforceps biopsy in the evaluation of pancreatic cystic lesions: a multicenter study.
      • Yang D.
      • Trindade A.J.
      • Yachimski P.
      • et al.
      Histologic analysis of endoscopic ultrasound-guided through the needle microforceps biopsies accurately identifies mucinous pancreas cysts.
      The studies that have reported the use of these microforceps have for the most part targeted larger cysts with high-risk stigmata and worrisome features or previous nondiagnostic FNA. The mean cyst sizes in these studies have ranged from 28 to 38 mm (41 mm in the current study), and the resultant histologic diagnostic rates vary from 36% to 89%. Although the histologic diagnostic rate is higher compared with FNA, there is also a higher adverse event rate (up to 16%),
      • Yang D.
      • Trindade A.J.
      • Yachimski P.
      • et al.
      Histologic analysis of endoscopic ultrasound-guided through the needle microforceps biopsies accurately identifies mucinous pancreas cysts.
      with intracystic bleeding (usually self-limited) and mild pancreatitis occurring the most frequently.
      A recent publication of a prospective TTNB series stated that future studies were needed to determine the appropriate number of passes (and resultant specimens) required to maximize tissue acquisition (and resultant histologic) yield without additional risk to the patient.
      • Yang D.
      • Trindade A.J.
      • Yachimski P.
      • et al.
      Histologic analysis of endoscopic ultrasound-guided through the needle microforceps biopsies accurately identifies mucinous pancreas cysts.
      Ask and ye shall receive. In this issue of Gastrointestinal Endoscopy, Crinó et al
      • Crinó S.F.
      • Bernardoni L.
      • Brozzi L.
      • et al.
      Association between macroscopically visible tissue samples and diagnostic accuracy of EUS-guided through-the-needle microforceps biopsy sampling of pancreatic cystic lesions.
      report that 2 macroscopically visible specimens allowed 100% histologic adequacy, without the incremental benefit of a third specimen. Thus, 2 biopsies as opposed to 3. Compared with both cytology and a single biopsy specimen, 2 specimens improved the ability to differentiate between mucinous and nonmucinous lesions, obtain cyst epithelium, and determine the grade of dysplasia and ultimate histologic diagnosis.
      Although this was a relatively small (61 patients) retrospective report of a prospectively collected database, the authors used formalized biopsy and specimen handling protocols. Specifically, single bites were obtained only when the “tent sign” was seen, ensuring that the microforceps had grasped the cyst epithelium. The specimen was manually extracted from the microforceps and was expressed onto a glass slide with a drop of saline solution. It was then transferred between 2 paper discs, placed in a cassette, and put in formalin for histologic analysis. Whether or not this transfer process is beneficial is unknown because previous studies have placed the sample directly into formalin. However, the single biopsy per pass of the microforceps is likely important, taken only when the “tent sign” was seen; as when 2 to 3 bites per pass were performed, there was a lower specimen adequacy yield (83%).
      • Yang D.
      • Trindade A.J.
      • Yachimski P.
      • et al.
      Histologic analysis of endoscopic ultrasound-guided through the needle microforceps biopsies accurately identifies mucinous pancreas cysts.
      This single biopsy per pass resulted in a mean specimen size of 189 μm (almost 2 mm) in the current study, and size does matter, inasmuch as larger specimens correlated with improved diagnostic yield.
      The overall diagnostic accuracy of TTNB with 2 macroscopically visible specimens was 74%, with a diagnostic concordance rate of 90% as compared with surgically resected specimens (n = 20). This is similar to previous reports regarding each parameter. The ability to differentiate mucinous from nonmucinous PCLs was 79% (the same as the landmark CEA cutoff value study that serves as the reference standard).
      • Brugge W.R.
      • Lewandrowski K.
      • Lee-Lewandrowski E.
      • et al.
      Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study.
      CEA and cytology were 62% and 49% accurate, respectively, to distinguish mucinous lesions in this study. Importantly, higher-risk regions of the cyst wall/septation/mural nodule may be specifically targeted with TTNB. In the absence of targetable high-risk stigmata or a worrisome feature, sampling error may occur, and although a diagnosis may be obtained, the true biologic risk of the lesion may not be evident.
      The adverse event rate, as previously mentioned, is higher with TTNB. The higher pancreatitis rate is likely due to the need to use a 19-gauge needle, and potentially the “dwell” time because the needle is left within the cyst as the microforceps are withdrawn and the specimen is extracted. Therefore, more microforceps passes result in a longer needle “dwell” time, which may increase the risk. The increased intracystic bleeding rate of TTNB is due to the biopsy of the cyst epithelial wall. In Crinó et al,
      • Crinó S.F.
      • Bernardoni L.
      • Brozzi L.
      • et al.
      Association between macroscopically visible tissue samples and diagnostic accuracy of EUS-guided through-the-needle microforceps biopsy sampling of pancreatic cystic lesions.
      the adverse event rate was 23%, which is higher than that in other reports. The intracystic bleeding rate was 16.4%; however, all were self-limited and asymptomatic. The pancreatitis rate was 3.3%, in line with other studies, with all cases being classified as minor requiring a brief hospitalization. Hence, many of these adverse events did not appear to be clinically significant, but judgement and selectivity should be exercised because these rates are higher than those of FNA. Interestingly, no intracystic bleeding was seen as a result of the third pass in the current study.
      TTNB is superior to FNA cytology in the selected pancreatic cysts in which it is used. How might it compare with molecular analysis, which has also demonstrated superiority over CEA and cytology for differentiating mucinous cysts? In a recent large series, the presence of K-ras/G-nas mutations detected by next-generation sequencing was 89% sensitive and 100% specific for diagnosing mucinous cysts.
      • Singhi A.D.
      • McGrath K.
      • Brand R.E.
      • et al.
      Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia.
      The presence of K-ras and/or G-nas reached 100% sensitivity for IPMN, and a G-nas mutation was 100% specific for IPMN. However, K-ras was detected only in the minority of mucinous cystic neoplasms (MCNs); thus, TTNB has an apparent advantage for diagnosing MCNs. The additional benefit of risk assessment is inherent with molecular analysis, and the combination of K-ras/G-nas with high-risk mutations (TP53, PIK3CA, PTEN) had an 89% sensitivity and a 100% specificity for advanced neoplasia (high-grade dysplasia, adenocarcinoma). Granted, this was a surgically biased study (as are the majority of cyst studies), inasmuch as typically, only patients with high-risk stigmata or worrisome features proceed to surgical resection. In this regard, the operating characteristics of next-generation sequencing for advanced neoplasia were superior to those for a mural nodule, duct dilation, and even preoperative malignant cytology.
      In the absence of advanced neoplasia on histologic analysis of TTNB specimens of mucinous cystic lesions, and given the heterogeneity of the cyst wall and potential sampling error, molecular analysis may provide an incremental benefit for further diagnosis and/or risk stratification. And it may be a better stand-alone test, given the diagnostic and prognostic performance, and a lower adverse event rate because FNA is all that is required. A comparative study between TTNB histology and molecular analysis seems to be warranted, particularly given the higher adverse event rate associated with TTNB.
      It remains unclear where TTNB falls into the ever-evolving algorithm for diagnosis and management of PCLs, but currently, its selected use has shown diagnostic superiority to assist in patients’ treatment. The current study, although small, provides a framework for a standardized sampling protocol that may minimize risk. Short of a comparative study of biopsy technique for histologic yield, 2 macroscopically visible samples should be the goal.

      Disclosure

      All authors disclosed no financial relationships relevant to this publication.

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