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EUS-guided FNA for GI stromal tumors: caveat lector
Letters to the Editor 2. Dierkes-Globish A, Goeller T, Mohr HH. Gastric stromal tumor: a rare cause of an upper gastrointestinal bleeding. Z Gastroenterol 2001;39: 467-70. 3. Cheng AW, Chiu PW, Chan PC, et al. Endoscopic hemostasis for bleeding gastric stromal tumors by application of a hemoclip. J Laparoendosc Adv Surg Tech 2004;14:169-71. 4. Vats HS, Wengert TJ, Torbey CF. Gastrointestinal stromal tumor with Dieulafoy lesion: a novel association. Clin Med Res 2006;4:228-9. 5. Seya T, Tanaka N, Yokoi K, et al. Life-threatening bleeding from gastrointestinal stromal tumor of the stomach. J Nippon Med Sch 2008;75:306-11. doi:10.1016/j.gie.2009.06.032
REFERENCES
Response:
EUS-guided FNA for GI stromal tumors: caveat lector
We thank Drs. Ustundag and Cindoruk for their interest in our article. We recognize that, without an external criterion standard, we cannot calculate the sensitivity or specificity of EUS-guided FNA for GI stromal tumors (GISTs). However, in the majority (O60%), a very specific diagnosis can be made, and in nearly all cases, a diagnosis of at least a spindle cell neoplasm can be made. Endoscopic appearance alone, including the presence of ulcerations, is inadequate to distinguish the etiology of one subepithelial mass from another. EUS features may be suggestive but not definitive. Clinical factors such as tumor location (eg, GISTs are rare in the esophagus) and medical history (especially of malignancies) may also be useful. Severe bleeding from an ulcerated mass may require immediate treatment, including surgery, if bleeding cannot be adequately controlled. In our experience, bleeding is self-limited, allowing a diagnostic evaluation. In many cases, these bleeding tumors are not GISTs, and the etiology may prompt nonsurgical treatment, especially for lymphomas and metastases. In the case of large and/or symptomatic GISTs, a preoperative diagnosis allows neoadjuvant therapy with imatinib mesylate.1 We rarely perform a second endoscopy to perform a biopsy of the ulcerated portion of the mass, but do this at the time of the EUS, especially if in-room cytology is nondiagnostic. Finally, regarding gain-of-function mutations in the platelet-derived growth factor receptor a (PDGRFa) genes, although this seems to be important in the pathogenesis of a small number of c-kit negative tumors, it is not specific for GIST.2 Unlike testing for c-kit, which is done with immunohistochemical stains against CD-117, testing for PDGRFa requires DNA mutational analysis that is not widely available. As a practical matter, PDGRFa mutational analysis is reserved for selected patients with CCD-117–negative spindle cell tumors that are also negative on immunohistochemical staining for leiomyomas and neural tumors (schwannomas). Katherine M. Hoda, MD Sarah A. Rodriguez, MD Douglas O. Faigel, MD, FASGE Division of Gastroenterology and Hepatology Oregon Health & Science University Portland, Oregon, USA www.giejournal.org
1. Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009;99:42-7. 2. Lasota J, Wang ZF, Sobin LH, et al. Gain-of-function PDGFRA mutations, earlier reported in gastrointestinal stromal tumors, are common in small intestinal inflammatory fibroid polyps. A study of 60 cases. Mod Pathol 2009 May 15 [Epub ahead of print]. doi:10.1016/j.gie.2009.07.030
To the Editor: GIE recently addressed EUS-guided tissue sampling in GI stromal tumors (GISTs) in 2 separate articles aimed at determining the diagnostic yield of this technique.1,2 Although similar in their retrospective designs, the investigations differed in a few methodological aspects that deserve some comments because they could explain the significant discrepancies in the results. Sepe et al2 studied fewer participants, but their results were powerful enough to identify predictors of a positive EUS-guided FNA in GISTs, as previously demonstrated by others.3 Other major strengths of their study included the availability of a criterion standard (surgical pathology) that allowed them to calculate the test properties of EUS-FNA with a high degree of confidence: the endosonographic appearance of lesions, the size of the needle used, and the inclusion of patients with tumors in the third layer. In contrast, Hoda et al1 included only tumors in the fourth layer because all third-layer lesions, irrespective of size and location, were removed by endoscopic mucosal resection. Nonetheless, the exclusion of this subgroup of patients is a potential source of selection bias because thirdand fourth-layer GISTs might not exhibit a similar exposure (EUS-FNA) to the outcome (diagnostic yield) relationship. In fact, Sepe et al2 showed that the origin of a GIST within a specific wall layer seemed to be the best predictor of cytological yield. The report of patient outcomes could have strengthened the investigation because the clinical significance of a ‘‘suspicious FNA’’ (positive for spindle cells but insufficient material for diagnostic stains) and its impact on patient management was not presented. As addressed in the accompanying editorial,4 the lack of a reliable criterion standard was a major limitation and indeed a threat to the validity of the study by Hoda et al. Its absence limited the main objective of the study (evaluation of the test performance characteristics of EUS-FNA), albeit feasible if the authors had used the appropriate statistical methods.5 The deleterious effect of the lack of a criterion standard became even more obvious in their logistic regression analysis, bearing its own methodological problems. Five of the 7 independent variables selected for the Volume 71, No. 3 : 2010 GASTROINTESTINAL ENDOSCOPY 659
Letters to the Editor
multivariate analysis were automatically excluded from the model (reported as not available) by the statistical software. There is a significant difference between variables ‘‘not statistically significant’’ and ‘‘not available.’’ The former consist of independent variables that did not reach a b coefficient level (slope of the curve) of statistical significance. In contrast, the latter represent an automatic deletion of variables by the statistical software, which unavoidably occurs when variables have a high degree of colinearity, suggesting a suboptimal model selection. This could explain some of the unexpected findings and limitations annotated by the excellent editorial review provided by Al-Haddad and DeWitt4 as well as the significant differences in results if compared with the work of Sepe et al.2 Although both studies provide substantial information on a similar topic and their differences are relevant to clinical practice, good-quality data can still provide biased information if not properly analyzed. As it stands, the significant discrepancy in results raises concern about potentially overlooked methodological errors. Caveat Lector!
In his letter entitled ‘‘Caveat lector,’’ Dr da Silveira states that there are significant discrepancies between our paper,1 a recent publication by Sepe et al,2 and an abstract by O’Neil et al,3 which is commented on by two of the abstract’s authors (Al-Haddad and Dewitt) in an editorial4 regarding our article. Indeed, the primary endpoint of these 3 reports, the yield of EUS-guided FNA (EUS-FNA), is quite similar.
Ours was an unselected consecutive series of 112 patients undergoing EUS-FNA evaluation of suspected GI stromal tumors (GIST). This is a population that a consultant endosonographer would be asked to evaluate, in contrast to both Sepe et al2 and O’Neil et al,3 who looked at highly selected cohorts of patients who had undergone both EUS-FNA and subsequent surgical resection. Theirs represents a small subset of relevant patients. For example, in the Sepe et al2 article, the authors reviewed a pathology database of 460 resected patients with GIST to identify 37 patients (8%) who had had previous EUS-FNA. The O’Neil et al3 study of 54 patients does not report the denominator. Nonetheless, the cytological yields (finding cells compatible with a mesenchymal tumor irrespective of immunohistochemistry) were similar among our study (83.9%), the Sepe et al2 study (78.4%), and the O’Neil et al3 study (86%). Immunohistochemical yields were also similar between our study (61.6%) and that of O’Neil et al3 (54%-56%); Sepe et al2 performed immunohistochemistry on only a small minority of their patients, which is a major limitation of their study. We acknowledge that, without an external criterion standard, we cannot calculate test characteristics such as sensitivity and specificity, but we strongly disagree that this threatens the validity of our findings, especially with regard to the primary endpoint of diagnostic yield. Furthermore, we disagree that Sepe et al2 are able to calculate with any degree of confidence test properties of EUS-FNA for GIST. To make that calculation, the criterion standard must be applied independently from the test of interest, and there must be clinical doubt as to the diagnosis. Sepe et al2 violate both of these principles, because, in the first place, it is likely that the EUS and FNA results were used to select patients for subsequent surgery, and, in the second place, by using a database of surgically and pathologically confirmed GIST, there can be no doubt of the diagnosis. This introduces bias that has the effect of falsely elevating the accuracy of the test being evaluated.5 We also disagree that using statistical means to estimate test characteristics in the absence of a criterion standard is applicable to our data because we are looking at not one but several diseases (GIST, leiomyoma, neuroma, etc) for which the underlying prevalence rates are inadequately known. There does seem to be some discrepancy as to predictors of FNA yield, primarily related to tumor size and number of FNA passes. We found no associations with yield. We disagree that this is because of erroneous data analysis. Even a cursory examination of the size data in Figure 3 would show this. The univariate P values for size and FNA passes were 0.654 and 0.795, respectively; values so high that normally one would not even do multivariate statistics. Sepe et al2 also found no relationship to number of passes but did report a negative association with size; that is, larger tumors (especially those O10 cm) had lower yields. The validity of their statistical analysis on these secondary endpoints is questionable, because they evaluated 19 variables in 37
660 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 3 : 2010
www.giejournal.org
Eduardo B. da Silveira, MD, MSc (Clinical Epidemiology) Everson L. Artifon, MD, PhD, FASGE Ruel T. Garcia, MD San Jose Gastroenterology San Jose, California, USA University of Sao Paulo Sao Paulo, Brazil REFERENCES 1. Hoda KM, Rodriguez SA, Faigel DO. EUS-guided sampling of suspected GI stromal tumors. Gastrointest Endosc 2009;69:1218-23. 2. Sepe PS, Moparty B, Pitman MB, et al. EUS-guided FNA for the diagnosis of GI stromal cell tumors: sensitivity and cytologic yield. Gastrointest Endosc 2009;70:254-61. 3. O’Neil J, Al-Haddad M, Leblanc J, et al. Endoscopic ultrasound-guided fine-needle aspiration of suspected mesenchymal tumors of the gastrointestinal tract: correlation with surgical pathology [abstract]. Gastrointest Endosc 2008;67:AB207-8. 4. Al-Haddad M, Dewitt J. EUS-guided sampling of suspected GI mesenchymal tumors: cells, cores, or a combination? Gastrointest Endosc 2009;69:1224-7. 5. Joseph L, Gyorkos TW, Coupal L. Bayesian estimation of disease prevalence and the parameters of diagnostic tests in the absence of a gold standard. Am J Epidemiol 1995;141:263-72. doi:10.1016/j.gie.2009.07.034
Response:
REFERENCES
Response:
EUS-guided FNA for GI stromal tumors: caveat lector
We thank Drs. Ustundag and Cindoruk for their interest in our article. We recognize that, without an external criterion standard, we cannot calculate the sensitivity or specificity of EUS-guided FNA for GI stromal tumors (GISTs). However, in the majority (O60%), a very specific diagnosis can be made, and in nearly all cases, a diagnosis of at least a spindle cell neoplasm can be made. Endoscopic appearance alone, including the presence of ulcerations, is inadequate to distinguish the etiology of one subepithelial mass from another. EUS features may be suggestive but not definitive. Clinical factors such as tumor location (eg, GISTs are rare in the esophagus) and medical history (especially of malignancies) may also be useful. Severe bleeding from an ulcerated mass may require immediate treatment, including surgery, if bleeding cannot be adequately controlled. In our experience, bleeding is self-limited, allowing a diagnostic evaluation. In many cases, these bleeding tumors are not GISTs, and the etiology may prompt nonsurgical treatment, especially for lymphomas and metastases. In the case of large and/or symptomatic GISTs, a preoperative diagnosis allows neoadjuvant therapy with imatinib mesylate.1 We rarely perform a second endoscopy to perform a biopsy of the ulcerated portion of the mass, but do this at the time of the EUS, especially if in-room cytology is nondiagnostic. Finally, regarding gain-of-function mutations in the platelet-derived growth factor receptor a (PDGRFa) genes, although this seems to be important in the pathogenesis of a small number of c-kit negative tumors, it is not specific for GIST.2 Unlike testing for c-kit, which is done with immunohistochemical stains against CD-117, testing for PDGRFa requires DNA mutational analysis that is not widely available. As a practical matter, PDGRFa mutational analysis is reserved for selected patients with CCD-117–negative spindle cell tumors that are also negative on immunohistochemical staining for leiomyomas and neural tumors (schwannomas). Katherine M. Hoda, MD Sarah A. Rodriguez, MD Douglas O. Faigel, MD, FASGE Division of Gastroenterology and Hepatology Oregon Health & Science University Portland, Oregon, USA www.giejournal.org
1. Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009;99:42-7. 2. Lasota J, Wang ZF, Sobin LH, et al. Gain-of-function PDGFRA mutations, earlier reported in gastrointestinal stromal tumors, are common in small intestinal inflammatory fibroid polyps. A study of 60 cases. Mod Pathol 2009 May 15 [Epub ahead of print]. doi:10.1016/j.gie.2009.07.030
To the Editor: GIE recently addressed EUS-guided tissue sampling in GI stromal tumors (GISTs) in 2 separate articles aimed at determining the diagnostic yield of this technique.1,2 Although similar in their retrospective designs, the investigations differed in a few methodological aspects that deserve some comments because they could explain the significant discrepancies in the results. Sepe et al2 studied fewer participants, but their results were powerful enough to identify predictors of a positive EUS-guided FNA in GISTs, as previously demonstrated by others.3 Other major strengths of their study included the availability of a criterion standard (surgical pathology) that allowed them to calculate the test properties of EUS-FNA with a high degree of confidence: the endosonographic appearance of lesions, the size of the needle used, and the inclusion of patients with tumors in the third layer. In contrast, Hoda et al1 included only tumors in the fourth layer because all third-layer lesions, irrespective of size and location, were removed by endoscopic mucosal resection. Nonetheless, the exclusion of this subgroup of patients is a potential source of selection bias because thirdand fourth-layer GISTs might not exhibit a similar exposure (EUS-FNA) to the outcome (diagnostic yield) relationship. In fact, Sepe et al2 showed that the origin of a GIST within a specific wall layer seemed to be the best predictor of cytological yield. The report of patient outcomes could have strengthened the investigation because the clinical significance of a ‘‘suspicious FNA’’ (positive for spindle cells but insufficient material for diagnostic stains) and its impact on patient management was not presented. As addressed in the accompanying editorial,4 the lack of a reliable criterion standard was a major limitation and indeed a threat to the validity of the study by Hoda et al. Its absence limited the main objective of the study (evaluation of the test performance characteristics of EUS-FNA), albeit feasible if the authors had used the appropriate statistical methods.5 The deleterious effect of the lack of a criterion standard became even more obvious in their logistic regression analysis, bearing its own methodological problems. Five of the 7 independent variables selected for the Volume 71, No. 3 : 2010 GASTROINTESTINAL ENDOSCOPY 659
Letters to the Editor
multivariate analysis were automatically excluded from the model (reported as not available) by the statistical software. There is a significant difference between variables ‘‘not statistically significant’’ and ‘‘not available.’’ The former consist of independent variables that did not reach a b coefficient level (slope of the curve) of statistical significance. In contrast, the latter represent an automatic deletion of variables by the statistical software, which unavoidably occurs when variables have a high degree of colinearity, suggesting a suboptimal model selection. This could explain some of the unexpected findings and limitations annotated by the excellent editorial review provided by Al-Haddad and DeWitt4 as well as the significant differences in results if compared with the work of Sepe et al.2 Although both studies provide substantial information on a similar topic and their differences are relevant to clinical practice, good-quality data can still provide biased information if not properly analyzed. As it stands, the significant discrepancy in results raises concern about potentially overlooked methodological errors. Caveat Lector!
In his letter entitled ‘‘Caveat lector,’’ Dr da Silveira states that there are significant discrepancies between our paper,1 a recent publication by Sepe et al,2 and an abstract by O’Neil et al,3 which is commented on by two of the abstract’s authors (Al-Haddad and Dewitt) in an editorial4 regarding our article. Indeed, the primary endpoint of these 3 reports, the yield of EUS-guided FNA (EUS-FNA), is quite similar.
Ours was an unselected consecutive series of 112 patients undergoing EUS-FNA evaluation of suspected GI stromal tumors (GIST). This is a population that a consultant endosonographer would be asked to evaluate, in contrast to both Sepe et al2 and O’Neil et al,3 who looked at highly selected cohorts of patients who had undergone both EUS-FNA and subsequent surgical resection. Theirs represents a small subset of relevant patients. For example, in the Sepe et al2 article, the authors reviewed a pathology database of 460 resected patients with GIST to identify 37 patients (8%) who had had previous EUS-FNA. The O’Neil et al3 study of 54 patients does not report the denominator. Nonetheless, the cytological yields (finding cells compatible with a mesenchymal tumor irrespective of immunohistochemistry) were similar among our study (83.9%), the Sepe et al2 study (78.4%), and the O’Neil et al3 study (86%). Immunohistochemical yields were also similar between our study (61.6%) and that of O’Neil et al3 (54%-56%); Sepe et al2 performed immunohistochemistry on only a small minority of their patients, which is a major limitation of their study. We acknowledge that, without an external criterion standard, we cannot calculate test characteristics such as sensitivity and specificity, but we strongly disagree that this threatens the validity of our findings, especially with regard to the primary endpoint of diagnostic yield. Furthermore, we disagree that Sepe et al2 are able to calculate with any degree of confidence test properties of EUS-FNA for GIST. To make that calculation, the criterion standard must be applied independently from the test of interest, and there must be clinical doubt as to the diagnosis. Sepe et al2 violate both of these principles, because, in the first place, it is likely that the EUS and FNA results were used to select patients for subsequent surgery, and, in the second place, by using a database of surgically and pathologically confirmed GIST, there can be no doubt of the diagnosis. This introduces bias that has the effect of falsely elevating the accuracy of the test being evaluated.5 We also disagree that using statistical means to estimate test characteristics in the absence of a criterion standard is applicable to our data because we are looking at not one but several diseases (GIST, leiomyoma, neuroma, etc) for which the underlying prevalence rates are inadequately known. There does seem to be some discrepancy as to predictors of FNA yield, primarily related to tumor size and number of FNA passes. We found no associations with yield. We disagree that this is because of erroneous data analysis. Even a cursory examination of the size data in Figure 3 would show this. The univariate P values for size and FNA passes were 0.654 and 0.795, respectively; values so high that normally one would not even do multivariate statistics. Sepe et al2 also found no relationship to number of passes but did report a negative association with size; that is, larger tumors (especially those O10 cm) had lower yields. The validity of their statistical analysis on these secondary endpoints is questionable, because they evaluated 19 variables in 37
660 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 3 : 2010
www.giejournal.org
Eduardo B. da Silveira, MD, MSc (Clinical Epidemiology) Everson L. Artifon, MD, PhD, FASGE Ruel T. Garcia, MD San Jose Gastroenterology San Jose, California, USA University of Sao Paulo Sao Paulo, Brazil REFERENCES 1. Hoda KM, Rodriguez SA, Faigel DO. EUS-guided sampling of suspected GI stromal tumors. Gastrointest Endosc 2009;69:1218-23. 2. Sepe PS, Moparty B, Pitman MB, et al. EUS-guided FNA for the diagnosis of GI stromal cell tumors: sensitivity and cytologic yield. Gastrointest Endosc 2009;70:254-61. 3. O’Neil J, Al-Haddad M, Leblanc J, et al. Endoscopic ultrasound-guided fine-needle aspiration of suspected mesenchymal tumors of the gastrointestinal tract: correlation with surgical pathology [abstract]. Gastrointest Endosc 2008;67:AB207-8. 4. Al-Haddad M, Dewitt J. EUS-guided sampling of suspected GI mesenchymal tumors: cells, cores, or a combination? Gastrointest Endosc 2009;69:1224-7. 5. Joseph L, Gyorkos TW, Coupal L. Bayesian estimation of disease prevalence and the parameters of diagnostic tests in the absence of a gold standard. Am J Epidemiol 1995;141:263-72. doi:10.1016/j.gie.2009.07.034
Response: