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BACKGROUND The objectives of this study were to determine threshold probabilities needed to perform endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and those needed to treat patients suspected of having malignancy and then to compare these thresholds to the pre- and posttest probabilities of malignancy associated with benign, atypical, suspicious, and malignant diagnoses. The goal was to aid endoscopists in making appropriate clinical decisions based on both quantitative and qualitative approaches. METHODS The study included 633 consecutive patients. A decision tree was constructed to estimate the “treatment” threshold. Using treatment threshold and likelihood ratios, the authors determined the “no-test-test” and “test-treatment” thresholds. Pretest probability was compared with no-test-test and test-treatment thresholds, and the post-EUS-FNA probability of malignancy for each diagnostic category with the treatment threshold. Results were stratified by lesion site, lesion size, and cytopathologist. RESULTS EUS-FNA has a wide range of pretest probabilities within which it could be performed (0.06–0.98). The posttest probabilities for malignancy, 0.99 (95% confidence interval [CI], 0.967–0.996) and 0.09 (95% CI, 0.057–0.126), after a positive or a negative result, respectively, were significantly different from the treatment threshold but not those of suspicious, 0.92 (95% CI, 0.767–0.994) diagnosis. The posttest probability of atypical diagnosis, 0.60 (95% CI, 0.407–0.772), was not significantly different from that of pretest probability. Results did not vary by lesion size, organ site, or cytopathologist. CONCLUSION The authors demonstrated the uncertainty associated with EUS-FNA diagnostic categories and used the threshold approach to qualify quantitatively the decision to perform EUS-FNA and the decision to treat patients suspected of having malignancy. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

BACKGROUND Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy allows the detailed imaging and FNA not only of both intramural and extramural structures and lesions of the gastrointestinal (GI) tract but also of various intraabdominal organs. Thus, EUS-FNA biopsy offers a novel opportunity to evaluate and obtain cytology samples from adrenal gland lesions. The objective of the current study was to determine the utility of EUS-FNA in the diagnosis of adrenal lesions. METHODS The authors conducted a prospective evaluation of 24 consecutive EUS-FNA biopsy specimens obtained from patients with adrenal lesions. An attending cytopathologist was present on site to assess specimen adequacy and to provide rapid interpretation of air-dried material that had been stained with Diff-Quik (Baxter Scientific Products, McGraw Park, IL). Additional samples were obtained for ThinPrep (Cytyc Corporation, Boxborough, MA) preparation, and cell blocks subsequently were prepared. Appropriate immunohistochemical staining was performed as indicated. The cytologic diagnosis was then analyzed for correlations with the final diagnosis, which was based on relevant correlative cytologic or histologic examination of biopsied/resected pathology materials and/or final clinical follow-up. RESULTS In total, 24 EUS-FNA biopsy specimens (from 18 males and 6 females) were obtained from adrenal glands. The mean patient age was 62.2 years (range, 48–81 years). Adequate cellularity was noted in all 24 samples. Seven of 24 samples (29%) were reported to be positive for carcinoma. All samples that were diagnosed as metastatic carcinoma were confirmed on subsequent follow-up. EUS-FNA performed simultaneously with adrenal gland aspiration either from the primary site (n = 1) or from metastases to lymph nodes (n = 3) supported diagnoses of metastatic carcinoma. Six of seven samples were metastatic from the lung, and one specimen was a direct extension of a transitional renal cell carcinoma. EUS-FNA biopsy of the right adrenal gland in one patient revealed myelolipoma. In 16 patients, benign adrenal gland cells were noted on EUS-FNA biopsy specimens from enlarged adrenal glands. In 5 samples (31%), signs of adenoma were evident. Morphology alone could not distinguish between adrenal adenoma and adrenal hyperplasia. No significant complications were reported after EUS-FNA biopsy of adrenal glands. CONCLUSIONS EUS-FNA biopsy is a highly specific and safe technique for confirming the diagnosis of carcinoma metastatic to the adrenal glands. Along with cytologic evaluation, EUS imaging is needed to support the diagnosis of adrenal adenoma. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

BACKGROUND Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) allows detailed imaging of both intramural and extramural structures of the gastrointestinal (GI) tract and also allows tissue samples to be obtained from masses and lesions in the GI tract. The objective of the current study was to determine the diagnostic utility of EUS-FNA in evaluating intramural and extramural GI tract lesions. METHODS The authors evaluated all EUS-FNA specimens of GI tract lesions obtained over a 30-month period (from August 2000 to February 2003). Samples of pancreatic and intrabdominal/mediastinal lymph nodes were excluded from the study. A single endosonographer performed all procedures. An attending cytopathologist also was present on site to assess specimen adequacy. Cytologic diagnoses were analyzed for correlations with final diagnoses, which were based on histologic examination of biopsied/resected pathology materials and/or clinical follow-up findings. RESULTS Sixty-two EUS-FNA specimens of intramural and extramural GI tract lesions were obtained from a total of 60 patients. The mean patient age was 58.8 years (standard deviation, 15.3 years). Thirty-six patients (60%) were male, and 24 (40%) were female. Twenty-eight patients had surgical pathologic evaluation of the corresponding lesions. The remaining 32 patients were followed clinically for a mean duration of 9.5 months (standard deviation, 7.7 months). The anatomic sites of the lesions were as follows: esophagus in 23 patients (37%), stomach in 13 patients (21%), duodenum in 15 patients (24%), and rectum/sigmoid in 11 patients (18%). It is noteworthy that 29 patients (43%) previously had experienced unsuccessful attempts at tissue diagnosis by endoscopic forceps biopsy. Of the 62 EUS-FNA specimens, 43, 4, and 15 were reported as being positive for a neoplasm, suspicious, and benign, respectively. Neoplastic lesions included carcinoma (n = 24), gastrointestinal stromal tumor (GIST; n = 18), neuroendocrine neoplasm (n = 2), and lymphoma (n = 1). There were two cases of endometriosis, three foregut duplication cysts, and one case of diverticulosis. There were two lesions that yielded false-negative findings (one gastric lymphoma and one GIST) secondary to sampling or interpretive error. There also were three cases that yielded false-positive findings (one case of endometriosis, one case of duodenal diverticula with smooth muscle hyperplasia, and one case of normal pancreas, which presented as a periduodenal mass). The sensitivity, specificity, and diagnostic accuracy of EUS-FNA in diagnosing GI tract neoplastic lesions were 89%, 88%, and 89%, respectively. CONCLUSIONS EUS-FNA provides accurate tissue diagnosis in a wide variety of extraintestinal mass lesions and intramural GI tumors, particularly in patients for whom previous endoscopic forceps biopsy was unsuccessful in establishing a diagnosis. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

BACKGROUND Although atypical or suspicious cytology may support a clinical diagnosis of a malignancy, it is often not sufficient for the implementation of therapy in patients with pancreatic carcinoma. Endoscopic ultrasound–guided fine-needle aspiration biopsy (EUS-FNAB) is a relatively new method for obtaining cytology samples, and one that may decrease the number of atypical/suspicious diagnoses. The goals of the current study were to prospectively evaluate the yield of EUS-FNAB in the diagnosis of patients presenting with solid pancreatic lesions and to evaluate the significance of atypical, suspicious, and false-negative aspirates. METHODS All patients who presented with a solid pancreatic lesion and underwent EUS-FNAB over a 13-month period were included in the current study. One endoscopist performed all EUS-FNABs. On-site evaluation of specimen adequacy by a cytopathologist was available for each case. Follow-up included histologic correlation (n = 21) and clinical and/or imaging follow-up (n = 80), including 38 patients who died of the disease. RESULTS EUS-FNABs were obtained from 101 patients (mean age, 62 ± 11.8 years; age range, 34–89 years). The male-to-female ratio was 2:1. Sixty-five percent of the lesions were located in the head of the pancreas, 12% were located in the uncinate, 17% were located in the body, and 6% were located in the tail. The mean size of the tumors was 3.3 cm (range, 1.3–7 cm). A median of 4 needle passes were performed (range, 1–11 needle passes). Sixty-two biopsies (61.4%) were interpreted as malignant on cytologic evaluation, 5 (5%) as suspicious for a malignancy, 6 (5.9%) as atypical/indeterminate, and 26 (25.7%) as benign processes. Of the 76 malignant lesions, 71 were adenocarcinomas, 3 were neuroendocrine tumors, 1 was a lymphoma, and 1 was a metastatic renal cell carcinoma. All except one of the suspicious/atypical aspirates were subsequently confirmed to be malignant. Agreement was complete for the atypical cases. Among the suspicious cases, 2 of the 5 were identified as carcinoma by one cytopathologist and as suspicious lesions by the other, yielding a 40% disagreement rate between the 2 cytopathologists. Therefore, for the 10 atypical or suspicious cases that later were confirmed to be malignant, the final diagnosis of malignant disease was not made due to scant cellularity that could be attributed to sampling error in 8 cases and to interpretative disagreement in 2 cases (20%). All four false-negative diagnoses were attributed to sampling error. Two percent of all biopsies were inadequate for interpretation. Of the 99 adequate specimens, 72 yielded true-positive results, 23 yielded true-negative results, and 4 yielded false-negative results. No false-positives were encountered. Therefore, the sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNAB for solid pancreatic masses were 94.7% (95% confidence interval [CI], 89.7–99.8%), 100%, 100%, and 85.2% (95% CI, 71.8–98.6%), respectively. CONCLUSIONS EUS-FNAB is a safe and highly accurate method for tissue diagnosis of patients with solid pancreatic lesions. Patients with suspicious and atypical EUS-FNAB aspirates deserve further clinical evaluation. Cancer (Cancer Cytopathol) 2003;99:285–92. © 2003 American Cancer Society. DOI 10.1002/cncr.11643

BACKGROUND Computerized tomographic (CT)-guided fine-needle aspiration (FNA) cytology is a well-established tool in the diagnosis of hepatic lesions. Endoscopic ultrasound-guided FNA (EUS-FNA), developed recently and used predominantly in evaluating mediastinal and pancreatic lesions, provides access to a significant portion of the liver and to perihepatic structures not readily accessible by a percutaneous approach. METHODS A recent experience (1997-2002) with CT-guided FNA of liver lesions at the University of Alabama Birmingham (UAB) was compared with the first 2.5 years of EUS-FNA experience (2000-2002). Cases were identified using a SNOMED search and all reports and cytologic slides were retrieved for review. RESULTS In 6 years, 34 percutaneous CT-FNA liver biopsies were performed at UAB; in approximately 2.5 years, 16 EUS-FNA liver biopsies were done. In both groups the primary clinical indication was suspected metastatic carcinoma (CT, 41% of cases vs. EUS, 56%). The 2 techniques yielded a similar range of benign, atypical, and malignant diagnoses (CT: 26%, 18%, and 56% vs. EUS: 19%, 25%, and 56%). Because of the clinical setting in which EUS-FNA is usually performed, a much narrower range of neoplasms was sampled by EUS-FNA. Benign gastrointestinal epithelial cells were identified in 60% of the EUS-FNA specimens. CONCLUSIONS Early experience suggests EUS-FNA is comparable to CT-FNA in terms of diagnostic utility for hepatic lesions. Anatomy limits EUS-FNA to only a fraction of the hepatic parenchyma, but that fraction includes the hilum and left lobe of the liver and the proximal biliary tract. The gallbladder, extrahepatic biliary system, and perihilar lymph nodes are readily accessible. Proximate high-resolution ultrasound imaging and cytopathologist involvement in the EUS-FNA process are further advantages. Awareness of artifacts inherent in EUS-FNA sampling (i.e., gut epithelial cells) can minimize a potential diagnostic pitfall. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

BACKGROUND Endoscopic ultrasound (EUS) is a powerful imaging modality to identify and determine the extent of a lesion. In addition, EUS is superior to a computed tomography scan in detecting lesions < 3 cm. The objective of the current study was to determine whether small lesions (≤ 25 mm) affected the specimen adequacy and the diagnostic accuracy for lesions aspirated under EUS guidance. METHODS In the current study, 209 consecutive EUS-guided fine-needle aspiration biopsy (EUS-FNAB) samples ≤ 25 mm (100 samples) or > 25 mm (109 samples) as determined by EUS were obtained from 151 patients with a mean age of 62 years (range, 39–94 years). A cytopathologist present in the endoscopy suite determined specimen adequacy. Yield of adequate samples for diagnosis, number of passes, and operating characteristics of EUS-FNAB for small (≤ 25 mm) and large lesions (>25 mm) were compared. RESULTS The overall yield of obtaining adequate samples for diagnosis was 96% (201 of 209). There was no difference noted with regard to the yield of obtaining samples (96% vs. 96%) from small or large lesions. A mean of 2.5 passes (range, 1–9 passes) was needed to obtain adequate samples from lesions ≤ 25 mm, whereas a mean of 4.5 passes (range, 1–11 passes) was needed to obtain adequate samples from lesions > 25 mm. The sensitivity (96% vs. 96%), specificity (100% vs. 100%), and diagnostic accuracy (98% vs. 97%) for EUS-FNAB were comparable whether the lesion was ≤ 25 mm or > 25 mm. CONCLUSIONS EUS-FNAB was a highly effective technique to obtain samples from small (≤ 25 mm) and large (> 25 mm) lesions without affecting the sensitivity, specificity, or diagnostic accuracy. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

BACKGROUND Mucins are high molecular weight glycoproteins that are produced by various epithelial cells including those found in the pancreas. MUC1 and MUC2 are two well characterized mucin antigens. The objective of the current study was to examine the pattern of phenotypic expression of MUC1 and MUC2 in pancreatic lesions obtained by fine-needle aspiration biopsy (FNA) and to determine the utility of MUC1 and MUC2 as markers for pancreatic ductal carcinoma. METHODS Thirty-nine cell blocks of pancreatic FNA obtained under endoscopic ultrasound guidance were retrieved from the archives and immunostained with a monoclonal antibody directed against MUC1 and MUC2. These cell blocks were taken from 39 patients (16 females and 23 males) who had a median age of 64 years. Eleven FNAs were taken from patients with reactive/inflammatory conditions. The remaining 28 FNAs included 24 ductal carcinomas, 2 neuroendocrine tumors, 1 lymphoma sample, and 1 sarcoma sample. The presence of immunoreactivity, irrespective of the level of intensity or the percentage of cells, was considered as positive for MUC1 and MUC2 expression. Follow-up included correlation with pathology materials obtained at surgery and review of medical records. RESULTS Twenty-three of 24 pancreatic ductal carcinomas (96%) demonstrated positive staining with MUC1. Twenty-one positive cases demonstrated either apical or diffuse membranous staining with variable cytoplasmic staining. The remaining two positive cases showed only cytoplasmic staining. One of the 11 cases of chronic pancreatitis and benign conditions demonstrated weak apical membranous MUC1 staining in the acinic cells. The difference between the two groups was statistically significant (P < 0.001, using the Fisher exact test). Three pancreatic ductal carcinomas and one chronic pancreatitis specimen demonstrated cytoplasmic staining with MUC2; the difference between the two groups was not found to be statistically significant. None of the nonductal neoplasms demonstrated expression of either MUC1 or MUC2. The sensitivity and specificity of MUC1 as a marker for pancreatic ductal carcinomas were 96% and 94%, respectively. CONCLUSIONS MUC1 is overexpressed in pancreatic ductal carcinoma with a predominantly membranous and variable cytoplasmic staining pattern. The results of the current study suggest that the phenotypic expression of MUC1 can be used as an ancillary marker for diagnosing pancreatic ductal carcinoma in cytologic preparations. Conversely, MUC2 does not appear to be a useful marker for recognizing pancreatic ductal carcinoma in FNA specimens. Cancer (Cancer Cytopathol) 2003;99:365–71. © 2003 American Cancer Society.

Although atypical or suspicious cytology may support a clinical diagnosis of a malignancy, it is often not sufficient for the implementation of therapy in patients with pancreatic carcinoma. Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is a relatively new method for obtaining cytology samples, and one that may decrease the number of atypical/suspicious diagnoses. The goals of the current study were to prospectively evaluate the yield of EUS-FNAB in the diagnosis of patients presenting with solid pancreatic lesions and to evaluate the significance of atypical, suspicious, and false-negative aspirates.All patients who presented with a solid pancreatic lesion and underwent EUS-FNAB over a 13-month period were included in the current study. One endoscopist performed all EUS-FNABs. On-site evaluation of specimen adequacy by a cytopathologist was available for each case. Follow-up included histologic correlation (n = 21) and clinical and/or imaging follow-up (n = 80), including 38 patients who died of the disease.EUS-FNABs were obtained from 101 patients (mean age, 62 +/- 11.8 years; age range, 34-89 years). The male-to-female ratio was 2:1. Sixty-five percent of the lesions were located in the head of the pancreas, 12% were located in the uncinate, 17% were located in the body, and 6% were located in the tail. The mean size of the tumors was 3.3 cm (range, 1.3-7 cm). A median of 4 needle passes were performed (range, 1-11 needle passes). Sixty-two biopsies (61.4%) were interpreted as malignant on cytologic evaluation, 5 (5%) as suspicious for a malignancy, 6 (5.9%) as atypical/indeterminate, and 26 (25.7%) as benign processes. Of the 76 malignant lesions, 71 were adenocarcinomas, 3 were neuroendocrine tumors, 1 was a lymphoma, and 1 was a metastatic renal cell carcinoma. All except one of the suspicious/atypical aspirates were subsequently confirmed to be malignant. Agreement was complete for the atypical cases. Among the suspicious cases, 2 of the 5 were identified as carcinoma by one cytopathologist and as suspicious lesions by the other, yielding a 40% disagreement rate between the 2 cytopathologists. Therefore, for the 10 atypical or suspicious cases that later were confirmed to be malignant, the final diagnosis of malignant disease was not made due to scant cellularity that could be attributed to sampling error in 8 cases and to interpretative disagreement in 2 cases (20%). All four false-negative diagnoses were attributed to sampling error. Two percent of all biopsies were inadequate for interpretation. Of the 99 adequate specimens, 72 yielded true-positive results, 23 yielded true-negative results, and 4 yielded false-negative results. No false-positives were encountered. Therefore, the sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNAB for solid pancreatic masses were 94.7% (95% confidence interval [CI], 89.7-99.8%), 100%, 100%, and 85.2% (95% CI, 71.8-98.6%), respectively.EUS-FNAB is a safe and highly accurate method for tissue diagnosis of patients with solid pancreatic lesions. Patients with suspicious and atypical EUS-FNAB aspirates deserve further clinical evaluation.

BACKGROUND The current TNM classification system does not consider tumor length or the number of lymph nodes in the staging and classification scheme for patients with esophageal carcinoma. Using data from the National Cancer Institute SEER Program, the authors explored the effect of tumor length and number of positive lymph nodes on survival in patients with esophageal carcinoma. METHODS Patients with esophageal adenocarcinoma or squamous cell carcinoma were subgrouped according to historic stage with localized, regional, or distant disease. Demographic factors (age at diagnosis, race, and gender) and tumor characteristics (morphology, histologic grade, tumor length, primary site, depth of invasion, number of positive lymph nodes, proportion of positive lymph nodes dissected, and distant metastatic sites) were examined. RESULTS Overall factors that were associated with an increased mortality risk included increasing age at diagnosis, black race versus white race, histologic grade, primary tumor site in the lower esophagus and abdomen versus upper regions, and increasing depth of invasion. Among patients with regional disease, the number of positive lymph nodes (≥ 5 vs. < 5) was related to an increasing risk (hazard ratio [HR], 1.29; 95% confidence interval [95%CI], 1.06–1.56). The proportion of positive lymph nodes compared with the number of lymph nodes dissected conferred an increased risk (HR, 1.63; 95%CI, 1.26–2.11). Among patients with distant disease, sites other than distant lymph nodes implied an increased mortality risk (HR, 1.37; 95%CI, 1.37–1.65). Tumor length was an independent predictor of mortality when controlling for depth of invasion in patients with localized disease (HR, 1.15; 95%CI, 1.08–1.21). CONCLUSIONS Tumor length, the number of involved lymph nodes, and the ratio of positive lymph nodes are important prognostic factors for survival in patients with esophageal carcinoma. A revised TNM classification system for patients with esophageal carcinoma might consider adding tumor length and number of positive lymph nodes as two important prognostic factors. Cancer 2002;95:1434–43. © 2002 American Cancer Society. DOI 10.1002/cncr.10868

BACKGROUND Endoscopic ultrasound (EUS) provides detailed imaging of both intramural and extramural structures within the abdomen and mediastinum. However, EUS is limited in its ability to differentiate an inflammatory/reactive process from a malignancy. Fine-needle aspiration biopsy (FNAB), coupled with EUS, allows for the sampling of the target lesion under ultrasound guidance in real time. To better evaluate the clinical utility and efficiency of EUS-FNAB, a retrospective analysis of the first 103 EUS-FNABs performed at our institute was undertaken. METHODS EUS-FNABs was performed in 80 patients with 103 lesions. Both air-dried and alcohol-fixed smears were prepared and stained with Diff-Quik (American Scientific Products, McGraw Park, IL) and Papanicolaou stains, respectively. In addition, ThinPrep slides (Cytyc, Boxborough, MA) and cell blocks, when additional material was available, were also prepared. Immunohistochemical stains were performed on cell blocks wherever required. Cytologic diagnoses were then correlated with the final diagnoses. The latter was based on histologic examination of biopsies/resected pathology materials (n = 54) and clinical follow up (n = 48). Follow-up information was not available for one lesion. RESULTS Of 103 EUS-FNABs, 42 FNABs were from the pancreas, 38 from the lymph nodes (10 mediastinal and 28 intraabdominal), 10 from the gastrointestinal tract, 7 from the liver, 4 from the adrenal gland, 1 from the biliary tract, and 1 from a retroperitoneal mass. The mean number of passes to obtain diagnostic materials was 3.3. Of 103 EUS-FNABs, 45, 9, 6, and 37 were reported as malignant, suspicious, atypical, and benign, respectively. Six FNABs were nondiagnostic. The authors did not encounter any false-positive cases. There were three false-negative cases (two pancreatic carcinomas and one gastrointestinal stromal tumor of the stomach). No complications were encountered. The sensitivity, specificity, and accuracy were 71%, 100%, and 81%, respectively. If the FNABs that were classified as suspicious were considered as malignant, the sensitivity, specificity, and accuracy were 86%, 100%, and 91%, respectively. CONCLUSIONS EUS-FNAB is a safe and accurate diagnostic procedure for the evaluation of intramural and extramural lesions of the gastrointestinal tract. In the majority of cases, it obviates the need for more invasive diagnostic procedures to obtain a tissue diagnosis. Cancer (Cancer Cytopathol) 2002. © 2002 American Cancer Society. DOI 10.1002/cncr.10714