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BACKGROUND:The management of patients with pancreatic cysts is based on the preoperative distinction of nonmucinous and mucinous cysts in general and of benign and malignant cysts in particular. An accurate diagnosis is challenging, because endoscopic ultrasound EUS and cyst fluid analysis for carcinoembryonic antigen CEA and cytology have low sensitivity and specificity. Currently, molecular analysis is a commercially available test that promises an accurate diagnosis. The objective of the current study was to correlate a commercially provided molecular diagnosis MDx with a clinical consensus diagnosis CCD in the general categories of malignant, benign mucinous, and benign nonmucinous pancreatic cysts.METHODS:Pancreatic cysts that had aspirated fluid submitted for a commercially available molecular test PathFinderTG were reviewed. The CCD, defined by histology, malignant cytology, or 2 concordant tests such as EUS, cytology, or CEA ≥192 ngmL for mucinous cysts, was categorized as malignant, benign mucinous, or benign nonmucinous cyst in 35 patients. Their MDx, based on the PathFinderTG report, including analysis of krasmutation, loss of heterozygosity, and quantityquality of DNA, also was classified as malignant, benign mucinous, or benign nonmucinous cyst. These 2 diagnoses were compared and correlated.RESULTS:The concordance between CCD and MDx was 5 of 6 83, 13 of 15 87, and 13 of 14 93, respectively, for malignant, benign mucinous, and benign nonmucinous cysts, with an overall Cohen kappa statistic of 0.816. The sensitivity, specificity, and positive predictive value of the MDx were 83, 100, and 100, respectively, for a malignant cyst and 86, 93, and 95, respectively for a benign mucinous cyst.CONCLUSIONS:Molecular analysis of pancreatic cyst fluid adds diagnostic value to the preoperative diagnosis with high sensitivity, specificity, and positive predictive value for the diagnosis of malignant and benign mucinous pancreatic cysts. Cancer Cancer Cytopathol 2009. © 2009 American Cancer Society.

BACKGROUNDExpectant management of serous cystadenoma SCA of the pancreas requires an accurate preoperative diagnosis. Previously published cytologic diagnostic sensitivities have ranged widely, from 10 to 100. In the current study, the authors evaluated the diagnostic sensitivity of endoscopic ultrasound EUSguided fineneedle aspiration biopsy FNAB and crosssectional imaging for SCA.METHODSGroup I consisted of 21 histologically confirmed SCAs. Group II n 7 lesions lacked histologic confirmation and was defined by EUS findings that were consistent with SCA and a cyst fluid carcinoembryonic antigen CEA level <5 ngmL. Group III was comprised of 2 nonserous and potentially malignant cysts of the pancreas for which a preoperative diagnosis of SCA was considered. Crosssectional imaging data were recorded. The smears were evaluated for the presence of serous lining epithelium, gastrointestinalcontaminating epithelium, and inflammatory cells including hemosiderinladen macrophages. The authors also evaluated the presence of hemosiderinladen macrophages in a series of 110 FNA specimens from histologically confirmed neoplastic mucinous cysts of the pancreas and 45 pseudocysts of the pancreas.RESULTSProspectively among Group I lesions, the appearance on computed tomography CT was considered definitive for SCA in 3 of 12 cases 25. The histologically confirmed SCA cases had CEA levels of <5 ngmL, except for 1 case for which the CEA level was 176.5 ngmL. A cytologic diagnosis of SCA was made prospectively in only 1 CTguided case. Retrospectively, 3 intraoperative FNAs and 1 additional CTguided aspirate contained rare epithelial cells of a SCA. None of the EUSguided aspirates demonstrated serous epithelium. Among Group II aspiration specimens, only 1 contained serous epithelial cells. Approximately 52 of the EUSguided aspirates demonstrated gastrointestinal contamination. This glandular epithelium was categorized as atypical in 2 cases. Hemosiderinladen macrophages were identified in 43 of the SCAs. Conversely, only 2 of neoplastic mucinous cysts and 9 of pseudocysts produced hemosiderinladen macrophages in aspirate fluid.CONCLUSIONSIn the current study, serous epithelial cells were identified in <20 of cases. Gastrointestinalcontaminating epithelium, often observed in EUSguided aspirates, further contributes to difficulties in interpretation. The presence of hemosiderinladen macrophages as a surrogate marker for SCA requires further study. A preoperative diagnosis of SCA remains a challenge, and an EUSguided FNAB is unlikely to provide the high level of diagnostic accuracy necessary to permit a nonoperative approach. Cancer Cancer Cytopathol 2008. © 2008 American Cancer Society.

Lesions of the thyroid gland composed of Hurthle cells encompass pathologic entities ranging from hyperplastic nodules with Hurthle cell metaplasia to Hurthle cell carcinomas. The cytologic distinction between these entities can be diagnostically challenging. Many cytologic features of Hurthle cell lesions that distinguish neoplastic Hurthle cell lesions requiring surgery from those that are benign and nonneoplastic have been described, but with variable usefulness. This is due, in part, to the small numbers of cases examined in previous studies and the limited application of statistical analysis. A morphologic study was made of 139 Hurthle cell lesions of the thyroid gland and statistical analysis applied to identify a set of cytomorphologic features that distinguish benign Hurthle cell lesions (BHCL) from Hurthle cell neoplasms (HCN).Fine‐needle aspiration biopsies (FNABs) of thyroid nodules with a predominant Hurthle cell component and corresponding histologic followup were included in the study. Cases were divided into BHCL and HCN groups on the basis of the histologic diagnosis. All cases were reviewed to assess the following 14 cytologic features: overall cellularity, cytoarchitecture, percentage of Hurthle cells, percentage of single cells, percentage of follicular cells observed as naked Hurthle cell nuclei, background colloid, chronic inflammation, cystic change, transgressing blood vessels (TBV), intracytoplasmic lumina, presence of multinucleated Hurthle cells, nuclear to cytoplasmic ratio, nuclear pleomorphism/atypia, and nucleolar prominence. The results were evaluated by using univariate and stepwise logistic regression (SLR) analysis; statistical significance was achieved at P‐values < 0.05.One hundred thirty‐nine FNAB specimens, corresponding to 56 HCN and 83 BHCL, fulfilled the study criteria. Six of the 14 cytologic features evaluated were shown by univariate analysis to be statistically significant in predicting HCN: nonmacrofollicular architecture (P < 0.001), absence of background colloid (P < 0.001), absence of chronic inflammation (P < 0.001), presence of TBV (P < 0.001), > 90% Hurthle cells (P < 0.001), and >10% single Hurthle cells (P = 0.014). The first four of these features were also shown to be statistically significant in the SLR analysis (P = 0.005, 0.010, 0.016, and 0.045, respectively), and when all four of these features were present HCN was correctly identified 86% of the time.In the current study of 139 FNAB specimens of thyroid Hurthle cell nodules, 14 cytologic features were examined and 6 were found to be statistically significant in identifying HCN. The following four features, when found in combination, were found to be highly predictive of HCN: nonmacrofollicular architecture, absence of colloid, absence of inflammation, and presence of TBV. Cancer (Cancer Cytopathol) 2006. © 2006 American Cancer Society.

Anti-hepatocyte antibody, hepatocyte paraffin 1, is a monoclonal antibody that is highly specific for normal and neoplastic hepatocytes and that can differentiate hepatocytic from nonhepatocytic tumors. This marker has been rarely studied in extra-hepatic tumors and to our knowledge has not been investigated in ovarian tumors with hepatoid differentiation. We studied hepatocyte paraffin 1 immunoreactivity in a series of ovarian hepatoid carcinomas, ovarian hepatoid yolk sac tumors (YSTs), and hepatocellular carcinomas metastatic to the ovary to assess the potential utility of hepatocyte paraffin 1 in differential diagnosis. Hepatocyte paraffin 1 positivity was seen in three of seven ovarian hepatoid carcinomas, five of eight hepatoid yolk sac tumors, and six of eight metastatic hepatocellular carcinomas. The extent of positivity ranged from <25 to >50 of the tumor cells. There was strong coarsely granular cytoplasmic staining in all three tumor types without a distinctive staining pattern in any group. The degree of hepatic differentiation correlated with hepatocyte paraffin 1 positivity in the three groups 83 of the well differentiated tumors, 50 of the moderately differentiated tumors, and none of the poorly differentiated tumors were positive. All ovarian hepatoid carcinomas were either immunoreactive for alpha-fetoprotein or had an elevated serum alpha-fetoprotein level; more than half of these tumors were hepatocyte paraffin 1 negative. All but one hepatocyte paraffin 1 negative hepatoid yolk sac tumor and ovarian hepatocellular carcinoma were also negative for alpha-fetoprotein. In conclusion, hepatocyte paraffin 1 is positive in primary ovarian tumors with hepatoid differentiation, with the degree of hepatocyte paraffin 1 positivity correlating with the degree of hepatoid differentiation. Hepatocyte paraffin 1, however, is not useful in distinguishing metastatic hepatocellular carcinoma from primary ovarian hepatoid carcinoma or hepatoid yolk sac tumor.

Adenosquamous carcinoma (ASCa) is a rare subtype of ductal adenocarcinoma of the pancreas with what to the authors' knowledge are limited cytologic descriptions. In the current study, the authors describe their experience with the fine-aspiration biopsy (FNAB) diagnosis of ASCa and characterize cytologic features in 14 cases. Fourteen cases of ASCa were identified from pathology case files. Cytologic material was examined for cellularity, grade, tumor cell necrosis, and specific features of glandular and squamous differentiation. The 10 females and 4 males had an average age of 70 years. Nine patients (64%) were reported to have Stage IV disease at the time of presentation. All tumors were high grade, with moderate to high cellularity. Tumor cell necrosis was noted in 12. Nine of the 14 cases (64%) demonstrated predominantly squamous differentiation with keratinization. Seven of these nine contained at least focal intracellular mucin or honeycombed glandular sheets. Two of the nine had rare cytoplasmic vacuoles as the only evidence of glandular differentiation. Five cases (36%) were predominantly glandular. All but one of these five cases contained atypical to malignant keratinized cells. One of the five cases lacked keratinization but had tumor cells with dense cytoplasm; the diagnosis of ASCa was confirmed on histology. In 13 patients for whom followup was known, 12 had died of disease (mean, 5.6 months) and 1 was alive at 13 months of follow-up. A specific diagnosis of ASCa is possible when aspirates show evidence of both squamous and glandular differentiation, although one component often predominates and features of dual differentiation may be focal. A purely squamous tumor should raise the suspicion of a metastasis, but also may represent undersampling of an ASCa. Cancer (Cancer Cytopathol) 2003;99:372–8. © 2003 American Cancer Society.

The diagnosis of “atypical squamous cells of undetermined significance” (ASCUS) is controversial, not only for the clinical utility of its subcategories (favor reactive vs. favor dysplasia), but for its very existence as an expression of uncertainty. In the current study, the authors investigated the impact of reducing and eliminating this category on the sensitivity and predictive values for detecting squamous intraepithelial lesions (SILs).One hundred cervical Papanicolaou (Pap) smears originally diagnosed as ASCUS, all of which had histologic follow‐up, were reviewed blindly and reclassified as either negative (within normal limits/benign cellular changes), low‐grade SIL (LSIL), or high‐grade SIL (HSIL) by 1 reviewer who eliminated ASCUS as a diagnostic possibility entirely. A second reviewer reinterpreted the cases but attempted to use the ASCUS diagnosis (favor reactive or favor dysplasia) sparingly. All histologic diagnoses were reviewed, and an adjudicated final diagnosis was established. Reviewed smear interpretations were correlated with the histologic diagnosis (original, reviewed, and adjudicated). Statistical analysis was performed using the Fisher exact test.Thirty‐eight women had histologically confirmed SIL (21 LSIL cases and 17 HSIL cases [including 1 case of endocervical adenocarcinoma]); 31 of these 38 cases originally were classified as ASCUS, not otherwise specified, 1 case was classified as ASCUS favor reactive, and 6 cases were classified as ASCUS favor dysplasia. The reviewer who used the ASCUS diagnosis sparingly reclassified the smears as negative (62 cases); ASCUS, favor reactive (3 cases); ASCUS, favor dysplasia (13 cases); LSIL (19 cases); and HSIL (3 cases). The reviewer who eliminated the ASCUS category reclassified the smears as negative (59 cases), LSIL (29 cases), and HSIL (12 cases). The rate of SIL/HSIL in those cases interpreted as abnormal was 38%/17% originally, 42%/24% with a reduced ASCUS interpretation, and 37%/17% when the ASCUS category was eliminated. In those ASCUS smears that were reclassified as negative, the SIL/HSIL rate was 35%/13% with the reduced ASCUS interpretation and 39%/17% when the ASCUS category was eliminated. The sensitivity for detecting a SIL/HSIL was reduced from 100%/100% for the original ASCUS interpretation to 42%/53% for the reduced ASCUS interpretation to 39%/41% with the elimination of the ASCUS interpretation.Although in the current study utilization of the ASCUS diagnosis was found to result in a 62% negative or reactive outcome on biopsy, a significant number of patients with SIL were detected (38% in the current series, 17% with HSIL). Despite the improved correlation with negative biopsies, reducing or eliminating the ASCUS diagnosis appears to decrease the sensitivity of the Pap smear significantly and appears to be no better than chance at predicting a diagnosis of SIL on biopsy, including HSIL. Cancer (Cancer Cytopathol) 2002. © 2002 American Cancer Society.

Biliary duct brushing cytology is the standard of care for the assessment of bile duct strictures but suffers from low sensitivity for the detection of a high-risk stricture. Pathologic diagnosis of strictures is optimized by integration of cytomorphology and molecular analysis with fluorescence in situ hybridization or next-generation sequencing. Bile duct cancers are genetically heterogeneous, requiring analysis of multiple gene panels to increase sensitivity. Using molecular analysis as an ancillary test for bile duct brushing samples aids in the identification of mutations that support the diagnosis of a high-risk stricture as well as the identification of actionable mutations for targeted therapies currently in clinical trials for the treatment of patients with bile duct cancer.

Germ cell tumors (GCTs) and their metastases may be found in numerous sites that are accessible to cytologic sampling, and many are responsive to chemotherapy. The authors reviewed 20 examples of GCT cytology from 16 males and 3 females ranging in age from 1.5 to 61 years (median, 34 years). With two exceptions, one benign cystic ovarian teratoma in which intraoperative cytology was used to diagnose an associated adult-type carcinoma and one undescended testis in which seminoma presented as an abdominal mass, the material reviewed included no examples of primary gonadal GCT. The authors studied 7 primary and 13 metastatic GCTs; these studies were based on 13 in vivo aspirations, 4 intraoperative preparations, and 3 samples of body cavity fluids. All samples were correctly interpreted as malignant, and only one was incorrectly classified as a non-GCT malignancy. Clinical and cytologic findings are useful in the diagnosis of GCTs and their metastases. Incorrect interpretation of these neoplasms as poorly differentiated malignancies of other types may deprive the patient of effective chemotherapy. Air-dried, Romanowsky-stained smear material and cell block sections may contribute to the resolution of diagnostic dilemmas. Cancer (Cancer Cytopathol) 1997; 81:220-7. © 1997 American Cancer Society.

Malignant lymphomas and solid tumors that mimic or are associated with epithelioid granulomas are widely recognized in surgical pathology, but have received little attention in the cytopathology literature. In this study the authors present their experience with six such cases in which the presence of granulomas or granuloma-like features posed a diagnostic difficulty on fine-needle aspiration cytology (FNAC). Clinical data, FNAC, and follow-up surgical specimens from six patients presenting with neck masses were reviewed. Only one case was diagnosed confidently as metastatic squamous cell carcinoma with an extensive granulomatous response; the other five were interpreted as "atypical" with descriptive cytology and a differential diagnoses including granulomatous inflammation, in addition to a caveat of "cannot exclude malignancy." Biopsy studies in these cases were recommended in view of the atypical cytologic findings and strong clinical suspicion of malignancy in each case. The histologic findings in two cases revealed Hodgkin's disease with exuberant granulomatous response. The remaining three cases were found to be malignant neoplasms with epithelioid morphologic features and included one example each of diffuse large cell lymphoma, anaplastic carcinoma of the thyroid, and lymphoepithelial carcinoma. Malignancies associated with granulomas and tumor cells mimicking epithelioid histiocytes may be difficult to diagnose accurately on FNAC. The cytologic differential diagnosis of a "granulomatous" process should include malignant neoplasms. Excisional biopsy studies may be required for definitive diagnosis. Cancer (Cancer Cytopathol) 1998;84:84-91. © 1998 American Cancer Society.

Determining the risk of malignancy in a pancreatic cyst (PC) is a clinical and diagnostic challenge. Das-1 monoclonal antibody (mAb) test was shown to have high sensitivity, specificity, and accuracy in detecting high-risk (HR) cysts. Das-1 mAb test detects HR mucinous cysts with high-grade dysplasia (HGD), invasive carcinoma, and/or intestinal-type epithelium. Correlation of mAb Das-1 testing of PC fluids with cytomorphologic findings has not been evaluated.

Objectives: Endosonographic imaging of the pancreas is a widely accepted method of evaluating patients with suspected pancreatic malignancy. Patients with pancreatic neoplasia often have dilated pancreatic ducts which are easily sampled with FNA facilitated by EUS guidance.We reviewed retrospectively a consecutive series of patients over a 28 months who had EUS guided pancreatic duct aspiration for diagnostic yield, ease of performance, and complications. Methods: All patients who underwent EUS guided FNA of the pancreatic duct from July 1997 to November 1999 were reviewed. Cytologic diagnosis was compared to initial EUS interpretation and final diagnosis (surgical pathology on pancreatic resection or diagnostic FNA of a pancreatic mass). Results: Thirty-three consecutive pancreatic duct FNA's were identified during a 28 month interval. Of these, three aspirates (9%) were deemed unsatisfactory for cytologic analysis. Eight aspirates (24%) were interpreted as negative, five patients were later proven to have adenocarcinoma, and three had chronic pancreatitis. Nine (27%) aspirates were cytologically diagnostic and confirmed the initial EUS findings: six with pancreatic adenocarcinoma and three with IPMT. Thirteen aspirates (39%) were interpreted as indeterminate; 11 of these proved to be associated with pancreatic adenocarcinoma and 2 IPMT's. Nineteen aspirates were obtained from pancreatic mass lesions. Sixteen were diagnostic for adenocarcinoma, 1 unsatisfactory for evaluation and 3 were indeterminate. Six aspirates were obtained from pancreatic mass lesions in patients later proven to have IPMT: 4 were diagnostic, 1 unsatisfactory and 1 indeterminate. All were performed successfully with one pass of a 22 gauge needle through the working channel of the echoendoscope. None of the patients had complications related to the procedure (bleeding, pancreatitis, or infection). Conclusions: Although technically straightforward, safe and specific, EUS-guided FNA of the pancreatic duct is an insensitive test for the presence of malignancy.