Molecular analysis of pancreatic cyst fluid

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 ng/mL 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 k‐ras mutation, loss of heterozygosity, and quantity/quality 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.     

Prospective analysis of atypical epithelial cells as a high‐risk cytologic feature for malignancy in pancreatic cysts

BACKGROUND:

Pancreatic cysts are aspirated to assess whether a cyst is mucinous on one hand and malignant on the other. The authors' retrospective data have indicated that high‐grade atypical epithelial cells (AECs) identified on cytology are a high‐risk feature and a better threshold than “positive” for detecting malignancy. The objective of the current study was to assess the accuracy of AECs in predicting malignancy in pancreatic cysts.

METHODS:

Cysts aspirated by endoscopic ultrasound (EUS)‐guided fine‐needle aspiration (EUS‐FNAs) obtained between January 2006 and June 2011 were evaluated. Cytologic, histologic, imaging, and cyst fluid analysis data were recorded. AECs were defined as cells that had an increased nuclear‐to‐cytoplasmic ratio and nuclear hyperchromasia with or without membrane abnormalities and with or without cytoplasmic vacuoles, but of insufficient quality and quantity for a “positive” interpretation. Malignancy included mucinous cysts with high‐grade dysplasia and invasive carcinoma. Performance characteristics of cytology with AECs or worse (high‐grade atypia [HGA]) for predicting malignancy were assessed.

RESULTS:

There were 70 FNAs that had histologic confirmation from 404 EUS‐FNAs in 352 patients. Excluding 4 nondiagnostic FNAs, the study cohort consisted of 66 FNAs for analysis. There were 24 malignant cysts with 20 true‐positive, 4 false‐negative, 36 true‐negative, and 6 false‐positive results. For the detection of malignancy, HGA had 83% sensitivity, 86% specificity, a positive predictive value of 77%, a negative predictive value of 90%, and 85% overall accuracy. The lower threshold for malignancy with AECs resulted in a 12% increase in the detection of malignancy.

CONCLUSIONS:

A finding of AECs on cytology is a high‐risk feature for malignancy and is an accurate triage threshold for resection. Cancer (Cancer Cytopathol) 2013;121:29–36 © 2012 American Cancer Society.     

Human pancreatic cancer fusion 2 (HPC2) 1‐B3: A novel monoclonal antibody to screen for pancreatic ductal dysplasia

BACKGROUND.

Pancreatic ductal adenocarcinoma is rarely detected early enough for patients to be cured. The objective of the authors was to develop a monoclonal antibody to distinguish adenocarcinoma and precancerous intraductal papillary mucinous neoplasia (IPMN) from benign epithelium.

METHODS.

Mice were immunized with human pancreatic adenocarcinoma cells and monoclonal antibodies were screened against a panel of archived pancreatic tissue sections, including pancreatitis (23 cases), grade 1 IPMN (16 cases), grade 2 IPMN (9 cases), grade 3 IPMN (13 cases), and various grades of adenocarcinoma (17 cases). One monoclonal antibody, human pancreatic cancer fusion 2 (HPC2) 1‐B3, which specifically immunostained adenocarcinoma and all grades of IPMN, was isolated. Subsequently, HPC2 1‐B3 was evaluated in a retrospective series of 31 fine‐needle aspiration (FNA) biopsies from clinically suspicious pancreatic lesions that had long‐term clinical follow‐up.

RESULTS.

HPC2 1‐B3 was negative in all 31 cases of chronic pancreatitis that were tested. In contrast, HPC2 1‐B3 immunostained the cytoplasm and luminal surface of all 16 well‐ to moderately differentiated pancreatic ductal adenocarcinomas. It demonstrated only weak focal staining of poorly differentiated carcinomas. All high‐grade IPMNs were found to be positive for HPC2 1‐B3. The majority of low‐grade to intermediate‐grade IPMNs were positive (66% of cases). Immunostaining a separate series of pancreatic FNA cell blocks for HPC2 1‐B3 demonstrated that the relative risk for detecting at least low‐grade dysplasia (2.0 [95% confidence interval, 1.23‐3.26]) was statistically significant (P = .002 by the Fisher exact test).

CONCLUSIONS.

To reduce the mortality of pancreatic cancer, more effective early screening methods are necessary. The data from the current study indicate that a novel monoclonal antibody, HPC2 1‐B3, may facilitate the diagnosis of early pancreatic dysplasia. Cancer (Cancer Cytopathol) 2013;121:37–46 © 2012 American Cancer Society.     

Main-duct intraductal papillary mucinous adenoma of the pancreas with a large mural nodule

Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized entity representing a spectrum of benign and malignant neoplasms of the pancreas. Preoperative distinction between benign and malignant IPMNs remains difficult. Reported predictive factors for malignancy are size of the main pancreatic duct, cystic neoplasm, and mural nodule. We report herein the case of a 50-year-old woman in whom a large mural nodule (30 mm) in the dilated main pancreatic duct (16 mm in diameter) was detected by ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography. Because the large mural nodule and dilatation of the main pancreatic duct were also detected by endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS), the main-duct IPMN was considered to have malignant potential. Thus, pylorus-preserving pancreaticoduodenectomy with lymph node dissection was performed. The resected intraductal tumor appeared polypoid with a broad stalk and comprised a proliferation of mucin-containing columnar epithelial cells with papillary structures without malignant features. The final diagnosis was intraductal papillary mucinous adenoma of the pancreas. The size of the mural nodule and the final diagnosis in this case suggest that the introduction of a novel molecular-biological approach might be necessary for the precise preoperative diagnosis of main-duct IPMN and adequate surgical treatment.     

Pseudocyst of the pancreas

BACKGROUND:

Currently, the preoperative diagnosis of a pancreatic cyst is based on clinical and imaging findings, frequently in conjunction with chemical analysis of cyst fluid and cytologic evaluation. The purpose of these diagnostic tests is to distinguish benign from malignant cysts of the pancreas. Accordingly, it is imperative to distinguish pancreatic pseudocysts from their mimics. In this study, the authors explored the cytomorphologic features of pseudocyst of the pancreas and evaluated the role of Alcian blue and mucicarmine stains in the cytologic evaluation of pancreatic cysts.

METHODS:

Forty‐two patients were identified who had an eventual diagnosis of pancreatic pseudocyst and had an endoscopic ultrasound‐guided fine‐needle aspirate available. Clinical and imaging findings and chemical analyses of cyst fluid were recorded. The cytologic preparations were evaluated for gastrointestinal contamination, inflammatory cells, mucin, and pigmented material. The cytomorphologic features of 110 neoplastic mucinous cysts (intraductal papillary‐mucinous neoplasms/mucinous cystic neoplasms of the pancreas) were evaluated and compared with the pseudocysts.

RESULTS:

The majority of patients (95%) had a prior episode of pancreatitis. On imaging, the pseudocysts were unilocular (92%). In 69% of cases, the endosonographic diagnosis was that of a pseudocyst. The mean carcinoembryonic antigen level was 41 ng/mL. In contrast, the cytopathologist rendered a definitive diagnosis of pseudocyst in only 10% of cases. The majority of smears (75%) revealed neutrophils and/or histiocytes. Atypical epithelial clusters were identified in 3 cases, 1 of which was diagnosed as suspicious for carcinoma. Yellow pigmented material, which was identified in 13 pseudocysts (31%), was not observed in neoplastic mucinous cysts. Alcian blue‐ and mucicarmine‐positive material was identified in 64% and 40% of pseudocysts, respectively, and in 57% and 38% of neoplastic mucinous cysts, respectively.

CONCLUSIONS:

The diagnosis of a pseudocyst depended primarily on clinical and imaging findings and on chemical analysis of cyst fluid. The cytologic features frequently were nonspecific. The presence of yellow pigmented material served as a surrogate marker of a pseudocyst. Special stains for mucin did not distinguish pseudocysts from neoplastic mucinous cysts. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Validation of the clinical utility of 4 guidelines in the initial triage of mucinous cystic lesions of the pancreas based on cross-sectional imaging: Experience with 188 surgically-treated patients

IntroductionOver the years, several guidelines have been introduced to guide management of mucinous pancreatic cystic neoplasms (mPCN). In this study, we aimed to evaluate and compare the clinically utility of the Sendai-06, Fukuoka-12, Fukuoka-17 and European-18 guidelines in predicting malignancy of mPCN.MethodsOne hundred and eighty-eight patients with mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasm (IPMN) who underwent surgery were retrospectively reviewed and classified under the 4 guidelines. Malignancy was defined as high grade dysplasia and invasive carcinoma.ResultsRaised CA19-9>37U/ml, enhancing mural nodule≥5 mm and main pancreatic duct≥10 mm were significantly associated with malignancy on multivariate analysis. Increasing number of high risk features, absolute indications (European-18), worrisome risk or relative indications (European-18) were significantly associated with an increased likelihood of malignancy. The positive predictive values (PPV) of high risk features for Sendai-06, Fukuoka-12, Fukuoka-17 and absolute indications (European-18) for malignancy were 53%, 76%, 78% and 78% respectively. The negative predictive values (NPV) of the Sendai-06, Fukuoka-12 and Fukuoka-17 were 100%, while that of the European-18 was 92%. Risk of malignancy for patients with ≥4 worrisome features (Fukuoka-17) and ≥3 relative indications (European-18) was 66.7% and 75.0% respectively.ConclusionsAll 4 guidelines studied were useful in the initial triage of mPCN for the risk stratification of malignancy. The Fukuoka-17 had the highest PPV and NPV.     

Diagnostic value of K-ras mutation analysis for pancreaticobiliary cytology specimens with indeterminate diagnosis

BACKGROUND:

Fine‐needle aspiration and bile duct brushing cytology have been traditionally used for early detection of pancreaticobiliary malignancy. Quite frequently, the cytological interpretations of these specimens are indeterminate. In this retrospective study, we evaluated the diagnostic value of detecting K‐ras (v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog) mutation in pancreaticobiliary cytology specimens that had equivocal cytological diagnoses.

METHODS:

A total of 129 cases that had indeterminate cytology diagnoses, K‐ras mutational analysis, and histopathological follow‐up were retrieved. The cytological interpretations, histopathological diagnoses, and K‐ras mutation results were reviewed and analyzed.

RESULTS:

Overall, the sensitivity and specificity of K‐ras mutation for detection of pancreaticobiliary malignancy including adenocarcinoma, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm were 57% and 94%, respectively. The positive and negative predictive values of K‐ras mutation for the presence of pancreaticobiliary malignancy were 94% and 60%, respectively.

CONCLUSIONS:

The results demonstrate that K‐ras mutation has a high predictive value for malignancy in patients with indeterminate pancreaticobiliary cytology and should be included as an important adjuvant diagnostic marker. It should be noted that a negative K‐ras mutation result does not rule out malignancy, and K‐ras mutation can be detected, although infrequently, in morphologically benign conditions. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.     

Predictors of malignancy in thyroid fine‐needle aspirates “cyst fluid only” cases

BACKGROUND:

A recent consensus conference on thyroid fine‐needle aspiration (FNA) cytology concluded that specimens with abundant histiocytes and few or no follicular cells should be interpreted as “cyst fluid only,” under the category of “nondiagnostic.” The purpose of the current study was to identify any cytomorphologic characteristics in this type of specimen that are predictive of an underlying malignancy.

METHODS:

Thyroid FNA cases with a report of cyst fluid only and a follow‐up thyroidectomy specimen were identified during a 3‐year period. A blinded retrospective review of 6 morphologic features in the thyroid FNA specimens was conducted. These review findings were then correlated with the histopathologic diagnosis (benign or malignant).

RESULTS:

Of the 76 cyst fluid only cases with subsequent thyroidectomy, 10 cases had an ipsilateral diagnosis of papillary carcinoma measuring ≥1.0 cm. There was no association found between the number or amount of acute inflammatory cells, blood, colloid, macrophages, and pigmented macrophages and the histologic outcome. In only 4 of the 10 cases with a malignant outcome was the specimen assessed as being truly inadequate on retrospective review, and in 1 of these cases, the cytology was suggestive of malignancy.

CONCLUSIONS:

The only cytomorphologic characteristic found to be predictive of subsequent malignancy in cyst fluid only cases was the presence of follicular epithelium with atypical or suspicious features. Therefore, cases containing atypical epithelial cells should not be categorized as nondiagnostic or cyst fluid only, but rather diagnosed as atypical or suspicious. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Adjuvant chemotherapy seems beneficial for invasive intraductal papillary mucinous neoplasms

Aims

The incidence of intraductal papillary mucinous neoplasm (IPMN) is rising and these neoplasms now represent up to 25% of resected pancreatic neoplasms. The optimal postoperative management of resected invasive IPMN is still debated in the absence of large prospective clinical trials and of validated prognostic factors in this setting. The objective of our study was to identify potential prognostic factors and to investigate the role of adjuvant therapies for patients radically resected for invasive IPMN.

Methods

We retrospectively reviewed clinical and pathological data regarding a large series of patients with invasive IPMN who underwent surgical resection in the last six years at University Hospital of Pisa.

Results

Sixty-four patients were considered for the analysis, thirty-three of whom received adjuvant chemotherapy with gemcitabine. In our series node involvement and high tumoral grade emerged as the major pathologic prognostic factors. Patients treated with adjuvant chemotherapy with gemcitabine experienced a longer disease-free survival than those who received surgery alone.

Conclusions

Gemcitabine-based chemotherapy seems beneficial as adjuvant treatment for patients with resected invasive IPMN.     

Cyst fluid metabolites distinguish malignant from benign pancreatic cysts

OBJECTIVESCurrent standard of care imaging, cytology, or cystic fluid analysis cannot reliably differentiate malignant from benign pancreatic cystic neoplasms. This study sought to determine if the metabolic profile of cystic fluid could distinguish benign and malignant lesions, as well as mucinous and non-mucinous lesions.MethodsMetabolic profiling by untargeted mass spectrometry and quantitative nuclear magnetic resonance was performed in 24 pancreatic cyst fluid from surgically resected samples with pathological diagnoses and clinicopathological correlation.Results(Iso)-butyrylcarnitine distinguished malignant from benign pancreatic cysts, with a diagnostic accuracy of 89%. (Iso)-butyrylcarnitine was 28-fold more abundant in malignant cyst fluid compared with benign cyst fluid (P=.048). Furthermore, 5-oxoproline (P=.01) differentiated mucinous from non-mucinous cysts with a diagnostic accuracy of 90%, better than glucose (82% accuracy), a previously described metabolite that distinguishes mucinous from non-mucinous cysts. Combined analysis of glucose and 5-oxoproline did not improve the diagnostic accuracy. In comparison, standard of care cyst fluid carcinoembryonic antigen (CEA) and cytology had a diagnostic accuracy of 40% and 60% respectively for mucinous cysts. (Iso)-butyrylcarnitine and 5-oxoproline correlated with cyst fluid CEA levels (P<.0001 and P<.05 respectively). For diagnosing malignant pancreatic cysts, the diagnostic accuracies of cyst size > 3 cm, ≥ 1 high-risk features, cyst fluid CEA, and cytology are 38%, 75%, 80%, and 75%, respectively.Conclusions(Iso)-butyrylcarnitine has potential clinical application for accurately distinguishing malignant from benign pancreatic cysts, and 5-oxoproline for distinguishing mucinous from non-mucinous cysts.     

Optimizing the multimodal approach to pancreatic cyst fluid diagnosis

BACKGROUND

The objective of this study was to develop a triage algorithm to optimize diagnostic yield from cytology, carcinoembryonic antigen (CEA), and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) testing on different components of a single pancreatic cyst fluid specimen. The authors also sought to determine whether cell block supernatant was suitable for CEA and KRAS testing.

METHODS

Fifty‐four pancreatic cysts were triaged according to a volume‐dependent protocol to generate fluid (neat and supernatant) and cell block specimens for cytology, comparative CEA, and KRAS testing. Follow‐up histology, diagnostic cytology, or a combined clinicopathologic interpretation was recorded as the final diagnosis.

RESULTS

There were 26 mucinous cystic lesions and 28 nonmucinous cystic lesions with volumes ranging from 0.3 mL to 55 mL. Testing different components of the specimens (cell block, neat, and/or supernatant) enabled all laboratory investigations to be performed on 50 of 54 cyst fluids (92.6%). Interpretive concordance was observed in 17 of 17 cases (100%) and in 35 of 40 cases (87.5%) that had multiple components tested for CEA and KRAS mutations, respectively. An elevated CEA level (>192 ng/mL) was the most sensitive test for the detection of a mucinous cystic lesion (62.5%) versus KRAS mutation (56%) and “positive” cytology (61.5%). KRAS mutations were identified in 2 of 25 mucinous cystic lesions (8%) in which cytology and CEA levels were not contributory.

CONCLUSIONS

A volume‐based protocol using different components of the specimen was able to optimize diagnostic yield in pancreatic cyst fluids. KRAS mutation testing increased diagnostic yield when combined with cytology and CEA analysis. The current results demonstrated that supernatant is comparable to neat fluid and cell block material for CEA and KRAS testing. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

Intraductal papillary mucinous neoplasm of the pancreas rapidly xenografts in chicken eggs and predicts aggressiveness

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has a high risk of progressing to invasive pancreatic ductal adenocarcinoma (PDA), but experimental models for IPMN are largely missing. New experimental systems for the molecular characterization of IPMN and for personalized prognosis and treatment options for IPMN are urgently needed. We analyzed the potential use of fertilized chicken eggs for the culture of freshly resected IPMN tissue. We transplanted 49 freshly resected IPMN tissues into eggs and compared the growth characteristics to IPMN tissues transplanted into mice; this was followed by an analysis of histology, morphology, and marker expression. Of the IPMN tissues transplanted into eggs, 63% formed tumor xenografts within 4 days, while none of the 12 IPMN tissues transplanted into immunodeficient mice engrafted. In the eggs, the grafting efficiency of high‐grade (n = 14) and intermediate‐grade (n = 17) dysplasia was 77% and was significantly higher than the 39% grafting efficiency of low‐grade dysplasia (n = 18). According to mucinous expression, 46 IPMN tissues were classified into gastric (n = 6), intestinal (n = 3), oncocytic (n = 23), and pancreatobiliary (n = 14) subtypes. The grafting efficiency was highest for the pancreatobiliary subtype (86%), followed by the oncocytic (70%), gastric (33%) and intestinal (33%) subtypes. The morphology and expression patterns of mucins, progression markers and pancreatic ductal markers were comparable between the primary IPMN tissues and their xenograft copies. The individual tumor environment was largely maintained during subtransplantation, as evaluated upon passage 6. This new IPMN model may facilitate experimental studies and treatment decisions for the optimal personalized management of IPMN.     

胰腺囊性肿瘤222例临床诊治分析

目的 总结本中心收治的胰腺囊性肿瘤（PCN）的诊治情况及预后,为PCN的临床处理提供一定依据。方法 回顾性分析2005年1月至2016年10月南京鼓楼医院收治的PCN病例,分析各类PCN的临床特征、超声内镜下表现、治疗方式及预后情况。结果 本研究共纳入222例PCN病例,包括94例导管内乳头状黏液瘤（IPMN）,58例黏液性囊性肿瘤（MCN）,43例浆液性囊性肿瘤（SCN）及27例实性假乳头状肿瘤（SPN）。各型PCN患者的男女比例1∶1.55,平均年龄为（56.0±15.7）岁,大部分PCN患者（64.0％,142／222）在就诊时有临床表现,其中以腹痛最常见（47.3％,105／222）。各型PCN术后病理提示分别有7例IPMN（16.3％,7／43）和5例MCN（9.1％,5／55）为恶性（伴浸润性癌或重度异型增生）,而SCN和SPN术后病理均为良性（P=0.027）。未手术的PCN患者中,分别有4例IPMN（8.3％,4／48）和2例SPN（66.7％,2／3）在随访过程中发生癌变。获随访的188例PCN患者的5年生存率为86.0％。124例PCN患者术后的5年生存率为90.0%,SCN、MCN和SPN的术后5年生存率分别为100.0％、92.1％和938％,而IPMN仅为74.0％,差异有统计学意义（P=0.003）。结论 PCN好发于中年女性,大部分患者就诊时有临床症状,最常表现为腹痛。MCN、IPMN和SPN具有恶变倾向,应在符合手术条件的情况下行手术切除;而SCN则可采取保守治疗。各类PCN预后差异显著,IPMN预后最差,MCN、SCN及SPN术后预后均较好。     

Pathological features and diagnosis of intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a noninvasive epithelial neoplasm of mucin-producing cells arising in the main duct (MD) and/or branch ducts (BD) of the pancreas. Involved ducts are dilated and filled with neoplastic papillae and mucus in variable intensity. IPMN lacks ovarian-type stroma, unlike mucinous cystic neoplasm, and is defined as a grossly visible entity (≥ 5 mm), unlike pancreatic intraepithelial neoplasm. With the use of high-resolution imaging techniques, very small IPMNs are increasingly being identified. Most IPMNs are solitary and located in the pancreatic head, although 20%-40% are multifocal. Macroscopic classification in MD type, BD type and mixed or combined type reflects biological differences with important prognostic and preoperative clinical management implications. Based on cytoarchitectural atypia, IPMN is classified into low-grade, intermediate-grade and high-grade dysplasia. Based on histological features and mucin (MUC) immunophenotype, IPMNs are classified into gastric, intestinal, pancreatobiliary and oncocytic types. These different phenotypes can be observed together, with the IPMN classified according to the predominant type. Two pathways have been suggested: gastric phenotype corresponds to less aggressive uncommitted cells (MUC1 -, MUC2 -, MUC5AC +, MUC6 +) with the capacity to evolve to intestinal phenotype (intestinal pathway) (MUC1 -, MUC2 +, MUC5AC +, MUC6 - or weak +) or pancreatobiliary /oncocytic phenotypes (pyloropancreatic pathway) (MUC1 +, MUC 2-, MUC5AC +, MUC 6 +) becoming more aggressive. Prognosis of IPMN is excellent but critically worsens when invasive carcinoma arises (about 40% of IPMNs), except in some cases of minimal invasion. The clinical challenge is to establish which IPMNs should be removed because of their higher risk of developing invasive cancer. Once resected, they must be extensively sampled or, much better, submitted in its entirety for microscopic study to completely rule out associated invasive carcinoma.     

Fine‐needle aspiration of thyroid nodules: A study of 4703 patients with histologic and clinical correlations

BACKGROUND.

The Papanicolaou Society of Cytopathology recently proposed 6 diagnostic categories for the classification of thyroid fine‐needle aspiration (FNA) cytology. Using these categories, the experience with FNA from 2 institutions was studied with emphasis on cytologic‐histologic correlation, source of errors, and clinical management.

METHODS.

Patient cytology data were retrieved by a retrospective search of thyroid FNA in the institutional databases. Cytologic diagnoses were classified as unsatisfactory, benign, atypical cellular lesion (ACL), follicular neoplasm (FN), suspicious for malignancy, and positive for malignancy. Samples with a histologic discrepancy were re‐evaluated, and clinical follow‐up information was recorded.

RESULTS.

Of of 4703 FNA samples, 10.4% were classified as unsatisfactory, 64.6% were classified as benign, 3.2% were classified as ACL, 11.6% were classified as FN, 2.6% were classified as suspicious, and 7.6% were classified as malignant. Five hundred twelve patients had at least 1 repeat FNA, mainly for results in the unsatisfactory and ACL categories. One thousand fifty‐two patients had surgical follow‐up, including 14.9% of patients with unsatisfactory FNA results, 9.8% of patients with benign results, 40.6% of patients with ACL results, 63.1% of patients with FN results, 86.1% of patients with suspicious results, and 79.3% of patients with malignant results. The rates for histologically confirmed malignancy in these categories were 10.9%, 7.3%, 13.5%, 32.2%, 64.7%, and 98.6%, respectively. The cytologic‐histologic diagnostic discrepancy rate was 15.3%. Sources of errors included diagnoses on inadequate specimens, sample errors, and overlapping cytologic features between hyperplastic nodules and follicular adenoma. The sensitivity and specificity of thyroid FNA for the diagnosis of malignancy were 94% and 98.5%, respectively.

CONCLUSIONS.

The current results indicated that FNA provides an accurate diagnosis of thyroid malignancy. The 6 diagnostic categories were beneficial for triaging patients for either clinical follow‐up or surgical management. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.     

Correlation between hybrid capture II high‐risk human papillomavirus DNA test chemiluminescence intensity from cervical samples with follow‐up histologic results

BACKGROUND:

The Hybrid Capture II high‐risk human papillomavirus (hrHPV) DNA test is a US Food and Drug Administration‐approved nucleic acid hybridization assay using chemiluminescence for the semiquantitative detection of hrHPV in cervical samples. Patient samples and controls are used to calculate results as negative for hrHPV if <1.0, positive for hrHPV if >2.5, and “equivocal” if between 1.0 and 2.5.

METHODS:

The authors reported on the cervical histologic results of 209 patients demonstrating “equivocal” results for hrHPV from SurePath (204 patients) or ThinPrep (5 patients) vials, and compared patients in this cohort with atypical squamous cells of undetermined significance (ASC‐US) cytology on the index cervical Papanicolaou (Pap) test (Group 1; n = 148 patients) with a patient cohort demonstrating unequivocal positive hrHPV test results (Group 2; n = 148 patients). The chemiluminescence intensity of hrHPV tests from patients in Group 2 were correlated with the presence and severity of dysplasia on subsequent histologic results, and patients were thereby stratified for their subsequent risk of cervical intraepithelial neoplasia (CIN) types II/III.

RESULTS:

Approximately 97% of hrHPV tests demonstrating “equivocal” results were found to be positive at the time of retesting, and 15% of biopsied cases demonstrated CIN II or III. Results of follow‐up histology after an ASC‐US diagnosis, expressed as a percentage of the biopsied cohort, were: CIN II/III: 16.5% in Group 1 and 22.4% in Group 2; CIN I: 27% in Group 1 and 23.5% in Group 2; and negative: 56.5% in Group 1 and 54.1% in Group 2. Chemiluminescence intensity did not appear to be correlated with the severity of dysplasia.

CONCLUSIONS:

The percentage of high‐grade CIN in the “equivocal” hrHPV cohort is highly significant and therefore the management of these patients should be similar to the unequivocally positive population. After an unequivocal positive hrHPV test, the hrHPV chemiluminescence intensity does not appear to further predict the rate of high‐grade CIN. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

NA cohort study of thyroid cancer and other thyroid diseases after the Chernobyl accident

BACKGROUND:

The Ukrainian American Cohort Study was established to evaluate the risk of thyroid disorders in a group exposed as children and adolescents to ¹³¹I by the Chernobyl accident (arithmetic mean thyroid dose, 0.79 grays). Individuals are screened by palpation and ultrasound and are referred to surgery according to fine‐needle aspiration biopsy (FNA). However, the accuracy of FNA cytology for detecting histopathologically confirmed malignancy after this level of internal exposure to radioiodines is unknown.

METHODS:

During the first screening cycle (1998‐2000), 13,243 individuals were examined, 356 individuals with thyroid nodules were referred for FNA, 288 individuals completed the procedure, 85 individuals were referred to surgery, 82 individuals underwent surgery, and preoperative cytology was available for review in 78 individuals. Cytologic interpretation for the nodule that resulted in surgical referral was correlated with final pathomorphology; discrepancies were reviewed retrospectively; and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FNA cytology were calculated.

RESULTS:

All 24 cytologic interpretations that were definite for papillary thyroid cancer (PTC) were confirmed histopathologically (PPV, 100%); and, of 11 cytologic interpretations that were suspicious for PTC, 10 were confirmed (PPV, 90.9%). Ten of 41 FNAs that were interpreted as either definite or suspect for follicular neoplasm were confirmed as malignant (PPV, 24.4%), including 2 follicular thyroid cancers and 8 PTCs (all but 1 of the follicular or mixed subtypes). Depending on whether a cytologic interpretation of follicular neoplasm was considered “positive” or “negative,” the sensitivity was 100% and 77.3%, respectively; similarly, the respective specificity was 17.6% and 97.1%, the respective PPV was 61.1% and 97.1%, and the respective NPV was 100% and 76.7%.

CONCLUSIONS:

Among children and adolescents who were exposed to ¹³¹I after the Chernobyl accident and were evaluated 12 to 14 years later, thyroid cytology had a sensitivity and a predictive value similar to those reported in unexposed populations. Cancer (Cancer Cytopathol) 2009. Published 2009 by the American Cancer Society.     

Intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND/AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are neoplasms of the pancreatic duct epithelium characterized by intraductal papillary growth and thick mucin secretion. Quantities of mucin fill the main and/or branches of pancreatic ducts and cause ductal dilatation. This review encompasses IPMNs, including symptoms, diagnosis, management, and prognosis. METHODS: A Pubmed database search was performed. All abstracts were reviewed and all articles in which cases of IPMNs could be identified were further scrutinized. Further references were extracted by cross-referencing. RESULTS: Only one-third of all patients are symptomatic. According to the site of involvement, IPMNs are classified into three types: main duct type, branch duct type, and combined type. Most branch type IPMNs are benign, while the other two types are frequently malignant. The presence of large mural nodules increases the possibility of malignancy in all types. Presence of a large branch type IPMN and marked dilatation of the main duct indicate the existence of adenoma at least. Synchronous or metachronous malignancies may be developed in various organs. Endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, and intraductal ultrasonography clearly demonstrate ductal dilatation and mural nodules, while magnetic resonance pancreatography best visualizes the entire outline of IPMNs. CONCLUSIONS: Prognosis is excellent after complete resection of benign and non-invasive malignant IPMNs. The extent of pancreatic resection and the intraoperative management of resection margins remain controversial. Total pancreatectomy should be reserved for patients with resectable but extensive IPMNs involving the whole pancreas; its benefits, however, must be balanced against operative and postoperative risks. Regular monitoring for disease recurrence is important after surgery.