Endoscopic ultrasound-guided pancreatic duct aspiration: diagnostic yield and safety.

BACKGROUND AND STUDY AIMS: Endoscopic ultrasound (EUS)-guided fine-needle aspiration provides useful diagnostic material in solid and cystic pancreatic lesions. It is logical that EUS-guided pancreatic duct aspiration may be useful in cases of suspected intraductal or duct-obstructing tumors. We evaluated the safety and efficacy of EUS-guided pancreatic duct aspiration. PATIENTS AND METHODS: Twelve patients with dilated pancreatic ducts underwent EUS-guided duct aspiration. Aspirates were submitted for cytology and mucin staining. Patients were followed for up to 13 months. RESULTS: There were no procedure-related complications. Cytology was diagnostic in nine of the 12 patients (six with intraductal papillary mucinous tumor, one with pancreatic clonorchiasis, and two with obstructing solid pancreatic adenocarcinomas). Cytology in the remaining three patients, all with solid obstructing masses, was nondiagnostic. Overall, the diagnostic yield was 75%; however, the yield was 100% in patients without extrinsic obstruction. CONCLUSION: This preliminary experience suggests that EUS-guided pancreatic duct aspiration is safe and can provide diagnostic material in a significant number of patients with unexplained pancreatic duct dilation.

Transient expression of cyclin D1 is sufficient to promote hepatocyte replication and liver growth in vivo.

Cyclin D1 regulates mitogen-dependent progression through G(1) phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. However, previous studies in cell lines have not demonstrated that cyclin D1 is sufficient to trigger cell replication. In this study, we found that transient transfection of adult hepatocytes with cyclin D1 stimulated assembly of active cyclin D1/cdk4 complexes, robust hepatocyte proliferation, and liver growth in the intact animal. After several days, hepatocyte proliferation was inhibited despite the persistence of high levels of cyclin D1 and cyclin E, suggesting that endogenous antiproliferative mechanisms were induced. Our data suggest that this antiproliferative response includes the marked up-regulation of p21, which in turn inhibits cyclin D1/cdk4 and cyclin E/cdk2 complexes. This study offers further evidence that cyclin D1 plays a pivotal role in the regulation of hepatocyte proliferation in the liver. Furthermore, this model may offer a unique system to study the normal cellular response to cyclin D1 expression in vivo.

Soft tissue masses in patients with multiple myeloma: a fine-needle aspiration study of 30 cases with flow cytometry and clinical correlation.

BACKGROUND: To the authors' knowledge, the prognostic significance of plasma cell cytology in soft tissue (ST) masses from patients with multiple myeloma (MM) is unknown. Myeloma patients usually are monitored by bone marrow (BM) aspirates and biopsies to assess plasma cell differentiation, tumor burden, and response to treatment. Monitoring of ST lesions by fine-needle aspiration (FNA) is not performed routinely. The objective of the current study was to examine ST masses in MM patients using FNA and to classify and determine the prognostic significance of MM in these lesions based on cytologic features. METHODS: FNAs of 30 ST masses from 27 patients with a history of MM were examined for disease involvement. In the patients with MM, the cytologic features were evaluated and the lesions were graded as low grade, intermediate grade, or high grade based on the classification of Bartl et al. for MM in BM specimens. Concurrent BM samples as well as cytogenetic and flow cytometric results also were reviewed. RESULTS: Twenty-seven of the FNA specimens (90%) were positive for MM, and three specimens (10%) were negative (one case each of lipoma, keratinous cyst, and aspergillosis). Among the MM cases, 5 (18.5%) were low grade, 15 (55.6%) were intermediate grade, and 7 (25.9%) were high grade (blastic MM). Simultaneous BM involvement was present in 23.5% of low-grade MM (4 of 17 cases), 35.3% of intermediate-grade MM (6 of 17 cases), and 71% of high-grade MM (5 of 7 cases). Clinically, 10 of 24 patients (42%) died within 9 months (median, 2 months). Patients with high-grade myeloma (blastic MM) in ST masses appeared to have worse survival; 43% (3 of 7 patients) died by a median time of 2 months, compared with 12% of patients with low-grade and intermediate-grade MM (2 of 17 patients). CONCLUSIONS: FNA of ST masses appears to improve the management of MM patients by providing diagnostic material, samples for ancillary studies, and prognostic information. ST MM can be classified reliably into grades of prognostic significance utilizing the classification of Bartl et al. Intermediate-grade MM was the most frequent subtype present in ST masses.

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2.

Cells in culture become competent to replicate in the absence of growth factor after progressing beyond the late G1 restriction point, suggesting that a set of genes expressed during G1 phase is sufficient to trigger completion of the cell cycle. However, this has not been demonstrated in an in vivo system. In this study, we examined whether transfection of genes associated with the G1/S transition could trigger hepatocyte replication. Co-transfection of cyclin E and skp2 synergistically promoted cell cycle progression in cultured primary hepatocytes in the absence of mitogen or in the presence of growth inhibitors. Furthermore, transfection of hepatocytes in vivo with cyclin E and skp2 promoted abundant hepatocyte replication and hyperplasia of the liver. These studies confirm that transfection with a small number of genes can trigger proliferation of quiescent hepatocytes in vivo, and suggest that therapies to enhance liver regeneration by targeting cell cycle control genes may be feasible.

Can fine needle aspiration cytology adequately diagnose and predict the behavior of gastrointestinal stromal tumors?

The use of endoscopic ultrasound-guided fine needle aspiration is expanding rapidly in many centers. This method can be used to produce aspirate specimens from masses in the pancreas, liver, retroperitoneum, adrenals, and mediastinum, as well as mural nodules in the upper gastrointestinal tract. As application of this method continues to grow, it is reasonable to expect that the demand for cytologic diagnosis of gastrointestinal stromal tumors will increase. In this commentary, the cytologic presentation of one such case is offered. This is used to illustrate the clinical, immunohistochemical, and molecular biologic features that are used to suggest the prognosis of a given lesion.

Tissue effects of salivary gland fine-needle aspiration. Does this procedure preclude accurate histologic diagnosis?

Recent reports have alluded to various tissue effects secondary to fine-needle aspiration (FNA), particularly infarction observed in resected salivary gland masses, precluding accurate histologic diagnosis. Our experience with the use of 25-gauge needles indicates otherwise. We retrospectively reviewed 94 resected salivary gland masses previously sampled by FNA, looking for infarction, hemorrhage, needle track tumor seeding, and fibrosis. We assessed the significance of these complications and their impact on the histologic diagnosis. The median interval from FNA to excision was 25 days. Variable degrees of infarction and hemorrhage were present in 7 cases (7%) and 9 cases (10%), respectively. Infarction ranged from 5% to 80% (average, 20%), while hemorrhage averaged less than 20% of the material on the tissue sections. Significant infarction was present in acinic cell carcinomas (3/7), but histologic diagnosis was not compromised, and tissue alterations were absent. We conclude that FNA of salivary gland lesions using 25-gauge needles is safe and does not significantly alter the histologic diagnosis. The tissue effects observed did not preclude accurate diagnostic interpretation in any case.

Quality assurance and risk reduction guidelines.

Cervical cancer continues to be a major cause of death in women worldwide. The major problem facing most women is the unavailability of screening Pap tests in poor and underdeveloped countries. While rates of cancer deaths have decreased 60-80% in developed countries since the Pap test became available, the accuracy of Paps was challenged recently. In order to instill public confidence and promote optimal patient care, measures to improve the quality of the entire screening process should be undertaken. Continuous quality improvement processes are more appropriate than traditional quality assurance monitors. Although no standards can be defined that are applicable to all laboratory settings and nations, this document provides current views on universal quality procedures and risk reduction. Procedure/policy manuals, workload assessment, hierarchic/peer review, discrepancy analysis, rescreening studies and cytohistologic correlation are examples of universally applicable quality tools. The variability in practices in different parts of the world is also discussed.

Cytology of angiosarcoma. Findings in fourteen fine-needle aspiration biopsy specimens and one pleural fluid specimen.

We report the cytologic features of 15 cases of angiosarcoma from various sites and include 14 fine-needle aspiration (FNA) biopsy specimens and 1 pleural fluid specimen. Six were initial diagnoses with histologic confirmation; an additional case in the liver was an initial diagnosis without tissue confirmation. One case represented lymph node metastasis from a primary prostatic epithelioid angiosarcoma. In 10 cases, immunohistochemical staining for factor VIII-related antigen, CD34, CD31, or Ulex europaeus agglutinin I was performed on the cytology or histology specimen. The aspirates varied in cellularity, and the degree of nuclear atypia ranged from relatively bland in a case of low-grade angiosarcoma of the prostate to highly pleomorphic in a lymph node metastasis from a facial cutaneous angiosarcoma. Vasoformative features such as intracellular RBCs, well-formed vessels, attempts at microacinar/lumen formation, and intracytoplasmic lumens were variably present. The background was bloody in all specimens, with necrosis in rare cases. This cytologic series emphasizes that the cytologic features are heterogeneous but that the diagnosis can be suggested by fine-needle aspiration (FNA) when vasoformative features are present. The diagnosis can be made conclusively by FNA with immunocytochemical confirmation of endothelial differentiation.

Current issues in breast cytopathology.

This article explores 3 aspects of breast diagnosis that are currently under investigation and about which our thinking has recently undergone considerable reshaping. The trend toward more frequent evaluation of clinically subtle lesions has suggested that it might be necessary to understand thefine-needle aspiration (FNA) presentation of proliferative breast disease. Efforts to do so, as well as our suggestions for additional studies and their potential limitations open this discussion. Following this section, the increasingly useful method of intraoperative cytology for evaluation of resected breast masses is considered in detail. In the final section, optimization of nonoperative sampling by combination of mammography, ultrasonography, fine-needle aspiration, and core biopsy is discussed and illustrated.

Cost benefit and outcomes analysis for fine-needle aspiration. Why do we know so little?

In many areas of anatomic pathology, there have been little application of health services research methods. Diagnostic fine-needle aspiration has been performed for decades in the United States, but there is still little knowledge of the benefits and limitations of this procedure. This article examines some of the research regarding fine-needle aspiration cytology and hypothesizes why there has been so little evaluation.

Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma.

Loss of expression of the heparan sulfate proteoglycan syndecan-1 leads to reduced cell adhesion, increased invasive potential, and dysregulated growth of mammary epithelial cells in vitro. We compared syndecan-1 expression in malignant and nonmalignant breast tissues using immunohisto-chemistry with monoclonal antibody B-B4. Staining for syndecan-1 is greatly diminished on malignant cells within infiltrating ductal carcinomas (n = 20) as compared with ductal epithelium of both normal breast (n = 14) and stromal-epithelial neoplasms (n = 10), which exhibit extensive basolateral epithelial staining. Surprisingly, comparison of malignant and nonmalignant breast tissue also reveals a striking difference in expression of syndecan-1 within the stromal compartment. In infiltrating ductal carcinomas, strong staining for syndecan-1 is present both within the connective tissue and on stromal cell surfaces, whereas syndecan-1 expression is absent in the stroma of both normal breast and stromal-epithelial neoplasms. Because syndecan-1 interacts with heparin-binding growth factors such as FGF-2, accumulation of syndecan-1 within the tumor stroma may contribute to the extensive angiogenesis and stromal proliferation characteristic of infiltrating breast carcinoma. Moreover, the induction of syndecan-1 within the stroma, coupled with the loss of syndecan-1 on malignant cells, suggests that changes in syndecan-1 expression are critical in promoting the metastatic phenotype of infiltrating ductal carcinoma of the breast.

Are benign cellular changes on a Papanicolaou smear really benign? A prospective cohort study.

OBJECTIVES: To determine the underlying prevalence of cervical intraepithelial neoplasia (CIN) in women with benign cellular changes on a Papanicolaou smear, and to evaluate follow-up strategies to identify women at high risk for serious underlying pathology. METHODS: Nonpregnant women aged 18 to 75 years with benign cellular changes on a Papanicolaou smear were recruited from primary care clinics of an urban teaching hospital. The subjects (N = 132) were tested at baseline for the presence of human papillomavirus using the polymerase chain reaction technique, and underwent repeated cervicovaginal smears at 3, 6, and 9 months. At 12 months colposcopy was performed. The main study outcome was the proportion of subjects with CIN as determined by colposcopic biopsy specimens. We determined the sensitivity, specificity, and predictive values of historical risk factor information, human papillomavirus testing, and repeated cervicovaginal smears for the detection of CIN. RESULTS: Cervical intraepithelial neoplasia was found in 30 of 132 women, of whom 27 (20%) had low-grade CIN (CIN I) and 3 (2%) had high-grade CIN (CIN II). Underlying CIN was significantly more common in women younger than 35 years or who had a history of Trichomonas infection or venereal warts, a positive human papillomavirus test result, or abnormal follow-up smears. However, no follow-up strategy combined high sensitivity with a low referral rate for colposcopy. CONCLUSIONS: The prevalence of underlying high-grade CIN in women with benign cellular changes is low. However, further prospective studies in other settings are needed before routine follow-up can unequivocally be recommended.

Interobserver variability of a Papanicolaou smear diagnosis of atypical glandular cells of undetermined significance.

The interobserver variability of a Papanicolaou smear diagnosis of atypical glandular cells of undetermined significance (AGUS) has not been measured. Four expert cytopathologists retrospectively reclassified 100 smears originally diagnosed as AGUS; on follow-up examination, 54 had a clinically significant lesion and 46 had a benign lesion. The mean sensitivity and specificity of reclassification were 86% and 21%, respectively. The kappa statistic for pairwise cytopathologist comparison varied from 0.16 to 0.27. In 45% of cases the cytopathologists all used different Bethesda System diagnoses, and in no case did all the cytopathologists use the same diagnosis. There was little agreement on which cytologic criteria were important in separating clinically significant and benign lesions. We conclude the following: interobserver agreement in reclassifying AGUS lesions is very poor; the AGUS category is poorly understood, and there is no agreement on diagnostic cytologic criteria; and when reclassifying slides, cytopathologists make a number of false-negative diagnoses.

Aspiration cytology of malignant neoplasms associated with granulomas and granuloma-like features: diagnostic dilemmas.

BACKGROUND: 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). METHODS: Clinical data, FNAC, and follow-up surgical specimens from six patients presenting with neck masses were reviewed. RESULTS: 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. CONCLUSIONS: 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.

Diagnostic value of brush cytology in the diagnosis of duodenal, biliary, and ampullary neoplasms.

Endoscopy is a valuable tool in the diagnosis and management of duodenal lesions and biliary strictures. We assessed the value of cytology in the evaluation of these lesions and analyzed the causes of discrepancy among clinical, histologic, and cytologic parameters. The study included 118 patients with duodenal ulcers, ampullary neoplasms, or biliary strictures who were examined between 1975 and 1995; 120 cytologic examinations were performed. The specimens included brushings of the duodenum (DB, n = 50), ampulla (AB, n = 32), and biliary ducts (BB, n = 38). Endoscopic biopsies performed concurrently included the duodenum (n = 37), the ampulla (n = 22), and the biliary ducts (n = 23). Comparison of cytologic and histologic results showed the following sensitivity and specificity: DB, 40% and 97%, respectively; AB, 100% each; BB, 75% and 93%, respectively. The DB, AB, and BB revealed malignant neoplasms in 2 of 5, 7 of 7, and 6 of 8 cases, respectively. Twenty-three duodenal neoplasms were diagnosed by either modality and included 11 adenocarcinomas, 9 villous tumors, 2 metastatic renal cell carcinomas, and 1 large cell non-Hodgkin's lymphoma. Endoscopic brush cytology is an effective means of diagnosing ampullary neoplasms, and it complements tissue biopsy in cases of bile duct stricture. Location, predominance of tumor-induced stroma, an extramucosal growth pattern, sampling error, and interpretative experience influence the diagnostic evaluation. Cytologic diagnosis of an adenoma does not exclude an underlying malignant neoplasm in ampullary tumors. In some instances, it may be difficult to distinguish between villous tumors with severe dysplasia and adenocarcinomas by cytology alone.

Urine cytology of primary and secondary urinary bladder adenocarcinoma.

BACKGROUND: Primary and secondary adenocarcinomas of the urinary bladder are uncommon, and the urine cytology of these tumors has rarely been described. Familiarity with the cytomorphology of these neoplasms may facilitate their detection in urine cytology specimens. METHODS: The authors reviewed 46 urine samples (19 voided, 19 instrumented, and 8 bladder washings) from 41 patients with biopsy-proven primary urinary bladder adenocarcinoma (n = 11) or metastatic adenocarcinoma (n = 35) from the prostate (n = 17), colon (n = 10), breast (n = 3), kidney (n = 3), or uterus (n = 1), or from unknown origin (n = 1). Cytomorphology, the role of cytology, and causes for negative diagnoses were evaluated. RESULTS: Cytologic diagnoses of malignancy, adenocarcinoma not otherwise specified, and adenocarcinoma of a specific type were given in 87%, 28%, and 39% of cases, respectively. Columnar cells, coarse chromatin, and necrosis were found in adenocarcinoma of the colon. Syncytial and acinar arrangements, round or oval nuclei, vesicular chromatin, and prominent nucleoli were commonly found in adenocarcinoma of the prostate. These features permitted us to make a specific diagnosis in 90% of cases of adenocarcinoma of the colon and 41% of cases of adenocarcinoma of the prostate. Cytologic examination failed to lead to a diagnosis of malignancy in 18% of primary adenocarcinoma cases. CONCLUSIONS: A large number of adenocarcinomas of the colon and prostate have sufficient cytologic features to suggest the correct diagnosis in urine samples. The cytomorphology of primary bladder adenocarcinoma is not as easily characterized. The submucosal nature of some metastatic deposits and tumor differentiation influence the diagnostic accuracy.

Cytology of germ cell tumors: extragonadal, extracranial masses and intraoperative problems.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Quality and liability issues with the Papanicolaou smear: the role of professional organizations in reform initiatives.

The professional societies of cytotechnologists, cytopathologists, and general pathologists have recognized growing problems that attend medicolegal issues in gynecologic cytology practice. Current trends imply two factors may soon adversely affect society's effort to stop deaths due to cervical cancer. First, the cost of gynecologic cytology services may rise sharply owing to extraordinary increases in the cost of malpractice coverage and the expenses entailed in growing quality assurance programs. Second, many practitioners and institutions may seek to avoid gynecologic cytology practice altogether as the malpractice burden increasingly becomes intolerable. The result of these trends would be increased numbers of deaths from largely preventable cervical carcinomas. After outlining these and related issues, this article seeks to provide some educational and medicolegal suggestions for concerted action by our societies. The goal remains unaltered from the time when Papanicolaou tests were new; we have the most effective cancer prevention screening tool ever devised and must make it widely available to all who may benefit from it.