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Study objectiveTo determine whether monoclonal antibody (Mab) detection of tumor-associated antigen expressed on sputum epithelial cells precedes clinical presentation of second primary lung cancer. DESIGN SETTING/PARTICIPANTS: Eleven oncology centers collaborate in the accrual of 1,000 patients with stage I non-small cell lung cancer (NSCLC) who had undergone resection. The Mabs examined in this study (624H12, 703D4) detect two promising oncofetal/differentiation markers (ie, a difucosylated Lewis X and a 31-Kd glycoprotein antigen).InterventionsInduced sputum specimens are evaluated for quality, then are Papanicolaou and immunostained by independent central laboratories at enrollment and annually thereafter. The predictive value of Mab markers is compared with routine morphologic study for detection of second primary lung cancer during an anticipated 3 years of accrual and 1 year of follow-up.Measurements and resultsFive hundred eighty of an anticipated 1,000 patients have been accrued on schedule. Patients are primarily white (88.6%), former smokers (75.9%), men (55.6%), with a median age of 66.7, and joined the study at an average of 3.7 years following resection of a stage 1 NSCLC (34.4% squamous, 43.6% adenocarcinoma). Central laboratories found less dysplasia and more unsatisfactory specimens (27.3%) than do the accrual institution laboratories. Immunostaining identifies more suspicious cells than does morphologic study. However, only two second primary lung cancers (eight total deaths) have occurred to date.ConclusionsHalfway through the accrual, we describe the study design and preliminary observations. This study illustrates rational selection of carcinogenesis markers by linkage of marker expression on preneoplastic specimens with subsequent expression on tumor tissue.

Why the Bethesda System: The Bethesda System for cervical and vaginal diagnoses was devised to improve communication between the cytopathologist and referring physician, notably by providing descriptive diagnoses rather than numerical ones. The Bethesda System also correlates cytologic and histologic findings. In contrast to the Papanicolaou classification, the newer system describes the cellular changes with regard to their etiology. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is an uncommon thyroid tumor that usually behaves aggressively. After resection, serological surveillance for calcitonin and carcinoembryonic antigen (CEA) is used to prompt a radiographic search for metastatic disease. We report a case of a 65-year-old woman who presented with a large liver metastasis 37 years after she underwent thyroidectomy for organ-confined MTC. Her clinical course over that time showed a smoldering pattern in which she was symptom free until presentation even though her serum calcitonin and CEA concentrations were elevated for 17 years, and a small equivocal radiographic lesion in the liver was detected 10 years prior to presentation. Cytopathology from an ultrasound guided fine needle aspiration of the hepatic lesion was diagnostic for metastatic MTC. This case highlights the ability for smoldering residual MTC to suddenly transform to aggressive biological behavior after a long period of clinical remission., (© 2014 Wiley Periodicals, Inc.)

Introduction: Cytologic screening for urothelial carcinoma is fraught with low sensitivity, a high indeterminate rate, and until recently, poor standardization of terminology. The Johns Hopkins Hospital John K. Frost Cytopathology Laboratory has recently developed and published a template for reporting urine cytopathology; herein, we evaluate its interobserver reproducibility., Materials and Methods: Two sets of 100 cases each were deidentified; each set was reviewed by 5 of 10 observers in a randomized order at the direction of computerized data collection software that tracked observation time as well as observer classification of the atypia-no atypia, atypia (AUC-US), or atypia suggestive of high-grade urothelial carcinoma (AUC-H). Specific morphologic features were also recorded. Cases were grouped into low-, intermediate-, and high-agreement based on the number of observers who made the assessment. The findings were correlated against clinical outcomes., Results: High agreement among observers about the presence or absence of high-grade features was possible in approximately two-thirds of indeterminate urine cases. Time and order did not factor significantly into observer propensity for identifying atypical features or favoring either AUC-US or AUC-H, and cases with high agreement about the presence of high-grade features were more likely to have a malignant follow-up. Furthermore, AUC-H diagnoses based on 2 or more high-grade features had a significantly higher malignancy risk than AUC-US diagnoses did., Conclusions: AUC-H is a valid diagnostic category with specific, reproducibly identified features that portend a higher risk of malignancy than the findings of AUC-US., (Copyright © 2014 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Intraductal tubulopapillary neoplasm (ITPN) is a rare primary pancreatic neoplasm accounting for less than 1% of all pancreatic exocrine neoplasms and 3% of intraductal neoplasms of the pancreas. Data on this entity are still limited. Here, we report a case of ITPN with cytopathologic and histopathologic findings. A 41-year-old woman with a 2.2 cm cyst in the head of the pancreas for five years was referred to our institution. The endoscopic ultrasound-guided fine-needle aspiration produced cytospins were moderately cellular with a few fragments of markedly atypical epithelium. The neoplastic cells displayed high-grade nuclear atypia with enlarged, eccentric nuclei, anisonucleosis and prominent nucleoli, irregular nuclear membranes, high nucleus to cytoplasmic (N/C) ratios, and a moderate amount of cytoplasm with no intracytoplasmic mucin. Histologically, the lesion was found to be an ITPN with focal high-grade dysplasia. No invasive carcinoma was identified. The neoplastic cells exhibited luminal immunolabeling for MUC-1, but were negative for MUC-2, trypsin, chymotrypsin, and P53. Approximately 5% of the neoplastic cells showed Ki-67 immunoreactivity. ITPN of pancreas may be a source of markedly atypical epithelial cells in pancreatic cystic aspiration. Clinical and radiographic findings, molecular mutational analysis, in combination with cytological features are essential to differentiate it from other disease entities., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: The tall cell variant of papillary thyroid carcinoma (TCV-PTC) is an aggressive variant of PTC requiring accurate cytopathologic diagnosis for early aggressive management., Study Design: Twenty-five cases of TCV-PTC in which the tall cells comprised at least 30% of surgically resected tumor were included in the study. The direct smears from a preoperative fine needle aspiration (FNA) and available hematoxylin and eosin cell block sections were reviewed. Ten cases of TCV-PTC were randomly selected and blinded with an equal number of conventional PTC cases. Representative slides were independently reviewed by 7 cytologists., Results: In a majority of the cases, the FNA direct smears were hypercellular and displayed flat monolayer sheets of cells. Tall columnar cells with cytoplasmic tails were seen in 56% of cases. The presence of large polygonal follicular cells with abundant granular oncocytic cytoplasm and distinct cell borders was the most common feature seen in all cases. Seventeen (68%) cases displayed intranuclear pseudoinclusions in cells with abundant granular cytoplasm. A correct diagnosis of TCV-PTC was made in 30-40% of cases by 7 study participants., Conclusions: The correct recognition of TCV-PTC features in preoperative FNA is important for clinical management, and reporting these features in a cytopathology report is suggested.

Mullerianosis of the urinary bladder is a rare entity characterized by the presence of an admixture of at least two types of mullerian tissue in the muscularis propria of the bladder. We report a case of mullerianosis of the urinary bladder in a 28-year-old nulliparous woman with no history of pelvic surgery or endometriosis, and the diagnosis of mullerianosis was suggested initially in urine cytopathology report. In this study, previously reported cases of mullerianosis of urinary bladder are reviewed, and differential diagnosis of endometrial-like cells in the urine has been discussed. Fewer than 20 cases of mullerianosis of the urinary bladder have been reported in the literature, and only one of these cases had cytological description in a urine specimen. Most of patients were of reproductive age ranging from 28 to 53 years and had no previous history of pelvic surgery or Cesarean section. The clinical presentations frequently were abdominal/pelvic pain and dysuria/hematuria, which may or may not be associated with menstruation. Radiologic study revealed polypoid, mass-like lesion ranging from 1 to 4.5 cm in size, predominantly involving the dome or posterior wall of the bladder. Histological sections showed two or more of the three related benign mullerian glandular epithelial proliferations-endometriosis, endosalpingiosis, and endocervicosis. Most of the patients have good prognosis with medical management., (Copyright © 2011 Wiley Periodicals, Inc.)

The Fuhrman grading system of renal cell carcinoma (RCC) consists of four grades based on nuclear size/contour and nucleolar conspicuousness. Fuhrman grading of histpathologic material is an independent prognostic parameter for RCC. Although widely used in surgical pathology, Fuhrman grading is not routinely performed on cytologic material. Thirty-three cases of renal fine needle aspirations (FNAs) with histologically proven RCC were retrieved from the cytopathology archives at Johns Hopkins Hospital. Fuhrman grade was determined independently and blindly by three faculty cytopathologists and compared with the Fuhrman grade of the subsequent surgical pathology specimen. The 33 resection specimens had the following Fuhrman grades: 0/33, grade I; 24/33 (73%), grade II; 9/33 (27%), grade III; and 0/33, grade IV. After Fuhrman grading was applied to the FNA material, diagnostic sensitivity was 83% for grade II versus 44% for grade III. The specificity and accuracy were 50 and 75%, respectively, for grade II versus 100% and 84% for grade III. Diagnostic sensitivity for grade II tumors ranged from 38 to 83%, grade III 44-62%. Diagnostic specificity for grade II tumors ranged from 50 to 78%, grade III 80-100%. Accuracy ranged from 48 to 75% for grade II and 75-87% for grade III. Using a two-tier grading model, accuracy improved to 84.2%. In our experience, Fuhrman grading of FNA specimens yielded variable results. There was only moderate agreement between cytopathologists, with an overall tendency to undergrade the tumor when compared with the resection specimen. Averaging the participants' grading and using a two-tier instead of four-tier system improved overall performance., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: To determine if focal 'nuclear atypia' or 'microfollicular architecture' portends a higher risk of malignancy than other subcategories of atypia of undetermined significance (AUS) in thyroid fine-needle aspirations (FNAs)., Study Design: The frequencies of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories were calculated from 3,956 thyroid FNAs interpreted over a 26-month period at The Johns Hopkins Hospital after adoption of TBSRTC. TBSRTC criteria were applied strictly. The risk of malignancy, specifically for AUS subcategories, was analyzed by cyto-histo correlation., Results: Of the 133 cases diagnosed as AUS, 32% were found to have stageable carcinoma (not incidental microcarcinoma) on resection. When the subset of AUS with 'nuclear atypia' (AUS-N) was separated from other AUS cases, 48% (30/62) of them had stageable carcinoma on resection; of the AUS subset with 'microfollicular architecture' (AUS-F), 27% (8/30) were malignant on resection. The 'suspicious for papillary thyroid carcinoma' (SPTC) group maintained a higher risk of malignancy versus AUS-N (relative risk, RR 1.57; 95% CI 1.23-1.81)., Conclusion: The subcategory of 'nuclear atypia' within AUS indicates a higher risk of malignancy than other subcategories of AUS but has a lower risk of malignancy than SPTC does. Thus, it is an important distinction with potential clinical implications., (Copyright © 2011 S. Karger AG, Basel.)

Screening for HPV-driven cervical dysplasia and neoplasia is a significant public health concern in the developing world. The purpose of this study was to use a manual, low-cost liquid-based Pap preparation to determine HPV prevalence in HIV-positive and HIV-negative young women in Kampala, Uganda and to correlate cervical cytopathology with HPV-DNA genotype. About 196 post-partum women aged 18-30 years underwent rapid HIV testing and pelvic examination. Liquid-based cervical cytology samples were processed using a low-cost manual technique. A DNA collection device was used to collect specimens for HPV genotyping. HIV and HPV prevalence was 18 and 64%, respectively. Overall, 49% of women were infected with a high-risk HPV genotype. The most common high-risk HPV genotypes were 16 (8.2%), 33 (7.7%), 35 (6.6%), 45 (5.1%), and 58 (5.1%). The prevalence of HPV 18 was 3.6%. HIV-positive women had an HPV prevalence of 86% compared to 59% in HIV-negative women (P = 0.003). The prevalence of HPV 16/18 did not differ by HIV status. HIV-positive women were infected with a significantly greater number of HPV genotypes compared to HIV-negative women. By multivariate analysis, the main risk factor for HPV infection was coinfection with HIV. HIV-positive women were four times more likely to have abnormal cytology than HIV-negative women (43% vs. 11.6%, P < 0.001). These data highlight that HIV infection is a strong risk factor for HPV infection and resultant abnormal cervical cytology. Notably, the manual low-cost liquid-based Pap preparation is practical in this setting and offers an alternate method for local studies of HPV vaccine efficacy., (2009 Wiley-Liss, Inc.)

Background: The objective of this study was to assess the frequency of premalignant and malignant cells in sputum from patients with lung cancer and to measure the dependence of these cells on cancer stage, histologic type, tumor size, and tumor location., Methods: This analysis included 444 patients with lung cancer. First, all patients were asked to produce sputum spontaneously; then, they underwent sputum induction. Slide preparations of the sputa were screened for the presence of abnormal cells., Results: Of all patients with lung cancer who had produced adequate specimens, 74.6% had sputum that was positive for premalignant or worse cells, whereas 48.7% had sputum that was positive for malignant cells alone. Surprisingly, the presence of premalignant or worse cells in sputum depended only moderately on disease stage (82.9% of stage IV cancers vs 65.9% of stage I cancers), tumor size (78.6% of tumors >2 cm vs 64.7% of tumors

Background: Pineal gland lesions are rare, with only a few cytologic descriptions occurring in the literature, according to the authors' knowledge. The current article describes the cytopathologic characteristics of 20 such lesions with discussion of differential diagnoses., Methods: Cytologic material was obtained either by fine-needle aspiration biopsy (FNAB) under stearotactic radiologic guidance or by touch imprinting (TI) at the time of frozen sectioning. The 20 specimens include pineoblastoma (five specimens), pineocytoma (four specimens), astrocytoma (three specimens), germ cell tumor (three specimens), meningioma (one specimen), epidermoid cyst (three specimens), and pineal cyst (one specimen). Smears were stained with Diff-Quik and with Papanicolaou and hematoxylin and eosin stains. In selected specimens, immunoperoxidase (IPOX) stains were performed on cell block sections using synaptophysin, neuron-specific enolase, placental alkaline phosphatase, glial fibrillary acidic protein, leukocyte common antigen, cytokeratins, and human chorionic gonadotropin antibodies., Results: Several cytomorphologic characteristics unique to each lesional category with occasional overlapping features were observed. The unique features included the following: small, hyperchromatic, round to oval cells with frequent rosetting (pineocytoma), with a few specimens in addition showing hypercellularity, crowding, mitoses, and necrosis (pineoblastoma); pleomorphic round cells in a fibrillary background (astrocytoma); large polygonal cells with prominent nucleoli and clear cytoplasm (germ cell tumor); spindled fibroblastic cells (meningioma); anucleate squames and mature squamous cells (epidermoid cyst); and small uniform polygonal cells (pineal cyst). When necessary, IPOX studies supported the morphologic diagnoses., Conclusions: FNAB and TI cytology were found to provide a rapid and reliable diagnosis of pineal lesions. This is particularly important when dealing with minute amounts of tissue material. Both techniques appeared to provide equally good cytomorphology on smears. IPOX studies played an important complementary role in difficult cases when performed on cell blocks., (2005 American Cancer Society.)

Inflammatory pseudotumor (IPT) is a rare space-occupying lesion of unknown etiology that can mimic malignancy on clinicoradiological and pathological examination. A review of the cytopathology archives at The Johns Hopkins Hospital identified 12 cases from eight patients with histologically proven IPT (lung, seven patients; liver, five patients). There were six men and two women with an age range of 28-84 yr (mean age, 59 yr). Presenting complaints of IPT of the lung included shortness of breath and hemoptysis, and in cases of IPT of the liver complaints included abdominal pain and elevated liver function tests (LFTs). All cases were found to have mass lesions suspicious for a neoplasm on radiographic examination. Cytological specimens consisted of fine-needle aspiration (FNA; seven specimens) and bronchial brush/wash (five specimens). Diagnostic accuracy of cytology for IPT was low (5/12, 42%). IPT showed hypercellular smears (on FNA) with an admixture of various cell types including inflammatory cells with predominance of plasma cells, fibroblastic proliferation, granulation tissue formation, and atypical-appearing histiocytes with enlarged nuclei and intranuclear inclusions. Fibroblastic proliferation with mitoses may mimic mesenchymal neoplasms. Cytomorphology is nonspecific and IPT usually is a diagnosis of exclusion., (2004 Wiley-Liss, Inc.)

Background: Hepatocellular carcinoma (HCC) is routinely graded histopathologically using a modified Edmondson system (ES). The cytologic grading of HCC has been used predominantly as an adjunct in differential diagnoses (i.e., to help distinguish HCC from other tumors as well as nonneoplastic lesions). However, there are unanswered questions regarding the reliability of the cytologic grading of HCC and its correlation with histologic follow-up., Methods: A total of 106 cases of HCC were identified in the authors' cytopathology files from 1977 to the present. Of these cases, 64 had either a core needle or excisional biopsy sample that was judged to be adequate for histologic grading. From each case smears were graded independently in a blinded fashion by two cytopathologists, and tissue slides were graded by a liver pathologist. The cytopathologists' grading was then adjudicated by considering the histologic diagnosis as the "truth standard". Finally, after the scores were calculated, a statistical analysis was performed to ascertain the accuracy of the cytopathologic grading., Results: The sensitivity for accurate grading was found to be highest for well differentiated (WD) lesions; the specificity was found to be highest for poorly differentiated (PD) HCC for both cytopathologists. Interobserver agreement was highest for WD HCC. WD HCC displayed cohesive fragments, often associated with characteristic vascular/endothelial patterns. In addition, moderately differentiated (MD) HCC demonstrated numerous single cells and atypical naked nuclei, usually with prominent nucleoli. PD HCC displayed loose nests and three-dimensional fragments (often gland-like), pleomorphism, macronucleoli, and focal necrosis., Conclusions: In the authors' experience, the three-tier cytologic grading of HCC was found to be only moderately accurate. The accuracy of cytologic grading was reported to be high for WD/PD HCC and low for MD HCC. The architectural criteria appear to be more useful for WD HCC, whereas marked cellular pleomorphism is specific for PD HCC. The authors propose that a two-tier grading system may be more useful, given the recent studies of HCC recurrence.

Although cancers metastatic to the thyroid are frequently mentioned in autopsy studies, such a finding is quite rare in routine clinical practice. Metastatic non-small-cell carcinomas to the thyroid may present a diagnostic dilemma, particularly when they share morphological similarities with primary thyroid tumors. Herein, we report a case of metastatic bronchioloalveolar carcinoma that presented as an isolated left thyroid nodule in a 68-year-old woman. The aspirates were cellular and showed numerous papillary-like tissue fragments, elongated nuclei with prominent nuclear grooves, frequent mitoses, and psammoma bodies. The latter features raised the possibility of papillary thyroid carcinoma. However, also seen were three-dimensional tumor nests and acinar-forming fragments. Immunostains (positive for cytokeratin-7 and carcinoembryonic antigen and negative for cytokeratin-20 and thyroglobulin) confirmed the metastatic nature of the carcinoma. In a patient with known primary neoplasm, the differential diagnosis of a thyroid nodule should always include a metastatic lesion along with primary neoplasia., (Copyright 2004 Wiley-Liss, Inc.)

Objective: To analyze the differential diagnosis when keratinized squamous cells are found in a brain aspirate., Study Design: Twenty cases of brain aspirates with keratinized squamous cells were retrieved (1982-2001). Diagnoses included craniopharyngioma (CP) (n = 11), metastatic squamous cell carcinoma (SCC) (n = 5), epidermoid cyst (EC) (n = 3) and Rathke cleft cyst (RCC) (n = 1). Aspirates were obtained under stereotactic radiologic (CT) guidance. Smears were stained with Diff-Quik or Papanicolaou stain, and cell block sections were stained with hematoxylin and eosin. Radiologic and histopathologic correlation with subsequent resection specimens was performed in selected cases., Results: CP showed cellular smears with numerous keratinized squamous cells in a background of degenerated cellular and keratinaceous debris. Also noted were clusters of anucleate squamous cells, multinucleated giant cells, histiocytes, calcified debris and characteristic fragments of basaloid epithelial cells. Metastatic SCC showed single cells and tissue fragments of markedly atypical and focally keratinized cells with enlarged, hyperchromatic nuclei; prominent pleomorphism in a background of necrotic cellular debris and acute inflammatory exudate. EC showed numerous isolated keratinized squamous cells often with prominent keratohyaline granules and occasional parakeratotic cells in a relatively clean background. RCC showed single cells and aggregates of benign-appearing squamous cells admixed with numerous anucleate squames and hemosiderin-laden macrophages. Glandular-type epithelium was present only rarely., Conclusion: Squamous cell-containing lesions in the brain present a spectrum of pathologic entities. Although they all display the common morphologic denominator of keratinizing squamous cells, subtle cytomorphologic differences exist in these lesions, permitting an accurate cytopathologic diagnosis. Clinicardiologic features and anatomic location of the tumor in the brain are additionally helpful.

Objective: To investigate the role of reverse transcriptase polymerase chain reaction (RT-PCR) in determining telomerase catalytic subunit (hTERT) mRNA to assist with the diagnosis of colonic adenocarcinoma (CCA) in colonic brush cytology specimens., Study Design: Twenty-seven colonic brushes of CCA were obtained. Initial cytologic diagnoses included CCA, suspicious for CCA (SFC), atypical (ATY) and unsatisfactory. The cytologic specimens were reviewed. A homogeneous RT-PCR assay for hTERT mRNA was performed on 27 colonic brushes of CCA and 24 controls (10 negative brushes, 6 resected CCA and 8 benign colonic mucosa from resected specimens). A RT-PCR assay for beta 2-microglobulin was used as an internal control for mRNA quality., Results: On review, the initial cytopathologic diagnosis of CCA was confirmed in all 7 cases. In addition, 7 of 19 initially interpreted as SFC and ATY seemed to demonstrate unequivocal cytomorphologic features of malignancy. Telomerase mRNA was more often expressed in CCA than in negative controls in both brush (30%) and resected specimens (57%) (P < .05). Seven cases with hTERT mRNA expression were initially diagnosed as CCA (three), SFC (three) and ATY (one)., Conclusion: CCA may be underdiagnosed in brush cytopathology. The expression of hTERT mRNA may be determined by RT-PCR in brush specimens and may eventually prove to be a useful diagnostic adjunct in the interpretation of inconclusive cases of CCA. Sparse cellularity in brush specimens may result in a relatively low rate of hTERT detection in colonic brushes of CCA; inflammatory changes may contribute to a higher-than-expected rate of hTERT expression in benign colonic epithelium.

Stereotactic brain fine-needle aspiration (FNA) is a valuable diagnostic modality for evaluating space-occupying central nervous system disorders. Colloid cyst (CC) is a rare nonneoplastic lesion thought to arise from misplaced endodermal tissue in the anterosuperior portion of the third ventricle. This study summarizes cytomorphologic features of CC on FNA along with clinical, radiologic, and histopathologic correlation. Ten cases of CC of the third ventricle diagnosed on FNA were retrospectively reviewed for a period of 12 yr (1989-2000). Material was obtained under stereotactic radiologic guidance. Smears were stained with Diff-Quik and Papanicolaou stains and cell block sections with hematoxylin and eosin. The aspirates showed a characteristic sticky and viscous quality on gross examination. Smears showed abundant, amorphous, proteinaceous material with staining qualities similar to colloid aspirated from thyroid. This included a purplish, filmlike coating of the slide with occasional "cracking" artifact; thick, globular, eosinophilic fragments; and granular, ropelike, and somewhat viscous, mucinous material. Pathognomonic radiating hyphae-like structures were not seen. The cellular components varied from isolated cuboidal/columnar cells to large tissue fragments of glandular-type epithelium with focal ciliated border. Goblet cells were frequently identifiable, as were fragments of collagenous cyst wall. Stereotactic FNA of the CC of the third ventricle is an accurate and cost-effective diagnostic modality. Cytomorphology coupled with the radiologic features is sufficiently unique for the diagnosis of this rare pathologic entity., (Copyright 2002 Wiley-Liss, Inc.)

Cervical thymic masses are congenital lesions that result from aberrant thymic migration during embryogenesis. Although most of these masses are asymptomatic, they may cause debilitating symptoms secondary to encroachment on adjacent aerodigestive structures. Preoperative diagnosis of ectopic thymic tissue is rare; most cases are clinically misinterpreted as branchial cleft remnants or cystic hygromas. Definitive diagnosis has relied on histopathologic examination in nearly all reported cases. However, the invasiveness of open incisional or excisional biopsy carries the risk of surgical and anesthetic complications. Inadvertent surgical thymectomy may result in cell-mediated immune deficiencies in infants and young children. The utility of fine needle aspiration is gaining wider acceptance in the diagnostic evaluation of neck masses. We describe an infant with an asymptomatic cervical thymic mass diagnosed by fine needle aspiration.

Objective: Gastrointestinal stromal tumors (GISTs) are uncommon mesenchymal tumors of the gastrointestinal tract. Fine needle aspiration (FNA) is one option for diagnosing GISTs before surgery. This study was designed to evaluate the clinical utility of FNA in the diagnosis of GISTs., Study Design: FNAs from 19 GISTs originating in the stomach, small bowel and colon obtained from 1988 to 1998 were studied. Immunocytochemistry was performed on 12 cases. The GISTs were classified as benign, borderline and malignant, according to location, size, mitotic activity and clinical outcome., Results: Benign (three) and borderline (five) GISTs were all spindle cell type; malignant GISTs included five spindle cell type and six epithelioid type. Most smears contained abundant cellular material. Benign and borderline GISTs of spindle cell type tended to have cells arranged in tightly cohesive clusters, while malignant GISTs were more likely to exhibit loosely cohesive groups with many single cells, occasional nuclear pleomorphism, hyperchromasia and irregular nuclear contours. Epithelioid-type GISTs mimicked adenocarcinoma. Mitoses were seldom observed in either type. CD117 (KIT protein product) was demonstrated by immunocytochemistry in 9 cases, CD34 in 11, desmin in 3, S-100 protein in 2 and smooth muscle actin in 6 cases., Conclusion: FNA can be used to diagnose GISTs as spindle cell and epithelioid types, but cytomorphology alone cannot be used to assess malignant potential. Immunocytochemical staining for CD117 is helpful in confirming the diagnosis. Care must be taken to differentiate epithelioid-type GISTs from adenocarcinoma.

Objective: To determine if sequencing the KIT gene could facilitate more definitive FNA diagnosis., Study Design: Sixteen cases of gastrointestinal stromal/smooth muscle tumor (GIST) in which fine needle aspiration (FNA) was performed (mean age, 67; M/F = 12/4) were studied. DNA was extracted from cytologic preparations from all patients (15 cell blocks, 1 alcohol-fixed smear) and seven subsequent resection specimens. DNA was amplified by polymerase chain reaction, using primers designed to amplify a segment of the KIT gene exon 11 and sequenced on an ABI Prism 377 DNA sequence analyzer (Applied Biosystems, Indianapolis, Indiana, U.S.A.). Immunocytochemical staining for CD 117 (the KIT gene product) was performed on sections from 12 cell blocks and 7 surgical resections., Results: In-frame deletion of exon 11 was detected in eight cases (7 monoalleic, 1 bialleic); a point mutation was found in one case. Mutation was found only in histologically malignant (6 of 10 cases) and borderline GISTs (3 of 4 cases). No mutation was identified in benign tumors. In three cases, scant cellularity or blood precluded sequencing. CD 117 was expressed in 12 of 15 cases., Conclusion: Immunocytochemical staining for CD 117 is useful in confirming a cytologic diagnosis of GIST but does not facilitate diagnosis of malignancy. FNA biopsy specimens are suitable for KIT gene sequencing; detection of a KIT mutation favors a malignant diagnosis, though absence of mutation does not preclude malignancy.

Objective: Cytopathologic descriptions of thymoma are limited. This study was undertaken to elaborate on the cytomorphologic features along with clinicoradiologic findings of this entity, with special emphasis on the differential diagnosis., Study Design: Twenty cases of thymoma were retrospectively studied. Material was obtained by fine needle aspiration (FNA). Smears were stained with Diff-Quik and Papanicolaou stain, and cell block sections were stained with hematoxylin and eosin. Immunocytochemical (ICC) studies were done in selected cases using cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, placental alkaline phosphatase, neuron-specific enolase, chromogranin and lymphocytic markers (CD3 and UCHL-1)., Results: Fourteen thymomas were from the anterior mediastinum; the remaining 6 were invasive or metastatic to the lung (2), pleura (2), liver (1) and abdominal wall (1). The key diagnostic feature was a biphasic population of epithelial cells and lymphocytes in varying proportions. Medullary thymomas showed cohesive, spindled epithelial cells, whereas cortical subtypes displayed more epithelioid epithelial cells singly and in discohesive clusters. All cases of invasive or metastatic thymoma were of the cortical subtype. ICC studies were positive for cytokeratins and epithelial membrane antigen., Conclusion: FNA, coupled with clinicoradiologic information and appropriate immunocytochemical studies, is highly accurate in the diagnosis of primary and metastatic thymomas.

Pulmonary metastasis of sarcomas is not uncommon. Rarely, endobronchial involvement may result in exfoliation of diagnostic cells in sputum. This case report is of a 71-yr-old man with a history of lower leg leiomyosarcoma who developed multiple lung metastases. Sputum examination revealed malignant cells with pleomorphic, elongated, and cigar-shaped nuclei and occasional bipolar cytoplasmic processes. Immunoperoxidase studies on the smears using desmin and smooth muscle actin were strongly positive, consistent with leiomyosarcoma. Confirmation of metastatic lung disease by sputum cytology not only has prognostic importance but also obviates the need for further investigations.

The accuracy of using a combination of cytopathologic and histopathologic techniques to diagnose stereotactically guided brain biopsies was investigated in 74 patients. Diagnostic accuracy was assessed by determining whether classification of the biopsies as gliosis, astrocytoma (A), anaplastic astrocytoma (AA), or glioblastoma multiforme (GBM) predicted survival. The utility of on-site evaluation using Diff-Quik-stained crush preparations was also assessed. The patients ranged in age from 5 to 88 years (mean, 55 years) and were followed for over 2 years in most cases. Four cases (5%) were classified as gliosis (G), 7 (9%) as atypical gliosis (AG), 4 (5%) as high-grade mixed oligodendroglioma/astrocytoma (OA), 11 (15%) as astrocytoma (A), 21 (28%) as anaplastic astrocytoma (AA), and 27 (36%) as glioblastoma multiforme (GBM). Median survival was 11 months in patient with OA, 57 months in patients with A, 10 months in patients with AA, and 5 months in patients with GBM. Diagnosis of Diff-Quik-stained crush preparations made during the biopsy procedure was highly correlated with the final diagnosis and survival. We conclude that the diagnosis of stereotactic brain biopsies using cytopathology with on-site evaluation in combination with histopathological evaluation of needle cores is accurate based on a survival analysis. However, A and G may be difficult to distinguish.

The United States lung cancer epidemic has not yet been controlled by present prevention and treatment strategies. Overexpression of a Mr 31,000 protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, had shown promise as a marker of lung cancer. In a pilot study of archived preneoplastic sputum specimens, hnRNP A2/B1 overexpression more accurately detected preclinical lung cancer than standard cytomorphology. In separate, ongoing prospective studies, sputum is collected annually from stage I resected non-small cell lung cancer patients at high risk of developing a second primary lung cancer and Yunnan tin miners at high risk of primary lung cancer. After the first year of follow-up, preclinical detection of lung cancer by routine cytology was compared with hnRNP A2/B1 overexpression as measured by quantitative densitometry of immunostained slides. Up-regulation of hnRNP A2/B1 in sputum specimens accurately predicted the outcome in 32 of 40 primary lung cancer and control patients within 12 months, whereas cytological change suggestive of lung cancer was found in only 1 patient. In the primary lung cancer study, overexpressed hnRNP A2/B1 accurately predicted the outcome in 69 of 94 primary lung cancer and control miners, whereas only 10 with primary lung cancer were diagnosed cytologically. These two prospective studies accurately predicted that 67 and 69% of those with hnRNP A2/B1 up-regulation in their sputum would develop lung cancer in the first year of follow-up, compared with background lung cancer risks of 2.2 and 0.9% (35- and 76-fold increase, respectively). Using sputum cells to monitor hnRNP A2/B1 expression may greatly improve the accuracy of preclinical lung cancer detection.

Purpose: To examine risk factors and establish a biologic specimen and data bank for the study of early markers of lung cancer., Methods: We designed a dynamic cohort using an ongoing lung cancer screening program among radon- and arsenic-exposed tin miners in Yunnan China. Through the first four years of the study, 8,346 miners aged 40 years and older with over 10 years of occupational exposure have been enrolled, risk factors have been assessed, annual sputum and chest radiographs have been obtained, and numerous biologic specimens have been collected., Results: A total of 243 new lung cancer cases have been identified through 1995. Radon and arsenic exposures are the predominant risk factors, but lung cancer risk is also associated with chronic bronchitis and silicosis, as well as a number of exposure to tobacco smoke, including early age of first use, duration, and cumulative exposure. Tumor and sputum samples are being examined for early markers of lung cancer., Conclusion: A cohort of occupationally-exposed tin miners with an extensive biologic specimen repository has been successfully established to simultaneously study the etiology and early detection of lung cancer.

We initiated the present study to evaluate the accuracy of a new epithelial biomarker of early lung cancer. We tested the hypothesis that expression of a tumor-associated antigen by exfoliated sputum epithelial cells has greater accuracy (sensitivity and specificity) for the detection of preclinical, localized lung cancer than do routine clinical detection methods. Monoclonal antibody (MAb) 703D4 recognizes heterogeneous nuclear ribonuclear protein (hnRNP) A2/B1. We compared the accuracy of hnRNP up-regulation with cytology and radiographic screening for lung cancer detection in miners who were highly exposed to tobacco smoke, radon, and arsenic in southwestern China. The results showed that MAb 703D4 detection of hnRNP expression by sputum epithelial cells had greater accuracy for the detection of lung cancer than did routine screening methods, particularly for early (localized) disease. Among 57 cases and 76 noncases at the first screening, overall MAb detection of hnRNP was more sensitive (74 versus 21% for cytology and 42% for chest x-ray) but had lower specificity (70 versus 100% for cytology and 90% for chest x-ray) than standard methods. Recognizing hnRNP up-regulation resulted in detection of approximately one-third more early cases than did the combination of X-ray and cytology. Detection of hnRNP A2/B1 expression appears to be a good initial screening test for lung carcinogenesis, as it identified 74% of those who developed subsequent clinical lung cancer. Future studies might separate individuals with high lung cancer risk by MAb detection, confirming the positives with markers having greater specificity (e.g., clinical studies that become positive later in the morphological progression).

Rationale and Objectives: The authors evaluate the role of immediate cytologic evaluation (ICE) with fine-needle aspiration biopsy (FNAB) for lung lesions at highest risk for pneumothorax., Methods: A prospective randomized study was conducted of 80 patients with lung lesions surrounded by aerated parenchyma undergoing FNAB with and without ICE (47 and 33 patients, respectively). An analysis of needle passes, procedure time, complications, specimen adequacy, diagnostic yield, and accuracy of procedure was made., Results: There was an increased number of needle passes with ICE (> or = three passes: 23% [11 biopsies] versus 3% [1 biopsy]; P = 0.01). Fluoroscopic procedures took longer with ICE (median time: 15 versus 9 minutes; P = 0.002) with no difference in complication rates. Specimen adequacy was similar (74% and 64%) and the procedure was diagnostic in 79% (37 biopsies) with ICE and in 70% (33 biopsies) without ICE. There were no significant differences in the sensitivity, specificity, or accuracy of the biopsy., Conclusions: Immediate cytologic evaluation improved results marginally with increased procedure time and needle passes. Immediate cytologic evaluation may be most useful for lesions at lowest risk of complications to assure that a second procedure is not required.

Objective: Peritoneal washings are routinely performed during gynecologic surgery. The presence or absence of malignant cells in washings helps determine the stage of the malignancy. However, the efficacy of this procedure has not been studied recently., Design: All intraoperative washings for gynecologic disease at our hospital from 1992 through 1994 (901 cases) were reviewed. Of these, 380 were gynecologic malignancies that were reviewed for changes in staging based on the presence of malignant cells., Results: Histologically, 380 cases were gynecologic malignancies, 521 benign, 79 nongynecologic, and 25 had no accompanying surgical pathology. Of the malignancies, 125 had a diagnosis of cancer on washings. In 12 cases (3.1%), a change in stage resulted., Conclusions: In a small but significant number of cases, malignant cells in the washings changed postoperative staging, impacting therapeutic measures and prognosis for these patients greatly. Peritoneal washings remain a simple yet effective tool in the evaluation and management of gynecologic malignancies.

Pulmonary sequestration is defined as a congenital malformation of abnormal lung tissue that does not communicate with the airway system and that receives blood supply from anomalous arteries. The majority of these sequestrations are encountered in the pediatric population. Surgical excision is the treatment of choice, with excellent prognosis. We studied a case of an extralobar pulmonary sequestration in a young adult, presenting as an intrathoracic mass; it was aspirated twice, final diagnosis being rendered after surgical resection. The cytologic findings and the accompanying diagnostic difficulties to our knowledge have never been reported.

Background: Malacoplakia is an uncommon, peculiar inflammatory disease with few cytologic descriptions. It is seen mostly in the lower urinary tract, with rare occurrences in the lungs. Escherichia coli is the most common underlying etiologic agent, with only a few cases reported with Rhodococcus equi infection., Case: A 36-year-old female with AIDS presented with dysphagia, dry cough and fever. Physical examination revealed diffuse bronchi and wheezing. Chest roentgenography showed multiple cavitary lesions bilaterally in the lungs. Fine needle aspiration (FNA) of one of these lesions revealed clusters of granular histiocytes with numerous intracytoplasmic and extracytoplasmic Michaelis-Gutman bodies. Also noted were numerous coccobacillary bacteria, which, on culture, were identified as R equi. Ultrastructural findings are also presented., Conclusion: The case illustrates the cytologic findings of malacoplakia in a rare pulmonary lesion associated with R equi infection in an AIDS patient. It reiterates the diagnostic role of FNA in dealing with a nonneoplastic entity for timely and definitive treatment and follow-up.

Tumoral calcium pyrophosphate dihydrate deposition disease (CPPD) is a rare non-neoplastic entity which mimics primary or metastatic soft-tissue or skeletal malignancy. Fewer than a dozen cases have been reported in the literature with only histologic descriptions. We present cytologic findings of a unique case of CPPD in a 73-year-old black female with a history of end-stage renal disease. A fine-needle aspiration (FNA) was done on a 4 x 4-cm neck mass which was clinically thought to be malignant. Cytopathologic examination showed numerous macrophages with markedly distended cytoplasm and containing multiple yellowish-orange, short rhomboid crystals. These were strongly birefringent on polarized microscopy, consistent with CPPD crystals.

Background: Cysticercosis is the most common parasitic infection of the central nervous system in the United States., Case: A case of cerebral cysticercosis radiographically and pathologically mimicked a high grade glioma. A symptomatic solitary cerebral hemispheric lesion in a child, unknown at the time to have been born in Korea and adopted by U.S. residents, was initially evaluated by stereotactically guided needle biopsy and diagnosed as having malignant glioma in accord with the radiographic impression. The subsequently excised mass revealed cysticercus with an exuberant granulomatous inflammation and gliosis surrounding a fibrous-walled cyst., Conclusion: In the setting of a solitary parenchymal cyst, the radiographic differential diagnosis of neurocysticercosis often includes a primary neoplasm. However, to our knowledge, this is the first report of cysticercosis's also simulating a brain neoplasm pathologically.

Microsatellite DNA markers have been widely used as a tool for the detection of loss of heterozygosity and genomic instability in primary tumors. In a blinded study, urine samples from 25 patients with suspicious bladder lesions that had been identified cystoscopically were analyzed by this molecular method and by conventional cytology. Microsatellite changes matching those in the tumor were detected in the urine sediment of 19 of the 20 patients (95 percent) who were diagnosed with bladder cancer, whereas urine cytology detected cancer cells in 9 of 18 (50 percent) of the samples. These results suggest that microsatellite analysis, which in principle can be performed at about one-third the cost of cytology, may be a useful addition to current screening methods for detecting bladder cancer.

Objective: To compare the safety and efficacy of homogenizing sputum with deoxyribonuclease I (DNAse I), dithiothreitol (DTT), N-acetyl-L-cysteine, sodium EDTA and trypsin against standard mechanical blending to provide mucus-free, single-cell suspensions for quantitative analysis., Study Design: Clinical sputum specimens or cultured human bronchogenic carcinoma cells were preserved in 2% polyethylene glycol/50% ethanol, divided into aliquots, counted and stained (Papanicolaou and avidin-biotin complex immunostained) at baseline. Cells of each aliquot were separated from mucus by the standard physical blending method or by chemical or enzymatic mucus liquefaction. After staining, washing and resuspending in the original volume of polyethylene glycol/ethanol mixture, aliquots were again counted and stained., Results: Cell counts, Papanicolaou staining and immunostaining showed that homogenization of induced, preserved sputum with 0.5 mM DTT is safe and provides mucus-free monolayers for immunocytochemistry and single-cell suspensions for flow cytometry. Mucolysis with 0.5 mM DTT resulted in a significant (16%) increase in cells available. In contrast, mechanical blending resulted in up to a 24% reduction in specimen cellularity., Conclusion: Homogenization with low-concentration DTT will probably facilitate the exploration of sputum for protein and gene markers of carcino genesis.

This report describes the diagnosis of progressive multifocal leukoencephalopathy (PML) in nine patients using cytopathologic and histopathologic examination of computed tomographically guided stereotactic brain biopsies in combination with immunostaining for SV-40-related antigen and the polymerase chain reaction (PCR) for the JC virus. In four patients the diagnosis of PML was based on the microscopic appearance of the biopsies and immunostaining for SV-40-related antigen. In one of these patients the diagnosis was also supported by PCR for the JC virus. In two patients whose biopsies were only suggestive of PML, a definitive diagnosis was possible utilizing immunohistochemistry and PCR. In another case the histopathologic features were atypical of PML, and the diagnosis was established with immunostaining and PCR. The diagnosis of PML was established by PCR alone in two patients whose biopsies showed only suggestive or nonspecific findings. We conclude that the accuracy of stereotactic biopsy in the diagnosis of PML is enhanced by using a combination of light microscopy, immunohistochemistry and PCR.

Microsatellite instability has been reported to be an important feature of tumors from hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. The recent discovery of genetic instability in small cell lung carcinoma, a neoplasm not associated with HNPCC, led us to investigate the possible presence of microsatellite alterations in other tumor types. We examined 52 microsatellite repeat sequences in the DNA of normal and tumor pairs from 100 head and neck, bladder, and lung cancer patients by the polymerase chain reaction. Although alterations were rare in dinucleotide repeats, larger (tri- or tetranucleotide) repeats were found to be more prone to expansion or deletion. We screened 100 tumors with a panel of nine tri- and tetranucleotide repeat markers and identified 26 (26%) that displayed alterations in at least one locus. This observation prompted us to examine the possibility of using microsatellite alterations as markers to detect clonal tumor-derived cell populations in pathologic samples. The identical microsatellite alterations detected in the primary tumors were successfully identified in corresponding urine, sputum, and surgical margins from affected patients. This study demonstrates that appropriately selected microsatellite loci are commonly altered in many cancers and can serve as clonal markers for their detection.

Cancer of the uterine cervix, the sixth most common cancer among women, is still considered a significant health problem, despite declining mortality rates during recent decades. In Baltimore, the age-adjusted mortality rates for cervical cancer are significantly higher than the U.S. average, for both black and white women. Early detection of cervical cancer through screening with the Papanicolaou (Pap) test has shown to decrease mortality by preventing development of invasive disease, and intervention programs have been developed to increase use of Pap testing. However, the evaluation of those programs is difficult, as self-reports of Pap screening may be inaccurate, and repeated inquiries about Pap tests may influence the behavior being studied. We report in this article a method to use data from cytopathology laboratories to estimate the use of Pap screening by women in a defined population. This approach can be used to evaluate changes in receipt of Pap smears and to provide feedback to intervention programs.

The gastric brushings (GBRs) and endoscopic biopsies obtained concurrently from 27 patients in whom malignant lymphoma was diagnosed or suggested by either modality were assessed to evaluate the utility of cytologic examination in the diagnosis of gastric lymphoma. GBRs provided a definitive diagnosis of lymphoma in 2 (28%) of 7 patients with a prior history of lymphoma and 10 (56%) of 18 patients with primary gastric lymphoma, yielding an overall sensitivity of 48%. All the lymphomas diagnosed cytologically were large cell type. GBRs were suspicious for a malignant neoplasm in four lymphoma patients whose concurrent biopsies were negative. GBRs obtained from two patients who had gastritis were reported as suspicious for lymphoma. There were no false-positive diagnoses.