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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. Diagn. Cytopathol. 2015;43:45–48. © 2014 Wiley Periodicals, Inc.

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.

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. Cancer (Cancer Cytopathol) 2005. © 2005 American Cancer Society.

We report the case of a suspicious parotid mass in which molecular determination of loss of heterozygosity (LOH) of chromosome arms 1p and 19q in combination with cytologic and immunohistochemical analysis defined the tumor to be metastatic oligodendroglioma. The patient was a 41-year-old woman who developed a World Health Organization grade II oligodendroglioma in her right frontal lobe at age 32, for which no adjuvant chemo- or radiotherapy was administered. Five years following this diagnosis, radiological assessment revealed a 10-centimeter mass in the tumor bed, suspicious for a recurrence. Resection of this lesion revealed an anaplastic oligodendroglioma (grade III) and adjuvant radiotherapy was given. Eleven months after this surgery the patient presented with a 5.5-cm subcutaneous, non-mobile, non-tender mass in the region of the right parotid gland. Fine needle aspiration (FNA) yielded highly cellular material, morphologically and immunohistochemically suspicious for oligodendroglioma. Molecular analysis of microsatellite loci residing on chromosome arms 1p and 19q was performed using DNA extracted from the patient's recurrent brain oliogdendroglioma and the FNA specimen. This analysis revealed evidence of LOH at all eight of the microsatellite loci tested. The combination of cytologic and molecular findings defined the extracranial tumor to be metastatic oligodendroglioma.

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.

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.

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. Diagn. Cytopathol. 2002;27:27–31. © 2002 Wiley-Liss, Inc.

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.

This chapter presents cytopathologic features of bronchial asthma, sarcoidosis, pulmonary alveolar proteinosis, lipid pneumonia, amyloidosis, and pulmonary infarct. Brief descriptions of the disease and differential diagnosis from other entities with similar morphology are also given.

This chapter has been updated according to the newly proposed classification of lung carcinomas and its application to small biopsies and cytology specimens which provides uniform terminology and criteria for diagnosing subtypes of lung carcinomas, specifically adenocarcinomas and poorly differentiated carcinomas.

Reactive and hyperplastic changes in cytologic specimens, specifically in bronchoscopic and FNA samples, are frequent causes of problems in differential diagnosis. Changes involving bronchial and alveolar epithelium are presented along with differential diagnosis from neoplastic conditions.

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.

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.

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.

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.

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.

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.

Study objective : To 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). Interventions : Induced 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 results : Five 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. Conclusions : Halfway 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.

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.

Eighty consecutive gynecologic specimens obtained with the Cavitron Ultrasonic Surgical Aspirator (CUSA) were evaluated pathologically. Fifty specimens were obtained during intraabdominal tumor debulking and thirty resulted from ablation of lower genital tract lesions. In 98% of intraabdominal specimens and in 93% of patients with a history of lower genital tract lesions, the CUSA material permitted an accurate diagnosis. Although artifacts related to cellular thermal injury were ubiquitous, nearly all cases were interpretable with a combination of cytologic (smear, Cytospin, Millipore filter) and histologic (cell block) preparations. Squamous intraepithelial lesions (SILs) of the lower genital tract were better preserved in cell block preparations, whereas intraabdominal adenocarcinomas were readily diagnosed by both cytologic and histologic techniques. Accurate grading of SILs and exclusion of invasion were difficult in some cell blocks due to the fragmented and superficial nature of the samples. Cytologic preparations of lower genital tract lesions often consisted of thick uninterpretable fragments and degenerated single cells that contributed little to the evaluation of SILs. We conclude that examination of CUSA specimens confirmed the surgical removal of pathologic tissue in 96% of cases, but an exact diagnosis of SILs was not possible in all cases.

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 ≤2 cm), and location (83.3% of central lesions vs 68% of peripheral lesions) and was found to be independent of histologic tumor type (78.4% of squamous cell carcinomas vs 71.5% of adenocarcinomas, 74.5% of small cell carcinomas, and 75% of large cell carcinomas). CONCLUSIONS: The findings of the current study suggested the important potential of sputum cytology for lung cancer detection and risk assessment across all stages, histologic types, tumor sizes, and locations. However, the high sensitivities in this study were achieved with a level of scrutiny not feasible in the laboratory routine. The diagnostic potential of sputum cytology may be exploited better through the standardization and automation of sputum preparation and analysis. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.

This chapter is devoted mostly to lymphomas, presenting their cytopathologic features as well as ancillary techniques to determine their specific type and differential diagnosis from other neoplasms.

Fine-needle aspiration of the prostate has failed to gain widespread acceptance among pathologists more familiar with histologic sections. The authors aspirated 27 freshly excised radical prostatectomy specimens with needles of varying caliber and type and found a 22-gauge Turner needle (Cook Incorporated, Bloomington, IN) which obtained large tissue fragments suitable for cell block preparation as well as high quality cytologic specimens. Thirty men with prostate nodules each had 14-gauge transperineal core biopsy and fine-needle aspiration. In 20 cases, cytologic smears and cell blocks and core biopsies agreed on a diagnosis: 12 benign and eight carcinoma. Of seven cases that were atypical by cytologic smears, five were benign on cell block and core; one was benign on cell block and carcinoma on core; and one was carcinoma on cell block and core. Three cases with scant specimens and diagnoses of carcinoma by cytologic smears were benign on cell blocks and cores: one contained seminal vesicle on review; one had repeat benign biopsies; and one had three microscopic foci of low-grade carcinoma in his radical prostatectomy specimen. This fine-needle aspiration technique provides histologic sections which are especially useful to those gaining experience with cytologic specimens of the prostate. Cases with discordant diagnoses on cell block and cytologic preparations warrant further evaluation.

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 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. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

Monoclonal antibody 703D4 recognizes a 31 kD lung cancer associated antigen (p31) expressed both in resected lung tumor and in sputum cells shed from the bronchial epithelium in advance of clinical cancer [1, 2]. Originally developed by mouse immunization using a whole non-small cell lung cancer (NSCLC) tumor-cell extract, 703D4 recognizes a protein expressed by most NSCLC as well as small cell lung cancer (SCLC) cell lines [1,3]. Recently, the 703D4 antigen has been purified by a seven-step chromatographic procedure, guided by Western blotting [4]. Sequencing of the principal immunostaining protein identified a heterogeneous nuclear ribonucleoprotein-A2 (hnRNP-A2). A splice variant, hnRNP-B1, was identified as a minor copurifying immunoreactive protein. Table 1 presents a summary of the advances in understanding of p31 expression in pulmonary tissues.

Fifteen patients with cerebral involvement by malignant non-Hodgkin's lymphoma were identified, among more than 200 patients who underwent stereotactic biopsy at The Johns Hopkins Hospital. All but one of these cases were diagnosed accurately by the stereotactic biopsy procedure. In 12 of 14 patients, the material was adequate to classify the lymphoma according to the Working Formulation. Because all but one of the lesions were intermediate or high-grade neoplasms, a diagnosis of lymphoma was often possible by conventional light microscopic examination alone. Monotypic light chain expression was demonstrated by immunohistochemical techniques in six patients, and positivity for B-cell markers was observed in an additional case. In one instance, two stereotactic biopsy specimens were interpreted as being suggestive of lymphoma, but necrosis and inflammation prevented a definitive diagnosis. Nine patients had no known risk factors for cerebral lymphoma, and the diagnosis often was unsuspected clinically.

Metastatic carcinoma is the most common form of intraocular malignancy. Metastatic carcinoma in the anterior segment is much less common than posterior involvement, and may be confused with uveitis of nonmalignant origin. Two cases of metastatic carcinoma to the iris, with diagnosis by a cytopathologic technique, are reported.

Barrett esophagus, the columnar-lined distal esophagus acquired as a consequence of chronic gastroesophageal reflux, is associated with the development of columnar epithelial dysplasia and esophageal adenocarcinoma. To determine the efficacy of cytopathology in identifying Barrett esophagus and related neoplasia, observations were compared on 150 esophageal cytology samples with concurrent endoscopic biopsy specimens. Sixty-six specimens that contained benign columnar epithelium in either cytologic or biopsy material were identified. Distinctive-type Barrett mucosa with incomplete intestinalization, considered diagnostic of Barrett esophagus, was found in 34 of 66 cases (52%) and was present only in cytologic material in 11 cases. Twenty-two specimens contained cardiac-type mucosa (present only in cytology in ten cases), a finding of uncertain significance due to lack of localization of the sample with respect to the gastroesophageal junction. Fundic-type mucosa was not observed in any specimen. Two cases of distinctive-type Barrett mucosa with columnar epithelial dysplasia were identified in both biopsy and cytology specimens. Among eight Barrett-associated carcinomas (seven adenocarcinomas and one squamous), cytologic material was diagnostic for malignancy in seven and highly suspicious in one. It was concluded that cytopathologic studies are a useful adjunct to biopsy histopathology in the diagnosis of Barrett esophagus and associated carcinoma. The role of cytopathology in the diagnosis of Barrett-related columnar epithelial dysplasia requires further study, and at present a cautious approach with biopsy confirmation is recommended.

The morphologic changes in 10 patients who were found to have squamous cell carcinoma of the lung before they became evident on chest x ray are discussed. It is suggested that these cases have a long preclinical course as invasive carcinomas that ranges from a microscopic focus of microinvasion (possibly originating from in situ carcinoma in submucosal gland epithelium) to a large concentric carcinoma which may have metastasized to regional lymph nodes. Although the duration of the in situ phase of squamous cell carcinoma of the bronchus in not known, it was evident that the expanse of in situ carcinoma frequently far exceeded that of the invasive carcinoma, and usually extended proximal to the invasive lesion. It is important that the extent of the in situ lesion is determined preoperatively. Finally, multifocal in situ (or invasive) carcinoma was found in at least two of the cases, either synchronously or metachronously.

A comparison was made of the efficacy of pleural needle biopsy and pleural-fluid cytopathology in the diagnosis of pleural tumor in a group of 271 patients. A malignant tumor involving the pleura was present in 95 cases. Needle biopsy alone provided a diagnosis of tumor in 53 instances, and cytopathologic preparations were diagnostic in 69 patients. A diagnosis was established on either the biopsy or cytopathology, or both, in 86 cases (90 percent). These results indicate the value of using both biopsy and fluid cytology in the evaluation of pleural effusion, which often is due to involvement of the pleura by malignant neoplasm.

In recent years we have witnessed increased reliance on 2 modalities in the management of patients with superficial transitional cell cancer of the bladder, that is intravesical chemotherapy for the control of existing and recurrent disease, and urinary cytology for the diagnosis of persistent or new neoplastic cells. This development has prompted some concern as to whether the use of chemotherapy might affect the morphological appearance of cells so as to make the interpretation of cytological specimens in this setting unreliable. We describe morphological differences between neoplastic cells and normal as well as cancer cells exposed in situ and in vitro to thiotepa. An appreciation of these differences has permitted accurate diagnosis of urinary cells in the presence or absence of cancer despite the regular use of this agent. Thus, it appears that the status of bladder cancer can be monitored successfully by an assessment of urinary cytology in the context of long-term treatment and prophylaxis with this agent.

The histopathology of Fuchs' heterochronic iridocyclitis has been infrequently documented. It is surprising for, in the opinion of some observers, the syndrome constitutes about 2% of all cases of uveitis. 1 Its etiology and pathogenesis are largely unknown. It is characterized by unilateral (rarely bilateral) hypopigmentation of the iris, low-grade signs of chronic inflammation in the anterior chamber and vitreous, and, in some cases, cataract and glaucoma. 2 The striking transillumination of the iris has been considered to be a secondary manifestation of atrophy and sclerosis of the stroma and of patchy depigmentation of the epithelium. In large measure, lack of interest in this syndrome has been engendered by the belief that there may be no cause-and-effect relationship between this type of heterochromia and a specific, unique form of uveal inflammation. If true, there would be no reason to consider Fuch's heterochromic iridocyclitis a distinct nosologic entity. 3 In the

Thirty-two consecutive patients with mediastinal lesions suggestive of bronchogenic carcinoma underwent transbronchial needle aspiration. Eighteen of 20 patients (90 percent) with proved bronchogenic carcinoma had malignant cytology specimens or tissue fragments. Of 12 patients with normal cytology specimens, six were subsequently proved to have nonneoplastic disease. Transbronchial needle aspiration appears to offer a sensitive and specific alternative to more invasive surgical techniques used in the diagnosis of malignancies with mediastinal involvement

Lung cancer is rarely diagnosed and treated while still localized. Sputum cytology allows detection of radiologically occult tumors but conventional endoscopic procedures frequently prove inadequate for localization. It is the purpose of this report to outline the endoscopic observations and methods we have developed in successfully localizing 17 consecutive, radiologically occult carcinomas discovered in the sputum of 15 patients. A detailed examination of the upper respiratory tract demonstrated occult tumors in two patients. A segment by segment fiberbronchoscopic study under anesthesia allows multiple brushings and meticulous handling of specimens. Lesion localization is provided as well as identification of synchronous second primary tumors. Biopsies at the lobar spur and carina assist in determining the proximal extent of carcinoma in situ at potential surgical margins. Newer methods should enhance our recognition of inapparent carcinoma in situ allowing more efficient and more accurate tumor localization and a better appreciation of its extent.

The Saccomanno technique of sputum preparation is widely used. This study evaluates the role of this preparation in conjunction with fresh smears in the diagnosis of lung cancer. All sputum samples from September 1973 to July 1975 showing atypia were randomized and negative controls added. The Saccomanno and fresh smears were evaluated independently and blindly and classified as negative, atypical, suspicious, or cancer. When each preparation was compared with the original diagnosis, the diagnostic accuracy for 55 squamous carcinomas was similar (fresh 95%, Saccomanno 86%) but significantly less in the Saccomanno preparations of 22 small cell carcinomas (fresh 100%, Saccomanno 24%) and 26 adenocarcinomas (fresh 96%, Saccomanno 52%). Four cases negative on fresh smears were suspicious or diagnostic of cancer on the Saccomanno slides. There were no cases of small cell carcinoma in which the Saccomanno preparations added information not available on the fresh smears. The authors conclude that in conjunction with fresh smears, the Saccomanno preparation may contribute to the diagnosis of non-small cell carcinomas but does not appear to aid in the diagnosis of small cell carcinoma.

The diagnostic accuracy of fine-needle aspiration of salivary gland lesions is now widely accepted. The cytologic appearance of two rare monomorphic variants of pleomorphic adenomas is described. The trabecular-tubular adenoma consisted of a trabecular arrangement of uniform small cells with scant basophilic cytoplasm and round nuclei. No mucoid spheres were present. The canalicular adenoma also had a distinctive cytologic appearance consisting of papillae and interconnected canaliculi lined by a layer of columnar epithelium. Monomorphic adenomas have unique morphologic appearances that can be recognized in fine-needle aspiration cytology. Preoperative diagnosis can greatly aid the surgeon in the planning of definitive surgical excision of salivary gland neoplasms.

• Two cases are reported in which pars plana vitrectomy was employed to restore vision and confirm the diagnosis of "primary" intraocular reticulum cell sarcoma. Cytologic study of material removed from the vitreous cavity confirmed the clinical diagnosis. The clinical, histologic, and cytologic features of intraocular reticulum cell sarcoma are reviewed.

Pleural fluids from 182 patients were studied prospectively. Although red blood cell (RBC) counts of greater than 10,000/cu mm were common with all types of effusions, an RBC count greater than 100,000/cu mm strongly suggested malignant neoplasm, pulmonary infarction, or trauma. Of 31 exudative effusions with a lymphocytic predominance, 30 were due either to tuberculosis or neoplasm. No tuberculous effusions had more than 1% mesothelial cells, while most other effusions contained at least 5% mesothelial cells. Pleural fluid cytological studies showed malignant cells in 33 of 43 patients with effusions due to tumor. More than 50% of the effusions with originally inconclusive pleural fluid cytological findings were proved to be due to neoplasm. When tumor is suspected, at least three separate pleural fluid specimens should be submitted for cytological examination.