A review of reporting systems and terminology for urine cytology.

Urine cytology continues to play an important role in the diagnosis and management of urothelial carcinoma, a common cancer of adults with significant morbidity and mortality. Because of its high sensitivity for high-grade urothelial tumors, including lesions that may be cystoscopically occult, urine cytology nicely compliments cystoscopic examination, a method that detects most low-grade tumors. Over the decades, several reporting schemes for urine cytology have been published in the literature, each of which has relative strengths and weaknesses. Unlike cervical cytology, there has not been widespread acceptance and use of any particular reporting scheme for urine cytology studies. Thus, terminology and criteria for urine cytology reporting are not uniform among pathologists, which can frustrate clinicians and hinders interlaboratory comparisons.

The Johns Hopkins Hospital template for urologic cytology samples: parts II and III: improving the predictability of indeterminate results in urinary cytologic samples: an outcomes and cytomorphologic study.

BACKGROUND: Urine cytology represents a major portion of testing volume in many cytopathology laboratories. METHODS: The authors previously reported a template designed to standardize urothelial diagnostic categories to enable clinicians to uniformly manage their patients. In this study, they examined the common cytomorphologic features observed in specimens diagnosed with atypical urothelial cells, cannot exclude high-grade urothelial carcinoma (AUC-H), which prove most predictive of high-grade urothelial carcinoma (HGUC). RESULTS: The most common morphologic features observed in the AUC-H specimens were hyperchromasia, irregular nuclear borders, increased nucleus-to-cytoplasm ratio, and anisonucleosis. Of the 58 patients who had specimens diagnosed with AUC-H, 95% ultimately were diagnosed with HGUC on follow-up biopsy over the study period. The small number of patients who had AUC-H with non-HGUC follow-up did not allow for a statistical comparison to determine the predictive ability of the selected criteria for HGUC. Next, the authors used the same features to examine a subset of urine samples that were diagnosed with atypical urothelial cells of unknown significance (AUC-US) in an attempt to improve the predictive value of this clinically frustrating category. A blind review was performed of 290 urine specimens from 217 patients. In contrast to the AUC-H specimen cohort, the majority of specimens with AUC-US did not contain atypical cells with the 4 common morphologic features. All 4 features significantly predicted HGUC in surveillance patients, but not in patients with hematuria. CONCLUSIONS: Hyperchromasia was the strongest predictor of HGUC by far in patients who were undergoing surveillance (odds ratio, 9.81). Hyperchromasia remained statistically significant in multivariate analysis, indicating its predictive strength even in the absence of other features.

The Johns Hopkins Hospital template for urologic cytology samples: part I-creating the template.

BACKGROUND: The most important indicator for urologic surgeons at The Johns Hopkins Hospital to have a patient undergo cystoscopy is a cytologic diagnosis of high-grade urothelial carcinoma. The template was designed to standardize diagnostic categories so clinicians can manage their patients uniformly. The template was based in part on the Bethesda System for cervical cytology. METHODS: According to the template, reactive/inflammatory changes were included in the negative group (no urothelial atypia or malignancy identified). The category atypical urothelial cells of undetermined significance (AUC-US) was akin to atypical squamous cells of undetermined significance (ASC-US), as was the category of atypical urothelial cells, favor high-grade carcinoma (AUC-H). The categories high-grade urothelial carcinoma (HGUC) and low-grade urothelial carcinoma also were added. RESULTS: The Pathology Data System at the Johns Hopkins Hospital was searched for cases that met the following criteria over a period from July 1, 2007 to June 30, 2009: all cytologic specimens from the urinary tract and all surgical specimens with a diagnosis of HGUC, regardless of invasion status. All cytologic specimens were then matched with biopsies during the same period, and all surgical specimens from patients who had a cytologic diagnosis of AUC-US or AUC-H were retrieved for 18 months after the end of the 2-year study period. Greater than 50% of patients who had biopsy-confirmed HGUC had a preceding cytologic diagnosis of AUC-H or HGUC. When patients with AUC-US were added to the analysis, 80% of patients with HGUC had at least 1 abnormal urinary cytology result. Of those patients who had a diagnosis of AUC-H, 38% had urothelial cancer discovered at biopsy compared with only 10% of those with an AUC-US diagnosis. CONCLUSIONS: The authors concluded that their template is effective in targeting those patients who need to undergo cystoscopy.

Lymphoma, leukemia, and pleiocytosis in cerebrospinal fluid: is accurate cytopathologic diagnosis possible based on morphology alone?

The differentiation of benign versus malignant hematologic processes on cerebrospinal fluid (CSF) is difficult given the significant morphologic overlap and frequently scant specimen. Our study compared the diagnostic power of cytomorphologic analyses and FC analyses in the context of CSF hematologic malignancies. We identified 32 cases of CSF submitted for cytopathologic analysis with corresponding FC data, histologic, or clinical follow-up. The slides were blinded and the study participants (one hematopathologist, two cytopathologists, and one cytotechnologist) reviewed the key slides of each case without additional information. These diagnoses were compared with the original diagnoses made in the context of clinical information and ancillary studies. The spectrum of disease ranged from acute myeloid leukemia, mantle cell lymphoma, chronic lymphocytic lymphoma, Burkitt lymphoma, large cell lymphoma, T cell lymphoma, and non-Hodgkin lymphoma. Parallel diagnoses were made in 62.5% of the cases. Interestingly, the correct diagnoses were rendered in 73% of benign cases, compared with 52% of malignant cases. Of the malignant cases, there was a higher proportion of correct diagnosis based on morphology in the acute malignancies (67%) versus the chronic malignancies (47%). The sensitivity, specificity, positive predictive value, and negative predictive value were 73, 52, 60, and 66% respectively. Features most useful for diagnosis of malignancy included cellular monotony and nuclear contour irregularity. The diagnosis of malignancy based on morphology alone is difficult in CSF. Ancillary studies such as FC analyses greatly enhance the ability to accurately distinguish between benign and malignant hematologic processes.

"Low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion" is a distinct cytologic category: histologic outcomes and HPV prevalence.

We examined the histologic outcomes and prevalence of high-risk human papillomavirus (HR-HPV) in women with liquid-based Papanicolaou (Pap) tests interpreted as "low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion" (LSIL-H) compared with the 2001 Bethesda System (TBS 2001) cytologic categories of LSIL, high-grade SIL (HSIL), and atypical squamous cells, cannot exclude HSIL (ASC-H). A computer search identified 426 LSIL, 86 ASC-H, 81 LSIL-H, and 110 HSIL cytologic interpretations during a 1-year period, each with up to 2 years of histologic follow-up. The risk of histologic cervical intraepithelial neoplasia (CIN) 2 or worse (CIN 2+) associated with LSIL-H (32/81 [40%]) was intermediate between LSIL (46/426 [10.8%]) and HSIL (72/110 [65.5%]), but not significantly different from ASC-H (23/86 [27%]). However, LSIL-H was more frequently associated with a definitive histologic diagnosis of any CIN (CIN 1+) than ASC-H (53/81 [65%] vs 35/86 [41%]). Moreover, the prevalence of HR-HPV was significantly greater in patients with LSIL-H than in patients with ASC-H (15/15 [100%] vs 43/73 [59%]). The histologic outcomes and HR-HPV prevalence associated with LSIL-H differ significantly from the established categories of TBS 2001 and provide evidence to support the recognition of LSIL-H as a distinct cytologic category.

Cytopathologic findings in an immature cystic teratoma: report of an unusual case.

Teratomas are uncommon, usually benign tumors often found in young women. We describe the cytopathology of an unusual case of a large congenital teratoma in a 6-day-old girl. The patient initially showed signs of abdominal distention and a follow-up ultrasound and computerized-tomography (CT) revealed a cystic mass in the pelvis. An ultrasound-guided fine-needle aspiration (FNA) showed small round blue cells suspicious for a primitive neuronal tumor. Resection of the mass displayed a cystic teratoma with distinct nests of small round blue cells representing immature neuroepithelial and glial tissue. Also noted were admixed mature elements of a cystic teratoma. Cytologic finding of a small round blue cell tumor, therefore, was the immature component of the teratoma. This case illustrates the difficulties in diagnosing teratomas due to their extraordinary diversity.

Thyroglossal duct cyst: a cytopathologic study of 26 cases.

Thyroglossal duct cyst (TDC), or embryologic remnants of thyroid gland, is a common congenital anomaly. TDC may cause a midline neck mass, which occasionally may become infected, and rarely gives rise to carcinoma. As a number of other nonneoplastic and neoplastic lesions can cause cystic masses in the neck, we explored the role of fine-needle aspiration (FNA) in making a preoperative diagnosis of TDC for a more accurate and timely clinical intervention. Twenty-six cases of TDC were identified from the cytopathology files of The Johns Hopkins Hospital in a 15-yr period (1990-2004). Material was obtained by FNA with or without radiologic (ultrasound) guidance. Smears were air-dried and stained with Diff-Quik, or wet-fixed and stained with Papanicolaou stain. Cytomorphologic characteristics were serially analyzed. Follow-up (tissue resection [n = 9] and clinical charts [n = 17]) was reviewed in all cases. Patients ranged in age from 8 to 83 yr (mean age, 55) with M:F ratio of 1.4:1. The size of the cyst ranged from 1.2 to 5 cm (mean 2.5 cm), as evaluated on radiological scans. The most common clinical presentation was a non-tender, mobile neck mass, which was painful on swallowing. Follow-up confirmed TDC in 18/26 cases (69%), whereas 8/26 cases resulted in various other benign lesions. During the same time period, 11/18 (61%) cases of surgically resected TDC were missed on prior FNA. Therefore, FNA showed a diagnostic sensitivity of 62% and a positive predictive value (PPV) of 69% for the diagnosis of TDC. The cytomorphologic features of TDC included the following: colloid (thick and fragmented, thin and watery, or mucinous), macrophages, lymphocytes, or predominantly neutrophils. The epithelium was ciliated columnar, metaplastic squamous or of mature squamous type. Thyroid epithelium was only rarely present (11%). FNA is only moderately sensitive for a preoperative evaluation of TDC. Cytomorphologic features are not unique; however, in the right clinicoradiologic setting should lead to an accurate diagnosis. Abundant colloid, most often with ciliated columnar epithelium, is the predominant cytopathologic finding. Thyroid epithelium is rarely identified. Differential diagnosis involves branchial cleft cyst, lymphoepithelial cyst, thyroid gland lesions, and lymphadenopathy (of various etiologies).

Exfoliative sputum cytology of cancers metastatic to the lung.

Although largely replaced by fine-needle aspiration (FNA) and bronchoscopy, cytological examination of sputum for exfoliated malignant cells still is considered a valuable initial diagnostic test in patients presenting with a lung mass. Thirty-five cases of secondary/metastatic tumors involving the lung and diagnosed on sputum were retrospectively reviewed from our cytopathology files for a period of 22 yr (1980-2001). Clinical history and the relevant histopathological material were examined and correlated with the cytological findings. In all cases, a history of malignancy was known. Cytological diagnoses included colonic adenocarcinoma (7 cases); non-Hodgkin's lymphoma (NHL; 5 cases); malignant melanoma (MM; 5 cases); breast carcinoma (5 cases); Hodgkin's lymphoma (HL; 3 cases); pancreatic adenocarcinoma (2 cases); prostatic adenocarcinoma (2 cases); and 1 case each of urothelial carcinoma, endometrial carcinoma, renal cell carcinoma, hepatic small-cell carcinoma, squamous-cell carcinoma (cervix), and leiomyosarcoma (LMS). Cellular preservation was optimal in all cases. The smear background was relatively clean in 25 (71%) cases and predominantly inflamed and/or necrotic in 10 (29%) cases. In non-lymphoid tumors (27 cases), isolated single malignant cells were seen in 7 (26%) cases (all cases of MM and prostatic adenocarcinoma), whereas 20 (74%) cases displayed fragments with intact tumor architecture. Overall, only 10/35 (29%) cases showed noticeable tumor-cell necrosis. In one case (LMS), cell block sections were used for immunoperoxidase (IPOX) studies with positive staining for desmin and actin. Exfoliation of cancer cells in sputum from secondary tumors in the lung is a rare phenomenon in current-day practice, with metastatic colonic adenocarcinoma seen most commonly. Intact tumor architecture was observed in exfoliated cells in 75% of the cases.

"Parapharyngeal space" tumors: a cytopathological study of 24 cases on fine-needle aspiration.

The parapharyngeal space (PPS) is a well-defined anatomic zone of loose connective tissue lying deep to the tonsil and lateral to the pharynx. Neoplasms arising within the PPS are rare. We retrospectively reviewed 24 PPS fine-needle aspirations (FNAs) performed at The Johns Hopkins Hospital over the past 16 years (1987-2002). Patients presented with neck pain, dysphagia, and/or intraoral swelling of varying duration. Radiographic imaging disclosed PPS masses, varying in size from 2.5 to 8 cm. The most common clinicoradiographic suspicion was a nerve sheath tumor. Six cases had FNA performed using a 23-gauge needle via a transoral approach in the outpatient suite whereas the remainder were aspirated via a 22-gauge Franseen needle under CT guidance. Six of 24 cases (25%) were nondiagnostic due to lack of adequate cellular material. Of the 18 cases considered diagnostic, there were nine (50%) pleomorphic adenomas (PAs); three (17%) squamous-cell carcinomas (SCC); and one each of oncocytoma, adenocarcinoma, not otherwise specified (NOS), adenoid cystic carcinoma, lipoma, neurofibroma, and non-Hodgkin lymphoma, together comprising the remaining 33%. Four of the six cases deemed nondiagnostic (consisting predominantly of blood) on subsequent tissue follow-up revealed paraganglioma (two cases), SCC (one case), and schwannoma (one case). PPS is an uncommon target of an FNA procedure. PPS masses represent a heterogeneous group of neoplasms of which PA appears most common, representing 50% of our diagnostic cases. The rate of nondiagnostic FNA samples is moderately high due to excessive bleeding encountered in this location and other technical problems relating to adequately targeting the lesion in close vicinity of major neck vessels.

Detection of genomic amplification of the human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia.

Invasive cervical carcinomas frequently reveal additional copies of the long arm of chromosome 3. The detection of this genetic aberration in diagnostic samples could therefore complement the morphological interpretation. We have developed a triple-color DNA probe set for the visualization of chromosomal copy number changes directly in thin-layer cervical cytology slides by fluorescence in situ hybridization. The probe set consists of a BAC contig that contains sequences for the RNA component of the human telomerase gene (TERC) on chromosome band 3q26, and repeat sequences specific for the centromeres of chromosomes 3 and 7 as controls. In a blinded study, we analyzed 57 thin-layer slides that had been rigorously screened and classified as normal (n = 13), atypical squamous cells (ASC, n = 5), low-grade squamous intraepithelial lesions (LSIL, n = 14), and high-grade squamous intraepithelial lesions (HSIL) grade 2 (CIN2, n = 8), and grade 3 (CIN3, n = 17). The percentage of tetraploid cells (P(Trend) < 0.0005) and cells with multiple 3q signals increased with the severity of the cytologic interpretation (P(Trend) < 0.0005). While only few normal samples, ASC and LSIL lesions, revealed copy number increases of 3q, 63% of the HSIL (CIN2) lesions and 76% of the HSIL (CIN3) lesions showed extra copies of 3q. We conclude that the visualization of chromosome 3q copy numbers in routinely prepared cytological material using BAC clones specific for TERC serves as an independent screening test for HSIL and may help to determine the progressive potential of individual lesions.

Teaching cytopathology to second-year medical students. An interactive, case-based approach.

OBJECTIVE: To develop and implement an electronic, interactive, case-based cytopathology educational system for second-year medical students. STUDY DESIGN: Ten different learning modules, corresponding to various organ systems in pathology and encompassing the essence of clinical cytopathology, were developed. The modules are software-based, menu-driven, digital programs that are displayed on a computer monitor and can be projected onto a large screen via LCD projectors. Each module takes 15-20 minutes to complete and contains three to four case-based interactive clinical scenarios. Each case contains sequenced, multiple-choice questions with immediate feedback. Each module also includes an atlas mode for viewing all the case images plus additional images to enrich the learning experience. RESULTS: Preliminary feedback from students taking the pathology course has shown encouraging responses. The students enjoyed the practical approach of the modules, finding them easy to use. Their interest level remained high as they discovered how their general medical knowledge could apply to solving real-life clinical cytopathology cases. CONCLUSION: By utilizing these unique instructional modules in the second-year pathology course, medical students learn the application of clinical cytopathology in everyday medical practice. This not only provides them with the theoretical background and morphologic knowledge of the diseases taught but also gives them the ability to apply it in simulated real-life clinical scenarios.

Endometrial-type cells in cervico-vaginal smears: clinical significance and cytopathologic correlates.

This study assessed the significance of endometrial-type cells (ETC) in cervico-vaginal (CV) smears in patients 45 yr and older by evaluating quantitatively and qualitatively the relationship of ETC to subsequent endometrial pathology. In a 3-yr period (1997-1999) at the Johns Hopkins Cytopathology Laboratory, 1,162 CV smears with ETC were found in patients 45 yr and older. In all cases with positive follow-up by tissue biopsy/resection, i.e., endometrial hyperplasia (EHP) and endometrial adenocarcinoma (EACA), the CV smears were reevaluated and compared to the control group (i.e., patients with normal endometrial biopsies). The following cytologic characteristics were recorded: quantity of ETC, type of ETC (epithelial, stromal/histiocyte-type, or mixed), cellular atypism, presence of inflammation, smear background, and associated estrogen effect. Of the 1,162 patients with ETC, 432 cases (37%) had tissue follow-up as follows: EACA, 18 (4.2%); EHP, 20 (4.6%); leiomyomata, 17 (3.9%); endometrial polyp, 21 (4.9%); benign/within normal limits (WNL), 339 (78.5%); nondiagnostic, 17 (3.9%). Cytologic characteristics of ETC showed subtle but definite quantitative and qualitative differences in the major pathologic groups examined. All instances of cancers and hyperplasia occurred in postmenopausal (PM) women. Abnormal vaginal bleeding was the presenting complaint in 66.7% of EACA, 45% of EHP, and 28.6% of benign endometrium. ETC in PM CV smears are associated with significant endometrial lesions (carcinoma, hyperplasia) in less than 9% of the patients. It is concluded that the distinction between EACA and EHP can be difficult. The presence of a large number of ETC, predominantly of epithelial or a mixed (epithelial and stromal) type, is more often associated with EACA or EHP than with benign endometrium. The presence of cytologic atypia and/or diathesis is additionally helpful for the diagnosis of EACA.