RESUMEN
BACKGROUND: This study was designed to optimize a liquid-based Papanicolaou (Pap) test by using common cytopathology laboratory equipment and resulted in an inexpensive test that was equivalent at least diagnostically to the conventional Papanicolaou (Pap) smear. METHODS: Adult women (n = 482) were consented, enrolled, and included in this Institutional Review Board-approved study. After conventional Pap smear slides were obtained, clinicians placed the collection device with residual cells from the uterine cervix in a preservative fluid. In the cytopathology laboratory, a conventional centrifuge device was used to deposit the cells from the liquid onto a glass slide. RESULTS: Among the conventional Pap smears, 43 were categorized as low-grade squamous intraepithelial lesions (LSIL), and 30 were categorized as high-grade squamous intraepithelial lesions or greater (HSIL+). Among the PapSpin samples, 49 were categorized as LSIL and 24 were categorized as HSIL+. Biopsy confirmation was obtained in 124 patients. There were 23 women diagnosed with LSIL and 27 women diagnosed with HSIL+. Diagnostic agreement between cytologic samples and biopsies is as follows: for conventional Pap smears, there was agreement on 11 of 23 LSIL diagnoses and on 15 of 27 HSIL+ diagnoses; for PapSpin samples, there was agreement on 11 of 23 LSIL diagnoses and on 14 of 27 HSIL+ diagnoses. Exact agreement was achieved between PapSpin and conventional smears in 404 patients (84%). Quality indictors were better in the PapSpin group, except for inadequate endocervical component, which was greater in the PapSpin samples, a difference that was explained by the split-sample study design, which favored the conventional smear. CONCLUSIONS: The current results indicated that PapSpin is a legitimate, inexpensive alternative to the conventional Pap smear for the detection of cervical intraepithelial neoplasia, resulting in better preservation and improved cell visualization. In addition, the liquid residual allows for reflex human papillomavirus-DNA or polymerase chain reaction testing.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Prueba de Papanicolaou , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal/métodos , Adulto , Animales , Carcinoma de Células Escamosas/microbiología , Carcinoma de Células Escamosas/parasitología , Reacciones Falso Negativas , Femenino , Humanos , Reproducibilidad de los Resultados , Neoplasias del Cuello Uterino/microbiología , Neoplasias del Cuello Uterino/parasitología , Displasia del Cuello del Útero/microbiología , Displasia del Cuello del Útero/parasitologíaRESUMEN
High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions of the colon, stomach, esophagus, oral cavity, prostate, and breast. Inhibition of FAS with C75 has led to a significant antitumor effect in both human breast and prostate cancer xenografts. Recently, HER2/neu, which has also been identified in preneoplastic breast lesions, has been shown to regulate FAS expression through the PI3K/Akt signal transduction pathway rendering them susceptible to FAS inhibition. Utilizing the neu-N transgenic mouse model of mammary cancer, weekly treatment of the neu-N mice with C75 (30 mg/kg) for 10 weeks significantly delayed tumor progression. Only 20% of the C75-treated transgenic mice developed mammary carcinoma by 220 days, compared to 50% in the vehicle control animals. Two C75-treated animals never developed mammary cancer. Analysis of mammary tissue following 10 weeks of C75 treatment revealed a significant delay in mammary maturation as manifested by a reduction of the number and caliber of mammary ducts and budding epithelial structures. Apoptotic changes were increased, DNA synthesis was decreased, and the expressions of FAS, neu, Akt, phospho-Akt, and p21(waf1) were all decreased when compared to vehicle controls and FVB/N mice. Importantly, these effects were restricted to the breast epithelial cells that overexpressed neu, not involving other normal duct structures in the skin, liver, or kidney. C247, an FAS inhibitor chemically distinct from C75, significantly delayed mammary maturation similar to C75. Thus, pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance of the malignant phenotype. Moreover, these data identify FAS as a potential novel drug target for breast cancer chemoprevention.
Asunto(s)
4-Butirolactona/análogos & derivados , Ácido Graso Sintasas/antagonistas & inhibidores , Neoplasias Mamarias Animales/prevención & control , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , 4-Butirolactona/farmacología , Animales , Proteínas de Unión al ADN , Femenino , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/crecimiento & desarrollo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Células Tumorales Cultivadas , Receptor fasRESUMEN
Methylation of tumor suppressor genes has been implicated in breast cancer development. However, methylation profiles of different breast lesions, subtypes of carcinoma in particular, have not been examined in detail. In this study, we use methylation-specific PCR (MSP) to generate gene methylation profiles of different breast lesions and to test the clinical utility of such profiles. We examined the methylation status of three genes, RARbeta2, RASSF1A, and cyclin D2, on 102 samples of breast tissue, from benign (n = 36), to in situ carcinoma (n = 21), to invasive carcinoma (n = 45). We found that almost all cases of invasive carcinoma (96%) contained at least one methylated gene from our panel, whereas gene methylation was less common among benign lesions (42%) and in situ carcinoma (76%). Of the three genes, cyclin D2 methylation was most specific for malignancy because only 1 of 35 benign cases was methylated at this gene (1 case was not informative). The major histologic subtypes of invasive carcinoma show similar methylation profiles in the genes examined. We next performed MSP analysis on archival breast fine-needle aspiration (FNA) biopsy samples and corresponding surgical biopsy specimens and found a high concordance between the two types of specimens. We then analyzed 17 breast FNA biopsy samples with an indeterminate diagnosis. In this setting, MSP had a high specificity (100%) and modest sensitivity (67%) for identifying malignancy.
Asunto(s)
Enfermedades de la Mama/genética , Enfermedades de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Metilación de ADN , Biopsia con Aguja , Carcinoma/genética , Carcinoma/patología , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Dermatoglifia del ADN , Femenino , Frecuencia de los Genes , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genéticaRESUMEN
The significance and clinical management of atypical squamous cells of undetermined significance (ASCUS) on cervical cytologic smears has been an area of much controversy. This study compiled a list of criteria useful in identifying the subset of cases that would be categorized as atypical squamous cells of undetermined significance- rule out high-grade squamous intraepithelial lesion (ASC-H) in the new Bethesda System terminology, which eventuate in a diagnosis of cervical intraepithelial neoplasia (CIN). The cytopathology files at Johns Hopkins Hospital were searched for ASC-H cases from the 3-yr period 1996-1998, which had definitive clinicopathologic follow-up (colposcopy and cervical biopsies). The smears were reviewed, cytomorphologic features studied, and clinical correlations performed. ASC-H was diagnosed in 257 of 45,428 gynecologic smears (0.6%), 72 having had clinicopathologic follow-up. Of these 72 cases, 35 (49%) on follow-up had a negative/reactive diagnosis (NR), whereas 37 (51%) turned out to be CIN [CIN-I-18 (49%) and CIN II and III-19 (51%)]. The significant cytomorphologic differences in the ASC-H category with a CIN follow-up (compared with an NR follow-up) were fewer atypical cells, more often discohesive or seen singly, more monomorphic, a higher nuclear-to-cytoplasmic (N/C) ratio, greater nuclear hyperchromasia, more coarse, unevenly dispersed chromatin, more prominent nuclear membrane irregularities, lack of nucleoli, chromocenters or nuclear grooves, and lack of an inflammatory background. Careful attention to subtle cytomorphologic characteristics may be helpful for a more definitive subdivision of ASC-H terminology into a NR and a CIN diagnosis.
Asunto(s)
Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Frotis Vaginal , Femenino , Estudios de Seguimiento , Humanos , Frotis Vaginal/clasificaciónRESUMEN
BACKGROUND: Micropapillary serous carcinoma (MPSC), a recently described entity, is an ovarian tumor with a distinctive histologic architecture that lacks a destructive infiltrative growth pattern and behaves like a low-grade neoplasm. The purpose of this study was to determine if specific cytomorphologic features were associated with this tumor in peritoneal/ pelvic washings. METHODS: Eight cases of MPSC were retrieved from the cytopathology files at The Johns Hopkins Hospital. Patients ranged in age from 31 to 74 years (mean, 58 years). A cytomorphologic comparison was made with pelvic washings of eight cases of papillary serous carcinoma (PSC) of the ovary. RESULTS: MPSC demonstrated small but well formed papillary fragments (generally < 30 cells) composed of monotonous, relatively small epithelial cells, often with multiple nucleoli. Single, large atypical cells were seldom present and were seen in less than one half of cases. Cellularity was generally high and slide background was clear with minimal inflammatory cells. In comparison, PSC, in addition to the smaller papillary fragments, also exhibited larger more complex papillary fragments (generally > 30 cells) composed of pleomorphic, hyperchromatic cells often with single prominent nucleoli. Single, large tumor cells exhibiting eccentric atypical nuclei or multinucleation were present in high concentration in the majority of PSCs. Psammoma bodies were observed in one half of cases in both tumor types. CONCLUSIONS: Although MPSC shares cytomorphologic similarities with PSC, it can be diagnosed adequately in peritoneal/ pelvic washings. Careful interpretation of the subtle cytologic differences seen in the two tumor types may facilitate the differentiation of these neoplasms for a more appropriate management of the patient.