Biomedical subjects

Anais Malpica

Publications and source records attributed to Anais Malpica.

At least 19 recordsLinked to original sources

PubMed2006

Deficiencies in myeloid antigen-presenting cells in women with cervical squamous intraepithelial lesions.

BACKGROUND: There is little information on the function of dendritic cells in women with human papillomavirus (HPV)-related cervical squamous intraepithelial lesions (SILs). In the current study the functions of dendritic cells in the development of T-cell immunity in women with cervical SILs were assessed. METHODS: The percentage of myeloid dendritic cells (MDCs) and plasmacytoid dendritic cells (PDCs) in peripheral blood were enumerated of 44 patients with SIL (low-grade, 19; high-grade, 25), 19 patients with atypical squamous cells of undetermined significance (ASCUS), and 18 controls. The expression of costimulatory receptors was assessed and the ability of monocyte-derived dendritic cells (MDDC) to present HPV16-E6 and HPV16-E7 antigens to autologous T cells. RESULTS: Patients with either low (L)-grade or high (H)-grade SIL had significantly lower median plasma levels of interferon-gamma than did the controls (P = .038 and .031, respectively). Compared with the controls, patients with ASCUS or LSILs had significantly lower median percentages of MDCs (P = .002 and P < .001, respectively), and significantly lower median percentages of MDDCs that expressed CD86 (P < .001 and P = .003, respectively) and major histocompatability complex class-II antigen human leukocyte antigen DR (HLA-DR) (P = .012 and P < .001, respectively). T cells of patients with ASCUS or LSILs proliferated less than those of the controls in response to HPV16-E7 (P = .002 and .046, respectively). CONCLUSIONS: Low levels of peripheral blood MDCs and of MDDCs expressing CD86 and HLA-DR suggest that deficiencies in the ability of MDDC to present antigen to autologous T cells may lead to persistent infection with HPV and the development of cervical SILs in HPV-infected women.

Adult↗

PubMed2006

Cyclin E expression is correlated with tumor progression and predicts a poor prognosis in patients with ovarian carcinoma.

BACKGROUND: Cyclins, cyclin dependent kinases (cdks), and their inhibitors act in combination to regulate progression through the cell cycle and often are dysregulated in carcinoma. The authors hypothesized that cyclin E plays an important role in ovarian carcinogenesis and that its overexpression may be an indicator of a poor prognosis. METHODS: Immunohistochemical analysis of cyclin E expression was performed by image analysis in normal ovaries, cystadenomas, tumors of low malignant potential, and 405 primary ovarian carcinomas by using tissue microarray technology. RESULTS: Overexpression of cyclin E was found in 63.2% of the samples and was associated with clear cell, poorly differentiated, and serous carcinoma (P < or = .001), high-grade tumors (P < or = .001), late-stage disease (P = .002), age older than 60 years at the time of diagnosis (P = .04), and suboptimal cytoreduction (P = .001). A high percentage of cyclin E-expressing cells was associated with a poor outcome in univariate and in multivariate analyses. In addition, cyclin E levels also reduced survival in the late-stage disease group and in patients who underwent suboptimal debulking. CONCLUSIONS: Cyclin E was identified as an independent prognostic factor in patients with ovarian carcinoma. The accumulation of cyclin E protein may be a late event in tumorigenesis and may contribute to disease progression in these patients.

Adult↗

PubMed2006

Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary.

OBJECTIVE: To analyze the clinical behavior of patients with stage II-IV low-grade serous carcinoma of the ovary seen at our institution who underwent primary surgery followed by platinum-based chemotherapy. METHODS: Patients with stage II-IV low-grade serous carcinoma of the ovary from 1978 to 2003 were identified using existing databases. Clinicopathologic information was obtained from medical records. Progression-free survival and overall survival were estimated by the method of Kaplan and Meier. The log-rank test was used to compare differences between survival curves. Univariable and multivariable analyses were performed using Cox proportional hazards regression. RESULTS: We identified 112 eligible patients. Median age was 43 years.; 90% had stage III disease. Preoperative serum CA 125 was elevated in 86% of patients. The most common sites of extraovarian disease were omentum, fallopian tubes, pelvic peritoneum, and uterus. Response rate to platinum-based chemotherapy in 10 evaluable patients (15% of patients with gross residual disease) was 80%, and 42 patients underwent second-look surgery: microscopically negative findings, 2 (5%); microscopically positive disease, 13 (33%); macroscopically positive disease, 24 (62%); and insufficient information, 3 (7%). Median progression-free survival and overall survival times were 19.5 and 81.8 months. Persistent disease after primary chemotherapy was the only factor associated with shorter overall survival time (hazard ratio 3.46, 95% confidence interval 2.00-5.97, P<.001). CONCLUSION: Metastatic low-grade serous carcinoma of the ovary is characterized by young age at diagnosis and prolonged overall survival. Segregating women with this diagnosis in future clinical trials is warranted.

Adolescent↗

PubMed2006

Ovarian involvement by metastatic colorectal adenocarcinoma: still a diagnostic challenge.

Ovarian involvement by metastatic colorectal adenocarcinoma, although not an uncommon occurrence, remains a diagnostic challenge. The gross and histologic features of such metastases overlap those of primary ovarian epithelial neoplasms such as endometrioid or mucinous adenocarcinoma. The clinical and pathologic features of 86 cases of metastatic colorectal adenocarcinoma involving the ovary were reviewed. Patients ranged in age from 19 to 85 years (median, 51 years); 24% were younger than 40 years. Presenting symptoms included abdominal or pelvic pain (45 cases), rectal bleeding (13 cases), change in bowel habits (20 cases), and vaginal bleeding (5 cases). In 23 cases, an ovarian mass was the first manifestation of the disease. Ovarian involvement was bilateral in 49 cases and unilateral in 33 (including 20 cases in which the only involved ovary measured at least 10 cm in greatest dimension). Involved ovaries ranged from 2 to 24 cm (mean, 10.1 cm), and most featured both solid and cystic areas. Many involved ovaries featured smooth capsules without gross evidence of surface involvement by tumor. In general, the tumors had typical histologic features of metastatic colorectal adenocarcinoma, including a garland pattern and dirty necrosis. In 23 cases, foci with a benign or low malignant potential appearance were seen. Immunohistochemical studies showed that 29 of 29 tumors (100%) were positive for CK20; focal CK7 positivity was seen in 5 of 30 cases (17%). In 9 of the cases, an ovarian primary was diagnosed or favored initially, and 5 of these cases were initially treated as ovarian primaries. Metastatic colorectal adenocarcinoma should be considered in the differential diagnosis of an ovarian mass, even if the mass is large and unilateral or in a young patient, to secure proper treatment of these patients.

Adenocarcinoma↗

PubMed2006

Endometrioid carcinoma simultaneously involving the uterus and the fallopian tube: a clinicopathologic study of 13 cases.

Although the simultaneous presentation of endometrial and ovarian carcinomas of the endometrioid type is well described, little is known about a similar phenomenon involving the endometrium and fallopian tube (FT). We present the clinicopathologic features of 13 such cases seen in the Department of Pathology at The University of Texas M.D. Anderson Cancer Center over an 8 year period (1995 to 2002). FT tumors that could have represented luminal extension of the endometrial carcinoma or that represented an unequivocal metastasis to the FT were excluded. The patients' ages ranged from 34 to 77 years (median 54). The most common symptom was abnormal uterine/vaginal bleeding (11) and all of the patients were considered overweight or obese (mean body mass index was 41). The size of the endometrial carcinomas ranged from 0.3 to 8 cm. According to the FIGO grading of the endometrial endometrioid carcinomas, the cases were distributed as follows: Grade 1 (3) and Grade 2 (10). In 2 cases, there were also small areas of other histologic types, papillary serous carcinoma (1 case), and papillary endometrial carcinoma of intermediate grade (another case). The size of the fallopian tube carcinomas ranged from 0.2 to 17.5 cm. Seven of these tumors were located in the distal/fimbriated end of the FT. There was bilateral involvement in 2 cases. Three of the FT tumors were in situ. The grades of the fallopian tube carcinomas were as follows: Grade 1 (2), Grade 2 (6), and Grade 3 (2). In situ components were seen in all cases. One fallopian tube carcinoma was mixed with serous carcinoma. In 4 cases, there was also an endometrioid carcinoma involving the ovary, all of them with an intact ovarian capsule. Patients were treated as follows: total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) (4), TAH/BSO/chemotherapy (chemo) (4), TAH/BSO/radiation (3), and TAH/BSO/chemo/radiation (2). Follow-up ranging from 6 to 54 months was available in 10 patients: 1 patient died of disease (at 38 mo), 1 patient is alive with disease (at 9 mo), 7 patients have no evidence of disease (6 to 54 mo), and 1 patient died of metastatic endometrial carcinoma (at 9 mo). Simultaneous endometrioid carcinomas of the uterus and FT are unusual and occur primarily in obese perimenopausal women. The tumors are predominantly well or moderately differentiated with dissimilar endometrial and FT grades. The FT carcinoma is usually unilateral and located at the distal end of the tube.

Adult↗

PubMed2006

The recurrence and the overall survival rates of ovarian serous borderline neoplasms with noninvasive implants is time dependent.

Ovarian serous borderline neoplasm with noninvasive implants traditionally have been considered to be nonaggressive tumors associated with an excellent prognosis. However, in our experience, recurrences commonly develop as patients are followed over many years. Eighty cases of advanced-stage ovarian serous borderline tumor with noninvasive implants were identified; the minimum follow-up period for these cases was 5 years or until the death of the patient. The following cases were excluded: patients treated by cystectomy, patients who died of other causes, patients who developed other tumors, and patients who had as the only positive material after resection of the primary borderline neoplasm a tumor detected on a second look or third look operation. Hematoxylin and eosin-stained slides from the original ovarian tumor and the staging biopsies were reviewed in all cases. Slides of the recurrent tumor were available in all cases except for 2 in which the diagnosis was established clinically. The presence or absence of a micropapillary/cribriform pattern and microinvasion in the ovarian tumor was recorded. Follow-up was obtained from the patients' charts. Fischer exact test was used for statistical analysis. The patients' ages ranged from 17 to 67 years (median 36 y). Seventy-three patients were treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. Seven patients were treated by total abdominal hysterectomy and unilateral salpingo-oophorectomy. The International Federation of Gynecology and Obstetrics stage was as follows: stage II (29 cases), stage III (50 cases), and stage IV (1 case). After surgery, 58 patients were treated with chemotherapy, 7 with radiotherapy, and 1 with hormonal therapy. The follow-up ranged from 5 to 31 years (median 15.7 y). Thirty-five patients (44%) developed recurrences. Only 10% of the patients had a recurrence in less than 5 years, 19% had their recurrences between 5 and 10 years, 10% between 10 and 15 years, and 5% more than 15 years after resection of the primary neoplasm. The only statistically significant feature associated with recurrence was the presence of a micropapillary/cribriform pattern, although this pattern was present in only 26% of the cases that recurred. Of the 35 patients who had a recurrence, 2 were diagnosed clinically, both are alive with progressive disease at 1 and 5 years after the diagnosis of the recurrence; 6 had recurrent serous borderline tumors, all are without evidence of disease with a follow-up ranging from 7 to 18 years after resection of the ovarian borderline tumor (median 14 y); and 27 patients subsequently developed low-grade serous carcinoma, 7 are alive with progressive disease with a follow-up ranging from 10 to 29 years (median 15 y) and 20 died of disease between 3 to 25 years after resection of the ovarian borderline tumor (median 16 y). In summary, the true recurrence rate of ovarian serous borderline tumors with noninvasive implants can only be obtained through a long follow-up. In this group of patients, 77% and 34% of the subsequent tumors developed 5 years and 10 years after diagnosis of the ovarian tumor, respectively. Histologic examination of the recurrent tumor is important in determining further therapy and prognosis for these patients; all patients who recurred with borderline tumor are without evidence of disease, whereas 74% of the patients who recurred with low-grade serous carcinoma died of disease. We propose that patients be followed for a minimum of 10 years to evaluate for recurrences and for 20 years to evaluate for survival.

Adolescent↗

PubMed2006

Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma?

Low-grade endometrioid carcinomas, either of the endometrium or the ovaries, usually have an excellent prognosis. The association of this type of tumor with undifferentiated carcinoma is rare. In this study, we present the clinicopathologic features of 25 such cases. The age of the patients ranged from 30 to 82 years (median, 51 years). At presentation, the patients had either vaginal bleeding or pelvic pain. The endometrioid carcinoma involved the endometrium in 14 cases, the endometrium and 1 or both ovaries in 9 cases, and the ovaries in 2 cases. Undifferentiated carcinoma associated with low-grade endometrioid carcinoma was found at presentation in 19 grade 1 or 2 endometrioid carcinomas: 15 in the endometrium and 5 in the ovary. In one of these cases, undifferentiated carcinoma was found in the endometrium and the ovary. Undifferentiated carcinoma was found after resection of low-grade endometrioid carcinoma in six cases, involving the retroperitoneum, pelvis, vagina, or liver. The undifferentiated carcinoma was composed exclusively of diffuse sheets and solid nests of epithelial cells in l0 cases. Epithelial cells with isolated foci of keratinization were seen in nine cases and rhabdoid cells in a myxoid background in six cases. Twenty-four patients were treated with total abdominal hysterectomy and with bilateral salpingo-oophorectomy. Twenty-two patients received additional therapy as follows: chemotherapy (), radiotherapy (), and tamoxifen (). Follow-up showed that 15 patients died of disease in 1 to 60 months (median, 6 months), and 5 patients are alive with progressive disease with a follow-up between 6 and 8 months; 1 patient is alive with no evidence of disease at 104 months. In four cases, the diagnosis was made recently, with short follow-ups of 3 and 4 months. Foci of undifferentiated carcinoma may be confused with solid endometrioid adenocarcinoma erroneously leading to the diagnosis of a grade 3 or a significantly less aggressive grade 2 endometrioid carcinoma. The recognition of undifferentiated carcinoma in an otherwise low-grade endometrioid adenocarcinoma is extremely important because it indicates aggressive behavior. In asynchronous cases, being aware of this association can explain the absence of a second primary.

Adult↗

PubMed2005

Results of a pilot study of multispectral digital colposcopy for the in vivo detection of cervical intraepithelial neoplasia.

OBJECTIVE: Fluorescence spectroscopy is a promising technology for the detection of cervical squamous intraepithelial precancers and cancers. To date, many investigators have focused on point spectroscopy as an adjunct to diagnostic colposcopy. A device that visualizes the whole field of the cervix is needed for screening. To that end, we have developed a multispectral digital colposcope that works through the colposcope to image with white light, UV excitation at 345 nm, and blue light at 440 nm excitation. Here, we report the pilot study that precedes a Phase I trial. METHODS: The MDC system is composed of a light source, a colposcope, and a video rate color CCD camera with a frame grabber and takes approximately less than 1 min to make images of the cervix. Patients were measured at baseline and after acetic acid placement with white light, 345 nm excitation, and 440 nm excitation from the xenon arc lamp. The white light is in the visible spectrum, 345 nm excitation is in the UV spectrum and is not visible, and 440 nm excitation is blue light in the visible spectrum. White light generates a pink image of the cervix. 345 nm excitation, the UV light, excites fluorophores to emit a blue image. 440 nm excitation, the blue light, excites fluorophores to emit a green image. The patients underwent a loop excision procedure and the histopathology was inked and cut into 12 sections by the study pathologists. The histopathologic slides were scanned and the images were then reconstructed into maps. A diagnostic algorithm was calculated. The data were preprocessed, transformed, and analyzed by the K-means clustering method. Disease maps were generated using the algorithm and classifier and compared to white light colposcopy and the blue and green images obtained at 345 and 440 nm. RESULTS: Forty-six patients were measured at four clinical sites. Images were made of the cervix with white light, 345 nm excitation, and 440 nm excitation and are presented in the figures. As the study went on, images improved with improvements in the instrument. The white light and fluorescence images are presented with crudely constructed histopathologic maps and algorithmic maps. At 345 nm excitation, the UV light, histologically confirmed CIN appears darker blue; while at 440 nm excitation, the blue light, histologically confirmed CIN appears lighter green. CONCLUSIONS: This pilot study shows that MDC images can be matched to both histopathologic and algorithmic maps. The device and the algorithm are evolving but show promise. A Phase I trial is planned.

Adult↗

PubMed2005

Subvisual chromatin changes in cervical epithelium measured by texture image analysis and correlated with HPV.

OBJECTIVES: In this study, we are testing the hypothesis that human papillomavirus (HPV) positivity is correlated with chromatin texture in the cell. Interim analyses are important since this study involves 2000 patients and generates 6000 biopsy specimens that will be subjected to quantitative histopathological analysis and correlated to HPV positivity as measured by the Hybrid Capture II test (Digene; Gaithersberg, MD) and both HPV-DNA and mRNA by the polymerase chain reaction (PCR). The studies of optical technologies, from which we derive this sample, use the colposcopically directed and histopathologically classified cervical biopsy as the gold standard. In this report, we describe the results of an interim analysis of quantitative histopathology and chromatin texture as correlates of HPV infection using the cyto-savant system in cytologically and histopathologically negative specimens. METHODS: A group of 1544 patients entered the optical technology trials, generating 3275 biopsies and 1544 Papanicolaou readings. Two hundred forty-eight patients were cytologically and histopathologically negative. Study pathologists reviewed histologic samples 3 times in a blinded fashion. Non-overlapping, quantitatively stained nuclei were selected from the samples by the pathologists. HPV testing was done using the PCR method and the Hybrid Capture II test. Statistical analysis involved the creation of a classification matrix using a linear discriminant analysis. The matrix was trained on HPV-positive cells by PCR. The analysis included the random creation of both a training set and a validation set that were classified based on the discrimination score obtained by correlating nuclear texture with HPV positivity. RESULTS: The sensitivity of the classification was 52-54% and the specificity was 77-78%. Overall, a 68% predicted accuracy was achieved for both the training set and the test set. The agreement of a test and training set shows that the sets created randomly are indeed similar, and that the discrimination score worked equally well in both sets of cells. Once a cell-by-cell algorithm for HPV positivity was derived, HPV positivity was recalculated on the basis of cell-by-cell texture features. HPV positivity was then recalculated on both a per-biopsy basis and a per-patient basis. For HPV 16 and 18, the positivity rate was 70% on a per-biopsy basis and 73% on a per-patient basis. CONCLUSIONS: Although these results are preliminary, they suggest that texture features reflecting chromatin condensation may correlate with HPV positivity. The current sample is histologic, the analysis suggests that in a cytologic sample, HPV positivity could be detected or confirmed by texture features computed as part of an HPV-associated score. Additional biologic markers could be used as needed. While this study was performed on histologic samples, a study of cytologic samples would be more useful. Future studies will examine chromatin texture compared to HPV integration and mRNA HPV expression.

Adolescent↗

PubMed2005

Classification using the cumulative log-odds in the quantitative pathologic diagnosis of adenocarcinoma of the cervix.

INTRODUCTION: This study develops a method that discriminates between normal and cancerous tissue sections (i.e., populations of cells) using a statistical model applied to high-dimensional quantitative measurements made on a sample of cells. MATERIALS AND METHODS: We use a cumulative log-odds model to create a score for a tissue section using the information from the cells within that tissue section. Then, a threshold is determined using receiver operating characteristic (ROC) curve analysis. The method was tested using data from cervical adenocarcinomas, adenocarcinoma in situ, and normal columnar tissue. RESULTS: Using 120 potential features, we analyzed the data for staining-independent features. Twenty-two features were statistically significant. We then calculated the log-odds and created a score, followed by ROC curve analysis. The operating point which maximizes the sum of the specificity and sensitivity achieved a sensitivity of 100% with a specificity of 85%. CONCLUSION: The cumulative log-odds performs well in classifying tissue sections using high-dimensional data measured at the cellular level, like that of quantitative pathology. This methodology potentially has applications in pathology, radiology, and optical technologies.

Adenocarcinoma↗

PubMed2005

Kappa statistics to measure interrater and intrarater agreement for 1790 cervical biopsy specimens among twelve pathologists: qualitative histopathologic analysis and methodologic issues.

BACKGROUND: As part of a program project to evaluate emerging optical technologies for cervical neoplasia, we performed fluorescence and reflectance spectroscopic examinations of patients with abnormal Papanicolaou smears. Biopsy specimens were taken from each area and measured optically, and study pathologists performed qualitative histopathologic readings. Several methodologic issues arose in this analysis: (1) the interpathologist and intrapathologist agreement between institutions for the 1790 biopsy specimens; (2) the interinstitutional agreement among the two institutions conducting the trials on 117 randomly chosen biopsy specimens; (3) the interinstitutional agreement among the two institutions and a third expert gynecologic pathologist to ensure the expert readings were comparable to those outside both institutions on 117 randomly chosen biopsy specimens; and (4) an additional three reviews of the 106 difficult biopsy specimens by all three institutions. METHODS: All 1790 specimens from 850 patients were reviewed three times at each institution in blinded fashion; those for which the first and second reviews were identical were not reviewed a third time. A randomly selected sample of 117 specimens was randomly ordered and read by study pathologists at The University of Texas M. D. Anderson Cancer Center, British Columbia Cancer Agency (BCCA), and Brigham and Women's Hospital (BWH). The 106 difficult cases were treated in the same manner as the randomized and random-ordered cases. Generalized, unweighted, and weighted kappas and their 95% confidence intervals were used to assess agreement. Binary comparisons were used to compare diagnostic categories. FINDINGS: The kappas for the three readings of the overall data set using eight-category World Health Organization (WHO) criteria were as follows: 0.66 for the generalized, 0.72 for weighted, and ranged from 0.59 to 0.94 unweighted binary categories; those read using four-category Bethesda criteria: 0.70 for generalized, 0.69 for weighted, and 0.56-0.94 for unweighted binary categories. For the pool versus the study pathologist readings, the eight-category kappa was 0.51 for generalized, 0.72 for weighted, and 0.56-0.82 for unweighted binary categories; for those read using Bethesda criteria: 0.70 for generalized, 0.70 for weighted, and 0.59-0.82 for the unweighted binary categories. The interpathologist and intrapathologist readings were fair by Landis standards at the low end of the diagnostic scale (atypia, human papillomavirus, and CIN1) and substantial to almost perfect at the high end (CIN2, CIN3, and CIS). The randomly selected and randomly ordered sample of 117 specimens read with the WHO system yielded a generalized kappa of 0.45; among the three institutions (M. D. Anderson Cancer Center vs. BCCA, M. D. Anderson vs. BWH, and BCCA vs. BWH), the unweighted kappas were 0.46, 0.41, and 0.49 and the weighted were 0.65, 0.66, and 0.68, respectively; for the Bethesda, a generalized kappa of 0.65, unweighted kappas of 0.66, 0.65, and 0.47, and weighted of 0.74, 0.72, and 0.74. The difficult specimens read with the WHO system yielded a generalized kappa of 0.23; among the three institutions the unweighted kappas were 0.20, 0.30, and 0.37, and the weighted were 0.17, 0.34, and 0.31; for the Bethesda, a generalized kappa of 0.25; among the three institutions, the unweighted kappas were 0.21, 0.32, and 0.37, and the weighted were: 0.07, 0.21, and 0.37, respectively. INTERPRETATION: Kappas in this expert group of pathologists were in the moderate, substantial, and almost perfect ranges for the overall and randomized samples. The randomized sample was representative of the larger sample. The kappa of the specimens for which disagreements arose was, predictably, in the slight range. Our findings will aid both the correlations with optical measurements using fluorescence and reflectance spectroscopy and the quantitative histopathologic analysis of these study specimens.

Biopsy↗

PubMed2005

Cervical chromosome 9 polysomy: validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial.

BACKGROUND: Several genetic alterations have been described in cervical cancers including: human papillomavirus (HPV) E6 and E7 oncoproteins, subtle sequence changes, alterations in chromosome number, chromosome translocations, and gene amplifications. This report focuses on establishing chromosome 9 polysomy as a cervical biomarker of chromosome instability and using it in a chemoprevention trial. Chromosomal instability is a feature of most human cancers and is probably an early event in the process. METHODS: We used 37 cervical cone specimens to validate chromosome 9 polysomy as a biomarker and then tested its modulation in a randomized clinical trial of 4-hydroxyphenylretinamide (4-HPR) in 39 patients with three blinded histopathologic reviews. No confounders were identified. In the present study, immunohistocytochemical analysis of Chromosome 9 polysomy was carried out and quantitatively measured. RESULTS: The Cell Index, the ratio of the number of total chromosome 9 copies to the total number of ells, increases significantly in archival samples as the cervix changes from normal to CIN to invasive cancer. In the chemoprevention trial, chromosome 9 polysomy was used as a biomarker and supported the histological analysis showing that 4-HPR impaired the natural regression response. CONCLUSIONS: Chromosome 9 polysomy appears to be a marker of genetic instability that can be used in chemoprevention trials as a surrogate endpoint biomarker. In this randomized trial of 4-HPR, the chromosome 9 polysomy measurements supported the clinical histopathologic reading in a quantitative manner suggesting that 4-HPR at 200 mg/day may have been inhibiting the regression seen in the placebo arm by inducing genetic instability.

Aneuploidy↗

PubMed2005

Sources of scattering in cervical tissue: determination of the scattering coefficient by confocal microscopy.

Most models of light propagation through tissue assume that the scattering properties of various tissue layers are the same. We present evidence that the scattering coefficient of cervical epithelium varies by a factor of 3 within the epithelium owing to variations in nuclear density and to the presence of keratin. We estimated the scattering coefficient from regions of normal and precancerous cervical epithelium by fitting reflectance measurements from confocal images to an exponential function of depth based on Beer's law of attenuation. The results suggest that the normal cervix is characterized by highly variable scattering in the superficial epithelium, low scattering in the intermediate epithelium, and high scattering in the basal and stromal regions. In high-grade dysplasia, high scattering from high-density nuclei is observed throughout the entire epithelium.

Algorithms↗

PubMed2005

Results of a phase II double-blinded randomized clinical trial of difluoromethylornithine for cervical intraepithelial neoplasia grades 2 to 3.

PURPOSE: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m2, versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels. EXPERIMENTAL DESIGN: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix. RESULTS: There were no statistically significant differences among the arms in histopathologic response. This could no be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology. CONCLUSIONS: DFMO is no active at 0.125 and 0.5 gm/m2 for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noted in trials of actinic keratoses.

Adolescent↗

PubMed2005

Undifferentiated carcinoma of the endometrium.

Undifferentiated carcinoma arising in the endometrium is considered a rare neoplasm with only a few studies published thus far. This limited number of studies is most likely a reflection of the underrecognition of this tumor because of a lack of diagnostic criteria to separate it from endometrial endometrioid adenocarcinoma, FIGO grade 3. In this study, we present the clinicopathologic features of 16 cases of endometrial undifferentiated carcinoma. In addition, we review the clinicopathologic features of 33 cases of endometrial endometrioid adenocarcinoma, FIGO grade 3, and compare them with the undifferentiated cases. The age of the 16 patients with undifferentiated carcinoma of the endometrium ranged from 40 and 69 years (mean, 59 years). Stage was known in 13 patients. Six (46%) patients presented with early stage disease (4 stage I and 2 stage II). Seven (54%) patients presented with advanced stage disease (2 stage III and 5 stage IV). Staging information was not available for 3 patients. Undifferentiated carcinoma was characterized by a proliferation of medium-sized, monotonous, epithelial cells growing in solid sheets with no specific pattern. Glands were not identified. Keratin immunostaining was focally positive in 11 of 12 cases, and EMA was focally positive in all 12 cases. The age of the 33 patients with endometrial endometrioid carcinoma, FIGO grade 3, ranged from 40 to 90 years (mean, 68 years). Twenty-three (70%) patients presented with early stage disease (21 stage I and 2 stage II), and 10 (30%) patients presented with advanced stage disease (8 stage III and 2 stage IV). Focal glandular differentiation was seen in all cases. The solid component was different from the one seen in the undifferentiated carcinomas because well demarcated trabeculae, cords, or groups of cells were identified in all cases. The tumor cells in the solid areas resembled the cells in the glandular component of the tumor. Immunoperoxidase studies for keratin and EMA were positive in 23 of 23 cases. Twelve of the 16 (75%) patients with undifferentiated carcinoma died of disease; 10 (62.5%) of them within 5 years after diagnosis. In contrast, 13 of 33 (39.4%) patients with endometrial endometrioid carcinoma, FIGO grade 3, died of disease. Twelve (36.4%) died within 5 years after diagnosis. In summary, undifferentiated carcinoma of the endometrium appears to be more aggressive than endometrial endometrioid adenocarcinoma, FIGO grade 3. Its proper recognition is important for prognosis and potentially for therapy.

Adenocarcinoma↗

PubMed2005

An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms.

Ovarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Recently, a dualistic pathway of ovarian serous carcinogenesis has been proposed based on morphologic observations and molecular genetic analysis. In this scheme, low-grade OSC arises in a stepwise fashion from a benign serous cystadenoma through a usual serous borderline tumor through a micropapillary variant of serous borderline tumor. In contrast, the more common high-grade OSC arises de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts with an as yet unrecognized precursor lesion. Although the division of OSC into low- and high-grade variants is gaining greater acceptance, and although there is accumulating molecular genetic evidence for this, there is little published information regarding a comparison of protein expression between these two types of OSC. In this study, we have investigated the immunohistochemical expression of a wide range of proteins in cases of low-grade (n = 22) and high-grade (n = 47) OSC. Antibodies used were p53, MIB1, BCL2, WT1, HER-2/neu, C-KIT, osteopontin, and survivin. For all antibodies, except MIB1, cases were scored as 0 (negative or occasional positive cells), 1+ (<10% cells positive), 2+ (10%-25% cells positive), 3+ (26%-50% cells positive), 4+ (51%-75% cells positive) or 5+ (>75% cells positive). For MIB1, the percentage of positive nuclei was calculated. There was a statistically significant higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade compared with low-grade OSC (P < 0.05). Thirty of 47 (64%) cases of high-grade OSC exhibited 5+ staining with p53 compared with 4 of 22 (18%) low-grade neoplasms. Twelve of 47 (26%) high-grade OSCs exhibited 5+ staining with BCL2 compared with 1 of 22 (5%) low-grade OSCs. The mean MIB1 proliferative index in high-grade OSCs was 55.4% compared with 23.0% in low-grade OSCs. Virtually all cases of both low-grade and high-grade OSCs exhibited diffuse nuclear positivity with WT1 and diffuse cytoplasmic positivity with survivin. Osteopontin expression was variable with no significant difference in expression between low-grade and high-grade OSC. Although expression of both HER-2/neu and C-KIT was significantly higher in high-grade compared with low-grade OSC, only rare cases exhibited strong positivity with these antibodies, which could be of therapeutic value in individual cases, although this would require additional molecular investigations. The significant differences in protein expression between low-grade and high-grade OSC provides further support for a different underlying pathogenesis. In particular, the differences in p53 immunoreactivity are in keeping with the observation that p53 gene mutation is more common in high-grade than low-grade OSC.

Biomarkers, Tumor↗

PubMed2005

Differential expression of WT-1 in serous carcinomas in the peritoneum with or without associated serous carcinoma in endometrial polyps.

Although differential WT-1 expression between ovarian and uterine serous carcinoma has been discussed in the literature, there have been no studies of WT-1 expression in serous carcinomas in the peritoneum with or without concurrent serous carcinoma in an endometrial polyp. This study addresses this issue and includes a small series of uterine and ovarian serous carcinomas for comparison. Nine peritoneal serous carcinomas with coexistent serous carcinoma in an endometrial polyp, 10 peritoneal serous carcinomas without serous carcinoma in an endometrial polyp, 9 uterine serous carcinomas, and 12 ovarian serous carcinomas were stained with antibody to WT-1. Ninety-two percent of ovarian serous carcinomas and 80% of peritoneal serous carcinomas without serous carcinoma involving an endometrial polyp expressed WT-1. In contrast, 12% of peritoneal serous carcinomas with serous carcinoma in an endometrial polyp expressed WT-1 with the serous carcinoma in the endometrial polyp staining concordantly. For uterine serous carcinoma without an endometrial polyp, only 11% expressed WT-1. Peritoneal serous carcinomas without coexistent serous carcinoma in an endometrial polyp have a WT-1 expression pattern similar to ovarian serous carcinoma while peritoneal serous carcinomas with coexistent serous carcinoma in an endometrial polyp have a staining pattern similar to uterine serous carcinoma. The difference in WT-1 expression among serous carcinomas suggests a difference in biology based on the site of origin. Additionally, the difference in WT-1 expression between peritoneal serous carcinomas with and without coexistent serous carcinoma in endometrial polyps suggests that peritoneal serous carcinoma may have different pathogenetic pathways.

Cystadenocarcinoma, Serous↗

PubMed2004

Exploratory analysis of quantitative histopathology of cervical intraepithelial neoplasia: objectivity, reproducibility, malignancy-associated changes, and human papillomavirus.

BACKGROUND: As part of a project to evaluate emerging optical technologies for cervical neoplasia, our group is performing quantitative histopathological analyses of biopsy specimens from 1,190 patients. Objectives in the interim analysis are (a) quantitatively assessing progression of the neoplastic process of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesions (SIL), (b) detecting malignancy-associated changes (MACs), and (c) phenotypically measuring human papillomavirus (HPV) detected by DNA testing. METHODS: The diagnostic region of interest (ROI) from immediately adjacent sections were imaged, and the basal lamina and surface of the superficial layer were delimited. Nonoverlapping quantitatively stained nuclei were selected from 1,190 samples with histopathological characteristics of normal (929), koilocytosis (130), CIN 1 (40), CIN 2 (23), and CIN 3/carcinoma in situ (CIS) (68). A fully automatic procedure located and recorded the center of every nucleus in the region of interest (ROI). We used linear discriminant analysis to assess the changes between normal and CIN 3/CIS. RESULTS: Scores computed from the cell-by cell features and the clinical grade of CIN/SIL were highly correlated, as were those of the architectural features and the clinical grade of CIN/SIL. We found even higher correlations between a combination of cell-by-cell and architectural scores, and clinical grade. Using these scores, we found MACs in the normal biopsy specimens from patients with high-grade CIN/SIL. Furthermore, the same scores correlated with the molecular detection of HPV. CONCLUSIONS: Quantitative histopathology can be used in large clinical trials as an objective and reproducible measure of CIN/SIL. Detectable phenotypic changes correlate well with CIN/SIL neoplastic progression. It can also be used to infer the presence of CIN/SIL (MACs) and molecular changes associated with increased risk of cancer development (high-risk HPV).

DNA, Viral↗