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The human brain’s interregional communication is vital for its proper functioning. A promising direction for investigating how these regions communicate relies on the assumption that the brain is a complex network. In this context, images derived from positron emission tomography (PET) have been proposed as a potential source for understanding brain networks. However, such networks are often assembled via direct computation of inter-subject correlations, neglecting variabilities between subjects and jeopardizing the construction of group representative networks. Here, we used [18F]FDG-PET data from 1027 individuals at different syndromal stages (352 CU, 621 MCI and 234 AD) to develop a novel method for constructing stable (i.e. resilient to spurious data points) metabolic brain networks. Our multiple sampling (MS) scheme generates brain networks with higher stability when compared to the conventional approach. In addition, the proposed method is robust to imbalanced datasets and requires 50% fewer subjects to achieve stability than the conventional approach. Our method has the potential to considerably boost PET data reutilization and advance our understating of human brain network patterns in health and disease.

Background Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers. Methods We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer’s Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by [18F]flurodeoxyglucose ([18F]FDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model. Results A total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional [18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the [18F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [18F]FDG uptake in DIAD mutation non-carriers. Conclusions The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterised neurological syndromes involving the peripheral and central nervous system (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with central nervous system inflammation (encephalitis and acute disseminated encephalomyelitis) (14800pg/mL [400, 32400]), compared to those with encephalopathy (1410pg/mL [756, 1446], peripheral syndromes (GBS) (740pg/mL [507, 881]) and controls (872pg/mL [654,1200]). Serum neurofilament light levels were elevated across patients hospitalised with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19., Graphical Abstract Graphical Abstract

STAGING In 2000 FIGO recommended a clinical staging of gestational trophoblastic tumors and requested that such cases should be reported to the Annual Report on the Results of Treatment in Gynecological Cancer. For this purpose the definitions of the clinical stages of gestational trophoblastic tumors are presented in Table 1. According to FIGO, hydatidiform mole should be registered but not be staged as Stage 0 because if hCG persists and the patient requires chemotherapy restaging would be required. Such restaging transgresses the basic principle of any staging system. Patients with hydatidiform mole are placed on record but staging only applies to trophoblastic neoplasia. Cases which do not fulfill the criteria for any given stage should be listed separately as unstaged. It should be realized that most cases of low risk metastatic disease are comprised by Stage III, while the high risk group of metastatic tumors first described by Hammond is the group that comes under Stage IV. In 2000 FIGO accepted the World Health Organization scoring system based on prognostic factors that were first devised by Prof. Kenneth Bagshawe. The score values for the risk factors will be 1, 2 and 4. Blood groups will not be used in the scoring system. Liver metastases will be given a score of 4. The cut-off score for low-risk and high-risk neoplasia was ratified by the June 2002 FIGO Committee on Gynecologic Oncology announcement. A score of 6 or less is low risk disease treatable by single agent chemotherapy. A score of 7 or greater is high risk disease that requires combination chemotherapy. Medium risk disease has been eliminated. This combining of the modified WHO risk factor scoring system with the FIGO staging was accepted by the FIGO Committee on Gynecologic Oncology in September 2000 and ratified in June 2002 with the FIGO announcement. It is now part of the FIGO staging and scoring system for gestational trophoblastic neoplasia.

The major task faced by a clinician having made a diagnosis of cancer is to determine the most effective therapy and formulate a prognosis for the patient. In order to optimally manage a cancer, both the extent of the disease and the knowledge of its biology are essential. The extent of the disease is generally expressed in terms of its stage. The major purpose of staging that has been agreed upon internationally is to offer a classification of a cancer’s extent so as to provide a method of conveying ones clinical experience to others for the comparison of treatment methods without confusion or ambiguity. Cancer staging is central to the modern management of cancer patients. Cancer is also a biologic continuum and a dynamic process, which is artificially compartmentalized by staging systems. It is clear, however, that the phases or sub-stages must have clinical relevance. Cancer staging systems should also be evidence-based and they should be user friendly. Staging systems need to be based on the best available knowledge at hand and this implies that the changes will occur over time based upon the development or the acquisition of new knowledge. It also follows that the acquisition of this knowledge is facilitated by the use of staging system insofar as staging will help with knowledge creation by facilitating clinical research, producing new data on similar groups of patients and also by integrating this new data about similar patients from diverse sources. Staging also helps knowledge dissemination by providing a common international language for information sharing and facilitates the teaching of both new and established health care workers. Gynecologists have a long and proud tradition of using staging systems for female cancers, dating back to the League of Nations staging system for cervical cancer, first published in 1920. In 1954 FIGO assumed the patronage of the Annual Report on the Treatment of Gynecological Cancer. With it also came the responsibility for overseeing the staging of gynecological cancers, which were at the heart of the Annual Report data and information system. Since that time the FIGO Oncology Committee has made several modifications to the various staging systems for gynecological cancer, most notably those for cervix and endometrial cancer. 1954 also saw the UICC set up a committee on clinical stage classification and applied statistics, which had as its aim the extension of the general technique of classification of cancer at all sites by anatomical extent of the disease using the TNM system. The FIGO system of classification was originally based on clinical examination, essentially of the anatomical extent of disease. Over the years all staging systems for gynecological cancers, with the exception of cervical cancer and gestational trophoblastic neoplasia, have moved from a clinical basis to one of a surgical pathological nature. The classification system and stage grouping, once established, must remain unchanged in medical records. Clinical stage is essential to select and evaluate therapy, while the pathological stage provides the most precise data to estimate prognosis and calculate end results. The FIGO and TNM classifications are virtually identical. The TNM Prognostic Factor Project Committee has graciously agreed to defer to all questions regarding staging of gynecological cancer to the FIGO Committee on Gynecologic Oncology. In conclusion, any good staging system must have three basic characteristics. It must be valid, reliable, and above all, it must be practical. Validity means that the staging system must allow for the creation of groups of cases, that experience similar outcomes at the same time reflecting a full range of possible presentations for each type of cancer. Also over time, the system in order to retain its validity must be flexible so that it can adapt to important changes in medical care. A reliable staging system should ensure that identical cases would always be assigned to the same stage category. It should be unambiguous; it should be based as far as possible on measurement quantities that have been evaluated objectively. The system should also not be subject to frequent changes until sufficient data and information is obtained to warrant such changes. Finally, a practical staging system must be suitable for day to day use in a wide range of clinical environments and must not require diagnostic procedures that are not readily available to most practitioners or extraordinary expertise or knowledge regarding a particular malignancy. The staging classification is reported at the beginning of each tumor site section, along with rules and recommendations.

Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1,000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed, and 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92-1.00] and an estimated specificity of 0.71 [95% CI = 0.62-0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI = 0.81-0.89). The per-patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer.

We evaluated the performance of the Papanicolaou smear in screening and diagnostic settings.We analyzed Papanicolaou smear results of 1,850 women recruited into a clinical trial to evaluate an emerging technology for the detection of cervical cancer. Screening and diagnosis groups were based on the history of previous Papanicolaou smear results. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic curves, and areas under the receiver operating characteristic curve (AUC).In the screening group, by defining disease as cervical intraepithelial neoplasia (CIN) 2,3/cancer or worse and using high-grade squamous intraepithelial lesion (HSIL) as the test cutpoint, the AUC was 0.689, and the LR+ and LR- were 39.25 and 0.67, respectively. In the diagnosis group, the AUC was 0.764, and the LR+ and LR- were 3.79 and 0.56, respectively. By defining disease as human papillomavirus/CIN 1 or worse and HSIL as the test cutpoint, the AUC was 0.586, and the LR+ and LR- were 17.01 and 0.92 in the screening group; in the diagnosis group, the AUC was 0.686, and the LR+ and LR- were 2.77 and 0.75, respectively.In a screening setting, a Papanicolaou smear result of HSIL or worse is 39 times more likely in a patient with CIN 2,3/cancer than in a patient without it. This compares to 4 times more likely in the diagnostic setting. The magnitude of the positive likelihood ratio observed in the screening group indicated that abnormal Papanicolaou smear results obtained in the screening setting should have more impact on clinical decision making than those from results obtained in the diagnostic setting.

BACKGROUND. Because 80% of cervical cancers arise in low-resource settings, many inexpensive strategies are being tested. In that spirit, the authors are testing large-scale genomic or DNA ploidy measurements as an inexpensive and semiautomated strategy. METHODS. Patients entered either a screening or diagnostic study of several optical technologies: quantitative cytology, quantitative histopathology, and fluorescence and reflectance spectroscopy using a point probe, a multispectral digital colposcope, or a combination of the two. We calculated sensitivities, specificities, positive and negative predictive values, and their confidence interval testing conventional cytology, Hybrid Capture (HC) II testing, and DNA ploidy measured on the Feulgen-stained quantitative Pap smear. RESULTS. The current investigation reports on 1555 patients for whom colposcopically directed biopsies were read 3 times by study pathologists. The final histopathologic diagnosis was high grade (cervical intraepithelial neoplasia [CIN] 2, CIN 3, carcinoma in situ [CIS], and cancer) in 16% of patients. Using high-grade squamous intraepithelial lesions (SILs) histopathology as the threshold and gold standard, the sensitivity and specificity, respectively, were: 0.47 and 0.96 for conventional cytology, 0.91 and 0.80 for HC II, and 0.59 and 0.93 for DNA ploidy. The positive and negative predictive values (PPV, NPV) for conventional cytology were 0.70 and 0.90, 0.46 and 0.98 for HC II, and 0.63 and 0.92 for DNA ploidy. CONCLUSIONS. DNA ploidy shows comparable sensitivity, specificity, PPV, and NPV values to conventional cytology and HC II. Unlike conventional cytology, DNA ploidy is semiautomated and can be performed in less than 8 hours. Cost effectiveness studies are under way, but in the authors' laboratory DNA ploidy is inexpensive. Cancer 2006. © 2006 American Cancer Society.

Objective To determine the probabilities of transition of stages in the natural history of cervical cancer by conducting a meta-analysis of published studies on the topic. Study Design We identified health states of interest in the natural history of cervical precancer, identified all possible papers that could meet selection criteria, developed relevance and acceptability criteria for inclusion, then thoroughly reviewed the selected studies. To determine the transition probability data we used a random effects model. Results We determined probabilities for 4 health state transitions. The 6-month mean predictive transition probability (95% confidence intervals with prediction interval in parentheses) for high grade squamous intraepithelial lesions (HSIL) to cancer was 0.0037 (0.00004, 0.03386), for low grade squamous intraepithelial lesions (LSIL) to HSIL was 0.0362 (0.00055, 0.23220), for HSIL to LSIL was 0.0282 (0.00027, 0.35782), and for LSIL to normal was 0.0740 (0.00119, 0.42672). Conclusion The transition probabilities between cervical cancer health states for 6-month intervals are small; however, the cumulative risk of cervical cancer is significant. Markers to identify the cervical precursors that will lead to the transition to cervical cancer are needed.

Objectives: To determine the factors that influence risk of cervical cancer after three consecutive negative Pap smears. Methods: A cohort study was conducted using data from the British Columbia Cervical Cancer Screening Program and British Columbia Cancer Registry. Analysis was based on a one percent sample of women aged 20-69 years with Pap smears enriched with all invasive cervical cancer cases diagnosed between 1994-99. Screening intervals, after three negative screens, were created with the following variables: age at beginning of interval, interval length, previous cytologic abnormality and previous cervical procedure. The risk of cervical cancer by histologic type was calculated using survival analysis methods. Results: The sample consisted of 10,509 women, who contributed 28,309 intervals, and 371 cervical cancer cases. The incidence rate of invasive squamous cervical cancer increased with time since last screen up to six years. Women with a history of dysplasia remained at elevated risk for squamous cancer, hazard ratio=2.6 (95% confidence interval [CI]=1.9, 3.4) but age or previous procedure were not related to risk. No relationship between time since last screen and non-squamous cancer risk was found although history of a previous procedure was significant. The marginal effectiveness of Pap smears declined with increasing frequency of use. Conclusions: This study confirmed the preventive effect of Pap smear screening and its dependency on frequency of use. Women with a history of dysplasia, prior to three consecutive negatives, were at increased risk of developing invasive squamous cervical cancer compared with women with no such history.

In 1991, FIGO added non-surgical-pathologic prognostic risk factors to the classic anatomical staging system. These include urinary hCG levels >100000mIU/ml and/or serum b-hCG >40000mIU/ml and the duration of an antecedent pregnancy being >6 months. Since gestational trophoblastic diseases (GTD) have a very high cure rate in virtually all patients, the ultimate goal of staging is to differentiate patients who are likely to respond to less intensive chemotherapeutic protocols, from those who will require more intensive chemotherapy in order to achieve remission. Staging should be based on history, clinical examination, and appropriate laboratory and radiological studies. Since hCG and b-hCG titers accurately reflect clinical disease, histologic verification is not required for diagnosis, although it may aid in therapy.

Primary site The vagina extends from the vulva upward to the uterine cervix. Cases should be classified as carcinoma of the vagina when the primary site of the growth is in the vagina. Tumors present in the vagina as secondary growths from either genital or extra-genital sites should be excluded. A growth that has extended to the portio and reached the area of the external os should always be allotted to carcinoma of the cervix. A growth limited to the urethra should be classified as carcinoma of the urethra. Tumor involving the vulva should be classified as carcinoma of the vulva. There should be histologic verification of the disease. Nodal stations The vagina is drained by lymphatics to the pelvic nodes in its upper two-thirds and to the inguinal nodes in the lower third. Metastatic sites The most common sites of distant spread include the lungs, liver and bony skeleton. The rules for staging are similar to those for carcinoma of the cervix.

Slow but steady progress has been made in the earlier diagnosis and better treatment of gynecological cancers, particularly over the last 50 years. Cervical cytology screening programs, where implemented, have led to a remarkable reduction in both the incidence and mortality from clinically invasive cervical cancer. This relatively simple technology has been truly one of the major success stories of modern medicine, but unfortunately this technique has not been uniformly applied to all women in the world, particularly to women in developing countries. New research into cervical cancer etiology, the role of HPV, and the development of vaccines against this virus offer a great hope particularly for developing countries. In addition, the combination of radiotherapy and chemotherapy has resulted in a marked improvement in outcome results for women with advanced cervical cancer. Ovarian cancer has seen the development of effective chemotherapy strategies for this disease. Currently this disease remains one of the major scourges in industrialized countries but the continued evolution of knowledge with regard to optimum sequencing of chemotherapeutic agents and surgery offers the prospect for better outcomes, less morbidity and a better quality of life. Ongoing research into the development of newer chemotherapeutic agents and a better understanding of the actual mechanisms regarding the efficacy of chemotherapy and drug resistance offers great promise for the future. Endoscopic surgery for staging and also for therapy shows promise for improved quality of life as well as outcomes for patients in the future and offers the challenge of trying to make this technology readily available to all women in the world. As we gain a better understanding of the molecular basis of disease and health we will truly be able to intervene in a preventive mode in the new millennium.

Organized cervical cancer screening services consisting of conventional Papanicolaou cervical smears, colposcopy, and related treatment modalities are readily available in all provinces. The purpose of this report was to study the impact of colposcopy usage and costs on cervical cancer incidence and mortality rates in several Canadian provinces. Knowledge of such information is essential before newer technology such as liquid-based cytology and human papillomavirus testing is introduced or replaces the traditional systems used.The Ministries of Health of five provinces were contacted and asked to furnish information on the number of colposcopic services and fee-for-service costs for these and for cryosurgery, carbon dioxide laser vaporization, loop electrosurgical excisions, and cold-knife conizations for the year 2000. Canadian Cancer Society estimates of incidence and mortality rates for cervical cancer were also obtained.All provinces had similar incidence and mortality rates for cervical cancer; however, the number of colposcopic services on a per-capita basis varied substantially, with Manitoba and Ontario having rates that were approximately two or three times higher. Fee-for-service payments for colposcopy were similar in the Provinces studied but unit costs for surgical treatment services were highest in Ontario and British Columbia.Although both the incidence and mortality rates for cervical cancer in Canada fell dramatically after the Walton Report in 1976, these rates have plateaued over the past decade despite widespread availability of colposcopy and related ambulatory treatment services. Higher rates of colposcopy usage do not seem to result in lower incidence rates for this disease. Unit costs for colposcopy are similar among the provinces reviewed, but substantial difference exists for certain treatment services. Additional studies are recommended before the widespread introduction or replacement of existing methods with newer, more costly techniques.

The purpose of this study was to document some of the results of a comprehensive provincial cytology and colposcopy program for the year 1988 and also to review the impact on the incidence and mortality rates for a clinical carcinoma of the cervix.This study is a retrospective analysis of the cytologic results of all patients examined provincially in 1988 and a review of the clinical records of patients diagnosed with invasive cancer and those who died of disease.In 1988 490,985 women (40% of all women over the age of 15 in the population) were screened, with 9.2% showing abnormal cells. A total of 79% of women screened were less than 50 years old and accounted for 86.3% of all abnormal smears. Women less than 35 years old were more likely than older women to have moderate dyskaryosis or worse.Intensive comprehensive cytology and colposcopy programs reduce not only the incidence and mortality of clinical carcinoma of the cervix but also rates of in situ disease and other precursors.

Objective: We sought to evaluate the performance of the human papillomavirus high-risk DNA test in patients 30 years and older. Materials and Methods: Screening (n = 835) and diagnosis (n = 518) groups were defined based on prior Papanicolaou smear results as part of a clinical trial for cervical cancer detection. We compared the Hybrid Capture II (HCII) test result with the worst histologic report. We used cervical intraepithelial neoplasia (CIN) 2/3 or worse as the reference of disease. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR−), receiver operating characteristic (ROC) curves, and areas under the ROC curves for the HCII test. We also considered alternative strategies, including Papanicolaou smear, a combination of Papanicolaou smear and the HCII test, a sequence of Papanicolaou smear followed by the HCII test, and a sequence of the HCII test followed by Papanicolaou smear. Results: For the screening group, the sensitivity was 0.69 and the specificity was 0.93; the area under the ROC curve was 0.81. The LR+ and LR− were 10.24 and 0.34, respectively. For the diagnosis group, the sensitivity was 0.88 and the specificity was 0.78; the area under the ROC curve was 0.83. The LR+ and LR− were 4.06 and 0.14, respectively. Sequential testing showed little or no improvement over the combination testing. Conclusions: The HCII test in the screening group had a greater LR+ for the detection of CIN 2/3 or worse. HCII testing may be an additional screening tool for cervical cancer in women 30 years and older. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2865–71)

Objective The study was undertaken to provide consensus guidelines for the management of women with a cytologic interpretation of high-grade squamous intraepithelial lesion (HSIL) on cytologic examination. This review article presents relevant literature supporting the proposed guidelines. Participants An independent panel of 121 experts in various aspects of the diagnosis and management of cervical cancer precursors, including representatives from 29 participating professional organizations, federal agencies, national and international health organizations, and others were invited by the American Society for Colposcopy and Cervical Pathology. Consensus process Guidelines for the management of women with HSIL cytologic results were developed through a multistep process. Draft management guidelines were developed by the HSIL working group after formal literature reviews and obtained input from the professional community at large by way of an interactive internet-based bulletin board. At the American Society for Colposcopy and Cervical Pathology Consensus Conference, September 6 through 8, 2001, in Bethesda, Maryland, the guidelines were discussed, revised, and adopted by formal vote. Conclusions Evidence-based guidelines have been developed for the management of women with HSIL cytologic results.

Summary In a see-and-treat protocol, patients referred for colposcopy because of an abnormal Pap smear in cervical-cancer screening can be treated by loop excision, without biopsy, during one visit to the clinic. However, overtreatment in the see-and-treat strategy has been reported to be 1·2–83·3% for low-grade squamous intraepithelial lesions (SIL) and to be 13·3–83·3% for high-grade SIL. Range of overtreatment narrowed to 4·0–23·5% for those with normal pathology and to 18·0–29·4% for those with normal or low-grade pathology when calculation of overtreatment was restricted to patients diagnosed with high-grade SIL on colposcopy and referral Pap smear. Most common treatment complications are bleeding and infection. Nonetheless, the strategy has become accepted internationally: low costs, decreased patient anxiety, and increased compliance make it appealing, especially in settings with limited health resources, and for patients at risk of not being treated in a timely manner or of not returning for a second appointment. Mathematical modelling may give information about the appropriateness and usefulness of this treatment while the results of long-term clinical trials are awaited.

Rules related to staging: • Corpus cancer is now surgically staged, therefore procedures previously used for determination of stages are no longer applicable (e.g. the findings of fractional curettage to differentiate between Stage I and Stage II). • It is appreciated that there may be a small number of patients with corpus cancer who will be treated primarily with radiation therapy. In these cases, the clinical staging adopted by FIGO in 1971 would still apply, but designation of that staging system would be noted. • Ideally, width of the myometrium should be measured along with the depth of tumor invasion.

Primary site The Fallopian tube extends from the posterior superior aspect of the uterine fundus laterally and anteriorly to the ovary. Its length is approximately 10 cm. The lateral end opens to the peritoneal cavity. Metastatic sites Carcinoma of the oviduct can metastasize to the regional lymph nodes, including the para-aortic nodes. Direct extension to surrounding organs, as well as intraperitoneal seeding, occurs frequently. Peritoneal implants may occur with an intact tube.

Objective . To determine the diagnostic correlation between referral cytology, initial biopsies and colposcopic impression in patients assessed in a provincial cytology screening program. Methods . A retrospective review of the computerized cytology screening database for British Columbia (BC), to identify all patients having their first colposcopy between 1986 and 2000 in 24 participating clinics constituted the study population. 84,244 patient records were identified for analysis. Colposcopies were performed mainly by 37 general gynecologists as part of a province-wide colposcopy program. Correlation of cytology, colposcopic impression and directed biopsies was performed. Results . The colposcopic impression correlated with the referral cytology within one degree in over 90% of cases. Colposcopists felt cytology underestimated disease in 1.5% and overestimated disease in 8.3%. Cytology–histology correlation within one degree occurred in 82%. Cytology underestimated the result of the biopsies in 2.3% and appeared to overestimate disease in 16.1% of patients. Patients with HSIL cytology had corresponding lesions in 77%, with a further 4.9% having LSIL disease. The predictive accuracy of colposcopy increased with advancing severity of disease expected. As the degree of cytological abnormality worsened, the predictive accuracy of colposcopic diagnosis increased. Conclusions . Both cytology and colposcopy have high sensitivity but low to moderate specificity. Colposcopy is most accurate in identifying high-grade diseases. Colposcopic impression correlates closely with the cytology diagnosis and combining the two produces optimum results.

To estimate the quality of community colposcopic practice in British Columbia through an assessment of the degree of correlation between colposcopy, cytology, and histology.We reviewed all new-patient colposcopies in British Columbia during 2001 by 37 gynecologists in 24 hospital-based clinics.Colposcopic impression closely mirrored the referral cytology diagnosis in 89.8% of cases. As with cytology-biopsy comparisons, discordant cases were more likely to be overestimates of disease rather than underestimates, 18.8% versus 1.8%. Overestimates were usually biopsy sampling errors rather than false positive cytology. The overall correlation between cytology and biopsy was considered satisfactory in 79.4% of cases. Satisfactory agreement between the colposcopic diagnosis and accompanying biopsies occurred in 86.8% of patients. Five colposcopists had performance scores below this standard. Colposcopy with a sensitivity of 90.3% and a specificity of 57.3% as practiced in this provincial program would appear to be of a satisfactory level. The rate of intraepithelial or invasive disease increased from 40.6% in patients with low-grade squamous intraepithelial changes to 91.9% in patients with suspicious or malignant cytology. The value of the colposcopic impression to identify disease correlated best with the higher the grade of disease predicted (64.6% to 92.6%).A measure of the colposcopic proficiency in the community can be estimated by comparing the level of agreement between the presenting cytology, colposcopic impression, and corresponding directed biopsies. The results of this study would indicate that 5 individuals had practice standards that were below average. An integrated cytology-colposcopy program facilitates the assessment and identification of below-average practice standards in a community.

Primary site Cases should be classified as carcinoma of the vulva when the primary site of growth is in the vulva. Tumors present in the vulva as secondary growths, from either a genital or extra-genital site, have to be excluded. Malignant melanoma should be separately reported. A carcinoma of the vulva that extends into the vagina should be considered as a carcinoma of the vulva. There must be histologic confirmation of the cancer.

The Annual Report on the Results of Treatment in Gynecologic Cancer has its roots in work originally produced by the Radiological Subcommission of the Cancer Commission of the Health Organisation of the League of Nations. In 1928, this group was asked to explore the possibility of having uniform statistical information on the results of radiotherapeutic treatment methods for uterine cervical cancer. This Subcommission recommended that this could only be accomplished if various institutions would produce their results in a uniform and consistent manner. The task of producing such results was given to J Heyman from the Radiumhemmet in Stockholm, A Lacassagne from Radium Institute of the University of Paris, and F Voltz from Munich. The recommendations of these experts, with minor modifications, were adopted by the Subcommission and published in April of 1929 [1]. One of the major items that emerged from this activity was a classification system for grouping carcinoma of the uterine cervix into different stages according to the extent of the growth. This system became known as the League of Nations Classification for cervical cancer and was amongst the first attempts at having an international staging system for this disease. Although the recommendations made by the Radiological Subcommission for collecting and analyzing materials were adopted in several countries, widespread use did not occur. In July 1934, the Health Organisation held a conference in Zurich, attended by former members of the Subcommission and other international experts, to advise what further action might be pursued to facilitate wider endorsement and adoption of these principles. This conference recommended that a publication in the form of an annual report should be issued by the Health Organisation analyzing the results of treatment by radiotherapy in cancer of the uterine cervix, estimated after an observation of 5 or more years. It was stated that the primary objective of the proposed annual statistical report should be to provide a convenient work of reference for those who wished to know the results and statistics regarding patients treated with radiotherapy for cancer of the cervix uteri. The recommendations of the Zurich conference were adopted by the Health Committee in 1935 and in October of that year an Advisory Committee, chaired by J Heyman, was appointed to carry out this task. The first three Annual Reports were issued in 1937, 1938 and 1939, and contained only the results of cervical cancer treated by radiotherapy, but indicated that future reports would be expanded to hopefully include material relating to carcinoma of the corpus uteri and of the vagina. The first Annual Report contained statements from the six participating institutions listed in Table 1. In an attempt to promote more uniform grouping of cases, to minimize variation and to secure comparabilities and statistics for the Annual Report, Heyman and Strandquist published the first Atlas on Cervical Cancer Staging, in 1938. The second Annual Report, published in 1938, contained changes to the wording and definitions for the various stages of cervical cancer and, as such, represents the first recorded changes to the cervical cancer staging system. No further changes were made until 1950, at which time the Editorial Committee met with nine American representatives at the International Gynecological Congress and Fourth American Congress of Obstetrics and Gynecology, held in New York in May 1950.

Objective To review our experience and that in the recent literature regarding basal cell carcinoma of the vulva to see whether current management guidelines are appropriate. Methods Twenty-eight women with basal cell carcinoma of the vulva were seen over 25 years at the BC Cancer Agency. The clinical-pathologic features were tabulated and the outcome was analyzed. Results The mean age was 74 years, and almost two-thirds were over the age of 70 at diagnosis. Patients typically presented with an irritation or soreness, with a symptom duration ranging from a few months to several years. Most lesions were confined to the anterior half of the vulva, and 23 of the 28 patients had T1 lesions. Wide local excision was the treatment method used most commonly. Only one patient was known to have died from disease metastasis. Ten women had other basal cell carcinomas, either before or after the diagnosis of their vulvar lesions, and in ten patients 11 other malignancies were diagnosed. Conclusion Basal cell carcinoma of the vulva is an extremely uncommon tumor that rarely metastasizes or spreads. Primary treatment should consist of wide local excision and continued follow-up.

In many countries, carcinoma of the corpus uteri (endometrial carcinoma) has now surpassed cervical carcinoma as the most common form of malignancy affecting the female genital tract. This has occurred as the result of two factors. Firstly, the effective population-based cervical carcinoma screening programs have effectively identified the preclinical phases of this disease with a subsequent reduction in its incidence and mortality rates. Second, the increased life-expectancy in many countries today has, in turn, led to an increased number of patients being diagnosed with endometrial carcinoma, which is predominantly a disease of post-menopausal women. Endometrial carcinoma most often presents as postmenopausal bleeding, which results in women presenting promptly for investigation of this complaint. The majority of endometrial carcinomas are diagnosed as stage I lesions [37]. Nonetheless, this condition has the potential to behave in an aggressive fashion, resulting in recurrence and ultimately death. The identification of prognostic factors has been the primary focus of the research on this condition in the past 20 years. Prognostic factors in stage I and II and in stage III and IV disease are shown in Tables 1 and 2, respectively.

PURPOSE At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatin-based combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. PATIENTS AND METHODS One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cisplatin at 50 mg/m2 every 3 weeks until a total dose of doxorubicin of 450 mg/m2 had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altretamine) was administered to patients who did not have a documented histologic complete remission. RESULTS The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. CONCLUSIONS Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease.

Two common tissue sampling techniques--colposcopic biopsy and cervical scrape--and two common human papillomavirus (HPV) detection techniques--Southern blot and dot blot (SB and ViraPap [VP])--were compared to determine whether differences in these techniques alter correlations between "oncogenic" HPVs and cervical neoplasia. In 87 women with persistently abnormal Papanicolaou (Pap) smears, concurrent biopsy and scrape specimens contained HPV in 21 (24%) and contained no HPV in 26 (30%); 30 scrape specimens (34.5%) tested positive when the biopsy tested negative and 10 (11.5%) scrape specimens tested negative when the biopsy tested positive (overall concordance, 54%). Concordance for the most prevalent HPVs (16/18) was 59%. In carcinoma in situ, HPV was found in biopsy samples significantly more frequently than in scrape specimens: 17 of 23 (75%) biopsy samples versus 9 of 23 (39%) scrape specimens (P = 0.018). Conversely, in mild or no dysplasia, 0 of 42 biopsy samples tested positive for HPV 16/18 compared with 12 of 42 scrape specimens (29%; P = 0.0001). Of 229 specimens analyzed by SB and VP, 43 (19%) tested positive and 148 (65%) tested negative for HPV by both methods (concordance, 84%). Corroborative results indicated that 29 of 35 (83%) VP-positive SB-negative results were truly positive compared with none of three SB-positive VP-negative results. Both the cervical sampling technique and the method for HPV detection can significantly affect statistical correlations between cervical dysplasia and HPV type.

Twenty-one cases of vulvar Paget's disease were studied to assess possible prognostic indicators, including presence and depth of invasion, status of resection margins, tumor DNA cell content, and immunoreactivity for p53 and estrogen receptor proteins. Immunostaining for cytokeratin 7 (CK7), cytokeratin 20 (CK20), and gross cystic disease fluid protein-15 (GCDFP) were also performed. Patients were 45 to 82 years of age (mean, 66.9 years). Ten of 21 patients (47.6%) had invasive Paget's disease. Dermal invasion wasor = 1 mm in 7 of 10 cases and 2 mm, 3 mm, and 8 mm in the remaining three invasive tumors. Of the seven patients with minimally invasive Paget's disease (or = 1 mm depth of invasion), five are alive with no evidence of disease, one died of an unrelated illness, and one is alive with biopsy-proven in situ Paget's disease, having refused operative treatment. Of the three patients with more than minimally invasive Paget's disease (1 mm), all had nodal metastases; one patient is alive with no evidence of disease, one died of undertermined causes, and one died of metastatic Paget's disease. The remaining 11 patients had Paget's disease confined to the epidermis and its adnexal structures. Seven of these patients were alive at last follow-up with no evidence of disease. Of the remaining four patients, one died of metastatic cervical cancer, one died of metastatic bladder cancer, one died of an unrelated illness, and one patient is alive with biopsy-proven in situ Paget's disease and awaiting operative treatment. Twenty of the 21 cases represented primary vulvar Paget's disease while one represented possible local spread from a cervical adenocarcinoma. The immunoprofiles were GCDFP+/CK7+/CK20- in 14 cases, GCDFP+/CK7+/CK20+ in 4 cases, and GCDFP-/CK7+/CK20- in 2 cases. All tumors were estrogen receptor-negative. Immunostaining for p53 was positive in 16 tumors and negative in four tumors. Seven of 12 (58%) patients with positive margins experienced local recurrence of Paget's disease, while the disease recurred in 1 of 4 patients with negative margins. Recurrence was observed in 3 of 5 patients with diploid tumors and in 4 of 10 patients with aneuploid tumors. Neither of these differences is statistically significant. This study supports the recognition of a category of minimally invasive vulvar Paget's disease that has a low risk of distant metastasis and death caused by disease. Status of surgical resection margins, tumor cell DNA ploidy, estrogen receptor expression, and p53 immunoreactivity are not predictive of local recurrence.

Cryotherapy and laser surgery have been the most frequently used conservative methods to treat cervical intraepithelial neoplasia (CIN) in the past decade. This report documents our experience using these modalities to treat 2773 patients between the years 1984-1989. One thousand eight hundred eleven women received laser surgery and the remaining 962 were treated with cryotherapy. In the first 2 years of the study period, only 78 patients were treated with laser surgery. Conversely, only 69 of the 979 patients treated in 1988 and 1989 had cryotherapy. As greater experience was gained with laser surgery, the success rates rose from 58.3% in 1984 to 95.5% in 1988. The success rate was similar for all grades of CIN. Overall, 11.2% of all patients were lost to follow-up. Among patients treated with laser surgery, 4.8% had postoperative bleeding that required either packing or, in two instances, sutures for hemostasis. Success with these methods appeared to be related to the size of lesion and not to the degree of histologic abnormality. The shift toward increasing use of laser surgery in our clinic was due to its precision in destroying identified lesions in the transformation zone. Our results indicate that both cryotherapy and laser surgery are simple, effective methods for the treatment of CIN.

The results after cryosurgical treatment of cervical intraepithelial neoplasia at 1, 5, and 10 years are reported. Ninety-four percent of the 1675 patients eligible for assessment at 1 year were successfully treated, with only 5.6% lost to follow-up. After 5 years, 14% of patients were lost to follow-up, but the corrected success rate remained essentially unchanged. No major differences in success rates were noted for the various histologic grades of cervical intraepithelial neoplasia treated. A small but definite percentage of patients developed further disease over the ensuing years, indicating the need for long-term, continued surveillance of these patients.

Colposcopy was used to examine 401 pregnant patients with cytologic or clinical abnormalities of the cervix to determine if routine biopsy could be safely omitted except where the colposcopic impression was one of possible invasive carcinoma. A comparison of the antepartum colposcopic impressions with the postpartum histologic diagnosis revealed agreement to within one degree in 87% of patients, with 3% of patients showing a more advanced lesion than that anticipated. Only 2% of patients showed a progression of cytologic abnormalities at postpartum examination; 39% showed marked improvement. Four of nine patients with invasive carcinoma were diagnosed at antepartum colposcopy, with an additional two patients recognized as having invasive cancer at the postpartum colposcopic examination. The omission of routine biopsy is less than ideal if only one antepartum colposcopy is performed, since a considerable period of time may elapse before the patient is seen again postpartum. Those situations in which it may be omitted, together with guidelines for the management of pregnant patients with abnormal cervical cytologic findings, are presented.

The clinical and pathological features of a case of adenocarcinoma in situ of the vagina diagnosed in a 40-year-old woman with a negative history for intrauterine DES exposure are reported. The lesion was diagnosed 15 months following hysterectomy for in situ squamous cell and in situ adenocarcinoma of the cervix. The vaginal lesion closely resembled colposcopically, cytologically, and histologically previously described cases of cervical adenocarcinoma in situ. The case was of additional interest pathologically because of a focal signet-ring cell component which exhibited extensive pagetoid invasion of the adjacent squamous mucosa. No previously reported examples of vaginal adenocarcinoma in situ could be found. The histogenesis of this entity is briefly discussed.

PreviewInvasive squamous cell carcinoma of the cervix is no longer the leading cause of cancer-related death in women, thanks to widespread use of the cervical Pap test. This is not to say that cervical cancer no longer poses a grave threat to sexually active women between 18 and 60 years of age. Indeed, Canadian physicians Benedet and Murphy report that the incidence of preclinical disease appears to be on the rise in women in their mid or late 20s. In an effort to assure the demonstrated effectiveness of cytologic screening in curbing the incidence and mortality of cervical cancer, the authors of this article discuss risk factors and recommendations on the frequency of testing plus such practical matters as properly obtaining tissue specimens, fixing smears, and preparing a Pap smear report.

Primary site The cervix is the lower third of the uterus. It is roughly cylindrical in shape, projects through the upper, anterior vaginal wall and communicates with the vagina through an orifice called the external os. Cancer of the cervix may originate on the vaginal surface or in the canal. Nodal stations The cervix is drained by preureteral, postureteral, and uterosacral routes into the following first station nodes: parametrial, internal (obturator – hypogastric), external iliac, presacral and common iliac. Para-aortic nodes are second station and are considered metastases.