A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study.

OBJECTIVE: The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group.

Prevalence, risk factors, and accuracy of cytologic screening for cervical intraepithelial neoplasia in women with the human immunodeficiency virus.

OBJECTIVES: The objective was to evaluate the sensitivity and specificity of cervical cytology in women infected with the human immunodeficiency virus (HIV), risk factors for abnormal cytology in HIV-infected and uninfected women, and risk factors for histologic diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-infected women. METHODS: Methods included a cross-sectional analysis of cervical cytology, colposcopic impression, and histology in 248 HIV-infected women and multivariate analyses of risk factors for abnormal cytology in 253 HIV-infected and 220 uninfected women and risk factors for CIN in 186 HIV-infected women. RESULTS: The sensitivity and specificity of cytology for all CIN grades were 0.60 and 0.80 and, for high-grade CIN, 0.83 and 0.74. The prevalence of abnormal cytology was 32.9% in HIV-infected and 7.6% in HIV-negative women. Independent risk factors for abnormal cytology were immunodeficiency [odds ratio (OR) 8-17, P < 0.001] and human papillomavirus (HPV) infection (OR = 5, P < 0.001). The prevalence of CIN on histology was 32% in HIV-infected women, and the only independent risk factor for CIN was oncogenic HPV type (OR = 5, P = 0.005). CONCLUSION: Given the high prevalence of abnormal cytology and CIN in HIV-infected women, cytologic screening has significant limitations. Both immunodeficiency and type of HPV infection are important risk factors.

Endometriosis with massive ascites.

We present 4 cases of endometriosis complicated by massive ascites from our institution and a review of 27 cases from the literature. In most of these patients, the presence of ascites with its related symptoms in association with pelvic masses suggested a neoplastic disease. However, a large proportion of these women had also classical manifestations of endometriosis, e.g., dysmenorrhea, cul-de-sac nodularities, and exacerbation of ascites and other symptoms during the menses. The response to hormonal therapy including GnRH agonists was often unsatisfactory. Repeat recurrences and severe complications required multiple laparotomies and thoracotomies for associated pleural and pulmonary involvement.

Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women.

OBJECTIVE: To investigate the significance of race and histologic type as prognostic factors in endometrial carcinoma. METHODS: We conducted a retrospective review of the medical records of all patients diagnosed with endometrial cancer from 1982 to 1995. Patients' clinical and pathologic characteristics were analyzed. RESULTS: The sample consisted of 401 patients, 59.9% (N = 229) were blacks and 40.1% (N = 153) were non-blacks. The mean age was 63.7 +/- 11.6 years. The histologic subtypes of endometrial carcinoma included 346 endometrioid (86.3%), 42 papillary serous (10.5%), and 13 clear cell (3.2%) adenocarcinomas. We found 79% of endometrioid adenocarcinomas were stage I or II compared to 26% of papillary serous tumors and 58% of clear cell carcinomas (P < 0.01). Eighty-eight percent of patients with papillary serous and 77% of patients with clear cell cancers were black (P < 0.01). Within each stage, patients were treated similarly irrespective of cell type or race. Five-year survival for endometrioid, papillary serous and clear cell adenocarcinomas was 69, 18, and 25%, respectively (P < 0.01). Black women had poorer 5-year survival (56%) than non-black women (71%). In multivariate analyses using age, stage, race, and histology, only stage and histology were independent risk factors for survival. CONCLUSIONS: Patients with papillary serous and clear cell endometrial cancer were more likely to be black, present at an advanced stage of disease, and have poor survival compared to patients with endometrioid adenocarcinoma. This may help to explain the poorer survival reported in blacks with endometrial cancer.

Vaginal intraepithelial neoplasia: risk factors for persistence, recurrence, and invasion and its management.

OBJECTIVE: Our purpose was to profile patients with vaginal intraepithelial neoplasia, evaluate the response to treatment and define risk factors for persistence and progression. STUDY DESIGN: We reviewed records and histopathology slides of 94 patients with vaginal intraepithelial neoplasia diagnosed from 1977 to 1986. For 74 patients with follow-up, we evaluated risk factors by univariate and multivariate analyses. RESULTS: Sixty-four of 94 patients (68%) had prior or concurrent anogenital squamous neoplasia, including 21 with invasive and 43 with intraepithelial. Twenty-three had prior radiotherapy, 10 had anogenital neoplastic syndrome, and 11 were immunosuppressed. In 52 of 74 treated patients (70%), vaginal intraepithelial neoplasia went into remission after a single treatment. In 18 patients (70%) vaginal intraepithelial neoplasia went into remission after a single treatment. In 18 patients (24%) recurrent vaginal intraepithelial neoplasia went into remission after chemosurgery, upper vaginectomy, or other treatments; in 4 (5%) it progressed to invasion. Significant multivariate risk factors for persistence or progression were multifocal lesions and anogenital neoplastic syndrome but not vaginal intraepithelial neoplasia grade, associated cervical neoplasia, or immunosuppression. CONCLUSIONS: Although most vaginal intraepithelial neoplasia goes into remission after treatment, 5% of cases may progress from occult foci to invasion in spite of close follow-up.

Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus.

OBJECTIVE: To evaluate the long-term outcomes after treatment of cervical intraepithelial neoplasia (CIN) in women infected with the human immunodeficiency virus (HIV). METHODS: Human immunodeficiency virus-infected and HIV-negative women treated for CIN by ablation or excision were followed-up prospectively by cytology and colposcopy for periods of up to 73 months. RESULTS: Among 127 HIV-infected CIN patients, 62% developed recurrent CIN by 36 months after treatment, compared with 18% of the 193 HIV-negative CIN patients. Recurrence rates reached 87% in 41 HIV-infected women with CD4 counts less than 200 cells/mm3. Progression to higher-grade neoplasia, including one invasive cancer, occurred by 36 months in 25% of HIV-infected and 2% of HIV-negative women. After adjusting for age, CIN severity, and treatment type, predictors of recurrence included HIV infection (rate ratio 4.4), and, in HIV-positive women, low CD4 count (rate ratio 2.2). In patients treated by excision, predictors of recurrence included HIV infection (rate ratio 2.0) and residual CIN after treatment (rate ratio 2.7). After a second treatment,a second CIN recurrence developed in 14 of 33 HIV-infected and in one of 17 HIV-negative women. After a third treatment, three of six HIV-infected women developed a third recurrence. With long-term follow-up, 45% of treated HIV-infected CIN patients had chronic condylomatous changes in the cervix compared with 5% of HIV-negative women. CONCLUSION: In HIV-infected women, CIN may recur despite multiple treatments, and chronic condylomatous changes are common. Innovative therapies for controlling CIN in HIV-infected women are needed.

The adequacy of cytology and colposcopy in diagnosing cervical neoplasia in HIV-seropositive women.

The purpose of this study was to compare cytology and colposcopy as predictors of cervical intraepithelial neoplasia (CIN) in women infected with the human immunodeficiency virus (HIV). A cross-sectional analysis of cytology, colposcopy, and colposcopic biopsy results from 51 HIV-seropositive women attending an ambulatory HIV service was conducted. Cytology slides were reviewed by two cytopathologists blinded to patients' HIV status. There was strong agreement in the readings of two cytopathologists, with a kappa score of 0.9. Of 29 women with normal cytology, 21 (72%) had pathology on histology, including 7 (24%) with CIN. Colposcopic impression correlated well with histology results. Of 22 women with abnormal cytology, 82% had abnormal histology. The overall prevalence of CIN was high at 45%, increasing from 35% in women with CD4 counts over 400 to 56% in women with CD4 counts below 200. In conclusion, screening cytology is limited by false-negative results; routine colposcopy should be considered in this high-risk population.

Recurrent cervical intraepithelial neoplasia in human immunodeficiency virus-seropositive women.

OBJECTIVE: To determine the effect of human immunodeficiency virus (HIV) infection on the rate of recurrence of cervical intraepithelial neoplasia (CIN) after standard ablative therapy, and to correlate the degree of immunosuppression with treatment results. METHODS: The clinical courses of 44 HIV-positive women with CIN were compared with those of 125 HIV-negative women. Patients were treated with cryotherapy, laser therapy, or cone biopsy per standard indications and were followed with cytology at regular intervals, with a range of follow-up of 3-43 months. RESULTS: Seventeen of 44 HIV-positive women (39%) developed biopsy-proven recurrent CIN, compared to 11 of 125 HIV-negative women (9%) (P < .01). The distributions of CIN severity, lesion size, and modality of treatment were similar in the two groups. In HIV-negative patients, recurrent CIN was associated with increasing grade, but in HIV-positive patients, recurrence was related to increasing immunosuppression. The mean CD4 count in HIV-positive patients with recurrence was 239/mm3, compared to 367/mm3 in HIV-positive patients who remained free of CIN. Only 18% of HIV-positive patients with CD4 counts over 500/mm3 had recurrence, compared to 45% of those with CD4 counts under 500. There was a trend toward poorer treatment results with the use of cryotherapy in HIV-positive patients. All recurrences occurred in patients whose mode of acquisition of HIV was heterosexual transmission. CONCLUSION: Recurrence rates of CIN after standard treatment in HIV-positive women are high, and recurrence is related to immune status in this high-risk group. Therapeutic strategies that address these treatment failures should be developed for HIV-seropositive women.

Prognostic factors for groin node metastasis in squamous cell carcinoma of the vulva (a Gynecologic Oncology Group study)

From 1977 to 1984 the Gynecologic Oncology Group (GOG) conducted a prospective clinical and surgical staging protocol of squamous cell carcinoma of the vulva (n = 637). The patients with superficial (5 mm or less invasion) lesions were the subject of a previous report (n = 272). The subject of this report is on factors that predict groin node metastasis based on all 588 evaluable patients. Comparisons between the two reports are made. Almost half of this group (49.3%) had minimal tumor thickness (< or = mm). Almost one-third of patients had small vulvar lesions (< or = cm). Groin node metastasis was 18.9% for the < or = 2-cm diameter tumors and 41.6% for the > 2-cm diameter lesions. The inaccuracy of clinical palpation of the groin nodes (23.9% false negative) largely accounts for underestimation of extent of disease. Body weight was not related to the sensitivity of detecting positive groin nodes (P = 0.26). Using the logistic model, independent predictors of positive groin nodes were identified (in order of importance): less tumor differentiation by GOG criteria (P < 0.0001), suspicious or fixed/-ulcerated nodes (P < 0.0001), presence of capillary-lymphatic involvement (P < 0.0001), older age (P = 0.0002), and greater tumor thickness (invasion) (P = 0.03). Lesion size and location were not independent predictors of positive groin nodes.

Oral condyloma lesions in patients with extensive genital human papillomavirus infection.

OBJECTIVES: The incidence, location, and morphologic appearances of human papillomavirus oral lesions in patients with genital condylomatosis were investigated with clinical, colposcopic, and histologic examination as diagnostic procedures. The human papillomavirus types were also evaluated with filter in situ hybridization. STUDY DESIGN: One hundred one patients, 66 female and 35 male, with genital condyloma underwent an oral cavity examination. Ninety-nine (99%) practiced orogenital sex, and all were asymptomatic for oral lesions. RESULTS: Ninety-one underwent biopsy; histologic studies gave a diagnosis of condyloma in 48% of 101 specimens collected. In 8 of 91 (9%) oral lesions were suspected by naked-eye examination; they were confirmed histologically in all eight. Of 83 patients suspected of having oral condyloma on colposcopic examination, 38 (46%) were confirmed histologically. Thus 38 of 46 patients (83%) had oral condyloma not visible to the naked eye. Colposcopically, oral lesions appeared filiform (50%), moruloid (26%), and mixed (24%). Twenty cytologic oral samples were also collected for deoxyribonucleic filter in situ hybridization analysis. Human papillomavirus deoxyribonucleic genital types were observed in 45% (9/20) of all oral scrapings collected, and all were histologically confirmed. CONCLUSION: Our data indicate that genital human papillomavirus types are capable of establishing a local infection in the oral cavity and demonstrate a high incidence of human papillomavirus oral lesions in patients with genital condyloma.

Papanicolaou smear abnormalities in ambulatory care sites for women infected with the human immunodeficiency virus.

OBJECTIVE: We attempted to determine the prevalence of cervical dysplasia in human immunodeficiency virus-infected women in ambulatory care settings and to correlate Papanicolaou smears with demographic and clinical variables. STUDY DESIGN: Papanicolaou smears of 135 women attending three ambulatory care clinics were reviewed. Chart review identified demographic and clinical variables, including CD4 count. Prevalence of abnormal smears was compared with baseline community rates. Demographic and clinical variables were correlated with Papanicolaou results with the chi 2 test. RESULTS: Fivefold to eightfold increased rates of abnormal smears in human immunodeficiency virus-infected women were observed. Prevalence of abnormal smears increased from 21% in women with CD4 counts greater than 600/mm3 to 45% in women with CD4 counts less than 400/mm3. Age, ethnicity, or mode of human immunodeficiency virus transmission was not significantly correlated with Papanicolaou smear findings. CONCLUSION: Increased rates of abnormal Papanicolaou smears and significant correlation with CD4 counts were observed in human immunodeficiency virus-infected women at ambulatory care sites. We recommend comprehensive gynecologic care, including semiannual Papanicolaou smears, for all human immunodeficiency virus-infected women.

From Papanicolaou to Bethesda: the rationale for a new cervical cytologic classification.

The Bethesda System for reporting cervical/vaginal diagnoses was introduced to replace the numerical Papanicolaou class designations, thereby facilitating precise communication between cytopathologist and clinician. The terminology for squamous epithelial lesions includes the following categories: 1) atypical squamous cells of undetermined significance; 2) squamous intraepithelial lesion (SIL), which encompasses the spectrum of squamous cell carcinoma precursors, divided into low-grade SIL (human papillomavirus [HPV]-associated cellular changes, mild dysplasia, and cervical intraepithelial neoplasia [CIN] I) and high-grade SIL (moderate dysplasia, severe dysplasia, and carcinoma in situ and CIN II and III); and 3) squamous cell carcinoma. The rationale for including HPV-related changes (koilocytosis) with CIN I within low-grade SIL is based on the morphologic, behavioral, and virologic similarity of these two lesions, which precludes their separation in a consistent and reliable fashion. For the same reasons, CIN II and III lesions have been combined within the category of high-grade SIL. The term "atypical squamous cells of undetermined significance" is used for cytologic findings that do not fulfill the criteria for defined benign reactive changes or SIL. Therefore, this term is more restricted in usage as compared with the wide range of interpretations previously ascribed to "atypia" or "inflammatory atypia."

Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study).

Analysis of 588 patients with vulvar carcinoma delineated four risk groups by the proportional hazards model. Groin node status (laterality and number positive) and lesion diameter were the only two important independent prognostic factors. The 5-year relative survival rates were 98%, 87%, 75%, and 29% for the risk group categories of minimal (negative groin nodes and lesion diameter less than or equal to 2 cm), low (one positive groin node and lesion diameter less than or equal to 2 cm or negative groin nodes and fewer than two lesions less than or equal to 8 cm diameter), intermediate (negative groin nodes and lesion diameter greater than 8 cm diameter, one positive groin node and lesion diameter greater than 2 cm, or two unilaterally positive groin nodes and lesion diameter less than or equal to 8 cm), and high (three or more positive groin nodes or two bilaterally positive groin nodes), respectively. Applying the International Federation of Gynecology and Obstetrics staging (1988) to these data discriminated risk of death (caused by recurrent vulvar cancer); the 5-year rates were 98%, 85%, 74%, and 31% for stages I, II, III, and IV, respectively. However, within International Federation of Gynecology and Obstetrics stage III there were 47 low-, 95 intermediate-, and 28 high-risk patients with relative survivals of 95%, 74%, and 34%, respectively. Overall, this assessment validates current International Federation of Gynecology and Obstetrics vulvar carcinoma staging, but further refinements are warranted in stage III.

Anogenital papillomavirus infection and neoplasia in immunodeficient women: an update.

People with deficient cell-mediated immunity have an increased susceptibility to viral infections and certain cancers, particularly non-Hodgkin's lymphomas and cancers of the skin and anogenital region. These are linked to viral origins. Anogenital neoplasms in immunodeficient patients show a strong association with HPV infection; often occur at relatively young ages; involve multifocal locations; and tend to persist, recur, and progress rapidly, despite standard therapy. Because standard therapy of anogenital HPV lesions and neoplasia is often not effective in immunodeficient patients (and others with an anogenital neoplastic syndrome), special treatment is required. 5-Fluorouracil chemosurgery, followed by maintenance 5-fluorouracil therapy, is often effective and provides field suppression against recurrent HPV infection and neoplasia, with minimal damage to affected organs. After removal of all detectable HPV and neoplastic lesions, immunodeficient patients require close surveillance of the entire anogenital tract. Immunodeficient patients are an in vivo human laboratory in which to study the natural history of HPV and its oncogenic effects on the anogenital tract. The theory of HPV oncogenesis is supported by the evidence gathered from these patients.

Sexually transmitted diseases and human immunodeficiency virus infection among women with pelvic inflammatory disease.

Both human immunodeficiency virus infections and pelvic inflammatory diseases are sexually acquired illnesses of great consequence to women. This study was undertaken to determine if women hospitalized with pelvic inflammatory disease, in a community endemic for human immunodeficiency virus, were at high risk to be infected with human immunodeficiency virus and if human immunodeficiency virus infections altered their hospital course. One hundred ten women hospitalized with pelvic inflammatory disease in Brooklyn (in a hospital in which 2% of parturients are human immunodeficiency virus seropositive) agreed to human immunodeficiency virus testing; 15 (13.6%) were found to be seropositive. Seropositive women were significantly more likely to have an admission white blood cell count less than 10,000/mm3 (p = 0.001). Human immunodeficiency virus seropositivity was not associated with a higher frequency of other sexually transmitted diseases although there was a trend toward more cases of syphilis among human immunodeficiency virus-infected women. Similarly, although there was no significant difference in rates of operative intervention (26.6% among seropositive and 8.4% among seronegative; p = 0.058), there was a trend toward more surgery among those who were human immunodeficiency virus infected. Women hospitalized with pelvic inflammatory disease, in a community endemic for human immunodeficiency virus, are at high risk for human immunodeficiency virus infection. More research is needed to verify a trend toward more refractory infections among human immunodeficiency virus-infected women.

Adjunctive radiation after radical hysterectomy in stage IB squamous cell carcinoma of the cervix.

The clinical-pathologic records of 178 women with stage IB squamous cell carcinoma treated by radical hysterectomy and pelvic node dissection were reviewed to assess prognostic factors and outcome in relation to adjunctive pelvic radiation. Among 32 women with pelvic nodes metastases, 19 treated with adjunctive radiation had longer recurrence-free intervals and more extrapelvic metastases than 13 nonirradiated women. However, among irradiated women recurrences were more rapidly fatal, so that the survival of the two groups was similar. Among 54 women with deeply invading (10 mm or more) carcinomas confined to the uterus, 17 with adjunctive radiation had recurrence-free intervals and survivals similar to 37 women without radiation, despite more high-risk factors in the irradiated group. The findings suggest that adjunctive pelvic radiation may control pelvic recurrence but not extend survival.

Assessment of criteria used in the histologic diagnosis of human papillomavirus-related disease of the female lower genital tract.

The goal of this study was to evaluate the histologic criteria used to establish the diagnosis of human papillomavirus (HPV)-associated disease, especially in borderline lesions. In a completely blinded study, 21 patients had one biopsy each of the cervix and vulva. Each specimen was evaluated by RNA and DNA in situ hybridization, a histologic diagnosis was rendered, and then each was evaluated for 12 histologic criteria commonly associated with HPV. On the cervix only binucleation and dysplasia correlated well with in situ hybridization. Koilocytosis correlated very strongly with the histologic diagnosis. On the vulva, koilocytosis, papillomatosis, elongated rete pegs, binucleation, and hypergranulosis correlated well with in situ hybridization. When four other pathologists reviewed the slides, they agreed on the histologic diagnosis and the presence of koilocytosis, binucleation, and dysplasia on the cervix but on none of the other criteria. On the vulva the pathologists disagreed on the overall diagnosis and the presence of any of the criteria with the exception of papillomatosis. Nonclassic histologic criteria should not, by themselves, be used to make the diagnosis of condyloma. The use of such terminology as "suggestive of condyloma" in histologic diagnoses should be avoided in favor of more descriptive terminology to avoid possibly unnecessary treatment for lesions of questionable significance.

Anogenital papillomavirus infection and neoplasia in immunodeficient women.

People with deficient cell-mediated immunity have an increased susceptibility to viral infections and certain cancers, particularly large cell lymphomas and cancers of the skin and anogenital region. All are linked to viral origins. Neoplasms in the immunodeficient patient often occur at a relatively young age, involve multifocal locations, tend to persist, recur, and progress rapidly. Anogenital neoplasms show a strong association with HPV infection and also persist, extend, and progress, in spite of standard therapy. Since standard therapy of anogenital HPV infection and neoplasia is often not effective in immunodeficient patients (and others with an anogenital neoplastic syndrome), special treatment is required. 5-Fluorouracil chemosurgery, followed by maintenance 5-fluorouracil therapy, is effective and provides field suppression against recurrent HPV infection and neoplasia, with minimal damage to affected organs. After removal of all detectable HPV infection or neoplastic lesions, immunodeficient patients require close surveillance of the entire anogenital tract. Immunodeficient patients are an in-vivo human laboratory in which to study the natural history of HPV and its oncogenic effects on the anogenital tract. The theory of HPV oncogenesis is supported by the evidence gathered from these patients.