P53 and bcl-2 assessment in serous ovarian carcinoma.

The study objective was to determine the prognostic value of assessment of staining of p53 and bcl-2 in a well-selected group of serous ovarian carcinomas. Immunohistochemical detection was used to identify both p53 and bcl-2 positive tumors. One hundred thirty-two tumors were analyzed for positivity of staining, grade of staining intensity, and for p53 alone, percent expression rates. These were analyzed alongside traditional clinicopathologic parameters for their ability to predict overall survival (OS), disease-free survival (DFS), and response to chemotherapy (CR). Univariate COX analysis revealed percent p53 expression (P = 0.012) and p53 grade (P = 0.01) to be significant predictors of DFS. Neither the p53 nor bcl-2 measurement parameters were found significant for OS or prediction of CR. On multivariate analysis, incorporating clinicopathologic parameters, p53 parameters did not retain independent significance for any outcome measure. As in primary reported studies, bcl-2 was not found to be of clear independent prognostic value in this group of ovarian tumors. If mutation of p53 and its consequent overexpression is an early event in ovarian tumorigenesis, then p53 assessment may prove useful prognostically in the assessment of either low-grade ovarian carcinomas, as a possible indicator for progression, or in early-stage ovarian tumors, as a marker of tumor aggression or likelihood of recurrence. p53 analysis of a larger group of stage I ovarian tumors would be desirable to further explain the potential association with DFS.

The prognostic value of nuclear morphometric analysis in serous ovarian carcinoma.

The objective of this study was to determine whether nuclear morphometric data can predict survival, disease progression, and chemotherapeutic response in ovarian serous carcinoma. Nuclear morphometric parameters were determined from archival hematoxylin and eosin sections of 132 serous tumors. Clinicopathologic and morphometric parameters were evaluated as to their individual and independent prognostic value and prediction of chemotherapy response. Nuclear parameters were found to strongly correlate with extent of disease residuum, tumor grade, and FIGO stage. Univariate analysis revealed stage, grade, preoperative CA125, presence of ascites, extent of disease residuum, standard deviation of nuclear area (SDNA), nuclear perimeter (NP), SDNP, nuclear length (NL), nuclear breadth (NB), orthoferet, and equivalent diameter (ED) to be significant predictors of overall survival (OS) and disease-free survival (DFS). Grade, stage, extent of disease residuum, presence of ascites, SDNA, NP, NL, NB, and orthoferet were found to be significant predictors of chemotherapy response. Multivariate analysis revealed extent of disease residuum (P

Atypical mucinous metaplasia and intraepithelial neoplasia of the female genital tract--a case report and review of the literature.

Müllerian metaplasia of the female genital tract is usually of limited extent and subtype. We describe the replacement of the lining of the entire genital tract and much of the overlying pelvic serosa by metaplastic müllerian epithelium, in a nulliparous 65-year-old woman with cervical agenesis. She did not have Peutz-Jeghers syndrome and had not had any form of prior hormonal treatment. The metaplastic epithelium extended from the vagina to the serosal surface of the pelvic organs. Mucinous epithelium predominated. In addition, there was multifocal dysplasia of the metaplastic epithelium; this was most prominent in the fallopian tubes where there was marked papillation with cytoarchitectural features reminiscent of a borderline mucinous ovarian tumor. Although müllerian metaplasia is well recognized at different sites within the female genital tract, this highly unusual finding of multiple metaplastic epithelial subtypes and dysplasia involving the mucinous metaplastic epithelium along the entire genital tract and pelvic serosal surface has not, to the best of our knowledge, been reported previously in the absence of Peutz-Jeghers syndrome.

Pregnancy following recurrent angiosarcoma of the ovary--a case report and review of literature.

BACKGROUND: Ovarian angiosarcomas are rare tumors which may to be distinguished from other unusual primary ovarian tumors such as clear cell carcinoma, yolk sac tumor and leiomyosarcoma on the basis of histological appearance and immunohistochemistry. Angiosarcomas of the ovary occur in all age groups but are more frequent in women of child bearing age (less than 40 years). Surgery and radiotherapy have been the traditional treatment modalities. CASE: The case we present is the only reported long-term survivor of recurrent ovarian angiosarcoma. Her initial treatment was surgical, both at presentation and relapse but since she wished conservation of fertility, radical surgery and radiotherapy were avoided and she underwent further adjuvant chemotherapy with doxorubicin and ifosfamide. She remains in remission 6 years after treatment of recurrence of the primary tumor and has had a successful pregnancy following treatment. CONCLUSION: Adjuvant chemotherapy of ovarian angiosarcoma with a combination of doxorubicin and ifosfamide appears effective and should be considered in women at risk of relapse who wish to conserve fertility.

Superficial myofibroblastoma of the lower female genital tract: report of a series including tumours with a vulval location.

AIMS: To describe the clinical and pathological features of 12 further cases (in 11 patients) of superficial cervicovaginal myofibroblastomas (SCVM), rare tumours that hitherto have been described only in a single series of cases involving the cervix and vagina. METHODS AND RESULTS: The patients' ages ranged from 23 to 80 years. Ten tumours were located in the vagina and two in the vulva. Three patients had been taking tamoxifen. The tumours ranged in size from 2 to 45 mm and morphologically were well-circumscribed lesions composed of bland ovoid to spindle-shaped cells, often with wavy nuclei. These cells were arranged in a variety of architectural patterns and were set in a finely collagenous stroma. Five cases exhibited stromal oedema or myxoid change and in eight cases hyalinized areas with thick, dense collagen bundles were present. Immunohistochemically, there was positivity with vimentin (11 of 11 cases tested), CD34 (six of 12 cases), desmin (nine of 12 cases) and oestrogen receptor (nine of 11 cases). All cases tested were negative for smooth muscle actin, S100, h-caldesmon, HMB45, and CD31. In this study we expand on the morphological spectrum of these rare lesions and reiterate their association with tamoxifen. CONCLUSIONS: Since these lesions may occur on the vulva, as well as the cervix and vagina, we propose the term 'superficial myofibroblastoma of the lower female genital tract'.

Cellular angiofibroma and related fibromatous lesions of the vulva: report of a series of cases with a morphological spectrum wider than previously described.

AIMS: Cellular angiofibroma (CA) is a rare benign mesenchymal lesion with a predilection for the vulval region. In this report we aim to describe the clinical, pathological and immunohistochemical features of a series of vulval mesenchymal lesions, some of which have the classically described histological appearance of CA while others exhibit atypical features. We believe these lesions fall within the broad spectrum of fibromatous lesions of the vulva. METHODS AND RESULTS: Seven cases were included. Histological sections were examined and immunohistochemical staining with vimentin, desmin, alpha smooth muscle actin, h-caldesmon, S100, EMA, AE1/3, CD34, CD10, ER, PR and MIB1 was performed. The patients' ages ranged from 20 to 65 years and the lesions ranged in size from 10 to 50 mm. All lesions were well circumscribed, moderately cellular lesions and were composed of bland spindle-shaped cells set in a fibrous stroma. Many blood vessels with thick hyalinized walls were present in four cases, in one case occasional such blood vessels were present and in two cases vessels with thick hyalinized walls were not present. In five cases the vessels were at least focally dilated resulting in a haemangiopericytomatous pattern. Histological features identified in a variable numbers of cases included peripheral adipose tissue (four cases), adipose tissue within the centre of the lesion (one case), stromal mast cells (six cases), stromal lymphoid aggregates (five cases), scattered multinucleate cells (five cases), hypocellular hyalinized areas (two cases), myxoid areas (four cases) and focal areas of marked cellular atypia reminiscent of symplastic change within a uterine leiomyoma (one case). Mitotic figures were identified in four cases, all with a mitotic count of < 1 per 10 high-power fields. Immunohistochemically all neoplasms were positive with vimentin and all but one with ER and PR (PR staining was not performed in one tumour). In all cases desmin, alpha smooth muscle actin, h-caldesmon, S100 and AE1/3 were negative (h-caldesmon and AE1/3 staining were not performed in one case). Three cases were positive with CD34, one with EMA and two with CD10. All exhibited a low MIB1 proliferation index of approximately 1%. One lesion recurred locally 6 months following initial removal. CONCLUSIONS: CA is a rare benign vulval mesenchymal lesion with limited potential for local recurrence. We describe several hitherto unreported histological features which add to the morphological spectrum. Although not all lesions exhibit the classically described histological features of CA, we believe all fall within the broad spectrum of benign vulval fibromatous lesions. These cases are characterized by vimentin positivity but negative staining with smooth muscle markers which assists in excluding many of the other vulvovaginal mesenchymal lesions which enter into the differential diagnosis. The immunophenotype indicates that CA probably exhibits fibroblastic rather than myofibroblastic differentiation. These lesions are almost always positive with ER and PR, suggesting that they probably arise from the hormone receptor-positive subepithelial mesenchymal layer within the lower female genital tract.

Recent advances in the pathology of smooth muscle tumours of the uterus.

Smooth muscle tumours of the uterus are common and the majority are benign leiomyomas. However, there are some tumours which exhibit unusual morphological features or growth patterns that cause difficulty in their distinction from malignant neoplasms and those with endometrial stromal differentiation. Such lesions are reviewed in this article with detailed descriptions of their morphology, differential diagnosis and correlation with biological behaviour.

Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study.

BACKGROUND: Laboratory and epidemiological research suggests an association between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN). We studied the natural history of incident cervical HPV infection and its relation to the development of CIN. METHODS: We recruited 2011 women aged 15-19 years who had recently become sexually active. We took a cervical smear every 6 months and stored samples for virological analysis. We immediately referred all women with any cytological abnormality for colposcopic assessment, but postponed treatment until there was histological evidence of progression to high-grade CIN. FINDINGS: In 1075 women who were cytologically normal and HPV negative at recruitment, the cumulative risk at 3 years of any HPV infection was 44% (95% CI 40-48): HPV 16 was the most common type. The cumulative risk at 3 years of detecting an HPV type not present in the first positive sample was 26% (20-32). 246 women had an abnormal smear during follow-up, of whom 28 progressed to high-grade CIN. The risk of high-grade CIN was greatest in women who tested positive for HPV 16 (risk ratio 8.5 [3.7-19.2]); this risk was maximum 6-12 months after first detection of HPV 16. All HPV types under consideration were associated with cytologically abnormal smears. Although abnormality was significantly less likely to be associated with low-viral-load samples, the cumulative risk at 3 years of a high-viral-load sample after a low-viral-load sample was 45% (95% CI 35-56). Five women who progressed to high-grade CIN consistently tested negative for HPV. INTERPRETATION: Our findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programmes might be undermined by the limited inferences that can be drawn from the characterisation of a woman's HPV status at a single point in time, and the short lead time gained by its detection.

Vasculitis of the female genital tract with clinicopathologic correlation: a study of 46 cases with follow-up.

Forty-six cases of vasculitis affecting the female genital tract are described; only 41 similar cases have been previously reported, either as case reports or small series. The age range of the patients was from 22 to 80 years, and most of them presented with abnormal bleeding or were being treated conditions unrelated to the vasculitis. There were 39 hysterectomy specimens (26 of which were derived from total abdominal hysterectomies) and seven specimens of the cervix only. The vasculitis was confined to the cervix in 30 of the 46 cases; in 24 of these, the entire uterus was available for examination. In 23 cases, only a single vessel was involved, and in the other 23 there was more extensive vessel involvement. In all cases, the involved vessels were arterioles and small arteries. In 42 cases, the arteritis was of the polyarteritis nodosa (PAN) type, and in four, of the giant cell type (GCA). Follow-up ranged from < 1 year to 23 (mean, 3) years. Systemic manifestations were previously diagnosed or subsequently developed in only four patients, three with PAN and one with GCA; in each of them, the genital tract vasculitis was found only in the cervix (in one of these, however, the specimen was a loop excision of the cervix and the rest of the uterus was not assessable). The three patients with PAN subsequently developed extragenital PAN (one case), PAN and rheumatoid arthritis (one case), or PAN and polymyalgia rheumatica (one case). The patient with GCA had previously documented temporal arteritis and temperomandibular arthritis. The findings in this series and in previously reported cases indicate that vasculitis of the female genital tract is only rarely associated with systemic vasculitis.

Mitotically active haemorrhagic cellular (apoplectic) leiomyoma.

Apoplectic leiomyoma is a distinctive smooth muscle tumour usually occurring in women either taking oral contraceptives or who are pregnant or recently postpartum. Most of these tumours show 0-2 mitoses per 10 high power fields, but a mitotic index of up to 8 per 10 high power fields is allowed in such tumours. We describe an apoplectic leiomyoma with a number of atypical features including a high mitotic index (up to 20 per 10 high power fields) in a 47-year-old woman. Follow-up clinically and by computerised tomography (CT) for 3 years demonstrates no recurrence.

Randomised trial of immediate versus deferred treatment strategies for the management of minor cervical cytological abnormalities.

OBJECTIVE: To compare immediate and deferred treatment in women with cervical smears showing borderline nuclear abnormalities or mild dyskaryosis. DESIGN: Prospective randomised trial. SETTING: Colposcopy clinics at Birmingham and Midland Hospital for Women and the City Hospital NHS Trust, Dudley Road, Birmingham. PARTICIPANTS: Four hundred and thirty-five women with minor cytological abnormality younger than 35 years of age, of whom 353 were randomised to immediate treatment or deferred treatment. MAIN OUTCOME MEASURES: Comparison of histologies in the subsequent two years in the immediate and deferred treatment groups. RESULTS: Thirty-six women (21%) defaulted from follow up. The percentage of high grade abnormalities (CIN II and III) in the deferred treatment arm at two years is similar to that in the immediate treated arm at first colposcopy (25% vs 24%). Cytology failed to pick up two cases of CIN III and there was one case of early invasive carcinoma at the six month follow up. If treatment is deferred, the proportion with CIN I is almost halved (25% vs 13%); the proportion with koilocytic atypia is slightly reduced (51% vs 42%) and the proportion with no abnormality is substantially increased (0.6% vs 20%). CONCLUSION: Immediate referral and a select-and-treat management strategy of all women with any degree of dyskaryosis is recommended based on the case of invasive cervical cancer, high default rate and the failure of cytology to pick up two cases of CIN III.

Is loop excision adequate primary management of adenocarcinoma in situ of the cervix?

OBJECTIVE: To assess the efficacy of cervical loop excision as primary management of adenocarcinoma in situ. DESIGN: A two-centre retrospective study. SETTING: Birmingham and Midlands Hospital for Women and City Hospital NHS Trust. POPULATION: Nineteen women with a histological diagnosis of adenocarcinoma in situ (high grade CIGN) of the cervix made on diathermy loop excision. MAIN OUTCOME MEASURES: Presence or absence of adenocarcinoma in situ at loop specimen margins, results of cervical cytological examinations following loop excision, results of histopathological assessment of any surgical specimens taken after initial loop excision. RESULTS: Of the 19 women with confirmed adenocarcinoma in situ on loop excision, the median age was 31, and 8 (42%) were nulliparous. The median follow up of these women was 19 months. Eleven women were treated by loop excision alone and have had normal follow up to 18 months. Five women have undergone further surgical procedures, four had a hysterectomy and one had a repeat loop excision. No residual disease was found in any of these surgical specimens, confirming that loop excision was adequate primary management of the disease. Three women have had abnormal endocervical follow up cytology suggestive of residual disease. One of these three women may represent a case of residual endocervical disease. Excision margins of the loop specimen were not involved by adenocarcinoma in situ in 11 women. However, excision margin status of the loop specimen did not appear to be predictive of residual disease. CONCLUSIONS: Our small retrospective study suggests that diathermy loop excision of the cervix is adequate primary management of adenocarcinoma in situ of the cervix. Cytological and colposcopic follow up, including cytobrush endocervical cytological sampling and long term follow up, is recommended in these women.

Vulvoperineal reconstruction after excision of anogenital multifocal intraepithelial neoplasia ("MIN").

Over the past 7 years, 12 women have been treated utilising a radical surgical approach for extensive vulval involvement as a component of multifocal intraepithelial neoplasia (MIN) of the female genital tract. The patients were analysed with respect to the anatomical site of involvement, age, presenting complaints and their duration, colposcopic examination, histopathology and surgical treatment. Gynaecologists, general surgeons and plastic surgeons were involved in the surgical treatment which was an initial colostomy followed by a definitive vulvoperineal resection and simultaneous vulval reconstruction using meshed split skin grafts or a combination of skin grafts and local flaps. 17 vulvoperineal reconstructions were done for 12 patients. Three had an incomplete histopathological clearance at the initial operation. Apart from these three patients, one had recurrence of symptoms alone, without any evidence of MIN, which was possibly due to human papilloma virus infection. One patient developed malignant squamous invasion 4 years later, which was cured with surgical excision and reconstruction. Colostomy closure was done after achieving local control of the disease. This staged approach does achieve the objectives of eliminating disease and alleviating symptoms. It preserves function and attempts to reconstruct normal anatomy without compromising the principles of surgical oncology and results in a high patient satisfaction.