An immunohistochemical and morphological analysis of post-chemotherapy ovarian carcinoma.

AIMS: Traditional management of advanced ovarian carcinoma is surgical debulking followed by chemotherapy; however, there is an increasing tendency for neoadjuvant chemotherapy followed by surgery. The morphology of ovarian carcinoma following chemotherapy often differs markedly from native tumour. This study aimed to compare the immunophenotype of post-chemotherapy ovarian carcinomas with that of untreated tumour. METHODS: Post-chemotherapy ovarian carcinomas (n = 16) were stained with a range of antibodies. In six cases, pre-chemotherapy core biopsies were also stained; all were high-grade serous carcinomas. Antibodies used in the study were CK7, CA125, WT1, ER, PR, p53, p16, p63 and MIB1. RESULTS: In eight post-treatment cases, there was minimal or no morphological response to chemotherapy, and in eight there was a significant response (in two additional cases, no residual tumour was identified). All pre-chemotherapy biopsies showed diffuse positivity of the tumour cells with CK7, CA125 and WT1. ER, p53 and p16 were diffusely positive in five, four and three cases respectively. One case was focally PR positive, and all were p63 negative. MIB1 staining was high; all but one case exhibited a proliferation index of >60%. Post-chemotherapy tumours exhibited a similar immunophenotype: diffuse positivity with CK7 in all cases and with CA125, WT1, ER, p53 and p16 in the majority, an immunophenotype in keeping with a serous carcinoma. All were negative with p63, and all but two with PR. The MIB1 proliferation index was lower in those cases exhibiting a significant morphological response, and p53 was less likely to be positive in cases with minimal or no response. CONCLUSIONS: The immunophenotype of post-chemotherapy ovarian carcinomas is very similar to that of native untreated tumours, illustrating that CK7, CA125, WT1, ER, p53 and p16 may be of value in identifying residual tumour cells and in subtyping the neoplasm if a pre-chemotherapy biopsy has not been obtained.

Endometrial hyperplasia involving endometrial polyps: report of a series and discussion of the significance in an endometrial biopsy specimen.

OBJECTIVES: Endometrial polyps are a common cause of abnormal uterine bleeding. Rarely, a hyperplasia, either complex or atypical in type, is identified within a polyp in a biopsy or polypectomy specimen. Currently, it is not known whether the hyperplasia is likely to be confined to the polyp or also involve nonpolypoid endometrium. We aim to assess the likelihood of hyperplasia being confined to an endometrial polyp. DESIGN: In this study, we identified 32 women from pathology archives in whom endometrial hyperplasia was present within a polyp. The number of endometrial polyps during the study period was 1031 and therefore 3.1% of all endometrial polyps diagnosed during the study period contained a hyperplasia. SETTING: A major teaching hospital in the UK. METHODS: The biopsies were retrieved from the pathology archives of Royal Group of Hospitals, Belfast, between 2000 and 2006. We traced any follow-up biopsy or hysterectomy specimens to evaluate the status of the surrounding endometrium. RESULTS: The hyperplasias were complex (n = 23) or atypical (n = 9) in type. In 14 of 27 (52%) women in whom nonpolypoid endometrium was available for histological evaluation, either on the original biopsy or in a follow-up specimen, hyperplasia involved the nonpolypoid endometrium, and in three other women, hyperplasia was present in a polyp in follow-up specimens. Women with atypical hyperplasia in a polyp were slightly more likely to have hyperplasia in the surrounding endometrium than those with complex hyperplasia. CONCLUSIONS: Our study illustrates that the risk of endometrial hyperplasia in a polyp concurrently involving nonpolypoid endometrium is significant. We suggest a strategy for the management of women with hyperplasia identified within an endometrial polyp in a biopsy or polypectomy specimen.

Is laparoscopically assisted radical vaginal hysterectomy for cervical carcinoma safe? A case control study with follow up.

OBJECTIVE: To compare a new surgical approach, laparoscopically assisted radical vaginal hysterectomy (LARVH) with open radical hysterectomy in women with cervical cancer. Can selected women benefit from the minimally invasive approach without compromising safety (recurrence rate) and morbidity (complications)? DESIGN: Retrospective case control study. SETTING: A tertiary referral unit for gynaecological malignancies. POPULATION: Thirty women undergoing LARVH were included and compared with 30 women undergoing open radical surgery. The control group was matched for age, body mass index and disease stage. METHODS: Retrospective collection of data from patient files and follow up. MAIN OUTCOME MEASURES: Recurrence rate, complication rate, hospital stay, nodal counts, blood loss, operating time. RESULTS: Recurrence rates were equal (6.7%). There was one death, in the LARVH group. Follow up was mean 31 months in the LARVH group and 30.9 months in the open group. Blood loss as measured by mean drop in haemoglobin was greater in the open group (2.03 versus 3.01 g/dl, P = 0.02). Transfusions were given in 40% of women in the open group and 16.7% in the LARVH group. Hospital stay was significantly less in the LARVH group (5.9 versus 7.8 nights, P = 0.003). Mean operating time was longer in the LARVH group (131 versus 187 minutes P = 0.0001). Mean nodal counts did not differ significantly (17.4 in open vs 14.8 in LARVH, P > 0.05). There were seven perioperative complications in the open group and four in the LARVH group. There have been two recurrences in each group (6.67%) at mean follow up of 31 (LARVH) and 30.9 (open) months. CONCLUSIONS: The first 30 LARVH procedures performed in this unit are comparable in terms of safety (recurrence rate and complication rate) and economic factors (shorter hospital stay mitigating longer operating time). Further development of this technique is warranted.

the management of vulval intraepithelial neoplasia in Northern Ireland.

In this study, we present the findings of a regional retrospective audit of all cases of vulval intraepithelial neoplasia (VIN) diagnosed in Northern Ireland (NI) over an 11-year period (1989-1999). During the period of the study, there were 97 cases of VIN. Cases of VIN were treated by many different clinicians at 14 hospitals. The commonest symptom at presentation was pruritus vulvae. The most common histopathologic diagnosis was VIN III (73%). In 52% of the cases, there was multifocal VIN, and in 43%, there was involvement of other sites such as the cervix, vagina, or anal region. The most common initial treatment was surgical excision, but a multitude of different treatments were performed initially. During the study period, 18 of 90 patients (20%) for whom follow-up was available developed invasive vulval squamous carcinoma. Most of the vulval cancers were superficially invasive, but three patients died of vulval cancer during the study period. This study illustrates that in NI, VIN is treated at many institutions by a multitude of clinicians. Management seems largely dependent on personal clinician preference and has been haphazard with little central coordination and organized strategy. VIN should be managed by clinicians with expertise in this field and who are treating significant numbers of patients according to evidence-based protocols.

Aggressive angiomyxoma of the vulva: Dramatic response to gonadotropin-releasing hormone agonist therapy.

BACKGROUND: Aggressive angiomyxoma (AA) is a vulvovaginal mesenchymal neoplasm with a marked tendency to local recurrence but which usually does not metastasise. Most cases exhibit positive immunohistochemical staining with oestrogen receptor (ER) and, or, progesterone receptor (PR). CASE: We report a case of AA which exhibited positive immunohistochemical staining with ER and in which radiological examination following resection showed extensive residual tumour. The patient was commenced on gonadotropin-releasing hormone (GnRH) agonist therapy which resulted in complete radiological remission with replacement by scar tissue. The patient is currently maintained on a GnRH agonist. CONCLUSION: The present case, together with several others reported in the literature, suggests that GnRH agonists may be of value in managing cases of AA, either primary or recurrent, which are not amenable to surgical excision. These agents may also be used to effect a reduction in size, so that more conservative surgery can be undertaken.

The large loop excision of the transformation zone cut or blend thermal artefact study: a randomized controlled trial.

The objective of this randomized controlled trial was to determine whether the pure cut setting results in less thermal artefact than the traditional blend setting when performing a large loop excision of the transformation zone (LLETZ). Forty-nine consenting women were randomized to undergo an LLETZ procedure using either the pure cut or the blend setting. Two histopathologists, who were blind to the randomization, examined the specimens and then graded and measured the degree of thermal artefact. No significant difference was noted at the epithelial margin. At the deep stromal margins, in the blend group, the mean thickness of thermal artefact was 0.382 mm (95% CI, 0.350-0.414) and in the cut group 0.325 mm (95% CI, 0.297-0.353). This was statistically significant. No significant difference was detected in terms of grading of thermal artefact, the presence of dysplasia at the specimen margins, or in positive follow-up smears. Although there was less thermal artefact at the deep stromal margin, cautery at this margin does not generally interfere with pathological assessment of the specimen and the pure cut setting does not produce a clinically significant decrease in the degree of thermal artefact.

Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm following hereditary retinoblastoma.

This report describes two patients who developed leiomyosarcomas, one involving the subcutaneous tissue of the thigh and the pelvic soft tissues and the other the urinary bladder, following hereditary retinoblastoma 36 and 38 years earlier, respectively. There is an increased risk of the development of sarcoma, most commonly osteosarcoma, as a second malignancy following hereditary retinoblastoma. Leiomyosarcoma developing as a second malignancy has rarely been reported and most have occurred in the field of previous radiotherapy. The literature on leiomyosarcoma occurring as a second neoplasm following retinoblastoma is reviewed.

Extragenital müllerian carcinosarcoma arising from the peritoneum: report of two cases.

Müllerian carcinosarcomas occurring outside the female genital tract are extremely rare but occasionally they may arise from the peritoneum as part of the secondary müllerian system. This report describes two cases of extragenital müllerian carcinosarcoma with heterologous elements in the form of malignant cartilage. We wish to highlight the fact that these aggressive neoplasms may occasionally have a peritoneal origin, similar to primary peritoneal serous carcinomas.

Morphological effects of chemotherapy on ovarian carcinoma.

AIMS: Traditionally, advanced stage ovarian carcinoma is treated by debulking surgery followed by chemotherapy. However, in some circumstances preoperative chemotherapy may be given before optimal surgical debulking. This study aims to describe the morphological features found in ovarian carcinoma after chemotherapy because these have not been detailed previously. METHODS: Histological sections were examined from 18 cases of ovarian carcinoma that had been treated by preoperative chemotherapy. The morphology was compared with any pre-chemotherapy biopsies that had been performed. Tumours were classified as showing morphological features suggesting a good response to chemotherapy (n = 14) or as showing little or no response (n = 4). Serum CA125 values before and after chemotherapy were compared. In all cases, the mitotic activity index (MAI), volume percentage of epithelium (VPE), and mean nuclear area (MNA) of tumour cells were calculated. RESULTS: The preoperative biopsies were all typical ovarian serous or endometrioid adenocarcinomas. Morphological features present in the group responding to chemotherapy included the presence of small groups or single tumour cells in a densely fibrotic stroma. Tumour cells were characterised by both nuclear and cytoplasmic alteration, making accurate tumour typing and grading impossible. Nuclear features included the presence of bizarre enlargement with hyperchromatism, irregularity of outline, and chromatin clumping or smudging. Cytoplasmic alterations included intense eosinophilia, vacuolation, or foam cell change. There were pronounced stromal changes of fibrosis, inflammation, collections of foamy histiocytes, cholesterol cleft formation, haemosiderin deposition, fat necrosis, and dystrophic calcification, including the presence of many free psammoma bodies. There was no correlation between morphological response and biochemical response, as determined by serum CA125 values. In all nine cases in which pre-chemotherapy and post-chemotherapy biopsies were available, the MNA increased post-chemotherapy (p = 0.007, paired Wilcoxon test) and in six of nine cases the MAI decreased (p = 0.093). CONCLUSIONS: Because preoperative chemotherapy is being used increasingly in the management of ovarian cancer, pathologists should be aware of the resultant morphological effects. Accurate tumour typing and grading is impossible. In some cases, it may be difficult to confirm the presence of residual tumour, making it imperative that pre-chemotherapy tissue biopsies are obtained. Definite confirmation of residual tumour may require the examination of multiple histological sections from areas showing pronounced stromal changes, sometimes with multiple levels and immunohistochemistry. In the absence of definite residual tumour, the report should state that the features are consistent with the prior presence of tumour.

Primary adenocarcinoma of the vagina arising in endocervicosis.

Endocervicosis is a rare condition, being one of the triad of non-neoplastic secondary mullerian lesions. This report describes a primary vaginal adenocarcinoma arising in endocervicosis. Histologic examination showed a mucin-secreting adenocarcinoma admixed with benign mucin-containing endocervical-type glands with a transition from dysplastic glands to obvious adenocarcinoma. There were bilateral groin lymph node metastases at presentation and the tumor recurred locally 9 and 12 months after treatment. This is the second reported case of vaginal endocervicosis and the first documented report of adenocarcinoma arising in endocervicosis at any site.

Platelet-derived endothelial cell growth factor expression and angiogenesis in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix.

Growth and metastatic spread of invasive carcinoma depends on angiogenesis, the formation of new blood vessels. Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic growth factor for a number of solid tumors, including lung, bladder, colorectal, and renal cell cancer. Cervical intraepithelial neoplasia (CIN) is the precursor to squamous cell cervical carcinoma (SCC). Mean vessel density (MVD) increases from normal cervical tissue, through low- and high-grade CIN to SCC. We evaluated PD-ECGF immunoreactivity and correlated its expression with MVD in normal, premalignant, and malignant cervical tissue. PD-ECGF expression was assessed visually within the epithelial tissues and scored on the extent and intensity of staining. MVD was calculated by counting the number of vessels positive for von Willebrand factor per unit area subtending normal or CIN epithelium or within tumor hotspots for SCC. Cytoplasmic and/or nuclear PD-ECGF immunoreactivity was seen in normal epithelium. PD-ECGF expression significantly increased with histologic grade from normal, through low- and high-grade CIN, to SCC (P < .02). A progressive significant increase in the microvessel density was also seen, ranging from a mean of 28 vessels for normal tissue to 57 for SCC (P < .0005). No correlation was found between PD-ECGF expression and MVD (P = .45). We conclude that PD-ECGF expression and MVD increase as the cervix transforms from a normal to a malignant phenotype. PD-ECGF is thymidine phosphorylase, a key enzyme in the activation of fluoropyrimidines, including 5-fluorouracil. Evaluation of PD-ECGF thymidine phosphorylase expression may be important in designing future chemotherapeutic trials in cervical cancer.

Does histological incomplete excision of cervical intraepithelial neoplasia following large loop excision of transformation zone increase recurrence rates? A six year cytological follow up.

OBJECTIVE: To determine the risk of recurrent cervical intraepithelial neoplasia (CIN) in women with complete or incomplete excision of cervical intraepithelial neoplasia treated by large loop excision of transformation zone (LLETZ). DESIGN: A retrospective study SETTING: One consultant-led colposcopy clinic at Leicester Royal Infirmary POPULATION: Three hundred and ninety-four women referred consecutively to the colposcopy clinic between 1991 and 1992. MAIN OUTCOME MEASURES: The histological recurrence rate of CIN, length of cytological follow up following treatment related to degree of completeness of excision at initial treatment. RESULTS: Three hundred and twenty-two women had complete cytological or histological follow up. The mean length of follow up was 73 months with a mean number of six smears. Women with incomplete excision of CIN had a significantly higher risk of recurrent CIN (relative risk 8.23) occurring in a significantly shorter time compared with women with complete excision. CONCLUSIONS: This study demonstrates that large loop excision of transformation zone is successful in over 95% of cases. Cytological surveillance is satisfactory for follow up of women who have complete excision of CIN. Women with incomplete excision of CIN at initial LLETZ remain at significant risk of developing further CIN and long term colposcopic and cytological follow up is necessary.

Cervical disease in women referred to colposcopy following inadequate smears.

The aim of this audit was to determine if inadequate cervical smears are associated with significant cervical pathology. Case records for 52 women with three consecutive inadequate smears referred for colposcopy to the Leicester Royal Infirmary (LRI) were retrieved. Sixteen women underwent large loop excision of the transformation zone (LLETZ) and cervical intraepithelial neoplasia (CIN) was identified in six cases. There were no cases of inadequate smears initiating the diagnosis in 100 consecutive women with invasive cervical cancer. Inadequate smears are associated with high rates of treatment for a low yield of CIN. To reduce morbidity associated with colposcopy it may be acceptable to repeat an inadequate smear after 6 months rather than arranging immediate recall.

Borderline malignant change in recurrent müllerian papilloma of the vagina.

Malignant change occurred in a benign, recurrent vaginal müllerian polyp. The patient, a 49 year old woman with cerebral palsy, presented with a polypoid mass in the vagina. At four years of age she had presented with a haemorrhagic polyp, and over the following years she had recurrent irregular bleeding and regrowth of the polypoidal mass, requiring a total of 10 operations to excise the polyp. Histological examination of the specimen showed typical müllerian features with tubal, endometrioid, and endocervical cell types. There were significantly abnormal nuclei, indicating low grade or borderline malignancy. Review of previous biopsies showed similar müllerian features but no atypia. This is the first reported case of borderline malignant change in a previously benign recurrent müllerian papilloma of the vagina. Definitive radical surgery or radiotherapy is contraindicated in this patient and she remains under follow up.

Patient satisfaction with daycase laparoscopy.

A prospective audit was performed on all patients preselected for daycase surgery over a 3-month period. The aim of the study was to evaluate patient acceptability and satisfaction with laparoscopy performed as a daycase procedure. Patients completed standard questionnaires before operation and at 4 weeks after surgery. Questions included satisfaction with daycase surgery, subjective pain experience, time taken to resume normal activities, adequacy of analgesia and necessity to call general practioners. Analysis of results revealed that 69% of patients were satisfied with day surgery laparoscopy. However there were highly significant differences (P less than 0.001) between resumption of normal activity, pain experienced and length of stay between patients satisfied and dissatisfied with daycase surgery. This study suggests that guidelines for daycase procedures may be overambitious as 31% of patients already pre-selected, were dissatisfied with daycase surgery.

A prospective, randomized trial comparing continuous bladder drainage with catheterization at abdominal hysterectomy.

OBJECTIVE: To compare the infection rate and post-operative morbidity between in-dwelling urinary catheterization and 'in-out' catheterization at the time of routine total abdominal hysterectomy. PATIENTS AND METHODS: The study comprised 100 patients who were blindly randomized to have either an indwelling Foley catheter or an 'in-out' catheterization at the time of surgery. Follow-up data on the retention of urine, urinary symptoms and infection were obtained. RESULTS: Of the 95 patients with complete data, 36% of those undergoing in-out catheterization had urinary retention after operation, requiring bladder emptying, compared with 4% of those receiving an indwelling catheter (P < 0.001). In addition, 29% of the catheterized group had urinary tract bacteriuria compared with 13% of the uncatheterized group (P < 0.025). CONCLUSION: This randomized controlled trial showed that in-out urinary catheterization at the time of routine abdominal hysterectomy was associated with a significantly higher incidence of post-operative urinary retention compared with in-dwelling catheterization, and may have implications for long-term bladder function.

Angiogenesis is associated with vascular endothelial growth factor expression in cervical intraepithelial neoplasia.

Squamous cell carcinoma of the cervix (SCC) is preceded by a premalignant condition known as cervical intraepithelial neoplasia (CIN). The majority of cases of CIN regress spontaneously; however, methods are needed to identify those lesions likely to progress. Increased blood vessel density, signifying angiogenesis, is an independent prognostic indicator in a number of cancers, although little is known about its significance in premalignant lesions. The aim of the present study was to determine the relationship between vessel density, expression of the potent angiogenic factor vascular endothelial growth factor (VEGF) and CIN grade. Using immunohistochemistry, mean vessel density (MVD) and VEGF expression were assessed in samples from 54 patients who had undergone cone biopsy for CIN or hysterectomy for SCC and from 16 patients with no cervical pathology. There were significant increases in MVD and VEGF expression from normal cervix through CIN I to CIN III to invasive SCC, but no difference in mean vessel diameter between groups. There was a strong correlation between mean vessel density and VEGF expression, and both were associated with histological grade of CIN. The original MVDs for a small group of patients later presenting with recurrent disease were found to be equal to or greater than the mean for their histological grade. We conclude that the onset of angiogenesis is an early event in premalignant changes of the cervix due, in part, to enhanced expression of VEGF by the abnormal epithelium.

Second-line treatment with ifosfamide and carboplatin in patients with ovarian carcinoma relapsing after treatment with carboplatin.

20 patients with ovarian carcinoma whose disease had relapsed (1-42 months, median 4 months) after showing either response or stable disease to carboplatin, were treated with ifosfamide (5 g/m2 intravenously over 24 h, day 1) and carboplatin (200 mg/m2 intravenously day 2) as second-line treatment. The mean number of treatment cycles was 3.5 (range 1-6). The major toxicities were thrombocytopenia (WHO grade 3/4, 25%), neutropenia (WHO grade 3/4, 40%) and encephalopathy (WHO grade 3/4, 15%). Overall response rate was 15% [complete response, 0; partial response, 3 (15%); no change, 5 (25%) and progressive disease, 12 (60%)]. The median survival from the date of second-line treatment was 7 months. This combination offers no advantage over either agent used alone.