Reflectance confocal microscopy for diagnosis of mammary and extramammary Paget's disease.

BACKGROUND: Paget's disease is an intraepidermal adenocarcinoma that is difficult to diagnose clinically as it mimics inflammatory or infectious diseases. As a consequence, it may be clinically misdiagnosed resulting in a delay in appropriate management. Reflectance confocal microscopy allows the visualization of the upper layers of the skin and mucosa at cellular resolution. Paget's disease is characterized histologically by the presence of neoplastic cells scattered throughout all layers of the epidermis in a pattern similar to that also observed in melanoma (and termed Pagetoid spread). OBJECTIVE: In vivo confocal microscopy is an excellent diagnostic tool for detecting Pagetoid spread and for diagnosing melanoma. We therefore hypothesized that it may also assist in the diagnosis of Paget's disease. METHODS: In this study, we describe the confocal features of nine cases of extramammary Paget's disease and one case of mammary one. RESULTS: Large atypical Pagetoid cells were present singly and in clusters in all 10 cases and were readily visualized on ex vivo and in vivo confocal microscopy. The presence of Pagetoid spread and other confocal features, in the appropriate clinical context, is suggestive Paget's disease and should allow distinction from other inflammatory diseases that may appear similar clinically. CONCLUSION: The use of confocal microscopy is likely to facilitate earlier diagnosis of Paget's disease and the instigation of appropriate management with concomitant improvement in clinical outcomes.

Endometrioid ovarian carcinoma in a woman with a history of infertility and multiple in-vitro fertilization treatment cycles.

Ovarian cancer is rarely diagnosed during assisted reproduction. Several case-control and cohort studies have described its incidence within the infertile population well after the assisted reproductive process. We present a case of endometrioid adenocarcinoma that developed during the ovarian stimulation process and show corresponding ultrasound images of its development.

Cold knife versus laser cone biopsy for adenocarcinoma in situ of the cervix--a comparison of management and outcome.

Eighty-two patients with adenocarcinoma in situ of the cervix managed at Royal Prince Alfred Hospital were reviewed and data were collected on those treated by cold knife cone biopsy (n= 38) and laser cone biopsy (n= 44). No differences were found in patient age, cytologic or referral history, or outcomes. Having laser excision did not compromise margin status or subsequent management. Invasive disease was found in 24 patients, 16 of whom were managed conservatively with good outcome. Twelve of these were in the laser cone group. In those patients from both groups managed conservatively, there was only one recurrence, squamous preinvasive disease after 8 years. Laser cone biopsy is as effective as cold knife cone biopsy with no compromise of outcome for these patients.

High grade abnormalities following an 'inconclusive' smear.

OBJECTIVE: The National Health and Medical Research Council (NHMRC) recommends a report of 'inconclusive possible high grade epithelial abnormality', but many laboratories only report 'inconclusive' with reference to any possible high grade disease elsewhere in the report. This study was performed to determine possible reasons for cytological difficulties resulting in this category of report and to determine the rate of significant disease within this category. DESIGN: Retrospective record review. Clinical details were extracted without patient-identifying data. SETTING: Gynaecological Oncology Department, King George V/Royal Prince Alfred Hospital. POPULATION: Two hundred patients referred with the cytological abnormality. MATERIALS AND METHODS: An adequate colposcopic diagram documenting size, distribution and grade of lesion was required. All patients had colposcopy with management according to colposcopic and histological results as appropriate to their disease. OUTCOME MEASURES: Colposcopic features, topography and size of any lesion, histological results, treatments performed and subsequent review of untreated patients. RESULTS: Colposcopy found high-grade lesions in 43% and carcinoma in 1%. Histopathology found 49% and 4% respectively. Treatment was performed in 124 patients. Inflammation was found in 27%, a small lesion in 43% and endocervical disease in 21%. CONCLUSIONS: The high rate of endocervical disease, inflammation and small lesions may explain the cytological difficulties leading to an 'inconclusive' result. The authors believe that the term 'inconclusive' alone does not adequately convey the high level of risk faced by these patients.

Analysis of clinicopathologic factors in malignant mixed Müllerian tumors of the uterine corpus.

The aim of this study was to retrospectively analyze the clinical and pathologic data of a series of patients presenting to our unit with uterine malignant mixed Müllerian tumors (MMMT) to attempt to identify prognostic factors and relate them to survival. Thirty-seven patients diagnosed with MMMT of the uterus from 1988 through 2000 were identified from the gynecological tumor registry. Data was abstracted and analyzed. The effect of a variety of clinical, histopathologic, and surgical variables on recurrence and survival were analyzed by univariate and multivariate analyses. Patients tended to be postmenopausal, overweight, hypertensive, and presented with abnormal bleeding. Preoperatively 28 (76%) were thought to have clinical stage I-II disease. Nine (32%) were upstaged based on surgical data. Five (56%) of these patients were found to have gross extrauterine disease and four (44%) were found subsequently to have microscopic extrauterine disease. Twenty (54%) patients underwent lymph node dissection and positive nodes were found in seven (35%) patients. Nine patients underwent omentectomy and disease was found in three (33%). Peritoneal washings were positive in three of 16 patients (19%). At the completion of primary surgery, 27 (75%) patients had no residual disease. Twelve (44%) of these patients had recurrence of disease. Median disease-free interval prior to first recurrence was 15 months. Median overall survival was 30 months. Log-rank analysis performed on multiple variables, including stage, age, residual disease, and depth of myometrial invasion showed a statistically significant association with overall survival probability. Only stage remained a significant independent variable predictive of overall survival (P = 0.034). We found that stage was an independent prognostic factor for overall survival in patients with uterine MMMT. Age, depth of myometrial invasion, and residual tumor were significant prognostic factors on univariate analysis. These factors may be a guide in order to select a group of high risk patients that may benefit from adjuvant therapy.

Locally advanced cervix cancer: chemotherapy prior to definitive surgery or radiotherapy. A single institutional experience.

Primary or neoadjuvant chemotherapy prior to definitive local therapy has potential advantages for locally advanced cervix cancer. It can downstage a cancer and allow definitive local therapy to be technically possible (surgery), or potentially more effective (radiotherapy). It can also eradicate subclinical systemic metastases. This report reviews a single institution's experience of neoadjuvant chemotherapy prior to definitive local therapy for cervix cancer over a 13-year period. One hundred and six patients were treated with this intent. The patients were analysed for their response to chemotherapy, treatment received, survival, relapse and toxicity. The chemotherapy was feasible and the majority of patients had a complete or partial response (58.5%). Eight patients did not proceed to local treatment. Forty-six patients had definitive surgery and 52 had definitive radiotherapy. The 5-year overall survival was 27% and the majority of patients died with disease. The first site of relapse was usually in the pelvis (46.2%). Late complications that required ongoing medical therapy (n=6) or surgical intervention (n=2) were recorded in eight patients (7.5%). On univariate analysis stage (P=0.04), tumour size (P=0.01), lymph node status (P=0.003), response to chemotherapy (P=0.045) and treatment (P=0.003) were all significant predictors of survival. On multivariate analysis, tumour size (P < 0.0001) and nodal status (P=0.02) were significant predictors of survival. Despite the impressive responses to chemotherapy of advanced cervix cancer, there is evidence from randomized trials that it does not improve or compromise survival prior to radiotherapy. As its role prior to surgery remains unclear, it should not be used in this setting outside a prospective randomized trial.

Surgery and post-operative radiotherapy for early stage cervical cancer.

The use of post-operative radiotherapy in the treatment of cervical cancer is controversial. The aim of this study was to document the results and toxicity of adjuvant irradiation in patients with Stage 1B and 2A cervical cancer. We performed a retrospective review of all patients treated with post-operative radiotherapy at Royal Prince Alfred Hospital between 1986 and 1993. Patient, tumour and treatment factors and late toxicity were recorded. Relapse-free and overall survival were calculated. Eighty-one patients form the study population. The median follow-up was 6.1 years. Fifty-eight patients (72%) had stage 1B cervical cancer and 23 (28%) stage 2A. The 5 year relapse-free and overall survival were 78% and 80% respectively. Six patients (7%) had late toxicity requiring inpatient medical treatment and 6 patients (7%) required surgery. The survival was comparable to other series reported in the literature. There was an incidence of 14% late toxicity requiring medical or surgical intervention which is greater than with hysterectomy or pelvic irradiation alone. Clinical prognostic factors should be used to select patients for either surgery or radiotherapy alone to minimise the increased toxicities associated with a combination of surgery and radiotherapy.

Validation of women's self-reported smoking status in a Sydney colposcopy clinic.

This study validated a self-reported smoking prevalence questionnaire against urinary cotinine levels among women referred to a Sydney based public hospital colposcopy clinic over the period November 1997 to June 1998. Of 213 eligible women, 160 (75%) agreed to participate. Of these, 151 (94%) completed the smoking prevalence item and 130 (86%) also provided a urine specimen. 40% (95% CI: 33%-49%) of respondents self-reported as current smokers. Observed agreement between self-reported and biochemically validated smoking status was 94% compared with 52% chance agreement (kappa = 0.87, p<0.001). This high level of agreement was also robust to sensitivity analyses using a more conservative cutoff for the urinary cotinine levels. We conclude that self-reported smoking status provides valid estimates of actual rates of smoking among women referred with abnormal cervical smears.

Whole abdominal radiotherapy following second-look laparotomy for ovarian carcinoma.

AIM: The safety and efficacy of whole abdominal radiotherapy was evaluated as salvage or consolidation treatment for ovarian cancer patients treated with primary surgery and chemotherapy, followed by second-look laparotomy (SLL). Overall survival and acute and late toxicity of treated patients were assessed. METHODS: Patients were recruited between April 1981 and June 1994. All patients had SLL performed at Royal Prince Alfred Hospital after completion of primary chemotherapy. Data collected included demographic details, diagnosis, tumor stage, histology, grade, adjuvant chemotherapy, and radiotherapy. Radiation dose and fractionation, field size, boost volume and dose, failure to complete treatment and treatment interruptions, renal dose, and acute and late toxicity were recorded. RESULTS: Fifty-one patients were evaluated; the median age was 51 years. Median follow-up for patients still alive was 62 months. Prior to 1988, chemotherapy comprised oral chlorambucil, with or without cisplatin (n = 25), while after this date all patients (n = 26) received primary cisplatin-based therapy. A radiation dose of 22. 5 Gy over 22 fractions was planned to the whole abdomen followed by a pelvic boost of 22 Gy in 11 fractions. Radiotherapy was completed in 37 (73%) patients. Treatment interruptions were necessary in 12 (24%) patients. Thrombocytopenia, neutropenia, nausea, vomiting, and diarrhea were the main causes of incomplete or interrupted treatment. Late bowel toxicity was seen in 6 (12%) patients, 2 of whom required laparotomy to relieve obstruction. There were no treatment-related deaths. Seven of the 51 patients are alive and free of disease, 2 died from other causes, and 2 are alive with evidence of recurrent or progressive disease. Mean follow-up time for surviving patients is 78.5 months. Overall survival at 2, 5, and 10 years was 65, 27, and 10%, respectively. Residual disease after primary surgery, smaller preirradiation tumor residuum, and completion of radiotherapy were independently associated with improved overall survival. CONCLUSION: In this poor-prognosis group of patients, a combined approach of surgery, chemotherapy, and radiotherapy, while associated with acceptable toxicity, may not afford a prolongation of survival.

Thermal artefact after diathermy loop excision and laser excision cone biopsy.

Whether or not thermal artefact precludes accurate histopathologic assessment of excision biopsies of the uterine cervix is currently controversial. Some authors state that margins cannot be assessed at all while others feel that the pathologist can 'see through' the artefact in the majority of cases. Over a 7-month period, 164 patients had loop excision and 84 patients had laser cone biopsy. The zone of coagulation at the specimen periphery was measured and the adequacy of excision assessed. The average width for this zone of coagulation in diathermy loop was 0.32 mm and for laser cone biopsies was 0.31 mm. In 12% of the loop specimens the line of excision was compromised by dysplasia or its assessment was rendered uncertain by thermal artefact. This was far more common in fragmented specimens (20%) compared to those removed as a single specimen (6%). In this study, 40% of patients had fragmented loop specimens. Thus, in attempting to replace cone biopsy with loop excision, we are asking pathologists to reassemble a pathologic jigsaw, then look through the thermal artefact for a decision on margins. We believe that this fragmentation should preclude the use of loop excision for lesions which would previously have been managed by cone biopsy.

Adjuvant high-dose rate brachytherapy with or without external beam radiotherapy post-hysterectomy for endometrial cancer.

The purpose of this study was to evaluate patient selection, local control, survival and late toxicity of posthysterectomy adjuvant radiotherapy and compare adjuvant external beam therapy and high-dose rate (HDR) brachytherapy versus HDR brachytherapy alone. A retrospective analysis was performed on a series of 225 patients with endometrial cancer treated with external beam radiotherapy and HDR brachytherapy or HDR brachytherapy alone posthysterectomy from 1985 to June 1993. Of these 225 patients, 82 received external beam radiotherapy and brachytherapy and 143 received brachytherapy alone. The HDR fraction size was 8.5 Gy prescribed to the mucosal surface; two fractions were given after external beam and four fractions if brachytherapy alone was used. The median follow-up was 6.9 years. The patients who received combined external beam and brachytherapy had higher stage and grade tumors. The survival outcome was similar for either group when matched for stage. Overall relapse-free survival at five years was 96% and 81%, respectively for brachytherapy alone and combined adjuvant therapy. Pelvic recurrence was seen in 2.7% of patients. Toxicity was more common with external beam radiotherapy and brachytherapy compared to brachytherapy alone (45.1% vs 23.1%, P = 0.003). However, moderate or severe toxicity was rare but again was more common in the combined radiotherapy group (8.5% vs 2.1%, P = 0.04). There was a non-significant trend to increased toxicity after lymphadenectomy and external beam radiotherapy compared with patients who did not have a staging lymphadenectomy prior to external beam radiotherapy (62% vs 38%, P = 0.16). Adjuvant radiotherapy can be individualized and be based upon the information provided by the pathological specimens, which excluded external beam radiotherapy if a lymphadenectomy was performed and there was no evidence of extra-uterine disease. This study found more toxicity associated with adjuvant radiotherapy compared with other studies, but this may reflect different reporting criteria. There was more toxicity related to external beam radiotherapy and brachytherapy compared to brachytherapy alone. The two HDR brachytherapy protocols used in this series appear effective and safe.

Argument for the surgical staging of apparent early endometrial cancer.

Cancer of the uterine corpus, commonly referred to as cancer of the endometrium or cancer of the uterus, continues to be the most common pelvic genital malignancy affecting western women (1). In 1998 in the United States 36,100 women were diagnosed with this cancer, and there were 6,300 deaths from this condition in that year. Of concern is that despite a relatively stable incidence over the last decade, the annual number of deaths since 1987 from endometrial cancer has more than doubled (2). Many controversies exist in the management of apparent early endometrial cancer. These include: 1. The role of surgical staging which includes pelvic lymphadenectomy. 2. The role of the subspecialist gynaecological oncologist in primary surgical treatment. 3. Indications for vaginal and external beam radiotherapy. 4. Who is at risk for recurrence? 5. The role of laparoscopic approach to the management of this disease. Despite their importance, these and other issues have not been appropriately addressed by prospective randomized studies. Treatment strategies and algorithms have thus been based upon a combination of clinicopathological studies and uncontrolled reviews. The views expressed in this clinical opinion are those of the Sydney Gynaecologic Oncology Group and reflect our philosophy on the current management of this tumour, supported by recent and appropriate peer reviewed scientific literature.

High-dose-rate brachytherapy alone post-hysterectomy for endometrial cancer.

PURPOSE: To evaluate the outcome of post-hysterectomy adjuvant vaginal high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: A retrospective analysis was performed on a series of 143 patients with endometrial cancer treated with HDR brachytherapy alone post-hysterectomy from 1985 to June 1993. Of these patients, 141 received 34 Gy in four fractions prescribed to the vaginal mucosa in a 2-week period. The median follow-up was 6.9 years. Patients were analyzed for treatment parameters, survival, local recurrence, distant relapse, and toxicity. RESULTS: Five-year relapse free survival and overall survival was 100% and 88% for Stage 1A, 98% and 94% for Stage IB, 100% and 86% for Stage IC, and 92% and 92% for Stage IIA. The overall vaginal recurrence rate was 1.4%. The overall late-toxicity rate was low, and no RTOG grade 3, 4, or 5 complications were recorded. CONCLUSION: These results are similar to reported international series that have used either low-dose-rate or HDR brachytherapy. The biological effective dose was low for both acute and late responding tissues compared with some of the HDR brachytherapy series, and supports using this lower dose and possibly decreasing late side-effects with no apparent increased risk of vaginal recurrence.

High-dose-rate brachytherapy in the management of carcinoma of the cervix: an 8-year Australian experience.

High-dose-rate brachytherapy was introduced at this hospital for the treatment of gynaecological malignancy in 1985. A retrospective analysis was performed of 103 patients with cervix cancer treated with this technique from 1985 to June, 1993. The patients were analyzed for treatment parameters, response, survival, relapse and toxicity. Five-year survival was 78% for Stage 1B, 72% for Stage 2A, 42% for Stage 2B and 29% for Stage 3B. The severe late toxicity rate was 4.9%. These results are similar to reported international series that have used either low-dose-rate or high-dose-rate brachytherapy.

High-dose-rate brachytherapy in the management of high-grade intraepithelial neoplasia of the vagina.

The majority of women with high-grade intraepithelial neoplasia (VAIN 3) are over 60 years of age and have a history of premalignant or malignant disease of the cervix. Although the natural history of VAIN is not well defined, high-grade lesions are premalignant. Ablative treatment with laser or 5-fluorouracil cream is commonly unsatisfactory. Several series have reported a low rate of recurrence and complications if VAIN 3 is treated with low-dose-rate brachytherapy. This retrospective review reports the outcome of 14 patients treated with high-dose-rate brachytherapy, with a dose of 34 to 45 Gy in 4.5- to 8.5-Gy fractions. Treatment was well tolerated with no severe early or late toxicity observed. At a median follow-up of 46 months 1 patient progressed to invasive carcinoma of the vagina; in another patient VAIN 3 persisted.

Human papillomavirus deoxyribonucleic acid as a prognostic indicator in early-stage cervical cancer: a possible role for type 18.

OBJECTIVE: Our purpose was to determine the prognostic significance of human papillomavirus deoxyribonucleic acid in cervical cancers. STUDY DESIGN: The polymerase chain reaction was used to detect human papillomavirus deoxyribonucleic acid types 6, 11, 16, 18, 31, 33, 52, or 58 in tumors from 148 patients (equal numbers of whom were disease free or had relapses) surgically treated for stage IB or IIA cancers in a major Australian hospital. Cox regression modeling was used to assess the effect of human papillomavirus status on tumor recurrence, taking into account patient age, clinical stage, histologic node status, and type of tumor. RESULTS: Seventy of 74 (95%) of the recurring tumors and 62 of 74 (84%) of the nonrecurring tumors were human papillomavirus deoxyribonucleic acid positive. The rates of positivity of types 16 and 18 were 64% versus 31% in the recurrers and 65% versus 14% in the nonrecurrers. Human papillomavirus type 18 positivity was associated with a greater risk of recurrence than was type 16 positivity (hazard ratio 1.8; p = 0.03). Clinical stage, nodal metastasis, and young age (< or = 35 years) also had adverse effects on relapse (hazard ratio for each approximately 2). CONCLUSION: Human papillomavirus type 18 positivity is a risk factor for tumor recurrence in surgically treated cervical cancer.

Coexistent complete and partial hydatidiform moles in a twin pregnancy.

A case of twin pregnancy with complete and partial molar disease is presented. Aspects of diagnosis, ploidy studies and management are discussed.

Identification of E6/E7 transcription patterns in HPV 16-positive cervical cancers using the reverse transcription/polymerase chain reaction.

Studies indicate the presence of four different forms of human papillomavirus (HPV) E6/E7 mRNA resulting from differences in transcription patterns and post-transcriptional nuclear splicing. Through a retrospective analysis of 28 cervical cancer patients, correlations were sought between E6/E7 transcription patterns and histologic type, FIGO stage, and tumor aggression. A combined reverse transcription/polymerase chain reaction was used to study E6/E7 transcription patterns in fresh and/or fixed paraffin-embedded tissues of HPV 16-positive cervical cancers. Random cervical biopsies from nine women with no history of cervical disease were included as controls. Two sets of primers used in the investigations detected the full-length (FL) E6, E6*I, and E6*II mRNAs and the FL E6 and E6*I mRNAs, respectively; eight of the tumors were also analyzed using a third primer combination designed to identify the E6*III mRNA. At least two of the transcripts were detected in all of the tumors, whereas E6/E7 mRNAs were not identified in any of the control cervical biopsies. Overall, the transcription patterns were consistent, but the major E6*I mRNA was not detected in two of the tumors. No relationship was found between the E6/E7 transcription patterns and the histological type and differentiation of the tumors, nor with the FIGO stage and the clinical behavior of the disease. The study confirms that E6/E7 transcription is a constant feature of HPV 16-related carcinoma, but the findings indicate that there may be no clinical advantage in adding E6/E7 mRNA detection to the routine assessment of cervical tumors.

Detection of human papillomavirus type 16 E6/E7 transcripts in histologically cancer-free pelvic lymph nodes of patients with cervical carcinoma.

Human papillomavirus (HPV) 16 E6/E7 mRNAs have been detected in paraffin-embedded sections of histologically cancer-free pelvic lymph nodes from four of six patients with HPV 16-associated cervical cancer. The cDNA obtained from the viral mRNA by reverse transcription was amplified by the polymerase chain reaction (PCR). Transcripts were present in a small but significant proportion (6/42, 14%) of the histologically negative/HPV 16 DNA-positive lymph node blocks; but neither HPV 16 DNA nor transcripts were found in 12 lymph node blocks from two patients whose cervical cancers were not HPV-related. Both of the HPV 16 mRNAs detectable by the PCR primers used in the assay (the E6*I and the full-length E6 transcript) were found in the primary tumors, but the transcription patterns in the lymph nodes were variable. The presence of HPV E6/E7 mRNAs in lymph nodes of patients with HPV-related cancer may be a more sensitive indicator of metastasis than conventional histology. In addition, their detections is likely to be more significant than that of HPV DNA sequences alone. The practical significance of the findings, however, awaits correlation with the ultimate clinical outcome.