Peter Russell

Nonpigmented endometriosis: Clinical, laparoscopic, and pathologic definition☆☆☆

Abstract We describe the morphologic characteristics and clinical importance of peritoneal lesions that have the histologic features of endometriosis but are devoid of the pigmented stigmas typical of this disease. A total of 137 laparoscopic biopsy specimens were taken of nonpigmented peritoneal lesions in 77 patients, among whom 70 were infertile. Seventy-three biopsy specimens showed endometrium-like glands and stroma, and another 12 showed only endometrioid stroma; no such histologic features of endometriosis were present in 10 biopsy specimens of normal uterosacral ligament peritoneum (p = 0.005, Fishers test). Nonpigmented lesions that were commonly endometriotic were: (1) white opacified peritoneum (endometriosis in 81% of n = 52 biopsy specimens). (2) red flamelike lesions (81% of n = 16), and (3) glandular lesions (resembling endometrium at hysteroscopy) (67% of n = 21). Lesions that were sometimes endometriotic were: (1) subovarian adhesions (50% of n = 4), (2) yellow-brown peritoneal patches (47% of n = 19), and (3) circular peritoneal defects (45% of n = 11). However, thickened cribriform peritoneum usually was not endometriotic (9% of n = 11) and vesicular excrescences were, in every case, reactions to oil-based salpingographic medium (n = 5). Six patients underwent another laparoscopy within 6 to 24 months and each had developed pigmented endometriotic lesions in previously nonpigmented but abnormal areas. Visualization of pigment is not necessary to diagnose endometriosis, and definition of its early, nonpigmented appearance keeps the clinical category of “unexplained infertility” exclusive.

Intra-Abdominal Desmoplastic Small Round Cell Tumor

&NA; A rarely encountered but distinctive type of aggressive malignant tumor of childhood and adolescence has been recently described as occurring predominantly or exclusively intra‐abdominally. It is characterized by a generally diffuse pattern of growth of small cells with hyperchromatic nuclei, scanty cytoplasm, patchy epithelial differentiation, immunohistochemical co‐expression of keratin and desmin intermediate filaments and a focal but pronounced desmoplastic stromal component. It is regarded as yet another variant in the group of small round cell tumors (SRCT) of infancy and childhood. This case report of a mass in the greater omentum of a 15 yr‐old girl adds to the 33 cases already described in the English literature.

Hormone replacement therapy and risk of epithelial ovarian cancer

SummaryIt has been suggested that oestrogen replacement therapy is associated with risk of epithelial ovarian cancer of the endometrioid type. Using data from an Australian population-based case–control study, the relation between unopposed oestrogen replacement therapy and epithelial ovarian cancer, both overall and according to histological type, was examined. A total of 793 eligible incident cases of epithelial ovarian cancer diagnosed from 1990 to 1993 among women living in Queensland, New South Wales and Victoria were identified. These were compared with 855 eligible female controls selected at random from the electoral roll, stratified by age and geographic region. Trained interviewers administered standard questionnaires to obtain detailed reproductive and contraceptive histories, as well as details about hormone replacement therapy and pelvic operations. No clear associations were observed between use of hormone replacement therapy overall and risk of ovarian cancer. Unopposed oestrogen replacement therapy was, however, associated with a significant increase in risk of endometrioid or clear cell epithelial ovarian tumours (odds ratio (OR) 2.56; 95% confidence interval (CI) 1.32–4.94). In addition, the risk associated with oestrogen replacement therapy was much larger in women with an intact genital tract (OR 3.00; 95% Cl 1.54–5.85) than in those with a history of either hysterectomy or tubal ligation. Post-menopausal oestrogen replacement therapy may, therefore, be a risk factor associated with endometrioid and clear cell tumours in particular. Additionally, the risk may be increased predominantly in women with an intact genital tract. These associations could reflect a possible role of endometriosis in the development of endometrioid or clear cell ovarian tumours.

Ploidy as a Prognostic Factor in Ovarian Cancer

SummaryThe cellular DNA content of 50 ovarian common epithelial carcinomas was determined by flow cytometry, and tumours were classified as being either diploid or aneuploid. A significant association between tumour stage and ploidy was demonstrated, with all diploid tumours being of an early stage (p < 0.001). Forty percent of early-stage tumours (FIGO stages I and II) and all late-stage tumours (FIGO stages III and IV) were aneuploid. This heterogeneity with respect to DNA content among tumours of a similar stage may allow the identification of neoplasms with a different natural history. The proportion of S-phase cells determined by flow cytometry is a measure of cellular proliferation and may also be of prognostic significance. Diploid tumours had a median S phase of 9.8% (2.4–14.1%), while aneuploid tumours had a significantly higher S phase of 19.6% (7–24.7%; p < 0.05). In this study there was no relationship between histological grading of invasive carcinomas and ploidy, but in view of the relatively small numbers and limited follow-up, it was_not possible to perform a multivariate analysis of all known prognostic factors in ovarian cancer. Our results suggest that ploidy reflects tumour behaviour, but prolonged follow-up and increased patient accrual is necessary to assess whether the flow cytometric analysis of DNA content will provide clinically important information in ovarian cancer.

The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer.

Between 1960 and 1985 hysterectomy was performed on 811 FIGO stage I and 116 stage II endometrial cancers which were divided into three groups: low-risk stage Ii (grade 1 and 2 lesions confined to the inner third of the myometrium; high-risk stage Iii (grade 3 and/or invading to the middle third of the myometrium or beyond); and FIGO stage II tumors (also high-risk). Hysterectomy was the only treatment in 492; in 145 the vaginal vault alone was radiated and in 290 the whole vagina, in each instance by an intracavity dose of 60Gy; in 34 of the latter high-risk tumors the pelvis received an additional 46Gy by external beam therapy. Forty isolated vaginal recurrences were detected; 10 in 308 low-risk and 22 in 184 high-risk tumors treated by surgery alone, and two and five in 40 low and 105 high-risk patients, respectively, who received adjuvant vault irradiation. No recurrences followed irradiation of the whole vaginal mucosa in 163 stage Ii low-risk and 40 stage II lesions and one, 9 years later, in 87 high-risk stage Iii tumors. Nearly 45% of patients with vaginal recurrence died from cancer within 1 year, 77% within 5 years and only 10% survived their recurrence 10 years. Total vaginal irradiation eliminated vaginal recurrences in low risk and reduced the incidence to 2.1% at 20 years after high-risk tumors.

p16iNK4a as a complementary marker of high-grade intraepithelial lesions of the uterine cervix. I: Experience with squamous lesions in 189 consecutive cervical biopsies

Aim: To test the usefulness of p16INK4a immunostaining for improving the diagnostic accuracy of cervical punch biopsies referred to a routine laboratory setting during the investigation of women with abnormal Papanicolaou smears. Methods: A total of 188 consecutive and unselected colposcopically directed cervical biopsies and a single contemporaneous cervical polyp were accessioned prospectively over a 3‐month period, step‐serially sectioned and examined by H&E and immunostained for p16INK4a. The clinical context, results of concurrent Papanicolaou smears/ThinPrep slides and Digene hybrid capture tests for high‐risk human papillomavirus (HPV) subtypes, as well as follow‐up cervical smears/ThinPrep, biopsies and loop excisions of transformation zones or cone biopsies were all correlated with the morphological and immunohistochemical findings. Results: Seventy‐seven biopsies (40.7%) displayed a high‐grade squamous intraepithelial lesion (HGSIL; cervical intraepithelial neoplasia [CIN] 2–3), 27 (14.3%) showed a low grade squamous intraepithelial lesion (HPV +/− CIN1) and 85 (45%) showed a range of non‐dysplastic (inflammatory or reactive) changes. Diffuse strong parabasal immunostaining for p16INK4a, suggestive of integrated high‐risk HPV DNA into the host genome, was observed in 81 biopsies (42.9%, including the cervical polyp) and correlated (>90%) with HGSIL in the H&E sections. Only one case revealed irreconcilable discordance between the histological features and this strong parabasal immunostaining pattern. Focal and weaker midzonal or superficial p16INK4a immunostaining, suggestive of episomal HPV infection, was noted in 19 biopsies (10%) and these biopsies exhibited a range of histological changes but predominantly low grade squamous intraepithelial lesion (LGSIL). No staining of the squamous epithelium was seen in 89 biopsies (47.1%). Again, only one case revealed irreconcilable discordance between the histological features and this negative immunostaining pattern. On review of all cases where discordant results were noted between the H&E appearances and expected p16INK4a immunostaining, we found 26 cases (13.7%) in which this discordance prompted justifiable modification of the original diagnosis. Conclusions: Thus, within a routine diagnostic laboratory, p16INK4a immunostaining appears to be a very useful adjunctive test in the examination of colposcopically directed cervical biopsies, in the diagnostic cascade of women investigated for abnormal Papanicolaou smears. It is possible, as further data accumulate concerning the importance of integration of high‐risk HPV DNA into the host cell genome and the reliability with which this can be identified by p16INK4a immunostaining, that this will become the diagnostic ‘lesion of interest’, replacing the subjective histological grading of cervical dysplasia, in the management of such patients; i.e., the discriminatory watershed between continued surveillance and active intervention.

Cervical carcinoma: A drug-responsive tumor—experience with combined cisplatin, vinblastine, and bleomycin therapy

Thirty-five patients with advanced cervical cancer were treated with a combination chemotherapy regimen comprising cisplatin, vinblastine, and bleomycin (PVB). Sixty-six percent of 33 evaluable patients showed objective tumor response and complete remissions were seen in six (18%) patients. The median duration of tumor response in patients with recurrent cervical cancer was 24 weeks (range 8 to 104 weeks). Multivariate analysis of pretreatment variables including prior radiotherapy did not identify patients with a higher response probability. Nausea and vomiting were usual side effects of chemotherapy and there was one definite treatment-related death. Cervical cancer is responsive to cisplatin based combination chemotherapy. The role of chemotherapy in conjunction with radiotherapy or surgery in the treatment of locally advanced cervical cancer remains to be defined.

The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study

Chemotherapy has been traditionally reserved as a last-time treatment for cervical cancer patients and in this setting long-term remissions are unusual. Platinum-based combination chemotherapy has been associated with high tumor response rates in patients with advanced and metastatic cervical tumors and past experience encouraged evaluation of chemotherapy as a first-line treatment in patients with locally advanced tumors where there is a high likelihood of relapse with local treatment. Thirty patients were treated initially with three courses of cis-platinum, vinblastine, and bleomycin with an overall response rate of 67%, and then had either radiotherapy or surgical resection. The initial results have been encouraging and the integration of chemotherapy into the management of locally advanced cervical cancer warrants further investigation.

Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors.

Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with ∼12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important. (Mol Cancer Res 2008;6(11):1678–90)

The role of Foxp3+ regulatory T-cells in endometriosis: a potential controlling mechanism for a complex, chronic immunological condition

BACKGROUND Endometriosis is an inflammatory condition, associated with highly dysregulated immune response at both uterine and peritoneal levels. Surprisingly, Foxp3+ regulatory T-cells, which control and suppress a range of immune responses, have not previously been investigated in endometriosis. METHODS AND RESULTS Immunohistochemical analysis of Foxp3+ cells in 127 eutopic endometrial samples and 59 ectopic peritoneal lesions revealed that these immune cell populations are highly disturbed in women suffering from endometriosis. We showed that Foxp3+ cells remained highly up-regulated during the secretory phase of the menstrual cycle, while at this time their expression is significantly down-regulated in women without endometriosis (P < 0.001). Foxp3+ cells were detected in the stroma of 18 of the 59 peritoneal endometriotic lesions, but not in the surrounding or control peritoneal tissue. CONCLUSIONS We propose that in eutopic endometrium in women with endometriosis Foxp3+ cells decrease the ability of newly recruited immune cell populations to effectively recognize and target endometrial antigens shed during menstruation, allowing their survival and ability to implant in ectopic sites. At these ectopic sites, variable expression of Foxp3+ cells within some peritoneal endometriotic lesions is likely to be linked to the characteristics and stage of individual lesion development and be playing key roles in pathogenesis and progression of this unique condition.