Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer.

Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation. Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ). Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70). Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).

Recent trends in breast, cervical, and colorectal cancer screening test utilization in Canada, using self-reported data from 2008 and 2012.

In Canada, self-reported data from the Canadian Community Health Survey 2008 and 2012 provide an opportunity to examine overall utilization of breast, cervical, and colorectal cancer screening tests for both programmatic and opportunistic screening. Among women 50-74 years of age, utilization of screening mammography was stable (62.0% in 2008 and 63.0% in 2012). Pap test utilization for women 25-69 years of age remained high and stable across Canada in 2008 and 2012 (78.9% in 2012). The percentage of individuals 50-74 years of age who reporting having at least 1 fecal test within the preceding 2 years increased in 2012 (to 23.0% from 16.9% in 2008), but remains low. Stable rates of screening mammography utilization (about 30%) were reported in 2008 and 2012 among women 40-49 years of age, a group for which population-based screening is not recommended. Although declining over time, cervical cancer screening rates were high for women less than 25 years of age (for whom screening is not recommended). Interestingly, an increased percentage of women 70-74 years of age reported having a Pap test. In 2012, a smaller percentage of women 50-69 years of age reported having no screening test (5.9% vs. 8.5% in 2008), and more women reported having the three types of cancer screening tests (19.0% vs. 13.2%). Efforts to encourage use of screening within the recommended average-risk age groups are needed, and education for stakeholders about the possible harms of screening outside those age groups has to continue.

Surgery as sole treatment for serous borderline tumors of the ovary with noninvasive implants.

OBJECTIVES: The objectives were to describe the clinical characteristics and prognosis of surgically treated patients with stage II and III serous borderline tumors of the ovary with noninvasive implants. MATERIALS AND METHODS: From 1990 to 2000, 16 patients with stage II and III ovarian serous borderline tumors and noninvasive implants were diagnosed and prospectively followed at our center. All patients underwent surgical treatment including staging and their pathology was reviewed. Fifteen patients had thorough surgical staging by laparotomy, while one patient was staged laparoscopically. No patient was treated with adjuvant therapy (radiation or chemotherapy) after surgical treatment and none were lost to follow-up. RESULTS: The mean age at diagnosis was 42 years (range 26-59). Fourteen patients were treated by abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and multiple peritoneal biopsies, while 2 patients were treated conservatively for fertility preservation. Two patients underwent pelvic and para-aortic lymph node dissection. Fifteen of 16 patients had ovarian surface involvement with tumor. All patients but 2 had clinical evidence of extraovarian disease at the time of surgery. The mean duration of follow-up was 60.7 months (range 2-134 months). Thirteen patients (81%) are alive without evidence of disease. Four patients (25%) required subsequent surgery for recurrent disease and all are still alive. Two patients have been treated with chemotherapy (paclitaxel/carboplatin) for progressive borderline disease, while an additional patient was treated after first relapse with chemotherapy for an invasive recurrence. CONCLUSIONS: Carefully staged patients with advanced serous borderline tumors of the ovary and noninvasive implants have a good prognosis without adjuvant therapy.

Human papillomavirus in cervical neoplasia. Role, risk factors, and implications.

A rapidly increasing body of evidence links human papillomavirus (HPV) to cervical neoplasia through epidemiologic associations, pathologic features, molecular detection, and mechanisms of oncogenesis. HPV is now accepted as the primary cause of cervical neoplasia and accounts for most of the risk factors traditionally associated with this disease. The role that HPV plays in the induction and progression of cervical neoplasia is becoming clearer; however, the challenge now is to find other factors that may play a role in the outcome of cervical cancer and that might serve as targets for novel treatments.

Prostatic secretory protein (PSP94) expression in human female reproductive tissues, breast and in endometrial cancer cell lines.

PSP94 (beta microseminoprotein, beta MSP) is one of the three major proteins secreted by the normal human prostate gland. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blotting, PSP94 transcripts were shown in human endometrium, myometrium, ovary, breast, placenta and in the human endometrial cancer cell lines KLE and AN3 CA. Primers used in these studies were specific for human prostate PSP94, and were derived from its flanking non-coding regions. The results were confirmed by sequence analysis of two independently derived clones from normal human breast tissues and the other two from KLE cells respectively. The sequences were identical with the coding sequence of human prostate PSP94 cDNA. Using RNA from the endometrial tissues, two different transcripts of approximately 487 bp, equivalent to prostate PSP94 and approximately 381 bp, corresponding to prostate PSP57, its alternately spliced form, were amplified by RT-PCR. Human ovary, breast, placenta and endometrial cancer cell lines (KLE, AN3 CA), however, showed only the full length, approximately 487 bp, PSP94 transcript. We further demonstrated by in situ hybridization that PSP94 mRNA is expressed specifically in the glandular epithelial cells, and not in the stroma of both the human endometrial and breast tissues. Further, using image analysis of in situ hybridization data, the levels of PSP94 mRNA in the cycling endometrial tissues and in breast confirmed the differential levels of expression in the cycling endometrium (P<0.005). This study distinctly demonstrated significant expression of PSP94 mRNA in human uterine, breast and other female reproductive tissues as well in the endometrial cancer cell lines, suggesting that it may have a role in these tissues as a local autocrine paracrine factor.

Hybrid Capture Human Papillomavirus Testing as an Adjunct to the Follow-Up of Patients with ASCUS and LGSIL Pap Smears: A Study of a Screening Population.

OBJECTIVES: We set out to evaluate Hybrid Capture (Digene Corporation, Silver Spring, MD) testing for human papillomavirus (HPV) in the management of a screening population with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LGSIL). METHODS: A total of 619 patients with ASCUS or LGSIL Papanicolaou smears were tested for high-risk HPV types. They then were followed at 6-month intervals with Papanicolaou smears and repeat HPV testing. Patients with persistent or progressive disease were referred for colposcopy. HPV results were compared to the most significant follow-up cytological or colposcopic diagnosis to determine whether Hybrid Capture HPV testing was predictive of outcome. A cost analysis was performed. RESULTS: Follow-up of 12 to 30 months was available for 471 patients (76.1%). Outcome diagnoses for 190 patients who initially tested HPV-positive were as follows: 49% benign, 14% ASCUS, 19% LGSIL, 18% HGSIL, and 0.5% cancer. For 281 patients who initially tested HPV-negative, outcomes were 77% benign, 14% ASCUS, 6% LGSIL, 2% HGSIL, and 0.3% cancer. Twenty-six of the patients with HGSIL had two or more HPV tests, and all these patients had at least one positive result. CONCLUSIONS: Hybrid Capture testing for high-risk HPV types was predictive of which patients presenting with ASCUS/LGSIL would persist or progress to HGSIL (p < .001). The cost of adding Hybrid Capture testing was intermediate between the cost of cytological follow-up and referral of all patients with ASCUS/LGSIL to colposcopy.

Assessment of cytologic follow-up as the recommended management for patients with atypical squamous cells of undetermined significance or low grade squamous intraepithelial lesions.

BACKGROUND: The optimal management of low grade Papanicolaou (Pap) smear abnormalities remains controversial. This center's experience with recommending cytologic follow-up for women with atypical cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesions (LSIL) was reviewed to determine outcome and patient/physician compliance. METHODS: The records were reviewed on women with Pap smears reported as either ASCUS (320) or LSIL (112) who did not have a history of dysplasia. The cytologic and colposcopic follow-up for a 2-year period was obtained from the laboratory data base that includes the colposcopy and cancer referrals for this region. Repeat Pap smear in 6 months was recommended. If patients subsequently demonstrated high grade SIL (HSIL) or persistent ASCUS or LSIL over three time intervals, colposcopic evaluation was recommended. RESULTS: The outcome was determined by the most significant diagnosis among the follow-up Pap smears or colposcopic biopsies. 29% of patients were lost to follow-up. Of the remaining patients, 70.5% reverted to normal or benign cellular changes, 25.3% persisted as ASCUS or LSIL, and 5.2% progressed to HSIL. The majority of patients (68%) were referred for colposcopy for persistent mildly abnormal Pap smears. The timing of referral ranged from 3-30 months. CONCLUSIONS: These results suggest that cytologic follow-up of women with low grade Pap smear abnormalities will identify a large number whose smears will regress to normal. A small but significant proportion of women showed subsequent HSIL. Most HSIL was detected within 1 year of the initial abnormal Pap smear and the majority of intervening Pap smears also were abnormal. Approximately one third of patients did not have follow-up within the study system and their outcome was uncertain. Although the recommendations are standard, patterns of follow-up and referral to colposcopy varied widely, suggesting that the guidelines need to be reinforced to both patients and physicians. [See editorial on pages 1-4, this issue.]

Disparities in mean age and histopathologic grade between human papillomavirus type-specific early cervical neoplasms.

Noninvasive squamous and glandular precursor lesions associated with human papillomavirus (HPV) types 16 and 18 have been reported to vary in morphology. HPV 16 is associated predominantly with high-grade squamous intraepithelial lesions (HSIL; cervical intraepithelial neoplasia (CIN 2 and 3), and HPV 18 is associated with low-grade squamous intraepithelial lesions (condyloma/CIN 1) and CIN 3/adenocarcinoma in situ (ACIS). This study explored the relationship of morphologic growth pattern in these precursor groups with age of presentation. One hundred fourteen CIN lesions (including those with ACIS), associated with HPV 16 or 18, were subdivided into well-differentiated low- and high-grade SIL (CIN 1 and 2, respectively), poorly differentiated HSIL (CIN 3) with or without ACIS. HPV was detected by polymerase chain reaction (PCR) amplification with L1 consensus or type-specific E7 primers and typed by restriction fragment length polymorphism (RFLP) analysis. Age of the patient was obtained from the pathology report. Mean age for each group was as follows: Low-risk HPVs, 25 years; HPV 18 CIN 1-2, 21.6 yrs; HPV 18 CIN 3/ACIS, 35.2 yrs; HPV 16 CIN 1,2, 25.9 yrs; and HPV 16 CIN 3, 29.8 yrs. There were significant differences in mean ages between HPV 18 CIN 1 and 2 and HPV 16 CIN 1 to 2 (P = .04), HPV 16 CIN 1-2 and CIN 3 (P = .01) and HPV 18 CIN 1 to 2 and HPV 18 CIN 3/ACIS (P = .00001). None of the cases of HPV 18-associated CIN3/ACIS was associated with a CINI lesion. The disparity in mean ages between well and poorly differentiated HPV 16/18 related that precursor lesions could reflect factors such as morphologic progression with increasing age, different rates of lesion persistence, depending on grade, or efficiency of detection between the two groups. The marked difference in mean age between HPV 18-associated CIN 1-2 and CIN 3/ACIS, combined with their lack of coexistence in the same cervix, raises alternate possibilities that specific viral or host factors may determine the morphological phenotype associated with some HPV 18 infections. In the latter, the possibility that age independently confers an increased risk for higher-grade lesions should be considered.

Disseminated peritoneal leiomyomatosis. Clonality analysis by X chromosome inactivation and cytogenetics of a clinically benign smooth muscle proliferation.

Disseminated peritoneal leiomyomatosis (DPL, leiomyomatosis peritonealis disseminata) is a rare condition in which multiple histologically benign smooth muscle tumorlets diffusely stud peritoneal and omental surfaces in females, predominantly of reproductive age. Although the distribution of these lesions suggests a metastatic process, DPL generally has a benign clinical course and has been regarded as a metaplastic process. We assessed clonality of 42 tumorlets and 15 normal tissues from four females with DPL by analyzing X chromosome inactivation as indicated by the methylation status of the androgen receptor gene (HUMARA). In each of the four patients, the same parental X chromosome was nonrandomly inactivated in all tumorlets, consistent with a metastatic unicentric neoplasm, or alternatively, selection for an X-linked allele in clonal multicentric lesions. Anomalous demethylation of the marker for X inactivation (HUMARA) was associated with loss of heterozygosity for markers spanning the X chromosome, or monosomy X, in part of one leiomyomatous lesion. Biallelic demethylation of the HUMARA microsatellite polymorphism was also found in one intramural leiomyoma. Two of six DPL lesions karyotyped had cytogenetic abnormalities involving chromosomes 7, 12, and 18, suggesting a pathogenesis in common with uterine leiomyomas.

Pathobiology of vulvar squamous neoplasia.

Vulvar squamous carcinoma is an uncommon neoplasm that afflicts a spectrum of women and has been associated with granulomatous vulvar diseases, papillomaviruses, and chronic inflammatory disorders of the vulva. Histopathological, molecular, and epidemiological studies have revealed two subsets of vulvar squamous neoplasia, which are distinguished by their association with human papillomaviruses and patient demographics. This review summarizes the evidence both supporting the diverse pathogenesis of these tumors and the existence of factors that may be common to both groups. Ultimately, the pathway to both human papillomavirus positive and negative vulvar cancers may involve not only obvious precancerous changes but also biological events in the vulvar mucosa that precede the onset of morphological atypia.

A comparison of early (E7) and late (L1) primer-mediated amplification of papillomaviral DNA in cervical neoplasia.

Studies have demonstrated that in 50-90% of cervical carcinomas, human papillomavirus (HPV) DNA sequences are covalently bound (integrated) to the chromosomal DNA. All evidence shows that when integration takes place disruption of the viral genome occurs downstream to the E7 open reading frame, which is invariably retained in functional form. Theoretically, this phenomenon could result in loss of HPV sequences (L1) not critical to the presumed tumourigenic functions and if so, could influence primer selection for HPV DNA detection in these tumours. A series of cervical carcinomas (CA, n = 133), adenocarcinomas in situ (ACIS, n = 28) and high grade squamous intraepithelial lesions (HSIL, n = 30) were analysed for HPV nucleic acids using primers designed to amplify the E7 and L1 regions. Primer sizes and sensitivities were adjusted to produce equivalent amplification efficiency. Of 191 cases studied, 134 (70%) scored positive for HPV16 or 18 with either the E7 or L1 primer set. Of these, 116 (87%) were positive with both primer pairs. There were no significant differences in proportions of HPV 16/18 positives or lesion types scoring positive exclusively with the E7 vs the L1 primer sets. However, HPV18 associated, E7 positive carcinomas were slightly less likely than HPV16 associated carcinomas to be L1 positive (P = 0.07). Although a high proportion of HPV16 and particularly HPV18 positive carcinomas have been associated with exclusively integrated HPV DNA, there is little evidence that this influences detection sensitivity with E7 vs L1 primers. The combination of E7 and L1 primers provided the maximum sensitivity in this study, with 18 of 134 cases scoring positive with only one primer set.

Prevalence and histologic significance of cervical human papillomavirus DNA detected in women at low and high risk for cervical neoplasia.

OBJECTIVES: To determine and compare the prevalence and histologic significance of human papillomavirus (HPV) nucleic acids in cervical specimens from women at low (routine hysterectomy) and high (suspicion of cervical neoplasia) risk for cervical neoplasia. METHODS: Cervical brushings were taken from the cervices of hysterectomy and conization or loop electrical excision specimens and analyzed for HPV nucleic acids by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathology was confirmed by review of reports or, for HPV-positive results, re-review of the histopathology. Statistical analysis used Student t test or Fisher exact test. RESULTS: Four hundred seventeen and 43 low- and high-risk cervices, respectively, were studied. Statistically significant differences were observed in the index of HPV positivity between the low- and high-risk groups (1.7 versus 42%, P < .001) and the proportion of HPV being cancer-associated HPV types (14 versus 78%, P = .005). None of the 417 cervices from low-risk women contained HPV 16. In the high-risk group, histologically confirmed cervical intraepithelial neoplasia lesion was statistically more likely to be associated with HPV (59 versus 13%, P = .005). CONCLUSION: Cervices from routine, low-risk hysterectomies in predominately middle-aged women have an extremely low index of cancer-associated HPVs. Considering the strong association of HPV with histologically proven disease, prospective studies exploring the relationship of cancer-associated HPVs to neoplasia in middle-aged women merit consideration.

Postmenopausal squamous atypia: a spectrum including "pseudo-koilocytosis".

In addition to typical atrophy, the postmenopausal cervix may exhibit a spectrum of epithelial and cellular alterations, including prominent perinuclear halos, nuclear hyperchromasia, variation in nuclear size, and multinucleation. It has not been determined whether such changes, termed postmenopausal squamous atypia (PSA), represent age-related epithelial disturbances or human papillomavirus (HPV)-related low-grade squamous intraepithelial lesions (condyloma). We surveyed 30 cervical biopsies from 26 women over the age of 50 that contained cytoplasmic halos and a spectrum of nuclear alterations, either alone or in association with atrophy. Twenty-three exhibited epithelium with 2- to 3-fold nuclear enlargement, and 18 had moderate or marked nuclear staining intensity. Eleven had a maximum of one or more multinucleated cells in a high-power field. Despite the nuclear alterations, none of the biopsies were positive for HPV by PCR analysis. This is in contrast to 104 of 141 low- and high-grade squamous intraepithelial lesions from a wide age range of women analyzed in the same manner (P = .000006). Features distinguishing PSA from HPV-associated low-grade squamous intraepithelial lesions (condyloma) included less variation in nuclear size and staining intensity, more finely and evenly distributed nuclear chromatin, and greater uniformity of perinuclear halos in PSA. In menopausal or postmenopausal women, PSA should be excluded when considering the diagnosis of a low-grade squamous intraepithelial lesion, specifically if the diagnosis rests on the interpretation of koilocytotic atypia.

Vulvar intraepithelial neoplasia: age, morphological phenotype, papillomavirus DNA, and coexisting invasive carcinoma.

Recent studies suggest that subsets of vulvar intraepithelial neoplasia (VIN) may be distinguished based on morphological presentation, the presence or absence of human papillomavirus (HPV) nucleic acids, and patient age. We analyzed 65 VIN lesions, including 15 with associated squamous cell carcinoma, to determine the relationship between pathological parameters associated with common types of VIN (multinucleation, koilocytosis, verruco-papillary morphology, diffuse atypia), rarer variants (differentiation, basal atypia), patient age, and papillomavirus nucleic acids. For all lesions higher mean ages were observed in patients with lesions that were associated with cancer and with well differentiated VIN variants with basal atypia only. A strong negative correlation with HPV nucleic acids was observed for differentiated variants with basal atypia (P = .002). In the common or "classic" VIN group patients with lesions with koilocytotic atypia, multinucleation, and verruco-papillary morphology were generally younger. However, no parameter or group of parameters defined a subset of patients with a significantly lower mean age or lesions with a higher index of HPV nucleic acids. Three of six lesions of lichen sclerosus (LS)-associated VIN, including one involving invasive carcinoma in elderly women, contained HPV nucleic acids; all three lesions exhibited the features of classic VIN. The finding of HPV across a broad age range suggests that this virus may play a role in vulvar neoplasia at any point in life. The direct demonstration of HPV nucleic acids within three LS-associated VINs is intriguing because it links two distinct risk factors to the same neoplasm.

Pathology of human papillomavirus in the female genital tract.

Human papillomavirus (HPV) has emerged as a major factor in the genesis of intraepithelial and invasive neoplasms of the female genital tract. The strength of the relationship of HPV to genital neoplasia has been supported by studies involving epidemiologic, clinical, pathologic and molecular data. The many subtypes of HPV have been characterized into risk groups that reflect their propensity to be associated with cancer precursors and invasive disease. The strong correlation between HPV and squamous dysplasia suggests that classification of cervical intraepithelial lesions into similar risk categories should be possible. However, the clinical predictive value of HPV testing and typing remains controversial.

Cervical intraepithelial neoplasia.

Cervical intraepithelial neoplasia (CIN) has been traditionally defined as a continuum of intraepithelial squamous abnormalities which exhibit nuclear atypia in all epithelial layers and possess some potential for progression to invasive carcinoma if not removed. Efforts to subdivide this spectrum into categories of low and high cancer risk have been based previously on the strong association between CIN III (carcinoma in situ) and subsequent invasive carcinoma. However, in practice, this distinction has been discouraged because CIN I and II may be associated with CIN III and a small proportion may progress to invasive carcinoma. As human papillomaviruses (HPV) have emerged as potential markers for subdividing precursor lesions, so-called "high-risk" HPV types have been associated with all grades of CIN, whereas "low-risk" HPV types have segregated primarily in lesions closely resembling condylomata. The place of condyloma in the spectrum of CIN, as well as the precise definition of CIN I, has been controversial. Some authors distinguish condyloma from CIN I and other use similar criteria for the diagnosis of both. Currently, the trend among pathologists and cytopathologists is to classify CIN I as a process either identical to or closely resembling condyloma (low-grade), and CIN II and III as lesions falling within the spectrum of CIN as classically described (high-grade). As new etiologic perspectives (HPV), classifications (Bethesda) and outpatient managements (LEEP) evolve, morphologic definitions of CIN will remain important to patient care, particularly if management decisions are based on nuances of histologic or cytologic grade. When using cervical lesion morphology as an endpoint in chemoprevention studies, investigators must understand that "morphologic progression" of CIN may not be synonymous with biologic progression, that discrepancies between HPV type and morphology exist, and that cytology and histology provide variable, and at times conflicting, information.

Multinucleated atypia of the vulva. Report of a distinct entity not associated with human papillomavirus.

The vulvar mucosa often demonstrates epithelial nuclear atypia in association with reactive and inflammatory conditions. These nuclear changes are usually mild and can be readily distinguished from vulvar intraepithelial neoplasia (VIN) and human papillomavirus (HPV)-related lesions. In a recent survey of vulvar biopsies in reproductive-aged women, we identified 12 cases of an unusual pattern of atypia associated with multinucleated epithelial cells but lacking the usual stigmata of reactive changes, condyloma, or VIN. The average age of the patients with multinucleated atypia of the vulva (MAV) was 37 years. The multinucleated cells were commonly in the lower to middle epithelial layers and contained between two and 10 nuclei, often with prominent nucleoli. In contrast to condyloma and VIN, there was no surface atypia, and the multinucleated cells lacked hyperchromasia, irregularity, or variation in nuclear size. No significant inflammation or identifiable infectious process was present, and none of the patients had received any topical treatment other than mild corticosteroids. Two of the patients had a history of VIN at a noncontiguous site. None of the 12 cases contained HPV DNA by either in situ hybridization or polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) analysis. This is in contrast to 49 of 65 women with VIN and 21 of 26 with condyloma who had HPV demonstrable by the PCR method (p < 0.00001). Immunoperoxidase stains for herpes types I and II were also negative in all the cases. Thus, MAV appears to be a distinct entity occurring in relatively young women; when it is not associated with condyloma or VIN, MAV is not related to HPV. As the morphologic features may overlap with both condyloma and VIN, it is important that MAV not be confused with these lesions or vice versa. It is not known whether MAV is a risk factor for VIN, represents an exaggerated reactive response, or is an entity with a distinct origin.

Pseudomyxoma peritonei: a review of 23 cases.

OBJECTIVE: To review the experience at the Massachusetts General and Brigham and Women's Hospitals with 23 women treated for pseudomyxoma peritonei between 1961 and 1991. METHODS: Patients were identified retrospectively from the tumor registry at the Massachusetts General and Brigham and Women's Hospitals, and all charts were reviewed. The median follow-up interval was 2.5 years (range 3 months to 31 years). RESULTS: The mean age at diagnosis was 58 years (range 26-76). Pseudomyxoma peritonei was found in association with ten (44%) ovarian tumors of borderline malignancy, nine (39%) ovarian cystadenocarcinomas, and four (17%) appendiceal cystadenocarcinomas. Three patients had synchronous tumors in the ovary and appendix. All patients underwent surgical staging and cytoreduction. Eleven patients received postoperative therapy and, of these, nine developed a recurrence; 12 patients received no further therapy and, of these, three developed a recurrence. However, these groups were not pathologically comparable. With respect to survival, of the ten patients with borderline malignancies, seven had no evidence of disease, one was alive with disease, and two died of disease. For the nine patients with ovarian cystadenocarcinomas, three had no evidence of disease, one was alive with disease, and five died of disease (median time to death 18 months). For the four patients with appendiceal carcinomas, two had no disease, one was alive with disease, and one died with disease. Among all 23 patients, 12 (52%) developed a recurrence, with a range of time to first recurrence of 3 months to 19 years. Eight women required at least one additional laparotomy because of accumulation of gelatinous material. CONCLUSIONS: Although pseudomyxoma peritonei is associated with borderline and well-differentiated tumors, recurrence is common and the prognosis after recurrence is guarded. Involvement of the appendix is common; therefore, appendectomy is indicated when pseudomyxoma is encountered. To date, surgery has been the only effective therapy for this disease, and adjuvant therapy has not been shown conclusively to be of benefit.

Histologic correlates of vulvar human papillomavirus infection in children and young adults.

Two clinically important issues in the treatment of vulvar wartlike lesions are the histologic criteria for the recognition of human papilloma virus (HPV)-related lesions and the exclusion of lesions derived from cutaneous rather than genital HPV types. We analyzed a series of 70 biopsies from the vulva or distal vagina of 57 children and 13 young adults for HPV nucleic acids by polymerase chain reaction (PCR) amplification and typed the isolates following isotope labeling and restriction digestion (restriction fragment length polymorphism [RFLP] analysis). Lesions were classified as condyloma, suggestive of condyloma (papillary/verrucous architecture without koilocytotic atypia), or nonspecific epithelial alterations. Three observers independently agreed on the presence of papillary/verrucous architecture and koilocytotic atypia with a high degree of concordance (kappa = 0.74 and 0.71, respectively). By RFLP analysis, 77% of the lesions diagnosed as condyloma and 68% of those diagnosed as suggestive of condyloma contained HPV nucleic acids versus 9% of the nonspecific group. The HPV types identified were HPV 6 (67%), HPV 11 (17%), HPV 16 (3%), and unknown types (14%). No cutaneous HPV types were identified. Three patients with unknown HPV types had a history of sexual abuse, implying a genital source. These findings indicate that verrucopapillary external genital lesions, as defined in this report, are likely to be associated with HPV and that the vast majority contain genital HPV types irrespective of histologic presentation.