Impact of oophorectomy and hormone suppression in low grade endometrial stromal sarcoma: A multicenter review.

OBJECTIVES: Low grade endometrial stromal sarcoma (LG-ESS) is a rare cancer with an indolent course. We aimed to assess the effectiveness of adjuvant hormonal suppression (HT) with or without oophorectomy (BSO) in prolonging progression free survival (PFS) and overall survival (OS) in patients with LG-ESS. METHODS: We performed a multi-institutional retrospective review of patients treated for low grade LG-ESS from 1985 to 2014. Demographics, treatment and recurrence data were abstracted from medical records. Pathologic diagnosis was confirmed by a gynecologic pathologist. Long-term patient-reported outcomes were obtained via mailed survey. RESULTS: One-hundred-twelve patients underwent surgery for LG-ESS; 59 had postoperative data with a median follow-up of 55months (1-325months). The mean age at diagnosis was 48.5years (22-82years). Forty-nine (61%) had stage I disease. The most common presenting symptoms were abnormal uterine bleeding (38%) and pelvic mass (17%). Seventy-one (63%) patients had BSO at the time of diagnosis. Of the 59 patients with postoperative follow-up information, 49 (73%) underwent BSO, 26 (44%) received HT, 20 (33%) were expectantly managed, and 6 (10%) received chemotherapy, radiation or both. Median PFS for the entire group was 53months and OS was 63months. PFS for those who underwent BSO compared with those who retained their ovaries was 38 vs 11months, p=0.071. PFS for HT vs no HT was 28 vs 23months, p=0.77. CONCLUSIONS: Consistent with prior series, our results support BSO to prolong PFS in LG-ESS but are limited by sample size. Larger studies with more complete follow-up are needed to determine the effect of adjuvant hormonal suppression.

Adenocarcinoma of the testicular adnexa presenting with metastatic disease.

Primary epididymal adenocarcinoma is a rare malignancy with fewer than 30 documented cases. We report a case of a 57-year-old patient with a paratesticular mass in the presence of retroperitoneal metastatic disease. Histology confirmed the presence of primary paratesticular adenocarcinoma. In this report we review the index case, the pertinent literature and discuss adjuvant therapy.

Early uterine serous carcinoma: clonal origin of extrauterine disease.

Uterine serous carcinoma (USC) is an uncommon but aggressive type of endometrial carcinoma that is frequently associated with extrauterine disease despite minimal or no myometrial invasion. The origin of the extrauterine tumors in this setting remains controversial. The majority of USCs (90%) and endometrial intraepithelial carcinomas (78%), the putative precursor of USC, have p53 mutations, suggesting that p53 alterations occur early in the pathogenesis of USC. To determine if the extrauterine tumors associated with minimally invasive USC and endometrial intraepithelial carcinoma (EIC) represent metastases or multifocal primary tumors, we examined the mutational pattern of the p53 gene in 3 cases of minimally invasive USC and 1 case of EIC and in the corresponding extrauterine tumors associated with each of the cases. In all 4 cases, the primary tumors and the associated extrauterine tumor foci had identical p53 mutations. Our results support the premise that extrauterine serous tumors found in association with EIC or minimally invasive USC represent a unifocal process and thus are early metastases.

Long-term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia.

Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long-term safety profile of mifepristone, especially at high doses, is less well-established. Long-term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25--100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium. We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6-month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment. In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long-term mifepristone may be prudent.

Cyclin D1 expression in high-grade endometrial carcinomas--association with histologic subtype.

Endometrial endometrioid adenocarcinoma (EC) and serous carcinoma (ESC) are associated with different epidemiologic risk factors, precursor lesions, morphology, and survival outcomes. They also possess distinct molecular profiles. We investigated the expression of cyclin D1, a member of the G1 cyclin family that regulates the G1/S transition in the cell cycle, and estrogen and progesterone receptors (ERs and PRs, respectively) in a group of ECs and ESCs matched for histological grade. We also sought to correlate the expression of cyclin D1 with ER and PR because cyclin D1 has been reported to stimulate transcription of ER- and PR-regulated genes (1,2). We hypothesize that cyclin D1 expression covaries with histologic subtype and is related to the expression of ER and PR. Twenty ESCs and 21 ECs were examined histologically and evaluated immunohistochemically for cyclin D1, ER, and PR using commercially available monoclonal antibodies in archival, formalin-fixed, and paraffin-embedded tissue. Three ESCs (15%) and 10 ECs (48%) expressed cyclin D1 (p = 0.02). Twelve ESCs (60%) and 16 ECs (76%) expressed ER, which is not significantly different. ER-positive ECs were significantly more likely to express cyclin D1 compared with ER-positive ESCs (p = 0.03), but a relationship between cyclin D1 and ER expression in EC was not found. We also did not find a significant relationship between cyclin D1 and PR expression. Therefore, cyclin D1 expression in poorly differentiated endometrial carcinomas is associated with endometrioid histology. This is consistent with pathobiologic divergence in poorly differentiated endometrial carcinomas.

Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma.

The prevalence of human papilloma virus (HPV) DNA in different histological subtypes of cervical adenocarcinoma and related tumors was examined using formalin-fixed, paraffin-embedded tissue samples from 105 primary cervical adenocarcinomas and adenosquamous carcinomas. Broad-spectrum HPV DNA amplification and genotyping was performed with the SPF10 primer set and line probe assay (LiPA), respectively. HPV DNA was detected in 82 of 90 (91%) mucinous adenocarcinomas, encompassing endocervical, intestinal, and endometrioid histological subtypes, and in nine of nine adenosquamous tumors (100%). HPV DNA was not detected in any nonmucinous adenocarcinomas including clear cell, serous, and mesonephric carcinomas (0/6). The most common viral types detected in adenocarcinoma were HPV 16 (50%) and HPV 18 (40%), followed by HPV 45 (10%), HPV52 (2%), and HPV 35 (1%). Multiple HPV types were detected in 9.7% of the cases. In conclusion, mucinous adenocarcinomas and adenosquamous carcinomas of the cervix demonstrate a very high prevalence of HPV DNA, similar to that reported for cervical squamous cell carcinoma. Only rare histological variants of cervical adenocarcinoma seem unrelated to HPV infection.

MIB-1 immunostaining is a beneficial adjunct test for accurate diagnosis of vulvar condyloma acuminatum.

The histopathologic diagnosis of vulvar condyloma acuminatum is often based on architectural features that are not specific for human papillomavirus (HPV) infection. Because HPV-associated lesions show increased cellular proliferation, the authors evaluated the usefulness of MIB-1 immunostaining as an aid in the differential diagnosis of cases equivocal for condyloma. The MIB-1 immunostaining pattern was correlated with HPV DNA detection in condyloma acuminatum (CON-A; n = 15), "consistent with condyloma" (c/w CON-A; n = 26), fibroepithelial polyp (FEP; n = 14), and squamous papilloma (n = 10). HPV was detected in 100% of the CON-A cases, and all cases demonstrated MIB-1-positive nuclei in the upper two thirds of the epithelial thickness. With this definition of MIB-1 positivity, there was complete concordance between MIB-1 positivity and HPV detection for all cases (kappa = 0.88). Of the cases c/w CON-A, 17 of 26 (65%) were positive for both MIB-1 and HPV, and could be reclassified as CON-A, whereas 35% were identified as an overdiagnosis based on negative results. In addition, two cases of FEP were MIB-1 and HPV positive, and thus were identified as an underdiagnosis. These results suggest significant overdiagnosis of cases equivocal for condyloma, and indicate that MIB-1 immunostaining is a beneficial adjunctive test when the morphologic features are suggestive but not diagnostic for CON-A.

Endometrial intraepithelial carcinoma with associated peritoneal carcinomatosis.

Endometrial intraepithelial carcinoma (EIC) is a recently described entity, defined as a noninvasive, cytologically malignant lesion that replaces the endometrial surface epithelium. EIC frequently coexists with uterine serous carcinoma (USC) and is hypothesized to be its precursor lesion. However, the clinical significance and biologic potential of finding EIC without USC is not known. We report three postmenopausal women with EIC alone who were found to have multiple, synchronous foci of extrauterine serous carcinoma at presentation. Because the clinical findings in these patients simulated primary peritoneal serous carcinoma (PSC), we compared the clinicopathologic features of these cases with a group of nine bona fide PSCs for which exhaustively sectioned endometria, fallopian tubes, and ovaries were available for review. The average age of the EIC patients was 73 years. Two patients presented with abdominal distention and one with vaginal bleeding. Hysterectomy in each case showed endometrial polyps with EIC, but without invasive USC, in a background of atrophic endometrium. Bilateral salpingo-oophorectomy and staging showed serous carcinoma involving the ovarian hilum, the surfaces of the fallopian tubes and ovaries, in addition to peritoneal carcinomatosis. p53 overexpression was observed in both EIC and the extrauterine deposits of serous carcinoma in each case. The average age of the PSC patients was 66 years. All nine patients presented with abdominal distention. EIC was not identified in any of the hysterectomy specimens. Bilateral salpingo-oophorectomies, omentectomies, and peritoneal biopsies showed peritoneal carcinomatosis, including bulky peritoneal tumor deposits, but only minimal ovarian surface involvement. p53 overexpression was observed in seven cases. These findings indicate that EIC without coincident USC can be associated with invasive, extrauterine serous carcinomatosis. We did not, however, find any significant differences between the clinicopathologic features of primary extrauterine serous carcinomas (PSCs) and those associated with EIC. We conclude that the finding of EIC in an endometrial curettage specimen should prompt a thorough search for an invasive uterine and/or extrauterine serous carcinoma. Conversely, an endometrial origin should be excluded in patients with peritoneal carcinomatosis.

Atypical immature metaplasia (AIM) of the cervix: is it related to high-grade squamous intraepithelial lesion (HSIL)?

Atypical immature metaplasia (AIM) is a poorly characterized cervical lesion with uncertain biological and clinical significance. AIM shares some, but not all, morphological features of squamous intraepithelial lesions (SILs). SILs are characterized by human papillomavirus (HPV) positivity and increased cellular proliferation, but these features have not been fully evaluated in AIM. Genomic DNA was extracted from 27 microdissected cervical biopsy specimens diagnosed as AIM. HPV DNA was detected by polymerase chain reaction (PCR), using two different sets of L1 gene consensus primers. HPV types were identified by sequence analysis of PCR products and comparison with published HPV sequences. The cell proliferation index was assessed by immunohistochemical staining for Ki-67 (MIB-1) antigen and expressed as the percentage of Ki-67-positive cells. Comparison groups included normal cervix (n = 10) and low-grade (LSILs, n = 19) and high-grade squamous intraepithelial lesions (HSILs, n = 11). Intermediate- or high-risk HPV DNA was detected in 67% (18 of 27) of AIM cases. Low-risk HPV DNA was not detected in any of the specimens. The Ki-67 index in AIM (mean, 33.0 +/- 20.3; median, 29) was comparable to that of LSILs (mean, 21.4 +/- 4.6; median, 21) and was significantly higher than that of normal cervix (mean, 11.0 +/- 2.1; median, 11) (P< .01) and lower than that of HSILs (mean, 60.4 +/- 13.2; median, 60) (P < .01). Of the cases with available follow-up, HPV-positive AIMs were significantly more likely to have a concurrent or subsequent diagnosis of typical HSIL (12 of 15, 80%) than HPV-negative AIMs (one of six, 45%) (P = .014). The wide range of Ki-67 indices and variable HPV status in AIM suggest that AIM represents a heterogeneous group of lesions including bona fide HSILs (high-risk HPV-positive, high Ki-67 index), antecedents (precursors?) of HSILs (high-risk HPV-positive, low to moderate Ki-67 index), and benign reactive conditions (HPV-negative, variable Ki-67 index). HPV testing may be useful in the assessment of atypical epithelial proliferations of the cervix for which a diagnosis of AIM is considered.

Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma.

Many studies have attempted to identify histologic features that aid in the distinction of atypical hyperplasia (AH) from hyperplasia without atypia and well-differentiated endometrioid carcinoma, but few have evaluated the reproducibility of these diagnoses. Five pathologists independently reviewed 100 endometrial biopsy and curettage specimens chosen to represent the entire spectrum of proliferative lesions of the endometrium, including proliferative endometrium (PEM), hyperplasia without atypia, AH, and well-differentiated endometrioid carcinoma. Slides were reviewed twice for diagnosis, with an intervening evaluation of a checklist of histologic features. Intraobserver and interobserver agreement were assessed using the kappa statistic. Intraobserver kappa values ranged from 0.67 to 0.89 (76% to 89% agreement). Interobserver kappa values by diagnostic category were: proliferative endometrium: 0.86; hyperplasia without atypia: 0.60; AH: 0.47; well-differentiated endometrioid carcinoma: 0.83; with a kappa value of 0.69 for all cases combined. Associations between the selected histologic features and the given diagnoses for each pathologist were analyzed using multiple logistic regressions to identify features that were useful for distinguishing among diagnostic categories. Histologic features determined by univariable and multivariable analyses that were found to be most associated with distinguishing diagnostic categories were: proliferative endometrium versus hyperplasia without atypia: gland crowding (univariable, multivariable), and gland branching (univariable); hyperplasia without atypia versus AH: presence of nucleoli (univariable, multivariable), nuclear enlargement (univariable), vesicular chromatin change (univariable), nuclear pleomorphism (univariable), chromatin irregularities (univariable), and loss of polarity (univariable); hyperplasia without atypia versus carcinoma: glandular confluence/complex cribriform pattern (univariable, multivariable), stromal alteration (univariable, multivariable), and necrosis (univariable). In summary, interobserver agreement was good but was lowest for AH. Only the presence of nucleoli was strongly associated with distinction of AH from hyperplasia without atypia. Individual pathologists use additional features to diagnose atypia, but these features are not consistently associated with that diagnosis. Cribriform architectural pattern and stromal alteration were associated with the distinction of well-differentiated endometrioid carcinoma from AH.

Distinctive p53 and mdm2 immunohistochemical expression profiles suggest different pathogenetic pathways in poorly differentiated endometrial carcinoma.

Endometrial serous carcinoma (ESC) and FIGO (International Federation of Gynecology and Obstetrics) grade 3 endometrioid adenocarcinoma (EC) are high-grade endometrial tumors that have different clinical and morphologic attributes. Alteration of p53 tumor suppressor protein function has been implicated in the pathogenesis of both tumors, although the mechanisms may differ. We sought to investigate this difference by comparing immunohistochemical expression of p53 and mdm2. p53 immunoreactivity often correlates with gene mutation, whereas increased mdm2 expression is linked to complex formation with wild-type p53 resulting in its inactivation. Twenty cases of ESC and 21 cases of EC were evaluated and an immunoreactivity score (IRS) was assigned using both the percentage of cells stained and the intensity of staining. The overall IRSs were significantly different in ESCs versus ECs for both p53 and mdm2 (p < 0.001 and p < 0.01, respectively). Strong mean immunoreactivity for p53 was detected in 15 (75%) ESCs as compared to only weak mean immunoreactivity in 17 (81%) ECs. Conversely, for mdm2 expression, 17 (81%) ECs had moderate mean immunoreactivity whereas 9 (45%) ESCs showed only weak mean immunoreactivity. mdm2 expression more closely correlated with p53 expression in ECs than in ESCs. In ECs, mdm2 was detected in 16 of 17 (94%) p53-positive tumors but in only 1 of 3 (33%) p53-negative tumors (p < 0.025). In ESCs, mdm2 was detected in 9 of 15 (60%) p53-positive tumors but in none of the 5 p53-negative tumors (p < 0.10). Overall, our results demonstrate an inverse relationship between the expression of p53 and mdm2 in ESC versus high-grade EC. Specifically, strong p53 immunoreactivity is associated with weak mdm2 expression-in ESC and weak p53 expression is associated with moderate mdm2 expression in EC. These results suggest different pathogenetic pathways resulting in loss of normal p53 function in these two tumors: by p53 gene mutation (strong p53 overexpression) in ESCs, or by mdm2 complex formation and inactivation of p53 in high-grade ECs.

The CD44v6-negative phenotype in high-grade uterine carcinomas correlates with serous histologic subtype.

Uterine serous carcinomas (USCs) and poorly differentiated (International Federation of Gynecology and Obstetrics Grade 3) endometrioid adenocarcinomas (ECs) are two histologic subtypes of high-grade uterine carcinoma that differ in clinical presentation, patterns of dissemination, and biologic aggressiveness. To investigate the mechanisms responsible for this heterogeneity, we studied CD44 and CD44v6 expression in a series of 20 USCs and 21 poorly differentiated ECs. CD44 is a protein involved in cell adhesion and lymphocyte homing, and one of its isoforms, CD44v6, might be related to capillary-lymphatic space invasion and metastasis. Eight (40%) of 20 USCs expressed CD44, compared with 18 (86%) of 21 ECs (P < .005). None of the USCs were reactive with antibodies against CD44v6, whereas 45% of the ECs were immunoreactive (P < .001). CD44v6 expression was observed in the myoinvasive ECs but was not seen in foci of capillary-lymphatic space invasion in either the ECs or the USCs. In summary, the USCs were significantly more likely to demonstrate a CD44- and CD44v6-negative phenotype than were the poorly differentiated ECs.

Squamous metaplasia of the endometrium associated with HPV 6 and 11.

Although uncommon in the endometrium, squamous metaplasia, dysplasia, and squamous carcinoma have been observed. Associated human papillomavirus (HPV) infection is also unusual, due at least in part to the fact that HPV requires specific characteristics of the target epithelium for infectivity. We report a case of extensive squamous metaplasia with focal low-grade squamous intraepithelial neoplasia of the endometrium coexistent with low-grade cervical intraepithelial neoplasia and an invasive squamous carcinoma of the vagina. In situ hybridization studies revealed HPV types 6 and 11 in both the cervical and endometrial lesions. This is the first report to date to demonstrate squamous epithelial metaplasia and dysplasia of the endometrium, associated with HPV DNA of viruses typically of low oncogenic potential.

Microsatellite instability is uncommon in uterine serous carcinoma.

Thirty-four uterine serous carcinomas, a type of endometrial carcinoma with aggressive behavior and a high frequency (90%) of p53 gene mutations, were analyzed for microsatellite instability (MI). Genomic DNA isolated from paired normal and tumor tissue was analyzed at eight microsatellite loci (D2S119, D2S123, D2S147, D10S197, D13S175, D18S58, D18S69, and ATn) located on four different chromosomes. All 34 tumors failed to meet the criteria for MI, defined as an alteration in the size of at least two of the microsatellite loci in tumor DNA when compared with normal DNA. Only three tumors demonstrated a shift in the size of a single microsatellite locus. Previously we reported MI in 20% of uterine endometrioid carcinomas, the most common type of endometrial carcinoma. The observed difference in the MI frequency between endometrioid and serous carcinoma is statistically significant (P = 0.003). Our data demonstrate that MI is uncommon in uterine serous carcinoma and support that different pathogenetic mechanisms are involved in the development of the two most common types of endometrial carcinoma.

p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis.

Uterine serous carcinoma (USC) is an uncommon but aggressive type of endometrial cancer associated with rapid progression of disease and a poor prognosis. Both USC and its recently described putative precursor, endometrial intraepithelial carcinoma (EIC), demonstrate strong p53 overexpression by immunohistochemistry, suggesting alteration of the p53 gene in their pathogenesis. In the present study, we evaluated 21 USCs and 9 EICs for mutations in the p53 gene using direct sequence analysis and found that 90% of USCs and 78% of EICs contain mutations. Significantly, mutations were found in 3 cases of EIC without associated invasive carcinoma and identical mutations were detected in cases with synchronous USC and EIC. Strong p53 immunoreactivity was seen in the majority of USCs and EICs and correlated with p53 gene mutation, although lack of reactivity did not always indicate the absence of a gene mutation. Loss of heterozygosity of chromosome 17p was observed in 100% of USCs and in 43% of EICs, demonstrating that loss of the wild-type p53 allele occurs early in the development of serous carcinoma. Overall, our results reveal that p53 mutations are very common in USC and EIC. The presence of p53 gene mutations in EIC further suggests that p53 alteration plays an important role early in the pathogenesis of serous carcinoma, possibly accounting for its aggressive biological behavior.

Ultrasonic surgical aspiration to treat genital condyloma acuminata in children.

We report on the technique of ultrasonic surgical aspiration for the treatment of genital condyloma acuminata in three prepubertal girls. All surgical procedures were done under general anesthesia, and no patient required hospitalization. Adequate samples for pathologic evaluation were obtained. This technique resulted in minimal discomfort, rapid healing, and no scarring.

Telecytology: diagnostic accuracy in cervical-vaginal smears.

Although cervical-vaginal telecytology is a promising tool, diagnostic accuracy has not been extensively evaluated. The authors examined the accuracy of five cytotechnologists who retrospectively reviewed 50 cervical-vaginal smears using the video monitor, and 2 months later, using the light microscope. Accuracy was expressed in terms of crude agreement with the original diagnosis and number of false positives (FPs) and false negatives (FNs). With a greater than one step difference as discrepant, the group crude agreement using the video monitor and the light microscope was 85.6% and 95.6%, respectively. The group number of FNs and FPs for the light microscope was 8 and 7, respectively, and for the video monitor was 34 and 7, respectively. There was a wide range of individual performance. We conclude that accuracy of telecytology is high, but less than that of light microscopy. The major reason for lower telecytologic accuracy was undercalling dysplasia.

Ambiguous genitalia in an elderly woman with a mosaic 45,X/46,X,dic(Y)(Q11.2) karyotype.

A 66-year-old woman presented with clitoromegaly since childhood, primary amenorrhea, no breast development, and a large right inguinal hernia. A mosaic karyotype was identified containing a predominant 45,X cell line and a cell line with 46 chromosomes, one X chromosome, and a small dicentric Y chromosome with a breakpoint in band qII.2. The patient underwent hysterectomy, bilateral gonadectomy, inguinal hernia repair, clitoral recession, and formation of a neointroitus. A dysgerminoma was identified in the right dysgenetic gonad. This report demonstrates the natural history of untreated mixed gonadal dysgenesis and the importance of early evaluation and treatment, as well as the molecular characterization of a dicentric Y chromosome.

Both cell proliferation and apoptosis increase with lesion grade in cervical neoplasia but do not correlate with human papillomavirus type.

Recent molecular studies suggest that the expression of high-risk but not low-risk human papillomavirus (HPV) oncoproteins E6 and E7 can significantly alter normal cell cycle regulation. The alterations in cell cycle regulation may be reflected by changes in the balance between cell growth and cell loss through apoptosis in cell populations expressing E6 and/or E7. We evaluated the kinetic indices of cell proliferation and apoptosis in a histopathological spectrum of cervical neoplasia and compared low-versus high-risk HPV-associated lesions. The cell proliferation index, as determined by detection of the nuclear antigen Ki67, increased with increasing lesion grade. Apoptotic cells were identified with terminal deoxynucleotidyl transferase-labeling of the 3'-hydroxyl ends of DNA nucleosomes. No apoptosis was observed in normal epithelium, and only occasional apoptotic cells were seen in low-grade lesions. However, there was a low but measurable apoptotic index in the higher grade lesions, which increased with lesion grade. There was no significant difference in the proliferative and apoptotic indices in similar grade lesions when stratified into low-versus high-risk HPV types. These findings suggest that apoptosis in HPV-infected lesions correlates with proliferative activity rather than HPV type.