A cost comparison of two strategies for treating stage IB2 cervical cancer.

Patients with stage IB2 cervical cancer at our institution are treated primarily with definitive chemoradiation, or chemoradiation followed by adjuvant hysterectomy. We sought to compare the cost differences associated with these two strategies. We identified all patients with stage IB2 cervical cancer who received their entire treatment regimen at our institution between 1995 and 2004. All patients received a combination of chemotherapy, external beam radiation, and one brachytherapy procedure, followed by either a second brachytherapy procedure or a simple hysterectomy. We retrieved cost data associated with hospitalization for the completion of respective treatment, including pharmacy, laboratory and pathology, radiation, and operating room services, as well as the costs of supplies and room and board. We identified 46 patients with stage IB2 cervical cancer, 23 who received a second brachytherapy procedure and 23 who underwent simple hysterectomy. Patients displayed similar demographics and similar disease characteristics including initial tumor diameter and histology. The cost of care for adjuvant hysterectomy group was greater ($8,316.70 vs 5,508.70, P < 0.0001). Specific differences included higher operating room costs ($1520 vs 414, P < 0.0001), pharmacy costs ($675 vs 342, P < 0.0001), and laboratory/pathology costs ($597 vs 89, P < 0.0001). We conclude that definitive chemoradiation appears to be associated with lower costs for management of stage IB2 cervical cancer when compared to simple adjuvant hysterectomy.

Chemoradiation with and without adjuvant extrafascial hysterectomy for IB2 cervical carcinoma.

The optimal treatment strategy for stage IB2 cervical carcinoma that maximizes survival while minimizing toxicity remains controversial. The purpose of this study was to compare survival and toxicity in stage IB2 cervical cancer patients treated with chemoradiation and adjuvant extrafascial hysterectomy (cRT + H) versus definitive chemoradiation (cRT). Data were abstracted from patients with IB2 cervical carcinoma primarily treated at a single institution from January 1994 to December 2004. All patients received chemotherapy concurrent with external beam radiation therapy. Patients were subsequently treated with either a single low-dose rate brachytherapy applicator followed by adjuvant extrafascial hysterectomy (n = 24) or a second brachytherapy application to complete full-dose definitive chemoradiation (n = 30). Analyses were conducted using Kaplan-Meier survival and Chi-square statistics. Groups did not differ demographically with the exception of smoking. Smokers were significantly (P = 0.04) more likely to have been treated with definitive chemoradiation. Median tumor size was similar between groups. There was no difference in overall or disease-free survival between patients who received cRT + H versus cRT (P = 0.82 and 0.75, respectively). All recurrences in the cRT arm were in smokers. There were two grade 3-4 toxicities in each group. No treatment-related deaths occurred. In this small retrospective cohort study, we observed no difference in survival between patients treated with cRT + H versus cRT. These data complement published results of Gynecologic Oncology Group studies in patients with IB2 cervical cancer. Definitive comparison between the two treatment strategies would require a randomized prospective trial with stratification based on smoking.

Vulvar melanoma: a retrospective analysis and literature review.

OBJECTIVE: This review focuses on current directions in the staging and treatment of melanoma of the vulva. METHODS: All women treated for invasive melanoma of the vulva at the University of Virginia Health Sciences Center from 1980 through 2000 were identified through a retrospective review of the records of the Division of Gynecologic Oncology. Their treatments and outcomes were then analyzed and presented. RESULTS: Over the 20-year study period, 14 cases of melanoma of the vulva were identified. Of the 14 patients treated with curative intent, 6 developed recurrences following the completion of primary therapy, and all are dead from their disease. The mean duration from completion of therapy to recurrence was 7.5 months; the mean survival following recurrence was 17 months. CONCLUSION: One-centimeter skin margins appear adequate for vulvar melanomas <1 mm thick, and 2-cm margins appear adequate for intermediate-thickness melanomas (1-4 mm). In all cases it is necessary to include at least a 1-cm-deep margin extending through the subcutaneous fat to the muscular fascia below. Elective node dissection seems to offer no additional advantage in superficial lesions <0.76 mm thick, and its role in deeper lesions is still uncertain.

Well-differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression.

Both the estrogen receptor (ER) and the progesterone receptor (PR) have two subtypes: ER-alpha and beta, and PR-A and -B, respectively. These subtypes differ in function and expression, and recent reports have correlated changes in the normal proportions of these isoforms with neoplastic states. We investigated ER and PR isoform expression in normal pre- and post-menopausal endometrium, well-differentiated endometrial adenocarcinoma, and poorly differentiated malignant mixed mullerian tumors (MMMTs). Semi-quantitative RT-PCR and immunoblotting were used to measure receptor mRNA and protein expression. Estrogen receptor-alpha/beta mRNA ratios were significantly higher in postmenopausal (27.3) compared to premenopausal endometrium (4.9) mainly as a result of lower ER-beta expression in the former. Compared to age-matched postmenopausal controls, the ER-alpha/beta ratio was reduced in both grade I adenocarcinoma and MMMT specimens (3.3 and 6.8, respectively), due to a selective loss of ER-alpha. The relative abundance of PR-A and PR-B mRNA remained unchanged between all tissue subtypes. Total PR protein, however, was significantly reduced in MMMTs compared to all other groups. Thus, sex steroid receptor expression is significantly and differentially altered in well-differentiated and poorly-differentiated endometrial cancers. Both cancers exhibit decreased ER-alpha expression and the MMMTs also demonstrate a significant loss of PR protein.

Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion.

How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin's inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17beta orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 microg/1.73 m(2).h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 microg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10(-4) interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 +/- 6.1% (mean +/- SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 +/- 1 to 245 +/- 35 pg/mL [42 +/- 4 to 920 +/- 110 pmol/L] (P < 10(-4)); decreased serum concentrations of LH (P = 0.018), FSH (P < 10(-4)), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 +/- 0.07 to 0.87 +/- 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin's maximal suppression of GH by 89 +/- 4.7% (P < 10(-4) below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38-0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2-7.0) (estradiol) microg/1.73 m(2)/h (P < 10(-4)), denoting muting of somatostatin's inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10(-4)). The foregoing effects were specific, because estrogen did not alter somatostatin's dose-dependent enhancement (P < 10(-4)) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic. In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin's dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin's reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.

Selective loss of estrogen receptor beta in malignant human colon.

Epidemiological data suggest a protective effect for estrogen replacement therapy on colon cancer. The estrogen receptor (ER) is required for the action of estrogen. The ER-beta isoform is functionally similar to ER-alpha but has a distinct pattern of expression and transcriptional response to selective estrogen response modulators. Our goal was to investigate the presence of ER-alpha and ER-beta in normal and malignant colon tissue. Human colon cancer tissue and adjacent normal colon tissue were harvested from five male and six female patients undergoing segmental colon resection for colon cancer. Western blot analysis revealed very low levels of ER-alpha protein in tumor and normal colon tissue. In both male and female patients, malignant colon tissue showed a selective loss of ER-beta protein expression when compared to normal colon tissue in the same patient. Semiquantitative reverse transcription-PCR revealed no difference in ER-beta mRNA levels between normal and malignant colon tissue. Malignant transformation of the colon is associated with a marked diminution of ER-beta protein expression, possibly through a posttranscriptional mechanism.

Expression of estrogen receptor alpha mRNA and protein variants in human endometrial carcinoma.

Breast cancer tissue has been shown to contain alternatively spliced estrogen receptor alpha (ER-alpha) mRNA variants, which have altered biological activities compared to the full-length ER-alpha. The development of endometrial cancer, as well as drug resistance in breast cancer patients undergoing tamoxifen therapy, may represent altered ER-alpha function secondary to specific exon deletions. While the literature is replete with ER mRNA variant data, little information is available regarding the presence and function of endometrial ER variant proteins. We evaluated the presence of human ER-alpha mRNA and protein variants in six premenopausal, six postmenopausal, and six endometrial carcinoma samples. Reverse transcription-polymerase chain reaction, DNA hybridization, and sequencing techniques identified exon 4, exon 5, and exon 7 mRNA splice variants in all patients as well as MCF-7 and Ishikawa cell lines. Presence of translated proteins for full-length ER-alpha, as well as splice variants, was investigated by Western blot analysis using antibodies directed against the N-terminus, hinge region, and C-terminus portions of the ER. These experiments confirmed the presence of immunopositive protein bands of approximately 64-66 kDa in all patients corresponding to wild-type ER-alpha. A protein band migrating at 41 kDa, consistent with an exon 5 splice variant, was only seen in endometrial adenocarcinoma samples. Premenopausal and postmenopausal endometrial samples did not contain detectable amounts of ER splice variant protein. Human ER-alpha mRNA variants are present in all human endometrial samples, but detectable levels of variant proteins are only observed in patients with endometrial adenocarcinoma.

Primary breast carcinoma of the vulva: a case report and literature review.

BACKGROUND: In 1872, Hartung was the first to describe the case of a fully formed mammary gland arising in the left labium majora of a 30-year-old woman. Since Hartung's initial report, 38 additional cases of ectopic vulvar breast tissue have been described. This case report describes the rare occurrence of primary mammary adenocarcinoma arising within the vulva. CASE: A 64-year-old G4P4 white female presented with a 4-year history of a 2 x 1 cm firm, indurated, raised lesion of the left lateral mons. A wide local excision with ipsilateral inguinofemoral lymphadenectomy was performed. Given histological findings characteristic of both invasive ductal carcinoma and invasive lobular carcinoma, in conjunction with the presence of estrogen and progesterone receptors within the tumor, a diagnosis of infiltrating adenocarcinoma arising within ectopic breast tissue was made. CONCLUSIONS: Thirty-nine reported cases of ectopic breast tissue arising within the vulva have been reported in the world literature. Though the diagnosis of primary breast carcinoma arising within the vulva is based primarily upon histologic pattern, estrogen and progesterone receptor positivity provide supporting evidence. Given the rarity of this condition, guidelines for therapy are unavailable; we therefore suggest looking to the current management of breast cancer in order to establish a sensible approach.

Atypical glandular cells of undetermined significance: a five-year retrospective histopathologic study.

OBJECTIVE: Our purpose was to ascertain the types and frequency of pathologic conditions associated with atypical glandular cells of undetermined significance on Papanicolaou smears. STUDY DESIGN: A 5-year retrospective review of screening cervical cytologic examinations diagnosed as atypical glandular cells of undetermined significance was performed at the University of Virginia to determine pathologic findings associated with atypical glandular cells of undetermined significance on Papanicolaou smears stratified by subtype and overall. RESULTS: Pathologic findings for the respective Papanicolaou smears with the diagnosis of atypical glandular cells of undetermined significance not otherwise specified, favor benign, squamous intraepithelial lesions, and favor neoplasia through the follow-up interval were as follows: squamous intraepithelial lesions in 11%, 8%, 38%, and 20%; adenocarcinoma in situ in 3%, 0%, 0%, and 10%; endometrial hyperplasia in 3%, 5%, 1%, and 2%; and cancer in 8%, 3%, 1%, and 7%. Overall, 63 patients (32%) had preinvasive or invasive lesions. CONCLUSIONS: Atypical glandular cells of undetermined significance on Papanicolaou smears were correlated with significant findings in 45% of patients (32% with preinvasive or invasive lesions and 13% with benign lesions). A prompt and aggressive workup is recommended.

Malignant melanoma of the vagina and locoregional control: radical surgery revisited.

BACKGROUND: Anecdotal reports and retrospective case reviews suggest improved locoregional control, and possibly overall survival, with radical surgical extirpation as the primary management of vaginal melanoma. This study seeks to reevaluate, through case presentation and literature review, the usefulness of radical pelvic surgical procedures in the management of vaginal melanoma. CASE: Seven cases of primary vaginal melanoma were seen at the University of Virginia Hospital from 1966 to 1996; each was compared in terms of primary management, disease-free interval, sites of relapse, and overall survival. All patients who died of their disease relapsed locally prior to their death, with the exception of two patients who underwent wide local excision (WLE) followed by postoperative high-dose fractionation teletherapy. CONCLUSIONS: The use of WLE followed by high-dose fractionation teletherapy in the primary management of vaginal melanoma appears to provide excellent locoregional control, without the attendant morbidity and physical disfigurement associated with more radical surgical resection. The results reported here, as well as other published reports, suggest that locoregional control may be obtained with even large melanomas with radiotherapy when administered in high individual fractions (greater than 400 cGy/fx). This type of response is consistent with the higher response rate seen with cutaneous melanomas when large individual fractions are compared to conventional fractionation. Because of the extremely poor survival with vaginal melanoma regardless of primary therapy, novel therapeutic strategies, including further investigation into the use of high-dose fractionation irradiation, are urgently needed.

Estrogen receptor mRNA splice variants in pre- and postmenopausal human endometrium and endometrial carcinoma.

Breast cancer tissue has been shown to contain alternatively spliced estrogen receptor (ER) mRNA variants which may result in alternate ER proteins. These ER variants lack specific functional domains and may alter breast cancer cells responses to both estrogen and antiestrogens. Specifically, ER variants might play a role in Tamoxifen resistance in breast cancer patients, as well as the development of endometrial carcinoma, an estrogen-dependent tumor, in patients taking this medication. We investigated the presence of ER variants in normal human endometrium and endometrial carcinoma. Ribonuclease protection assays (RPA) demonstrated ER mRNA variants in the DNA and hormone-binding domains. The reverse transcription-polymerase chain reaction (RT-PCR) assay was used to examine the ER complementary DNA (cDNA) from 25 patients, and generated two major products in both the exon 2 to 5 and 4 to 8 regions. Southern blot analysis of PCR products revealed exon 4 and 7 deletions in all 25 endometria without any qualitative differences in variant expression among premenopausal, postmenopausal, and adenocarcinoma samples. Cloning and sequencing of cDNA variants definitively identified exact deletions of either exon 4 or exon 7. These results demonstrate significant levels of ER mRNA splice variants as well as full-length ER mRNA in normal and neoplastic endometria.

Squamous cell carcinoma of the endometrium: a report of eight cases and a review of the literature.

BACKGROUND: Endometrial squamous cell carcinoma is extremely rare, with only 56 cases reported in the literature. METHODS: Six cases of endometrial squamous cell carcinoma were found in a review of 1182 cases of uterine corpus cancer treated at the Massachusetts General Hospital from 1975 to 1993. Two additional cases were seen in pathological consultation. The clinicopathological features of these 8 cases and the 56 reported cases were analyzed. RESULTS: The average age of the patients was 67 years; almost all of them were postmenopausal. The most frequent presenting symptom was vaginal bleeding. Chronic pyometra and nulliparity were predisposing factors. The average duration of symptoms before diagnosis was 11.5 months. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was the primary treatment in 58 patients. Eighty percent of the patients with Stage I tumors survived; the median follow-up time was 32 months. The survival rate for patients with Stage III tumors was only 20%, and all 6 patients with Stage IV disease died. CONCLUSIONS: The preoperative diagnosis of endometrial squamous cell carcinoma may be difficult, since curettage specimens may show only highly differentiated squamous epithelium. The strong relationship between tumor stage and survival suggests that early diagnosis and treatment are imperative.

Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease.

Between 1982 and 1992, 24 women with Stage III clear cell ovarian cancer were identified from the tumor registry. Thirty-four women with Stage III papillary serous tumors treated between 1987 and 1989 were used as a comparison. All patients underwent cytoreductive surgery followed by conventional platinum-based chemotherapy. In the women with clear cell histology, nine (37.5%) had endometriosis in the surgical specimen compared with one (3%) in the papillary serous group (P = 0.002). Ten women (42%) with clear cell histology experienced a thromboembolic event during the course of treatment, compared to six (18%) in the papillary serous group (P = 0.05). In the group with clear cell histology, overall, 70% of women had progressive disease. Fifty-two percent experienced clinical progression while receiving platinum-based chemotherapy. In addition, four patients were found to have progressive disease at second-look laparotomy. Only two patients had a pathologic complete response. In the group with papillary serous histology, 29% overall had progressive disease while on chemotherapy (P = 0.005). The median survival for the women with clear cell histology was 12 months compared to 22 months for those with papillary serous (P = 0.02). For women with clear cell histology, univariate analysis was used to evaluate prognostic factors. Age less than 50 was a poor prognostic factor (P = 0.045). The presence of endometriosis, thromboembolic event, or optimal cytoreduction were not prognostic factors (P = 0.67, P = 0.34, P = 0.39). Patients with advanced clear cell ovarian cancer have a poor response to conventional platinum-based chemotherapy and overall prognosis is poor.

Histologic transformation of benign endometriosis to early epithelial ovarian cancer.

Between 1975 and 1990, 79 patients with Stage I epithelial ovarian cancer were treated at Massachusetts General Hospital. Patients were identified from the tumor registry and medical records were retrospectively reviewed. Pathological slides were evaluated for the presence of endometriosis, specifically looking for malignancy arising in endometriosis. Evidence of endometriosis was found in 22 of the 79 cases (28%). In the 23 cases of endometrioid histology, 9 cases (39%) were associated with endometriosis and, in the 17 cases of clear cell tumors, 7 (41%) were associated with endometriosis. All 8 cases of mixed histology had clear cell and/or endometrioid components and 4 cases (50%) were associated with endometriosis. Endometrioid adenocarcinoma accounted for 41% of the tumors associated with endometriosis, clear cell carcinoma 31%, mixed (endometrioid and/or clear cell types) 18%, and other types 9%. Among the 22 patients with associated endometriosis, we found 7 carcinomas (32%) arising in endometriosis. In these 7 cases a spectrum of benign and atypical endometriosis with a transition to clear cell or endometrioid adenocarcinoma were identified. These premalignant changes were characterized by cytologic atypia and architectural proliferation. Endometriosis was frequently encountered among patients with Stage I epithelial ovarian cancer of endometrioid and clear cell histologies. Endometriosis may play a role in the pathogenesis of some early stage malignant ovarian epithelial neoplasms.

Uterine papillary serous carcinoma (UPSC): a clinicopathologic study of 30 cases.

Between 1975 and 1989, 896 patients were treated for endometrial carcinoma at the Massachusetts General Hospital. Thirty patients were identified from the tumor registry as having uterine papillary serous carcinomas. The survival for all patients and for groups of patients stratified on clinical and pathological parameters was examined in the Kaplan-Meier survival curves. Curves for the different strata were compared using the logrank test. The 5-year survival for the 30 patients was 30% +/- 9%. Patients with surgical stage I and II tumors had a 5-year survival rate of 79% +/- 14% compared to 25% +/- 10% in patients with stage III and IV tumors (P = 0.02). Clinical stage, depth of myometrial invasion, lymph-vascular space invasion, tumor grade, and DNA aneuploidy were not found to significantly impact on survival. However, a survival advantage was seen in patients diagnosed with early surgical stage tumors, reinforcing the need for thorough staging at the time of laparotomy.

Malignant mixed müllerian tumors of the ovary: experience with surgical cytoreduction and combination chemotherapy.

BACKGROUND: The role of surgical cytoreduction and combination chemotherapy for malignant mixed müllerian tumors (MMMT) of the ovary was evaluated. METHODS: A retrospective review of 27 women with ovarian MMMT treated from 1980 to 1990 was performed. RESULTS: The International Federation of Gynecology and Obstetrics stages for the 27 women were 1 Stage I, 3 Stage II, 17 Stage III, and 6 Stage IV. Only 10 of the 23 patients with Stage III or IV disease were cytoreduced optimally. With respect to postoperative therapy, 3 women received no treatment, 6 were treated with whole abdomen radiotherapy, 1 received melphalan, and 17 received chemotherapy incorporating a platinum agent (3), doxorubicin (4), or both (10). The significant prognostic factors were stage (P < 0.001) and, for women with Stage III or IV disease, the feasibility of cytoreductive surgery (P = 0.03). The four patients in Stages I or II remained disease free after an interval of at least 5 years. The median and 5-year survival rates for patients with Stages III or IV disease was 18 months and 8%, respectively. Patients in Stage III or IV for whom optimal cytoreduction was not possible had a 2-year survival of 14%, whereas optimal cytoreduction was associated with a 52% 2-year survival. Median survival for the 14 women with Stage III or IV ovarian MMMT treated with combination chemotherapy was 25 months and nine women achieved progression free intervals of greater than 18 months. CONCLUSIONS: Aggressive surgical cytoreduction followed by combination chemotherapy may result in improved progression free intervals for women with advanced ovarian MMMT. However, a major improvement in prognosis for this rare malignancy has not yet been achieved.