The Enlarged Fibroid Uterus: Aberrant Arterial Supply via the Omental Artery.

Uterine artery embolization is considered a first-line therapy for symptomatic fibroids and is occasionally required to mitigate operative risk prior to total abdominal hysterectomy or myomectomy. We present a pictorial review of parasitized omental artery supply to the enlarged fibroid uterus in three patients undergoing preoperative uterine artery embolization. A detailed understanding of variant uterine blood supplies is crucial when performing fibroid embolization. Although omental artery supply to the fibroid uterus is an unusual finding, aortography to include mesenteric arteries may be necessary when anomalous blood supply to the enlarged fibroid uterus is suspected.

Oncoprotein profiles of primary peritoneal malignant mixed müllerian tumors.

Primary peritoneal malignant mixed müllerian tumors (MMMTs) are extremely rare and highly aggressive malignancies associated with poor clinical prognoses. We present a clinicopathologic review of three cases of this rare tumor by examining expression of selected oncoproteins by immunohistochemistry. Three consecutive cases of primary peritoneal MMMT were examined by paraffin immunohistochemistry for expression of p53, p16, BCL2, CerbB2, and classical cadherins E-cadherin, P-cadherin, and N-cadherin. All three cases expressed p16, but showed less consistent expression of other markers, with one case expressing p53 and one expressing BCL2. All cases were negative for membrane expression of Cerb-B2. The three classical cadherins were expressed in two cases with one case showing only weak N- and P-cadherin expression. No difference in antigen expression was seen in the epithelial compared to sarcomatous components. We conclude that p16 may be a common tumor suppressor gene expressed in peritoneal MMMT. P53 overexpression may be of lesser frequency in peritoneal MMMT compared to MMMT from the ovary and the uterus. We did not observe any difference in antigen expression between areas of epithelial or sarcomatous differentiation, which would support a single pluripotential malignant clone in the histogenesis of these tumors.

Expression of cadherins, p53, and BCL2 in small cell carcinomas of the cervix: potential tumor suppressor role for N-cadherin.

Cadherins are tissue-specific cell adhesion molecules that function as tumor suppressors. Analysis of cadherin expression is useful for differentiation of tumor histogenesis, and because they serve as markers of tumor behavior and prognosis. Since the pattern of cadherin expression is not well characterized for small cell carcinoma of the cervix, we examined cases of these tumors for expression of cadherins, and two other oncoproteins p53 and BCL2. Four cases of small cell neuroendocrine carcinomas were identified from the Gynecologic Oncology Service with diagnoses confirmed by immunohistochemistry for neuroendocrine markers. Archival paraffin blocks were studied by heat-enhanced immunohistochemistry using commercially available antibodies specific for E-cadherin, P-cadherin, and N-cadherin, p53, and BCL2. Sections were examined for specific membrane staining of cadherins, nuclear staining of p53, and cytoplasmic staining of BCL2. E-cadherin was expressed in three of four cases, P-cadherin in one of four, and N-cadherin in none of four cases. P53 was expressed in one of four cases and BCL2 in one of four cases. The four cases showed three different patterns of immunohistochemical staining for the five oncoproteins. Specifically, two cases expressed E-cadherin only; one case lacked all three cadherins, was negative for BCL2, and was only positive for p53; and one case expressed E- and P-cadherin and BCL2. Prior studies of other neuroendocrine and small cell tumors of other organs showed E-cadherin expressed in 98% (42 /43), N-cadherin in 65% (28/43), and P-cadherin in 40% (17/43) of cases. Additionally, one case of vaginal small cell carcinoma showed expression of all three cadherins. The only significant difference between cervical primaries and other primary sites is that N-cadherin was not detected in our four cases vs. 65% expression in other sites (P < 0.001). We conclude that cadherin and oncoprotein profiles in small cell carcinoma of the cervix are different in the four cases analyzed. Additional cases need to be studied to determine the specificity and frequency of these oncoprotein profiles for small cell carcinoma of the cervix. These may possibly represent different oncogenic pathways in development of small cell cancer of the cervix. Also, our results suggest that N-cadherin may be a tumor suppressor gene in these tumors.

Uterine papillary serous carcinoma presenting as distant lymph node metastasis.

BACKGROUND: Uterine papillary serous carcinomas are highly aggressive malignancies that often present with high-stage disease. We report two cases that presented initially as distant metastatic disease. One case was found incidentally at the time of axillary dissection for breast cancer and the second case in the workup of a neck mass. CASES: Clinicopathologic review of the patient material including review of routine H&E pathology and immunohistochemical studies of the patients tumors was performed. Both cases showed high-grade papillary carcinomas with psammoma bodies metastatic to lymph nodes in the axilla or neck. Sampling of the endometrium in these patients confirmed primary uterine papillary serous carcinoma. Patients were treated with adjuvant chemotherapy. CONCLUSIONS: Metastatic uterine papillary serous carcinoma presenting initially in distant sites is an unusual manisfestation of this highly aggressive tumor. This tumor should be considered in the differential diagnosis when patients present with metastatic high-grade papillary serous carcinomas and the primary site is unknown.

Cadherin expression in glandular tumors of the cervix.

BACKGROUND: The cadherins are homotypic adhesion proteins that are important in cell sorting during organogenesis. Classic cadherins include several different types that show tissue specific expression. Specific tissue expression of cadherins often is preserved in neoplastic transformation, and cadherin phenotype can be used to differentiate morphologically similar but histogenetically distinct tumors. METHODS: The authors examined by using immunohistochemistry in paraffin sections the expression of E- (epithelial) and P- (placental) cadherin in 39 patients with glandular tumors of the cervix, including invasive adenocarcinoma, villoglandular adenocarcinoma, adenocarcinoma in situ (AIS), and adenoma malignum. RESULTS: In all cases, E-cadherin was expressed in both normal and malignant glands without appreciable differences. P-cadherin, normally confined to basal epithelial cells and not observed in benign glands, was aberrantly expressed in neoplastic glands in 27 cases, including 96%(23 of 24 cases) of invasive cancers, 40% (2 of 5) of villoglandular carcinomas, 25% (2 of 8) of AIS, and 0% (0 of 2) of adenoma malignum. CONCLUSIONS: The authors' results show that E-cadherin is uniformly expressed in glandular tumors of the cervix with no evidence of decreased expression in these tumors. In addition, P-cadherin is aberrantly expressed in most adenocarcinomas and appears to be preferentially expressed in invasive rather than in situ lesions. Thus, aberrant expression of P-cadherin may be a useful marker of invasive or aggressive clinical behavior in glandular lesions of the cervix.

Primary, localized vulvar B-cell lymphoma expressing CD44 variant 6 but not cadherins. A case report.

BACKGROUND: Primary extranodal lymphoma of the vulva is rare, with only 17 prior cases reported. Its immunohistochemical profile has not been characterized beyond B- or T-cell phenotype. CASE: A 64-year-old, white woman presented with a nontender enlargement of the right labium minus and labium majus. Bilateral vulvar punch biopsies revealed an infiltrate of neoplastic lymphocytes that filled the reticular dermis and extended down to the subcutaneous fat. Lymphoma cells were positive for CD20 and expressed CD43 in an aberrant manner. The tumor was examined for adhesion protein expression. There was expression of CD44 standard and variant 6 but not of E-, N- or P-cadherin. No systemic spread of this rare lymphoma was evident after one year. CONCLUSION: Adhesion protein expression in primary vulvar lymphoma may have prognostic implications.

Adenocarcinoma arising in extragonadal endometriosis: an immunohistochemical study.

BACKGROUND: Malignant transformation is an infrequent but reported complication of endometriosis. Previous reports of these cases have been limited to clinicopathologic studies based on routine histologic examination of these tumors, whereas, to the authors' knowledge, characterization of these lesions based on immunophenotype and hormone receptor and oncoprotein expression has not been described. METHODS: Using commercially available monoclonal antibodies, the authors studied three recent cases of adenocarcinoma arising in extragonadal endometriosis using paraffin immunohistochemistry. Proteins examined included different cytokeratin (CK) subtypes, as well as hormone receptor status, proliferation rate, and oncoprotein expression. RESULTS: All three cases presented clinically and macroscopically as colonic masses, and the tumors expressed an endometrial CK phenotype (CK7+, CK20-). In contrast, the adjacent benign colonic epithelium expressed the expected opposite phenotype (CK7-, CK20+). Estrogen receptor (ER) and progesterone receptor (PR) were expressed in one of the three tumors. Interestingly, in the ER/PR negative tumors, receptor expression was present in areas of benign endometriosis adjacent to malignancy, suggesting a loss of receptor expression with malignant transformation. The tumors also were examined for proliferation by Ki-67, and the expression of oncoproteins c-erb B-2, p53, cyclin D1, and bcl-2. All cases of malignancy had a high proliferation rate as measured by Ki-67, which was in contrast to areas of benign endometriosis which had a low proliferation rate. Of the other oncoproteins only p53 protein was detected at a significant level in all three cases. Cyclin D1 was overexpressed in two of the three cases. c-erb B2 and bcl-2 overexpression was not detected. CONCLUSIONS: The results of the current study 1) show the utility of CK subtypes in confirming endometrioid phenotype in tumors arising in extragonadal endometriosis with colonic involvement and 2) suggest that loss of hormone receptor expression and p53 oncoprotein abnormalities may be involved as mechanisms in malignant transformation in extragonadal endometriosis.

Neovaginal reconstruction after exenteration using an omental flap and split-thickness skin graft.

The earliest efforts at neovaginal reconstruction used split-thickness skin grafts when bladder and rectum remained in place. In patients undergoing total pelvic exenteration, the pelvic organs are not available to accept the skin graft. By modifying the omental flap normally used to close off the pelvic inlet after total pelvic exenteration with or without lower coloproctostomy, a cylinder can be created that provides anterior, posterior, and lateral walls for the neovagina. When this omental cylinder is lined with a split-thickness skin graft and secured in the postoperative period using a soft vaginal form, a satisfactory neovagina can be created. This article presents the authors' experience with 20 patients who underwent radical pelvic exenteration for gynecological malignancy and neovaginal reconstruction using an omental cylinder flap lined with a split-thickness skin graft. In this series, all flaps and skin grafts have remained soft and completely viable with no pelvic infections, perineal fistulae, or hernias, and they offer the potential for sexual function in approximately 80 percent of patients. Average reconstruction operating time is less than 2 hours. In the properly selected patient, this method provides distinct advantages over reconstruction with myocutaneous flaps, which may be too bulky, too difficult to pass into the pelvis, and require additional donor-site incision with prolonged operative time. Myocutaneous flaps may have greater potential for partial or complete tissue loss. Neovaginal reconstruction using an omental cylinder flap lined with a split-thickness skin graft compares favorably with previously described methods by providing support for the pelvic floor with primary healing while restoring the potential for sexual function with minimal overall morbidity.

Morbidity after intraperitoneal insertion of saline-filled tissue expanders for small bowel exclusion from radiotherapy treatment fields: a prospective four year experience with 34 patients.

UNLABELLED: When prolonged small bowel exclusion (SBE) from external radiotherapy (RT) fields or immediate exclusion of bowel from brachytherapy sources is required for a patient without adequate omentum, there are no simple proven methods available for accomplishing these goals. We report a prospective study of SBE by intraperitoneal, saline-filled tissue expanders (TE). Thirty-four patients had exclusion of small bowel from either external radiotherapy (RT) ports (20), afterloading catheter treatment fields (5), both (5), or from intracavitary implants (4). Twenty-seven TEs were placed in the pelvis and 7 in the iliolumbar fossa. TE volume ranged from 400-1500 cc (median 550 cc). Patients had rectal (n = 15), colon (6), endometrial (4), anal (3), and vaginal (1) cancers and sarcomas (5). Fifteen patients had recurrent neoplasms, 13 of which were in previously irradiated fields. Nine patients had colorectostomies directly behind the TE, and 12 had other bowel (6) or ureteral (3) anastomoses or bladder repairs (3) adjacent to the TE. RESULTS: TEs remained in the patients from 6 to 173 days (median 95). Morbidity included three early TE withdrawals before RT was begun, one for a prolonged ileus, one for a perineal wound dehiscence, and one for an unrelated small bowel obstruction. Two patients (5.9%) early in the series had post-withdrawal complications (non-lethal small bowel fistulas requiring reoperation), although in a recent cohort of patients no post-withdrawal complications occurred using a different placement technique (0/17 vs. 2/14, P = 0.2). The patient injury complication rate was 4/34 (11.8%). None of these limited or delayed RT, but RT was limited to less than that planned in one other by TE deflation (total complication rate 14.7%). There were no clinical infections involving the prostheses, even though one patient had an abdominal wound dehiscence, 3 had pelvic abscesses, and 2 had exposure of the TE through the vagina (1 planned, 1 at dehisced vaginal cuff) after TE placement. We noted no acute and one possible late RT complication in these patients (18 months median follow-up, range 3-43 months). Small bowel was displaced from > 95 per cent of the RT treatment volume in 70 per cent and from > 75 per cent of the treatment volume in 89 per cent of 27 evaluable patients treated with external RT. CONCLUSION: Intraperitoneal placement of a saline-filled tissue expander is a simple, safe and effective means of small bowel exclusion from RT portals.

Phase II trial of thio-TEPA in relapsed and refractory ovarian carcinoma.

On the basis of a Phase I reevaluation of thio-TEPA in which 3 of 9 patients with ovarian carcinoma responded, we instituted a Phase II study at high doses. Fourteen patients with a histologic diagnosis of epithelial carcinoma of the ovary, who had received at least one prior cisplatin-based regimen, were entered. Thio-TEPA was initially administered intravenously at a dose of 65 mg/m2 every 4 weeks, but was reduced to 50 mg/m2 after severe myelotoxicity developed in the first 5 patients. In 4 patients stable disease lasted 3, 4, 5, and 9 months; 10 patients progressed. There were no objective responses. At this dose and schedule, thio-TEPA has a response rate less than 20% in ovarian cancer patients previously treated with cisplatin.

Phase I pharmacokinetic study of intraperitoneal etoposide.

The synergistic interaction of etoposide with cisplatin in certain tumors prompted an evaluation of its potential role in the i.p. treatment of ovarian cancer and other intraabdominal malignancies. We conducted a Phase I evaluation of etoposide as a single agent to determine the maximum tolerated dose i.p., to describe dose-limiting and other toxic effects, and to examine the pharmacokinetics of etoposide in this setting. Etoposide was diluted in 2 liters of normal saline, and instilled i.p. over 10 to 25 min following maximal drainage of ascites. The dwelling time was 4 h, followed by peritoneal drainage. Twenty-two patients received 56 courses at doses which ranged from 100 to 800 mg/m2. The median age was 49, the median performance status was 1, and 18 patients had received prior chemotherapy, with or without radiation. The principal acute toxicity was abdominal pain in 10 patients; this was usually accompanied by signs of peritoneal irritation and was always responsive to nonsteroidal antiinflammatory medications. The major toxicity was dose-related neutropenia; Grade 3 or 4 toxicity affected five of six patients at 800 mg/m2. Thrombocytopenia, nausea and vomiting, and alopecia were also observed. The recommended dose for further study is 700 mg/m2. The pharmacokinetics of etoposide in plasma and peritoneal fluid was measured in 19 patients. Peritoneal levels over the 4-h dwelling time declined monoexponentially with a harmonic mean half-life of 3.5 h (range, 1.9 to 7.8). Plasma levels rose to a peak at 2.9 +/- 1.7 (SD) h and then declined exponentially with a harmonic mean terminal half-life of 7.7 h (range, 4.2 to 15.6). The plasma area under the concentration-time curve increased linearly with respect to dose. The relative pharmacological advantage (ratio of peritoneal to plasma area under concentration-time curve) for i.p. administration was measured as 2.8 and was independent of dose. Based on the high plasma protein binding of etoposide (94%) and the minimal protein binding in the fluid instilled i.p., the ratio of the areas under the concentration-time curves of free drug is estimated to be 4%. These results illustrate that tumor confined to the peritoneal cavity would be exposed to substantially higher free (diffusible) drug concentrations following i.p. than following i.v. administration and support the further evaluation of etoposide by this route.

Malignant struma ovarii.

Malignant struma ovarii is a very rare tumor, with considerable disagreement concerning the necessary histologic features for malignancy. The prognosis with patients with a malignant struma ovarii is difficult to make because of inadequate follow-up of the reported cases and long clinical courses. In most cases the patients responded well to surgical treatment but sometimes patients have died from malignant struma ovarii, in particular, if there is metastasis. There is evidence that radioactive iodine is effective in treating metastatic struma. The present case reports the use of intraperitoneal chronic phosphate for metastatic intraperitoneal disease, with thyroid suppression. Long-term follow-up will be necessary to properly evaluate this therapy. Prophylactic administration of thyroid hormone should be considered in cases of malignant struma ovarii.

Gonadotropin-releasing hormone radioimmunoassay and its measurement in normal human plasma, secondary amenorrhea, and postmenopausal syndrome.

A sensitive and specific double antibody radioimmunoassay for gonadotropin-releasing hormone (GnRH) has been developed for measurement in ethanol extracts of human plasma. Iodinated hormone was prepared with the use of the chloramine-T method, and antibodies were developed in rabbits over a six-month period with a GnRH synthetic copolymer immunogen. A Scatchard plot revealed at least three species of antibody. The assay can measure conservatively at the 5 pg. per milliliter level and shows no cross-reactivity with other available hypothalamic and pituitary hormones. The releasing hormone was quantitatively recovered from human plasma with immunologic identity to native hormone. Unextracted plasma could not be used because of nonspecific displacement. The measurement of GnRH in individuals receiving 100 mug of intravenous bolus infusions of the synthetic decapeptide show extremely elevated values with two half-lives: one of two to four minutes and another of 35 to 40 minutes. In our experiments, we have found measurable GnRH in patients with secondary amenorrhea and at the midcycle in normal women. In the normal cycling woman during the follicular and luteal phases, GnRH was undetectable. In postmenopausal women with extreme hypoestrogenism and markedly elevated luteinizing hormone values, GnRH was also undetectable. No bursts of GnRH could be detected in normal men when sampled every ten minutes over a two-hour period and every two hours throughout the day.