Loss of p53 function in uterine papillary serous carcinoma.

In contrast to endometrioid carcinoma, uterine papillary serous carcinoma (UPSC) is an aggressive type of endometrial cancer. Loss of p53 function is critical for the molecular pathogenesis of UPSC. Both UPSC and its putative precursor, endometrial intraepithelial carcinoma (EIC), show abnormal p53 overexpression in most tumors. To further assess the nature of p53 alterations in UPSC, we systematically reevaluated a subset of our previous cohort of UPSC patients. In the current study, we correlate mutations of the p53 gene as detected by direct sequencing of exons 5 through 8 with p53 accumulation and expression of Waf-1 in 32 UPSC tumors. Waf-1 is a downstream effector of p53-mediated G1 arrest after DNA damage and, thus, an indicator of p53 functionality. Although 78% of tumors exhibited strong nuclear p53 immunoreactivity in 100% of tumor cells, we were able to detect p53 mutations in 53%. As expected, all p53 mutant tumors (17 cases) exhibited p53 overexpression. Seventy percent of those (12 tumors) showed concomitant lack of Waf-1 expression consistent with transcriptionally inactive p53, whereas the other five tumors showed Waf-1 staining in only a minor fraction of tumor cells consistent with p53-independent Waf-1 expression. In contrast, 47% (15 cases) of tumors failed to exhibit p53 mutations; interestingly, more than half of those (eight cases) showed strong nuclear p53 accumulation in all tumor cells but lacked concomitant Waf-1 expression. These findings are consistent with a mutation-dependent and -independent type of p53 inactivation in UPSC that are both associated with nuclear overexpression. Our findings suggest that the combined immunocytochemical analysis of p53 and Waf-1 is a valuable means of assessing the functional status of p53. In summary, p53 alterations are common in UPSC and probably responsible for its aggressive biological behavior.

Necrosis in 84 ovarian carcinomas: a morphologic study of primary versus metastatic colonic carcinoma with a selective immunohistochemical analysis of cytokeratin subtypes and carcinoembryonic antigen.

Carcinomas metastatic to the ovary are often difficult to distinguish from primary ovarian carcinomas. Adenocarcinoma of the colon may simulate both primary endometrioid and mucinous ovarian tumors. The histologic finding of "dirty" necrosis in association with a "garland" or cribriform pattern has been suggested as a useful feature in distinguishing metastatic colonic carcinomas from primary endometrioid ovarian carcinomas. This study was performed to determine the use of "dirty" necrosis in distinguishing primary ovarian carcinoma from metastatic colonic carcinoma by studying 71 of the former and 10 of the latter. At least focal dirty necrosis was found in 68% of primary ovarian epithelial cancers, including 92% of the endometrioid subtype, and in 100% of the metastatic colonic carcinomas. A subgroup of cases was evaluated immunohistochemically using cytokeratin (CK) 7, CK 20 and carcinoembryonic antigen (CEA). The phenotype of CK 7 +/CK 20-/CEA-was present in 92% of primary ovarian carcinomas studied, whereas, 90% of metastatic colonic carcinomas were CK 7-/CK 20 +/CEA+. The finding of dirty necrosis is not specific for metastatic colonic cancer, and differential cytokeratin immunostaining is a useful adjunct in this differential diagnosis.

Role of p53 alteration in primary peritoneal carcinoma.

Although the clinicopathologic features of primary peritoneal carcinoma (PPC) in women are relatively well defined, the molecular pathogenesis of the disease has not been examined. The object of this study was to assess the biological significance of p53 alterations in PPC. Twenty-nine PPCs studied for p53 protein accumulation with monoclonal antibody DO-7 consisted of 26 serous carcinomas, one clear cell carcinoma, one tumor with endometrioid features, and one malignant mixed müllerian tumor. P53 was overexpressed in 83% of all PPCs and in 81% of the serous PPCs. Among eight immunopositive tumors with at least two distinct anatomic sites sampled, six tumors showed concordance, whereas two tumors showed discordance for p53 immunopositivity. The latter two tumors support the concept of a multifocal origin of PPC. This is the first report to suggest that loss of p53 function plays an important role in the development of PPC and might contribute to the poor prognosis of this disease. Parallels to serous papillary carcinomas of the uterus and ovary are discussed.

Morphologic effects of neoadjuvant chemotherapy in locally advanced breast cancer.

The use of chemotherapy as primary treatment in early and locally advanced breast cancer is rising. As a result, many resected tumors were exposed to cytotoxic drugs in vivo. To study resulting histopathologic changes, we examined 61 patients with locally advanced stage III breast cancer who had been treated with a standardized neoadjuvant polychemotherapy regimen before undergoing surgical resection 3 months later. Matched pairs of pre- and posttherapy breast tissue were evaluated for morphologic changes in the residual malignant and benign breast tissue compartment. A potential correlation between changes and the original p53 immunophenotype was examined as well. In 11 cases (18%), complete pathologic remission with no residual tumor in the mastectomy specimen was achieved. This response was not correlated to the original p53 status. The remaining 50 cases showed residual tumor. The most prominent histologic change was an increase in nuclear atypia of tumor cells (51% of the cases). This effect was independent of the presence or absence of nuclear p53 accumulation in the pre-treatment specimens. Nuclear atypia was frequently accompanied by tumor cell enlargement (in 49% of the cases). Most commonly, a tumor with relatively small cells presented with large epithelioid apocrine features after treatment. In 6 cases (13%), the mitotic rate decreased significantly, while in 12 cases (26%) the mitotic rate increased after chemotherapy. Elston histogrades remained unchanged in 70% of the cases but increased in 17% and decreased in 13%, mainly due to changes in mitotic rates. Extensive tumor cell vacuolization, a common change seen after radiotherapy, was a minor finding but was seen focally. Within the non-malignant compartment, lobular atrophy with hyalinization and minimal epithelial atypia of lobules and ducts were common. We conclude that changes in residual tumor and normal breast are common following systemic cytotoxic therapy. As neoadjuvant chemotherapy becomes mainstream management for locally advanced breast cancer, pathologists are required to recognize treatment induced changes. For correct histopathologic assessment, therapy induced morphologic alterations need to be distinguished from tumor-intrinsic morphologic features.

Uterine papillary serous carcinoma evolves via a p53-driven pathway.

Uterine papillary serous carcinoma (UPSC) is a highly aggressive type of endometrial cancer that occurs in the absence of hyperestrogenism and endometrial hyperplasia. Biologically, UPSC belongs to a distinct group of aggressive neoplasms of the extended Müllerian epithelium that are characterized by hypoestrogenism, advanced disease at diagnosis, a serous papillary histotype, and a dismal prognosis. There is mounting evidence that loss of p53 function is critical for the molecular genetic cause of all tumors in this group. To further assess the role of p53 alterations in UPSC, we studied 40 patients using immunohistochemical expression analysis. Thirty-four tumors (85%) showed intense nuclear overexpression of p53, whereas six tumors (15%) were p53 negative. Thirteen p53-positive tumors had multiple samplings from distinct anatomic sites, and all showed complete concordance in p53 staining, suggesting that p53 alterations occur early in UPSC carcinogenesis. p53 positivity was associated with loss of hormone receptors. Thirty-nine cases were concomitantly analyzed for estrogen or progesterone receptor expression. Among those, 31 tumors were p53 positive but hormone receptor negative throughout, in contrast to only two tumors that were diffusely p53 positive and focally hormone receptor positive. Patients whose tumors overexpressed p53 had a statistically significant shorter survival than those whose tumors did not at 24 and 48 months (P = .03). This study represents one of the two largest analyses published to date that confirm the strong association between UPSC and p53 overexpression. Furthermore, we suggest that the concept of UPSC be broadened: UPSC is a p53-driven neoplasm that biologically is a kin to other serous papillary malignancies of the ovaries and peritoneum. This group of tumors bypasses the slow hormone-dependent pathway of tumorigenesis but instead undergoes early p53 alterations that lead to rapid tumor development.

Ovarian lipoma of teratomatous origin.

BACKGROUND: Lipomatous tumors of ovarian origin are rare and may arise from overgrowth of metaplastic fat cells in the stroma. CASE: A 5-cm, circumscribed, grossly yellow tumor was an incidental finding at the time of hysterectomy for endometrial cancer. The ovarian tumor was composed almost exclusively of benign adipocytes. Small collections of benign sweat glands were present at the periphery of the tumor. CONCLUSION: This predominantly lipomatous ovarian tumor likely represents a fat-rich solid teratoma.

Primary retroperitoneal mucinous cystadenocarcinoma of low malignant potential: a case report and literature review.

A case of primary retroperitoneal mucinous cystadenocarcinoma of low malignant potential in the presence of normal ovaries is reported. The precise etiology of these neoplasms has not been defined; however, they may arise from heterotopic ovarian tissue, monodermal teratomas, embryonal urogenital remnants, intestinal duplication, or coelomic metaplasia. Although minimal data exist to define the appropriate management, it seems reasonable to extrapolate from the treatment of analogous ovarian neoplasms.

Duodenal trichobezoar caused by compression of the superior mesenteric artery.

Trichobezoars can occur in young women who have a history of trichotillomania, trichophagia, gastric dysmotility, and psychiatric dysfunction. A 6-year-old anorexic girl presented with a fixed right-upper-quadrant abdominal mass. Exploratory celiotomy for a duodenal trichobezoar led to removal of the large foreign body, via a duodenotomy, and prompted a Ladd procedure, in which the duodenum was moved from beneath the compressing superior mesenteric artery to relieve underlying duodenal narrowing.

Expression of connexin-43 in human myometrium and leiomyoma.

OBJECTIVES: The expression of connexin-43 was examined in human leiomyomas and in autologous myometrium. STUDY DESIGN: Indirect immunofluorescence was used to detect connexin-43 gap junctions in myometrial and leiomyoma tissues and in primary cultures. Immunoblot and Northern analyses were used to examine the levels of connexin-43 protein and cx43 messenger ribonucleic acid in primary cultures. RESULTS: Connexin-43 gap junctions were detected in leiomyoma tissue from nonpregnant premenopausal women but not in autologous myometrial tissue. Connexin-43 gap junctions form spontaneously in primary cultures of myometrium and leiomyoma in the presence of 17 beta-estradiol. Fluorescent dye injection confirmed that the gap junctions were coupled in the primary cells. Connexin-43 protein and messenger ribonucleic acid levels generally were higher in leiomyoma cells compared with those of autologous myometrial cells. Steady-state levels of cx43 messenger ribonucleic acid decreased with addition of medroxyprogesterone acetate to the cultures. CONCLUSIONS: Differences in the levels of cx43 expression in leiomyoma and myometrial cells may reflect differences in responses to steroid hormones.

Leuprolide acetate depot decreases the number of nucleolar organizer regions in uterine leiomyomata.

Women with symptomatic uterine myomas were randomized to receive LA depot or placebo for 12 weeks before myomectomy. Silver staining nucleolar organizer regions (AgNORs) per nuclei were assessed in the tissue obtained at the time of myomectomy. Myoma tissue from women treated with LA depot before myomectomy had significantly fewer AgNORs per nuclei than myoma tissue obtained from women treated with placebo. Leuprolide acetate depot may reduce the number of proliferating cells in myomas.

Management of borderline tumors of the ovary.

We retrospectively reviewed the cases of 51 patients with borderline ovarian tumors seen over a 9-year period. Half of these tumors were manifested by abdominal distention and pain; the remainder were found incidentally at the time of surgery planned for other reasons. Overall survival is excellent, but proper surgical staging reveals that approximately 15% of patients have metastasis beyond the ovaries, most commonly to the omentum, peritoneum, and retroperitoneal lymph nodes.

Steroid hormone receptors in endometrial stromal sarcomas. A biochemical and immunohistochemical study.

Seven cases of endometrial stromal sarcoma (five low grade and two high grade) were analyzed immunohistochemically for the presence of estrogen and progesterone receptors. In four cases (three low grade and one high grade), these results were compared to biochemical findings. All low-grade endometrial stromal sarcomas were positive for progesterone receptors using immunohistochemical techniques. These results correlated well with biochemical evaluation of progesterone receptors. The high-grade endometrial stromal sarcomas were negative for progesterone and estrogen receptors by both methods. The advantages of immunohistochemical evaluation of steroid receptors have been well established in breast and endometrial carcinomas. This study demonstrates the usefulness of this technique in endometrial stromal sarcomas.

The clinical significance of thrombocytosis in women presenting with a pelvic mass.

OBJECTIVES: We attempted to determine the clinical usefulness of a preoperative platelet count for predicting malignancy in patients presenting with a pelvic mass. Additionally, in patients in whom a preoperative serum CA 125 level was also determined, the clinical usefulness was compared. STUDY DESIGN: A retrospective review of charts of 241 patients presenting with a pelvic mass was carried out. The patients were then divided by pathologic diagnosis into group 1, benign disease (n = 102), and group 2, invasive (n = 121) or borderline (n = 18) malignancies. Thrombocytosis (platelet count greater than 400,000/microliters) was present in 16% (n = 16) of patients in group 1 and in 56% (n = 78) of patients in group 2 (p less than 0.0001). Of the 241 patients, 130 also had preoperative serum CA 125 levels measured. Elevated values of serum CA 125 (greater than 35 U/ml) occurred in 14% (n = 8) of group 1 and in 81% (n = 60) of group 2 (p less than 0.0001). The chi 2 test was used to analyze results of data. RESULTS: Statistically significant differences in preoperative platelet count and serum CA 125 values were found between group 1 and group 2 patients. The specificity and positive predictive value for thrombocytosis (84% and 83%) compared well with those for serum CA 125 (86% and 88%). The combined use of the tests resulted in specificity of 96% and positive predictive value of 95%. CONCLUSIONS: Preoperative platelet count is a test that is rapidly available and easily obtained. The test results may be of value in planning the original management of women presenting with a pelvic mass.

Myositis ossificans with atypical clinical, radiographic, or pathologic findings: a review of 23 cases.

Myositis ossificans is a relatively rare, well-defined entity. The 23 cases sent for consultation to two of us (L.V.A. and A.N.) were reviewed. Clinical, radiologic, and microscopic information was reexamined, and special attention was given to features infrequently seen in typical myositis ossificans. Average age at presentation was 23 years, but 1 patient was younger than 2 years, and 2 were younger than 10 years. Due to the uncommon location of 15 lesions and an unusual presentation in 5, the correct diagnosis was not obvious in these cases. A history of trauma was elicited in 8 patients, denied by 7, and was not queried in the remainder. Radiologic studies raised the possibility of a malignant bone-forming tumor in at least three instances; myositis ossificans was originally diagnosed in 6 cases radiologically. In 8 cases, histologic evidence suggested malignancy, including osteosarcoma, either parosteal or extraosseous, in 6. Other diagnoses included epithelioid sarcoma and callus formation. Presentation of these variations from the norm highlights the importance of recognizing the evolution of a nonneoplastic fibro-osseous and cartilaginous entity in which conservative treatment is curative.

Nucleolar organizer regions in endometriosis, atypical endometriosis, and clear cell and endometrioid carcinomas.

Nucleolar Organizer Regions (NORs) code for ribosomal RNA and are thought to be an accurate representation of the percentage of cells in S-phase. NORs are associated with nonhistone nucleoproteins, which can be stained with silver (AgNORs). An increased number of AgNORs has been observed in many malignancies. AgNORs were counted in three groups of patients with endometriosis (Group I), atypical endometriosis (Group II), and clear cell or endometrioid carcinomas (Group III) to assess the malignant potential of atypical endometriosis. Each group consisted of 10 patients. Mean AgNOR counts were 5.83 (Group I), 7.68 (Group II), and 15.42 (Group III). The results were analyzed and were significantly different for all groups (P less than 0.05 for Groups I and II, P less than 0.02 for Groups II and III, and P less than 0.01 for Groups I and III). A critical AgNOR count of 8.20 was calculated utilizing AgNOR counts from Group I. Three of the four patients with AgNORs greater than 8.20 and atypical endometriosis developed a malignancy. AgNOR counts provide useful information, represent an inexpensive test which can be obtained from fixed tissue, and may aid in clinical management of patients with atypical endometriosis.

Human papillomavirus detection in adenocarcinoma of the anus.

Human papillomavirus (HPV) is associated with carcinoma of the cervix but not with carcinoma of the endometrium. HPV 16 is the type most commonly detected in squamous cell carcinomas from this site, whereas HPV 18 predominates in adenocarcinomas. We analyzed eight anal carcinomas for HPV DNA using the polymerase chain reaction and type-specific (open reading frame E6) primers for HPV 16, 18, 31, and 35. HPV DNA sequences were amplified in two of six anal adenocarcinomas and, in each case, the type was HPV 18. Sequences homologous to HPV 16 were amplified in each of two anal squamous cell carcinomas; one also contained HPV 18. No amplification was detected in any of seven adenocarcinomas of the rectum or colon or in three adenomatous polyps of the colon. It is concluded that HPV is associated with anal adenocarcinomas but not colorectal adenocarcinomas. The reason(s) why HPV is associated with adenocarcinoma of the anus and cervix but not with the rectum and endometrium, despite the close proximity, requires further study.

Sebaceous tumors arising in ovarian dermoid cysts.

The clinicopathologic features of five cases of sebaceous tumors arising in ovarian dermoid cysts and of three previously reported cases are reviewed. They occurred in women with an average age of 58 years and were classified as sebaceous adenoma (five cases), basal cell carcinoma with sebaceous differentiation (two cases), and sebaceous carcinoma (one case). Follow-up information was available for all cases. One patient with basal cell carcinoma with sebaceous differentiation had a pelvic recurrence 2 1/2 years after diagnosis. In no other case did the sebaceous tumor recur or metastasize during follow-up periods of 1 to 6 years. One patient died of a squamous cell carcinoma that arose in the same dermoid cyst as the sebaceous tumor. These tumors represent a rare form of monodermal neoplasia in dermoid cysts.