Uterine artery embolization with trisacryl gelatin microspheres in women treated for leiomyomas: a clinicopathologic analysis of alterations in gynecologic surgical specimens.

To characterize the histologic range of alterations due to uterine artery embolization with trisacryl gelatin microspheres in gynecologic specimens containing leiomyomas in detail, we report our clinicopathologic experience with 26 cases (longest postuterine artery embolization interval, 1.9 yr). Microspheres were observed in 85% of cases and could be seen up to 1.9 years after embolization. They were mainly present in leiomyomas and nonneoplastic myometrium but could be found in other nontargeted sites, such as the cervix, endometrium, ovaries, and fallopian tubes; however, infarction (present in 96% of cases) was confined to leiomyomas and did not involve other nonneoplastic tissues. The appearance of the infarcts was correlated with time after embolization, and coagulative necrosis/necrosis of indeterminate type was restricted to the early period after uterine artery embolization (before 10 wk postuterine artery embolization) whereas hyaline necrosis was seen predominantly in the late period (mostly after 10 wk, up to 1.9 yr). Of the 14 hysterectomy specimens with microspheres in extravascular spaces (almost all of which were in close proximity to the arteries), pseudoaneurysms were also focally present in 8 (57%) specimens. Microspheres were usually associated with mild inflammatory reactions, which persisted >1 year after embolization but did not become more severe over time. Morphologic and histochemical features of trisacryl gelatin microspheres were compared with other embolization agents, which can also be encountered in surgical specimens [polyvinyl alcohol (PVA) particles and PVA microspheres]. Trisacryl gelatin microspheres were negative with periodic acid-Schiff and orange-pink with Movat stains whereas PVA was positive with periodic acid-Schiff and black with Movat. Our study, the largest histologic analysis to date, confirms and extends the observations of earlier studies of trisacryl gelatin microspheres. In addition, we conclude that, as expected, the histologic appearance of microsphere-induced infarcts is a function of time, similar to healing of infarcts in nongynecologic sites. Pseudoaneurysms are a likely mechanism for the production of microspheres in extravascular spaces. Inflammation associated with microspheres can persist in gynecologic tissues but does not seem to result in the destruction of nontargeted sites. Finally, trisacryl gelatin microspheres can be distinguished from PVA particles and PVA microspheres based on a combination of morphologic features and histochemical stains.

Women with undiagnosed colorectal adenocarcinomas presenting with ovarian metastases: clinicopathologic features and comparison with women having known colorectal adenocarcinomas and ovarian involvement.

Recognition of an ovarian tumor as a metastasis from an undiagnosed primary gastrointestinal tract carcinoma can be difficult when specific symptoms referable to the primary tumor are lacking and the tumor simulates a primary ovarian neoplasm grossly and microscopically. Ovarian metastases of colorectal adenocarcinomas, in particular, continue to pose diagnostic challenges both clinically and pathologically. Clinicopathologic features of 20 cases of ovarian metastases from undiagnosed colorectal adenocarcinomas (U-CRAs) were compared with those of 22 cases having metastases from known colorectal adenocarcinomas (K-CRAs). Women with ovarian metastases from U-CRAs were significantly younger (mean age, 48 years; median, 47 years) than those with ovarian metastases from K-CRAs (mean, 61 years; median, 63 years) (P = 0.002), presented with clinical findings related to the ovarian metastases, often had elevated CA-125 levels, and lacked specific symptoms due to the colorectal carcinomas, which were diagnosed only at the time of intraoperative evaluation of the ovarian tumors. Mean/median ovarian tumor sizes (12.8/13.0 cm for U-CRAs; 14.1/15.8 cm for K-CRAs) and frequencies of bilaterality (45% for U-CRAs and 36% for K-CRAs) were not significantly different for the 2 groups; frequencies of clinically unilateral tumors of more than 10 cm were similar in both groups (30% for U-CRAs and 45% for KCRAs). Other features more commonly observed in ovarian metastases from U-CRAs included mucinous differentiation, extracellular mucin production, and some degree of cytokeratin 7 expression; endometrioid-like differentiation was more common in metastases from K-CRA, but a garland pattern of necrosis and the presence of a confluent glandular, rather than infiltrative, pattern of invasion were similarly common in both groups. In cases having ovarian metastases from U-CRA, the younger age of the women, uniform presentation as pelvic masses without symptoms referable to the bowel, elevated CA-125 levels, occasional presentation as a large clinically unilateral tumor, frequent mucinous differentiation, and frequent coexpression of cytokeratin 7 are features that can contribute to misclassification of these metastases as primary ovarian neoplasms.

Distinction of primary and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification.

Distinction of primary ovarian mucinous tumors from metastatic/secondary mucinous tumors involving the ovaries is often challenging, not only at the time of intraoperative assessment when requested for surgical management (staging decisions) but also for final pathologic diagnosis. Previous studies have shown that a simple algorithm using tumor size and laterality (bilateral tumors of any size, or unilateral tumor <10 cm=metastatic; unilateral tumor > or =10 cm=primary) can accurately classify a substantial majority of tumors. To assess the general utility of this algorithm for distinction of primary and secondary mucinous tumors in the ovary and address the occurrence of exceptions (large unilateral metastases), analysis of tumor size and laterality data was performed using 194 tumors (52 primary tumors and 142 metastases), with metastases subclassified by primary site [colorectum (46), appendix (28 low-grade tumors, 20 carcinomas), pancreaticobiliary tract (20), small intestine (3), stomach (5), and endocervix (20)]. Performance of the algorithm was evaluated using the originally proposed method and modified size criteria were analyzed to optimize tumor classification. The original algorithm correctly classified 84% of tumors overall, including 100% of primary ovarian tumors and 77% of all metastases (colorectal: 74%; appendiceal: 79% of low-grade tumors, 100% of carcinomas; pancreaticobiliary: 95%; small intestinal: 33%; gastric: 80%; endocervical: 55%). By adjusting the size criterion to 12 cm, performance of the algorithm was both maintained for primary ovarian tumors and improved for metastases, with correct classification of 86% of tumors overall, including 100% of primary tumors and 80% of metastases. Performance was optimized at 13 cm, with correct classification of 87% of tumors overall, including 98% of primary tumors and 82% of metastases (colorectal: 80%; appendiceal: 79% of low-grade tumors, 100% of carcinomas; pancreaticobiliary: 100%; small intestinal: 33%; gastric: 100%; endocervical: 70%). Of the more common metastases, metastatic colorectal and endocervical carcinomas provided the greatest number of exceptions, even when analyzed with the optimized size criterion. Recognition that metastatic colorectal carcinomas represent the most common metastases and have a greater tendency to violate the algorithm should prompt lowering of the threshold for suggesting the possibility of metastatic colorectal carcinoma for tumors displaying any microscopic features suggestive of that diagnosis, even when a history of primary colorectal carcinoma is lacking. Use of the algorithm is intended as an adjunct to the complete clinicopathologic evaluation that ideally should occur when problematic mucinous tumors in the ovary are encountered.

Estrogen receptor alpha and progesterone receptor expression in ovarian adult granulosa cell tumors and Sertoli-Leydig cell tumors.

The biologic role that estrogen receptor (ER) and progesterone receptor (PR) play in ovarian sex cord-stromal tumors is poorly understood. Furthermore, immunohistochemical data on these hormone receptors in this group of neoplasms are limited and conflicting, with many reports suggesting that expression of ERalpha and/or PR is either infrequent or present at low levels in granulosa and Sertoli cell tumors. Immunohistochemical staining for ERalpha and PR was performed in 69 ovarian sex cord-stromal tumors: 41 adult granulosa cell tumors and 28 Sertoli-Leydig cell tumors. Extent of expression was scored based on the percentage of positive cells: 0, 5% or less; 1+, 6% to 25%; 2+, 26% to 50%; 3+, 51% to 75%; and 4+, 76% to 100%. Estrogen receptor alpha and PR were frequently expressed in adult granulosa cell tumors (66% and 98%, respectively) and Sertoli-Leydig cell tumors (79% and 86%, respectively). Diffuse (3+ or 4+) expression of PR was more common in adult granulosa cell tumors (68% vs. 36%; P = 0.013), whereas diffuse (3+ or 4+) expression of ERalpha was more frequent in Sertoli-Leydig cell tumors (50% vs. 20%; P = 0.010). In cases positive for both markers, adult granulosa cell tumors exhibited a focal (1+ or 2+) ERalpha/diffuse (3+ or 4+) PR coordinate profile more commonly than Sertoli-Leydig cell tumors (52% vs. 18%; P = 0.02), whereas Sertoli-Leydig cell tumors displayed a diffuse (3+ or 4+) ERalpha/focal (1+ or 2+) PR profile more frequently than adult granulosa cell tumors (36% vs. 0%; P = 0.0007). We conclude that expression of hormone receptors (based only on frequency of immunostaining) does not allow for distinction from other tumors in the differential diagnosis that are known to be frequently positive for ERalpha and PR such as endometrioid neoplasms. Most adult granulosa cell tumors and Sertoli-Leydig cell tumors share overlapping patterns of expression of ERalpha and PR with each other, but a subset of cases in each tumor category exhibits unique ERalpha/PR immunoprofiles (eg, focal ERalpha/diffuse PR in adult granulosa cell tumors and diffuse ERalpha/focal PR in Sertoli-Leydig cell tumors). These patterns of expression of ERalpha and PR may aid our understanding of the biologic differences between granulosa and Sertoli cell tumors.

The role of cytoreductive surgery for colon cancer metastatic to the ovary.

OBJECTIVE: We sought to further elucidate the survival impact of cytoreductive surgery among patients with colon cancer metastatic to the ovary. METHODS: All women diagnosed with primary colon cancer metastatic to the ovary at a single institution from 1980 to 2005 were retrospectively identified. Survival analyses and comparisons were performed using Kaplan-Meier plots and the log rank test. RESULTS: A total of 39 patients with 40 cases of colon cancer metastatic to the ovary were identified. Patients with metastatic disease confined to the ovaries (n=11) had a median overall survival (OS) time of 61 months (range 15-120) compared to 17 months (range 0.5-73) for those with more extensive metastases (n=24) (p=0.0428). Patients undergoing optimal cytoreduction (residual < or =1 cm) had a median progression-free survival (PFS) of 11 months (range 0.5-120, n=26) compared to 2.5 months (range 0.5-12, n=9) for those receiving suboptimal cytoreduction (p=0.0001). Optimal cytoreduction was also associated with a significantly longer median OS (35 months, range 0.5-120) compared to suboptimal cytoreduction (median OS=7 months, range=0.5-17) (p<0.0001). The peri-operative mortality rate was 5%. Significant morbidity occurred in 10% of the cases. All major complications occurred in women with diffuse disease who underwent extensive cytoreductive surgery. CONCLUSIONS: The observation that optimal cytoreduction was associated with prolonged PFS and OS in both patients with localized ovarian and widespread metastases of colon cancer suggests a role for surgical management of metastatic colon cancer in women.

p16 expression in primary ovarian mucinous and endometrioid tumors and metastatic adenocarcinomas in the ovary: utility for identification of metastatic HPV-related endocervical adenocarcinomas.

Distinction of primary ovarian epithelial tumors from metastatic adenocarcinomas is challenging for tumors exhibiting mucinous, endometrioid, or mixed endometrioid/mucinous differentiation. Metastatic carcinomas with these types of differentiation can be derived from several sites, including the gastrointestinal tract and the uterus. Most endocervical adenocarcinomas exhibit mucinous and/or endometrioid differentiation; they infrequently metastasize to the ovaries but may simulate primary ovarian tumors [both atypical proliferative (borderline) and carcinoma]. Most are high-risk human papillomavirus (HPV)-related and demonstrate diffuse p16 over-expression due to complex molecular mechanisms by which high-risk HPV transforming proteins interact with cell cycle regulatory proteins. The performance of this expression pattern for identifying metastatic endocervical adenocarcinomas in the ovaries among primary ovarian tumors and other metastatic adenocarcinomas having mucinous and/or endometrioid/endometrioidlike differentiation has not been evaluated. Immunohistochemical expression of p16 was assessed in 195 tumors, including 98 primary ovarian tumors (51 mucinous, 47 endometrioid, and 4 mixed mucinous-endometrioid tumors), 93 metastatic adenocarcinomas of known primary sites (colorectum: 34, endocervix: 19, pancreaticobiliary tract: 17, appendix: 7, stomach: 5), 11 metastatic adenocarcinomas of unknown origin (7 established as noncervical), and 4 adenocarcinomas of uncertain (primary ovarian vs. metastatic) origin. The HPV status of the endocervical adenocarcinomas was determined by in situ hybridization and polymerase chain reaction (when in situ hybridization was negative). Expression was assessed based on the percentage of moderately to strongly positive cells, estimated to the nearest 10%. Mean and median expression values for HPV-positive endocervical adenocarcinomas (99%, 100%; range 90% to 100%) were substantially higher than those for primary ovarian mucinous (5%, 0%; range 0% to 70%) and endometrioid (20%, 10%; range 0% to 100%) tumors, HPV-unrelated endocervical adenocarcinomas (0%, 0%; range 0% to 60%), metastatic adenocarcinomas of unknown origin (11%, 0%; range 0% to 30%), and adenocarcinomas of uncertain (primary ovarian vs. metastatic) origin (40%, 35%; range 0% to 90%); only the 15 HPV-positive endocervical adenocarcinomas and 6 other tumors had values of 80% or greater. Diffuse (>75% positive tumor cells) moderate to strong p16 expression is a sensitive (100%) and specific (97%) marker for identifying HPV-related endocervical adenocarcinomas metastatic to the ovary among the primary ovarian tumors and metastatic adenocarcinomas from other sites that are in the differential diagnosis of ovarian tumors having mucinous and/or endometrioid/endometrioidlike differentiation. p16 is useful as part of a panel of immunohistochemical markers for distinguishing primary ovarian tumors from metastases and, when diffusely positive, can suggest the cervix as a potential primary site for metastatic adenocarcinomas of unknown origin.

Utero-ovarian anastomosis: histopathologic correlation after uterine artery embolization with or without ovarian artery embolization.

PURPOSE: To study utero-ovarian anastomosis at angiography and its histologic effect on patients who were treated with uterine artery embolization (UAE) with or without ovarian artery embolization (OAE) for symptomatic uterine leiomyomata. MATERIALS AND METHODS: Four hundred patients (mean age, 43.6 years +/- 6.34) underwent UAE at the authors' institution from June 1998 to May 2005. Eight of the 400 patients underwent hysterectomy with removal of at least one adnexae after UAE. Five patients received tris-acryl gelatin microspheres and three received polyvinyl alcohol particles. Two patients also underwent OAE with gelatin sponges. Specimens from 16 fallopian tubes and 12 ovaries were reviewed. Histologic slides were prepared and reviewed by two pathologists who were blinded to the angiographic findings. The presence of utero-ovarian anastomoses at angiography, the histologic features of adnexa, the presence of particles in the adnexa, and the size and location of the particles were studied. RESULTS: Utero-ovarian anastomosis was present at angiography in three of the eight patients (38%) and five of the 16 adnexa (31%). Particles were present within the fallopian tube or ovary in all patients who demonstrated utero-ovarian anastomoses at angiography. When utero-ovarian anastomoses were identified bilaterally, particles were found in both adnexae. In cases with particles in the adnexa, the adnexal tissues were histologically viable without evidence of ischemic changes or infarction. Particles were not present in the ovary of patients without utero-ovarian anastomosis at angiography. CONCLUSION: The angiographic finding of a utero-ovarian anastomosis during UAE appears to correlate with particle embolization in the fallopian tube or ovary. Histologically normal fallopian tubes and ovaries can be expected after UAE with microsphere particles with and without OAE with gelatin sponges.

Intraductal spread by metastatic islet cell tumor (well-differentiated pancreatic endocrine neoplasm) involving the breast of a child, mimicking a primary mammary carcinoma.

Metastases to the breast are rare, accounting for an estimated 1% to 2% of malignant breast neoplasms. The key histopathologic features supporting a metastasis to the breast have been stated to be the absence of elastosis, presence of a pushing border (circumscribed lesion), multiple satellite foci, lymphatic emboli, and, most importantly, the absence of an in situ carcinoma component. We report a unique case of a pancreatic islet cell tumor metastatic to the breast of an 18-year-old girl. Clinically, the patient was thought to have a mammary primary because on her initial biopsy, the metastasis grew within mammary ducts and colonized a complex sclerosing lesion, simulating an in situ component. However, review of slides from the prior pancreatic neoplasm, review of slides from the subsequent mastectomy, and use of immunohistochemistry allowed recognition of the lesion as a metastasis, which proved to be the first clinical manifestation of a systemic relapse. To our knowledge, this is the second case of islet cell tumor reported to metastasize to the breast, and the first report of a metastasis proven to have grown within existing ducts of the breast by immunohistochemistry.

Blocking immune evasion as a novel approach for prevention and treatment of herpes simplex virus infection.

Many microorganisms encode immune evasion molecules to escape host defenses. Herpes simplex virus type 1 glycoprotein gC is an immunoevasin that inhibits complement activation by binding complement C3b. gC is expressed on the virus envelope and infected cell surface, which makes gC potentially accessible to blocking antibodies. Mice passively immunized with gC monoclonal antibodies prior to infection were protected against herpes simplex virus challenge only if the gC antibodies blocked C3b binding. Mice treated 1 or 2 days postinfection with gC monoclonal antibodies that block C3b binding had less severe disease than control mice treated with nonimmune immunoglobulin G (IgG). Mice immunized with gC protein produced antibodies that blocked C3b binding to gC. Immunized mice were significantly protected against challenge by wild-type virus, but not against a gC mutant virus lacking the C3b binding domain, suggesting that protection was mediated by antibodies that target the gC immune evasion domain. IgG and complement from subjects immunized with an experimental herpes simplex virus glycoprotein gD vaccine neutralized far more mutant virus defective in immune evasion than wild-type virus, supporting the importance of immune evasion molecules in reducing vaccine potency. These results suggest that it is possible to block immune evasion domains on herpes simplex virus and that this approach has therapeutic potential and may enhance vaccine efficacy.