Use of Cetuximab in Combination with Cisplatin and Adjuvant Pelvic Radiation for Stage IIIB Vulvar Carcinoma.

Vulvar cancer is a rare carcinoma constituting only 4% of gynecologic malignancies and 0.6% of female cancers. Most chemotherapy regimens have been created from extrapolation from anal and cervical cancer research. Advanced stages have the worst prognosis and oftentimes invasive surgical procedures are needed to cure disease with high recurrence rates. Case. A 50 yo G2P2 presented for a 2 cm mass in her right labia. The patient underwent a partial radical vulvectomy and bilateral superficial and deep inguinal lymph node dissection. Bilateral inguinal lymph nodes were positive for residual disease. The patient underwent whole pelvic radiation with cisplatin as a radiosensitizer. The primary tumor was epidermal growth factor receptor (EGFR) positive and cetuximab, a monoclonal antibody to EGFR, was added. The patient underwent seven cycles of chemotherapy including cisplatin and cetuximab with adjuvant radiation therapy to the pelvis. She currently is without evidence of disease recurrence since completing treatment 4 years ago. Conclusion. One previous case report showed short-term palliative success of five months for recurrent, metastatic vulvar cancer. This case suggests that cetuximab could possibly be used in initial management of patients with advanced stages of vulvar cancer to improve prognosis.

Idiopathic CD4 lymphocytopenia manifesting as refractory genital dysplasia.

BACKGROUND: Idiopathic CD4 lymphocytopenia is an immunodeficiency disorder with low absolute CD4 T-lymphocyte count with no evidence of human immunodeficiency virus or other known cause. CASE: A 22-year-old woman presented with a high-grade Pap test result. Work-up demonstrated cervical intraepithelial neoplasia 3 and vaginal intraepithelial neoplasia 3 with extensive condyloma. She presented 6 months after her initial treatment with recurrent disease and was referred to the immunology department, where she was found to have profound lymphopenia. After further evaluation, idiopathic CD4 lymphocytopenia was diagnosed. CONCLUSION: Idiopathic CD4 lymphocytopenia is a rare acquired immunodeficiency. Although genital dysplasia is common in young women, this case demonstrates the importance of determining other etiologies of recurrent human papillomavirus infections and possible immunodeficiencies that may affect management and outcomes.

Gene expression analysis of early stage endometrial cancers reveals unique transcripts associated with grade and histology but not depth of invasion.

Endometrial cancer is the most common gynecologic malignancy in the United States but it remains poorly understood at the molecular level. This investigation was conducted to specifically assess whether gene expression changes underlie the clinical and pathologic factors traditionally used for determining treatment regimens in women with stage I endometrial cancer. These include the effect of tumor grade, depth of myometrial invasion and histotype. We utilized oligonucleotide microarrays to assess the transcript expression profile in epithelial glandular cells laser microdissected from 79 endometrioid and 12 serous stage I endometrial cancers with a heterogeneous distribution of grade and depth of myometrial invasion, along with 12 normal post-menopausal endometrial samples. Unsupervised multidimensional scaling analyses revealed that serous and endometrioid stage I cancers have similar transcript expression patterns when compared to normal controls where 900 transcripts were identified to be differentially expressed by at least fourfold (univariate t-test, p < 0.001) between the cancers and normal endometrium. This analysis also identified transcript expression differences between serous and endometrioid cancers and tumor grade, but no apparent differences were identified as a function of depth of myometrial invasion. Four genes were validated by quantitative PCR on an independent set of cancer and normal endometrium samples. These findings indicate that unique gene expression profiles are associated with histologic type and grade, but not myometrial invasion among early stage endometrial cancers. These data provide a comprehensive perspective on the molecular alterations associated with stage I endometrial cancer, particularly those subtypes that have the worst prognosis.

Transcript expression in endometrial cancers from Black and White patients.

OBJECTIVE: Previous studies suggest that differences in molecular features of endometrial cancers between racial groups may contribute to the poorer survival in Blacks. The objective of this investigation was to determine whether gene expression among endometrial cancers is different between Blacks and Whites. METHODS: Fresh frozen tumors from 25 Black patients were matched by stage, grade, and histology to endometrial cancer specimens from 25 White patients. Each case was macrodissected to produce specimens possessing a minimum of 75% cancer cellularity. A subset of 10 matched pairs was also prepared using laser microdissection (LMD) to produce specimens possessing a minimum of 95% cancer cells. Total RNA isolated from each sample was analyzed using the Affymetrix Human Genome U133 Plus 2.0 arrays. Data were analyzed using principal component analysis and binary class comparison analyses. RESULTS: Unsupervised analysis of the 50 endometrial cancers failed to identify global gene expression profiles unique to Black or White patients. In a subset analysis of 10 matched pairs from Blacks and Whites prepared using LMD and macrodissection, unsupervised analysis did not reveal a unique gene expression profile associated with race in either set, but associations were identified that relate to sample preparation technique, histology and stage. CONCLUSIONS: Our microarray data revealed no global gene expression differences and identified few individual gene differences between endometrial cancers from Blacks and Whites. More comprehensive methods of transcriptome analysis could uncover RNAs that may underpin the disparity of outcome or prevalence of endometrial cancers in Blacks and Whites.

The use of middle cerebral artery Doppler ultrasonography to guide delivery of a viable pregnancy complicated by metastatic gestational chroriocarinoma.

Background: Choriocarcinoma is a rare, aggressive subtype of gestational trophoblastic neoplasia. The diagnosis of metastatic choriocarcinoma in the setting of a viable intrauterine pregnancy is exceedingly rare and often associated with feto-maternal hemorrhage. Case: An otherwise healthy Gravida 1 Para 0 at 34 weeks gestational age presented with metastatic choriocarcinoma and a viable fetus. Measured Doppler peak systolic velocity of the middle cerebral artery was used to detect fetal anemia, thus optimising the timing of delivery. Conclusion: This is the first case report to our knowledge using Doppler ultrasonography to detect fetal anemia in an effort to guide delivery in a case of choriocarcinoma diagnosed during pregnancy. If choriocarcinoma is diagnosed during pregnancy, middle cerebral artery Doppler ultrasonography may serve as a critical tool to help detect anemia, allowing pregnancy prolongation to promote fetal maturity while screening for the development of feto-maternal hemorrhage.

Analysis of PSPHL as a Candidate Gene Influencing the Racial Disparity in Endometrial Cancer.

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. A well recognized disparity by race in both incidence and survival outcome exists for this cancer. Specifically Caucasians are about two times more likely to develop endometrial cancer than are African-Americans. However, African-American women are more likely to die from this disease than are Caucasians. The basis for this disparity remains unknown. Previous studies have identified differences in the types and frequencies of gene mutations among endometrial cancers from Caucasians and African-Americans suggesting that the tumors from these two groups might have differing underlying genetic defects. We performed a gene expression microarray study in an effort to identify differentially expressed transcripts between African-American and Caucasian women's endometrial cancers. Our gene expression screen identified a list of potential biomarkers that are differentially expressed between these two groups of cancers. Of these we identified a poorly characterized transcript with a region of homology to phospho serine phosphatase (PSPH) and designated phospho serine phosphatase like (PSPHL) as the most differentially over-expressed gene in cancers from African-Americans. We further clarified the nature of expressed transcripts. Northern blot analysis confirmed the message was limited to a transcript of under 1 kB. Sequence analysis of transcripts confirmed two alternate open reading frame (ORF) isoforms due to alternative splicing events. Splice specific primer sets confirmed both isoforms were differentially expressed in tissues from Caucasians and African-Americans. We further examined the expression in other tissues from women to include normal endometrium, normal and malignant ovary. In all cases PSPHL expression was more often present in tissues from African-Americans than Caucasians. Our data confirm the African-American based expression of the PSPHL transcript in endometrial cancer and also identify its expression in other tissues from African-Americans including ovary and ovarian cancer. PSPHL represents a candidate gene that might influence the observed racial disparity in endometrial and other cancers.

Proteomic analysis of stage I endometrial cancer tissue: identification of proteins associated with oxidative processes and inflammation.

OBJECTIVE: The present study aimed to identify differentially expressed proteins employing a high resolution mass spectrometry (MS)-based proteomic analysis of endometrial cancer cells harvested using laser microdissection. METHODS: A differential MS-based proteomic analysis was conducted from discrete epithelial cell populations gathered by laser microdissection from 91 pathologically reviewed stage I endometrial cancer tissue samples (79 endometrioid and 12 serous) and 10 samples of normal endometrium from postmenopausal women. Hierarchical cluster analysis of protein abundance levels derived from a spectral count analysis revealed a number of proteins whose expression levels were common as well as unique to both histologic types. An independent set of endometrial cancer specimens from 394 patients were used to externally validate the differential expression of select proteins. RESULTS: 209 differentially expressed proteins were identified in a comparison of stage I endometrial cancers and normal post-menopausal endometrium controls (Q<0.005). A number of differentially abundant proteins in stage I endometrial cancer were identified and independently validated by western blot and tissue microarray analyses. Multiple proteins identified with elevated abundance in stage I endometrial cancer are functionally associated with inflammation (annexins) and oxidative processes (peroxiredoxins). PRDX1 and ANXA2 were both confirmed as being overexpressed in stage I cancer compared to normal endometrium by independent TMA (Q=0.008 and Q=0.00002 respectively). CONCLUSIONS: These data provide the basis for further investigation of previously unrecognized novel pathways involved in early stage endometrial carcinogenesis and provide possible targets for prevention strategies that are inclusive of both endometrioid and serous histologic subtypes.

Race disparities between black and white women in the incidence, treatment, and prognosis of endometrial cancer.

BACKGROUND: Uterine cancer is the most common gynecologic malignancy in the United States, with an estimated 40,100 new cases and 7,470 deaths occurring in 2008. Although the incidence of endometrial cancer is lower among black women compared with white women, the proportion of cancer-related deaths among blacks is higher and has continued to rise over the past two decades. METHODS: The authors conducted a survey of recent literature published in the English language and have used these articles as the basis for this review. RESULTS: The etiology for the racial disparity among black women with endometrial cancer is multifactorial and may be the result of barriers that impede access to care, an increased incidence of comorbidities among black women, inequalities in surgical care, adjuvant chemotherapy and radiation treatment, and underlying biological differences associated with more aggressive tumors that often develop in black women. CONCLUSIONS: Black women with endometrial cancer have a poorer prognosis compared with white women. Factors that contribute to this racial disparity include later diagnosis, treatment disparities, comorbid conditions, and genetic differences in tumors. An improved understanding of the causative factors associated with racial disparities in endometrial cancer outcome is needed to facilitate efforts aimed at correcting this important health care problem and providing individualized care to those at highest risk for poor outcome.

Overexpression of folate binding protein is associated with shortened progression-free survival in uterine adenocarcinomas.

OBJECTIVES: Oligonucleotide array and tissue microarray analysis (TMA) by our group has revealed that folate binding protein (FOLR1) is overexpressed in some types of uterine cancer, particularly tumors with serous histology. Since FOLR1 overexpression is a frequent event in some types of endometrial carcinoma, we examined the relationship between FOLR1 overexpression and clinical and pathologic features to determine its prognostic relevance. METHODS: A tissue microarray (TMA) comprised of primary tumor specimens from 485 patients diagnosed with endometrial adenocarcinoma was used to identify cases characterized by FOLR1 overexpression. A proportional hazards model was used to evaluate the association of FOLR1 overexpression with progression-free survival while accounting for confounding influences. RESULTS: Overexpression of FOLR1 was observed in 50/292 (17%) cases and was seen more often in poorly differentiated cancers (22/90 [24%], p=0.051) and tumors with serous histology (16/32 [50%], p<0.001). A shorter progression-free survival was noted in patients with FOLR1 overexpression (log-rank p=0.016) that persisted when the data were limited to patients with stage III/IV disease (log-rank p=0.021) or serous tumors (log-rank p=0.020). Multivariate Cox regression analysis revealed that patients with FOLR1 overexpression had a shorter progression-free survival (H.R. 2.14; 95% CI 1.07-4.28) even when controlling for stage, grade, myometrial invasion and adjuvant chemotherapy. CONCLUSIONS: Our data show that FOLR1 overexpression is not only a biomarker associated with endometrial cancer, but it also appears to be a prognostic factor associated with adverse outcome. These findings suggest that FOLR1 may be an appealing target for biological therapies in some types of endometrial carcinomas.

Biopsy site selection during colposcopy and distribution of cervical intraepithelial neoplasia.

OBJECTIVE: To determine if sites selected for colposcopic biopsy and histologically proven cervical intraepithelial neoplasia are distributed randomly across the cervix. MATERIALS AND METHODS: Data were evaluated from all patients who visited the Walter Reed Army Medical Center Colposcopy Clinic during a 20-month period. chi analysis was performed to assess the randomness of distribution of biopsies and cervical intraepithelial neoplasia. RESULTS: In 303 patients, 479 biopsies were performed. The 11-, 12-, and 1-o'clock positions were selected for 190 of 479 (40%) of biopsies, whereas the 6- and 12-o'clock positions were chosen for 186 of 479 (39%) of biopsies (p < 0.0001). Of 479 specimens, 161 (34%) were diagnosed as low-grade and 57 (12%) were diagnosed as high-grade. The 6-, 11-, and 12-o'clock positions accounted for 32 of 57 (56%) high-grade biopsies (p < 0.0001). The 6- and 12-o'clock positions accounted for 61 of 161 (38%) low-grade biopsies (p < 0.0001). CONCLUSIONS: Loci selected for biopsy and histologically confirmed cervical intraepithelial neoplasia are not randomly distributed across the cervix. There is a predilection for the locations anterior and posterior to the cervical os.

Vaginal metastasis and thrombocytopenia from renal cell carcinoma.

BACKGROUND: Vaginal cancer represents approximately 1-2% of genital tract malignancies. Most cases represent metastasis from the cervix, endometrium, or colon. Metastasis of renal cell carcinoma to the vagina is extremely rare. CASE: A 58-year-old female presented with a bleeding vaginal lesion. Laboratory studies revealed severe thrombocytopenia, and radiological studies revealed a left renal mass; excision was consistent with metastatic renal cell carcinoma. A subsequent nephrectomy confirmed renal cell carcinoma. Postoperatively, the patient underwent immunotherapy and the thrombocytopenia resolved. CONCLUSION: We report the first case of metastatic renal cell carcinoma presenting as a vaginal metastasis with thrombocytopenia as a paraneoplastic manifestation. Renal cell carcinoma must be in the differential diagnosis of a clear cell neoplasm in a postmenopausal woman, particularly with systemic symptoms suggestive of a paraneoplastic syndrome.