Metastatic malignant peripheral nerve sheath tumor of the uterus and cervix: Diagnostic Challenges, prognostic determinants and treatment.

•MPNST is an uncommon sarcoma of the nerve sheath that is rarely found in the female reproductive tract.•Preoperative uterine mass imaging should include pelvic MRI and thorough evaluation of imaging by an expert pelvic MRI radiologist.•Metastatic MPNST has a poor prognosis and systemic treatment options lack efficacy.

Cervical cancer in a transgender man: lessons learnt to improve care.

We describe a case of rapid progression of cervical dysplasia to stage IVB cervical cancer in a previously healthy transgender young adult man on testosterone therapy. The cancer diagnosis came 7 months after routine pap smear showed low-grade dysplasia with high-risk human papillomavirus in preparation for gender-affirming hysterectomy/bilateral-salpingo-oophorectomy. After diagnosis, our patient faced unique challenges as a transgender man receiving gynecologic oncology care. This case highlights the challenges of and barriers to cervical cancer screening and treatment that transgender men confront. This case also considers whether gender-affirming testosterone therapy is associated with cervical cancer risk. We offer suggestions on how to improve cervical cancer screening and treatment for the transgender population.

Doubling down on the future of gynecologic oncology: The SGO future of the profession summit report.

The original vision of the field of gynecologic oncology was to establish a multidisciplinary approach to the management of patients with gynecologic cancers. Fifty years later, scientific advances have markedly changed the overall practice of gynecologic oncology, but the profession continues to struggle to define its value-financial and otherwise. These issues were examined in full at the Society of Gynecologic Oncology (SGO) Future of the Profession Summit and the purpose of this document is to summarize the discussion, share the group's perceived strengths, weaknesses, opportunities, and threats (SWOT) for gynecologic oncologists, further educate members and others within the patient care team about the unique role of gynecologic oncologists, and plan future steps in the short- and long- term to preserve the subspecialty's critical mission of providing comprehensive, longitudinal care for people with gynecologic cancers.

Splenic metastases - hematogenous disease or invasive peritoneal implants? Case reports of two patients.

BACKGROUND: Metastases from gastrointestinal and gynecologic malignancy may occur through lymphatic channels, through venules of the cancer or into the peritoneal space. The metastatic process involves lymphatic, hematogenous or transcoelomic dissemination. METHODS: Two patients with splenic metastases are presented. Their clinical course is presented in an attempt to identify the route of cancer dissemination to the spleen. Lymphatic, hematogenous, or transcoelomic patterns of cancer dissemination are possible. Transcoelomic cancer dissemination into the peritoneal space results in peritoneal metastases. RESULTS: In a woman with ovarian cancer peritoneal metastases, a large lesion within the parenchyma of the spleen was described. This disease was present at multiple other sites as peritoneal metastases but no hematogenous or lymphatic metastases. A second patient with mucinous appendiceal neoplasm with peritoneal metastases was studied. Hematogenous metastases from this malignancy is extremely rare and lymphatic metastases were not present at the time of right colon resection. After studying these two patients, our hypothesis is that splenic metastases result from transcoelomic dissemination to the splenic hilum or splenic notches with progression of disease into the parenchyma of the spleen. CONCLUSIONS: When oncologists are considering aggressive local-regional treatments for peritoneal metastases important patient management decisions are influenced by the presence versus absence of hematogenous metastases. We suggest that the presence of splenic metastases does not indicate systemic (hematogenous) or lymphatic metastatic process but an extension of peritoneal metastases at the hilum of the spleen or within splenic notches deep into the parenchyma of the spleen.

Proteomic analysis of ovarian cancer proximal fluids: validation of elevated peroxiredoxin 1 in patient peripheral circulation.

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy in the United States. Unfortunately, a validated protein biomarker-screening test to detect early stage disease from peripheral blood has not yet been developed. The present investigation assesses the ability to identify tumor relevant proteins from ovarian cancer proximal fluids, including tissue interstitial fluid (TIF) and corresponding ascites, from patients with papillary serous EOC and translates these findings to targeted blood-based immunoassays. METHODOLOGY/PRINCIPAL FINDINGS: Paired TIF and ascites collected from four papillary serous EOC patients at the time of surgery underwent immunodepletion, resolution by 1D gel electrophoresis and in-gel digestion for analysis by liquid chromatography-tandem mass spectrometry, which resulted in an aggregate identification of 569 and 171 proteins from TIF and ascites, respectively. Of these, peroxiredoxin I (PRDX1) was selected for validation in serum by ELISA and demonstrated to be present and significantly elevated (p = 0.0188) in 20 EOC patients with a mean level of 26.0 ng/mL (±9.27 SEM) as compared to 4.19 ng/mL (±2.58 SEM) from 16 patients with normal/benign ovarian pathology. CONCLUSIONS/SIGNIFICANCE: We have utilized a workflow for harvesting EOC-relevant proximal biofluids, including TIF and ascites, for proteomic analysis. Among the differentially abundant proteins identified from these proximal fluids, PRDX1 was demonstrated to be present in serum and shown by ELISA to be elevated by nearly 6-fold in papillary serous EOC patients relative to normal/benign patients. Our findings demonstrate the facile ability to discover potential EOC-relevant proteins in proximal fluids and confirm their presence in peripheral blood serum. In addition, our finding of elevated levels of PRDX1 in the serum of EOC patients versus normal/benign patients warrants further evaluation as a tumor specific biomarker for EOC.

Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells.

OBJECTIVES: Secretory leukocyte protease inhibitor (SLPI) is amplified in serous ovarian cancer. We have dissected its function, showing it is a survival factor for ovarian cancer and promotes tumorigenesis and paclitaxel-resistance. We hypothesized that the protease inhibitory function was responsible for modulating SLPI's invasive capacity. METHODS: Stable HEYA8 ovarian cancer transfectants expressing vector, wild type SLPI, and protease inhibitor null (F-)SLPI were examined in vitro and in xenografts. Invasion, enzyme activity, and MMP production and function assays were applied. SLPI and MMP immunoexpression was graded on tissue microarray and clinical samples. Statistical comparisons used unpaired t test and ANOVA, where appropriate. RESULTS: SLPI and F-SLPI cells caused greater parenchymal and peritoneal dissemination over control cells in xenografts and invasion assays (p<0.001). MMP-9 protease activity was increased in SLPI and F-SLPI cells over control. SLPI, but not F-SLPI, inhibited plasmin activity, necessary for MMP-9 activation and release, and inhibited activation of MMP-9. However, paradoxically, both induced quantitative MMP-9 transcription (p<0.05) and protein (p<0.008), yielding an increased net MMP-9 activity in the face of plasmin inhibition. SLPI and MMP-9 expression were strongly correlated in serous ovarian cancers (r(2)=0.986) and a set of ovarian cancers (p<0.02). SLPI expression was greater in serous than endometrioid ovarian cancers (p=0.04). CONCLUSIONS: SLPI stimulates ovarian cancer invasion, modulated in part by its serine protease inhibitory activity attenuating MMP-9 release. However, SLPI induction of MMP-9, independent of protease inhibition activity, is greater yielding a net pro-invasive behavior. These findings further support SLPI as a molecular target for ovarian cancer.

Novel surgical approaches for sampling the ovarian surface epithelium and proximal fluid proteome.

The pathogenesis of ovarian, fallopian tube, and peritoneal cancers has been difficult to elucidate despite intense effort. Recently, though, the care of women felt to be at high risk due to a strong family history of breast and/or ovarian cancer or a known germline BRCA1 or BRCA2 mutation has provided potential insight into the development of these malignancies. Risk-reducing surgical removal of the fallopian tubes and ovaries, called risk-reducing bilateral salpingo-oopherectomy (RRBSO), is commonly performed as a laparoscopic procedure to minimize recovery time. We describe here an optimized surgical sampling workflow for analyzing the proteomes of peritoneal, fallopian tube, and ovarian surface epithelial (OSE) specimens collected at the time of laparoscopic RRBSO, a technique which has not been described previously. This methodology presents a unique opportunity for closer examination of the proteomic alterations in the tissues at risk for malignant transformation in women with an inherited susceptibility to ovarian, fallopian tube, and peritoneal cancer development.

Overexpression of protease inhibitor-dead secretory leukocyte protease inhibitor causes more aggressive ovarian cancer in vitro and in vivo.

The alarm anti-protease secretory leukocyte protease inhibitor (SLPI) is frequently overexpressed in ovarian cancer cells and has been proposed for inclusion in biomarker panels but function remains unclear. We hypothesized that SLPI overexpression promotes ovarian cancer growth and survival. Low SLPI-expressing Hey-A8 ovarian cancer cells were engineered to produce functional (WT) or protease inhibitor-null (PI-) mutant SLPI; lack of PI activity was confirmed by enzymatic assay. WT/SLPI and PI- mutants stimulated significant proliferation and survival of Hey-A8 ovarian cancer cells under basal culture conditions (P < or = 0.02), in soft agar colony number and size (P < or = 0.05), and in anoikis resistance (P < or = 0.005). SLPI protected the ovarian cancer survival factor, progranulin (PRGN), and HEY-A8 cells from degradation and apoptosis due to neutrophil elastase. PI-/SLPI cells had greater protective activity than WT/SLPI cells. HEY-A8 murine xenografts revealed enhanced solid tumor formation, dissemination, and invasion in WT/SLPI and PI-/SLPI mutants. Increased proliferation was demonstrated by Ki-67 staining (P < or = 0.02). Increased secreted PRGN was seen in culture and was also observed by immunohistochemistry in the SLPI transfectant xenografts. This study describes a PI-independent function for SLPI in ovarian cancer growth and dissemination.