Stefanie Burghaus

A tumor-specific cellular environment at the brain invasion border of adamantinomatous craniopharyngiomas

Craniopharyngiomas (CP) are benign epithelial tumors of the sellar region and can be clinicopathologically distinguished into adamantinomatous (adaCP) and papillary (papCP) variants. Both subtypes are classified according to the World Health Organization grade I, but their irregular digitate brain infiltration makes any complete surgical resection difficult to obtain. Herein, we characterized the cellular interface between the tumor and the surrounding brain tissue in 48 CP (41 adaCP and seven papCP) compared to non-neuroepithelial tumors, i.e., 12 cavernous hemangiomas, 10 meningiomas, and 14 metastases using antibodies directed against glial fibrillary acid protein (GFAP), vimentin, nestin, microtubule-associated protein 2 (MAP2) splice variants, and tenascin-C. We identified a specific cell population characterized by the coexpression of nestin, MAP2, and GFAP within the invasion niche of the adamantinomatous subtype. This was especially prominent along the finger-like protrusions. A similar population of presumably astroglial precursors was not visible in other lesions under study, which characterize them as distinct histopathological feature of adaCP. Furthermore, the outer tumor cell layer of adaCP showed a distinct expression of MAP2, a novel finding helpful in the differential diagnosis of epithelial tumors in the sellar region. Our data support the hypothesis that adaCP, unlike other non-neuroepithelial tumors of the central nervous system, create a tumor-specific cellular environment at the tumor–brain junction. Whether this facilitates the characteristic infiltrative growth pattern or is the consequence of an activated Wnt signaling pathway, detectable in 90% of these tumors, will need further consideration.

Genetic Variants in the Genes of the Stress Hormone Signalling Pathway and Depressive Symptoms during and after Pregnancy

Purpose. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes of the stress hormone signaling pathway, specifically FKBP5, NR3C1, and CRHR1, are associated with depressive symptoms during and after pregnancy. Methods. The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health including the assessment of depressiveness. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of the pregnancy, visit 2 was shortly after birth, and visit 3 was 6–8 months after birth. Germline DNA was collected from 361 pregnant women. Nine SNPs in the above mentioned genes were genotyped. After construction of haplotypes for each gene, a multifactorial linear mixed model was performed to analyse the depression values over time. Results. EPDS values were within expected ranges and comparable to previously published studies. Neither did the depression scores differ for comparisons among haplotypes at fixed time points nor did the change over time differ among haplotypes for the examined genes. No haplotype showed significant associations with depressive symptoms severity during pregnancy or the postpartum period. Conclusion. The analysed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show an association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.

Tissue Remodeling and Nonendometrium-Like Menstrual Cycling Are Hallmarks of Peritoneal Endometriosis Lesions

We identified differentially expressed genes comparing peritoneal endometriosis lesions (n = 18), eutopic endometrium (n = 17), and peritoneum (n = 22) from the same patients with complete menstrual cycles using microarrays (54 675 probe sets) and immunohistochemistry. Peritoneal lesions and peritoneum demonstrated 3901 and 4973 significantly differentially expressed genes compared to eutopic endometrium, respectively. Peritoneal lesions significantly revealed no correlation with a specific menstrual cycle phase by gene expression and histopathology, exhibited low expressed proliferation genes, and constant levels of steroid hormone receptor genes. Tissue remodeling genes in cytoskeleton, smooth muscle contraction, cellular adhesion, tight junctions, and O-glycan biosynthesis were the most significant to lesions, including desmin and smooth muscle myosin heavy chain 11. Protein expression and location of desmin, alpha-actin, and h-caldesmon in peritoneal lesions discriminated between smooth muscle hyperplasia and metaplasia. Peritoneal lesions demonstrate no menstrual cycle phasing but constant steroid hormone receptor expression where a slow but steady growth is linked with tissue remodeling. Our study contributes to the molecular pathology of peritoneal endometriosis and will help to identify clinical targets for treatment and management.

Genetic risk factors for ovarian cancer and their role for endometriosis risk

OBJECTIVE Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions. METHODS In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray™ analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors. RESULTS rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis. CONCLUSIONS As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer.

Visual pain mapping in endometriosis

PurposeTo construct pain maps in order to describe the distribution of pelvic pain in a group of endometriosis patients and endometriosis-free patients, to assess the feasibility of this method.MethodsA total of 159 patients with pelvic pain who were scheduled for diagnostic laparoscopy.ResultsA total of 117 patients with and 42 patients without endometriosis were included. The pain distribution between these two patient groups appeared to differ in some peripheral anatomical structures. In the endometriosis patients, the pain was most frequently located in the rectouterine pouch.ConclusionsIn endometriosis patients, pain mapping to assess preoperative pain sensations relative to the anatomic location of endometriotic lesions is feasible. The pain provoked by vaginal examination is frequently perceived as median relative to the actual anatomic location of the endometriotic lesions. Several anatomic and neurophysiological factors may explain this phenomenon.

Inhibition of adhesion, proliferation, and invasion of primary endometriosis and endometrial stromal and ovarian carcinoma cells by a nonhyaluronan adhesion barrier gel.

Endometriosis is a chronic disease of women in the reproductive age, defined as endometrial cells growing outside of the uterine cavity and associated with relapses. Relapses are hypothesized to correlate with incomplete surgical excision or result from nonrandom implantation of new endometrial implants in adjacent peritoneum. Thus, surgical excision could lead to free endometriotic cells or tissue residues, which readhere, grow, and invade into recurrent lesions. Barrier agents are frequently used to prevent postoperative adhesions. We tested if the absorbable cell adhesion barrier gel Intercoat consisting of polyethylene oxide and sodium carboxymethyl cellulose could inhibit cellular adhesion, proliferation, and invasion of primary endometriosis and endometrial cells. Due to an association of endometriosis with ovarian carcinoma, we tested two ovarian carcinoma cell lines. Prior to cell seeding, a drop of the barrier gel was placed in cell culture wells in order to test inhibition of adherence and proliferation or coated over a polymerized collagen gel to assay for prevention of invasion. Results showed that the barrier gel significantly inhibited cell adherence, proliferation, and invasion of endometriosis and endometrial stromal cells as well as ovarian carcinoma cells in culture. Our findings could help to prevent local cell growth/invasion and possible consequent recurrences.

Virilizing Hilus Cell Tumor of the Ovary Associated With Efferent Ductules-like Metaplasia Within Paratubal Mesonephric Remnants.

To the Editor: Virilization associated with ovarian hilus cell tumors is a well-recognized phenomenon. We herein present a case where besides macroscopic virilization and hyperandrogenemia also histologic ‘‘virilization’’ was seen. A 72-yr-old woman presented with hirsutism, hypertrophy of the clitoris, and alopecia. Clinical examination revealed hyperandrogenemia (blood testosterone 12.41nmol/L; normal range <0.35–2.6nmol/L) and hypertension which was treated with spironolactone. Ultrasonographically, no discernible tumor causing the hyperandrogenemia was seen. As the symptoms persisted elective bilateral salpingo-oophorectomy was performed. Macroscopic examination of the specimen showed a 1.5-cm, brown tumor in the hilus of one of the ovaries. The fallopian tubes were unremarkable. Histologically, the ovarian tumor consisted of tightly packed large epithelioid cells with pink granular cytoplasm and a central nucleus with a prominent nucleolus (Fig. 1A). Only 1 mitotic figure in 10 high-power fields was noted, and neither infiltrative growth nor necrosis was seen. Diligent examination revealed no Reinke crystals. Immunohistochemistry showed strong expression of calretinin and inhibin (Fig. 1B) in the tumor cells. In addition, scattered identical cells were seen in the fimbrial mucosa of the fallopian tube and the ovarian hilus. A diagnosis of a hilus cell tumor of the ovary and hilar and extrahilar steroid cell hyperplasia was rendered. In the paratubal tissue/mesosalpinx prominent mesonephric remnants consisting of tubular structures with hyaline secretions, and a smooth muscle cuff were noted. Some of these structures merged with more ectatic tubules (Fig. 1C) which showed a clearcut basal cell layer supporting a layer of cuboidal ciliated cells closely resembling efferent ductules of the epididymis or ductus deferens (Fig. 1D). P63 immunohistochemistry confirmed the basal cell layer in these structures, whereas mesonephric remnants and tubal epithelium showed no basal cells (Fig. 1E). Interestingly, the epididymis-like structures as well as the tubal epithelium and mesonephric remnants and the fibrotic stroma showed strong nuclear expression of the androgen receptor (Fig. 1F). Closely adjacent to these structures the inhibin immunostain revealed scattered aggregates of steroid cells. In normal male embryology, development of the fetal testis is triggered by the SRY (sex-determining region y) and AMH (anti-Müllerian hormone) gene on the Y chromosome. Subsequently, proliferation and differentiation of the Wolffian/mesonephric duct is induced by testosterone produced by the fetal testis (1). The Wolffian duct then gives rise to the efferent ductules of the inner male genitalia. Mesonephric remnants represent inactive residues of the Wolffian duct and are often found incidentally in the paratubal tissue/mesosalpinx, within the ovarian hilus, and the cervix in females. Apparently, the hilus cell tumor of the ovary not only caused clinical signs of virilization but also caused the differentiation/metaplasia of the mesonephric remnants into efferent ductules-like structures. This finding suggests that the normally inactive mesonephric remnants can still be induced to proliferate into differentiated tissue in adult life under certain circumstances. To our knowledge, this is the first report of such a metaplasia observed in the context of a hilus cell tumor of the ovary and extrahilar steroid cell hyperplasia with hyperandrogenemia. Literature review revealed a report of ovarian prostatic tissue originating from hilar mesonephric rests in which epididymis-like structures are described. However, the figures in this report show ciliated epithelium without a basal cell layer, different from the findings in our case (2). Another study examined 51 cases of mesonephric hyperplasia of the uterine cervix and described epididymal/endometrioid metaplasia in some cases. However, a clearcut basal cell layer or ciliated cells cannot be discerned from the corresponding figure (3). The observation in this case with true efferent ductules-like metaplasia is the first case convincingly showing the typical epithelium with an immunohistochemically proven basal cell layer. These lesions might give rise to tumors with ductuli efferentes-like differentiation in the female genital tract.