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PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

ObjectivesPoor survival of high-grade serous pelvic cancer is caused by a lack of effective screening measures. The detection of exfoliated cells from high-grade serous pelvic cancer, or precursor lesions, is a promising concept for earlier diagnosis. However, collecting those cells in the most efficient way while fulfilling all requirements for a screening approach is a challenge. We introduce a new catheter for uterine and tubal lavage (UtL) and the clinical evaluation of its performance.Methods/MaterialsIn study I, the clinical feasibility of the UtL using the new catheter was examined in 93 patients admitted for gynecologic surgery under general anesthesia. In study II, the safety of the UtL procedure was assessed. The pain during and after the UtL performed under local anesthesia was rated on a visual analog scale by 22 healthy women.ResultsIn study I, the UtL was carried out successfully in 92 (98.9%) of 93 cases by 16 different gynecologists. It was rated as easy to perform in 84.8% of patients but as rather difficult in cancer patients (odds ratio, 5.559; 95% confidence interval, 1.434–21.546; P = 0.007). For benign conditions, dilatation before UtL was associated with menopause status (odds ratio, 4.929; 95% confidence interval, 1.439–16.884; P = 0.016). In study II, the pain during UtL was rated with a median visual analog scale score of 1.6. During a period of 4 weeks after UtL, none of the participants had to use medication or developed symptoms requiring medical attention. The UtL took 6.5 minutes on average. The amount of extracted DNA was above the lower limit for a sensitive, deep-sequencing mutation analysis in all cases.ConclusionsOur studies demonstrate that the UtL, using the new catheter, is a safe, reliable, and well-tolerated procedure, which does not require elaborate training. Therefore, UtL fulfils all prerequisites to be used in a potential screening setting.

The aim of our study was to clarify whether the CD44 adhesion molecule as a cancer stem cell marker could also serve as a prognostic factor in patients with epithelial ovarian cancer (EOC). A retrospective study was performed on 87 patients with histologically verified EOC. Specimens of both primary tumour and implantation metastases were tested from 48 of them. CD44 expression was detected by immunohistochemistry. We looked for the cut-off levels of CD44 expression using the Cox regression model. We confirmed statistically significant prognostic factors for overall survival (OS) and disease-free interval (DFI) to be: stage of the disease, postoperative residual tumour and papillary serous histological type. We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%. CD44 was neither a prognostic factor of OS nor of DFI. IMPACT STATEMENT What is already known about this subject: Epithelial ovarian cancer is the second most common gynaecological cancer in developed countries. Despite great efforts devoted to ovarian cancer research during past decades, levels of patient mortality have changed very little. Cancer stem cells (CSCs) are subpopulations of cells with typical characteristics of stem cells - i.e. the ability to self-renew and differentiate in a variety of cell types. The main surface marker typical for CSCs is CD44. The aim of our study was to clarify whether the CD44 as a CSCs marker could serve as a prognostic factor in patients with epithelial ovarian cancer. Previous studies published on this topic revealed controversial results. The novelty of our study lies in looking for the cut-off using the Cox regression model.We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%, however, CD44 was neither a prognostic factor of overall survival nor of disease-free interval. We propose to investigate other markers including other CSCs as a prognostic factors or potential aims for targeted therapy in ovarian cancer.

Aim: To analyze the utility of HE4 assessment in preoperative management of patients with early-stage endometrial cancer for stratification into low-risk and high-risk groups. Patients and Methods: The following data were prospectively collected from patients operated for endometrial cancer from 05/2012 till 9/2016; age, HE4, CA125, expert ultrasound examination of the pelvis, histotype, grade, FIGO stage. Results: In total, 124 patients were enrolled. A cut-off of >= 113 pmol/l HE4 demonstrated 40.3% sensitivity and 83.9% specificity for detection of high-risk patients. Correlations of HE4 with age (p

Introduction/Background Poor survival of high-grade serous pelvic cancer (HGSC) is caused by a lack of effective screening measures. Uterine and tubal lavage (UtL) is the sampling technique for HGSC detection with the highest sensitivity ever reported. We combined UtL with the highest accuracy sequencing technology for TP53 mutations, Duplex Sequencing (DS) in order to develop a test potentially feasible for HGSC screening. Methodology In study I, the clinical feasibility of UtL using a new catheter was examined in 93 patients undergoing surgery for suspected HGSC. In study II, pain at UtL under local anesthesia was evaluated in 22 healthy women. In Study III, uterine lavages from 10 HGSC patients and 11 controls were subjected to DS to identify TP53 mutations. Results In study I, UtL was performed successfully in 92 (98.9%) of 93 cases by 16 gynecologists. In 84.8% of patients no cervical dilatation was required. For benign conditions, the need for dilatation was associated with menopause status (OR, 4.929; 95% CI, 1.439–16.884; P=0.016). In study II, pain during UtL was rated with a median VAS score of 1.6. During 4 weeks after UtL, no serious complications occurred. UtL took 6.5 minutes on average. The amount of extracted DNA was above the lower limit for sensitive, deep-sequencing mutation analysis in all cases. In study III, in 80% of all HGSC tumor-derived TP53 mutations in UtL samples were detected by DS. However, we detected low frequency TP53 mutations in nearly all samples tested. Mutations increased with age and shared the selection traits of clonal TP53 mutations commonly found in human tumors. However, tumor-derived TP53 mutations were present at frequencies at least 10-fold higher than background mutations. Conclusion The UtL concept fulfils all prerequisites to be used in a potential screening setting. Interpretation of DS results needs to consider TP53 biologic background mutations. Disclosure Philipp Harter COI: Honoraria: Astra Zeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab, MSD; Advisory Board: Astra Zeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, MSD/Merck; Research funding (Inst): Astra Zeneca, Roche, GSK, Boehringer Ingelheim, Medac, DFG, European Union, DKH, Tesaro, Genmab Rosana Risques COI: RAR shares equity in NanoString Technologies Inc. and is the principal investigator on an NIH SBIR subcontract research agreement with TwinStrand Biosciences Inc. Florian Heitz COI: Honoraria: AstraZeneca, Roche, Tesaro, Clovis; Advisory Board: Astra Zeneca, Roche, Tesaro, Clovis Christoph Grimm COI: Consultant: AstraZeneca, Celgene, MSD, PharmaMar, Roche, Tesaro, Vifor Pharma Speaker: Amgen, AstraZeneca, MSD, PharmaMar, Roche, Tesaro Direct research funding: Meda Pharma, Roche Diagnostics Ignace Vergote COI: CONSULTING = ADVISORY BOARD: Advaxis, Inc., Eisai Inc., MSD Belgium, Roche NV, Genmab, F. Hoffmann-La Roche Ltd, Pharmamar, Millennium Pharmaceuticals, Clovis Oncology Inc., AstraZeneca NV, Tesaro, Oncoinvent AS, Immunogen Inc, Sotio CONTRACTED RESEARCH (via KULeuven): Oncoinvent AS, Genmab GRANT = CORPORATE SPONSORED RESEARCH: Amgen, Roche, Stichting tegen Kanker Accomodations, travel Fabian Trillsch COI:Consultant: AstraZeneca, Roche, Tesaro Speaker/Travel Expenses: AstraZeneca, Medac, PharmaMar, Roche, Tesaro Paul Speisr: Share Holder OVARTEC GmbH.

Epithelial ovarian cancer (EOC) has the highest mortality among gynecological carcinomas. The lack of specific markers for prognostic determination of EOC progression hinders the search for novel effective therapies. The aim of the present study was (i) to explore differences in expressions of ATP-binding cassette (ABC) and solute carrier (SLC) transporter genes, genes associated with drug metabolism and cell cycle regulation between control ovarian tissues (n = 14), primary EOCs (n = 44) and intraperitoneal metastases (n = 29); (ii) to investigate associations of gene expression levels with prognosis of patients with intraperitoneal metastases. In all tissue samples, transcript levels of the above target genes were assessed using quantitative real-time PCR. Gene expression levels were compared between particular tissue types and evaluated with regard to progression-free survival (PFS) and drug-resistance status of patients with metastases. Gene expression of ABCA7 significantly increased and that of ESR2 decreased in the order control ovarian tissues - primary EOCs - metastases. High expressions of ABCA2/8/9/10, ABCB1, ABCC9, ABCG2, ATP7A, SLC16A14, and SOD3 genes were significantly associated with longer progression-free survival of patients. In intraperitoneal metastases, expression of all of these genes highly correlated and indicated prognostic profile. Transporters from the ABCA family, ABCG2, and ESR2 are involved mainly in lipid metabolism, membrane transport, and cell proliferation. These processes are thus probably the most important for EOC progression. Based on these results, we have proposed novel markers of ovarian carcinoma progression and metastatic spread which might be potentially useful as therapeutic targets. Their significance should be further explored on a larger independent set of patients.

To determine whether a subset of primary extramammary Paget disease (EMPD) may originate in anogenital mammary-like glands (AGMLG), the authors studied 181 specimens of EMPD, detailing alterations in AGMLG. The latter were identified in 33 specimens from 31 patients. All patients were women, ranging in age from 38 to 93 years (median, 65 y). In all cases, lesions involved the vulva and in 1 patient the perianal skin was affected. Histopathologically, AGMLG manifested changes identical to columnar cell change (CCC) (87.1%), usual ductal hyperplasia (22.6%), columnar cell hyperplasia (CCH) (9.7%), oxyphilic (apocrine) metaplasia (6.5%), and atypical duct hyperplasia (3.2%). Four cases (12.9%), in addition to intraepidermal carcinoma, harbored invasive carcinoma. In all 4 of these, AGMLG displayed a range of alterations including ductal carcinoma in situ, CCC, and CCH. Three further cases (9.7%) showed ductal carcinoma in situ without any definite invasive carcinoma. Colonization of AGMLG by neoplastic Paget cells was noted in 6 cases. As CCC and CCH may be encountered in normal AGMLG, these alterations are unlikely to play a significant role in the pathogenesis of the disease. However, by analogy with mammary Paget disease, rare cases of primary EMPD may originate in AGMLG with a subsequent upward migration of the neoplastic cells into the epidermis and possible later breach through the basal membrane. Usual ductal hyperplasia and atypical duct hyperplasia can then be regarded as earlier precursor lesions, linking both ends of the spectrum.

Background/Aim: The pro-angiogenic Cyr61 protein has been associated with tumorigenesis and cancer progression in different gynecological carcinomas. In this study, we evaluated the potential impact and clinical relevance of Cyr61 expression in patients with primary non-metastatic cervical cancer (CC). Patients and Methods: Cyr61 expression was assessed in tissue specimen of 48 patients with primary CC by immunohistochemical analysis. Expression levels were scored and correlated to clinico-pathological factors and outcome data. Results: High Cyr61 expression levels were present in 54.2% of CC tissues. Associations with histological grade (p=0.030), depth of tumor invasion (p=0.007) and GOG score (p=0.027) were observed. Patients who overexpressed Cyr61 displayed an increased death rate (30.8% vs. 18.2%) and a decreased 5-year-survival (76.9% vs. 86.4%). Conclusion: Our data indicate a potential functional impact of Cyr61 in development and the progression of CC. The definite tumor-relevant function (suppressive/promoting) of Cyr61 in CC and the prognostic relevance of Cyr61 overexpression has to be evaluated in larger cohorts.

Pigmented lesions in the anogenital area encompass a wide variety of disorders including squamous intraepithelial neoplasia. The authors sought to explore the mechanism(s) underlying clinically pigmented squamous intraepithelial neoplasia in the anogenital area. A light-microscopic and immunohistochemical study of 64 lesional specimens from 45 patients (32 women, 13 men; age range, 23-73 years) with pigmented lesions in the anogenital area was performed. Histopathologically, 63 (98%) specimens showed melanin incontinence into the superficial dermis beneath the dysplastic epithelium. A focal or total loss of basilar hyperpigmentation was detected in 30 (48%) and 13 (20%) of lesions, respectively. In 17 (27%) cases, absence of basal layer hyperpigmentation was accompanied by a subepithelial lichenoid infiltrate. Melanin within the upper part of dysplastic areas were seen in 63 cases (98%), whereas dendritic melanocytes colonization, mild in all but 1 specimen case, was observed in 53 (83%) cases. All cases proved to be the usual type of squamous intraepithelial neoplasia; no single case of the simplex (differentiated) variant was present. The main mechanisms of pigmented squamous intraepithelial neoplasia of the anogenital area include melanin incontinence and occurrence of melanin in dysplastic keratinocytes. Colonization of the dysplastic epithelium by dendritic melanocytes seems to contribute, but it is rarely a prominent feature.

Extramammary Paget disease (EMPD) is a rare neoplasm usually presenting in the anogenital area, most commonly in the vulva. Adnexal involvement in primary EMPD is a very common feature and serves as a pathway for carcinoma to spread into deeper tissue. The depth of carcinomatous spread along the appendages and the patterns of adnexal involvement were studied in 178 lesions from 146 patients with primary EMPD. Hair follicles and eccrine ducts were the adnexa most commonly affected by carcinoma cells. The maximal depth of involvement was 3.6 mm in this series. When planning topical therapy or developing novel local treatment modalities for EMPD, this potential for significant deep spread along adnexa should be taken into account.

Membrane transporters (such as ABCs, SLCs and ATPases) act in carcinogenesis and chemoresistance development, but their relevance for prognosis of epithelial ovarian cancer (EOC) remains poorly understood. We evaluated the gene expression profile of 39 ABC and 12 SLC transporters and three ATPases in EOC tissues and addressed their putative role in prognosis and clinical course of EOC patients. Relative gene expression in a set of primary EOC (n=57) and in control ovarian tissues (n=14) was estimated and compared with clinical data and survival of patients. Obtained data were validated in an independent set of patients (n=60). Six ABCs and SLC22A18 gene were significantly overexpressed in carcinomas when compared with controls, while expression of 12 ABCs, five SLCs, ATP7A and ATP11B was decreased. Expression of ABCA12, ABCC3, ABCC6, ABCD3, ABCG1 and SLC22A5 was higher in high grade serous carcinoma compared with other subtypes. ABCA2 gene expression significantly associated with EOC grade in both sets of patients. Notably, expression level of ABCA9, ABCA10, ABCC9 and SLC16A14 significantly associated with progression-free survival (PFS) of the disease in either pilot or validation sets. ABCG2 level associated with PFS in the pooled set of patients. In conclusion, ABCA2, ABCA9, ABCA10, ABCC9, ABCG2 and SLC16A14 present novel putative markers of EOC progression and together with the revealed relationship between ABCA12, ABCC3, ABCC6, ABCD3, ABCG1 and SLC22A5 expression, and high grade serous type of EOC should be further examined by larger follow-up study.

This study characterizes the clinicopathological spectrum of lymphoproliferations involving the breast nipple and/or areola. Morphologic, immunohistochemical, molecular-genetic, and clinical features of 58 specimens from 56 patients were analyzed. They were re-diagnosed as cutaneous lymphoid hyperplasia (CLH, n = 44); other benign lymphoid infiltrates (OBLI, n = 8); peripheral T-cell lymphoma, not otherwise specified (n = 1); cases with overlapping features of CLH and B-cell lymphoma (n = 3), one of them composed of spindle cells. Cutaneous lymphoid hyperplasia infiltrates were dense, composed mainly of B cells forming follicles with germinal centers (GC). Cutaneous lymphoid hyperplasia frequently showed features suggesting a malignancy as coalescing follicles with non-polarized germinal centers lacking mantle zones, and smudged infiltrates of lymphoid cells spreading into collagen (often as "Indian files"), smooth muscle, vessel walls, and nerve sheaths. Only two cutaneous lymphoid hyperplasias recurred; otherwise all patients are without disease (mean follow-up 62 months). Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in five, and of T-cell receptor gamma gene in two cutaneous lymphoid hyperplasias using polymerase chain reaction (PCR), but the patients fared well too. In 47% of cases Borrelia burgdorferi was detected by polymerase chain reaction and/or serology, of which one was monoclonal. We conclude that cutaneous lymphoid hyperplasia is the most common lymphoproliferation of the breast nipple, rarely recognized clinically, and often overdiagnosed histologically as lymphoma.

ObjectiveThe aim of this study was to clarify whether the evaluation of cell-cycle regulatory protein p27 can serve as a prognostic factor in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical carcinoma.Patients and MethodsA retrospective study was performed on 130 surgically treated patients with FIGO stage IB cervical carcinoma with at least a 5-year follow-up. The expression of p27 was investigated independently by 2 experienced pathologists using immunohistochemistry. The prognostic significance of established prognostic factors and p27 expression were analyzed using univariate and multivariate analyses.ResultsIn a univariate analysis, lymph node status, tumor diameter, Gynecologic Oncology Group (GOG) score, lymph vascular space invasion, and p27 expression were significant prognostic factors for overall survival (OS). We found a correlation between p27 expression and lymph node status, tumor diameter, invasion, and GOG score. The p27 expression was a statistically significant prognostic factor for OS in a univariate analysis (log-rank test, P = 0.03). In a multivariate analysis, only lymph node status and tumor diameter were statistically significant prognostic factors for OS.ConclusionsThis study demonstrated that a low p27 expression is associated with lymph node metastasis, deep stromal invasion, tumor diameter more than 20 mm, and high GOG score and had a prognostic influence on OS in a univariate analysis in a series of 130 women with FIGO stage IB cervical carcinoma. Lymph node status and the diameter of the tumor were the only statistically significant prognostic factors in multivariate analysis.

We present a case of multiple vulvar syringomas, some of which extended unusually deep into the dermis occasioning histopathologic resemblance to microcystic adnexal carcinoma. The pertinent literature is discussed.

Human Tra2-beta1, a member of the serine/arginine-rich splicing factors, is involved in C/A-dependent mRNA processing and regulation of gene expression. Since several genes involved in cervical carcinogenesis are alternatively spliced and contain C/A rich elements, we aimed to analyze hTra2-beta1 expression and subcellular localization in tumor tissue of women with cervical cancer and to determine its clinical significance.Retrospective study.Tertiary-care academic medical center.One hundred and five patients with cervical cancer and a mean follow up time of 73.1 months.Immunohistochemistry of paraffin-embedded tissues was performed and hTra2-beta1 expression was correlated with clinico-pathological variables including patient outcome.Cytoplasmic hTra2-beta1 protein expression was found in 20% of cases, while all tumors revealed nuclear immunoreactivity with strong expression in 54.3% of cases. There was a significant inverse correlation between nuclear and cytoplasmic protein expression, suggesting a potentially relevant shuttle process of hTra2-beta1 between both cellular compartments. Patients with weak expressing hTra2-beta1 tumors showed an improved survival with a tumor-related death rate of 8.3% compared to 23.7% in patients with moderate and high intranuclear hTra2-beta1 expression, respectively.Our data support the hypothesis of a biological relevance for hTra2-beta1 expression in cervical cancer. The observed shuttle process of this splicing factor with higher concentrations in the nucleus should have pronounced effects on the cellular function and tumor biology of the affected tumors, leading to the worse patient outcome.

Background: Cutaneous lymphomas co-expressing CD56 and CD30 are very rare. They share a clinicopathological overlap with natural killer- (NK)/T-cell lymphomas and anaplastic large-cell lymphomas (ALCLs), two entities with widely disparate clinical behavior. Methods: We present a case of an immunocompetent 57-year-old Caucasian woman with a rapidly growing, angiodestructive and neuroinvasive primary cutaneous ALCL (PCALCL). The neoplastic population of large anaplastic CD30+ and CD56+ T cells was masked by a massive admixture of histiocytes and neutrophils. The partially ulcerated and pus-secreting tumor involved the forehead and scalp and was assessed as clinical stage IAE. Results: After chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), the patient achieved a complete remission. Additionally, high-dose chemotherapy with autologous peripheral blood stem-cell transplantation was administered as a consolidation of complete remission, in which she has remained for 6 years. Conclusions: This is the first CD30+ and CD56+ primary skin lymphoma to be reported on the head. The presented case carries a remarkable combination of clinicopathological features of PCALCL and NK-/T-cell lymphoma.

Reported here are 18 cases of hidradenoma papilliferum with oxyphilic metaplasia. All patients were women ranging in age from 29 to 74 years. Each presented clinically with a small, solitary tumor in the anogenital region. Microscopically, in addition to classic histopathological features, in every case there was oxyphilic metaplasia of the constituent epithelial cells. This finding could be likened to apocrine metaplasia, a term used in breast pathology. Other histopathological findings observed in this series, analogous to benign breast disease, included sclerosing adenosis-like changes, atypical apocrine adenosis-like changes, changes corresponding to usual ductal epithelial hyperplasia, epitheliomatosis with a streaming growth pattern, lamprocyte-like changes, clear cell change of the myoepithelium, foamy histiocyte reaction, and stromal fibrosis. Immunohistochemistry inferred that in the majority of cases oxyphilic metaplasia resulted from more lysosomes, whereas numerous mitochondria were detected in only 3 cases. Using 2 different PCR methods we identified HPV in 4 of 15 cases of hidradenoma with oxyphilic metaplasia. In addition, HPV was detected in 3 of 16 conventional papillary hidradenomas used as a control group. The following HPV types were identified: 16, 31, 33, 53, and 56. The last type was found in 5 cases. More than one HPV type from a single lesion was seen in 5 cases. Our observations are consistent with previous publications noting similarities between tumors of the breast and sweat glands. Oxyphilic metaplasia, areas with solid growth, and changes simulating atypical apocrine adenosis are rare and poorly recognized in hidradenoma papilliferum and may cause diagnostic difficulties; in our cases several submitting pathologists suspected malignancy. A causal role for HPV in hidradenoma papilliferum cannot be confirmed from our results, as the detection rate is too low. The exact role of the HPV in etiology and pathogenesis of this neoplasm has yet to be determined.