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Introduction: We assessed the misdiagnosed prostate cancer in radical prostatectomy (RP) specimens and the associated parameters. Materials and methods: A total of 3,821 patients were treated by RP. A meticulous process to identify misdiagnosed PCa in the specimen was followed. This protocol included the review of biopsies, prostatic specimens after TURP and RP surgical specimens. The prostatic specimens were further sectioned. Immunohistochemistry was also performed. The clinical parameters of the cases that were confirmed to be pT0 stage were compared to 1,164 RP patients. Results: The incidence of pT0 was 0.7 % of the cases. Eighteen patients (Group A) were operated after TURP and 10 patients (Groups B) after transrectal ultrasound-guided biopsy of the prostate. Eleven (Group Ac) cases of Group A and seven (Group Bc) cases of Group B were confirmed to be pT0 cases. The re-examination of the slides and specimens revealed the presence of PCa in three cases. The remaining cases were detected by IHC. The comparison of Group Ac to the Group C (representative cohort, 1164 patients) showed that the pre-operative PSA value was significantly higher in the case of the Group C. The pre-operative Gleason, the percentage of biopsy cores for cancer and the length of cores containing cancer were observed to be significantly lower in the case of Group Bc in comparison with Group C. Conclusions: The meticulous search protocol in pT0 cases showed that 35.7 % of the specimens included undiagnosed PCa. This strengthens the need for further careful work-up of any RP specimen of stage pT0. [ABSTRACT FROM AUTHOR]

Abstract: Peritumoral desmoplastic stromal reaction (DSR) with myofibroblastic phenotype may be of prognostic impact in uterine cervical carcinoma. The present study evaluates the immunostaining (CD34 and smooth muscle actin; SMA) of 97 squamous cell cancers. Staining was scored as low/negative (<5% stroma positive), moderate (patchy/focal expression, 5%-50%), or high (diffuse expression throughout peritumoral stroma, >50%) and DSR as negative/weak and moderate/strong. The staining results were correlated to patient survival. Of the cases, 78.3% showed a decreased of CD34 (<5% stromal positivity) and 71.9% an increased SMA staining with more than 50% SMA positive stromal cells. Tumors representing moderate/strong DSR showed a significant decreased CD34 (P =.001) and an increased but not statistically significant SMA staining (P =0.345). Cases with low CD34 and high SMA staining showed reduced 5-year overall survival when compared to cases with high CD34 and low SMA positivity (59.9 vs 81.0%; P =0.025 and 64.6 vs 81.1%; P =0.243). Peritumoral stromal response in cervical carcinoma is immunohistochemically characterized by CD34low/SMAhigh and associated reduced overall survival. [Copyright &y& Elsevier]

Introduction: Targeted therapy with antibody-drug conjugates (ADCs) has achieved promising results in the treatment of different solid tumors. Sacituzumab-Govitecan (SG), a humanized anti-Trop2 monoclonal antibody linked with the cytotoxic topoisomerase I inhibitor SN-38, has been approved for the treatment of metastatic triple-negative breast cancer. The treatment approach with SG requires the expression of Trop2 within the tumor cells. Trop2 is overexpressed in many other cancer types, suggesting a broader therapeutic application beyond breast cancer to these ADCs. We explore expression of Trop2 vulvar squamous cell carcinomas (VSCCs) and how this relates to molecular classification. Methods: Immunohistochemical Trop2 expression was evaluated on diagnostic biopsies of VSCC using an immunoreactive score. Staining results were compared to the molecular subtype of VSCC. Results: Fifty-seven cases were included in the study. 63.2% of VSCC were p16−ve/p53abn (HPV-independent (p53abn)) molecular subtype, 29.8% p16+ve/p53wt (HPV-associated) and 1.4% p16−ve/p53wt (HPV-independent (p53wt)) tumors. All diagnostic biopsies (N = 57) showed at least a weak Trop2 expression. Moderate and strong expression was seen in 15/17 (88.2%) of the p16−ve/p53abn, 32/36 (88.8%) of the p16+ve/p53wt and 3/4 (75%) of the p16−ve/p53wt molecular subtype. Expression was significantly higher, as assessed by H score, in the HPV-associated VSCC, compared to HPV-independent. Conclusion: VSCCs have high expression of Trop2 and represents a promising therapeutic target. Clinical trials exploring Trop2-directed ADCs such as SG are warranted in this rare cancer type, including in the prognostically poor HPV-independent VSCC with a TP53-mutation (p16−ve/p53abn molecular subtype). The targetable molecule, Trop2, can be easily assessed by immunohistochemistry on diagnostic biopsies from VSCC. [ABSTRACT FROM AUTHOR]

Wide tumour excision is currently the standard approach to surgical treatment of solid cancers including carcinomas of the lower genital tract. This strategy is based on the premise that tumours exhibit isotropic growth potential. We reviewed and analysed local tumour spreading patterns in 518 patients with cancer of the uterine cervix who underwent surgical tumour resection. Based on data obtained from pathological examination of the surgical specimen, we applied computational modelling techniques to simulate local tumour spread in order to identify parameters influencing preferred infiltration patterns and used area-proportional Euler diagrams to detect and confirm ordered patterns of tumour spread. Some anatomical structures, e.g. tissues of the urinary bladder, were significantly more likely to be infiltrated than other structures, e.g. the ureter and the rectum. Computational models assuming isotropic growth could not explain these infiltration patterns. Introducing ontogenetic distance of a tissue relative to the uterine cervix as a parameter led to accurate predictions of the clinically observed infiltration likelihoods. The clinical data indicates that successive infiltration likelihoods of ontogenetically distant tissues are nearly perfect subsets of ontogenetically closer tissues. The prevailing assumption of isotropic tumour extension has significant shortcomings in the case of cervical cancer. Rather, cervical cancer spread seems to follow ontogenetically defined trajectories. [ABSTRACT FROM AUTHOR]

Vulvar squamous cell carcinoma (VSCC) can be stratified into three molecular subtypes based on the immunoexpression of p16 and p53: HPV-independent p53-abnormal (p53abn) (most common, biologically aggressive), HPV-associated, with p16-overexpression (second most common, prognostically more favourable) and more recently recognised HPV-independent p53-wildtype (p53wt) (rarest subtype, prognostically intermediate). Our aim was to determine whether molecular subtypes can be reliably identified in pre-operative biopsies and whether these correspond to the subsequent vulvectomy specimen. Matched-paired pre-surgical biopsies and subsequent resection specimen of 57 patients with VSCC were analysed for the immunohistochemical expression of p16 and p53 by performing a three-tiered molecular subtyping to test the accuracy rate. Most cases 36/57 (63.2%) belonged to the HPV-independent (p53-abn) molecular subtype, followed by HPV-associated 17/57 (29.8%) and HPV-independent (p53wt) 4/57 (7.0%). The overall accuracy rate on biopsy was 91.2% (52/57): 97.3% for p53-abnormal, 94.1% for p16-overexpression and 50% for p16-neg/p53-wt VSCC. Incorrect interpretation of immunohistochemical p53 staining pattern was the reason for discordant results in molecular subtyping in all five cases. In one case there was an underestimation of p53 pattern (wildtype instead of abnormal/aberrant) and in one case an overestimation of the p53 staining pattern (abnormal/aberrant instead of wildtype). In 3/5 there was a "double positive" staining result (p16 overexpression and abnormal/aberrant p53 staining pattern). In that cases additional molecular workup is required for correct molecular subtyping, resulting in an overall need for molecular examination of 3/57 (3.5%). Compared to the final resections specimen, the three-tiered molecular classification of VSCC can be determined on pre-surgical biopsies with a high accuracy rate. This enables more precise surgical planning, prediction of the response to (chemo) radiation, selection of targeted therapies and planning of the optimal follow-up strategy for patients in the age of personalised medicine. • Vulvar squamous cell carcinoma (VSCC) can be categorised into three molecular subtypes based on p53 and p16 immunoexpression. • Subtypes: HPV-independent p53-abnormal (63.2%), followed by HPV-associated (29.8%) and HPV-independent/ p53wt (7.0%). • Overall accuracy rate of molecular subtype, determined on biopsy compared to surgical resection specimen was 91.2%. • Incorrect interpretation of p53 immunostaining pattern was the reason for discordant results in molecular subtyping. • Molecular subtypes can be reliably identified in preoperative biopsies and correspond to the subsequent vulvectomy specimen. [ABSTRACT FROM AUTHOR]

In cancer of the uterine cervix, the role of desmoplasia, i.e., peritumoral stromal remodeling characterized by fibroblast activation and increased extracellular matrix deposition, is not established. We conducted a retrospective cohort study based on data from 438 patients who had undergone surgical treatment for cervical cancer as part of the prospective Leipzig Mesometrial Resection study between 1999 and 2021. Using non-parametric tests, Kaplan–Meier plotting, and Cox regression modeling, we calculated the prognostic impact of desmoplasia and its association with other risk factors. Desmoplasia was present in 80.6% of cases and was associated with a higher frequency of lymphovascular space involvement (76.5 vs. 56.5%, p < 0.001) and venous infiltration (14.4 vs. 2.4%, p < 0.001). Lymph node metastasis (23.0 vs. 11.8%, p < 0.05) and parametrial involvement (47.3 vs. 17.6%, p < 0.0001) were also more common in patients with desmoplasia. The presence of desmoplasia was associated with inferior overall (80.2% vs. 94.5% hazard ratio [HR] 3.8 [95% CI 1.4–10.4], p = 0.002) and recurrence-free survival (75.3% vs. 87.3%, HR 2.3 [95% CI 1.2–4.6], p = 0.008). In addition, desmoplasia was associated with significantly less peritumoral inflammation (rho − 0.43, p < 0.0001). In summary, we link desmoplasia to a more aggressive phenotype of cervical cancer, reduced peritumoral inflammation, and inferior survival. [ABSTRACT FROM AUTHOR]

Cancer progression is caused by genetic changes and associated with various alterations in cell properties, which also affect a tumor's mechanical state. While an increased stiffness has been well known for long for solid tumors, it has limited prognostic power. It is hypothesized that cancer progression is accompanied by tissue fluidization, where portions of the tissue can change position across different length scales. Supported by tabletop magnetic resonance elastography (MRE) on stroma mimicking collagen gels and microscopic analysis of live cells inside patient derived tumor explants, an overview is provided of how cancer associated mechanisms, including cellular unjamming, proliferation, microenvironment composition, and remodeling can alter a tissue's fluidity and stiffness. In vivo, state‐of‐the‐art multifrequency MRE can distinguish tumors from their surrounding host tissue by their rheological fingerprints. Most importantly, a meta‐analysis on the currently available clinical studies is conducted and universal trends are identified. The results and conclusions are condensed into a gedankenexperiment about how a tumor can grow and eventually metastasize into its environment from a physics perspective to deduce corresponding mechanical properties. Based on stiffness, fluidity, spatial heterogeneity, and texture of the tumor front a roadmap for a prognosis of a tumor's aggressiveness and metastatic potential is presented. [ABSTRACT FROM AUTHOR]

Abstract: The invasion front pattern of squamous cell carcinoma (SCC) is a conspicuous histological phenomenon, which is assessed without precise criteria. The current study was performed to introduce the classical (C C ) and discrete compactness (C D ) as new morphometric parameters for quantification of this pattern. A retrospective analysis of 76 surgically treated patients with cervical carcinoma was conducted and the pattern of invasion was qualitatively classified as closed, finger-like or diffuse, respectively, by two pathologists. After digitization of the histological slides with a field of view of 10.4mm×8.3mm, tumor areas were labeled and C C and C D were computed based on the drawings (binary images). Additionally, intraindividual variation of compactness was evaluated for 12 selected tumors. The qualitative pattern assessment by the pathologists was moderately reproducible with an interobserver agreement of 72% and a κ coefficient of 0.44. The values of C C and C D referring to the invasion front patterns assigned by both pathologists were significantly different between the three classified groups (p ≤0.01 and p ≤0.0001), so that, both theoretically and in practice, compactness regards the same morphological feature. In due consideration of the analysis of the area under the ROC (receiver operating characteristic) curves and the variation coefficient of different tumor regions, C D is more suitable for practical use than C C . Tumors with a microscopic invasion into the parametria and with lymph-vascular space invasion were found to have a lower value of C D , which indicates a more diffuse pattern of invasion (p =0.028 and p =0.033). We conclude that the discrete compactness C D is a new and reproducible parameter for a computer assisted quantification of the invasion front pattern and, thus, defines a further phenotypic feature of SCC of the uterine cervix. [Copyright &y& Elsevier]

Abstract: Objectives : The aim of this study was to investigate the expression of the proapoptotic protein Apaf-1 in cervical cancers. Moreover, we studied its correlation to intratumoral pO2 and to clinico-pathological parameters. Methods : 86 patients with cervical cancer were subjected to intratumoral pO2 measurement with the Eppendorf electrode. From these patients, cervical cancer tissue was used for immunohistochemistry with an anti-Apaf-1 antibody. Results : Apaf-1 is expressed in cervical cancer. Cervical cancers with strong or moderate Apaf-1 expression had significantly less lymph node metastases at time of surgery than tumors with weak or negative Apaf-1 expression (P = 0.022). There was no significant correlation between Apaf-1 expression and intratumoral pO2, pT stage, FIGO stage, lymphovascular space involvement, and grade. Conclusions : Loss of Apaf-1 expression may represent a marker of aggressive tumor behavior since it correlates significantly with the occurrence of lymph node metastasis in cervical cancer. [Copyright &y& Elsevier]

Simple Summary: All initial therapeutic decisions in early breast cancer are commonly based on the intrinsic subtype consisting of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, breast cancer is a very heterogeneous disease, and receptor expression is reported to change during progression. Little is known about receptor changes at the primary site. In a German single center study, we retrospectively analyzed a mostly therapy naive cohort of 215 primary breast cancer patients with axillary synchronous lymph node metastases (LNM). We compared core needle biopsy tissue of the primary tumor (t-CNB) to axillary LNM and detected receptor discordance for all three receptors at the primary site. In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment. [ABSTRACT FROM AUTHOR]

Purpose: Accurate disease classification is fundamental for the selection of the treatment approach, prognostication, selection of clinical trials and for research purposes in routine clinical practice. Extrauterine high-grade serous carcinoma (HG-SC) may arise from the ovary, the fallopian tube and rarely from the peritoneal surface epithelium. Regardless of its origin, the vast majority of patients with HG-SC share clinical symptoms, present with advanced stage disease and suffer from a poor prognosis. Recent data suggest that there is an increasing incidence of HG-SC arising from the fallopian tube. Methods: Data from the Clinical Cancer Registry of Leipzig of surgically treated non-uterine pelvic carcinomas were analyzed regarding their sites of origin. Depending on the histology, cases were separated into high-grade serous and non-high-grade serous tumors. Based on different approaches in the assessment of the site of origin, three distinct time periods were defined. The frequency of the specific sites of origin was compared to the different time periods and histologic subtypes. Results: The majority of cases (57.9%; 279/482) were high-grade serous carcinomas, 42.1% of the cases presented with endometrioid, clear cell or mucinous histology. Overall, a 1.7-fold decrease of carcinomas with ovarian origin, paralleled by a 10.3-fold increase of tubal carcinomas was noted between 2000 and 2019. Based on the histopathological subtype, there was a 2.1-fold decrease of ovarian and a 7.1-fold increase of tubal carcinomas in patients with HG-SC. In non-high-grade serous tumors, the frequency of the different sites of origin did not change. 83.7% of tumors with non-high-grade serous histology originated from the ovary, whereas 86.8% of the carcinomas with tubal origin were of high-grade serous histology. Conclusion: The present and published data of non-uterine pelvic cancers may suggest an increase of tubal and decrease of ovarian carcinomas. However, there is rising morphologic and molecular evidence that non-uterine HG-SC actually arise from the fallopian tubes via its precursor STIC instead of from the ovary. This evidence has had an impact on the handling and reporting of non-uterine surgical specimens and its definition of the site assessment. In conclusion, the increasing frequency of tubal carcinomas and the associated decrease in ovarian cancer appears to be due to the reclassification of tumors previously classified as ovarian and greater emphasis on examining the resection specimens of non-uterine pelvic carcinomas. [ABSTRACT FROM AUTHOR]

Mesonephric-like adenocarcinomas rarely occur in the uterus and the ovary. Benign mesonephric-like (ML) proliferations and hyperplasia have been described solely within the ovary. Pathogenetic data are very limited. We report a case with microscopic focus of benign ML-proliferation in association with mucinous cystadenoma in the ovary. The immunophenotype was distinct (mucinous tumor: focal weak nuclear positivity for PAX-8, CK 7, patchy cytoplasmic positivity for p16 and negativity for estrogen receptor, CD 10, TTF-1, p53 wildtype; mesonephric component: diffusely positive for PAX-8, CK 7, luminal CD 10, TTF-1, focal staining for estrogen receptor, patchy cytoplasmic for p16, p53 wildtype). On NGS-analysis there was clonal mutation of KRAS p.G12C. The data provide additional evidence for the concept of transdifferentiation (Müllerian tissue representing Wolffian/mesonephric features on histology and immunostaining) within the pathogenesis of mesonephric proliferation of the female genital tract and demonstrate the clonal relationship between these distinct morphologic components. [ABSTRACT FROM AUTHOR]

Background: Previous findings from our centre suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. We aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumour control without the need for adjuvant radiotherapy.Methods: We did the final clinical and histopathological evaluation of data from, the single-centre, observational, cohort study, the Leipzig School Mesometrial Resection Study. Patients of any age with stage IB1, IB2, IIA1, IIA2, or IIB cervical cancer (according to 2009 International Federation of Gynecology and Obstetrics [FIGO]) had total mesometrial resection or extended mesometrial resection and therapeutic lymph node dissection, done on the basis of ontogenetic cancer fields. We defined sentinel node, first-line, second-line, and third-line lymph node regions as progressive regional cancer fields. Primary outcomes were disease-specific survival and recurrence-free survival, and treatment-related morbidity (assessed with the Franco-Italian glossary). Applying Cox proportional hazard models, ontogenetic local (T) and regional (N) tumour staging was compared with pathological T and N staging. This trial is registered with the German Clinical Trials Register, number DRKS00015171.Findings: Between Oct 16, 1999, and June 27, 2017, 523 patients were treated per protocol and followed up for a median of 61·8 months (IQR 49·3-94·8). In 495 patients with cervical cancer treated with cancer field surgery, 5-year disease-specific survival was 89·4% (95% CI 86·5-92·4) and recurrence-free survival was 83·1% (79·7-86·6). In the per-protocol population of 523 patients, treatment-related morbidity comprised 112 (21%) grade 2 and 15 (3%) grade 3 complications. The most common moderate and severe treatment-related complications and sequelae were wound dehiscence (17 [3%]), hydronephrosis (17 [3%]), bowel obstruction (26 [5%]), and lymph oedema (33 [6%]). One patient (<1%), who received total mesometrial resection, died from postoperative brain infarction.Interpretation: Total or extended mesometrial resection with therapeutic lymph node dissection based on ontogenetic cancer fields results in good survival outcomes of patients with cervical cancer in our institution, but needs to be investigated further in multicentre trials.Funding: Leipzig School of Radical Pelvic Surgery, University of Leipzig Medical School, and the Gynecologic Oncology Research Foundation. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to compare Prostate Imaging Reporting and Data System (PI-RADS) versions v1 and v2 for the detection of prostate cancer (PCa) in multiparametric MRI (mpMRI) using whole-mount histological workup as reference standard.Material and Methods: MRI data of 40 patients with positive transrectal ultrasound-guided biopsy were analyzed retrospectively by two blinded readers (5 and 4 years' experience) with PI-RADS v1 and v2 for cancer-suspicious lesions. Prior to radical prostatectomy, patients had undergone IRB-approved mpMRI at 3 T according to PI-RADS recommendations: T2-weighted (T2w), diffusion-weighted (DWI) and dynamic contrast-enhanced (DCE) imaging. The reference standard was provided by whole-mount sections of the prostatectomy specimens. Versions v1 and v2 were compared with respect to sensitivity and positive predictive value (PPV) per lesion. Subgroups stratified by tumor location (peripheral vs. transition zone) and aggressiveness (high vs. low grade) were also analyzed. We also evaluated the concordance of the dominant MRI sequence in v2 (DWI or T2w) and the highest individual score under v1. Interobserver agreement for PI-RADS v1 and v2 was assessed by Cohen's kappa statistics.Results: Reader 1 (R1) described 66 and Reader 2 (R2) 72 MRI lesions. The average Gleason score of 58 PCa lesions was 6.5 (range: 6 = 3 + 3 to 8 = 4 + 4), most of them (65.5%) located in the peripheral zone. PI-RADS v2 showed a trend towards lower sensitivities, but differences were not significant for both readers: R1 72.4% (v1) vs. 63.8% (v2) (P = 0.426) and R2 77.6% (v1) vs. 69.0% (v2) (P = 0.402). The trends were more pronounced in the transition zone and for low-grade cancers but remained insignificant (p-values from 0.313 to 0.691). Likewise, the apparent PPV differences, overall as well as in each zone, were not significant. Agreement between high-score v1 and dominant v2 sequence was 48% for R1 and 53% for R2. Cohen's κ of PCa detection for two readers was 0.48 for both v1 and v2.Conclusion: Our findings indicate that the simplified, zone-specific approach of PI-RADS v2 (2015) for MRI assessment of prostate cancer may not necessarily be better than the original v1 criteria (2012). In specific cases, a strict interpretation of v2 criteria may even lead to false-negative findings. Therefore, the current PI-RADS criteria should be reconsidered, despite the low statistical evidence here. [ABSTRACT FROM AUTHOR]

Purpose: Successful embryo implantation into the endometrium depends on embryonic characteristics and proper endometrial development. Reproductive medicine often focuses on embryo quality, whereas reliable diagnostic tests for endometrial receptivity are still needed. We previously found that human chorionic gonadotropin (hCG), one of the earliest proteins secreted by the embryo, was also expressed by the luteal phase endometrium around the implantation window. Here, we tested our hypothesis of endometrial hCG as an implantation marker.Methods: Endometrial biopsies and serum samples were taken from patients undergoing routine infertility diagnostics. Correlations of immunohistochemically detected endometrial hCG expression with adequate endometrial secretory transformation, the infiltration of CD45-positive leukocytes, clinical diagnostic parameters, and endometrial thickness were analyzed.Results: A highly significant correlation between the endometrial score, as a measurement for regular secretory transformation, and the intensity of hCG staining was found. The invasion of CD45-positive leukocytes increased with progressing endometrial secretory transformation and rising endometrial hCG expression. In addition, serum progesterone concentrations correlated with hCG expression by the endometrial glands.Conclusions: Our results suggest endometrial hCG as a possible diagnostic parameter characterizing the endometrial secretory transformation and, thus, possibly also its implantation capability. [ABSTRACT FROM AUTHOR]

Background: The incidence of vulvar cancer is increasing, but surgical treatment-the current standard of care-often leads to unsatisfactory outcomes, especially in patients with node-positive disease. Preliminary results at our centre showed that locoregional spread of vulvar carcinoma occurs within tissue domains defined by stepwise embryonic and fetal development (ontogenetic cancer fields and associated lymph node regions). We propose that clinical translation of these insights into practice could improve outcomes of surgical treatment of vulvar cancer.Methods: We did a single-centre prospective trial at the University of Leipzig's Cancer Center. Eligible patients were aged 18 years or older, had ontogenetic stage 1-3b histologically proven primary carcinoma of the vulva, and had not undergone previous surgical or radiotherapy treatment for vulvar cancer or any other major perineal or pelvic disease. In view of staged morphogenesis of the vulva from the cloacal membrane endoderm at Carnegie stage 11 to adulthood, we defined the tissue domains of tumour spread according to the theory of ontogenetic cancer fields. On the basis of ontogenetic staging, patients were treated locally with partial, total, or extended vulvar field resection; regionally with therapeutic inguinopelvic lymph node dissection; and anatomical reconstruction without adjuvant radiotherapy. The primary endpoints were recurrence-free survival, disease-specific survival, and early postoperative complications. Analysis of tumour spread and early postoperative surgical complications was done by intention to treat (ie, all patients were included), whereas outcome analyses were done per protocol. This ongoing trial is registered with the German Clinical Trials Register, number DRKS00013358.Findings: Between March 1, 2009, and June 8, 2017, 97 consecutive patients were included in the study, of whom 94 were treated per protocol with vulvar field resection, therapeutic inguinopelvic lymph node dissection, and anatomical reconstruction without adjuvant radiotherapy. 46 patients had moderate or severe postoperative complications, especially infectious perineal and inguinal wound dehiscence. 3-year recurrence-free survival in all patients was 85·1% (95% CI 76·9-93·3), and 3-year disease-specific survival was 86·0% (78·2-93·8).Interpretation: Our results support the theory of ontogenetic cancer fields for vulvar carcinoma, accord with our previous findings in cervical cancer, and suggest the general applicability of the theory. Application of the concept of cancer field resection could improve outcomes in patients with vulvar carcinoma, but needs to be investigated further in multicentre randomised controlled trials.Funding: Leipzig School of Radical Pelvic Surgery and Gynecologic Oncology Research Foundation. [ABSTRACT FROM AUTHOR]

Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat’s cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent. [ABSTRACT FROM AUTHOR]