Search

Predictive criteria to determine the absence of node metastases from thyroid specimens are scarce for sporadic medullary thyroid cancer. Histopathologic stratification of patients with unifocal sporadic medullary thyroid cancer ≤25 mm with ≥10 neck nodes at thyroidectomy to evaluate the suitability of desmoplasia (7 increments) and tumor capsule integrity (5 decrements) for intraoperative prediction of node metastasis in unifocal sporadic medullary thyroid cancer. Paraffin-embedded thyroid specimens were available for 139 eligible patients. Significant (P <.001) associations were found between increasing desmoplasia and decreasing tumor capsule integrity and nodal disease (from 0 to 79% and 0 to 62%); the number of node metastases (medians, from 0 to 3 and 0 to 2 nodes); and biochemical cure (from 100 to 36% and 100 to 58%). Desmoplasia (low–moderate to high, with fibrosis >10%) and breach of the tumor capsule (>3 extensions; 1 extension >3 mm in width; or diffuse growth without tumor capsule) yielded excellent sensitivity and negative predictive value (100%), with moderate specificity (57 and 48%) and positive predictive value (50 and 46%). In retrospect, node dissection proved unnecessary in 55 (57%) and 47 (48%) patients who harbored desmoplasia-negative and encapsulated tumors. When available frozen sections were histopathologically compared with matching paraffin-embedded thyroid tumor specimens, concordance was 98% (53 of 54 pairs): 1 of 7 upgrades changed the diagnosis to desmoplasia, whereas 1 of 3 downgrades shifted the diagnosis of tumor capsule breach from "present" to "absent." Patients with desmoplasia-negative encapsulated sporadic medullary thyroid cancer may forgo node dissection at specialist centers. [ABSTRACT FROM AUTHOR]

Borderline ovarian tumors (BOT) arise from cystadenomas and represent a transition step within the development of low-grade ovarian carcinomas (Type I tumors). That pathway mirrors the adenoma-to-carcinoma sequence known for colorectal cancer. It has been suggested that papillary tubal hyperplasia (PTH) and salpingoliths may be associated with the development of BOT. To evaluate the frequency of the presence of benign cystadenoma and its transition to BOT in a given patient as well as the presence of PTH and salpingoliths we re-valuated in 74 consecutive cases of BOT with different histologic types. The majority of cases represented serous-BOT (60.8%), followed by mucinous BOT (25.7%), other histologic types were rare. 86.5% showed an adenoma-BOT sequence, which was seen in all mucinous BOT but was missed in 15.6% of serous BOT. Two cases had salpingoliths without associated PTH. PTH was seen in four out of the 74 (5.4%) BOT and occurred only in cases with serous histology. The vast majority of BOT represent a transition from benign cystadenoma to BOT in cases with mucinous and serous histology. Salpingoliths are rarely seen in association with BOT and occurred exclusively in BOT with serous histology. PTH may represent a distinct lesion but is rarely seen in association with BOT, especially in those with non-serous histology. Further studies are needed to evaluate the frequency and pathogenetic association of PTH with BOT. [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]

Abstract: There is a suggested pathogenetic role of cyclooxygenase-2 (COX-2) in endometriosis via angiogenesis and proproliferative mechanisms. The aim of the study was to investigate the immunohistochemical COX-2 expression in different anatomical sites of endometriosis and its correlation to proliferative activity and periendometriotic vascularization. Sixty endometrioses from different sites (ovarian, uterine, and peritoneal) were evaluated immunohistochemically for COX-2 expression. Cyclooxygenase-2 staining of 75% or more of the cells was defined as COX-2 overexpression and used as cutoff. Proliferative activity was determined by performing Ki-67–labeling index. Periendometriotic vascularization was evaluated by determining microvessel density surrounding the endometriotic focus using CD-34–immunostaining. Cyclooxygenase-2 overexpression was significant more frequent in ovarian endometriosis, when compared with uterine and peritoneal localization (70.8% versus 41.7%; P = .027). There was no significant correlation between COX-2 overexpression and perifocal neovascularization (P = .49). Endometriotic lesions with COX-2 overexpression represented reduced proliferative activity (P = .055). Cyclooxygenase-2 is expressed in the majority of endometriosis, but differences exist within the frequency of overexpression at different anatomical sites of the endometriosis. Cyclooxygenase-2 inhibitors are of clinical interest as treatment options. [Copyright &y& Elsevier]

Summary: Background: Radical hysterectomy based on empirical surgical anatomy to achieve a wide tumour resection is currently applied to treat early cervical cancer. Total mesometrial resection (TMMR) removes the embryologically defined uterovaginal (Müllerian) compartment except its distal part. Non-Müllerian paracervical and paravaginal tissues may remain in situ despite their possible close proximity to the tumour. We propose that in patients with early cervical cancer, the resection of the Müllerian compartment will lead to maximum local tumour control with low morbidity. We also propose that the relatively high rate of pelvic failure after conventional radical hysterectomy, despite adjuvant radiation, might be a consequence of the incomplete removal of the Müllerian compartment. The aim of our study was to test these hypotheses. Methods: We did a prospective trial to assess the effectiveness of TMMR without adjuvant radiation in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB, IIA, and selected IIB cervical cancer. We also generated MRI-based pelvic relapse landscapes from patients who had experienced pelvic failure after conventional radical hysterectomy. Findings: 212 consecutive patients underwent TMMR without adjuvant radiation. 134 patients (63%) had high-risk histopathological factors. At a median follow-up of 41 months (5–110), three patients developed pelvic recurrences, two patients developed pelvic and distant recurrences, and five patients developed distant recurrences. Recurrence-free and overall 5-year survival probabilities were 94% (95% CI 91–98) and 96% (93–99), respectively. Treatment-related grade 2 morbidity was detected in 20 (9%) patients, the most common being vascular complications. Resection of the Müllerian compartment resulted in local tumour control irrespective of the metric extension of the resection margins. The pelvic topography of the peak relapse probability after conventional radical hysterectomy indicates an incomplete resection of the posterior subperitoneal and retroperitoneal extension of the Müllerian compartment. Interpretation: Resection of the embryologically defined uterovaginal compartment seems to be pivotal for pelvic control in patients with cervical cancer. TMMR without adjuvant radiation has great potential to improve the effectiveness of surgical treatment of early-stage cervical cancer. Funding: University of Leipzig, Leipzig, Germany. [Copyright &y& Elsevier]

Abstract: Endometrial cancer (EC) is the most common malignancy of the female genital tract in the western world. Conceptually, a dualistic model of endometrial carcinogenesis exists for sporadic EC, based on molecular findings with a good correlation to the morphologic phenotype and clinical behavior. Type 1 endometrial carcinoma represents an estrogen-related tumor, which usually arises in the setting of endometrial hyperplasia, has endometrioid histology with low grade, and tends to be biologically indolent. Grade 3 endometrioid cancers, which constitute a minority of EC, also behave aggressively. The type 2 cancers are not estrogen-driven and have a higher grade, various histologies, particularly serous carcinomas and clear-cell carcinomas, and a poorer prognosis. The diagnostic criteria of endometrial hyperplasia, endometrial in situ carcinoma, and of the different histologic types of EC, according to the most recent World Health Organization classification, are given in detail. In addition, the risk of progression of endometrial hyperplasia into endometrioid type EC and their treatment modalities are discussed. Endometrial pathologies in patients with breast cancer, receiving tamoxifen, and women affected by hereditary nonpolyposis colorectal cancer syndrome are described, including their pathogenetic aspects. Finally, a short practical description for the handling of surgical specimens from fractional curetting and hysterctomies is given. [Copyright &y& Elsevier]

Abstract: Objectives: There is a paucity of data on cyclooxygenase (COX)-2 expression in normal breast tissue and on the changes in COX-2 expression from normal tissue via ductal carcinoma in situ (DCIS) lesions to invasive cancer. The aim of this study, therefore, was to investigate COX-2 protein expression in normal breast tissue, DCIS, and invasive breast cancer in samples from the same patients. Methods: In 39 patients, we investigated and compared COX-2 expression in paired samples of invasive cancer and normal adjacent breast epithelium by immunohistochemistry with a monoclonal COX-2 antibody. Furthermore, in 29 of these cases, we also analyzed a concomitant DCIS lesion. Results: Patients without COX-2 expression in normal breast tissue also do not express COX-2 in invasive breast cancer and in DCIS lesions, respectively. Conversely, COX-2 expression in normal breast tissue was an indicator for COX-2 expression in the paired breast tumors. There was no significant correlation between COX-2 expression and pathologic tumor stage, nodal status, hormone receptor status, tumor size, grading, and lymphovascular space involvement. Conclusions: This is the largest study to date investigating COX-2 in paired samples of breast tumors and normal adjacent breast tissue. Our data are consistent with the hypothesis that COX-2 overexpression is an early event in breast carcinogenesis. [Copyright &y& Elsevier]

Abstract: Pathogenetically, endometrioid adenocarcinomas of the endometrium are associated with hyperestrogenism and serous papillary carcinomas with alterations of p53. The etiology of primary endometrial squamous cell carcinoma (ESCC), however, is speculative. The purpose of this study was to evaluate the role of p14, p16, p53, cyclin D1, steroid hormone receptors, and human papillomaviruses (HPV) infection in the pathogenesis of primary endometrial squamous cell carcinoma. The expression of p16, p14, p53, cyclin D1, and steroid hormone receptors (estrogen, progesterone, and androgen) was examined immunohistochemically in 8 primary ESCCs. HPV analysis was performed using general primers and HPV typing. The median age of the patients was 62.1 years. Four cases showed positive nuclear and cytoplasmic p16 staining in an insular pattern, and 1 case nuclear positivity for p53 and estrogen receptors, respectively. Four of 8 cases were positive for progesterone receptor analysis and cyclin D1. All cases were negative for p14 and androgen receptor staining. All but one case were negative for HPV analysis. Five patients were alive with and without evidence of disease after a mean follow-up of 6.1 years. The results of this study suggest that alterations of the p16 pathway may play an etiologic role in at least a proportion of the ESCC, but without any association to HPV infection. Factors known to play a pathogenetic role in types 1 and 2 of endometrial carcinomas are not associated with primary ESCC. However, prognostically, ESCCs are more related to type 1 cancers. [Copyright &y& Elsevier]

Abstract: Small cell neuroendocrine carcinomas sometimes represent a non–small cell component. Because of infection with the high-risk human papillomavirus of small cell carcinomas (SmCCs), several host cell regulatory proteins are altered, thus causing altered proliferative activity. Knowledge regarding the prognostic impact of focal neuroendocrine differentiation in mixed SmCCs and the value of proliferative activity in these tumors is very limited. Small cell carcinomas were selected for immunohistochemical staining with neuroendocrine markers and Ki-67. In cases with mixed tumors, the percentage of the SmCC component was calculated and correlated with survival. Of 677 tumors, 9 (1.3%) were classified as SmCCs after Grimelius staining (8/9 positive tumors) and immunohistochemical reaction against neuron-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD56 (8/9 positive tumors); all specimens were positive for at least 2 of these. CD99 staining was completely negative. Two thirds of the SmCCs showed non–small cell differentiation. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months). Even an SmCC component of 17% was associated with a fatal course. Small cell carcinoma represented a significantly lower proliferation (Ki-67 labeling index) than did the non–small cell component in the same tumor (12.8% vs 70.8%; P < .001). Even a small SmCC component in mixed carcinomas of the uterine cervix was associated with adverse outcome. Proliferative activity, determined by Ki-67 labeling index, is of no prognostic value. [Copyright &y& Elsevier]

Summary: Background: Macroscopic, microscopic, and occult local tumour spread might be restricted to a permissive territory related to the morphogenesis of the tissue or organ from which the tumour originates. We aimed to define such a morphogenetic unit in Müllerian development, and to assess the role of total mesometrial resection in the treatment of patients with stage IB–IIB cervical carcinoma. Methods: We analysed uterovaginal development in serial sections of female human embryos and fetuses, and defined the distal Müllerian morphogenetic unit from the Müllerian mesenchyme. We assessed prospectively the histopathological and clinical findings from patients who underwent total mesometrial resection—modified surgery for stage IB–IIB cervical carcinoma that aims to remove the uterus, proximal vagina, and extracervical mesenchyme within the borders of the distal Müllerian morphogenetic unit. Findings: The spatial extension of the Müllerian mesenchyme, its vascularisation, and its innervation during early uterovaginal organogenesis determine a tissue territory that can be followed during fetal development and identified in women as a morphogenetic unit. 105 of 106 patients who had total mesometrial resection, 63 of whom were classed as high risk, had microscopically tumour-free resection margins (ie, R0). 48 (96%) of 50 patients had pelvic recurrence-free survival at 3 years (95% CI 92–100) without adjuvant radiotherapy. Interpretation: Radical en-bloc resection of a topographically defined anatomical territory derived from common precursor tissue leads to local tumour control, preservation of autonomic nerves, and a reduced need for adjuvant radiotherapy. [Copyright &y& Elsevier]

Objective: Evaluation of causes of death in stillborn infants. Methods: During a five-year period, 310 consecutive autopsies of stillborn infants were performed using a standardized protocol with systematic examination of all major cranial, thoracic and abdominal organs including microscopic examination. Results: In 71%, the intrauterine death (ID) occurred up to the end of the 37th week of gestation. Thirty-seven percent (115/310) stillbirths represented with maceration and about one-half with minor or major malformations. Thirty-one percent (53/171) of them were responsible for intrauterine death. In 83% (44/53), the intrauterine death of the malformed fetus occurred before the end of 37th week of gestation, most of them (48/53, 90.6%) were small for gestational age infants. In 75.5% (234/310), the placental villous tree and the umbilical cord represented pathologic conditions. In 191cases (61.1%), utero-placental pathology was responsible for intrauterine death. Intrauterine infections and traumatic lesions were accompanied by intrauterine death in 2.2 and 1.3%, respectively. In 15.2%, unexplained intrauterine death (because of severe maceration, the placenta was not available for autopsy or insufficient clinical data) occurred. Conclusions: Perinatal autopsy may be valuable in three ways: the confirmation of ante-mortem diagnoses; the identification of unexpected disorders; and exclusion of other (perhaps inheritable) conditions which might be have caused the intrauterine death. Clinically valuable information, obtained from the autopsy, can be improved by high autopsy rate and performing perinatal necropsies by specially trained pathologists. [Copyright &y& Elsevier]

Objectives: Several cancers show the tendency to aggregate in families. But the contribution of heredity to the causation of sporadic malignancies, like cervical cancer is unclear. Study Design: Seven hundred and thirty-seven women with operative treated cervical cancer (CX) were searched for familiar history of malignant tumours. Positive familial history was stated, if one first degree relative was affected by malignant tumour. The site of malignant tumour was stated and the mean age was compared. Results: Twenty-two percent of the women had malignancies at different sites in first degree relatives. In about one-half the mother, in 30% the father and in 11% more than one first degree relative was affected. Overall, first degree relatives of 21 patients (13%) had malignancies of the lungs or the oro-pharynx. Thirty-seven women had malignant tumours of the lower genital tract and 11 had invasive cervical cancer. Mean age of patients with positive familial history was the same as those without (43 versus 42 years) it. But, women whose first degree female relatives had cervical cancer were significantly younger than those with extragenital malignancies (37 versus 45 years). The mean 5-year survival rate was higher in patients with a positive familial cancer history (85.6% versus 74.6%; P=1.7). Conclusions: The data suggest, that a small number of patients have a familial susceptibility for cervical cancer and probably for HPV-associated neoplasms. Further studies establishing the immune status and the search for genetic polymorphisms of these patients are required. [Copyright &y& Elsevier]

Abstract: The pathogenesis of mixed endometrial adenocarcinoma with trophoblastic differentiation is quite unclear at times. The present study examines a serous carcinoma with choriocarcinomatous differentiation. p53 staining was seen in the serous component and the cytotrophoblastic cells of the choriocarcinomatous component, but not in the syncytiotrophoblastic cells. p53 mutational analysis showed a heterozygotic mutation at exon 8 for the choriocarcinomatous component and a homozygote deletion at exon 7 for the serous component. These alterations suggest that the multidirectional tumor differentiation might occur from a common stem cell in these malignancies. [Copyright &y& Elsevier]

Abstract: A complementary tool to gene-based arrays are tissue microarrays, which allow the validation of DNA/RNA-derived profiling results on the protein level and offer the possibility of exact location within the tissue structures. Here we describe the technical details of the application of tissue microarray in placental research. Although the placenta represents a very inhomogeneous organ, this technique is also usable in placental research. [Copyright &y& Elsevier]

Summary: Background: Our previous work provided evidence that early cervical cancer is locally confined to the Müllerian compartment that develops in women from the embryonic paramesonephric-mesonephric complex. We aimed to investigate if the concept of tumour permeation within ontogenetic domains is also valid for tumour progression and advanced disease. Methods: Starting from Carnegie stage 13, four successive steps in the organogenesis of the human uterine cervix were defined and an ontogenetic staging system for cervical cancer based on organ development was described. Histopathological and clinical data of patients with cervical cancer FIGO stages IB–IVA were raised prospectively from Oct 16, 1999, until Dec 20, 2012, and from March 8, 2000, until April 4, 2013, for two surgical trials of ontogenetic compartment resection without adjuvant radiation at the University of Leipzig (total or extended mesometrial resection [TMMR or EMMR]; and [laterally] extended endopelvic resection [LEER]). The primary endpoints of these trials were pathological resection state and locoregional tumour control. Patients who underwent TMMR and EMMR had follow-up assessment every 3–6 months for 5 years, and yearly thereafter. Patients who had (L)EER, every 3–6 months for 10 years, and yearly thereafter. By analysing the presence of disease within the classified tissues and disease outcome in these patients, and by examining relapse patterns, we were able to observe whether surgical excision within developmental compartments was sufficient for disease control. Survival curves were compared using the log-rank test. The effect of ontogenetic tumour stage and pathological tumour stage on overall survival was assessed by Cox proportional hazard models. The trials are registered as an ongoing observational monocentric study at the University of Leipzig Cancer Centre (ULCC012–13–28012013). Findings: 367 patients were included in our analysis. Staged organogenesis of the uterine cervix and progressive local growth of cervical carcinoma occur in the same tissue domains. The neoplasm originating in the uterine cervix, ontogenetic tumour stage 1 (oT1, n=217), permeates successively during its malignant progression the tissues developed from the Müllerian compartment (oT2, n=101), the genital metacompartment (oT3, n=38), and the urogenitorectal metacompartment (oT4, n=11). Ontogenetic staging, when comparing patients with oT1 and oT2 disease to those with oT3 and oT4 disease (hazard ratio 5·9, 95% CI 2·2–15·5; p=0·00036) was a better prognostic indicator for survival than pathological staging when comparing pT1b and pT2a with pT2b and pT4 disease (2·0, 95% CI 0·7–5·5; p=0·170). Resection of the stage-related ontogenetically specified tissue domains and their associated regional lymphoid tissues achieved an R0 resection in 363 (99%) of 367 patients and locoregional tumour control at 5 years was 94% (95% CI 92–97). 13 patients had grade 3 or 4 adverse events, the majority of which were urinary (10, 77%). Interpretation: Cervical cancer infiltrates the adult tissues established during ontogeny, pursuing the developmental steps in retrograde sequence. Clinical translation of these insights into ontogenetic tumour staging and compartment resection holds the potential to improve prognostic assessment and curative treatment. Funding: University of Leipzig and Leipzig School of Radical Pelvic Surgery. [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]

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]

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]

Background Standard treatment of advanced cervicovaginal cancer [international federation of gynecology and obstetrics (FIGO) stages II(B), III(A, B), IVA] is (chemo-)radiation excluding the possibility of systematic histopathological assessment of locoregional tumour spread. Laterally extended endopelvic resection (LEER) and therapeutic lymph node dissection (tLND) are novel surgical treatment options for advanced cervicovaginal cancer. Methods The therapeutic efficacy of LEER for locally advanced primary and recurrent cervicovaginal cancer was reassessed by an update of the prospective observational trial at the University of Leipzig. LEER specimens were histopathologically analysed for patterns of locoregional tumour spread with particular consideration of morphogenetic cancer fields. Histopathological features associated with malignant ureteral obstruction were evaluated. Clinical (FIGO), pathological (pT) and ontogenetic (oT) tumour staging were compared. Results Eighty-eight patients with locally advanced primary and recurrent cervicovaginal cancer were treated with LEER and tLND. LEER removed all but one tumour with microscopically clear margins (R0). After median follow-up of 40 months (7–191) five-year overall survival rate was 50% (95% confidence interval [CI]: 40–62) for the whole cohort and 46% (95% CI: 34–62) for 51 patients without a curative option from current treatment. The tissue domains of cervicovaginal cancer spread mirrored the derivatives of the morphogenetic fields instrumental for the formation of the lower genital ducts. Periureteral fibrosis accompanying mesometrial invasion, tumour infiltration of the mesureter and infiltration of the ureter itself were identified as histopathological correlates of ureteral obstruction associated with an increasingly worse prognosis. Ontogenetic tumour staging based on morphogenetic cancer fields predicted outcome better than pT and FIGO staging. Interpretation LEER and tLND expand the curative treatment options for advanced cervicovaginal cancer. Histopathological assessment of advanced disease supports the concept of tumour spread within morphogenetic cancer fields, provides insights into the pathomechanism of ureteral obstruction and allows precise tumour staging. [ABSTRACT FROM AUTHOR]

Ovarian carcinomas (OCX) have traditionally been thought to arise from the ovarian surface epithelium. However, recent (immuno-) histopathological and molecular analyses suggest that OCX consist of morphological subtypes with different epidemiologic features and a varying prognosis. The data of 482 OCX from the Clinical Cancer Registry of Leipzig who were surgically treated between 2000 and 2019 and were evaluated regarding incidence, clinico-pathologic characteristics and prognostic factors. Cases were separated into high-grade and non-high-grade serous tumors. Both groups were analyzed regarding the tumor stage, lymph node involvement, site of origin and prognosis. The overall incidence for OCX was 17.9. The most common histological subtype was high-grade serous OCX (57.9%; 279/482). Patients with high-grade were significantly older than those with a non-high-grade serous OCX (63.9 versus 58.5 years; p < 0.001), more frequently diagnosed at an advanced stage >pT3 (78.5% (219/279) versus 42.8% (87/203); p < 0.001) and showed a 2.4-fold higher frequency of lymph node metastases (53.4% vs. 21.2%; p < 0.02) with a 4.6-fold higher rate of > 1 cm metastatic deposits (pN1b) within the lymph nodes (14.8% vs. 4.6%; p < 0.02). Irrespective of tumor stage and morphological subtype, the 1- and 5-year overall survival (OAS) was 72.9% and 40.8%, respectively. Patients with high-grade serous OCX showed a shorter 5-year OAS compared to non-high-grade serous OCX (34.1% vs. 57.0%; p 0.001). This association was reproducible in patients with an advanced tumor stage irrespective of the histopathologic tumor type serous OCX (pT3: 32.4% vs. pT1: 75.1%; p 0.001) as well as within high-grade (pT3: 28.7% vs. pT1: 55.5%; p = 0.003) and non-high-grade serous OCX (pT3: 43.0% vs. 80.0%; p 0.001). There were no differences in OAS depending on the site of origin (fallopian tube, ovary, peritoneum) within the two histologic subgroups. OCX cases from a single institution with uniform surgical treatment and a standardized histopathological workup were evaluated. The poor prognostic outcome of patients with high-grade serous compared non-high-grade serous OCX as well as an advanced stage of the disease was confirmed. This study demonstrates for the first time that the histopathological distinction into high-grade serous and non-high-grade serous tumors may be much more prognostically relevant than the site of origin. [ABSTRACT FROM AUTHOR]

Objective: To compare the outcome of intrafascial nerve-sparing endoscopic extraperitoneal radical prostatectomy (nsEERPE) with interfascial (standard) nsEERPE. Methods: Four-hundred patients underwent nsEERPE; 200 patients underwent bilateral intrafascial nsEERPE (group A) and 200 bilateral standard nsEERPE (group B). Tumor stages of T1 and T2a, prostate-specific antigen level <10 ng/mL, maximal Gleason score 3+4 (not 4+3) and preoperative potency were considered as candidates for nsEERPE. Patients were randomized to the aforementioned groups. Perioperative data, and functional and oncological outcome were reviewed. Patients not requiring any pads or requiring 1 pad for safety were defined as continent. Patients responding positively to sexual encounter profile diary question numbers 2, 3, and 5 were considered as potent. Results: Perioperative data were similar between groups. At 3 months, 74% of group A and and 63% of group B were continent. At 6 months, the respective figures were 87.9% and 76.2%, respectively (A, B). At 12 months, 93.2% of group A and 90.7% of group B were continent. Potency rates of group A were 93.5% (<55 years), 83.3% (55-65 years), and 60% (>65 years) at 12 months. The respective figures for Group B were 77.1%, 50%, and 40%. Positive surgical margins were detected in 9% and 9.5% of groups A and B, respectively. Conclusions: Intrafascial nsEERPE provides significantly better potency in patients <55 years of age at 12 months and in patients 55-65 years of age at 6 and 12 months, with probably limited effect on the oncological outcome. Significantly improved continence was observed at 3 and 6 months in favor of intrafascial nsEEPRE. [Copyright &y& Elsevier]

Objectives: To study radical prostatectomy that has been reported to be more challenging and associated with complications in patients with history of transurethral resection of prostate (TURP). Methods: In our series, 100 of 2300 patients had undergone endoscopic extraperitoneal radical prostatectomy (EERPE) after previous TURP. All patients included in the study had at least 1-year follow-up. Patient demographics, mean blood loss, mean catheterization time, complications, functional and oncologic outcome were reviewed. Results: In all, 100 patients underwent EERPE and 26 of these patients were treated by nerve-sparing EERPE. Lymphadenectomy was performed in 45 patients. Operative time and mean blood loss were similar to previous EERPE series. The transfusion rate and mean time of catheterization were slightly higher than general EERPE population. Positive surgical margin rates were 7% for pT2 and 36% for pT3/4. At 12-month follow-up, 94% of the patients did not experience prostate-specific antigen level ≥ 0.1 ng/mL. The overall complication rate was 14%. At 12 months, 93% of patients were continent, 4% used 1-2 pads/day and 3% needed >2 pads/day. The potency rates for the 26 patients who underwent nerve-sparing EERPE were 52.6% and 66.7% at 6 and 12 months, respectively. Conclusions: Patients who had previously undergone TURP should be considered for radical treatment with EERPE. The procedure is safe even though technically more demanding. Perioperative, functional, and short-term oncologic outcome is promising and directly comparable to existing EERPE experience. Potency results were lower in comparison with existing EERPE series. [Copyright &y& Elsevier]

Objective: Pregnancy is described as a state of oxidative stress arising from the high metabolic turnover taking place during feto-placental development and little is known about the balance of oxidation and antioxidation in early human pregnancy. The aim of this study was to analyze placental expression of alpha-tocopherol transfer protein (alpha-TTP) as the major transport protein for the antioxidant alpha-tocopherol as well as the placental expression of two lipoperoxidation products, malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) in early first-trimester and term human placenta.Study Design: Placental tissue was obtained from 10 pregnancy interruptions at 6-8 weeks gestational age and 10 samples were obtained from term pregnancies after routine cesarean section. The placental expression of alpha-TTP, MDA and HNE has been investigated with immunohistochemistry by the use of specific human alpha-TTP, MDA and HNE antibodies.Results: While MDA and HNE showed similar expression in first-trimester and term placenta, alpha-TTP expression was less in first-trimester syncytiotrophoblast as compared to term. In first-trimester specimen, alpha-TTP showed major expression in extravillous trophoblast. In amniotic epithelial cells, a rising tendency in all three parameters investigated from immature to mature cells could be documented. No direct correlation between alpha-TTP, MDA and HNE expression was detected.Conclusions: Our study shows the presence of alpha-TTP not only in term, but in first-trimester extravillous trophoblast, syncytiotrophoblast and amniotic epithelium. Furthermore, lipoperoxidation products MDA and HNE are also present in first-trimester and term placenta, documenting the presence of oxidative processes in the placenta from early on. It therefore seems possible that scavenging of reactive oxygen species (ROS) by alpha-tocopherol is already required in first-trimester human pregnancy, but the missing correlation to MDA and HNE expression leads to the speculation that alpha-TTP and its ligand alpha-tocopherol have functions beyond the antioxidative capacity of alpha-tocopherol in early pregnancy. [ABSTRACT FROM AUTHOR]

Objectives: Focal therapy with high-intensity focused ultrasound (HIFU) is an emerging option for the treatment of prostate cancer and often followed up by MRI. Image assessment of treatment failure, however, requires proper knowledge about typical procedure-related changes in prostate MRI, which is sparse, in particular for unilateral HIFU treatment and late follow up (beyond 6 months). The goal of this study was therefore to compile the type and frequency of such MRI findings in selected patients without recurrent cancer 12 months after prostate hemiablation.Methods: Data from a prospective multicenter trial on HIFU hemiablation were reviewed retrospectively. Trial patients have had a late follow-up by MRI (at around 12 months) and either MRI/transrectal ultrasound (TRUS) fusion or standard TRUS-guided biopsy. This work deliberately included patients with non-recurrent cancer in the treated prostate lobe in per-protocol biopsy leaving 30 men with initial International Society of Urological Pathology (ISUP) Grade Group of 1 or 2. Six categories of potential HIFU-related MRI features were assessed by an expert committee and then evaluated by two readers in consensus: 1. shrinkage of the treated lobe, 2. residual prostate tissue, 3. fluid-filled cavity, 4. fibrosis, 5. hematoma residuals (in the prostate or seminal vesicles) and 6. contrast enhancement of the ablated area.Results: Shrinkage of the ablated lobe was seen in 93% of the cases with an average percent volume change of -37% (range: -70% to +108%). In the contralateral lobe, the volume remained practically the same (-2% on average, p = 0.804). In the ablated lobe, the frequency of fibrosis was 97%. Residual prostate tissue was seen in 93% of the cases. The frequency for fluid-filled cavities was 97%, with the wide majority (90%) contiguous with the urethra. Hematoma residuals in the prostate and in seminal vesicles were found in 47% and 10% of the patients, respectively. Contrast enhancement was both rim-like (50%) as well as diffuse (33%) within the ablated area.Conclusion: In our case series of HIFU hemiablation in the prostate, shrinkage, residual prostate tissue, fluid-filled cavities contiguous with the urethra and fibrosis were very common late MRI findings of the ablated lobe in non-recurrent patients. Rim-like contrast enhancement or diffuse one within the ablated area were less frequent. [ABSTRACT FROM AUTHOR]

Objective: Penile cancer is a rare disease in Europe and North America. Cancer registry data were used to estimate the incidence, mortality, and survival of penile cancer in Saxony, Germany.Methods: Data on incidence were analyzed for the period 1961 to 2012 and mortality for the period 1990 to 2012. Trend analyses of incidence and mortality were performed using joinpoint regression. Survival rates for primary penile cancer (ICD-10 C60) were estimated; overall, by T stage, UICC stage, and by year of diagnosis for the years 1963 to 2012.Results: Age-standardized incidence increased from 1.2 per 100,000 in 1961 to 1.8 per 100,000 in 2012, with a statistically significant increase between 2003 and 2012 (annual percent change: 4.66; 95% confidence interval, CI 0.62-8.86). There was a statistically significant negative trend in mortality between 1990 and 2012 (annual percent change: -3.46, 95% CI -5.21 to -1.67). A total of 430 new cases of penile cancer were registered between 2003 and 2012, with 63% of all penile cancers occurring in men aged 60 to 79 years. Almost half of those cases were located at the glans penis. The overall relative 5-year survival for the years of diagnosis 2003 to 2012 was 72.4% (95% CI 64.8%-80.0%). Relative 5-year survival decreased with higher UICC stages (I: 96%, 95% CI 84.7%-107.3%; II: 86.3%, 95% CI 71.0%-101.5%; III: 39.6%, 95% CI 19.9%-59.3%; IV: 20.3%, 95% CI 2.4%-38.2%).Conclusion: The incidence of penile cancer in Saxony has increased in recent years, while mortality has decreased. However, survival rates have remained constant over time. [ABSTRACT FROM AUTHOR]