Preservation of the mesureter to reduce urinary complications: analysis of data from the observational Leipzig School MMR study.

OBJECTIVE: To evaluate the feasibility and effect of mesureteral preservation on urinary complications in the context of total mesometrial resection (TMMR), a surgical treatment for cervical cancer. DESIGN: Retrospective cohort study with historic control. SETTING: Single tertiary academic centre. POPULATION: Women older than 18 with primary cervical cancer staged FIGO IB1-IIB enrolled in the prospective Leipzig School MMR study and underwent total mesometrial resection (TMMR) without adjuvant radiation. METHOD: We retrospectively analysed 100 consecutive TMMR procedures which were performed for cancer of the uterine cervix and in which the mesureter was preserved (intervention group, 01/2014-06/2017). We compared this group with the previous 100 consecutive TMMRs, which were performed before the introduction of mesureteral preservation (control group, 09/2010-01/2014). MAIN OUTCOME MEASURES: The occurrence of urological and specifically ureteral complications. RESULTS: Mesureteral preservation was feasible and was associated with a significant decrease in ureteral complications (11% without mesureteral preservation versus 3% with mesureteral preservation, P = 0.049). Furthermore, we found a significant decrease in the number of postoperative percutaneous nephrostomies and re-operations (7% versus none, P = 0.014). There was also a trend towards a decrease in other urinary complications such as postoperative bladder atony and uretero-vaginal fistulas. CONCLUSION: The mesureter constitutes a convenient dissection plane enabling the preservation of lateral ureteral blood supply during TMMR. In our study, maintenance of mesureteral integrity was associated with a significant reduction in ureteral complications. Mesureteral preservation might also be useful in other types of pelvic surgeries that carry a high risk of ureteral damage. TWEETABLE ABSTRACT: Surgical preservation of the mesureter in cervical cancer patients was associated with a reduction in urinary complications.

[Un- and dedifferentiated endometrial carcinoma : A rare entity with a wide range of differential diagnosis]. / Das un- und dedifferenzierte Endometriumkarzinom : Eine seltene Entität mit breitem differenzialdiagnostischem Spektrum.

Dedifferentiated endometrial carcinomas (ECs) are composed of undifferentiated EC and a FIGO grade 1 or 2 endometrioid carcinoma. The undifferentiated component represents a malignant epithelial neoplasm with no obvious differentiation and immunohistochemical loss of PAX8, E­cadherin and focal expression of EMA and/or CK18 and the predominant presence of nuclear staining for INI1 (SMARCB1) and BRG1 (SMARCA4). The main differential diagnoses include poorly differentiated endometrioid EC, neuroendocrine carcinoma, lymphoma, plasmocytoma, high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas (UUS), carcinosarcomas, and metastases to the endometrium. The histogenesis is not yet fully understood and molecular data are still limited. Some tumors represent a loss of MHL1 and PMS2 staining due to MLH1-promotor methylation. Rare cases are associated with Lynch syndrome or POLE mutation. The un- or dedifferentiated EC represents a high-grade endometrial carcinoma that requires extended surgery and indicates a poor prognosis. In cases with mismatch repair protein deficiency or POLE mutation, immuno-oncological treatment with checkpoint inhibitors are a therapeutic option.

[The 2019 FIGO classification for cervical carcinoma-what's new?] / FIGO-Klassifikation für das Zervixkarzinom 2019 ­ was ist neu?

Numerous therapeutic and prognostic studies of cervical carcinoma have necessitated a revision of the FIGO classification.For microinvasive carcinomas, the horizontal dimension is no longer considered and diagnosis and staging will solely be made by the depth of cervical stromal invasion. Lymphovascular invasion beyond the deepest point of stromal infiltration by tumor cells does not alter the stage.There will be a new subclassification of macroinvasive carcinoma confined to the uterine cervix, which will be made by largest tumor extension as follows: FIGO IB1/T1b1 - invasive carcinoma >0.5 cm depth of stromal invasion and ≤2 cm in largest dimension, FIGO IBII/T1b2: - invasive carcinoma >2 cm and ≤4 cm, FIGO IBII/T1b3 - invasive carcinoma >4 cm. Pelvic as well as para-aortic lymph nodes will be defined as regional nodes. Pelvic lymph node metastases only will be categorised as FIGO IIIC1/pN1a and para-aortic lymph node involvement with or without concomitant pelvic involvement will be FIGO IIIC2/pN1b. Uterine corpus as well as adnexal involvement are not relevant for staging purpose.

[TNM classification of gynecologic malignancies : What remains to be done beyond 2017?] / TNM-Klassifikation gynäkologischer Tumoren : Was bleibt über 2017 hinaus zu tun?

For some gynecologic malignancies, there are disagreements between the most recent WHO and TNM classifications and the recommendations of the International Collaboration of Cancer Reporting. These discrepancies are addressed and discussed in this paper. The WHO definition for primary vaginal cancer does not match the TNM definition. The paper also discusses and provides TNM classifications for rare gynecologic tumors like primary malignant vulvar melanomas, sarcomas of the vulva, perivascular epithelioid cell tumor (PECom) of the uterus, undifferentiated uterine sarcomas, and extra-intestinal gastrointestinal stromal tumors (GIST), and provides some recommendations for the reporting and categorization of regional lymph nodes in nonuterine serous pelvic cancer.

[S3 guidelines on the diagnosis and treatment of carcinoma of the endometrium : Requirements for pathology]. / S3-Leitlinie Diagnostik und Therapie des Endometriumkarzinoms : Anforderungen an die Pathologie.

The present article summarises the relevant aspects of the S3 guidelines on endometrioid carcinomas. The recommendations include the processing rules of fractional currettings as well as for hysterectomy specimens and lymph node resections (including sentinel lymph nodes). Besides practical aspects, the guidelines consider the needs of the clinicians for appropriate surgical and radiotherapeutic treatment of the patients. Carcinosarcomas are assigned to the endometrial carcinoma as a special variant. For the first time, an algorithmic approach for evaluation of the tumour tissue for Lynch syndrome is given. Prognostic factors based on morphologic findings are summarised.

[Histopathology and clinical aspects of extrauterine pregnancy]. / Histopathologie und Klinik der Extrauteringravidität.

Ectopic pregnancies are the main sources of pregnancy-related morbidity and mortality in the first trimester. They are usually located in the ampullary part of the fallopian tube and the incidence increases in the setting of assisted reproductive techniques, older age at the time of the first pregnancy, and prior adnexal procedures. The clinical aspects and diagnostic challenges of an ectopic pregnancy for the pathologist are to be outlined. A review of the relevant literature was performed. Proof of gestational tissue is of utmost importance in the pathological-anatomical evaluation of an ectopic pregnancy. A complete evaluation of the specimen of a presumed tubal abruption or after milking out should be performed. Abnormal placentations (blighted ovum, embryonal molar pregnancy) as well as gestational trophoblastic disease (GTD, e.g., partial/complete molar pregnancy, choriocarcinoma) can occur in the setting of an ectopic pregnancy. Caution must be taken to differentiate a trophoblast hyperplasia secondary to the tubal microenvironment from GTD. p57 immunohistochemistry can help exclude a molar pregnancy. Only 50% of ectopic pregnancies are associated with tubal pathologies (e. g. inflammation, tubal adhesions). Chorionic villi and trophoblast epithelia can demonstrate regressive changes after prior methotrexate treatment. Rarely, immunohistochemistry with GATA-3, p63, ß­HCG, PAX-8, and WT-1 can be used in the differential diagnosis of trophoblastic epithelium. Ectopic pregnancies are associated with significant morbidity and mortality. A thorough evaluation of the specimen can help guide management and follow-up.

Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma.

BACKGROUND: Human placental development resembles tumorigenesis, due to the invasive and fusogenic potential of trophoblasts. However, these features are tightly controlled in trophoblasts. Disturbance of this spatial and temporal regulation is thought to contribute to the rare formation of choriocarcinomas. Promoter hypermethylation and loss of the tumor suppressor Retinoic acid receptor responder 1 (RARRES1) were shown to contribute to cancer progression. Our study investigated the epigenetic and transcriptional regulation of RARRES1 in healthy human placenta in comparison to choriocarcinoma cell lines and cases. METHODS: Three choriocarcinoma cell lines (Jeg-3, JAR and BeWo) were treated with three different retinoic acid derivates (Am580, Tazarotene and all-trans retinoic acid) and 5-aza-2'-deoxycytidine. We analyzed RARRES1 promoter methylation by pyrosequencing and performed realtime-PCR quantification to determine RARRES1 expression in placental tissue and trophoblastic cell lines. Additionally, RARRES1 was stained in healthy placentas and in biopsies of choriocarcinoma cases (n = 10) as well as the first trimester trophoblast cell line Swan71 by immunofluorescence and immunohistochemistry. RESULTS: In the choriocarcinoma cell lines, RARRES1 expression could not be induced by sole retinoic acid treatment. Stimulation with 5-aza-2'-deoxycytidine significantly induced RARRES1 expression, which then could be further increased with Am580, Tazarotene and all-trans retinoic acid. In comparison to healthy placenta, choriocarcinoma cell lines showed a hypermethylation of the RARRES1 promoter, which correlated with a reduced RARRES1 expression. In concordance, RARRES1 protein expression was lost in choriocarcinoma tissue. Additionally, in the trophoblastic cell line Swan71, we found a significant induction of RARRES1 expression with increased cell density, during mitosis and in syncytial knots. CONCLUSIONS: Our findings showed that RARRES1 expression is absent in choriocarcinoma due to promoter methylation. Based on our analysis, we hypothesize that RARRES1 might exert tumor suppressive functions in multiple cellular processes (e.g. cell cycle regulation, adhesion, invasion and apoptosis).

[Interstitial cystitis : Diagnosis and pharmacological and surgical therapy]. / Interstitielle Zystitis : Diagnostik, medikamentöse und operative Therapie.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic debilitating condition which generally has a severely negative impact on quality of life. An autoimmune genetic predisposition correlates with the theory of pathogenesis. Diagnosis requires history, diaries, physical examination, exclusion of other diseases, cystoscopy with or without hydrodistension and/or bladder biopsy. Novel biological markers are upcoming but not established. Behavioural, pharmacological oral and intravesical, interventional and surgical therapies with a wide range of reported success are available. A multimodal approach is recommended, although most of the therapeutic options lack a high degree of evidence.

Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015.

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case.

[Cervical cancer : Update on morphology]. / Zervixkarzinom : Aktuelles zur Morphologie.

The World Health Organization (WHO) classification from 2014 differentiates between different subtypes of mucinous adenocarcinoma of the uterine cervix. A gastric subtype was recently described that showed no association with high-risk human papillomavirus (HPV) infections, has a poor prognosis, is mainly diagnosed in women of Asian origin and can occur in patients with Peutz-Jeghers syndrome. Although no clear grading system has been recommended in the WHO classification, it is likely that grading of adenocarcinomas of the uterine cervix will partly be based on the different patterns of invasion. Deep stromal infiltration of macroinvasive carcinomas is defined as an infiltration of >66 % of the cervical stroma. In the near future a maximum tumor size of 2 cm could act as a discriminator for planning of less radical surgery. Parameters of the histopathological report that are relevant for the prognostic assessment as well as the choice of adjuvant treatment and function as quality indicators during certification are described. The histological type of an adenocarcinoma alone is of no predictive or prognostic relevance for patients undergoing primary surgical treatment, neoadjuvant chemotherapy, combined chemo-radiotherapy or treatment with angiogenesis inhibitors. Currently, molecular parameters and biomarkers are of no relevance.

[Categorization of uterine cervix tumors : What's new in the 2014 WHO classification]. / Kategorisierung der Tumoren der Cervix uteri : Neues in der WHO-Klassifikation 2014.

In the 2014 WHO classification, squamous cell precursor lesions are classified as low-grade and high-grade intraepithelial lesions. LSIL corresponds to CIN1, HSIL includes CIN2 and CIN3. Only adenocarcinoma in situ (AIS) is accepted as precursor of adenocarcinoma and includes the stratified mucin-producing intraepithelial lesion (SMILE). Although relatively rare, adenocarcinoma and squamous cell carcinoma can be mixed with a poorly differentiated neuroendocrine carcinoma. Most cervical adenocarcinomas are low grade and of endocervical type. Mucinous carcinomas show marked intra- and extracellular mucin production. Almost all squamous cell carcinomas, the vast majority of adenocarcinomas, and many rare carcinoma types are HPV related. For low grade endocervical adenocarcinomas, the pattern-based classification according to Silva should be reported. Neuroendocrine tumors are rare and are classified into low-grade and high-grade, whereby the term carcinoid is still used.

[Nomenclature of squamous cell precursor lesions of the lower female genital tract : Current aspects]. / Nomenklatur der plattenepithelialen Präkanzerosen des unteren weiblichen Genitales : Aktuelle Aspekte.

The majority of precancerous lesions of the lower female genital tract (intraepithelial neoplasia, IN) are caused by human papillomavirus (HPV) infections resulting in cellular atypia and in turn an altered tissue architecture. Depending on the pathogenesis, a distinction is made between vulvar intraepithelial neoplasia (VIN) classified as classical VIN associated with high-risk HPV infections (u-VIN) and differentiated VIN (d-VIN), which is associated with lichen sclerosus et atrophicus and p53 alterations. In the current World Health Organization (WHO) classification a novel grading system for squamous cell precancerous lesions of the lower female genital tract has been proposed, differentiating low grade squamous intraepithelial lesions (L-SIL) including condyloma and HPV-associated alterations plus VIN 1, vaginal intraepithelial neoplasia (VaIN 1) and cervical intraepithelial neoplasia (CIN 1) from high grade squamous intraepithelial lesions (H-SIL) with VIN 2 and 3, VaIN 2 and 3 as well as CIN 2 and 3. The use of p16 immunohistochemistry can assist the differentiation. The new binary classification, however, contradicts the German cytological nomenclature (Munich nomenclature III), which differentiated three grades of dysplasia in order to avoid overtreatment of patients with moderate IN. The individual nomenclatures are compared to each other. It is recommended to report the grade of precancerous lesions in addition to the SIL classification of the WHO.

Indications and Route of Hysterectomy for Benign Diseases. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry No. 015/070, April 2015)

Background: Official guideline "indications and methods of hysterectomy" to assign indications for the different methods published and coordinated by the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (OEGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). Besides vaginal and abdominal hysterectomy, three additional techniques have been implemented due to the introduction of laparoscopy. Organ-sparing alternatives were also integrated. Methods: The guideline group consisted of 26 experts from Germany, Austria and Switzerland. Recommendations were developed using a structured consensus process and independent moderation. A systematic literature search and quality appraisal of benefits and harms of the therapeutic alternatives for symptomatic fibroids, dysfunctional bleeding and adenomyosis was done through MEDLINE up to 6/2014 focusing on systematic reviews and meta-analysis. Results: All types of hysterectomy led in studies to high rates of patient satisfaction. If possible, vaginal instead of abdominal hysterectomy should preferably be done. If a vaginal hysterectomy is not feasible, the possibility of a laparoscopic hysterectomy should be considered. An abdominal hysterectomy should only be done with a special indication. Organ-sparing interventions also led to high patient satisfaction rates, but contain the risk of symptom recurrence. Conclusion: As an aim, patients should be enabled to choose that therapeutic intervention for their benign disease of the uterus that convenes best to them and their personal life situation.

[Grading of gynecological tumors : Current aspects]. / Grading gynäkologischer Tumoren : Aktuelle Aspekte.

Histopathological assessment of the tumor grade and cell type is central to the management and prognosis of various gynecological malignancies. Conventional grading systems for squamous carcinomas and adenocarcinomas of the vulva, vagina and cervix are poorly defined. For endometrioid tumors of the female genital tract as well as for mucinous endometrial, ovarian and seromucinous ovarian carcinomas, the 3­tiered FIGO grading system is recommended. For uterine neuroendocrine tumors the grading system of the gastrointestinal counterparts has been adopted. Uterine leiomyosarcomas are not graded. Endometrial stromal sarcomas are divided into low and high grades, based on cellular morphology, immunohistochemical and molecular findings. A chemotherapy response score was established for chemotherapeutically treated high-grade serous pelvic cancer. For non-epithelial ovarian malignancies, only Sertoli-Leydig cell tumors and immature teratomas are graded. At this time molecular profiling has no impact on the grading of tumors of the female genital tract.

Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015).

Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non-gestational trophoblastic disease in accordance with the principles of evidence-based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma).

Sarcoma of the Uterus. Guideline of the DGGG (S2k-Level, AWMF Registry No. 015/074, August 2015).

Purpose: Official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). Due to their rarity and their heterogeneous histopathology uterine sarcomas remain challenging tumors to manage and need a multidisciplinary approach. To our knowledge so far there is no evidence-based guideline on the appropiate management of these heterogeneous tumors. Methods: This S2k-guideline is the work of an representative committee of experts from a variety of different professions who were commissioned by the DGGG to carry out a systematic literature review of uterine sarcoma. Members of the participating scientific societies developed a structured consensus in a formal procedure. Recommendations: 1. The incidence and histopathologic classification of uterine sarcoma. 2. The clinical manifestations, diagnosis and staging of uterine sarcoma. 3. The management of leiomyosarcoma. 4. The management of endometrial stromal sarcoma and undifferentiated uterine sarcoma. 5. The management of adenosarcoma as well as carcinosarcomas. 6. The management of morcellated uterine sarcoma.

[S3 guidelines on diagnostics and treatment of cervical cancer: Demands on pathology]. / S3-Leitlinie Diagnostik und Therapie des Zervixkarzinoms.

Between 2011 and the end of 2014 the former consensus S2k guidelines for the diagnostics and treatment of cervical cancer were updated and upgraded to S3 level, methodologically based on the regulations of the German Cancer Society (DKG). The present article summarizes the relevant aspects for the sectioning, histopathological workup, diagnostics and reporting for the pathology of invasive cancer of the uterine cervix. The recommendations are based on the most recent World Health Organization (WHO) and TNM classification systems and consider the needs of the clinician for appropriate surgical and radiotherapeutic treatment of patients. Detailed processing rules of colposcopy-guided diagnostic biopsies, conization and trachelectomy as well as for radical hysterectomy specimens and lymph node resection (including sentinel lymph node resection) are given. In the guidelines deep stromal invasion in macroinvasive cervical cancer is defined for the first time as tumor infiltration of > 66% of the cervical stromal wall. Furthermore, morphological prognostic factors for microinvasive and macroinvasive cervical cancer are summarized.

Erratum: Sarcoma of the Uterus. Guideline of the DGGG (S2k-Level, AWMF Registry No. 015/074, August 2015).

[This corrects the article DOI: 10.1055/s-0035-1558120.].

[Importance of the tumor stem cell hypothesis for understanding ovarian cancer]. / Bedeutung der Tumorstammzellhypothese für das Verständnis des Ovarialkarzinoms.

BACKGROUND: Despite complex surgical and systemic therapies epithelial ovarian cancer has a poor prognosis. A small quantity of tumorigenic cells termed cancer stem cells (CSC) are responsible for the development of chemoresistance and high rates of recurrence. OBJECTIVES: This review presents the CSC hypothesis and describes methods of identification and enrichment of CSCs as well as approaches for the therapeutic use of these findings. MATERIAL AND METHODS: A systematic literature review based on PubMed and Web of Science was carried out. RESULTS: The CSC model is based on a hierarchical structure of tumors with few CSCs and variably differentiated tumor cells constituting the tumor bulk. Only the CSCs possess tumorigenic potential. Other essential functional characteristics of CSCs are their potential for self-renewal and their ability to differentiate into further cell types. The CSCs are structurally characterized by different surface markers and changes in certain signaling pathways. Currently there are phase I and II studies in progress investigating specific influences on CSCs. CONCLUSION: Various clinical characteristics of the course of disease in ovarian cancer are aptly represented by the tumor stem cell model. In spite of precisely defined functional characteristics of CSCs, surface markers and signaling pathways show individual differences and vary between tumor entities. This complicates identification and enrichment. Current experimental findings in various approaches and even first clinical studies raise hopes for a personalized cancer therapy targeting CSCs.