[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.

Factors associated with non-participation and dropout among cancer patients in a cluster-randomised controlled trial.

We investigated the impact of demographic and disease related factors on non-participation and dropout in a cluster-randomised behavioural trial in cancer patients with measurements taken between hospitalisation and 6 months thereafter. The percentages of non-participation and dropout were documented at each time point. Factors considered to be potentially related with non-participation and dropout were as follows: age, sex, marital status, education, income, employment status, tumour site and stage of disease. Of 1,338 eligible patients, 24% declined participation at baseline. Non-participation was higher in older patients (Odds Ratio [OR] 2.1, CI: 0.6-0.9) and those with advanced disease (OR 2.0, CI: 0.1-1.3). Dropout by 6 months was 25%. Dropout was more frequent with increased age (OR 2.8, CI: 0.8-1.2), advanced disease (OR 3.0, CI: 1.0-1.2), being married (OR 2.4, CI 0.7-1.1) and less frequent with university education (OR 0.4, CI -1.3 to -0.8) and middle income (OR 0.4, CI -0.9 to -0.7). When planning clinical trials, it is important to be aware of patient groups at high risk of non-participation or dropout, for example older patients or those with advanced disease. Trial designs should consider their special needs to increase their rate of participation.

[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).

[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.

[New FIGO classification of ovarian, fallopian tube and primary peritoneal cancer]. / Neue FIGO-Klassifikation des Ovarial-, Tuben und primären Peritonealkarzinoms.

During recent years paramount changes have occurred in the pathogenesis of ovarian cancer and recent clinical studies identified new prognostic factors. Consequently, the FIGO has established a new staging system collectively covering carcinomas derived from the ovaries, the fallopian tubes and primary peritoneal cancers as well as malignant ovarian germ cell and sex-cord stromal tumors. The new staging system started on 01 January 2014. Major changes occurred in the FIGO IC/T1c stage with surgical spill (FIGO IC1/T1c1) versus capsule ruptured before surgery or tumor on ovarian or fallopian tube surface (FIGO IC2/T1c2) versus malignant cells in the ascites or peritoneal washings (FIGO IC3/T1c3). The regional lymph node metastases were subcategorised using a cut-off value of 10 mm as the largest dimension of the metastatic deposits. Distant metastases (excluding peritoneal metastases) were substaged as FIGO IVA/M1a in cases of cytologically or histologically proven pleural involvement and as FIGO IVB/M1b in cases of parenchymal metastases and metastases in extra-abdominal organs (including lymph nodes outside the peritoneal cavity and the inguinal lymph nodes).

[Morphology of secondary ovarian tumors and metastases]. / Morphologie sekundärer Ovarialtumoren/Ovarmetastasen.

The distinction between primary and secondary (metastatic) ovarian tumors is essential for the selection of appropriate surgical interventions, chemotherapeutic treatment and prognostic evaluation for the patient. Metastatic tumors of the ovary range between 5 % and 30 %. The majority of ovarian metastases in Europe and North America derive from colorectal (25-50 %) and breast cancers (8-25 %). A major issue is the differential diagnosis of mucinous tumors. Major features favoring metastasis include bilaterality, size < 10 cm, ovarian surface involvement, extensive intra-abdominal spread, and infiltrative growth within the ovary involving the corpus albicans and corpora lutea. An algorithm using bilaterality and tumor size (cut-off 10 cm) allows correct categorization in approximately 85 % of the cases. Although immunohistochemistry (especially CK7 and CK20 in mucinous tumors) using a panel of antibodies plays a valuable role and is paramount in the diagnosis, the results must be interpreted with caution and within the relevant clinical and histopathological context. It is necessary to note that the correct diagnosis of ovarian metastases always needs interdisciplinary and multidisciplinary approaches.

Co-morbid mental health conditions in cancer patients at working age--prevalence, risk profiles, and care uptake.

OBJECTIVE: This study examined the prevalence of mental health conditions in cancer patients, the role of socioeconomic position in relation to that, and the use of professional mental health care. METHODS: Prospective cohort with measurements at the beginning of inpatient treatment (baseline) and 3, 9, and 15 months after baseline using structured clinical interviews based on DSM-IV, questionnaires, and medical records. RESULTS: At baseline, 149 out of 502 cancer patients (30%) were diagnosed with a mental health condition. Prevalence was associated with unemployment (odds ratio [OR] 2.0), fatigue (OR 1.9), and pain (OR 1.7). Of those with mental health conditions, 9% saw a psychotherapist within 3 months of the diagnosis, 19% after 9 months, and 11% after 15 months. Mental health care use was higher in patients with children ≤18 years (OR 3.3) and somatic co-morbidity (OR 2.6). There was no evidence for an effect of sex on the use of mental health care. CONCLUSION: Few cancer patients with psychiatric disorders receive professional mental health care early enough. If patients are unemployed or if they suffer from fatigue or pain, special attention should be paid because the risk of having a mental health condition is increased in these patients.

Is it useful to calculate sum scores of the quality of life questionnaire EORTC QLQ-C30?

The aim of this paper is to test the psychometric properties of sum scores of the quality of life questionnaire EORTC QLQ-C30. A sample of cancer patients (n= 1529) and a sample of the general population (n= 1185) were tested with the EORTC QLQ-C30, the Hospital Anxiety and Depression Scale and the Multidimensional Fatigue Inventory. Three sum scores of the EORTC QLQ-C30 are defined: a score concerning functioning, a score concerning symptoms and a total score. Compared with the two-item quality of life scale of the EORTC QLQ-C30, the psychometric quality of the total score and the functioning score is superior with respect to reliability, convergent validity and discriminant validity. Cronbach's alpha of the total score is 0.94 (cancer patients) and 0.95 (general population). The effect size discriminating between patients and controls is d= 0.83 for the total score, compared to only 0.50 obtained with the two-item quality of life scale. The results prove that the calculation of sum scores provides useful information for clinicians who are interested in one generalising score of quality of life.

Peritumoral stromal remodeling, pattern of invasion and expression of c-met/HGF in advanced squamous cell carcinoma of the cervix uteri, FIGO stages III and IV.

OBJECTIVE: Different patterns of invasion (PIs) have prognostic impact in several types of cancer and are associated with different grades of peritumoral stromal remodeling, characterized by the desmoplastic stromal response (DSR). One key regulator influencing cellular motility and peritumoral stromal response is c-met/HGF. This study evaluates the association between different PI, peritumoral DSR and its correlation to the expression of c-met/HGF in squamous cell carcinomas of the uterine cervix (CX). STUDY DESIGN: 131 advanced stage CX (FIGO III/IV) were re-evaluated histologically regarding PI, using a two-level scoring system. The tumor grows in solid cords/trabeculae in finger-like PI and in very small groups or single cells in spray-like PI. DSR was categorized as none/weak and moderate/strong. The tumors were stained with antibodies against c-met and HGF. The staining of >30% of tumor cells was defined as overexpression. The PI was correlated to the prognostic outcome, different categories of DSR and expression status of c-met and HGF. RESULTS: 66.4% of the tumors showed a finger-like, and 33.6% a spray-like PI. The spray-like PI showed a reduced two-year overall survival when compared to the finger-like PI (14.0% vs. 29.1%, respectively; p=0.012), and was associated with moderate/strong DSR. The majority of the tumors showed overexpression of c-met (85.4%) and HGF (74.8%). There was no correlation between the expression status of c-met/HGF and the FIGO stage, peritumoral DSR or the prognostic outcome. CONCLUSIONS: Spray-like PI is of prognostic impact in cervical carcinoma FIGO III/IV and is associated with strong peritumoral stromal remodeling. There is no prognostic impact of the immunohistochemical expression of c-met/HGF in advanced stage cervical carcinomas.

Sequential chemotherapy with carboplatin followed by weekly paclitaxel in advanced ovarian cancer: results of a multicenter phase II study of the northeastern German society of gynecological oncology.

BACKGROUND: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index. METHODS: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally. RESULTS: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+). CONCLUSION: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.

[Histopathology of gestational trophoblastic disease. An update]. / Gestationsbedingte Trophoblasterkrankungen. Aktuelle Aspekte.

The differential diagnosis of villous forms of gestational trophoblastic disease (GTD) includes hydropic abortion, complete and partial hytatidiform mole and placental mesenchymal dysplasia. In addition to histologic criteria, p57(KIP2) immunohistochemistry might be helpful. Choriocarcinoma represents the most immature form of GTD. This and downregulation of HSP-27 might contribute to the high chemosensitivity, compared to placental site (PSTT) and epitheloid trophoblastic tumor (ETT). Within the differential diagnosis of the non-villous forms of GTD an algorithmic approach of immunohistochemistry is very helpful. With an incidence of 1.6% of all abortions within the first trimester the exaggerated placental site reaction (EPS) is rare. There is no molecular indication that the EPS represents a precursor lesion of PSTT. The morphologic prediction of the behaviour of PSTT is not well established. Factors which might be associated with adverse outcome are age >35 years, interval since last pregnancy >2 years, growth outside the uterus, deep myometrial invasion, destructive growth, extensive coagulative necrosis, presence of cells with clear cytoplasm, high mitotic rate and a Ki-67 labeling index >50%. Recent molecular data suggest a neoplastic transformation of (cyto-) trophoblastic stem cells, within the pathogenesis of (non-villous) GTD. The detection of target molecules for a targeted therapy is currently irrelevant.

Large histological serial sections for computational tissue volume reconstruction.

OBJECTIVES: A proof of principle study was conducted for microscopic tissue volume reconstructions using a new image processing chain operating on alternately stained large histological serial sections. METHODS: Digital histological images were obtained from conventional brightfield transmitted light microscopy. A powerful nonparametric nonlinear optical flow-based registration approach was used. In order to apply a simple but computationally feasible sum-of-squared-differences similarity measure even in case of differing histological stainings, a new consistent tissue segmentation procedure was placed upstream. RESULTS: Two reconstructions from uterine cervix carcinoma specimen were accomplished, one alternately stained with p16(INK4a) (surrogate tumor marker) and H&E (routine reference), and another with three different alternate stainings, H&E, p16(INK4a), and CD3 (a T-lymphocyte marker). For both cases, due to our segmentation-based reference-free nonlinear registration procedure, resulting tissue reconstructions exhibit utmost smooth image-to-image transitions without impairing warpings. CONCLUSIONS: Our combination of modern nonparametric nonlinear registration and consistent tissue segmentation has turned out to provide a superior tissue reconstruction quality.

[Pathoanatomical preparation and reporting for dysplasias and cancers of the cervix uteri: cervical biopsy, conization, radical hysterectomy and exenteration]. / Pathologisch-anatomische Aufarbeitung und Befundung von Dysplasien und Karzinomen der Cervix uteri. Zervixbiopsien, Konisationen, radikale Hysterektomien und Exenterate.

A careful macroscopic description with selection of representative tissue for histological examination is required for quality assurance, for assessing prognostic factors and for answering legal questions in (pre)cancerous lesions of the cervix uteri. Exact and standardized gross inspection and preparation are decisive for the quality of the histopathological statement. The extent of cervical carcinomas should be given in three dimensions, including the relative depth of invasion into the cervical wall. The report should include size, type (according to the WHO classification) and grading of the tumor, the presence of lymphatic as well as blood vessel invasion and perineural involvement. The statement for resection margins should include the vaginal, parametrial, rectal and vesical directions. It is also mandatory to document the number of lymph nodes with metastatic disease in relation to the total number of nodes investigated. The staging should follow the TNM system. In the handling of conisation specimens, it is important to appropriately document localization, horizontal expansion, depth of invasion including microinvasion of any dysplastic or malignant lesions. Clockwise dissection of the conisation specimen, total submission, and step sections are recommended. The preparation of exenteration specimens is a highly skilled job: the exact tumor dimension should be given in its relation to all resected organs and structures with special focus on resection margins.

Giant ovarian cysts: is a pre- and intraoperative drainage an advisable procedure?

There has been a considerable debate over the merits of a pre- or intraoperative drainage of giant ovarian cysts, which represented a very frequent approach before definitive surgery in the past. Including our presented case of a 57-year-old woman with a 49 kg mucinous cystadenoma, 19 patients with giant ovarian cysts weighing more than 40 kg were reported in the literature since 1970. An incidence of 37% of malignant and low malignant potential tumors was found. Based on a critical evaluation of the medical courses and the discussed miscellaneous advantages and complications, we conclude that a pre- and intraoperative drainage should be avoided.

Pattern of invasion is of prognostic value in surgically treated cervical cancer patients.

OBJECTIVES: Different patterns of invasion (representing different grades of tumor cell dissociation) are associated with prognostic outcome in cancer. We evaluated the prognostic value of different patterns of invasion (PI) in cervical carcinomas (CX). METHODS: Six hundred eleven surgically treated CX (FIGO IB to IIB) were re-evaluated histologically regarding the PI, using a three-level scoring system. Closed PI was defined as cohesive growth with well-delineated (pushing) borders. In finger-like PI the tumor grows in solid cords/trabecles. Highly dissociative growth in small groups or single cells was defined as spray-like PI. Types of PI were correlated to tumor stage, histo-morphologic factors and prognostic outcome. RESULTS: Sixty percent of the tumors showed a spray-like PI, 30% a finger-like PI and only 7.4% were of the closed type. Spray-like PI showed a significant correlation with advanced stage disease, lymphovascular space involvement, poorly differentiated tumors and pelvic lymph node metastases. Spray-like PI was accompanied by a reduced 5-year overall survival when compared to the finger-like and closed PI (68.7% vs. 80.9% vs. 88.5%; P=0.0004). The prognostic impact of the PI disappeared in node-positive patients (P=0.06) but persisted in patients without pelvic lymph node disease (P=0.03). In multivariate analysis, using COX regression model, the PI represented as independent prognostic factor. CONCLUSIONS: Spray-like PI (i.e., highest degree of tumor cell dissociation) is associated with advanced tumor stages, increased rate of recurrency and a reduced overall survival. In separate analysis of patients with and without lymph node metastases, the impact of PI persisted only in node-negative cases as a prognostic factor.

Clinicopathologic characteristics and subsequent pregnancy outcome in 139 complete hydatidiform moles.

OBJECTIVE: The most common form of gestational trophoblastic disease is the complete hydatidiform mole (CHM). The study reports our experience of clinicopathologic characteristics and subsequent pregnancy outcome of patients with CHM. STUDY DESIGN: One hundred fifty-one subsequent cases with initial diagnosis of CHM were re-evaluated histopathologically. Clinical characteristics, the need for chemotherapy and subsequent pregnancy outcome were evaluated. RESULTS: Twelve out of 151 cases were re-evaluated as hydropic abortion, as partial hydatidiform moles or were insufficient for morphologic examination and therefore excluded from further analysis. The leading clinical symptoms of the remaining 139 cases were irregular vaginal bleeding (67%) and uterine enlargement (41%). Twenty-six patients (19%) required chemotherapy because of gestational trophoblastic neoplasia (GTN; low-risk: 23 out of 26). All patients were cured successfully. The subsequent pregnancy rate was 15% (21/139). Five patients suffered from abortions, 12 women delivered a healthy offspring. Four women presented with recurrent CHM with a spontaneous normalization of HCG levels after D&C. CONCLUSIONS: The clinical and morphologic diagnosis of CHM is a challenge, and diagnosis as well as treatment should be multidisciplinary and centralised. One fifth of CHM are at risk of a GTN, but the cure rate is 100% with adequate management. Pregnancy outcome following CHM is complicated by an increased risk of abortion.

Prognostic value of trophoblastic proliferation in complete hydatidiform moles in predicting persistent disease.

The clinical outcome of patients with complete hydatidiform moles (CHM) is variable. The correlation between trophoblastic proliferation and development of persistent disease was evaluated. A hundred and fifty-one cases with the initial diagnosis of CHM were re-evaluated histopathologically. The need for chemotherapy and occurrence of metastatic disease was correlated with the histologic grade using a three-level score. Twelve out of 151 cases were re-evaluated as hydropic abortion, partial moles, or were insufficient for morphologic examination, representing a diagnostic agreement of 92%. A total of 63.4% of the CHM presented with low trophoblastic proliferation with focal areas of slight hyperplasia (grade 1), and 23.7% with moderate proliferation with slight anaplasia and medium-sized sheets of free trophoblast in between the villies (grade 2). In all, 12.9% of the cases showed marked hyperplasia with marked anaplasia and involvement of nearly all villies, as well as a large amount of intervillous trophoblastic sheets (grade 3). Twenty-six of the CHM (19%) required chemotherapy. Grade 3, on histology, showed a positive correlation with the necessity of chemotherapy (p=0.04), but not with the occurrence of metastatic disease. Histomorphology might predict the risk of persistent disease, indicating the necessity for closer a follow-up, but further studies are required.