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

Objective Emotional distress in cancer patients often goes unnoticed in daily routine; therefore, distress screening is now recommended in many national guidelines. However, screening alone does not necessarily translate into better well-being. We examined whether stepped psychooncological care improves referral to consultation-liaison (CL) services and improves well-being. Methods In a cluster-randomized trial, wards were randomly allocated to stepped versus standard care. Stepped care comprised screening for distress, consultation between doctor and patient about the patient's need for CL services, and provision of CL service. Primary outcomes were referral to psychosocial services and emotional well-being half a year after baseline, measured with the Hospital Anxiety and Depression Scale. A secondary endpoint was uptake of outpatient health care. Analysis employed mixed-effects multivariate regression modeling. Results Thirteen wards were randomized; 1012 patients participated. With stepped care (N = 570; 7 wards), 22% of the patients were referred to CL services and 3% with standard care (N = 442; 6 wards; odds ratio [OR] 10.0; P

ObjectivePrimary retroperitoneal mucinous tumors (PRMTs) are rare epithelial neoplasms arising in the retroperitoneal space whose pathogenesis is poorly understood. To date, only single-case reports and small case series on diagnosis and management of these tumors exist. The aim of this first-time meta-analysis was to provide more reliable data to inform the management of PRMTs.MethodsDatabase searches were conducted to identify case reports and case series between the years of 1975 and 2015. Two cases of patients treated at our institution were also included. Diagnostic, radiographic, surgical, and follow-up data were gathered. Regression modeling was used to identify factors aiding preoperative diagnosis and affecting treatment. Survival analysis including Cox regression modeling was performed to provide insights into treatment effects on the prognosis of female patients with PRMTs.ResultsOne hundred forty-four cases of PRMTs were included in this analysis. Eighty-nine percent occurred in women. Most of the PRMTs were found to be malignant (53%). No preoperative factors predicting tumor dignity were identified by multiple regression analysis. Five-year disease specific survival of patients with benign and borderline tumors was excellent, reaching 100%, whereas it was only 68% for patients with malignant disease. Adjuvant surgical treatments including hysterectomy, salpingoophorectomy, and lymph node dissection were not associated with a statistically significant survival advantage. However, there was a nonsignificant association of hysterectomy with improved survival (hazard ratio, 0.42; 95% confidence interval, 0.09–2.07; P = 0.285). Adjuvant chemotherapy was associated with reduced survival (hazard ratio 3.791; 95% confidence interval, 1.509–9.526; P = 0.0046).ConclusionsA reliable diagnosis of a PRMT can only be made by pathological examination of the tumor. Surgical excision is thus necessary to facilitate diagnosis while it also remains the mainstay of treatment. There is no conclusive evidence supporting the role of adjuvant surgical procedures or chemotherapy.

Cervical cancer metastases to the ovary may occur with advanced tumor stage, deep cervical stromal involvement and corpus involvement. Endocervical adenocarcinoma in situ (AIS) with ovarian involvement is exceptionally rare with about twelve reported cases. Here we present a case of endocervical AIS with ovarian and pulmonary involvement 39 months after the initial diagnosis. The characteristics of that case were compared and summarized with the eleven previously published cases. The patients’ age ranged between 30 and 40 years (median 37.4 years). The time interval between the diagnosis of AIS and ovarian involvement was 26.7 months (range 2–84 months). Majority of the patients are alive without evidence of disease after a median time of 63.4 months (range 9–156 months). All reported cases were positive for high-risk HPV which was associated with strong p16 expression on immunohistochemistry. The ovarian involvement by endocervical AIS suggests the concept of a transtubal spread of the neoplastic cervical cells with or without previous colonization within the endometrium without evidence of invasive growth, suggesting a seed and soil spread of the disease. In cases with ovarian involvement by the AIS and without additional extragenital spread, the prognosis may be favorable.

A 47-year-old woman presented with a history of 4 weeks of recurring pain in the right lower abdomen. Transvaginal ultrasound scan showed an irregular shaped solid mass of 45 × 26 × 45 mm in the right ovarian fossa with increased perfusion. CT-scan suspected an ovarian tumor with evidence of teeth in terms of a teratoma in the right adnexal area. Finally, our findings were suggestive of an ovarian teratoma and the decision for laparoscopy was made. Intraoperatively both ovaries were unsuspicious but a Meckel’s diverticulum with enterolithiasis was found in the right pelvis and removed. Meckel’s diverticulum is present in 1-2% of the population and here we will discuss general removel recommandations.

Context Cancer patients frequently suffer from fatigue. Recently, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life group developed a new 12-item fatigue assessment instrument. Objectives The aim of this study was to psychometrically test this questionnaire in comparison with the three-item fatigue scale of the EORTC QLQ-C30. Methods A sample of 354 patients who were being treated for breast cancer or gynecologic cancer were examined using the new fatigue questionnaire EORTC QLQ-FA12 and the EORTC QLQ-C30 during their hospital stay (t1) and three months after hospital discharge (t2). Confirmatory factorial analyses, item analyses, test-retest reliability analyses, and correlation analyses were performed. Results The analyses roughly supported the three-factorial structure of the FA12, which comprised the subscales physical, emotional, and cognitive fatigue. The fit indices of the confirmatory factorial analysis were worse than those of the original article but nevertheless acceptable. Cronbach alpha of the total scale was 0.92; the coefficients of the subscales were between 0.79 and 0.93. The correlation between the EORTC QLQ-FA12 total scale and the fatigue scale of the EORTC QLQ-C30 was 0.69 and the correlation between the t1 and t2 scores was 0.45 for the EORTC QLQ-FA12 total scale and between 0.37 and 0.47 for the subscales. Conclusion The psychometric coefficients justify the calculation of a sum score, which can be used by clinicians to assess the general degree of fatigue. Although the three-item fatigue scale of the EORTC QLQ-C30 stresses the physical aspect of fatigue, the new EORTC QLQ-FA12 covers its emotional and cognitive aspects as well.

Objective The aim of this examination was to study whether psychological resource variables (optimism and self-efficacy) decrease when cancer is present and to test the predictive power of these variables for anxiety, depression and quality of life (QoL). Methods The patient sample was comprised of 354 German women suffering from breast cancer or gynecological cancer. Participants filled in the resource assessment tools Life Orientation Test-Revised and the General Self-Efficacy Scale as well as the Hospital Anxiety and Depression Scale, the Patient Health Questionnaire-4 and the QoL instrument EORTC QLQ-C30 at two time points: (t1) during patients' hospital stay and (t2) 3 months later. Results The mean scores for optimism (total score: M = 16.2) and self-efficacy (M = 29.8) were even somewhat higher than the corresponding means of the general population. Optimism and self-efficacy were positively correlated with QoL (r between 0.15 and 0.17, P < 0.01) and negatively associated with anxiety and depression (r between -0.17 and -0.36, P < 0.01). However, only optimism was predictive of the t2 anxiety, depression and QoL scores when statistically taking into account the baseline levels of the outcome variables. Conclusions Having cancer does not generally reduce optimism and self-efficacy on the level of patients' mean scores. Cancer patients with a high level of habitual optimism will adapt to their disease better than pessimistic patients, even if the baseline levels of the outcome variables have been accounted for.

Gestational trophoblastic disease (GTD) is a clinically and morphologically very heterogeneous group of interrelated lesions, characterised by abnormal growth of the different types of trophoblastic cells, sometimes associated with villous dysmaturity. The management and follow up of the patients and risk calculation for persistent GTD is mainly based on histopathologic diagnosis. The morphologic and differential diagnostic criteria of the villous forms of GTD (complete, partial and invasive hydatidiform moles) are summarised in the paper as well as ancillary techniques for correct diagnoses. Exaggerated placental sites (EPS) and placental site nodules (PSN) represent benign lesions, derived from the intermediate trophoblast and their characteristics are given. The concept of atypical PSN as a recently defined lesion is discussed. Gestational choriocarcinoma (CC), placental site trophoblastic tumor (PSTT) and the epitheloid trophoblastic tumor (ETT) represent tumorous forms of GTD, also termed as gestational trophoblastic tumors (GTT). Their morphologic criteria and clues for differential diagnosis are given, including the discussion about the transition from one lesion into another.

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 CD34(low)/SMA(high) and associated reduced overall survival.

Recent new data in the pathogenesis of serous pelvic cancer and the introduction of serous tubal in situ carcinoma (STIC) and its precursors have raised the question that whether all primary peritoneal cancers (PPC) are in fact of tubal origin. Therefore, the present study evaluates the frequency of STIC and its precursor lesions in cases that were diagnosed as PPC using the morphologic criteria of the most recent WHO classification. The present study evaluates immunohistochemically (Ki-67 and p53 staining) the presence of STIC and its precursor lesions (p53 signature, serous tubal intraepithelial lesion [STIL]) in the completely processed Fallopian tubes of 46 consecutive PPCs. STIC was detected in 10 patients (21.7%) and p53 signature in 9 cases (19.6%). No STIL was observed. All except 1 STIC occurred at the fimbriated end of the Fallopian tube, and a bilateral involvement was detected in 2 cases. These precursor lesions were missed during the initial routine screening. Repeated staining for p53 was negative in STIC in 2 cases. STIC and p53 signature as precursor lesions of pelvic serous cancer are detected in some but not all the cases of primary serous peritoneal cancer. There might be the 2 different carcinogenetic pathways within PPC, and further studies are required to identify the source of serous cancer in cases without an STIC lesion.

Objective: The objective of this study is to examine the course of fatigue in female cancer patients during the first months after treatment. Methods: We examined a sample of 110 patients suffering from gynecological or breast cancer. Fatigue was assessed with two questionnaires, the Multidimensional Fatigue Inventory (MFI) and the fatigue scale of the quality of life questionnaire European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30). Participants were tested during their stay in the hospital (t1), two weeks after discharge (t2), and three months after discharge (t3). Results: Fatigue in the patients’ sample was markedly higher than the general population reference values. At t1, the effect sizes are d=0.81 (MFI) and d=1.21 (EORTC QLQ-C30 fatigue scale). Age and tumor stage had no significant influence on fatigue, but patients with a long time since diagnosis had higher fatigue levels than patients with a shorter time since diagnosis. From t1 to t3, fatigue mean scores decreased. The correlations between the t1 and the t3 fatigue scores were weak, with correlation coefficients of only about 0.30. Conclusion: Though the mean scores of fatigue, averaged across all patients, decreased over the first three months, the individual courses could not be predicted from the t1 score.

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.

In den letzten Jahren haben zahlreiche Studien prognostische und pradiktive Parameter analysiert, die auch beim Endometriumkarzinom (EC) die operative und adjuvante Therapie zunehmend patientinnen- und tumoradaptiert gestalten. Therapeutisch relevant sind das klinische FIGO-Stadium, der histologische Tumortyp, das Grading, eine Zervixbeteiligung und der Nachweis einer lymphogenen Metastasierung. Neben diesen Faktoren haben auch der Nachweis einer Lymphgefasinfiltration, die operative Radikalitat, Alter und Adipositas prognostische Relevanz. Das Verstandnis fur die Pathogenese auf molekularer Ebene ist entscheidend fur die Identifikation neuer prognoserelevanter Biomarker. Neue tumorbiologische Parameter und Genexpressionsanalysen identifizieren bereits verschiedene Typen beim endometroiden Adenokarzinom mit unterschiedlicher Prognose, jedoch reichen die Daten noch nicht fur den klinischen Einsatz.

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.

Einenkel J, Braumann U-D, Steller W, Binder H & Horn L-C (2012) Histopathology 60, 1084–1098 Suitability of infrared microspectroscopic imaging for histopathology of the uterine cervix Aims: Infrared microspectroscopy (IR-MSP) has been proposed for automated histological tissue differentiation of unstained specimens based on chemical analysis of cell and extracellular constituents. This study aimed to determine the accuracy of IR-MSP-based histopathology of cervical carcinoma sections with complex tissue architecture under practically relevant testing conditions. Methods and results: In total, 46 regions of interest, covering an area of almost 50 mm2 on sections derived from paraffin-embedded tissue of radical hysterectomy specimens, were analysed by IR-MSP (nominal resolution ∼4.2 μm). More than 2.8 million pixel spectra that were processed using fuzzy c-means clustering followed by hierarchical cluster analysis permitted image segmentation regarding different biochemical properties. Linear image registration was applied to compare these segmentation results with manual labelling on haematoxylin and eosin-stained references (resolution ∼0.7 μm). For recognition of nine tissue types, sensitivities were 42–91% and specificities were 79–100%, mostly being affected by peritumoral inflammatory responses. Algorithmic variation of the outline of dysplasia and carcinoma revealed a spatial preference of false values in tissue transition areas. Conclusions: This imaging technique has potential as a new method for tissue characterization; however, the recognition accuracy does not justify a pathologist-independent tissue analysis, and the application is only possible in combination with concomitant conventional histopathology.

Perivascular epithelioid cell tumor (PEComa) of the uterus is a rare mesenchymal lesion characterized by a proliferation of perivascular epitheloid cells with eosinophilic cytoplasm and immunohistochemical coexpression of both smooth muscle and melanocytic markers. The majority (∼ 92 %) of PEComas exhibit a benign behavior and are considered low-grade lesions. Nevertheless, a close follow-up of patients is necessary, and tumors should be staged like leiomyosarcomas. The presented case of a 65-year-old woman revealed a PEComa with diameter of 6 cm and adnexal involvement.

Background Local tumor spread of cervical cancer is currently considered as radial progressive intra- and extracervical permeation. For radical tumor resection or radiation the inclusion of a wide envelope of tumor-free tissue is demanded. However, this concept may lead to considerable treatment-related morbidity and does not prevent local relapse. We propose an alternative model of local tumor propagation involving permissive compartments related to embryonic development. Methods We analyzed local tumor spread macroscopically and microscopically in consecutive patients with advanced cervical cancer and post-irradiation recurrences. Results Macroscopically, all 33 stage I B (>2cm) tumors, 40 of 42 stage II tumors and 32 of 44 stage III B tumors were confined to the embryologically defined uterovaginal (Mullerian) compartment. Local tumor permeation deformed the uterovaginal compartment mirroring the mesenchyme distribution of the Mullerian anlage at the corresponding pelvic level in cases of symmetrical tumor growth. Tumor transgression into adjacent compartments mainly involved the embryologically related lower urinary tract. Compartmental transgression was associated with larger tumor size, paradox improvement in oxygenation and an increase in microvessel density. Post-irradiation pelvic relapse landscapes were congruent with the inflated Mullerian compartment. Microscopically, all locally advanced primary cancers and post-irradiation recurrences were confined to the uterovaginal and lower urinary tract compartments. Conclusion Cervical cancer spreads locally within the uterovaginal compartment derived from the Mullerian anlage. Compartment transgression is a relatively late event in the natural disease course associated with distinct phenotypic changes of the tumor. Compartmental tumor permeation suggests a new definition of local treatment radicality.

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 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.

Objective The aim of this study was to evaluate patients' acceptance and the reliability and validity of a recently developed instrument to assess quality of life among cervical cancer patients, the European Organization for Research and Treatment of Cancer Cervical Cancer Module (EORTC QLQ-CX24), in surgically treated patients after primary surgery. Methods The EORTC QLQ-CX24 was administered to 134 cervical cancer patients who had undergone pelvic surgery. Additional questionnaires completed were the EORTC QLQ-C30, and the Hospital Anxiety and Depression Scale. Sociodemographic and medical data were recorded. Results Missing values occurred in 4.5% of all non-optional items. Internal consistencies (Cronbach's alpha coefficients) for the three multi-item scales ranged from 0.70 to 0.87 (Symptom Experience 0.70, Body Image 0.87, Sexual/Vaginal Functioning 0.76), whereas scaling errors occurred in 6.8%, 0.0%, and 6.3% of the cases. In all domains, the entire range of the scale was used by patients. The scales were able to discriminate between different subgroups of patients. Conclusion These psychometric analyses confirm that the EORTC QLQ-CX24 is a useful tool for the assessment of quality of life in cervical cancer patients after surgery.

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.

Objectives Hypoxia enhances malignant progression by promoting the development of metastases and increasing invasiveness. One key regulator that controls growth, invasion and metastasis in cancer cells is the growth factor receptor c-met. The aim of this study, therefore, was to investigate the expression of the c-met protooncogene in cervical cancers in relation to intratumoral hypoxia levels and to clinico-pathological parameters. Methods 43 Patients with cervical cancer were subjected to intratumoral p O 2 measurement with the Eppendorf electrode and biopsies were taken. The tissue was subsequently analyzed by immunohistochemistry with an anti-c-met antibody. Results c-met was expressed in 72% of cervical cancers. There was a significantly stronger expression in poorly differentiated tumors ( r =0.4, p =0.008). Furthermore, c-met expression was significantly associated with a spray-like pattern of invasion ( p =0.008). However, there was no significant relationship between c-met expression and intratumoral hypoxia, pT stage, FIGO stage, lymphovascular space involvement, tumor size or overall survival. Conclusions Although c-met has been shown to be hypoxia-induced in vitro, our results suggest that it is not the mediator of deleterious effects of hypoxia on clinical outcome in cervical cancer.

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.

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.

Small cell carcinomas (SmCCs) of the uterine cervix are rare tumors. The knowledge regarding protein expression of several checkpoint candidates of cell cycle regulation is limited. Surgically treated SmCCs were selected from our files for immunohistochemical staining (neuroendocrine markers, p53, p16, p14, and cyclin D1). Polymerase chain reaction analysis, using general primers, was performed for human papillomavirus analysis. Nine of 677 tumors (1.3%) were classified as SmCCs after Grimelius staining (8/9 tumors positive) and immunohistochemical reaction against neurone-specific enolase, chromogranin A, synaptophysin (7/9 positive tumors), and CD 56 (8/9 positive tumors). All specimens were positive for at least two of the above. Two SmCCs were p53 positive and one case was p14 positive. Cyclin D1 staining was completely negative. All cases showed strong nuclear and/or cytoplasmic p16-immunostaining. Seven tumors represented human papillomavirus positivity for high-risk types. Four patients died of the tumor after a median time of 36.7 months (range, 15-56 months), representing a 5-year survival rate of 56%. The results suggest that p16 is up-regulated or accumulated in the SmCCs of the uterine cervix, probably caused by infection with human papillomavirus. p14 inactivation is of high prevalence in SmCCs and detection rate of p53 is similar to other histologic types of cervical carcinomas.

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.

The majority of modern hormone replacement therapy (HRT) regimens contain estrogen and progestogens, given either in a cyclical or continuous manner. About 15% of the endometrial biopsies taken from women on sequential HRT show proliferative activity including atypical endometrial hyperplasia in up to 1% of the cases. The majority of biopsies from women under continuous combined HRT show an endometrial atrophy. About 2-3% of these women will present proliferative activity, usually without atypical hyperplasia. Contrary to breast cancer, an increased risk of endometrial cancer has not been reported in the WHI- and HERS-studies. However, endogenous factors, such as obesity, diabetes mellitus, the distribution of estrogen receptors alpha and beta and genetic polymorphisms for receptors and enzymes might alter the endometrial stimulation under different types of HRT. There should be a liberal indication for endometrial biopsies in Hereditary Non-Polyposis Colorectal Cancer (HNPCC). HNPCC-patients under HRT as well as for ultrasonographic evaluation of the endometrium. The risk of atypical hyperplasias or carcinoma under unopposed estrogen-therapy varies from 2 to 10%. So, this kind of HRT should not be used in non-hysterectomised women. As far as the risk of endometrial cancer under any kind of HRT is concerned, the different molecular pathways of endometrial carcinogenesis (type 1 and 2 cancers) should be taken into account. The use of tibolone leaves the endometrium unaffected.

We report a case of an ectopic pregnancy in a caesarean section scar, which was initially misdiagnosed despite using ultrasound. For the first time, a strongly vascularised pelvic tumour developed while the titre of serum human chorionic gonadotrophin decreased after a curettage abortion for an unwanted pregnancy.Due to uncontrollable haemorrhage, an emergency hysterectomy had to be performed 8 weeks later.

The use of tissue microarrays (TMAs) is a new technique in molecular profiling of tumors using immunohistochemistry as well as molecular hybridisation techniques. It represents a mechanical technique which involves taking 0.6 to 2.0 mm tissue cores from multiple (donor) blocks of well characterised tumors with subsequent precise insertion (arraying) into empty (recipient) blocks - the TMA block. This block can be essentially processed as a regular paraffin block with nearly the same advantages and disadvantages. The problem of tumor heterogeneity is solved by including 2-3 cores from each tumor into the TMA block. Thus this technique offers significantly faster and cheaper evaluation of a large number (up to several hundreds of samples per TMA block) of tumors and provide an easy access to material for further studies using stored TMA blocks. TMAs will provide a valuable new tool for translational research, especially in the evaluation of predictive parameters in prospective multi-centre studies.

In most cases, the endometrioid adenocarcinoma of the endometrium is preceded by hyperplasia with different risk of progression into carcinoma. The original histologic slides from 560 consecutive cases with complex and atypical hyperplasia were re-examined to assess the interobserver-correlation. The hyperplasias were analyzed separately for their likelihood of progression to carcinoma in patients with and without progestogen hormonal therapy. In all cases, a fractional re-curreting was performed to establish the state of the disease.The leading symptom was vaginal bleeding in 65.5% of the cases in the postmenopausal period. Eighty-six percent of the patients presented with obesity (BMI > 30 kg/m2), 23% had had an exogeneous use of estrogens. Twenty-two cases were reclassified as simple hyperplasia and excluded from further analysis. The interobserver-correlation was 91% for complex, 92% for atypical hyperplasia, and 89% for endometrioid carcinoma, representing an overall correlation of 90%. Two percent of the cases with complex hyperplasia (8/390) progressed into carcinoma and 10.5% into atypical hyperplasia. Fifty-two percent of the atypical hyperplasias (58/112) progressed into carcinomas. In the case of progestogen treatment (n = 208; P < 0.0001) 61.5% showed remission confirmed by re-curetting, compared with 20.3% of the cases without hormonal treatment (n = 182; P < 0.0001).Endometrial hyperplasia without atypia is likely to respond to hormonal treatment. Especially in postmenopausal situation, atypical hyperplasia should be treated with total hysterectomy.

Gestational trophoblastic disease (GTD) comprises a spectrum of uncommon and unique clinical and pathologic entities. The process of GTD is now better understood and new entities such as placental-site trophoblastic tumor (PSST) and epitheloid trophoblastic tumor have been morphologically defined. Complete hydatiform mole, a form of the villous type of GTD, has to be distinguished from partial mole because of the different cytogenetic composition and risk for persistent disease. Choriocarcinoma is the most frequent form of nonvillous GTD. Both PSSTand epitheloid trophoblastic tumor derive from the intermediate trophoblastic cells and usually have a benign course. Optimal treatment requires a precise morphologic classification and close cooperation between the pathologist and the clinician. All patients treated for GTD require long-term monitoring of serum hCG. Patients with GTD should be registered, and possibly treated, at specialized centers.

Molecular studies have shown that the most prevalent mutations in serous ovarian borderline tumors (s-BOT) are BRAF and/or KRAS alterations. About one third of s-BOT represent peritoneal implants and/or lymph node involvement. These extraovarian deposits may be monoclonal or polyclonal in origin. To test both the hypotheses, mutational analyses using pyrosequencing for BRAF codon 600 and KRAS codon 12/13 and 61 of microdissected tissue was performed in 15 s-BOT and their invasive and noninvasive peritoneal implants. Two to 6 implants from different peritoneal sites were examined in 13 cases. Lymph node deposits were available for the analysis in 3 cases. Six s-BOT showed mutation in exon 2 codon 12 of the KRAS proto-oncogen. Five additional cases showed BRAF p.V600E mutation representing an overall mutation rate of 73.3%. Multiple (2-6) peritoneal implants were analyzed after microdissection in 13 of 15 cases. All showed identical mutational results when compared with the ovarian site of the disease. All lymph node deposits, including those with multiple deposits in different nodes, showed identical results, suggesting high intratumoral mutational homogeneity. The evidence presented in this study and the majority of data reported in the literature support the hypothesis that s-BOT with their peritoneal implants and lymph node deposits show identical mutational status of BRAF and KRAS suggesting a monoclonal rather than a polyclonal disease regarding these both tested genetic loci. In addition, a high intratumoral genetic homogeneity can be suggested. In conclusion, the results of the present study support the monoclonal origin of s-BOT and their peritoneal implants and lymph node deposits.

Limited knowledge exists about the value of tumor size in surgically treated cervical cancer (CX) using a tumor size of 2 cm as cut-off value.A total of 366 cases of CX FIGO stage IB who received upfront surgery were evaluated regarding tumor size, the prediction of pelvic lymph node involvement, and recurrence-free and overall survival during a median follow-up time of 94 months. Tumors ≤2.0 cm were defined as small, tumors 2.1-4.0 cm as medium sized and those larger than 4 cm as bulky disease.Small tumors were seen in 28.7%, medium sized in 52.5% and bulky tumors in 18.9%. There was a significant higher frequency of pelvic lymph node involvement with increasing tumor size (13.3% vs. 23.4% vs. 43.5%, respectively; p0.001) and an increase of recurrent disease (6.7% vs. 18.8% vs. 29.4%, respectively; p0.001). The 5-year overall survival rate was significantly reduced with increasing tumor size (94.0% vs. 85.1% vs. 69.9%, respectively; p0.001). Pelvic lymph node involvement and maximal tumor size were independent prognostic factors for both recurrence-free and overall survival in multivariate analysis.The results support that tumor size is of prognostic impact in FIGO stage IB cervical carcinomas. A further substaging is suggested for tumors up to 4.0 cm maximum dimension using a cut-off value of 2.0 cm as discriminator. Patients with tumors ≤2.0 cm may represent low risk disease.

A case of an intact primary ovarian pregnancy with ultrasonographic demonstration of heart motion following ovarian stimulation is presented. After preoperative ultrasonographic confirmation of an extrauterine pregnancy, proof of the ovarian localization was achieved by intra-operative ultrasonographic visualization during a diagnostic laparoscopy on post-menstrual day 48. A moderate ovarian hyperstimulation syndrome with a concomitant increase in size, vulnerability and vascularity of the ovaries presented an additional challenge for the surgical approach. However, thanks to the early diagnosis of the ectopic pregnancy localization, a laparoscopic organ-preserving removal of the intact ovarian pregnancy was successfully performed. In this way, the fertility of the patient, who had previously undergone contralateral ovariectomy, was preserved. To our knowledge, this represents the first such treatment to be reported in the medical literature. Improvements in diagnosis and therapy of ovarian pregnancy are reviewed.

article i nfo Objective. Pelvic exenteration is mainly applied as a salvage operation for a subset of patients with persis- tent and recurrent cervicovaginal cancer. The procedure can also cure locally advanced primary disease not suitable for radiotherapy. However, high operative abortion and intralesional tumor resection rates signifi- cantly limit its clinical benefit. To improve locoregional tumor control we have proposed to establish cancer surgery on ontogenetic anatomy and, consequently, we have developed the (Laterally) Extended Endopelvic Resection ((L)EER). Methods. (L)EER is clinically and histopathologically evaluated with a monocentric prospective observa- tional study. Patients with advanced and recurrent cervicovaginal cancer are treatment candidates if distant metastases and tumor fixation at the region of the sciatic foramen can be excluded. Results. 91 patients with locally advanced primary (n=30) and recurrent or persistent (n=61) carcino- ma of the cervix and vagina were treated with (L)EER. 74% of the tumors were fixed to the pelvic wall. No (L) EER treatment was aborted, R0 resection was histopathologically confirmed in all cases. (L)EER definitively controlled the locoregional cancer in 92% (95% CI: 85-99) of the patients. Five year overall survival probabil- ity was 61% (95% CI: 49-72). Conclusions. The results of (L)EER treatment confirm the concept of cancer surgery based on ontogenetic anatomy. In patients with locally advanced and recurrent cervicovaginal cancer (L)EER achieves locoregional tumor control both with central disease and with tumors fixed to the pelvic side wall except at the region of the sciatic foramen.

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.

The objective of this study was to evaluate the role of the fimbriated end and nonfimbriated epithelium of fallopian tubes with regard to p53 signature, tubal intraepithelial lesions in transition (TILT), and serous tubal in-situ carcinoma (STIC) in cases of different kinds of serous pelvic cancer. This study immunohistochemically evaluated (by Ki-67 and p53 staining) the presence of p53 signature, TILT lesions, and STIC in 14 consecutive cases of prophylactic salpingo-oophorectomy in women with BRCA-1/2 mutation (bilateral salpingo-oophorectomy), 11 cases of macroscopically inconspicuous adnexae of patients with primary contralateral tubal cancer (TC), 9 cases of primary peritoneal cancer (PPC), and 10 cases of serous ovarian borderline tumors, evaluating the fallopian tubes (using the Sectioning and Extensively Examining the FIMbria protocol), ovarian surface epithelium, and ovarian cortical inclusion cysts. The frequencies of p53 signature, TILT, and STIC were 35.7%, 7.1%, and 0% in cases of prophylactic surgery, 18.2%, 9.1%, and 18.2% in TC, and 11.1%, 0%, and 33.3% in PPC. These precursor lesions were missed during the initial routine screening and were found in the fimbriated end of the fallopian tubes in 94%. In 1 case of PPC, staining for p53 was negative in STIC. The studied adnexal tissue of serous ovarian borderline tumor and ovarian cortical inclusion cysts of all cases showed no alterations according to p53 signature, TILT, or STIC. STIC and p53 signature as precursor lesions of pelvic serous cancer were seen in macroscopically inconspicuous contralateral fallopian tubes in unilateral TC, in patients with elective bilateral salpingo-oophorectomy, and in patients affected by PPC. Therefore, we propose the complete processing of adnexal tissue and the use of step sectioning to establish the correct diagnosis. Immunohistochemistry for p53 and ki-67 may aid in the diagnosis, but is not necessary for routine investigation.

Objectives: The aim of this study was to determine the frequency of diaphragm involvement (DI) in cases of International Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV primary epithelial ovarian, fallopian tube, or peritoneal cancer; the frequency of use of different surgical techniques in managing diaphragm implants; and the procedure-associated morbidity. Methods: A retrospective analysis of consecutive patients undergoing primary surgery by a single surgical team between January 2005 and June 2007 was accomplished. Patients with tumors of low malignant potential and nonepithelial histologic diagnosis and those who received neoadjuvant chemotherapy were excluded. Results: Thirty-three patients met the inclusion criteria. Diaphragm involvement was found in 91% of the cases. Whereas the left hemidiaphragm is never involved alone, the right side is significantly affected more extensively (P = 0.002) and frequently (alone, 20%; both sides, 80%). The frequency of use of procedures varies considerably in the literature, whereas full-thickness diaphragm resection (DR) had to be performed in 53% of our patients with DI. Diaphragm resection at the left hemidiaphragm and bilateral DRs are very rare in primary cases. A specific histopathologic examination of the DR preparation is desirable. A simple 4-tiered classification of the infiltration depth is proposed. The most frequent complication is serothorax, but a generous indication for intraoperative chest tube placement is solely recommended in cases of DR. Conclusions: Surgical effort in achieving an optimum cytoreduction could be evaluated more precisely with parameters of DI and diaphragm-related treatment procedures. The usual quality criteria for ovarian cancer surgery, such as residual tumor state and morbidity, are more marked by subjectivity and inconsistent definitions.

The aim of this study was to compare the precision of two different methods in detecting clinical depression in tumor patients: the use of a screening questionnaire versus the assessment by health care providers (nurses and doctors). During their first days of inpatient cancer treatment, tumor patients were interviewed using the Structured Clinical Interview for DSM (SCID). Their physicians and nurses were asked to assess the mental health of the patients and their need for professional psychosocial support. Additionally, every patient completed the Hospital Anxiety and Depression Scale (HADS). Out of 329 patients, 28 were diagnosed with either a major or a minor depression according to the SCID. Physicians assessed 15 of the depressed patients as being depressed (sensitivity, 0.54; specificity, 0.38). Nurses identified 19 (sensitivity, 0.68; specificity, 0.45) and the HADS 27 (sensitivity, 0.96; specificity, 0.50) of the depressed patients. The HADS performed well in detecting depressed cancer patients in acute oncological care, whereas physicians and nurses often were unable to recognize depressed patients.

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 (Mullerian) compartment except its distal part. Non-Mullerian 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 Mullerian 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 Mullerian 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 Mullerian 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 Mullerian 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.