Leiomyomas (fibroids), the most common benign pelvic tumour, are classified by their location: submucosal, subserosal and intramural. A large proportion of women develop fibroids by menopause and about 15 to 30% become symptomatic. Clinically hypermenorrhea and dysmenorrhea may occur and, depending on the size, result in displacement of the urinary bladder or bowel. Submucosal fibroids are often associated with infertility as they affect the uterine cavity by altering sperm transportation and/or the implantation of the embryo. The differential diagnosis includes endometrial polyps and adenomyomas, but also malignant tumors such as uterine sarcomas. Treatment of symptomatic uterine fibroids includes medical, surgical and embolization techniques and should be adjusted to the patient symptoms, the patient's level of suffering and the possibility of organ preservation.

Background We explored the hypothesis that high-quality standards in diagnostic mammography can lead to an early diagnosis of breast cancers and identifies at risk populations outside screening programs. The histopathological features and distribution of the TNM classification were examined in relation to patient age in a large group of women with breast cancers participating in the Quality Assured Mamma Diagnostic (QuaMaDi) program of the state of Schleswig–Holstein. Patients and methods Surgical pathological reports were studied for clinicopathological characteristics, receptor status, molecular subtype and tumor stage. The analysis was conducted by dividing the study population into three age groups: women under 50 years (pre-screening), 50–69 years (peri-screening) and over 70 years (post-screening). Results 7.111 biopsies and 2.887 resection specimens were included. Breast cancer was diagnosed in 4.241 (59.7%) cases, one fourth of them in women < 50 years. Elderly women (> 70 years) had more well-differentiated, estrogen receptor (ER)-positive and HER2-negative carcinomas, whereas younger women (< 50 years) tended to have more poorly differentiated, ER negative, and HER2-positive carcinomas. 47% of breast carcinoma were luminal B tumors and were most common regardless of age. 70.4% of resected specimen had pT1 stage. Nodal negative were 71.2%. Conclusion In QuaMaDi breast cancer was diagnosed at an early and potentially curable stage of the disease due to high-quality standards in diagnostic mammography. In addition, regardless of age, an increased number of prognostically unfavorable molecular subtypes were detected. Thus, QuaMaDi helps to identify at risk populations. QuaMaDi significantly improves diagnostic mammography and complements mammography screening programs.

Leiomyome sind die häufigsten gutartigen Tumoren des Uterus. Bis zur Menopause entwickelt ein Großteil aller Frauen Myome. Symptomatisch werden davon ca. 15–30 %. Klinisch kann es zu Hyper-und Dysmenorrhö kommen, ferner, in Abhängigkeit der Größe, zu Verdrängungsbeschwerden von Harnblase oder Darm. Nicht selten sind submuköse Myome ein Grund für ungewollte Kinderlosigkeit. Differenzialdiagnostisch muss an Endometriumpolypen und Adenomyome gedacht werden, aber auch an maligne Tumoren, wie das Uterussarkom. Im Falle von symptomatischen Uterusmyomen kann die Indikation für eine Therapie gestellt werden. Diese umfasst medikamentöse, radiologisch-interventionelle und operative Verfahren. Maßgeblich für die Entscheidung sind die klinische Symptomatik, der Leidensdruck der Patientin und die Möglichkeit des Organerhalts.

Background: Hamartomas of the breast are rare benign tumors. Pre- and also postoperative differentiation from other benign or even malignant tumors is challenging. Case Presentation: A 36-year-old female presented with a giant tumor of the left breast. The patient had suffered from an early breast cancer of the contralateral right breast the year before, which was treated with breast-conserving therapy, radiation, and endocrine therapy ever since. The hamartoma was classified as BI-RADS 2 in mammography and BI-RADS 4 in ultrasound. On clinical examination, a tumor of nearly 15 cm in size led to an abstruse deformity of the breast and the nipple-areola complex. We found an indolent, grand bulging tumor with an elastic texture directly beneath the skin. A biopsy that had been performed before was compatible with the suspected hamartoma. Because of the remaining diagnostic uncertainties after contralateral breast cancer and the progressive malformation of the left breast, a tumor extirpation utilizing a reduction mammaplasty was performed without complications. Subsequent genetic analyses excluded a loss of PTEN in this patient. Conclusion: We presented the rare case of a 36-year-old woman with a history of breast cancer and a 700-g breast hamartoma. The preoperative and even the postoperative specification of a hamartoma remains challenging, and associations with genetic alterations should be considered.

Background Fibroids of the uterus are the most common benign pelvic tumors in women worldwide. Their diagnosis is usually not missed because of the widespread and well-established use of ultrasound in gynecological clinics. Hence, the development of an unusually large myoma is a rare event, particularly in first-world countries such as Germany. It is even more uncommon that a myoma is misdiagnosed as a dietary failure. Case presentation Herein, we report the case of a Caucasian woman with a giant fibroid that reached a size of over 50 cm, growing slowly over the past 15 years, and was misdiagnosed as abdominal fat due to weight gain. We aim to discuss the factors that lead to the growth of such a huge tumoral mass, including misdiagnosis and treatment, and the psychological impact. Through this case, we intend to increase the awareness among general physicians and gynecologists. Although menstrual disorders incorporate several pathologies, adequate assessment remains the primary responsibility of health care providers. A literature review revealed approximately 60 cases of giant uterine fibroids. Conclusion The use of clinical and diagnostic devices, especially ultrasound, in this case, is indispensable. In conclusion, the growth of a giant fibroid can have disastrous effects on a woman’s health, including surgical trauma and psychological issues.

Sekundärmalignome stellen eine seltene, gravierende Spätfolge einer Behandlung mit ionisierenden Strahlen dar. Jedoch ist nur ein Bruchteil von Zweittumoren onkologischer Patienten tatsächlich kausal durch eine Bestrahlung bedingt. Angiosarkome der Brust sind seltene Tumoren, die jedoch häufig mit einer vorangegangenen Bestrahlung assoziiert sind. Anhand eines Fallberichts werden Epidemiologie, Diagnostik und Therapie von Angiosarkomen der Brust erläutert.

A 36-year old young female presents with a giant hamartoma of the left breast. She suffered from an early breast cancer of the contralateral breast before, which was treated with breast conserving therapy, radiation, and endocrine therapy ever since.

In HNSCC, protein- and mRNA-expression of the antileukoproteinase SLPI are significantly inverse correlated with HPV-infection suggesting that elevated expression of SLPI protects against HPV-infections. Moreover, SLPI-expression is up-regulated in HNSCC-patients reporting a smoking habit. Here, we investigate the described correlation in other HPV-driven cancers, namely vulvar squamous cell carcinoma (VSCC). FFPE samples of 99 VSCC were analyzed by PCR for HPV-DNA-expression and by RT-qPCR for SLPI-mRNA-expression. Of 99 VSCC 10 (10.1%) are HPV-positive; 9 were HPV16; 1 HPV18; all were E6/E7 mRNA-positive. 33 of the 99 patients (33.3%) reported a smoking habit; 7 (21.1%) of these were HPV-positive. Of 66 (66.7%) non-smokers 3 (4.5%) were HPV-positive. SLPI-expression was 4.0-fold lower in HPV-positive than HPV-negative patients. Smoking resulted in 2.3-fold higher SLPI expression. The data presented here indicate that SLPI plays a pivotal role in HPV-infection not only in HNSCC but also in VSCC and possibly also in other HPV-driven cancers. This however, needs to be analyzed in future studies. Furthermore these data lead to the hypothesis that the smoking induced SLPI-increase is systemic rather than local, as assumed based on the HNSCC data.

Background While standard RNA expression tests stratify patients into risk groups, RNA-Seq can guide personalized drug selection based on expressed mutations, fusion genes, and differential expression (DE) between tumor and normal tissue. However, patient-matched normal tissue may be unavailable. Additionally, biological variability in normal tissue and technological biases may confound results. Therefore, we present normal expression reference data for two sequencing methods that are suitable for breast biopsies. Results We identified breast cancer related and drug related genes that are expressed uniformly across our normal samples. Large subsets of these genes are identical for formalin fixed paraffin embedded samples and fresh frozen samples. Adipocyte signatures were detected in frozen compared to formalin samples, prepared by surgeons and pathologists, respectively. Gene expression confounded by adipocytes was identified using fat tissue samples. Finally, immune repertoire statistics were obtained for healthy breast, tumor and fat tissues. Conclusions Our reference data can be used with patient tumor samples that are asservated and sequenced with a matching aforementioned method. Coefficients of variation are given for normal gene expression. Thus, potential drug selection can be based on confidently overexpressed genes and immune repertoire statistics. Materials and Methods Normal expression from formalin and frozen healthy breast tissue samples using Roche Kapa RiboErase (total RNA) (19 formalin, 9 frozen) and Illumina TruSeq RNA Access (targeted RNA-Seq, aka TruSeq RNA Exome) (11 formalin, 1 frozen), and fat tissue (6 frozen Access). Tumor DE using 10 formalin total RNA tumor samples and 1 frozen targeted RNA tumor sample.

Microsatellite instable gastric cancer (MSI-GC) is a specific molecular subtype of GC. We studied the phenotypes, genotypes, and clinicopathologic characteristics of MSI-GC in a white GC cohort and compared our findings with an extended literature review. The study cohort consisted of 482 patients. Specimens were available from 452 cases and were used for immunostaining (MLH1, PMS2, MSH2, MSH6) and molecular biological analyses (BAT-25, BAT-26, NR-21, NR-24, NR-27; Epstein-Barr virus in situ hybridization). Thirty-four (7.5%) GCs were MSI. Loss of MLH1 and/or PMS2 was found in 30 (88%) MSI-GC, 3 (9%) showed loss of MSH2 and/or MSH6. One (3%) MSI-GC was identified only by molecular biological testing. A single case was heterogeneous and contained microsatellite-stable and instable tumor areas. Twenty-one (62%) MSI-GCs showed unusual histologic features. MSI-GC was not found in diffuse-type or Epstein-Barr virus-positive GC. MSIGC was significantly more prevalent in elderly patients, distal stomach, and was associated with a significantly lower number of lymph node metastases and a significantly better overall and tumor-specific survival. MSI-GC constitutes a small but relevant subgroup of GC with distinct clinicopathologic characteristics. Our literature review illustrates the shortcomings of missing standardized testing algorithms with prevalences of MSI-GC ranging from 0% to 44.5%. Future studies should test the hypothesis that patients with MSI-GCs may not need adjuvant/perioperative chemotherapy. However, this will require a standardized, quality-controlled diagnostic algorithm of MSI for GC.

Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction.

PURPOSE:Tumor surgery is aimed at complete resection of the lesion while ensuring a sufficient tumor-specific safety distance. Nevertheless, in many cases the most peripheral part - the invasion front - remains in situ. Tumor cells at the tumor margin have been reported to lose their epithelial properties and acquire features of mesenchymal cells. The process of epithelial-to-mesenchymal transition (EMT) is believed to be of prime importance for tissue and vessel invasion. Furthermore, the detection of tumor-infiltrating lymphocytes in the microenvironment of breast cancer might serve as a reliable prognostic marker. METHODS:We investigated tissue microarrays of 352 breast cancer patients with regard to the presence and distribution of the EMT factor Snail, and the presence of FoxP3, CD3 and CD8 in the immune microenvironment. RESULTS:The expression of the transcription factor Snail is strongly associated with longer disease-free and overall survival. The presence of CD3, CD8 or FoxP3 is associated with a better outcome, although statistically significant results were noted only for FoxP3. The prognostic significance of FoxP3 and Snail were also proven in multivariate analysis. CONCLUSIONS:Based on previous studies concerning the intratumoral heterogeneity of EMT, our results suggest that Snail and FoxP3 are possible prognostic markers for breast cancer. The diverse presence of lymphocytes in the tumor microenvironment (CD3 and CD8) was confirmed. Although the importance of these markers is known, their specific role in tumor invasion and metastasis as well as their hierarchical organization in these tumors remain unclear.

Einleitung: Die anti-PD-L1/PD-1-Immuntherapie stellt eine neue vielversprechende Therapieoption des fortgeschrittenen Magenkarzinoms dar. Obwohl der Einfluss einer PD-L1-Expression von Tumorzellen auf das Therapieansprechen noch nicht abschließend geklärt ist, gibt es doch Anhaltspunkte, dass PD-L1-exprimierende Tumoren besser auf eine PD-L1/PD-1-Inhibition ansprechen. Der Einsatz von prädiktiven Biomarkern beim Magenkarzinom wird jedoch durch seine ausgeprägte intratumorale Heterogenität erschwert: Biopsien bergen das Risiko von falsch-negativen Ergebnissen.

BACKGROUND:Inadvertently retained sponges and instruments still constitute a major but preventable complication in surgery. Given the high geographic mobility of patients, the fluctuation of physician-patient contact, and communication problems due to language barriers, the conscientious use of structured safety protocols in clinical routine is an essential aspect of quality in health care.CASE PRESENTATION:We report the case of a 24-year-old refugee from Syria who presented at our gynecological outpatient department with a tumor in the lower abdomen, suspected to be a lump in the ovary or the uterus. Language barriers hindered exact recording of the patient's medical history. We knew she had undergone three Caesarean sections several years ago. The diagnostic laparoscopy unexpectedly revealed a tumor suspected to be a retained surgical sponge. The lesion was removed completely and the patient discharged from the clinic five days later.CONCLUSION:In ambiguous cases, the diagnostic and therapeutic potential of minimally invasive surgery ensures safe and effective treatment of the patient, a short hospital stay, and low rates of complications. Especially in cases of language and/or cultural barriers, structured safety protocols should be a part of clinical routine in order to prevent unnecessary complications.

Targeting the PD-1/PD-L1 immune checkpoint signaling is a novel promising treatment strategy in several tumor entities, and it is suggested that PD-L1/PD-1 expression is predictive for a PD-1/PD-L1 checkpoint inhibitor treatment response. We investigated the expression of PD-L1 and PD-1 by immunohistochemistry in a large and well characterized gastric cancer (GC) cohort of Caucasian patients, consisting of 465 GC samples and 15 corresponding liver metastases. Staining results were correlated with clinico-pathological characteristics and survival. PD-L1 expression was found in tumor cells of 140 GCs (30.1%) and 9 liver metastases (60%) respectively in immune cells of 411 GCs (88.4%) and 11 liver metastases (73.3%). PD-1 was expressed in tumor infiltrating lymphocytes in 250 GCs (53.8%) and in 11 liver metastases (73.3%). PD-L1 expression was significantly more prevalent in men, GCs of the proximal stomach, unclassified, papillary, Her2/neu-positive, Epstein-Barr-virus-positive, microsatellite instable, and PIK3CA-mutated GCs. A high PD-L1/PD-1 expression was associated with a significantly better patient outcome, and PD-L1 turned out to be an independent survival prognosticator. The correlation of PD-L1/PD-1 expression with distinct clinico-pathological patient characteristics may serve as a surrogate marker of PD-L1-positive GCs and may direct the use of immune checkpoint treatment strategies.

The application of Trastuzumab on gastric cancer patients is based on Her2/neu immunostaining. The testing method relies on visual estimation of both membranous staining intensity, and positive tumor ratio with respect to a 10% cutoff. We evaluated the effect of inter- and intraobserver variations of both factors on therapeutic decision, especially if the positive tumor ratio hovers around the 10% cutoff. Ten pathologists scored 12 Her2/neu immunohistologically stained whole sections of gastric cancer. Applying the common rules for Her2/neu testing for gastric cancer, they separately noted the strongest identifiable staining intensity and the corresponding positive tumor ratio. Scoring was done repeatedly using the microscope, plain virtual microscopy, and virtual microscopy with a manual outline drawing function. Agreements on the strongest identified staining intensities were moderate. Overall concordance correlation coefficients of positive tumor ratios ranged from 0.55 to 0.81. Reproducibility was not improved by virtual microscopy. Pathologists have a good ability to estimate ratios of clearly demarcated areas, but gradients in staining intensities hinder reproducible visual demarcation of positive tumor areas. When hovering around the 10% positive tumor ratio cutoff there is a risk of misinterpretation of the staining results. This could lead to a denial of Trastuzumab therapy. Assessment of Her2/neu expression should be carried out by experienced pathologists because they can more reproducibly rate membranous staining intensities. The low reproducibility of positive tumor ratio is inherent in the testing method and cannot be improved by virtual microscopy. Therefore, we propose to reconsider the 10% cut-off limit.

Background Breast cancer screening programs have been established worldwide and early detection of breast cancer has increased steadily. The most common way to confirm dignity of non-palpable and sonographically-occult suspicious findings on mammography is the stereotactically-guided vacuum-assisted breast biopsy Purpose To compare two stereotactically guided vacuum-assisted breast biopsy systems measuring time effectiveness and quality of harvested material in clinical practice. Material and Methods One hundred and forty-six patients presenting with suspicious microcalcifications on mammography were included in the study. Biopsies were carried out with either the Mammotome® system (11-gauge and 8-gauge) or the ATEC® system (12-gauge and 9-gauge). Lesions with a diameter <15 mm on mammography were biopsied with 11-gauge or 12-gauge devices whereas lesions >15 mm were targeted with 8-gauge and 9-gauge. Mammotome® system 8-gauge device was used in 34 patients, the 11-gauge system in 37 patients. The ATEC® system 9-gauge system was used in 37 patients and 12-gauge in 38 patients. Time was taken, focusing on preparing the system, time of collecting the samples, preparing the samples, and cleaning the site. During the biopsies 24 samples were taken. The histologic quality of the tissue samples was judged by a pathologist in a blinded fashion according to a specimen grading classification concerning tissue fragmentation, artefacts, and the adequacy of the tissue for diagnosis. Results The median overall time for the Mammotome® system was 879 s (11-gauge) and 934 s (8-gauge) and for the ATEC® system 671 s (12-gauge) and 673 s (9-gauge). The ATEC® system displays a significantly shorter overall time for small and large biopsy devices (U-test, P < 0.001). Concerning the mean time difference of the overall time comparing small and large systems the ATEC® system was 267.6 s faster using the small and 244.8 s faster using the large system. Comparing the histologic quality of tissue samples the Mammotome® system shows significantly higher values for the large and the small system (Chi-square test, P < 0.001). Conclusion Both biopsy systems meet all requirements for daily practice and confirm the diagnosis of suspicious microcalcifications. The ATEC® system was observed to be faster but this difference of about 250 s might not be relevant in daily practice. The Mammotome® system provides a better histologic quality of tissue samples.

Individualized therapy in breast cancer has progressed substantially in the last few years. HER2-positive patients in particular have benefitted from the development of various innovative therapies that involve the blockade of signal transduction pathways. How-ever, there are still many women who are over-treated with chemotherapy and who would not need this treatment if their individual risk of recurrence and benefit to be gained from adjuvant chemotherapy were known. Classic prognostic factors are not able to discriminate between patients with good and bad prognosis so as to reduce the group of intermediate-risk patients to an acceptable size, if at all. The individual risk of recurrence might also be an individual-dependent estimation. In this review we describe the present classification of intrinsic subtypes of breast cancer and provide information on current commercially available prognostic and predictive tests for breast cancer patients.

Die molekulare Klassifikation von Karzinomen nimmt in der Routinediagnostik und für Therapieentscheidungen einen immer größeren Raum ein. Der Beitrag beleuchtet, ob die für das Mammakarzinom vorgenommene Einteilung in Luminal A und B, Her2/neu-angereichert und Basalzelltyp für die tägliche Praxis praktikabel, validiert und verlässlich ist. Zudem werden wesentliche Neuerungen der im Jahr 2012 publizierten WHO-Klassifikation der Tumoren der Brust vorgestellt.

The purpose of this single-center study was to determine the practicability of the intra-operative use of one-step nucleic acid amplification (OSNA) as the only method for detection of SLN. The OSNA system has been well described and is supposed to be as accurate as conventional histology.