Wolfgang Weikel

Prognostic Effect of Epithelial Cell Adhesion Molecule Overexpression in Untreated Node-Negative Breast Cancer

Purpose: Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention not only as a prognostic factor in breast cancer but also as a potential target for immunotherapy. We examined Ep-CAM expression in 402 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting. Experimental Design: Ep-CAM expression was evaluated by immunostaining. Its prognostic effect was estimated relative to overexpression/amplification of HER-2, histologic grade, tumor size, age, and hormone receptor expression. Results: Ep-CAM status was positive in 106 (26.4%) patients. In multivariate analysis, Ep-CAM status was associated with disease-free survival independent of age, pT stage, histologic grade, estrogen receptor (ER), progesterone receptor (PR), as well as HER2 status (P = 0.028; hazard ratio, 1.60; 95% confidence interval, 1.05-2.44). Recently, so-called triple-negative (HER-2, ER, and PR) breast cancer has received increased attention. We noticed a similar association of Ep-CAM with disease-free survival in the triple-negative group as for the entire cohort. Conclusion: In this study of untreated breast cancer patients, Ep-CAM overexpression was associated with poor survival in the entire cohort and in the subgroup of triple-negative breast cancer. This suggests that Ep-CAM may be a well-suited target for specific therapies particularly in HER-2–, ER-, and PR-negative tumors.

Immunohistochemical evaluation of growth fractions in human breast cancers using monoclonal antibody Ki-67

SummaryWe performed immunohistochemical analyses of 568 breast/cancer specimens using Ki-67, a monoclonal antibody specific for a nuclear antigen present in proliferating cells. The specimens were divided into three groups (I–III) according to the proportion of Ki-positive cells detected. These findings were compared with features of tumor extension as well as with certain prognostic variables.There was no detectable correlation between Ki-67 reactivity and either tumor size or node involvement. In contrast, a statistically significant correlation was found between Ki-67 reactivity and tumor grading, in that G-I tumors had small growth fractions, while a high proportion of G-III tumors exhibited strong (group III) Ki-67 positivity. When growth fractions were compared with biochemical receptor status, a significant difference was detected between tumors with negative and positive findings for receptors. The same co-variation was observed with respect to the overexpression ofneu-protein P185, with mostneu-positive carcinomas being strongly positive for Ki-67 (group III).In the relapse cases examined, there was a close correspondence between Ki-67 reactivity and the duration of the disease-free period. Long-term observation of patients with primary breast carcinoma revealed that, with regard to overall survival, the less reactive groups I and II differed significantly from group III. With respect to disease-free survival, no difference was detectable between Ki-groups II and III, but when these two groups together were compared with group I, a significant trend emerged. Similar results for both overall and disease-free survival were obtained for subgroups of pT2 and G-II carcinomas as well as for receptor expression. Node-negative tumors in the highly reactive group III exhibited a strong trend indicating unfavorable overall survival rates, whereas no such difference was demonstrable with respect to disease-free survival. Node-positive tumors could not be differentiated on the basis of overall survival, but the correlation with growth fraction was significant for disease-free survival.In conclusion, Ki-67 offers a simple and effective method for defining the proliferating cell compartment of breast carcinoma, and may facilitate the assessment of individual tumors as well as efforts to predict the course of disease.

mdm2 mRNA expression is associated with survival in ovarian cancer

Expression of mdm‐2 mRNA was measured in 90 ovarian‐cancer tissue specimens using the S1 nuclease assay, to investigate a possible association between MDM2 expression and prognosis. mdm‐2 mRNA expression was an independent prognostic factor for patients with primary ovarian cancer, FIGO (International Federation of Gynecology and Obstetrics) stages III and IV (n = 57), who all received chemotherapy with carboplatin or cisplatin and cyclophosphamide. Median survival time for patients (FIGO stages III and IV) with no detectable expression of mdm‐2 mRNA (n = 14) was 171 days, as compared with 839 days for patients (n = 43) with detectable mdm‐2 mRNA (p = 0.0194; log‐rank test). However, no association between mdm‐2 mRNA expression and survival was observed for patients with FIGO stages I and II who did not receive chemotherapy. mdm‐2 expression was not associated with FIGO stage, residual disease, histologic grade and type. Our results suggest that mdm‐2, which is known to disrupt p53 function, sensitizes ovarian‐cancer cells to cisplatin/cyclophosphamide, possibly by inhibition of p53‐mediated G1 cell‐cycle arrest and p53‐stimulated nucleotide‐excision repair. Int. J. Cancer 74:438–442, 1997.

Long-term prognostic significance of HER-2/neu in untreated node-negative breast cancer depends on the method of testing.

IntroductionThe prognostic significance of HER-2/neu in breast cancer is a matter of controversy. We have performed a study in 101 node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting, and analysed the prognostic significance of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), both separately and in combination, in comparison with traditional prognostic factors.MethodsOverexpression was classified semiquantitatively according to a score (0 to 3+) (HER-2_SCO). FISH was used to analyse HER2/neu amplification (HER-2_AMP). Patients classified 2+ by IHC were examined with FISH for amplification (HER-2_ALG). Patients with 3+ overexpression as well as amplification of HER-2/neu were positive for the combined variable HER2_COM. These variables were compared with tumour size, histological grade and hormone receptor status.ResultsHER-2_SCO was 3+ in 20% of all tumours. HER-2_ALG was positive in 22% and amplification (HER-2_AMP) was found in 17% of all tumours. Eleven percent of the tumours showed simultaneous 3+ overexpression and amplification. Only histological grade (relative risk [RR] 3.22, 95% confidence interval [CI] 1.73–5.99, P = 0.0002) and HER-2_AMP (RR 2.47, 95% CI 1.12–5.48, P = 0.026) were significant for disease-free survival in multivariate analysis. For overall survival, both histological grade (RR 3.89, 95% CI 1.77–8.55, P = 0.0007) and HER-2_AMP (RR 3.08, 95% CI 1.24–7.66, P = 0.016) retained their independent significance.ConclusionThe prognostic significance of HER-2/neu in node-negative breast cancer depends on the method of testing: only the amplification of HER-2/neu is an independent prognostic factor for the long-term prognosis of untreated node-negative breast cancer.

Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathological parameters.

Abstract Ninety-eight patients with histologically confirmed ovarian tumors (77 primary ovarian carcinomas of stages T1 to T3 according to the postoperative histopathological classification pTNM classification, 14 ovarian metastases of various origins and seven benign ovarian tumors) were investigated with regard to the concentration of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in membrane extracts of tumors. The results were correlated with the clinical course and with histopathological findings. With more advanced stage of primary ovarian carcinomas, there was a highly significant rise in the membrane concentrations of both uPA and PAI-1. However, increasing dedifferentiation of the tumors correlated only with uPA, but not with PAI-1. There was no correlation between the number of steroid receptors for estradiol and progesterone and the content of uPA or PAI-1 in the primary ovarian carcinomas. In the 14 ovarian metastases of different origins incluced in the study, the contents of uPA and PAI-1 were comparable to those of primary ovarian carcinomas. Compared with the malignant ovarian tumors, the median uPA and PAI-1 concentrations in the membrane fraction were 2.5–6 fold lower (highly significant) in the group of seven benign tumors. A cut-off value of 4.8 ng/mg pellet protein for a prognostically favorable (< 4.8) or unfavorable course (> 4.8) could be determined for uPA (p = 0.0392) but not for PAI-1 on the basis of the Kaplan and Meier survival curves in the malignant primary ovarian carcinomas.

Invasives Zervixkarzinom (pT2b-pT4a) Wertigkeit der konventionellen und pharmakokinetischen Magnetresonanztomographie (MRT) im Vergleich zum Großflächenschnitt und dem histopathologischen Befund

ZusammenfassungZiel: Klassifikation des primären Zervixkarzinomes im fortgeschrittenen Tumorstadium (pT2b-pT4a) mittels der konventionellen und der pharmakokinetischen MRT in Korrelation zum Großflächenschnitt und dem histopathologischem Befund. Material und Methode: 17 Patientinnen mit bioptisch gesichertem Plattenepithelkarzinom der Zervix wurden prospektiv mittels konventioneller und pharmakokinetischer MRT untersucht. Für die dynamische MR-Untersuchung wurde eine „Saturation-Recovery-TurboFLASH (SRTF)-Sequenz“ gewählt mit der innerhalb von 13 s 10 Schichten gemessen werden können. Die Signalzeitänderungen wurden mit Hilfe eines pharmakokinetischen Modells quantifiziert und farbkodiert. Ergebnis: Auf der Basis der T 2-gewichteten, der kontrastmittelunterstützten T 1-gewichteten SE und der pharmakokinetischen MRT wurde eine Treffsicherheit im Nachweis eines parametranen Befalls von 85 % bzw. jeweils in 73 % beobachtet. Demgegenüber wurde mit der pharmakokinetischen MRT bei der Beurteilung einer Infiltration der Blase und/oder des Rektums (pT4a) im Vergleich zu T 2-Wichtung eine signifikant (p < 0,05) höhere Treffsicherheit mit 88 gegenüber 67 % erhalten. Schlußfolgerung: T 2-gewichtete SE Sequenzen sind bei der Abklärung eines parametranen Befalls kontrastmittelunterstützten, T 1-gewichteten SE oder dynamischen MR-Bildgebungstechniken überlegen. Demgegenüber gelingt die Beurteilung einer Tumorinfiltration in die Harnblase und/oder Rektum (pT4a) mit der höchsten Treffsicherheit in der pharmakokinetischen MRT.SummaryPurpose: To compare staging of advanced primary cervical carcinoma (pT2b-pT4a) by conventional and pharmacokinetic magnetic resonance imaging (MRI) with the giant cross section specimen and histopathological findings. Materials and methods: Seventeen patients with biopsy-proven cancer of the cervix and clinically suspected invasive cancer (FIGO II B-IVA) were prospectively examined by conventional (T 2 and contrast-enhanced T 1-weighted spin echo images) and pharmacokinetic MRI. All MRI findings were compared with the giant cross section specimen and histopathology as the standard of reference. For pharmacokinetic MRI, a saturation recovery TurboFLASH sequence was used with a high temporal resolution of 13 s per ten sections. Signal-time changes were analyzed using a pharmacokinetic model and the computed parameter values were visualized by color-coded overlay. Results: Analysis of parametrial invasion on T 2-weighted images resulted in an accuracy of 85 % and 73 % on contrast-enhanced T 1-weighted images and on pharmacokinetic MR images respectively. Accuracy of analysis of bladder and/or rectal wall invasion was significantly (P < 0.05) higher on pharmacokinetic MR images (88 %) than on T 2-weighted images (67 %). Contrast-enhanced T 1-weighted spin-echo images improved staging accuracy compared with T 2-weighted images (76 % vs 67 %). Conclusion: At present, conventional T 2-weighted SE images are superior to contrast-enhanced T 1-weighted SE and pharmacokinetic MR images in depicting infiltration of the parametrium. However, suspected infiltration of the bladder and/or rectum (pT4a) is diagnosed more accurately on pharmacokinetic images than on conventional MR images.

Angiogenesis of cancer of the cervix. Contrast-enhanced dynamic MRT, histological quantification of capillary density and lymph system infiltration

Purpose: It was the aim of this project to examine (i) the relationships between contrast-enhanced dynamic MR imaging derived characteristics and histologic microvessel density counts – a recognized surrogate of tumor angiogenesis – from tumors in patients with primary or recurrent cancer of the uterine cervix, and (ii) to correlate these parameters with lymphatic involvement (i. e. lymphatic channels) to assess tumorbiological aggressiveness in terms of lymphatic spread. Materials and methods: Pharmacokinetic MR imaging parameters (amplitude A, exchange rate constant k21) were derived from contrast-enhanced dynamic MR imaging in thirty-three patients with biopsy proven cancer of the uterine cervix. The pharmacokinetic MR imaging characteristics were correlated to histologic capillary density counts obtained from whole mount specimen. In addition, these data were correlated to the angiogenic activity as a marker for lymphatic system involvement. Results: Pharmacokinetic MR imaging derived parameters (A, k21) showed a weak but signifikant (p < 0.05) correlation with microvessel density counts. Lymphatic involvement was more comprehensibly assessed by the pharmacokinetic parameter k21 compared with histologic microvessel density, resulting in a significantly (p < 0.05) higher overall accuracy (85 % vs. 64 %), sensitivity (83 % vs. 54 %), and comparable specificity (89 % vs. 89 %), respectively. Conclusion: Our first results show that the signal-time curves measured by contrast-enhanced MR imaging are only in part influenced by microvessel density. In addition, MR imaging derived characteristics may assess tumorbiological aggressiveness in terms of lymphatic spread (i. e. lymphatic channels) more comprehensively than histologic microvessel density in patients with primary or recurrent cancer of the uterine cervix.ZusammenfassungIn dieser Studie wurde untersucht, ob es signifikante Zusammenhänge zwischen der histologischen Kapillardichte – einem anerkannten Marker der Tumorangiogenese – und der kontrastverstärkten, dynamischen MRT beim Zervixkarzinom gibt. Darüber hinaus gingen wir der Frage nach, ob mit Hilfe der dynamischen oder der histologischen Kapillardichte eine Lymphsysteminfiltration (insbesondere eine Lymphangiose) abgeschätzt werden kann. An 33 Patienten mit einem primären (n = 26) oder rezidivierenden (n = 7) Zervixkarzinom wurde das Tumorstadium, die Tumorgröße, die Beteiligung des lymphatischen Systems (Lymphspalten, Lymphknoten) und die histologische Tumorkapillardichte bestimmt. Präoperativ wurden kontrastverstärkte dynamische MR-Messungen an allen Patienten durchgeführt und diese Daten mittels eines pharmakokinetischen Modells (Amplitude A, Austauschkonstante k21) parametrisiert. Alle histopathologischen Parameter wurden an mediansagittalen oder axialen Großflächenschnitten, die kongruent zu der MRT-Meßebene plaziert wurden, bestimmt und miteinander korreliert. Es zeigte sich eine schwache, aber signifikante (p < 0,05) Korrelation zwischen der histologischen Bestimmung der Kapillardichte und den Parametern Amplitude A und k21. Die angiogenetische Aktivität als Prädiktor eines Befalls des lymphatischen Systems konnte besser durch den pharmakokinetischen Parameter k21 als durch die histologische Kapillardichte charakterisiert werden, resultierend in einer signifikant (p < 0,05) höheren Treffsicherheit (85 % vs. 64 %), Sensitivität (83 % vs. 54 %) bei identischer Spezifität (89 %). Aus den ersten Resultaten dieser fortlaufenden Studie ergibt sich, daß die im dynamischen MRT gemessene Signal-Zeit-Kurve nur bedingt durch die histologische Gefäßdichte beeinflußt wird. Darüber hinaus zeigt sich, daß der pharmakokinetische Parameter k21 die tumorbiologische Aggressivität im Sinne einer Lymphsysteminfiltration (insbesondere einer Lymphspalteninfiltration) detallierter als die reine Quantifizierung der histologischen Tumorkapillardichte beschreibt.

Hormonrezeptorbestimmung am Mammakarzinomgewebe Vergleich neuer immunhistologischer Techniken mit der biochemischen Rezeptortestung

ZusammenfassungZur routinemäßigen Bestimmung der Hormonrezeptoren am Mammakarzinomgewebe werden derzeit hauptsächlich 2 Verfahren verwendet: Die immunhistologische Detektion am Gefrierschnitt (ER-ICA und PgR-ICA) sowie die biochemische Rezeptoranalyse am Frischgewebe mit dem Radioliganden-Bindungs-Assay (DCC). Durch neue Antikörper ist jetzt die Rezeptorbestimmung an formalinfixiertem, in Paraffin eingebetteten Gewebe möglich. An 223 primären Mammakarzinomen und Mammakarzinomrezidiven wurden die Ergebnisse aller 3 Verfahren miteinander verglichen. Verwendet wurden die paraffingängigen Antikörper 1D5.26 gegen den Östrogenrezeptor (Fa. Immunotech, Hamburg) und mPR1 gegen den Progesteronrezeptor (Fa. Dianova, Hamburg). Die Übereinstimmung der positiven bzw. negativen Fälle in der Immunhistologie betrug 97,8 % für den Östrogen- und 85,7 % für den Progesteronrezeptor. Der Vergleich der Immunhistologie am Paraffinmaterial mit der Biochemie ergab eine Übereinstimmung für den Östrogenrezeptor von 74,7 % und für den Progesteronrezeptor von 68,7 %. Diese sind vergleichbar mit denen für ER-ICA und PgR-ICA gegenüber der Biochemie. Die Untersuchungen zeigen, daß die prognostisch und therapeutisch wichtigen Hormonrezeptoren auch an formalinfixiertem und in Paraffin eingebetteten Mammakarzinomgewebe immunhistologisch zuverlässig bestimmt werden können. Diese Ergebnisse sind zum einen wegen der Möglichkeit der Untersuchung eines nicht im Schnellschnitt gefundenen Karzinoms von großer Bedeutung, zum anderen bestehen deutliche Kostenunterschiede zwischen den verschiedenen Verfahren.SummaryFor evaluation of the hormone receptor status in breast cancer tissues two methods are mainly used: immunohistochemical detection by monoclonal antibodies on frozen sections (ER-ICA, PgR-ICA) and the biochemical radioligand-binding assay (DCC) of fresh tissue. Using new antibodies makes it possible to evaluate the estrogen and progesterone receptor status in formalin-fixed and paraffin-embedded tissue. In the present retrospective study, tissues from 223 primary breast carcinomas or breast carcinoma recurrences were reevaluated with the three methods mentioned above and the results were compared. We used antibody 1D5.26 reacting with the estrogen receptor and mPR1 specific for the progesterone receptor in paraffin-embedded tissue. The agreement of positive and negative cases between these two immunohistochemical procedures was 97.8 % for the estrogen receptor and 85.7 % for the progesterone receptor. Comparison of immunohistochemistry on paraffin-embedded tissue and biochemical evaluation showed an agreement of 74.7 % for the estrogen receptor and 68.7 % for the progesterone receptor. These results are comparable to the correspondence between ER-ICA and PgR-ICA and the DCC method. This study proves that the prognostically and therapeutically important hormone receptors can be reliably determined in formalin-fixed and paraffin-embedded tissues. These results are not only important for the evaluation of hormone receptors of a small breast carcinoma that is not found in the frozen section, but for the considerable difference in costs among the different methods.

Aspekte der Rehabilitation

Ist die spezifische Antitumorbehandlung beendet, so schliesen sich fur die meisten Patientinnen Rehabilitationsmasnahmen an. Unter dem Uberbegriff Rehabilitation werden medizinische Leistungen, Wiedereingliederungsmasnahmen in den Beruf und soziale Rehabilitation zusammengefasst. Ziel ist es, dass die Betroffenen mit so wenigen Einschrankungen wie moglich in ihr gewohntes Leben zuruckkehren, zum Beispiel die eigene Wohnung benutzen und den Alltag ohne fremde Hilfe bewaltigen konnen. Der Bedarf an Masnahmen ist individuell sehr unterschiedlich und abhangig von multiplen Faktoren wie Allgemeinzustand pratherapeutisch, Alter, Grunderkrankungen und bereits bestehenden tumorbedingten Einschrankungen. Hinzu kommen die durch die Therapie entstandenen Einschrankungen wie physische und psychische Veranderungen durch Operation, Strahlen- und Chemotherapie. Letztlich spielen auch die Lebensplanung der Patientin und damit das individuelle Rehabilitationsziel eine grose Rolle.

Plastische Rekonstruktion der Vulva

Die Therapie des Vulvakarzinoms erfolgt in der Regel durch eine operative Entfernung des Tumors und der Lymphknoten in der Inguinalregion. Je nach Lage, Grose und Ausdehnung des Tumors wird dieser durch eine lokale Resektion in sano, eine partielle oder komplette Vulvektomie reseziert. Ist der Wundverschluss nicht spannungsfrei moglich, ist eine Lappenplastik zum Wundverschluss erforderlich. Auch zur Verbesserung des funktionellen und/oder asthetischen Outcomes ist vor allem bei jungen Frauen haufig eine lokale Lappenplastik indiziert. In der Rezidivsituation oder bei extrem ausgedehnten Tumoren sind distante Lappen (z. B. vom Oberschenkel oder der Bauchdecke) notwendig, um diese grosen Defekte zu decken.