Prognosefaktoren bei der Planung organübergreifender Debulkingoperation und intraoperativer Strahlentherapie bei Beckenwandrezidiven gynäkologischer Karzinome

Zusammenfassung

Die prognostische Wertigkeit immunhistochemisch evaluierbarer Faktoren (Ki67, p53, CD31, BCL2, HER2) bei primären gynäkologischen Karzinomen wurde in Studien bestätigt. In der vorliegenden Arbeit wurde die prädiktive und prognostische Wertigkeit dieser Parameter bei fortgeschrittenen gynäkologischen Karzinomen, die mittels operativem Debulking und intraoperativer Radiotherapie behandelt wurden, untersucht.

22 Patientinnen mit fortgeschrittenen Beckenwandrezidiven verschiedener gynäkologischer Karzinome wurden nach Ausschluss einer Peritonealkarzinose mittels operativem Debulking und intraoperativer Radiotherapie behandelt. Die immunhistochemischen Bestimmungen (Ki67, p53, CD31, BCL2, HER2) erfolgten bei 17 Patientinnen aus Gewebeschnitten des Rezidivtumors.

Überraschenderweise fanden sich eine niedrige HER-2- und BCL-2- Expression (11,2 % bzw. 17,7 %). Patientinnen mit hoher intratumoraler Proliferationsrate (Ki67-Expression > 30 % der Zellen) zeigten eine signifikant schlechtere Prognose als Patientinnen mit niedriger Proliferationsrate (p = 0,015). Hohe CD31- und niedrige p53-Expressionsraten deuteten ebenfalls auf eine höhere Rezidivrate hin (p = 0,072 bzw. 0,092). Der tumorfreie Resektionsrand bleibt auch in fortgeschrittenen Stadien entscheidend für eine spätere Progression (p = 0,004).

In dieser Arbeit konnte die Bedeutung immunhistochemischer Faktoren im metastasierten Stadium gezeigt werden. Die Expression immunhistochemischer Faktoren ändert sich im komplexen Prozess der Metastasierung. Die Therapieform (adjuvant und/oder palliativ) könnte hierbei eine Rolle spielen. Der tumorfreie Resektionsrand bleibt auch in fortgeschrittenen Stadien entscheidend für die Prognose.

Abstract

Objective

We analyzed the prognostic value of the immunohistochemical factors Ki67, p53, CD31, BCL2 and HER2 in patients with recurrent gynecologic malignancies.

Methods

We reviewed 22 patients with advanced pelvic sidewall recurrence of gynecologic cancers treated with surgical debulking and intraoperative radiotherapy (IORT). Patients with peritoneal carcinomatosis were excluded. Ki67, p53, CD31, BCL2, and HER2 were evaluated in histologic specimens from 17 patients.

Results

The analyzed tumors showed low expression of HER2 and BCL2 (11 % and 18 %, respectively). Tumors with a high proliferative index (Ki67 expression > 30 % of cells) had a worse prognosis than those with a low proliferative index (P = 0.015). High CD31 expression and low p53 expression were also associated with a higher rate of recurrence (P = 0.07 and 0.09, respectively). Tumor-free resection margins were an important prognostic factor (P = 0.004).

Conclusion

Immunohistochemical parameters have prognostic relevance in patients with recurrent gynecologic cancer and can be considered when planning treatment. The expression of these factors changes during the progression of the disease. The status of the resection margins remains an important prognostic factor in patients with recurrent disease.

Literatur

• 1 Abe M, Shibamoto Y. The usefulness of intraoperative radiation therapy in the treatment of pelvic recurrence of cervical cancer.  Int J Radiation Oncology Biol Phys. 1996;  34 513-514
• 2 Allred D C, Elledge R, Clark G M, Fuqua S A. The p53 tumor-suppressor gene in human breast cancer.  Cancer Treat Res. 1994;  71 63-77
• 3 Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper J T, Dodge R, Clarke-Pearson D L, Marks P. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer.  Cancer Res. 1990;  50 4087-4091
• 4 Berchuck A, Rodriguez G, Kamel A, Soper J T, Clarke-Pearson D L, Bast R C. Expression of epidermal growth factor receptor and HEER-2/neu in normal and neoplastic cervix, vulva, and vagina.  Obstet Gynecol. 1990;  76 381-387
• 5 Berchuck A, Rodriguez G C, Kamel A, Dodge R K, Soper J T, Clarke Pearson D L, Bast R C. Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer.  Am J Obstet Gynecol. 1991;  164 669-674
• 6 Berchuck A, Rodriguez G, Kinney R B, Soper J T, Dodge R K, Clarke-Pearson D L, Bast R C. Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease.  Am J Obstet Gynecol. 1991;  164 15-21
• 7 Bottini A, Berruti A, Bersiga A, Brunelli A, Brizzi M P, Di Marco B, Cirillo F, Bolsi G, Bertoli G, Alquati P, Dogliotti L. Effect of neoadjuvant chemotherapy on Ki67 labelling index, c-erb-2 expression and steroid hormone receptor status in human breast tumours.  Anticancer Research. 1996;  16 3105-3110
• 8 Burke T W, Hoskins J W, Heller P B, Shen M C, Weiser E B, Park R C. Clinical patterns of tumor recurrence after radical hysterectomy in stage IB cervical carcinoma.  Obstet Gynecol. 1987;  69 382-385
• 9 Calvo F A, Micaily B, Brady L W. Intraoperative radiotherapy. A positive view.  Am J Clin Oncol. 1993;  16 418-423
• 10 Chiarugi V, Ruggiero M. Role of three cancer “master genes” p53, bcl2 and c-myc on the apoptotic process.  Tumori. 1996;  82 205-209
• 11 Clarke R B, Laidlaw I J, Jones L J, Howell A, Anderson E. Effect of tamoxifen on Ki67 labelling index in human breast tumours and its relationship to oestrogen and progesterone receptor status.  Br J Cancer. 1993;  67 606-611
• 12 Deutsch M, Parsons J A. Radiotherapy for carcinoma of the cervix recurrent after surgery.  Cancer. 1974;  34 2051-2055
• 13 Evans S R, Hilaris B S, Barker H RK. External vs. interstitial irradiation in unresectable recurrent cancer of the cervix.  Cancer. 1971;  28 1284-1288
• 14 Fox S B, Leek R D, Smith K, Hollyer J, Greenall M, Harris A L. Tumor angiogenesis in node-negative breast carcinomas - relationship with epidermal growth factor receptor, estrogen receptor, and survival.  Breast Cancer Res Treat. 1994;  29 109-116
• 15 Frindel E, Tubiana M. Radiobiology and cell cycle. Baserga R The Cell Cycle and Cancer. New York; Dekker 1971: 389-447
• 16 Garton G R, Gunderson L L, Webb M J, Wilson T O, Cha S A, Podratz K C. Intraoperative radiation therapy in gynecological cancer: Mayo Clinic Experience.  Gynecol Oncol. 1993;  48 328-332
• 17 Gasparini G, Bonoldi E, Viale G, Verderio P, Boracchi P, Panizzoni G A, Radaelli U, Di Bacco A, Guglielmi R B, Bevilacqua P. Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas.  Int J Cancer. 1996;  69 205-211
• 18 Gerard J P, Dargent D, Raudrant D, Braillon G, Gilly F N, Romestaining P, Sentenac I, Rocher F P, Berger C, Adeleine P. Place de la radiotherapie peroperatoire dans le traitement des cancers de l'uterus. Experience lyonnaise preliminaire.  Bull Cancer Radiother. 1994;  81 186-195
• 19 Goldson A L, Delgado G, Ashayeri E, Petrilli E S. Intraoperative electron beam radiation therapy for gynecological malignancies. Dobelbower RR, Abe M Intraoperative Radiation Therapy. Boca Raton, Fl; CRC 1989: 247-263
• 20 Grischke E M, Wallwiener D, Kaufmann M, Sinn H P, Solomayer E F, Bastert G. Angiogenese beim Mammakarzinom - Quantifizierung der Gefäßdichte mittels Morphometrie als neuer Prognosefaktor.  Geburtsh Frauenheilk. 1997;  57 321-327
• 21 Haas T, Buchsbaum H J, Lifshitz S. Nonresectable recurrent pelvic neoplasm. Outcome in patients explored for pelvic exenteration.  Gynecol Oncol. 1980;  9 177-181
• 22 Henriksen R, Strang P, Wilander E, Backstrom T, Tribukait B, Oberg K. p53 expression in epithelial ovarian neoplasms: relationship to clinical and pathological parameters, Ki-67 expression and flow cytometry.  Gynecol Oncol. 1994;  53 301-306
• 23 Höckel M, Kutzner J, Bauer H, Friedberg V. Eine neue experimentelle Methode zur Behandlung von Beckenwandrezidiven gynäkologischer Malignome.  Geburtsh Frauenheilk. 1989;  49 981
• 24 Höckel M, Schlenger K, Hamm H, Knapstein P G, Hohenfellner R, Rösler H P. Five-year experience with combinated operative and radiotherapeutic treatment of recurrent gynecologic tumors infiltrating the pelvic wall.  Cancer. 1996;  77 1918-1933
• 25 Horak E R, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris A L. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer.  Lancet. 1992;  340 1120-1124
• 26 Hughes-Davies L, Silver B, Kapp D S. Parametrial interstitial brachytherapy for advanced or recurrent pelvic malignancy: The Harvard/Standford experience.  Gynecologic Oncology. 1995;  58 24-27
• 27 Johnston S R, MacLennan K A, Sacks N P, Salter J, Smith I E, Dowsett M. Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen.  Eur J Cancer. 1994;  30 1663-1669
• 28 Jordan P A, Kerns B J, Pence J C, Kohler M F, Bast R C, Kinney R B, Berchuck A. Determination of proliferation index in advanced ovarian cancer using quantitative image analysis.  Am J Clin Pathol. 1993;  99 736-740
• 29 Kern J A, Schwartz D A, Nordberg J E. p185^neu expression in human lung adenocarcinomas predicts shortened survival.  Cancer Res. 1990;  50 5184-5191
• 30 Kinsella T J, Sindelar W F, De Luca W M, Terrill R. Tolerance of peripheral nerve to intraoperative radiotherapy (IORT) clinical and experimental studies.  Int J Radiat Oncol Biol Phys. 1985;  11 1579-1585
• 31 Kropveld A, Slootweg P J, van Mansfeld A D, Blankenstein M A, Hordijk G J. Radioresistance and p53 status of T2 laryngeal carcinoma. Analysis by immunohistochemistry and denaturing gradient gel electrophoresis.  Cancer. 1996;  78 991-997
• 32 MacGrogan G, Mauriac L, Bonichon F, Trojani M, de Mascarel, Coindre J M. Primary chemotherapy in breast invasive carcinoma: predictive value of the immunohistochemical detection of hormonal receptors, p53, c-erb-2, MiB1, pS2 and GSTπ.  Br J Cancer. 1996;  74 1458-1465
• 33 Mahe M A, Gerard J P, Dubois J B, Roussel A, Bussieres E, Delannes E, Guillemin F, Schmitt T, Dargent D, Guillard Y, Martel P, Richaud P, Cuilliere J C, De Ranieri J, Malissard L. Intraoperative radiation therapy in recurrent carcinoma of the uterine cervix: Report of the french intraoperative group on 70 patients.  Int J Radiation Oncology Biol Phys. 1996;  34 21-26
• 34 Marks J R, Davidoff A M, Kerns B J, Humphrey P A, Pence J C, Dodge R K, Clarke-Pearson D L, Iglehart J D, Bast R C, Berchuck A. Overexpression and mutation of p53 in epithelial ovarian cancer.  Cancer Res. 1991;  51 2979-2984
• 35 Meden H, Marx D, Rath W, Kron M, Fattahi-Meibodi A, Hinney B, Kuhn W, Schauer A. Overexpression of the oncogene c-erb-2 in primary ovarian cancer: Evaluation of the prognostic value in a Cox proportional hazards multiple regression.  Intern J Gynecol Pathol. 1994;  13 45-53
• 36 Milner B J, Allan L A, Eccles D M, Kitchener H C, Leonard R C, Kelly K F, Parkin D E, Haites N E. p53 mutation is a common genetic event in ovarian carcinoma.  Cancer Res. 1993;  53 2128-2132
• 37 Nakano T, Oka K. Transition of Ki-67 index of uterine cervical tumors during radiation therapy. Immunohistochemical study.  Cancer. 1991;  68 517-523
• 38 Nakano T, Oka K. Differential values of Ki-67 index and mitotic index of proliferating cell population. An assessment of cell cycle and prognosis in radiation therapy for cervical cancer.  Cancer. 1993;  72 2401-2408
• 39 Niehans G A, Singleton T P, Dykoski D, Kiang D T. Stability of HER-2/neu expression over time and at multiple metastatic sites.  J Natl Cancer Inst. 1993;  85 1230-1235
• 40 Pavelic Z P, Gluckman J L, Gapany M, Reising J, Craven J M, Kelley D J, Pavelic L, Gapany S, Biddinger P, Stambrook P J. Improved immunohistochemical detection of p53 protein in paraffin-embedded tissues reveals elevated levels in most head and neck and lung carcinomas: correlation with clinicopathological parameters.  Anticancer Res. 1992;  12 1389-1394
• 41 Railo M, Nordling S, von Boguslawsky K, Leivonen M, Kyllonen L, von Smitten K. Prognostic value of Ki-67 immunolabelling in primary operable breast cancer.  Br J Cancer. 1993;  68 579-583
• 42 Silvestrini R, Veneroni S, Daidone M G, Benini E, Boracchi P, Mezzetti M, Di-Fronzo G, Rilke F, Veronesi U. The Bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients.  J Natl Cancer Inst. 1994;  86 499-504
• 43 Sindelar W F, Kinsella T J, Tepper J, Travis E L, Rosenberg S A. Experimental and clinical studies with intraoperative radiotherapy.  Surg Obstet Gynecol. 1983;  157 205-219
• 44 Slamon D J, Clark G M, Wong S G, Levin W J, Ullrich A, McGuire W L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.  Science. 1987;  235 177-182
• 45 Slamon D J, Godolphin W, Jones L A, Holt J A, Wong S G, Keith D E, Levin W J, Stuart S G, Udove J, Ullrich A. Studies of the HER-2/NEU proto-oncogene in human breast and ovarian cancer.  Science. 1989;  244 707-712
• 46 Sommers G M, Grigsby P V, Perez C A, Camel H M, Kao M S, Galakatos A E, Lockett M A. Outcome of recurrent cervical carcinoma following definitive irradiation.  Gynecol Oncol. 1989;  35 150-155
• 47 Sun X F, Carstensen J M, Zhang H, Stal O, Wingren S, Hatschek T, Nordenskjold B. Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma.  Lancet. 1992;  340 1369-1373
• 48 Symmans W F, Liu J, Knowles D M, Inghirami G. Breast cancer heterogeneity: evaluation of clonality in primary and metastatic lesions.  Hum Pathol. 1995;  26 210-216
• 49 Tandon A K, Carlk G M, Chamness G C, Ullrich A, McGuire W L. HER-2/neu oncogene protein and prognosis in breast cancer.  J Clin Oncol. 1989;  7 1120-1128
• 50 Thor A D, Schwartz L H, Koerner F C. Analysis of c-erb-2 expression in breast carcinomas with clinical follow-up.  Cancer Res. 1989;  49 7147-7152
• 51 Ueda T, Aozasa K, Tsujimoto M. Prognostic significance of Ki-67 reactivity in soft tissue sarcomas.  Cancer. 1989;  63 1607-1611
• 52 Yordan E L, Jurado M, Kiel K, Reddy S, Kramer T, Calvo F, Roseman D L, Graham I E, Wilbanks G D. Intraoperative radiation therapy in the treatment of pelvic malignancies: A preliminary report.  Bailliere's Clin Obstet Gynecol. 1988;  2 1023-1030
• 53 Veronese S M, Gambacorta M, Gottardi O, Scanzi F, Ferrari M, Lampertico P. Proliferation index as a prognostic marker in breast cancer.  Cancer. 1993;  71 3926-3931
• 54 Wallen A C, Ridinger D N, Dethlefsen L A. Heterogeneity of X-ray cytotoxicity in proliferating and quiescent murine mammary carcinoma cells.  Cancer Res. 1985;  45 3064-3068
• 55 Wallwiener D, Eble M J, Solomayer E F, Junkermann H, Schmid H, Kaufmann M, Diel I J, Grische E M, Schönig T, Wannenmacher M, Bastert G, von Fournier D. Organübergreifendes Debulking in Kombination mit intraoperativer Strahlentherapie im multimodalen Therapiespektrum von Beckenrezidiven.  Geburtsh Frauenheilk. 1998;  58 56-61
• 56 Webb M J, Symmonds R E. Site of recurrence of cervical cancer after radical hysterectomy.  Am J Obstet Gynecol. 1980;  138 813-817
• 57 Weidner N, Semple J P, Welch W R, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma.  N Engl J Med. 1991;  324 1-8
• 58 Wintzer H O, Zipfel I, Schulte-Monting J, Hellerich U, von Kleist S. Ki-67 immunostaining in human breast tumors and its relationship to prognosis.  Cancer. 1991;  67 421-428
• 59 Wong F W. Immunhistochemical detection of proliferating tumor cells in cervical cancer using monoclonal antibody Ki-67.  Gynecol Obstet Invest. 1994;  37 123-126