Immunhistologischer Nachweis disseminierter Tumorzellen in Lymphknoten beim Pankreaskarzinom: Häufigkeit und prognostische Bedeutung

Zusammenfassung.

Die Prognose des Pankreaskarzinoms ist trotz radikal-chirurgischen Vorgehens durch das Auftreten eines Lokalrezidivs oder Metastasierung unverändert schlecht. Die Infiltration in regionale Lymphknoten ist mit einer signifikanten Verkürzung der Überlebenszeit verbunden. Ziel der Studie ist es, die Häufigkeit einer frühen Tumorzelldissemination in konventionell-histopathologisch als tumorfrei beurteilte Lymphknoten zum Operationszeitpunkt mit Hilfe immunhistologischer Methodik zu sichern.

25 Patienten mit einem Adenokarzinom des Pankreas (15 duktale Pankreaskopf- und 10 Papillenkarzinome) wurden chirurgisch radikal reseziert. Alle Patienten hatten ein Tumorstadium pT_xpN₀M₀. 229 histopathologisch tumorfreie Lymphknoten wurden auf disseminierte Tumorzellen untersucht. Der Nachweis erfolgt mit dem Zytokeratinantikörper AE1/AE3. Zur Prüfung der Methode wurden weitere 81 Lymphknoten von Patienten mit einer chronischen Pankreatitis analysiert. 55 von 229 Lymphknoten (26,3 %) wiesen disseminierte Tumorzellen auf. Alle Patienten (100 %) mit einem duktalen Pankreaskopfkarzinom hatten in mindestens einem Lymphknoten Tumorzellen. Beim Papillenkarzinom gelang in keinem Fall der Nachweis disseminierter Tumorzellen. Ebenso fand sich in der Kontrollgruppe kein falschpositiver Befund. Die schlechte Prognose des duktalen Pankreaskarzinoms gegenüber dem Papillenkarzinom (mediane Überlebenszeit 14,0 vs. 48,0 Monate) könnte auf die frühe Tumorzelldissemination in Lymphknoten zurückzuführen sein. Diese lymphogene Metastasierung bereits im niedrigen Tumorstadium pT_{1 - 3}N₀M₀ führt zur Forderung, den Stellenwert einer adjuvanten Therapie bei allen Patienten mit einem Pankreaskarzinom zu prüfen.

Immunhistochemical detection of disseminated tumor cells in lymph nodes in early pancreatic carcinoma: frequency and prognostic significance.

Outcome of surgical treatment of pancreatic carcinomas is often limited due to local recurrence and, in particular, due to the development of metastases. Tumor infiltration of regional lymph nodes is closely associated with a reduced life exspectancy. The aim of the study was to determine frequency and prognostic relevance of the micrometastatic tumor cells detectable by immunhistochemistry in lymph nodes of patients with totally resected pancreatic carcinoma (R0 resection). In total, 229 lymph nodes were classified as tumor-free with routine histopathology in 25 patients (15 patients with ductal carcinoma of the head of the pancreas, 10 patients with carcinoma of the papilla of Vater). In addition, samples were investigated for the presence of disseminated tumor cells with immunhistochemistry using antiepithelial monoclonal antibody AE1/AE3. In 55 of 229 lymph nodes (26.3 %), AE1/AE3-positive tumor cells were detected. In all patients with ductal carcinoma of the head of the pancreas (100 %), there were tumor cells detectable in minimally one lymph node. No disseminated tumor cells were found in each patient with carcinoma of the papilla of Vater. As a control, 81 lymph nodes from patients (n = 11) with chronic pancreatitis were stained. In this control group no false positive results were found. Prognostic differences between patients with ductal pancreatic carcinoma compared with carcinoma of the papilla of Vater (median survival time, 14.0 vs. 48.0 months, resp.) may be caused by the early dissemination of tumor cells into lymph nodes. The detection of early lymphogenic micrometastases in initial tumor stages (T_{1 - 3} N₀ M₀ ) may suggest that adjuvant treatment regimens have to be proven in all patients with pancreatic carcinoma.

Schlüsselwörter:

Pankreaskarzinom - Papillenkarzinom - Prognose - Chirurgie - disseminierte Tumorzellen - Tumorzelldetektion

Key words:

Pancreatic carcinoma - Carcinoma of the papilla of Vater - Surgery - Prognosis - Lymph nodes - Isolated disseminated tumor cells - Tumor cell detection

Literatur

• 1 Cameron J L, Pitt H A, Yeo C L, Lillemeo K D, Kaufman H S, Coleman J. One hundred and forty-five consecutive pancreatuodenectomies without mortality.  An Surg. 1993;  217 430-438
• 2 Traverso L E, Longmire W P. Preservation of the pylorus in pancreaticoduodenectomy.  Surg Gynecol Obstet. 1978;  146 959-963
• 3 Reinders M E, Allema J H, van Gullik T M,. et al . Outcome of microscopically nonradial, subtotal pancreaticoduodenectomy (Whipple's resection) for treatment of pancreatic head tumors.  World J Surg. 1995;  19 410-415
• 4 Howard J M. Development and progress in resective surgery for pancreatic cancer.  World J Surg. 1999;  23 901-906
• 5 Gall F P, Kessler H, Hermanek P. Surgical treatment of ductal pancreatic carcinoma.  Eur Surg Oncol. 1991 ;  17 173-181
• 6 Gudjonsson B. Carcinoma of pancreas: critical analysis of costs, results of resections, and the need for standardized reporting.  J Am Coll Surg. 1995;  181 483-503
• 7 Juhl H, Kalthoff H, Krüger U,. et al . Immuncytologischer Nachweis disseminierter Tumorzellen in der Bauchhöhle und im Knochenmark von Pankreaskarzinompatienten.  Chirurg. 1994;  65 1111-1115
• 8 Kremer B, Vogel I, Lüttges J, Klöppel G, Henne-Bruns D. Surgical possibilities for pancreatic cancer: Extended resection.  Ann Oncol. 1999;  10 ( Suppl) 252-256
• 9 Bussolati G, Gugliotta P, Morra I, Pietribiasi F, Beradengo E. The immunohistochemical detection of lymph node metastases from infiltrating lobular carcinoma of the breast.  Br J Cancer. 1986;  54 631-636
• 10 Chen Z L, Perez S, Holmes C E,. et al . Frequency and distribution of occult micrometastasis in lymph nodes of patients with non-small cell lung cancer.  J Natl cancer Inst. 1993;  85 493-498,
• 11 de Mascerel I, Bonichon F, Coindre J M, Trojani M. Prognostic significance of breast cancer axillary lymph node micrometastases assessed by two special techniques: reevaluation with longer follow up.  Br J Cancer. 1992;  66 523-527
• 12 Douglass Gastrointestinal Tumor Study Group: .Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer (GITSG). Cancer 1987 59: 2006
• 13 Shibamato Y, Manabe T, Baba N, Sasai K ,. et al . High dose external beam and intraoperative radiotherapy in the treatment of resectable and unresectable pancreatic cancer.  Int J Radiat Oncol Biol Phys. 1990;  19 605
• 14 Demeure M J, Doffek K M, Komorowski R A,. et al . Molecular metastases in stage I pancreatic cancer: Improved survival with adjuvant chemoradiation.  Surgery. 1998;  124 ((4)) 663-669
• 15 Colnaghi M i, Menard S, Canevari S. Evolution of the therapeutic use of new monoclonal antibodies.  Curr Opinion Oncol. 1993;  5 1035
• 16 Beger H G, Gansauge F, Buchler M W, Link K H. Intraarteriel adjuvant chemotherapy after pancreaticoduodenectomy for pancreatic cancer: significant reduction in occurrence of liver metastasis.  World J Surg. 1999;  23 ((9)) 946-949
• 17 Hamilton J. Adjuvant therapy for gastrointestinal cancer.  Oncol. 1994;  6 435-440
• 18 Schoof D D, Gramolini B A, Davidson D L, Massora A F,. et al . Adoptive immunotherapy of human cancer using lowdose recombinant interleukin and lymphokine-activated killer cells.  Cancer Res. 1988;  48 5007
• 19 Schmiegel W, Schmielau J, Henne-Bruns D ,. et al . Cytokine-mediated epidermal growth factor receptor manipulation: basis and therapeutic application in pancreatic cancer.  Proc Natl Acad Sci USA. 1997;  94 12 622-12 626
• 20 Simeone D, Cascarelli A, Logsdon C. Adenoviral-mediated gene transfer of a constitutively active retinoblastoma gene inhibits human pancreatic tumor cell proliferation.  Surgery (St Louis). 1997;  122 428-434
• 21 Herly M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means monoclonal antibodies.  Proc Natl Acd Sci USA. 1979;  76 1438
• 22 Juhl H, Stritzel M, Wroblewski A ,. et al . Immunocytological detection of micro-metastatic cells: Comperative evaluation of findings in the peritoneal cavity and bone marrow of gastric, colorectal and pancreatic cancer patients.  Int J Cancer. 1994;  75 330-335
• 23 Kalthof H, Holl K, Schmiegel W ,. et al . A new mucin reacting monoclonal antibody for serum diagnosis and radioimmunoscintigraphy of pancreatic cancer.  J Tumormark Oncol. 1987;  2 75
• 24 Schott A, Vogel I, Krüger U ,. et al . Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric and colorectal cancer patients and serve as a new prognostic marker.  Ann surg. 1998;  227 372-379
• 25 Molino A, Colombatti M, Bonetti F ,. et al . A comperative analysis of three different techniques for the detection of breast cancer cells in bone marrow.  Cancer (Phila.). 1991;  67 1033-1034
• 26 Hermanek P, Scheibe O, Spiessl B, Wagner G. UICC: TNM-Classification of malignant tumors. 4. Aufl. Springer Berlin Heidelberg New York; 1987
• 27 Garin-Chesa P, Rettig J, Melamed R. Expression of cytokeratin in normal and neoplastic colonic epithelial cells: implications for cellular differentiation and carcinogenesis.  Am J Surg Pathol. 1986;  10 829-835
• 28 Franke W W,. et al . Identification and characterization of epithelial cells in mammalian tissues by immunofluorescence microscopy using antibodies to prekeratin.  Differentiation. 1979;  15 7-125
• 29 Sun T T, Green H. Immunofluorescent staining of keratin fibers in cultural cells.  Cells. 1987;  14 468-476
• 30 Klempnauer J, Ridder G j, Pichlmayr R. Prognostic factors after resection of ampullary carcinoma: multivariate survival analysis in comparison with ductal cancer of the pancreatic head.  Br J Surg. 1995;  82 1686-1691
• 31 Roder J D, Stein J S, Hüttl W, Siewert J R. Pylorus-preserving versus standard pancreaticoduodenectomy: an analysis of 110 pancreatic and periampullary carcinomas.  Br J Surg. 1992;  79 152-155
• 32 Hosch S B, Knoefl W T, Metz S ,. et al . Early lymphatic tumor cell dissemination in pancreatic cancer: frequency and prognostic significance.  Pancreas. 1997;  15 ((2)) 154-159
• 33 Parkash V, Vidwans M, Carter D. Benign Mesothelial Cells in Mediastinal Lymph Nodes.  Am J of Surg Pathology. 1999;  23 ((10)) 1264-1269
• 34 Diel I, Kaufmann M, Costa S ,. et al . Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status.  J Natl Cancer Inst (Bethesda). 1996;  88 1652-1658
• 35 Pantel K, Izbicki J, Passlick B ,. et al . Frequency and prognostic significance of isolated tumor cells in bone marrow of patients with non-small-cell lung cancer without overt metastases.  Lancet. 1996;  347 649-653
• 36 Broll R, Schauer V, Schimmelpenning H ,. et al . Prognostic relevance of occult tumor cells in lymph nodes of colorectal carcinomas.  Dis Colon rectum. 1997;  40 ((12)) 1465-1471
• 37 Weitz J, Koch M, Lehnert T h,. et al . Nachweis isolierter disseminierter Tumorzellen colorectaler Carcinome in Lymphknoten.  Chirurg. 2000;  71 410-416
• 38 O'Sullivan G C, Collins J K, Kelly J, Morgan J, Madden M, Shanahan F. Micrometastases: marker of metastatic potnetial or evidence of residual disease.  Gut. 1997;  40 ((4)) 512-515
• 39 Heeckt P, Safi F, Binder T, Büchler M. Free intraperitoneal tumor cells with the pancreatic carcinoma - Significance for clinical course and treatment.  Der Chirurg (D). 1992;  63 563
• 40 Martin J K, Goellner J R. Abdominal fluid cytology in patients with gastrointestinal malignant lesions.  Mayo Clin Proc. 1986;  61 467
• 41 Warshaw A L. Implications of peritoneal cytology for staging of early pancreatic cancer.  Am J Surg. 1991;  161 26
• 42 Klöppel G. Pancreatic, non-endocrine tumors. In: Klöppel G, Heitz PU (Hrsg). Pancreatic pathology. Churchill Livingstone Edinburgh London Melbourne; 1984
• 43 Roder J, Thorban S, Pantel K, Siewert J R. Micrometastases in bone marrow: prognostic indicators for pancreatic cancer.  World J Surg. 1999;  23 888-891
• 44 Vogel I, Krüger U, Marxsen J ,. et al . Disseminated tumor cells in pancreatic cancer patients detected by immunocytology: a new prognostic factor.  Clin Can Res. 1999;  5 593-599
• 45 Thorban S, Roder J, Siewert J R. Detection of micrometastases in bone marrow of pancreatic cancer patients.  Ann Oncol. 1999;  10 ((4)) 111-113
• 46 Yamaguchi K, Enjoji M. Carcinoma of the pancreas: a clinicopathologic study of 96 cases with immunohistochemical observations.  Jpn J Clin Oncol. 1989;  19 ((1)) 14-22
• 47 Nishida K, Kaneko T, Yoneda M ,. et al . Doubling time of serum CA 19 - 9 in the clinical course of patients with pancreatic cancer and its significant association with prognosis.  J Surg Oncol. 1999;  71 140-146
• 48 Safi F, Schlosser W, Falkenreck S, Beger H G. CA 19- 9 serum and prognosis of pancreatic cancer.  Int J Pancreatol. 1996;  20 ((3)) 155-161
• 49 Bakkevold K E, Kambestad B. Long-term survival following radical and palliative treatment of patients with carcinoma of the pancreas and papilla of Vater - the prognostic factors influencing the long-term results. A prospective multicentre study.  Eur J Surg Oncol. 1993;  19 147-161