Prädiktoren der nodalen Metastasierung des Larynxkarzinoms als Entscheidungshilfe bei der Neck Dissection: Literaturanalyse zur Frage zuverlässiger Parameter

Zusammenfassung

Hintergrund: Bei fortgeschrittenen Plattenepithelkarzinomen des Larynx sind lokalisationsabhängig in bis zu 60 % histologisch keine Lymphknotenmetastasen nachweisbar (pN0). Andererseits enthalten über 30 % der klinisch tumorfreien Lymphknoten (cN0) okkulte Metastasen. Der Umfang der Neck Dissection (ND) ist nach den Leitlinien der Deutschen HNO-Gesellschaft abhängig vom klinischen Tumor- und Lymphknotenstadium. Bei geplanter adjuvanter Radiochemotherapie kann im Stadium cN0 auf die ND verzichtet werden. Zur besseren Planung des Umfangs der ND im Stadium cN0 stellt sich die Frage nach prädiktiven Parametern für das Risiko der Metastasierung, die an einer präoperativen Tumorbiopsie bestimmbar sind.Methode: In der vorliegenden Arbeit wurden 455 Publikationen zu folgenden Parametern analysiert: Tumorstadium, Grading, peritumoröse Entzündung, Lymphgefäßinvasion, Angioneogenese, Tumorproliferation, Überexpression von Cyclin D1 und p53, Inhibitoren der Cyclin-abhängigen Kinasen, Wachstumsfaktoren, Apoptoseindex, Zelladhäsion, nm23, Metalloproteinasen, DNA/Ploidiegrad und Tumorgenetik.Ergebnisse: In der Auswertung waren keine Parameter mit hinreichend sicherem prädiktiven Wert identifizierbar.Schlussfolgerungen: Somit bietet auch eine erweiterte Untersuchung präoperativer Biopsien keine zuverlässige Hilfe bei der Entscheidung für oder gegen eine Neck Dissection im Stadium cN0 (außerhalb von T1).

Abstract

Background: A subset of advanced laryngeal squamous cell carcinomas (SCC) does not metastasize in regional lymph nodes (pN0). However, more than 30 % of tumors without signs of metastasizing in the clinical examination (cN0) show occult metastases. The guidelines of the German ENT-Society intend the extent of neck dissection (ND) depending on clinical stage of tumor and lymph nodes. If laryngeal surgery is followed by an adjuvant radiation/chemotherapy, ND is not always necessary. Histomorphological, immunohistochemical, or molecular parameters with predictive value for nodal metastasizing could support the planning for ND, especially in patients with cN0.Methods: Within the last 20 years there were many publications concerning this problem. Herein, we analyzed the results of 455 publications. We have chosen studies regarding the predictive value of tumor stage, grading, peritumorous inflammation, invasion of lymphatic vessels, angioneogenesis, proliferation, overexpression of p53 or cyclin D1, inhibitors of cyclin-dependend kinases, growth factors, apoptosis, cell-adhesion, nm23, metalloproteinases, DNA/ploidy as well as tumor genetics.Results: All examined parameters did not allow a failsafe prediction of the risk for nodal metastasizing.Conclusions: Up to now, reliable predictors do not exist. The investigation of above mentioned parameters in pre-operative tumor biopsies is not helpful for the planning of ND in the stage cN0 (out of T1).

Schlüsselwörter

Plattenepithelkarzinom - Larynx - Metastasierung - Neck Dissection - Prädiktion

Key words

squamous cell carcinoma - larynx - metastasizing - neck dissection - prediction

Literatur

• 1 Buckley J G, MacLennan K. Cervical node metastases in laryngeal and hypopharyngeal cancer: a prospective analysis of prevalence and distribution.  Head Neck. 2000;  22 380-385
• 2 Liu M, Lawson G, Delos M, Jamart J, Chatelain B, Remacle M, Marbaix E. Prognostic value of cell proliferation markers, tumour suppressor proteins and cell adhesion molecules in primary squamous cell carcinoma of the larynx and hypopharynx.  Eur Arch Otorhinolaryngol. 2003;  260 28-34
• 3 Resnick J M, Uhlman D, Niehans G A, Gapany M, Adams G, Knapp D, Jaszcz W. Cervical lymph node status and survival in laryngeal carcinoma: prognostic factors.  Ann Otol Rhinol Laryngol. 1995;  104 685-694
• 4 Dong Y, Sui L, Sugimoto K, Tai Y, Tokuda M. Cyclin D1-CDK4 complex, a possible critical factor for cell proliferation and prognosis in laryngeal squamous cell carcinomas.  Int J Cancer. 2001;  95 209-215
• 5 Capaccio P, Pruneri G, Carboni N, Pagliari A V, Buffa R, Neri A, Ottaviani A, Pignataro L. Cyclin D1 protein expression is related to clinical progression in laryngeal squamous cell carcinomas.  J Laryngol Otol. 1997;  111 622-626
• 6 Morawski K, Gabriel A, Namyslowski G, Ziolkowski A, Pietrawska V, Steplewska K. Clinical application of proliferating cell nuclear antigen, oncoprotein p53 and tumor front grading analysis in patients operated on for laryngeal cancer.  Eur Arch Otorhinolaryngol. 1999;  256 378-383
• 7 Franchi A, Gallo O, Boddi V, Santucci M. Prediction of occult neck metastases in laryngeal carcinoma: role of proliferating cell nuclear antigen, MIB-1, and E-cadherin immunohistochemical determination.  Clin Cancer Res. 1996;  2 1801-1808
• 8 Takes R P, Baatenburg de Jong R J, Schuuring E, Hermans J, Vis A A, Litvinov S V, van Krieken J H. Markers for assessment of nodal metastasis in laryngeal carcinoma.  Arch Otolaryngol Head Neck Surg. 1997;  123 412-419
• 9 Kumar R V, Shenoy A M, Daniel R, Shah K V. Cyclin D1, p53, MIB1, intratumoral microvessel density, and human papillomavirus in advanced laryngeal carcinoma: association with nodal metastasis.  Otolaryngol Head Neck Surg. 2004;  131 509-513
• 10 Franchi A, Gallo O, Massi D, Baroni G, Santucci M. Tumor lymphangiogenesis in head and neck squamous cell carcinoma: a morphometric study with clinical correlations.  Cancer. 2004;  101 973-978
• 11 Chien C Y, Su C Y, Hwang C F, Chuang H C, Hsiao Y C, Wu S L, Huang C C. Clinicopathologic significance of CD105 expression in squamous cell carcinoma of the hypopharynx.  Head Neck. 2006;  28 441-446
• 12 O-Charoenat P , Rhys-Evans P, Eccles S A. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis.  Cancer. 2001;  92 556-568
• 13 Kyzas P A, Geleff S, Batistatou A, Agnantis N J, Stefanou D. Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma.  J Pathol. 2005;  206 170-177
• 14 Audet N, Beasley N J, MacMillan C, Jackson D G, Gullane P J, Kamel-Reid S. Lymphatic vessel density, nodal metastases, and prognosis in patients with head and neck cancer.  Arch Otolaryngol Head Neck Surg. 2005;  131 1065-1070
• 15 Acikalin M F, Oner U, Tel N, Pasaoglu O, Cakli H, Colak E. Prognostic significance of Ki-67 expression for patients with laryngeal squamous cell carcinoma primarily treated by total laryngectomy.  Eur Arch Otorhinolaryngol. 2004;  261 376-380
• 16 Boran C, Yildiz L, Kandemir B, Karagoz F, Baris S, Aydin O. Correlation of proliferating cell nuclear antigen and bcl-2 expression with tumor front grading and metastasis in laryngeal squamous cell carcinoma.  Neoplasma. 2003;  50 139-143
• 17 Spafford M F, Koeppe J, Pan Z, Archer P G, Meyers A D, Franklin W A. Correlation of tumor markers p53, bcl-2, CD34, CD44H, CD44v6, and Ki-67 with survival and metastasis in laryngeal squamous cell carcinoma.  Arch Otolaryngol Head Neck Surg. 1996;  122 627-632
• 18 Mielcarek-Kuchta D, Olofsson J, Golusinski W. p53, Ki67 and cyclin D1 as prognosticators of lymph node metastases in laryngeal carcinoma.  Eur Arch Otorhinolaryngol. 2003;  260 549-554
• 19 Bayazit Y, Bakir K, Ucak R, Mumbuc S, Ozer E, Kanlikama M. Clinical and histopathological correlates of the proliferative activity in squamous cell laryngeal carcinoma.  Rev Laryngol Otol Rhinol (Bord). 2002;  123 43-46
• 20 Golusinski W, Olofsson J, Szmeja Z, Biczysko W, Krygier-Stojalowska A, Kulczynski B. A comprehensive analysis of selected diagnostic methods with respect to their usefulness in evaluating the biology of neoplastic cells in patients with laryngeal cancer.  Eur Arch Otorhinolaryngol. 1999;  256 306-311
• 21 Izawa H, Yonemitsu N, Shin T, Sugihara H. Histopathological analysis of apoptosis, and expression of p53, bcl-2, bax, and Ki-67 in laryngeal squamous cell carcinomas and dysplasia.  Auris Nasus Larynx. 1999;  26 317-330
• 22 Grzanka A, Sujkowska R, Janiak A, Adamska M. Immunogold labelling of PCNA and Ki-67 antigen at the ultrastructural level in laryngeal squamous cell carcinoma and its correlation with lymph node metastasis and histological grade.  Acta Histochem. 2000;  102 139-149
• 23 Cappiello J, Nicolai P, Antonelli A R, Facchetti F, Cadei M, Cornacchiari A, Grigolato P G. DNA index, cellular proliferative activity and nucleolar organizer regions in cancers of the larynx.  Eur Arch Otorhinolaryngol. 1995;  252 353-358
• 24 Chow V, Yuen A P, Lam K Y, Ho W K, Wei W I. Prognostic significance of serum p53 protein and p53 antibody in patients with surgical treatment for head and neck squamous cell carcinoma.  Head Neck. 2001;  23 286-291
• 25 Yuen P W, Lam K Y, Choy J T, Ho W K, Wei W I. Clinicopathological significance of p53 and p21 expression in the surgical treatment of laryngeal carcinoma.  Anticancer Res. 2000;  20 4863-4866
• 26 Kazkayasi M, Hucumenoglu S, Siriner G I, Hucumenoglu M. Over-expression of p53 and c-erbB-2 oncoproteins in laryngeal carcinoma.  Eur Arch Otorhinolaryngol. 2001;  258 329-335
• 27 Mizokami H, Sawatsubashi M, Tokunaga O, Shin T. Loss of retinoblastoma protein expression in laryngeal squamous cell carcinoma.  Mod Pathol. 1999;  12 47-53
• 28 Fracchiolla N S, Pruneri G, Pignataro L, Carboni N, Capaccio P, Boletini A, Buffa R, Neri A. Molecular and immunohistochemical analysis of the bcl-1/cyclin D1 gene in laryngeal squamous cell carcinomas: correlation of protein expression with lymph node metastases and advanced clinical stage.  Cancer. 1997;  79 1114-1121
• 29 Pignataro L, Pruneri G, Carboni N, Capaccio P, Cesana B M, Neri A, Buffa R. Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma.  J Clin Oncol. 1998;  16 3069-3077
• 30 Myo K, Uzawa N, Miyamoto R, Sonoda I, Yuki Y, Amagasa T. Cyclin D1 gene numerical aberration is a predictive marker for occult cervical lymph node metastasis in TNM Stage I and II squamous cell carcinoma of the oral cavity.  Cancer. 2005;  104 2709-2716
• 31 Namazie A, Alavi S, Olopade O I, Pauletti G, Aghamohammadi N, Aghamohammadi M, Gornbein J A, Calcaterra T C, Slamon D J, Wang M B, Srivatsan E S. Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors.  Laryngoscope. 2002;  112 472-481
• 32 Yuen P W, Man M, Lam K Y, Kwong Y L. Clinicopathological significance of p16 gene expression in the surgical treatment of head and neck squamous cell carcinomas.  J Clin Pathol. 2002;  55 58-60
• 33 Fan G K, Xu F, Yang B, Fujieda S. p57(kip2) expression is related to carcinogenesis and tumor progression in laryngeal tissues.  Acta Otolaryngol. 2006;  126 301-305
• 34 Fan G K, Fujieda S, Sunaga H, Tsuzuki H, Ito N, Saito H. Expression of protein p27 is associated with progression and prognosis in laryngeal cancer.  Laryngoscope. 1999;  109 815-820
• 35 Tamura N, Dong Y, Sui L, Tai Y, Sugimoto K, Nagahata S, Tokuda M. Cyclin-dependent kinase inhibitor p27 is related to cell proliferation and prognosis in laryngeal squamous cell carcinomas.  J Laryngol Otol. 2001;  115 400-406
• 36 Bonner J A, Harari P M, Giralt J, Azarnia N, Shin D M, Cohen R B, Jones C U, Sur R, Raben D, Jassem J, Ove R, Kies M S, Baselga J, Youssoufian H, Amellal N, Rowinsky E K, Ang K K. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.  N Engl J Med. 2006;  354 567-578
• 37 Almadori G, Cadoni G, Galli J, Ferrandina G, Scambia G, Exarchakos G, Paludetti G, Ottaviani F. Epidermal growth factor receptor expression in primary laryngeal cancer: an independent prognostic factor of neck node relapse.  Int J Cancer. 1999;  84 188-191
• 38 Xia W, Lau Y K, Zhang H Z, Xiao F Y, Johnston D A, Liu A R, Li L, Katz R L, Hung M C. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members.  Clin Cancer Res. 1999;  5 4164-4174
• 39 O-Charoenat P , Rhys-Evans P H, Archer D J, Eccles S A. C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors.  Oral Oncol. 2002;  38 73-80
• 40 Jackel M C, Dorudian M A, Marx D, Brinck U, Schauer A, Steiner W. Spontaneous apoptosis in laryngeal squamous cell carcinoma is independent of bcl-2 and bax protein expression.  Cancer. 1999;  85 591-599
• 41 Yuen A P, Lam K Y, Choy J T, Ho W K, Wei W I. The clinicopathological significance of bcl-2 expression in the surgical treatment of laryngeal carcinoma.  Clin Otolaryngol Allied Sci. 2001;  26 129-133
• 42 Bosch F X, Andl C, Abel U, Kartenbeck J. E-cadherin is a selective and strongly dominant prognostic factor in squamous cell carcinoma: a comparison of E-cadherin with desmosomal components.  Int J Cancer. 2005;  114 779-790
• 43 Rodrigo J P, Dominguez F, Alvarez C, Manrique C, Herrero A, Suarez C. Expression of E-cadherin in squamous cell carcinomas of the supraglottic larynx with correlations to clinicopathological features.  Eur J Cancer. 2002;  38 1059-1064
• 44 Anttonen A, Kajanti M, Heikkila P, Jalkanen M, Joensuu H. Syndecan-1 expression has prognostic significance in head and neck carcinoma.  Br J Cancer. 1999;  79 558-564
• 45 Masuda M, Kuratomi Y, Shiratsuchi H, Nakashima T, Naonobu K, Komiyama S. Decreased CD44H expression in early-stage tongue carcinoma associates with late nodal metastases following interstitial brachytherapy.  Head Neck. 2000;  22 662-665
• 46 Scholnick S B, Sun P C, Shaw M E, Haughey B H, el-Mofty S K. Frequent loss of heterozygosity for Rb, TP53, and chromosome arm 3p, but not NME1 in squamous cell carcinomas of the supraglottic larynx.  Cancer. 1994;  73 2472-2480
• 47 Song A U, Mais D D, Groo S, Wright J R, Yoshida G Y. Expression of nm23 antimetastatic gene product in head and neck squamous cell carcinoma.  Otolaryngol Head Neck Surg. 2000;  122 96-99
• 48 Franchi A, Santucci M, Masini E, Sardi I, Paglierani M, Gallo O. Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck.  Cancer. 2002;  95 1902-1910
• 49 Xie M, Sun Y, Li Y. Expression of matrix metalloproteinases in supraglottic carcinoma and its clinical implication for estimating lymph node metastases.  Laryngoscope. 2004;  114 2243-2248
• 50 Kawano K, Yanagisawa S. Predictive value of laminin-5 and membrane type 1-matrix metalloproteinase expression for cervical lymph node metastasis in T1 and T2 squamous cell carcinomas of the tongue and floor of the mouth.  Head Neck. 2006;  28 525-533
• 51 O-Charoenat P , Rhys-Evans P H, Eccles S A. Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck.  Arch Otolaryngol Head Neck Surg. 2001;  127 813-820
• 52 Bockmuhl U, Petersen I. DNA ploidy and chromosomal alterations in head and neck squamous cell carcinoma.  Virchows Arch. 2002;  441 541-550
• 53 Hemmer J, Kraft K, Kreidler J. The significance of DNA flow cytometry in predicting survival and delayed clinical manifestation of occult lymph node metastasis to the untreated neck in patients with oral squamous cell carcinoma.  J Craniomaxillofac Surg. 1998;  26 405-410
• 54 Wennerberg J, Baldetorp B, Wahlberg P. Distribution of non-diploid flow-cytometric DNA indices and their relation to the nodal metastasis in squamous cell carcinomas of the head and neck.  Invasion Metastasis. 1998;  18 184-191
• 55 Wreesmann V B, Wang D, Goberdhan A, Prasad M, Ngai I, Schnaser E A, Sacks P G, Singh B. Genetic abnormalities associated with nodal metastasis in head and neck cancer.  Head Neck. 2004;  26 10-15
• 56 Belbin T J, Singh B, Smith R V, Socci N D, Wreesmann V B, Sanchez-Carbayo M, Masterson J, Patel S, Cordon-Cardo C, Prystowsky M B, Childs G. Molecular profiling of tumor progression in head and neck cancer.  Arch Otolaryngol Head Neck Surg. 2005;  131 10-18
• 57 Soder A I, Hopman A H, Ramaekers F C, Conradt C, Bosch F X. Distinct nonrandom patterns of chromosomal aberrations in the progression of squamous cell carcinomas of the head and neck.  Cancer Res. 1995;  55 5030-5037
• 58 Werner J A, Dunne A A, Ramaswamy A, Dalchow C, Behr T, Moll R, Folz B J, Davis R K. The sentinel node concept in head and neck cancer: solution for the controversies in the N0 neck?.  Head Neck. 2004;  26 603-611