Skip to main content
SpringerLink
Log in

Differenzialdiagnostik erblicher Dickdarmkarzinomsyndrome

Der Beitrag der Pathologie

Differential diagnostics of hereditary colorectal cancer syndromes

The role of pathology

  • Schwerpunkt
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Etwa ein Drittel der kolorektalen Karzinome (KRK) treten familiär gehäuft auf, wobei etwa 5% einen monogenetischen Erbgang aufweisen. Diagnostisch hilfreich ist die Unterscheidung zwischen Erkrankungen mit und ohne Polyposis sowie die Berücksichtigung von Tumorhistologie und Tumorspektrum des jeweiligen Patienten. Etwa 1% der KRK lassen sich auf die familiäre adenomatöse Polyposis coli (FAP) mit rasenartig vermehrten (>100) Adenomen zurückführen. Weitere 2–3% betreffen das nicht mit Polyposis assoziierte HNPCC- bzw. Lynch-Syndrom, für welches als einzigem Darmkrebssyndrom ein molekularer Gewebetest zur Verfügung steht. Immunhistochemisch erfolgt zunächst die Prüfung auf einen Verlust der Expression eines Mismatch-Reparatur-Gens, woran sich bei unsicherem oder negativem Ergebnis der Test auf Mikrosatelliteninstabilität (MSI) anschließt. Im Unterschied zu den vorgenannten Syndromen wird die MYH-assoziierte Polyposis (MAP) rezessiv vererbt und weist nur mäßig erhöhte Polypenzahlen (im Mittel 15–30) auf. Sie ist differenzialdiagnostisch von attenuierten Formen der FAP mit <100 Polypen abzugrenzen. Bei Verdacht auf ein familiäres Tumorsyndrom ist in jedem Fall eine humangenetische Beratung anzuschließen, in deren Rahmen letztlich die Indikation zu einer weitergehenden molekulargenetischen Testung (Nachweis einer Keimbahnmutation) gestellt wird.

Abstract

One third of colorectal carcinomas (CRC) show familial clustering of which about 5% have a monogenetic trait. Distinction between disease with and without polyposis, tumor histology and tumor spectrum in a given patient are all of diagnostic relevance. Familial adenomatous polyposis (FAP) underlies approximately 1% of CRC characterized by rapidly forming (>100) adenomas. In contrast to these about 2%–3% of CRC have a hereditary background without polyposis (HNPCC). This is the only hereditary tumour syndrome to date for which a tissue-based molecular screening test is available. Accordingly, expression analysis of mismatch repair genes (MSH2, MSH6 and MLH1, PMS2) is performed first. In the case of an equivocal result with no complete loss of expression testing of microsatellite instability (MSI) is added. In contrast to the other diseases MYH-associated polyposis (MAP) follows a recessive trait with polyp numbers usually between 15–30 adenomas and should be distinguished from attenuated forms of FAP with <100 polyps in the differential diagnosis. In the case of suspected familial cancer syndrome genetic counseling is warranted in order to decide ultimately whether there is an indication for genetic testing (evidence of a germ-line mutation).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5
Abb. 6

Abbreviations

ACF:

„Aberrant crypt focus“ (frühe oligokryptale Läsion)

AFAP:

Attenuierte adenomatöse Polyposis coli

APC:

Adenomatosis polyposis coli

CIMP:

„CpG island methylation pathway“ (Promotormethylierung)

CIN:

Chromosomale Instabilität

CS:

Cowden-Syndrom

FAP:

Familiäre adenomatöse Polyposis

FJP:

Familiäre juvenile Polypose

HNPCC:

Hhereditäres nicht-polypöses Kolonkarzinom

HP:

Hyperplastischer Polyp

HPP:

Hyperplastische Polyposis

KRAS/BRAF:

Onkogene Proteinkinasen zur intrazellulären Signaltransduktion

KRK:

Kolorektales Karzinom

MAP:

MYH-assoziierte Polyposis

MGMT :

O-6-Methylguanin-DNA Methyltransferase (Reparaturgen)

MSH2, MSH6, MLH1, PMS2:

Mismatch-Reparatur-Gene

MSI:

Mikrosatelliteninstabilität, hoch (MSI-H), niedrig (MSI-L)

MSS:

Mikrosatellitenstabil

p53 :

Onkogen

PJS:

Peutz-Jeghers-Syndrom

SPS:

„Serrated pathway syndrome“

5JÜLR:

5-Jahres-Überlebensrate

Literatur

  1. Aretz S (2010) The differential diagnosis and surveillance of hereditary gastrointestinal polyposis syndromes. Dtsch Arztebl Int 107:163–173

    PubMed  Google Scholar 

  2. Aust DE, Baretton GB (2010) Serrated polyps of the colon and rectum (hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed polyps)-proposal for diagnostic criteria. Virchows Arch 457:291–297

    Article  PubMed  Google Scholar 

  3. Baker K, Foulkes WD, Jass JR (2009) MSI-H colorectal cancers preferentially retain and expand intraepithelial lymphocytes rather than peripherally derived CD8+ T cells. Cancer Immunol Immunother 58:135–144

    Article  CAS  PubMed  Google Scholar 

  4. Boparai KS, Reitsma JB, Lemmens V et al (2010) Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome. Gut 59:1222–1225

    Article  CAS  PubMed  Google Scholar 

  5. Buchanan DD, Sweet K, Drini M et al (2010) Phenotypic diversity in patients with multiple serrated polyps: a genetics clinic study. Int J Colorectal Dis 25:703–712

    Article  PubMed  Google Scholar 

  6. Chow E, Lipton L, Lynch E et al (2006) Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Gastroenterology 131:30–39

    Article  CAS  PubMed  Google Scholar 

  7. Dietmaier W (2010) Mikrosatelliteninstabilität. Ein neuer prädiktiver Marker (?). Pathologe (Suppl 2) 31 (im Druck)

  8. Engel C, Rahner N, Schulmann K et al (2010) Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 8:174–182

    Article  PubMed  Google Scholar 

  9. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Article  CAS  PubMed  Google Scholar 

  10. Garg K, Soslow RA (2009) Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. J Clin Pathol 62:679–684

    Article  CAS  PubMed  Google Scholar 

  11. Goecke T, Schulmann K, Engel C et al (2006) Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium. J Clin Oncol 24:4285–4292

    Article  CAS  PubMed  Google Scholar 

  12. Hamilton S, Aaltonen L (2000) Pathology & genetics. Tumours of the digestive system. IARC, Lyon

  13. Hartmann A, Ruschoff J (2009) Pathologie familiärer Tumorsyndrome. IAP Lehrserie 126

  14. Heinemann V, Stintzing S, Kirchner T et al (2009) Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev 35:262–271

    Article  CAS  PubMed  Google Scholar 

  15. Iino H, Jass JR, Simms LA et al (1999) DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer? J Clin Pathol 52:5–9

    Article  CAS  PubMed  Google Scholar 

  16. Jass JR (2006) Colorectal cancer: a multipathway disease. Crit Rev Oncog 12:273–287

    PubMed  Google Scholar 

  17. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130

    Article  CAS  PubMed  Google Scholar 

  18. Jass JR, Iino H, Ruszkiewicz A et al (2000) Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 47:43–49

    Article  CAS  PubMed  Google Scholar 

  19. Kirchner T, Reu S (2008) Development of molecular-pathologic entities of colorectal cancer. Pathologe 29 (Suppl 2):264–269

    Article  PubMed  Google Scholar 

  20. Knudsen AL, Bülow S, Tomlinson I et al (2010) Attenuated Familial Adenomatous Polyposis (AFAP) Results from an international collaborative study. Colorectal Dis [Epub ahead of print Jan 22]

  21. Krüger S, Kinzel M, Walldorf C et al (2008) Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. Eur J Hum Genet 16:62–72

    Article  PubMed  Google Scholar 

  22. Kunstmann E, Vieland J, Brasch FE et al (2004) HNPCC: six new pathogenic mutations. BMC Med Genet 5:16

    Article  PubMed  Google Scholar 

  23. Lage P, Cravo M, Sousa R et al (2004) Management of Portuguese patients with hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution for future guidelines based on a clinical study. Am J Gastroenterol 99:1779–1784

    Article  CAS  PubMed  Google Scholar 

  24. Laiho P, Kokko A, Vanharanta S et al (2007) Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene 26:312–320

    Article  CAS  PubMed  Google Scholar 

  25. Lugli A, Zlobec I, Minoo P et al (2007) Prognostic significance of the wnt signalling pathway molecules APC, beta-catenin and E-cadherin in colorectal cancer: a tissue microarray-based analysis. Histopathology 50:453–464

    Article  CAS  PubMed  Google Scholar 

  26. Makinen MJ (2007) Colorectal serrated adenocarcinoma. Histopathology 50:131–150

    Article  CAS  PubMed  Google Scholar 

  27. Mueller JD, Haegle N, Keller G et al (1998) Loss of heterozygosity and microsatellite instability in de novo versus ex-adenoma carcinomas of the colorectum. Am J Pathol 153:1977–1984

    CAS  PubMed  Google Scholar 

  28. Müller A, Beckmann C, Westphal G et al (2006) Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study. Int J Colorectal Dis 21:632–641

    Article  PubMed  Google Scholar 

  29. Müller A, Schackert HK, Lange B et al (2006) A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years. Am J Med Genet 140:195–199

    Article  PubMed  Google Scholar 

  30. Obermair A, Youlden DR, Young JP et al (2010) Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer [Epub ahead of print Jun 7]

  31. Parc YR, Halling KC, Wang L et al (2000) HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60:2225–2231

    CAS  PubMed  Google Scholar 

  32. Pino MS, Mino-Kenudson M, Wildemore BM et al (2009) Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas. J Mol Diagn 11:238–247

    Article  CAS  PubMed  Google Scholar 

  33. Plaschke J, Engel C, Kruger S et al (2004) Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 22:4486–4494

    Article  CAS  PubMed  Google Scholar 

  34. Reinacher-Schick A, Arnold D, Trarbach T et al (2010) Adjuvant therapy in colon cancer. Onkologie 33 (Suppl 4):2–7

    Article  PubMed  Google Scholar 

  35. Ruschoff J, Dietmaier W, Bocker T et al (1998) Molecular cancer disposition diagnosis exemplified by colorectal carcinoma. What is the contribution of pathology? Pathologe 19:269–278

    Article  CAS  PubMed  Google Scholar 

  36. Ruschoff J, Dietmaier W, Luttges J et al (1997) Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol 150:1815–1825

    CAS  PubMed  Google Scholar 

  37. Ruschoff J, Roggendorf B, Brasch F et al (2004) Molecular pathology in hereditary colorectal cancer. Recommendations of the Collaborative German Study Group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe). Pathologe 25:178–192

    Article  CAS  PubMed  Google Scholar 

  38. Sargent DJ, Marsoni S, Monges G et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219–3226

    Article  CAS  PubMed  Google Scholar 

  39. Schulmann K, Reiser M, Schmiegel W (2002) Colonic cancer and polyps. Best Pract Res Clin Gastroenterol 16:91–114

    Article  PubMed  Google Scholar 

  40. Sieber OM, Lipton L, Crabtree M et al (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348:791–799

    Article  PubMed  Google Scholar 

  41. Steinke V, Rahner N, Morak M et al (2008) No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients. Eur J Hum Genet 16:587–592

    Article  CAS  PubMed  Google Scholar 

  42. Trano G, Sjursen W, Wasmuth HH et al (2010) Performance of clinical guidelines compared with molecular tumour screening methods in identifying possible Lynch syndrome among colorectal cancer patients: a Norwegian population-based study. Br J Cancer 102:482–488

    Article  CAS  PubMed  Google Scholar 

  43. Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    Article  CAS  PubMed  Google Scholar 

  44. Van der Post RS, Kiemeney LA, Ligtenberg MJ et al (2010) Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 47:464–470

    Article  Google Scholar 

  45. Vasen HF, Griffioen G, Offerhaus GJ et al (1990) The value of screening and central registration of families with familial adenomatous polyposis. A study of 82 families in The Netherlands. Dis Colon Rectum 33:227–230

    Article  CAS  PubMed  Google Scholar 

  46. Young J, Jass JR (2006) The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature. Cancer Epidemiol Biomarkers Prev 15:1778–1784

    Article  CAS  PubMed  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Institut für Pathologie Nordhessen, Germaniastr. 7, 34119, Kassel, Deutschland

    J. Rüschoff & E. Heinmöller

  2. Institut für Pathologie, Universitätsklinikum Erlangen, Erlangen, Deutschland

    A. Hartmann & T. Rau

  3. Institut für Pathologie, Universität Bonn, Bonn, Deutschland

    R. Büttner

Authors
  1. J. Rüschoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Heinmöller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Büttner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Rau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Rüschoff.

Additional information

Widmung

Herrn Prof. Dr. P. Propping in dankbarer Anerkennung seiner Arbeit als Sprecher der Studiengruppe des Verbundprojektes „Erblicher Darmkrebs“ der Deutschen Krebshilfe (seit 1999).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rüschoff, J., Heinmöller, E., Hartmann, A. et al. Differenzialdiagnostik erblicher Dickdarmkarzinomsyndrome. Pathologe 31, 412–422 (2010). https://doi.org/10.1007/s00292-010-1352-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-010-1352-8

Schlüsselwörter

Keywords

Search

Navigation