Präkanzerosen der Vulva: Klassifikation, Morphologie und molekulare Pathogenese

 

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Zusammenfassung

Das Vulvakarzinom ist mit 3–5 % aller malignen Tumoren des weiblichen Genitales selten. Auch hier existieren Präkanzerosen, die in Analogie zum Dysplasie-Konzept der Cervix uteri als vulväre intraepitheliale Neoplasien (VIN) bezeichnet werden. Aufgrund einer differenten Pathogenese und Morphologie werden prinzipiell 2 Arten der VIN definiert: Die mit bis zu 98 % häufigste Form der VIN ist die klassische VIN mit einer Inzidenz von ca. 5 : 100 000 und einem mittleren Erkrankungsalter von 30–40 Jahren. In bis zu 90 % gelingt der Nachweis von High-Risk-HPV. In 20–50 % weist sie eine Multifokalität und in bis zu 50 % eine Multizentrizität mit HPV-bedingten Läsionen im Bereich der Vagina, der Cervix uteri bzw. perianal auf. Eine Ausdehnung in die Talgdrüsen oder Haarfollikel ist häufig. Das mit der klassischen VIN assoziierte invasive Karzinom ist in der Regel ein nicht verhornendes Plattenepithelkarzinom. Die differenzierte VIN (Simplex Type) ist mit 2–5 % deutlich seltener. Sie wird in der Regel postmenopausal diagnostiziert (mittleres Erkrankungsalter ∼ 65 Jahre), weist keine HPV-Assoziation, wohl aber eine Alteration des p53-Tumorsuppressorgens auf. Die Mitbeteiligung von Hautanhangsgebilden ist bei der differenzierten VIN selten. Die differenzierte VIN wird meist im Zusammenhang mit einem invasiven (verhornenden) Vulvakarzinom diagnostiziert; selten als Präkanzerose per se. Die derzeit von der WHO favorisierte Unterteilung der VIN in VIN 1 bis 3 soll aufgrund neuerer molekularpathologischer und klinischer Daten sowie aufgrund eines Vorschlags der International Society for the Study of Vulvovaginal Diseases (ISSVD) ersetzt werden. Dabei entfällt die Kategorie der VIN 1; die VIN 2 und VIN 3 werden unter dem Begriff VIN subsumiert. An der Unterscheidung zwischen klassischer und differenzierter Form der VIN ändert sich als morphologische Kategorien nichts. Eine Sonderstellung nimmt der vulväre Morbus Paget ein. In der Mehrzahl handelt es sich um eine intraepitheliale Neoplasie apokrin bzw. ekkrin differenzierter, ortsständiger Zellen. In 2–15 % handelt es sich um eine intraepitheliale Ausbreitung lokoregionärer Malignome.

Abstract

Vulvar carcinoma is a rare malignant tumor with an incidence 3–5 % of all malignancies the female genital tract. It can also be preceded by precancerous lesions, termed vulvar intraepithelial neoplasias (VIN). The most recent WHO classification for these neoplasms favors the traditional 3-grade system of VIN 1–3, similar to the CIN concept for the cervix uteri. However, on the basis of clinical, histopathological and molecular data, the International Society for the Study of Vulvovaginal Disease (ISSVD) has proposed only a single classification. Thus, the ISSVD system would eliminate VIN 1 and combine VIN 2 and 3 into a single grade (VIN), on the grounds that VIN 1 has not been shown to be a reproducible diagnosis and VIN 2 and 3 cannot be reliably separated. Two types of VIN have been defined, based on the morphology and pathogenesis of the lesion: the common type is characterized by a strong association to high risk HPV infection, occurrence at a younger age, and multifocality, and is mostly associated with non-keratinizing squamous cell carcinoma. The differentiated (or simplex) type is rare and is associated with an older age and p53-alterations; it is typically diagnosed coincidentally with keratinizing squamous cell carcinoma. Vulvar Paget's disease is an uncommon, minimally invasive lesion that accounts for 2.5 % of all vulvar malignancies, affecting older patients. It has been hypothesized that Paget's cells derive from undifferentiated basal cells of the stratum germinativum showing apocrine and/or eccrine differentiation. Only a minority of lesions of vulvar Paget's disease (2–15 %) are associated with adenocarcinomas of the urogenital tract or the skin appendages, representing an intraepidermal spread of these malignancies.

Literatur

• 1 Al-Ghamdi A, Freedman D, Miller D. et al . Vulvar squamous cell carcinoma in young women: a clinicopathologic study of 21 cases.  Gynecol Oncol. 2002;  84 94-101
  CrossrefPubMedGoogle Scholar
• 2 Armes J E, Lourie R, Bowlay G. et al . Pagetoid squamous cell carcinoma in situ of the vulva: comparison with extramammary Paget disease and nonpagetoid squamous cell neoplasia.  Int J Gynecol Pathol. 2008;  27 118-124
  PubMedGoogle Scholar
• 3 Beller U, Quinn M A, Benedet J L. et al . Carcinoma of the vulva. FIGO 6th annual report on the results of treatment in gynecological cancer.  Int J Gynaecol Obstet. 2006;  95 (Suppl. 1) S7-S27
  CrossrefPubMedGoogle Scholar
• 4 Carli P, Cattaneo A, De Magnis A. et al . Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study.  Eur J Cancer Prev. 1995;  4 491-495
  PubMedGoogle Scholar
• 5 Chafe W, Richards A, Morgan L. et al . Unrecognized invasive carcinoma in vulvar intraepithelial neoplasia (VIN).  Gynecol Oncol. 1988;  31 154-165
  CrossrefPubMedGoogle Scholar
• 6 Carlson J A, Ambros R, Malfetano J. et al . Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia.  Hum Pathol. 1998;  29 932-948
  CrossrefPubMedGoogle Scholar
• 7 Daling J R, Madeleine M M, Schwartz S M. et al . A population-based study of squamous cell vaginal cancer: HPV and cofactors.  Gynecol Oncol. 2002;  84 263-270
  CrossrefPubMedGoogle Scholar
• 8 Ewing T, Sawicki J, Ciaravino G. et al . Microinvasive Paget's disease.  Gynecol Oncol. 2004;  95 755-758
  CrossrefPubMedGoogle Scholar
• 9 Fox H, Wells M. Recent advances in the pathology of the vulva.  Histopathology. 2003;  42 209-216
  CrossrefPubMedGoogle Scholar
• 10 Geyer A, Röcken M, Strölin A. Dermatologie. Hautveränderungen und Erkrankungen der Haut in der Schwangerschaft.  Geburtsh Frauenheilk. 2006;  66 910-913
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Goffin F, Mayrand M H, Gauthier P. et al . High-risk human papillomavirus infection of the genital tract of women with a previous history or current high-grade vulvar intraepithelial neoplasia.  J Med Virol. 2006;  78 814-819
  CrossrefPubMedGoogle Scholar
• 12 Hampl M, Wentzensen N, Vinokurova S. et al . Comprehensive analysis of 130 multicentric intraepithelial female lower genital tract lesions by HPV typing and p 16 expression profile.  J Cancer Res Clin Oncol. 2007;  133 235-245
  CrossrefPubMedGoogle Scholar
• 13 Hantschmann P, Sterzer S, Jeschke U. et al . P53 expression in vulvar carcinoma, vulvar intraepithelial neoplasia, squamous cell hyperplasia and lichen sclerosus.  Anticancer Res. 2005;  25 1739-1745
  PubMedGoogle Scholar
• 14 Hart W R. Vulvar intraepithelial neoplasia: historical aspects and current status.  Int J Gynecol Pathol. 2001;  20 16-30
  CrossrefPubMedGoogle Scholar
• 15 Heller D S. Report of a new ISSVD classification of VIN.  J Low Genit Tract Dis. 2007;  11 46-47
  PubMedGoogle Scholar
• 16 Hillemanns P, Mehlhorn G, Rinna F. et al . HPV-Infektion: Impfung, Diagnostik und Therapie.  Geburtsh Frauenheilk. 2007;  67 R1-R28
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Horn L C, Purz S, Krumpe C. et al . COX‐2 and Her-2/neu are overexpressed in Paget's disease of the vulva and the breast: results of a preliminary study.  Arch Gynecol Obstet. 2008;  277 135-138
  CrossrefPubMedGoogle Scholar
• 18 Jemal A, Siegel R, Ward E. et al . Cancer statistics, 2008.  CA Cancer J Clin. 2008;  58 71-96
  CrossrefPubMedGoogle Scholar
• 19 Jones R W, Baranyai J, Stables S. Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia.  Obstet Gynecol. 1997;  90 448-452
  CrossrefPubMedGoogle Scholar
• 20 Jones R W. The natural history of vulvar intraepithelial neoplasia.  Br J Obstet Gynaecol. 1995;  102 764-766
  PubMedGoogle Scholar
• 21 Jones R W, Rowan D M, Stewart A W. Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women.  Obstet Gynecol. 2005;  106 1319-1326
  CrossrefPubMedGoogle Scholar
• 22 Joura E A. Epidemiology, diagnosis and treatment of vulvar intraepithelial neoplasia.  Curr Opin Obstet Gynecol. 2002;  14 39-43
  CrossrefPubMedGoogle Scholar
• 23 Joura E A, Lösch A, Haider-Angeler M G. et al . Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women.  J Reprod Med. 2000;  45 613-615
  PubMedGoogle Scholar
• 24 Judson P L, Habermann E B, Baxter N N. et al . Trends in the incidence of invasive and in situ vulvar carcinoma.  Obstet Gynecol. 2006;  107 1018-1022
  CrossrefPubMedGoogle Scholar
• 25 Kagie M J, Kenter G G, Tollenaar R A. et al . p53 protein overexpression, a frequent observation in squamous cell carcinoma of the vulva and in various synchronous vulvar epithelia, has no value as a prognostic parameter.  Int J Gynecol Pathol. 1997;  16 124-130
  PubMedGoogle Scholar
• 26 Kagie M J, Kenter G G, Hermans J. et al . The relevance of various vulvar epithelial changes in the early detection of squamous cell carcinoma of the vulva.  Int J Gynecol Cancer. 1997;  7 50-57
  CrossrefPubMedGoogle Scholar
• 27 Kaufman R H, Boice E H, Knight W R. Paget's disease of the vulva.  Am J Obstet Gynecol. 1960;  79 451-454
  PubMedGoogle Scholar
• 28 Keskin N, Iyibozkurt A C, Topuz S. et al . Invasive squamous carcinoma of the vulva in women aged less than 40 years: report of two cases and a third case diagnosed during pregnancy.  Eur J Gynaecol Oncol. 2008;  29 399-401
  PubMedGoogle Scholar
• 29 Lara-Torre E, Perlman S E. Vulvar intraepithelial neoplasia in adolescents with abnormal Pap smear results: a series report.  J Pediatr Adolesc Gynecol. 2004;  17 45-48
  CrossrefPubMedGoogle Scholar
• 30 Le T, Hicks W, Menard C. et al . Preliminary results of 5 % imiquimod cream in the primary treatment of vulva intraepithelial neoplasia grade 2/3.  Am J Obstet Gynecol. 2006;  194 377-380
  CrossrefPubMedGoogle Scholar
• 31 Lerma E, Matias-Guiu X, Lee S J. et al . Squamous cell carcinoma of the vulva: study of ploidy, HPV, p53, and pRb.  Int J Gynecol Pathol. 1999;  18 191-197
  PubMedGoogle Scholar
• 32 Liegl B, Horn L C, Moinfar F. Androgen receptors are frequently expressed in mammary and extramammary Paget's disease.  Mod Pathol. 2005;  18 1283-1288
  CrossrefPubMedGoogle Scholar
• 33 Liegl B, Leibl S, Gogg-Kamerer M. et al . Mammary and extramammary Paget's disease: an immunohistochemical study of 83 cases.  Histopathology. 2007;  50 439-447
  CrossrefPubMedGoogle Scholar
• 34 Liegl B, Regauer S. p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulvar intraepithelial neoplasia (d-VIN).  Histopathology. 2006;  48 268-274
  CrossrefPubMedGoogle Scholar
• 35 Losch A, Joura E A. Vulvar neoplasia in young women.  Gynecol Oncol. 1999;  75 519
  CrossrefPubMedGoogle Scholar
• 36 Madsen B S, Jensen H L, van den Brule A J. et al . Risk factors for invasive squamous cell carcinoma of the vulva and vagina-population-based case-control study in Denmark.  Int J Cancer. 2008;  122 2827-2834
  CrossrefPubMedGoogle Scholar
• 37 McNally O M, Mulvany N J, Pagano R. et al . VIN 3: a clinicopathologic review.  Int J Gynecol Cancer. 2002;  12 490-495
  CrossrefPubMedGoogle Scholar
• 38 Medeiros F, Nascimento A F, Crum C P. Early vulvar squamous neoplasia: advances in classification, diagnosis, and differential diagnosis. Early vulvar squamous neoplasia: advances in classification, diagnosis, and differential diagnosis.  Adv Anat Pathol. 2005;  12 20-26
  CrossrefPubMedGoogle Scholar
• 39 Micheletti L, Bogliatto F, Lynch P J. Vulvoscopy: review of a diagnostic approach requiring clarification.  J Reprod Med. 2008;  53 179-182
  PubMedGoogle Scholar
• 40 Mulvany N J, Allen D G. Differentiated intraepithelial neoplasia of the vulva.  Int J Gynecol Pathol. 2008;  27 125-135
  PubMedGoogle Scholar
• 41 O'Neill C J, McCluggage W G. p16 expression in the female genital tract and its value in diagnosis.  Adv Anat Pathol. 2006;  13 8-15
  CrossrefPubMedGoogle Scholar
• 42 Preti M, Mezzetti M, Robertson C. et al . Inter-observer variation in histopathological diagnosis and grading of vulvar intraepithelial neoplasia: results of an European collaborative study.  BJOG. 2000;  107 594-599
  PubMedGoogle Scholar
• 43 Preti M, Micheletti L, Massobrio M. et al . Vulvar Paget disease: One century after first reported.  J Low Genit Tract Dis. 2003;  7 122-135
  CrossrefPubMedGoogle Scholar
• 44 Rodolakis A, Diakomanolis E, Vlachos G. et al . Vulvar intraepithelial neoplasia (VIN) – diagnostic and therapeutic challenges.  Eur J Gynaecol Oncol. 2003;  24 317-322
  PubMedGoogle Scholar
• 45 Roma A A, Hart W R. Progression of simplex (differentiated) vulvar intraepithelial neoplasia to invasive squamous cell carcinoma: a prospective case study confirming its precursor role in the pathogenesis of vulvar cancer.  Int J Gynecol Pathol. 2007;  26 248-253
  PubMedGoogle Scholar
• 46 Santegoets L A, van Seters M, Heijmans-Antonissen C. et al . Reduced local immunity in HPV-related VIN: expression of chemokines and involvement of immunocompetent cells.  Int J Cancer. 2008;  123 616-622
  CrossrefPubMedGoogle Scholar
• 47 Scurry J, Wilkinson E J. Review of terminology of precursors of vulvar squamous cell carcinoma.  J Low Genit Tract Dis. 2006;  10 161-169
  CrossrefPubMedGoogle Scholar
• 48 Shatz P, Bergeron C, Wilkinson E J. et al . Vulvar intraepithelial neoplasia and skin appendage involvement.  Obstet Gynecol. 1989;  74 769-774
  PubMedGoogle Scholar
• 49 Sideri M, Jones R W, Wilkinson E J. et al . Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee.  J Reprod Med. 2005;  50 807-810
  PubMedGoogle Scholar
• 50 Smith K J, Tuur S, Corvette D. et al . Cytokeratin 7 staining in mammary and extramammary Paget's disease.  Mod Pathol. 1997;  10 1069-1074
  PubMedGoogle Scholar
• 51 Srodon M, Stoler M H, Baber G B. et al . The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN).  Am J Surg Pathol. 2006;  30 1513-1518
  PubMedGoogle Scholar
• 52 Tasker G L, Wojnarowska F. Lichen sclerosus.  Clin Exp Dermatol. 2003;  28 128-133
  CrossrefPubMedGoogle Scholar
• 53 Urabe A, Matsukuma A, Shimizu N. et al . Extramammary Paget's disease: comparative histopathologic studies of intraductal carcinoma of the breast and apocrine adenocarcinoma.  J Cutan Pathol. 1990;  17 257-265
  CrossrefPubMedGoogle Scholar
• 54 van de Nieuwenhof H P, van der Avoort I A, de Hullu J A. Review of squamous premalignant vulvar lesions.  Crit Rev Oncol Hematol. 2008;  68 131-156
  CrossrefPubMedGoogle Scholar
• 55 van der Avoort I A, van der Laak J A, Paffen A. et al . MIB1 expression in basal cell layer: a diagnostic tool to identify premalignancies of the vulva.  Mod Pathol. 2007;  20 770-778
  CrossrefPubMedGoogle Scholar
• 56 van der Putte S C. Mammary-like glands of the vulva and their disorders.  Int J Gynecol Pathol. 1994;  13 150-160
  PubMedGoogle Scholar
• 57 van Seters M, van Beurden M, de Craen A J. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.  Gynecol Oncol. 2005;  97 645-651
  CrossrefPubMedGoogle Scholar
• 58 Wilkinson E J, Teixeira M R. Tumors of the Vulva. Tavassoli FA, Devilee P, eds. Pathology and genetics of tumours of the breast and female genital organs. World Health Organization Classification of Tumours. Lyon; IARC Press 2003: 313-334
  Google Scholar
• 59 Woodruff J D, Williams T F. The DOPA reaction in Paget's disease of the vulva.  Obstet Gynecol. 1959;  14 86-90
  PubMedGoogle Scholar
• 60 Yang B, Hart W R. Vulvar intraepithelial neoplasia of the simplex (differentiated) type: a clinicopathologic study including analysis of HPV and p53 expression.  Am J Surg Pathol. 2000;  24 429-441
  CrossrefPubMedGoogle Scholar
• 61 Zaloudek C, Rabban J T. Differentiated vulva intraepithelial neoplasia (VIN): An underrecognised form of high grade VIN associated with keratinising squamous cell carcinoma of the vulva.  Pathol Case Rev. 2005;  10 35-40
  PubMedGoogle Scholar

Prof. Dr. med. Lars-Christian Horn

Abteilung Mamma-, Gynäko- und Perinatalpathologie
Institut für Pathologie
Universität Leipzig

Liebigstraße 26

04103 Leipzig

Email: hornl@medizin.uni-leipzig.de