SIMULTANEOUS SQUAMOUS CELL CARCINOMAS OF THE LOWER FEMALE GENITAL TRACT

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1 SIMULTANEOUS SQUAMOUS CELL CARCINOMAS OF THE LOWER FEMALE GENITAL TRACT Mark H. Stoler, M.D. University of Virginia Health System INTRODUCTION For the average woman the diagnosis of squamous cell carcinoma of the cervix is potentially a devastating and life-changing event. Most patients are not aware that even when diagnosed with just an abnormal Pap smear that multiple other sites in that patient s genital tract are at risk for, or already have developed, a potential precursor or another squamous cell carcinoma. This concept of a field at risk, for development of squamous cell carcinoma is intimately tied to our understanding of papillomavirus (HPV) biology. The complex interplay between HPV and the different types of squamous epithelium in the lower female genital tract is the topic of what follows. MULTIFOCALITY For the purposes of this presentation, certain terms that often have confused and overlapping meaning must be defined. Multifocal will refer to multiple sites of squamous neoplasia within a single organ site. A patient may have 2 non-contiguous foci of CIN3 in the cervix, e.g., CIN3 at 12 o clock and a second independent focus of CIN3 at 6 o clock. Similarly, a patient with a vulvar carcinoma may have an independent focus of VIN physically distinct from the carcinoma in terms of anatomic location within the vulvar skin. The frequency of multifocality is difficult to determine with any accuracy because of inherent inaccuracy in biopsy diagnosis. It is clear from many contemporary trials that colposcopy often misses prevalent pathology. This is due in part to the fact that colposcopic skill is highly variable; however it may also be predominately related to issues of colposcopic resolution. Lesions have to be a certain size to be detected by colposcopy and lesions below this resolution cutoff (approximately 2-3 mm) are often missed. Multifocality is common but the exact magnitude of its frequency is difficult to estimate. MULTICENTRICITY Multicentricity, in contrast to multifocality and for purposes of this discussion, will be defined as the presence of squamous neoplasia, either in situ or invasive, within different sites of the lower female genital tract. Patients may have simultaneous cervical and vulvar neoplasia, cervical and anal neoplasia, anal and vulvar neoplasia, etc. Obviously multicentricity and multifocality are related phenomena that reflect the interplay of the epithelial area at risk with HPV infection or other risk factors for the development of squamous neoplasia. The frequency of multicentricity is difficult to estimate because of the inadequacies of clinical case detection. Cervical neoplasia is intensely screened for through the use of the Papanicolaou smear where repetitive screening on a relatively small area of squamous real estate leads to a very high frequency of detection of epithelial abnormality. Colposcopy, the magnified examination of the cervix for purposes of 1

2 disease correlation and biopsy placement, increases the bias towards cervical disease detection. In contrast there is relatively little screening for vaginal, vulvar or perianal neoplasia. When a patient has an abnormal Pap smear the conscientious clinician should make an effort to detect gross epithelial abnormality in all these sites. Gross inspection, however, or even colposcopic examination, which is usually not done, is much less sensitive in an extracervical site than the focused and experienced examination of the cervix. There is, therefore, a negative detection bias for the frequency of co-existing multicentric squamous neoplasia. Given these biases, one can make some estimates of frequency based on epidemiologic data. Carcinoma of the cervix has a frequency of approximately per 100,000 women in unscreened populations. In screened populations within the United States the incidence is reduced to approximately per 100,000 (a 90% reduction induced by screening). Clinically it is obvious that carcinoma of the vulva seems less frequent than carcinoma of the cervix. Approximately 2 women per 100,000 develop carcinoma of the vulva, but the frequency increases to approximately 20 per 100,000 for women in their 70 s. If anal carcinoma is considered part of the field at risk in the lower female genital tract then an incidence of 7-10 per 100,000 is evident. This rises to per 100,000 in HIV or other immunocompromised populations. Taken together these estimates suggest that cervical squamous cancer is approximately 10 X more frequent than carcinoma of the vagina, vulva or anal canal. Estimates of the frequency of precursor lesions are again biased by inadequate case findings. The relative rates of CIN3 vs. VIN3 co-occurrence may be much closer to 1 to 1. This suggests that the risk factors for the transition from preinvasive to invasive malignancy is in part mediated by either some local protective effect or lack of exposure of the vaginal, vulvar or anal mucosa compared to the cervix. Unlike cervical squamous neoplasia where virtually 100% of tumors are papillomavirus associated, only 40-50% of tumors of the vulva are related to HPV. Estimates of the relative frequency in vaginal cancer are probably intermediate based on studies of precursor lesions. The alternative route of vulvar squamous neoplasia is associated with an older mean age, existing lichen sclerosis, absence of detection, the presence of p53 mutation and a different precursor morphology, the latter known as differentiated VIN or carcinoma in situ, simplex type. Thus, depending on patient age and other risk factors, patients with vulvar neoplasia may have multicentric as well as multifocal squamous neoplasia due to two different pathogenetic pathways; however clinically a single pathway often dominates. Further complicating possibility is that multicentric and multifocal disease can occur synchronously or metachronously. Metachronous lesions may only appear metachronous due to the above issues of case identification. MULTIPLE HPV INFECTIONS As there are negative biases for the accurate detection of lesional pathology, there are problems in estimating the frequency of multiple HPV infections. Current risk estimates are that at least 50% of individuals will have an HPV infection of some kind during their lifetime. Risk factors for acquiring HPV include the number of sexual partners. Obviously the greater the number of sexual partners, the greater the risk of acquiring one or more HPV infections and there are more than 100 different HPV types - at least 30 of which are relatively mucosotropic and infect the lower female genital tract. 2

3 The frequency of multiple infections in cervical cytology specimens is on the order of 25-50%. The range is in part predicated by the sensitivity of the detection system, both for the spectrum of HPVs as well as the analytic sensitivity relative to the number of copies of HPV at the assay cutoff. Thus 30-50% is probably a conservative number, particularly given the fact the patients are not sampled very frequently. Similar concepts apply regarding synchronous vs. metachronous lesion development. There is also an interaction between the mucosal location and the type of HPV present. The cervix seems to be more susceptible or have a greater range of HPV types relative to the available data on the vulva or anal region, but I must emphasize that these estimates are biased by the research emphasis which has been on cervical neoplasia. If one restricts the discussion to high-grade pre-cancer, then HPV16, which accounts for approximately 50% of CIN3, accounts for even higher frequency VIN3 and AIN3, suggesting HPV16 has either a broader ecological niche or is a much more effective carcinogen within all mucosal sites. In the current era of HPV prophylactic vaccination, this could be advantageous. Natural history studies pre- and post-vaccination will ultimately define the spectrum of squamous neoplasia related to each viral type within vaccine formulations, although this will take many decades to be fully revealed. Obviously, multiple HPV infections have implications for simultaneous neoplasia. The most common situation is that each individual infecting HPV type induces its own lesion. Studies that have used in situ hybridization or PCR analysis of individual lesions demonstrate that most individual microscopic lesions contain a single HPV type. Approximately 10-15% of microdissected cases may contain multiple HPV DNAs with double infections being much more common than triple, quadruple, etc. Limited data suggest that a single viral type is dominant within any individual lesion with little interaction, if any, between viruses that may co-exist within a single cell. In summary, infection with multiple HPV types is very common in patients. Each individual type has a risk for developing clinical neoplasia and consequently a risk of being associated with invasive cancer. The best data available suggests that HPV16 dominates in all sites within the lower female genital tract and on a relative basis is even more important for vaginal, vulvar and anal neoplasia than it is in the cervix. Hence, HPV vaccines directed against type 16 will have a major impact upon the incidence of that fraction of lower female genital tract disease that is related to vaccine type HPVs. Unlike the situation in the cervix, vagina and perianal region, the 50% of vulvar cancer that is not associated with HPV may become the dominant form of pathology in vaccinated populations. MONOCLONAL or MULTICLONAL? Implicit in the above discussion is the concept that multiple HPV infections lead to multiple independent lesions and that this is overwhelmingly likely the basis for multifocality and multicentricity of squamous neoplasia within the lower female genital tract. However, a recent paper challenges this concept based on clonality analysis. Most neoplastic lesions of the female genital tract are associated with high-risk pathogenic HPV infections including HPV16 and 18. HPV16 and 18 often integrate into 3

4 the host genome as part of the pathogenesis of cancer development. Integration is thought to be a random process with respect to the host genome, although it is anything but random with respect to the virus. The virus invariably integrates by breaking its circular genome within the E2 open reading frame or the nearby E1-E2 junction. This knowledge has led to the development of assays for viral integration using PCR making it is possible to assess the potential relatedness of independent lesions by analyzing and sequencing the integration sites between independent lesions. Recently the integration sites in women who had simultaneous or metachronous lesions involving the cervix, vagina or vulva were analyzed. In 4 of 5 patients who had multiple evaluable lesions, the integration loci were found to be identical in the multicentric sites. This finding challenges the concept that multifocal or multicentric diseases are primarily due to independent infectious events. Rather it suggests that patients with multicentric disease may have an original clonal process, most likely of cervical origin, and through either migration of neoplastic cells or implantation, independent lesions may develop at a distance from the primary clone. This is obviously a very controversial concept and requires confirmation and analysis of other measures of clonality. For example, it is possible that within an individual the predisposition for HPV16 or 18 to integrate into that individual s host genome may be non-random, creating the need for independent correlates of clonality. SUMMARY Multicentricity is common but may be more often obvious as metachronous as opposed to synchronous lesions. The same applies for multifocality. Both are linked to HPV multiplicity. Multiple HPV infections lead most likely to multiclonal, multicentric pathology. Recent clonality analyses potentially challenge this, i.e., multicentric lesions may be monoclonal. SELECTED READINGS Stoler, M.H. The Pathology of Cervical Neoplasia. Chapter 1 In Rohan, T. and Shah, K. eds. Cervical Cancer: From Etiology to Prevention. Kluwer Academic Publishers (Netherlands), Stoler, M.H., Mills, S.E. and Frierson, H.F. The Vulva and Vagina, Chapter 51 in Diagnostic Surgical Pathology, Fourth Edition,edited by Stacey E. Mills. Lippincott Williams & Wilkins, Philadelphia Wilbur DC, Bonfiglio TA, Stoler MH. Continuity of human papillomavirus (HPV) type between neoplastic precursors and invasive cervical carcinoma. An in situ hybridization study. American Journal of Surgical Pathology. 1988;12(3): Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. Jan ;88(1): The ALTS Group. Results of a randomized trial on the management of cytology terpretations of atypical squamous cells of undetermined significance. Am J bstet Gynecol. Jun 2003;188(6):

5 Cox JT, Schiffman M, Solomon D for the ALTS Group. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol. Jun 2003;188(6): Srodon,M, Stoler, MH, Baber, BG and Kurman, RJ. The Distribution of Low and High Risk HPV Types in Vulvar and Vaginal Intraepithelial Neoplasia (VIN and VaIN) AJSP in press 2006 McCance DJ, Clarkson PK, Dyson JL, Walker PG, Singer A. Human papillomavirus types 6 and 16 in multifocal intraepithelial neoplasias of the female lower genital tract. British Journal of Obstetrics & Gynaecology. 1985;92(11): Beckmann AM, Kiviat NB, Daling JR, Sherman KJ, McDougall JK. Human papillomavirus type 16 in multifocal neoplasia of the female genital tract. International Journal of Gynecological Pathology. 1988;7(1): Bornstein J, Kaufman RH, Adam E, Adler SK. Multicentric intraepithelial neoplasia involving the vulva. Clinical features and association with human papillomavirus and herpes simplex virus. Cancer. 1988;62(8): Scholefield JH, Hickson WG, Smith JH, Rogers K, Sharp F. Anal intraepithelial neoplasia: part of a multifocal disease process. Lancet. 1992;340(8830): Hatch K. Colposcopy of vaginal and vulvar human papillomavirus and adjacent sites. [Review]. Obstetrics & Gynecology Clinics of North America. 1993;20(1): Mitchell MF, Prasad CJ, Silva EG, Rutledge FN, McArthur MC, Crum CP. Second genital primary squamous neoplasms in vulvar carcinoma: viral and histopathologic correlates. Obstetrics & Gynecology. 1993;81(1): Hording U, Daugaard S, Junge J, Lundvall F. Human papillomaviruses and multifocal genital neoplasia. Int J Gynecol Pathol. Jul 1996;15(3): Enomoto T, Haba T, Fujita M, et al. Clonal analysis of high-grade squamous intraepithelial lesions of the uterine cervix. Int J Cancer. Nov ;73(3): Larson AA, Liao SY, Stanbridge EJ, Cavenee WK, Hampton GM. Genetic alterations accumulate during cervical tumorigenesis and indicate a common origin for multifocal lesions. Cancer Research. 1997;57(19): Park J, Sun D, Genest DR, Trivijitsilp P, Suh I, Crum CP. Coexistence of low and high grade squamous intraepithelial lesions of the cervix: morphologic progression or multiple papillomaviruses? Gynecol Oncol. Sep 1998;70(3): Fife KH, Cramer HM, Schroeder JM, Brown DR. Detection of multiple human papillomavirus types in the lower genital tract correlates with cervical dysplasia. J Med Virol. Aug 2001;64(4): Ena P, Lorrai P, Pintus A, Marras V, Dessy LA. Development of multifocal squamous cell carcinoma in lichen sclerosus et atrophicus of the penis associated to HCV hepatitis. Andrologia. Feb 2004;36(1): Vinokurova S, Wentzensen N, Einenkel J, et al. Clonal history of papillomavirus-induced dysplasia in the female lower genital tract. J Natl Cancer Inst. Dec ;97(24):