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i.e. including HPV types not covered by the vaccine) are considered,
the reduction of lesions is less than 20% in vaccinees compared to
placebo recipients (“population impact”). These data demonstrate
that the currently available vaccines have an excellent preventive efficacy against the vaccine HPV types; but no therapeutic effect can be
expected, and cross protection against non-vaccine HPV types is at
best very limited. The vaccines are considered safe, serious sideeffects being extremely rare, and comparable to other vaccines that
are generally accepted as beneficial.
61
The ideal target population for
this vaccine are females before the onset of sexual activity, i.e. girls at
the age of 11–12 years. After sexual debut, “catch-up” vaccination
may still be beneficial or provide partial protection if the recipient
has not been exposed to all HPV types covered by the vaccine. Males
may benefit from the vaccine not so much in terms of protection
against the rather rare penile carcinoma, but also against condylomata acuminata, which are a frequent cause of emotional embarrassment and reason for cumbersome medical interventions. Also, if herd
immunity is desired, males need to be vaccinated in order to eliminate that viral reservoir. The usefulness of vaccinating other target
groups (e.g. older adults, victims of sexual abuse, HIV positive individuals, infants born to HIV positive mothers) is still under investigation. In addition to cervical, vaginal and penile carcinomas, a
significant subset of vulvar, anal, oropharyngeal and other carcinomas are associated with the same high risk HPV types, and it is
expected that the vaccine will provide protection against those cancers, too. Since HPV types 16 and 18 together cause approximately
“only” 70% of all cervical cancers, the vaccine does not provide protection against all cancers. Therefore it is most important to emphasize that vaccine recipients must not discontinue their screening
programs!
Although it is hoped that the advent of the HPV vaccine marks
the beginning of the end of cervical cancer, there is still a long way to
go. Considering that it takes on average at least ten years for a high
grade squamous intraepithelial lesion to progress to an invasive carcinoma, a significant reduction in the incidence of cervical cancer cannot
108 P Schlosshauer
be expected until about the year 2020. Developed countries have
already experienced a dramatic reduction in cervical cancer numbers
over the past decades due to efficient prevention programs. Here, the
impact of the vaccine on a further reduction of morbidity and mortality will be relatively small. Most cases of invasive cervical carcinoma
in industrialized countries occur in patients who did not participate in
screening programs anyway, and this population is unlikely to volunteer for a vaccine. On the other hand, the greatest population impact
of the HPV vaccine could be achieved in developing countries where
no screening programs are in effect. There the major drawbacks of the
currently available vaccines become evident: first of all, the high cost
makes them practically unaffordable for the population in need.
Furthermore, limited shelf life, the need to refrigerate the vaccine,
and the protocol of three separate injections over the course of six
months reduce the practicability in countries with compromised infrastructure. Current research efforts addressing these and other shortcomings of the first generation HPV vaccines include the following:
VLP-based vaccines against more (e.g. a total of eight) HPV types;
L2 (minor capsid protein)-based vaccines that evoke a broader cross
protection covering numerous HPV types; single dose application
vaccines; oral/nasal (inhalation) application vaccines; DNA vaccines
(plasmid-based) that are stable at room temperature; therapeutic
vaccines that elicit a cellular immunity against the viral E6 and E7
proteins; and chimeric vaccines that combine preventive and therapeutic properties.
REFERENCES
1. Wang SS, Sherman ME, Silverberg SG, et al., Pathological characteristics of cervical adenocarcinoma in a multi-center US-based study,
Gynecol Oncol 103:541–546, 2006.
2. Schlosshauer PW, Chen W, Chanderdatt D, et al., Monsel’s
artifact in gynecologic biopsies: a simple remedy, J Histotechnol 28:161–162,
2005.
3. Nucci MR, Young RH, Fletcher CD, Cellular pseudosarcomatous
fibroepithelial stromal polyps of the lower female genital tract: an
Early Diagnosis of Cervical and Vaginal Cancer 109
underrecognized lesion often misdiagnosed as sarcoma, Am J Surg
Pathol 24:231–240, 2000.
4. Deligdisch L, de Resende Miranda CR, Wu HS, et al., Human
papillomavirus-related cervical lesions in adolescents: a histologic and
morphometric study, Gynecol Oncol 89:52–59, 2003.
5. Clifford GM, Rana RK, Franceschi S, et al., Human papillomavirus
genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer, Cancer Epidemiol Biomarkers
Prev 14:1157–1164, 2005.
6. Evans MF, Adamson CS, Papillo JL, et al., Distribution of human
papillomavirus types in ThinPrep papanicolaou tests classified according to the Bethesda 2001 terminology and correlations with patient
age and biopsy outcomes, Cancer 106:1054–1064, 2006.
7. Missmer SA, Hankinson SE, Spiegelman D, et al., In utero exposures
and the incidence of endometriosis, Fertil Steril 82:1501–1508, 2004.
8. Wise-Draper TM, Wells SI, Papillomavirus E6 and E7 proteins and their
cellular targets, Front Biosci 13:1003–1017, 2008.
9. Thomas M, Banks L, Human papillomavirus (HPV) E6 interactions
with bak are conserved amongst E6 proteins from high and low risk
HPV types, J Gen Virol 80(Part 6):1513–1517, 1999.
10. Cho NH, Kim YT, Kim JW, Alteration of cell cycle in cervical tumor
associated with human papillomavirus: cyclin-dependent kinase
inhibitors, Yonsei Med J 43:722–728, 2002.
11. Kim YT, Zhao M, Aberrant cell cycle regulation in cervical carcinoma,
Yonsei Med J 46:597–613, 2005.
12. Nguyen CL, Eichwald C, Nibert ML, et al., Human papillomavirus type
16 E7 oncoprotein associates with the centrosomal component gammatubulin, J Virol 81: 13533–13543, 2007.
13. Stanley MA, Pett MR, Coleman N, HPV: from infection to cancer,
Biochem Soc Trans 35:1456–1460, 2007.
14. Tindle RW, Immune evasion in human papillomavirus-associated cervical cancer, Nat Rev Cancer 2:59–65, 2002.
15. Clifford GM, Smith JS, Aguado T, et al., Comparison of HPV type
distribution in high-grade cervical lesions and cervical cancer: a metaanalysis, Br J Cancer 89:101–105, 2003.
16. Pirog EC, Kleter B, Olgac S, et al., Prevalence of human papillomavirus
DNA in different histological subtypes of cervical adenocarcinoma,
Am J Pathol 157:1055–1062, 2000.
110 P Schlosshauer
17. Castellsague X, Diaz M, de Sanjose S, et al., International Agency for
Research on Cancer Multicenter Cervical Cancer Study Group.
Worldwide human papillomavirus etiology of cervical adenocarcinoma
and its cofactors: implications for screening and prevention,
J Natl Cancer Inst 98:303–315, 2006.
18. Appleby P, Beral V, Berrington de Gonzalez A, et al., Carcinoma of the
cervix and tobacco smoking: collaborative reanalysis of individual data
on 13,541 women with carcinoma of the cervix and 23,017 women
without carcinoma of the cervix from 23 epidemiological studies, Int J
Cancer 118:1481–1495, 2006.
19. Vaccarella S, Herrero R, Snijders PJ, et al., Smoking and human papillomavirus infection: pooled analysis of the international agency for research
on cancer HPV prevalence surveys, Int J Epidemiol 37:536–546, 2008.
20. Chan JK, Monk BJ, Brewer C, et al., HPV infection and number of life-
time sexual partners are strong predictors for ‘natural’ regression of CIN
2 and 3, Br J Cancer 89:1062–1066, 2003.
21. Trimble CL, Piantadosi S, Gravitt P, et al., Spontaneous regression of
high-grade cervical dysplasia: effects of human papillomavirus type and
HLA phenotype, Clin Cancer Res 11:4717–4723, 2005.
22. Ellerbrock TV, Chiasson MA, Bush TJ, et al., Incidence of cervical squamous intraepithelial lesions in HIV-infected women, JAMA 283:
1031–1037, 2000.
23. Hawes SE, Critchlow CW, Sow PS, et al., Incident high-grade squamous
intraepithelial lesions in senegalese women with and without human
immunodeficiency virus type 1 (HIV-1) and HIV-2, J Natl Cancer Inst
98:100–109, 2006.
24. Carreon JD, Sherman ME, Guillen D, et al., CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological
review of population-based cervical samples, Int J Gynecol Pathol
26:441–446, 2007.
25. Cai B, Ronnett BM, Stoler M, et al., Longitudinal evaluation of interobserver and intraobserver agreement of cervical intraepithelial neoplasia diagnosis among an experienced panel of gynecologic pathologists,
Am J Surg Pathol 31:1854–1860, 2007.
26. Monsonego J, Valensi P, Zerat L, et al., Simultaneous effects of aneuploidy and oncogenic human papillomavirus on histological grade of
cervical intraepithelial neoplasia, Br J Obstet Gynaecol 104:723–727,
1997.
Early Diagnosis of Cervical and Vaginal Cancer 111
27. Nagi CS, Schlosshauer PW, Endocervical glandular involvement is associated with high-grade SIL, Gynecol Oncol 102: 240–243, 2006.
28. Livasy CA, Maygarden SJ, Rajaratnam CT, et al., Predictors of recurrent
dysplasia after a cervical loop electrocautery excision procedure for
CIN3: a study of margin, endocervical gland, and quadrant involvement,
Mod Pathol 12:233–238, 1999.
29. Wang SS, Sherman ME, Hildesheim A, et al., Cervical adenocarcinoma and
squamous cell carcinoma incidence trends among white women and black
women in the United States for 1976–2000, Cancer 100: 1035–1044,
2004.
30. Zaino RJ, Symposium Part I: adenocarcinoma in situ, glandular dysplasia, and early invasive adenocarcinoma of the uterine cervix, Int J Gynecol
Pathol 21:314–326, 2002.
31. Schlesinger C, Silverberg SG, Endocervical adenocarcinoma in situ of
tubal type and its relation to atypical tubal metaplasia, Int J Gynecol
Pathol 18:1–4, 1999.
32. Young JL, Jazaeri AA, Lachance JA, et al., Cervical adenocarcinoma
in situ: the predictive value of conization margin status, Am J Obstet
Gynecol 197:195.e1–7; discussion 195.e7–8, 2007.
33. Goldstein NS, Mani A, The status and distance of cone biopsy margins
as a predictor of excision adequacy for endocervical adenocarcinoma
in situ, Am J Clin Pathol 109:727–732, 1998.
34. Witkiewicz A, Lee KR, Brodsky G, et al., Superficial (early) endocervical adenocarcinoma in situ: a study of 12 cases and comparison to
conventional AIS, Am J Surg Pathol 29:1609–1614, 2005.
35. Lee KR, Symposium Part 4: should pathologists diagnose endocervical
preneoplastic lesions “less than” adenocarcinoma in situ? Counterpoint,
Int J Gynecol Pathol 22:22–24, 2003.
36. Tavassoli FA, Devilee P, Tumours of the Breast and Female Genital
Organs, IARC Press, Lyon, France 2003.
37. Arias-Stella J, The Arias-Stella reaction: facts and fancies four decades
after, Adv Anat Pathol 9:12–23, 2002.
38. Raspagliesi F, Ditto A, Solima E, et al., Microinvasive squamous cell
cervical carcinoma, Crit Rev Oncol Hematol 48:251–261, 2003.
39. Lai CH, Chang CJ, Huang HJ, et al., Role of human papillomavirus
genotype in prognosis of early-stage cervical cancer undergoing primary
surgery, J Clin Oncol 25:3628–3634, 2007.
112 P Schlosshauer
40. Schwartz SM, Daling JR, Shera KA, et al., Human papillomavirus and
prognosis of invasive cervical cancer: a population-based study, J Clin
Oncol 19:1906–1915, 2001.
41. Van Calsteren K, Vergote I, Amant F, Cervical neoplasia during pregnancy: diagnosis, management and prognosis, Best Pract Res Clin Obstet
Gynaecol 19:611–630, 2005.
42. Smith HO, Tiffany MF, Qualls CR, et al., The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in
the United States — a 24-year population–based study, Gynecol Oncol
78:97–105, 2000.
43. Vinh-Hung V, Bourgain C, Vlastos G, et al., Prognostic value of
histopathology and trends in cervical cancer: a SEER population study,
BMC Cancer 7:164, 2007.
44. Smith HO, Qualls CR, Romero AA, et al., Is there a difference in survival for IA1 and IA2 adenocarcinoma of the uterine cervix? Gynecol
Oncol 85:229–241, 2002.
45. Quinn MA, Benedet JL, Odicino F, et al., Carcinoma of the cervix uteri.
FIGO 6th annual report on the results of treatment in gynecological
cancer, Int J Gynaecol Obstet 95(Suppl. 1):S43–S103, 2006.
46. Poynor EA, Marshall D, Sonoda Y, et al., Clinicopathologic features of
early adenocarcinoma of the cervix initially managed with cervical
conization, Gynecol Oncol 103:960–965, 2006.
47. An HJ, Kim KR, Kim IS, et al., Prevalence of human papillomavirus
DNA in various histological subtypes of cervical adenocarcinoma: a
population-based study, Mod Pathol 18:528–534, 2005.
48. Hayashi I, Tsuda H, Shimoda T, Reappraisal of orthodox histochemistry
for the diagnosis of minimal deviation adenocarcinoma of the cervix,
Am J Surg Pathol 24:559–562, 2000.
49. Mikami Y, Kiyokawa T, Hata S, et al., Gastrointestinal immunophenotype
in adenocarcinomas of the uterine cervix and related glandular lesions: a
possible link between lobular endocervical glandular hyperplasia/pyloric
gland metaplasia and ‘adenoma malignum’, Mod Pathol 17:962–972, 2004.
50. Farley JH, Hickey KW, Carlson JW, et al., Adenosquamous histology
predicts a poor outcome for patients with advanced-stage, but not
early-stage, cervical carcinoma, Cancer 97:2196–2202, 2003.
51. Yasuda S, Kojima A, Maeno Y, et al., Poor prognosis of patients with
stage Ib1 adenosquamous cell carcinoma of the uterine cervix with
pelvic lymphnode metastasis, Kobe J Med Sci 52:9–15, 2006.
Early Diagnosis of Cervical and Vaginal Cancer 113
52. Albores-Saavedra J, Gersell D, Gilks CB, et al., Terminology of
endocrine tumors of the uterine cervix: results of a workshop sponsored by the college of American pathologists and the national cancer
institute, Arch Pathol Lab Med 121:34–39, 1997.
53. Ayhan A, Celik H, Dursun P, Lymphatic mapping and sentinel node
biopsy in gynecological cancers: a critical review of the literature, World
J Surg Oncol 6:53, 2008.
54. Beller U, Benedet JL, Creasman WT, et al., Carcinoma of the vagina.
FIGO 6th annual report on the results of treatment in gynecological
cancer, Int J Gynaecol Obstet 95(Suppl. 1):S29–S42, 2006.
55. Waggoner SE, Mittendorf R, Biney N, et al., Influence of in utero
diethylstilbestrol exposure on the prognosis and biologic behavior of
vaginal clear-cell adenocarcinoma, Gynecol Oncol 55:238–244, 1994.
56. Deshpande AH, Munshi MM, Primary malignant melanoma of the uterine cervix: report of a case diagnosed by cervical scrape cytology and
review of the literature, Diagn Cytopathol 25:108–111, 2001.
57. Schlosshauer PW, Heller DS, Koulos JP, Malignant melanoma of the
uterine cervix diagnosed on a cervical cytologic smear, Acta Cytol 42:
1043–1045, 1998.
58. Chiesa-Vottero AG, Malpica A, Deavers MT, et al., Immunohistochemical
overexpression of p16 and p53 in uterine serous carcinoma and ovarian
high-grade serous carcinoma, Int J Gynecol Pathol 26:328–333, 2007.
59. Vang R, Barner R, Wheeler DT, et al., Immunohistochemical staining
for Ki-67 and p53 helps distinguish endometrial Arias-Stella
reaction from high-grade carcinoma, including clear cell carcinoma,
Int J Gynecol Pathol 23:223–233, 2004.
60. McCluggage WG, Ganesan R, Hirschowitz L, et al., Ectopic prostatic
tissue in the uterine cervix and vagina: report of a series with a detailed
immunohistochemical analysis, Am J Surg Pathol 30:209–215, 2006.
61. Villa LL, Overview of the clinical development and results of a quadrivalent HPV (types 6, 11, 16, 18) vaccine, Int J Infect Dis 11(Suppl. 2):
S17–S25, 2007.
62. Greene FL, Page DL, Fleming ID, et al., AJCC Cancer Staging
Manual, 6th edn., Springer Verlag, New York, 2002.
114 P Schlosshauer
EARLY DIAGNOSIS
OF CERVICAL, VAGINAL
AND VULVAR CANCER:
A CLINICIAN’S VIEW
Albert Altchek
CERVICAL CANCER
General Considerations
The risk for cervical cancer in the US is 1 in 135 women with 11,070
new cases and 3870 deaths predicted for 2008. There has been a great
decrease in the incidence of cervical cancer in the US because of Pap
cytology and HPV testing. Worldwide there are about 500,000 new
cases annually, mainly in the developing countries where it is the second
leading cause of mortality due to cancer. The high-grade lesion biopsies
or excisional procedures may be found to detect a small percentage of
early cervical cancer, according to Creasman.
1
Other guidelines are more
detailed with many exceptions and individualization depending on age
(adolescent, postmenopausal), desire to preserve fertility, pregnancy and
115
3
CHAPTER
different life styles. Endocervical glandular (adenomatous) cytology is
relatively unreliable and malignancy is readily overlooked. The American
College of Obstetricians and Gynecologists, the American Cancer
Society and the Bethesda System (2001) have slightly different guidelines. Of the 120 types of human papilloma virus (HPV), about 30 types
affect the squamous epithelium of the lower genital and anal areas of
females and males.
1
Types 6 and 11 (low-risk) cause condyloma acuminata. Types 16, 18, 31 and 45 (high-risk) may induce cancer if they persist over the years. Type 18 tends to be found in adenocarcinoma.
1
Screening for Cervical Neoplasia Precursors
A simplified management of cervical cytology (with individual modifications) was outlined:
1
1. For ASC-US: Atypical squamous cells of unknown significance.
Consider: Repeat cytology, colposcopy or HPV DNA testing. Cone
or loop excisional procedures should not be done if there is no
proven cervical intraepithelial neoplasia (CIN) or in adolescents.
2. For ASC-H: Atypical squamous cells — cannot exclude HSIL
(high-grade squamous intraepithelial lesion).
Recommend: Should have colposcopy.
3. For low-grade squamous intraepithelial lesions (LSIL).
Consider: Colposcopy; for adolescents repeat cytology.
4. For high-grade squamous intraepithelial lesions (HSIL).
Recommend: Colposcopy and endocervical sampling; sometimes
diagnostic excisional procedures; repeat cytology or HPV testing
is unacceptable because there should be prompt investigation.
1
5. For atypical glandular cells and adenocarcinoma in situ (AGC
and AIS) (based on 2001 Bethesda system).
Recommend: Colposcopy with endocervical sampling; consider
endometrial sampling. If negative, consider cold knife conization. Repeat cytology is unacceptable.
1
An excellent review of Cervical Cancer Screening (PDQR) Health
Professional Version was prepared by the National Cancer Institute,
116 A Altchek
last modified 4/10/2008.2The prevalence of CIN is highest among
women in their 20s and 30s; however, mortality is rare under age 30.
HSIL is rare in women older than age 65 who have been previously
screened. About 70% of ASCUS and CIN 1 lesions regress within six
years. About 6% of CIN 1 lesions progress to CIN 3 or worse. About
10% to 20% with CIN 3 progress to invasive cancer. Although mortality is higher in black women than white women, mortality in all is
rare if there has been regular screening. In low resource, underdeveloped countries there is ongoing research of one-time “screen and
treat” such as a one-time visual inspection of the cervix with acetic
acid (VIA) and immediate colposcopy, directed biopsy and cryotherapy when indicated.
The accuracy of the Papanicolau (Pap) test is measured by sensitivity (percent of “true-positives”) and specificity (percent of “truenegatives”). Such tests have rarely been done. For a single Pap test for
high-grade lesions the sensitivity is 55% to 80%. With regular Pap testing it is higher. To determine the sensitivity and specificity of the Pap
smear, both a test threshold (point at which it is “positive”) and a
reference-standard threshold (considered to be “positive”) must be
defined. Atypical squamous cells of undetermined significance is often
used as the test threshold and cervical intraepithelial neoplasm (CIN)
is used as the reference threshold. This gives a sensitivity of about 68%
and a specificity of about 75%. A better test threshold may be lowgrade squamous intraepithelial lesions with a reference threshold of
CIN 2–3 which gives a sensitivity of 70% to 80%, with a specificity of
about 95%.
An adequate specimen is critical. “Adequate training and using
such techniques as the cytobrush may improve sensitivity”
2
(Fig. 1).
Although the new liquid-based cytology (ThinPrep) gives mixed evidence for adequacy, it has the advantage of simultaneous HPV testing. (Comment: Advantages are simultaneous HPV testing and in the
near future testing for other diseases, such as gonorrhea, chlamydia,
herpes, trichomonads, candida, bacterial vaginosis. In addition, individual squamous cells are seen without overlapping other cells, therefore readings are faster). Women who have had a total hysterectomy
with removal of the cervix for benign disease rarely have Pap smear
Early Diagnosis of Cervical, Vaginal and Vulvar Cancer 117