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Background
The vagina is remarkably resistant to most diseases. In fact, diseases that may affect the vulva and spread to the cervix, may completely bypass the vagina. Pathologists, however, first identified the link with DES and a rare form of vaginal cancer.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE/
PREVALENCEAGE SEX GEOGRAPHY EPIDEMIOLOGIC ASSOCIATIONS DES-Diethylstilbestrol This hormone was used between 1938-1971 in pregnant women who had a threatened miscarriage
Unfortunately, daughters of mothers who had been exposed to this drug are at increaed risk (although overall <0.14% of all DES exposed women) for developing a rare form of vaginal cancer termed clear cell adenocarcinoma.
DISEASE ASSOCIATIONS CHARACTERIZATION
PATHOGENESIS CHARACTERIZATION HUMAN PAPILLOMA VIRUS
Departments of *Pathology double daggerGynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD daggerDepartment of Pathology, University of Virginia Health System, Charlottesville, VA.
It has been proposed that low-grade vulvar and vaginal lesions (VIN 1 and VaIN 1) are flat condylomas and should be designated as such. Moreover, their relationship to high-grade lesions (VIN 3 and VaIN 3) is unclear. Accordingly, this study was undertaken to address these issues by comparing the distribution of human papillomavirus (HPV) types in vulvar and vaginal intraepithelial lesions.
We identified 33 cases of VIN 1, 34 cases of VIN 3, 17 cases of VaIN 1, and 16 cases of VaIN 3. In addition, 36 cases of low-grade squamous intraepithelial lesion (LSIL) in the cervix and 116 cases of cervical high-grade squamous intraepithelial lesion were used for comparison. Polymerase chain reaction analysis was performed using both the Roche PGMY and DDL SPF 10 systems. In cases where HPV was detected, the majority of low-grade and high-grade lesions contained a single HPV type. However, a minority of cases were found to have multiple HPV types. Of the VIN 1 cases, a low-risk virus was seen in 22 (67%), with HPV 6 or 11 accounting for 14 (42%). A high-risk virus was detected in 14 (42%) of cases of which 2 (6%) contained HPV 16. Of the VIN 3 cases, all had high-risk HPV of which 31 (91%) were found to have HPV 16. Of the VaIN 1 cases, 6 (35%) were found to have low-risk HPV types. HPV 6 or 11 were not found in these cases. High-risk virus was seen in 13 (76%) VaIN 1 cases, with 1 (6%) containing HPV 16. HPV was detected in 15 of 16 (94%) VaIN 3 lesions, all of which had high-risk types. HPV 16 was found in 8 (50%). In contrast, 2 (6%) of cervical LSIL had low-risk HPV (HPV 6 and 11), whereas 34 (94%) of LSIL cases had high-risk HPVs.
Of the cervical high-grade squamous intraepithelial lesion cases, 100% had high-risk HPVs of which 87 (75%) were found to have HPV 16. The findings demonstrate that a significant number of low-grade vulvar and vaginal lesions contain high-risk HPV types, supporting their designation as low-grade intraepithelial lesions rather than flat condylomas. The low frequency of HPV 16 in VIN 1 compared with VIN 3 suggests they are distinct lesions or that HPV 16 is critical in the progression to VIN 3.
Finally, comparison of the distribution of HPV in the vagina and vulva suggests that VaIN is more closely related to cervical intraepithelial neoplasia than to VIN.
- Vaginal dysplastic lesions in women with hysterectomy and receiving radiotherapy are linked to high-risk human papillomavirus.
Barzon L, Pizzighella S, Corti L, Mengoli C, Palu G.
Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Padova, Italy.
J Med Virol. 2002 Jul;67(3):401-5. Abstract quote
Patients undergoing radiotherapy for advanced cervical and endometrial cancer bear a considerable risk of developing vaginal preneoplastic lesions.
Radiotherapy itself has been considered to have a role in the pathogenesis of vaginal dysplasia, although human papillomavirus (HPV) involvement has also been suggested. A series of 88 patients who underwent hysterectomy and were irradiated for gynecological cancer, including 43 with postradiation vaginal dysplasia at colposcopy and 45 without vaginal lesions, were included in this study. Detection and genotyping of HPV DNA in vaginal scraping were carried out by a PCR-based method and compared with colposcopic and cytological findings and with other clinical and laboratory data.
Forty-two (97.7%) colposcopy-positive subjects and 6 (13.3%) colposcopically-negative patients were PCR-positive for high-risk HPV DNA (P < 0.000001). Twenty-two out of the 43 patients with colposcopic lesions showed an abnormal Papanicolau (PAP) test. Cytologic examination was negative in all colposcopically negative women. Type 16 HPV DNA was more frequent in patients with high-grade squamous intraepithelial lesions and in patients treated with external radiotherapy, whereas other types of high-risk HPV were more common in patients with low-grade lesions and in those treated with brachytherapy.
When considering colposcopy as the standard for diagnosing vaginal dysplasia, HPV DNA testing was more sensitive than the PAP test. However, the specificity of the PAP test was higher with no false-positive case. In conclusion, vaginal preneoplastic changes in women post-hysterectomy and receiving radiotherapy for cervical, endometrial, and vaginal cancer represent an HPV-related nosologic entity.
Whereas colposcopic examination can detect these preneoplastic lesions, HPV genotyping is a sensitive, inexpensive, and noninvasive method that may complement colposcopy and the PAP test.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS
GROSS APPEARANCE/
CLINICAL
VARIANTSCHARACTERIZATION GENERAL VARIANTS MULTIFOCAL
- Multifocal squamous neoplasia of the female genital tract: significance of human papillomavirus infection of the vagina after hysterectomy.
Schneider A, de Villiers EM, Schneider V.
Obstet Gynecol. 1987 Sep;70(3 Pt 1):294-8. Abstract quote
Six hundred sixteen women with a history of hysterectomy were examined for the presence of human papillomavirus deoxyribonucleic acid (DNA) in vaginal smears using filter in situ hybridization.
One hundred twenty patients had had hysterectomy for cervical intraepithelial neoplasia and invasive neoplasia, 54 for noncervical anogenital cancer, and 442 for benign uterine disorders. Human papillomavirus DNA was detected in 18% of all vaginal smears. A history of cervical neoplasia was associated with a significantly higher human papillomavirus infection rate, compared with patients with benign disease (33 versus 14%).
Human papillomaviruses 16 and 18 were the most common types detected in patients with a history of cervical carcinoma, whereas the majority of patients with benign uterine disease were infected with human papillomavirus 6/11. Colposcopy identified lesions in more than half of the patients; these appeared in more than 90% as "condylomatous vaginitis." In 5% of the human papillomavirus-positive patients, human papillomavirus 16-positive vaginal intraepithelial neoplasia could be diagnosed.
Increased risk of vaginal intraepithelial neoplasia after hysterectomy is associated with vaginal human papillomavirus infection. Virologic results explain the higher risk for vaginal neoplasia in patients with a history of cervical neoplasia.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL VAIN (Vaginal Intraepithelial Neoplasia) This is a grading system similar to CIN in the cervix.
It is graded low grade to high grade and is considered a significant risk factor for the development of invasive carcinoma.
- Epidemiological aspects of vaginal intraepithelial neoplasia (VAIN).
Minucci D, Cinel A, Insacco E, Oselladore M.
Dept. of Obstetrics and Gynecology, University of Padua, Italy.
Clin Exp Obstet Gynecol. 1995;22(1):36-42. Abstract quote
In order to evaluate the natural history of Vaginal Intraepithelial Neoplasia (VAIN), its epidemiological characteristics and the risk of its evolving into Invasive Carcinoma, we studied direct vaginal biopsies from 376 outpatients, we ascertained the predominant disease site and investigated whether the lesions (uni or multicentric) were only vaginal, were present at both the cervix and the vagina or were an extension of cervical lesions (DES-like areas). Moreover, in cervical and vaginal biopsies from 265 patients, we compared the severity of intraepithelial neoplasia of the vagina and cervix.
In our series, vaginal lesions accounted for over half (52.6%) of the alterations attributable to HPV infection, while VAIN accounted for 46.5%; in 84.8% of cases, VAIN was associated with HPV. In 49.8% of cases, biopsies were from the upper third of the vagina and in 74.8% the pathological areas involved both the cervix and the vagina. The DES-like zone accounted for 7.9% of cases, vaginal wall involvement being limited to the upper third. Finally, the comparison of histological findings, in the 265 patients, confirmed that in 69.8% cases vaginal and cervical lesions were of the same grade; in 18.8% vaginal lesions were more severe than cervical lesions.
In our study a higher number of vaginal biopsies were taken than in previous years, and it is difficult to establish whether this depends on improved diagnostic methods or on changes in epithemiological factors, such as the reported increase in the incidence of HPV lesions. A systemic search for lesions and a study on their evolution are therefore required to clarify this aspect.VARIANTS ENDOMETRIOID ADENOCARCINOMA
*Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA †Department of Pathology, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Vaginal adenocarcinoma is the second most common primary cancer of the vagina, yet there has been very little study of most subtypes other than clear cell carcinoma.
We reviewed 18 cases of primary vaginal endometrioid adenocarcinoma, in our experience the second most common subtype. The patients ranged from 45 to 81 years of age (mean 60). Most presented with vaginal bleeding, and had had a prior hysterectomy. Five had a history of unopposed estrogen therapy but none had a history of intrauterine diethylstilbestrol exposure. The tumors were at the vaginal apex in 10 cases, in the posterior wall in 3, the lateral wall in 3, and the anterior wall in 1.
On microscopic examination, each of the tumors had a pure or predominant component of typical endometrioid adenocarcinoma. There was squamous metaplasia in 4 cases, mucinous metaplasia in 4, and prominent nonvillous papillae in 2. The tumors were grade 1 of 3 in 4 cases, grade 2 in 13, and grade 3 in 1. Eleven cases were FIGO stage I, 5 stage II, and 2 stage IV. Vaginal endometriosis was identified in 14 cases, and is important in indicating a primary vaginal tumor, rather than secondary spread from the endometrium. Other subtypes of adenocarcinoma (such as serous when the tumor has a papillary pattern) and atypical forms of endometriosis, including polypoid endometriosis, are the most common other differential diagnostic considerations.
The prognosis seems to be good in low-stage patients, with 11 patients alive and well and 2 alive with recurrent disease.MIXED TUMORS Mixed tumors of the vagina: an immunohistochemical study of 13 cases with emphasis on the cell of origin and potential aid in differential diagnosis.
Oliva E, Gonzalez L, Dionigi A, Young RH.
1James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2004 Oct;17(10):1243-50. Abstract quote
Mixed tumors of the vagina (MTsV) are rare benign neoplasms characterized by an admixture of well-differentiated epithelial cells and stromal-type cells in various proportions. In contrast to mixed tumors in other anatomic sites, the histogenesis of the vaginal tumors is unclear.
We studied the immunohistochemical profile of 13 examples to explore their histogenesis and determine whether their immunohistochemical profile might be useful in the differential diagnosis. The panel of antibodies used and the number of cases studied were: AE1/3 (12), cytokeratin 7 (CK7) (13), cytokeratin 20 (CK20) (13), epithelial membrane antigen (EMA) (13), muscle actin (MA) (12), desmin (11), h-Caldesmon (13), CD10 (13), CD34 (11), CD99 (8), and S-100 (7). Eight out of 12 tumors were positive for AE1/3, 7/13 for CK7, 2/13 for CK20, and 6/13 for EMA. MA was positive in 11/12 mixed tumors, desmin in 10/11 tumors and h-Caldesmon in 5/13. All tumors were extensively positive for CD10; CD34 was positive in 7/11; and none out of eight tumors showed membranous CD99 staining. Focal S-100 immunoreactivity was seen in 1/7 tumors. These results show that MTsV coexpress epithelial and mesenchymal markers. The expression of muscle actin (usually extensive), and focal desmin and h-Caldesmon positivity suggests the presence of a smooth muscle or myoepithelial component; however, the S-100 negativity and diffuse CD10 expression argue against it.
Positivity for muscle markers does not help distinguish MTsV from smooth muscle or skeletal muscle tumors. The frequent expression of CD10 negates its use in the differential diagnosis with endometrial stromal tumors, and the CD10 and CD34 expression suggests that mixed tumors may arise from a primitive pluripotential cell. MTsV are positive for h-Caldesmon and CD10, two markers that have been used in gynecologic pathology primarily to aid in establishing the smooth muscle or endometrial stromal phenotype of a neoplasm.NEUROENDOCRINE CARCINOMA Primary small cell neuroendocrine carcinoma of the vagina: a clinicopathologic study.
Bing Z, Levine L, Lucci JA, Hatch SS, Eltorky MA.
Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555-0588, USA.
Arch Pathol Lab Med. 2004 Aug;128(8):857-62. Abstract quote
CONTEXT: Primary small cell neuroendocrine carcinoma of the vagina is extremely rare, and its clinical behavior is aggressive. To our knowledge, 22 patients with this tumor have been reported in the English literature to date.
OBJECTIVE: To investigate 3 patients with this tumor clinically and pathologically.
DESIGN: The pathology database at the University of Texas Medical Branch at Galveston was searched, and 3 cases of primary small cell neuroendocrine carcinoma of the vagina were found. The histologic, immunohistochemical, and ultrastructural profiles of the tumors were investigated. The medical charts of the patients were reviewed, and the patients were followed up.
PATIENTS: Women with the diagnosis of primary small cell neuroendocrine carcinoma of vagina.
RESULTS: All 3 patients presented with advanced disease, and 2 patients died within 4 months of the initial diagnosis. One 38-year-old patient was newly diagnosed, and her clinical outcome had not yet been determined. The histologic features of all 3 tumors were similar to those of their pulmonary counterpart. All cases were positive for cytokeratin, chromogranin A, and synaptophysin. The expression pattern of thyroid transcription factor 1 was examined in all 3 patients, of whom 2 were negative and 1 was positive with negative clinical and radiologic thyroid or pulmonary findings. Ultrastructural evaluation showed scattered intracytoplasmic electron-dense neurosecretory granules.
CONCLUSION: Primary small cell neuroendocrine carcinoma of the vagina has histologic, immunohistochemical, and ultrastructural features similar to those of its pulmonary counterpart. Because thyroid transcription factor 1 can be positive, it should not be used to differentiate primary from metastatic disease. The current therapies have usually resulted in poor outcomes, and new therapeutic modalities should be explored.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE ELECTRON MICROSCOPY
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
PROGNOSIS CHARACTERIZATION Primary carcinoma of the vagina: factors influencing the age at diagnosis. The Radiumhemmet series 1956-96.
Hellman K, Silfversward C, Nilsson B, Hellstrom AC, Frankendal B, Pettersson F.
Department of Gynaecologic Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Int J Gynecol Cancer. 2004 May-Jun;14(3):491-501. Abstract quote
The objective to this retrospective study of 341 cases of primary carcinoma of vagina (PCV) diagnosed between 1956 and 1996 was to find whether epidemiological, clinical, and histopathological variables were related to the age at diagnosis of patients with PCV.
The univariate statistical analysis showed that younger age at diagnosis significantly correlated with a history of cervical dysplasia, hysterectomy, gynecological infections, and tumors located in the upper part of the vagina, whereas older age at diagnosis significantly correlated with late menarche and exophytically growing tumors.
In the multivariate regression analysis, the remaining independent predictors were a history of cervical dysplasia and age at menarche. Further, parity >/=4 as well as nulliparity, smoking, and unstable marital status were more common among patients with PCV than among those in the general Swedish female population. This study indicates that the etiology of vaginal carcinoma may be age related.
In young patients, the disease seems to be etiologically related to cervical neoplasia and thus human papillomavirus (HPV) dependent. However, in the most common age group, the older patients, there might be another (probably non-HPV-related) etiology associated with hormonal factors and trauma to the vagina.
TREATMENT CHARACTERIZATION GENERAL Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia.
Dodge JA, Eltabbakh GH, Mount SL, Walker RP, Morgan A.
Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington, Vermont 05401, USA.
Gynecol Oncol. 2001 Nov;83(2):363-9. Abstract quote
OBJECTIVE: The best treatment modality and factors affecting recurrence among women with vaginal intraepithelial neoplasia (VAIN) are yet to be determined. The aims of the current study were to describe the clinical features, results of treatment, and factors affecting recurrence among patients with VAIN.
METHODS: We conducted a retrospective review of 121 women with VAIN after confirming the histologic diagnosis. Patient demographics, clinical features, and results of therapy were recorded. Factors affecting recurrence were assessed using the odds ratio and the 95% confidence intervals among patients who were followed up for 7 months or more and had at least one posttreatment Papanicolaou smear. Significant univariate odds ratios were assessed jointly in a multivariate model with a stratified analysis.
RESULTS: The mean age of the patients was 35.0 (+/-17), 41% of the patients smoked, 39% had a history of human papillomavirus infection, 27% had history of sexually transmitted diseases, 22% had history of surgery for cervical intraepithelial neoplasia (CIN), and 23% had total hysterectomy. The upper third of the vagina was the most common site of VAIN and 61% of the lesions were multifocal. Associated cervical and vulvar intraepithelial neoplasia (VIN) were present in 65 and 10%, respectively. Recurrences of VAIN and progression to invasive vaginal cancer occurred in 33 and 2%, respectively. Recurrences following partial vaginectomy, laser, and 5-fluorouracil were 0, 38, and 59%, respectively (P = 0.0001). Multifocality and method of treatment were significant independent predictors of VAIN recurrences (odds ratio 3.3, 95% CI 1.2, 9.2, P = 0.02, and 22.4, 95% CI 1.3, 393.6, P = 0.001, respectively), with no interaction, based on a stratified analysis.
CONCLUSIONS: VAIN occurs most often among women with CIN or VIN, commonly involves the upper third of the vagina, and is often multifocal. Partial vaginectomy provides the highest cure rate and multifocality is a risk factor for recurrence.Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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