3.3.3: Neoplastic Disroders of the Vulva and Vagina

3.3.3.1 Condylomas

• Etiology and Risk Factors

These warty lesions secondary to sexually transmitted disease comprise two main forms: Condylomata Lata (flat lesions associated with secondary syphilis and less common) and Condylomata Acuminata (CA) (papillary, elevated or flat lesions caused by low-risk HPV strains 6 and 11 and more common). These two HPV types are responsible for over 90% of CA. Several risk factors are also involved, including smoking, hormonal contraceptives, multiple sexual partners, and early coital age^.36

• Pathogenesis

The initial site of infection is thought to be basal cells of the immature squamous epithelium that HPV reaches through defects in the epithelium. Once HPV enters the cells, two distinct biological sequences are possible. The first form is a “nonproductive or latent infection” in which HPV DNA persists in the basal cells without virus replication. Latent infections do not show morphologic alterations and can only be identified using molecular methods. The second form of HPV infection is a “productive infection.” Viral DNA replication in the intermediate and superficial cell layers of the squamous epithelium occurs independently of host chromosomal DNA synthesis. This allows large amounts of intact virions to be formed, leading to typical morphological aspects such as “koilocytic changes.”³⁷

• Pathologic Features

Grossly, the lesions are exophytic and may range from discrete papillary outgrowths to extensive and coalescent “cauliflower-like” masses. Microscopically (Figure 3.3.4), CA shows a striking papillary architecture. Papillae of different sizes and shapes are lined by acanthotic squamous epithelium (i.e., increasing the number of specialized squamous epithelial cells resulting in a thick epidermis with elongated rete pegs) and have a fibrovascular stroma, often containing scattered chronic inflammatory cells. Hyperkeratosis, parakeratosis (incomplete maturation of epidermal keratinocytes, resulting in abnormal retention of nuclei in the stratum corneum), hypergranulosis, and basal cell hyperplasia are seen. Koilocytic changes (rigid perinuclear halos, binucleated nuclei, and slightly enlarged nuclei with irregular contours and coarse chromatin) are sometimes focal in the most superficial layers of the squamous epidermis. The proliferation index by immunostaining (Ki67/MIB-1) in the upper third of the epithelium is considered as a confirmatory test to the diagnosis of CA, especially in lesions without evident koilocytic changes. The presence of Ki67/MIB-1 immunostaining has been further correlated with the detection of HPV DNA by polymerase chain reaction (PCR).³⁸

Figure 3.3.4 Histological characteristics of external genital warts. Note, the cauliflower-like architecture at the low power (I/a), Acanthosis, and parakeratosis with the presence of koilocytes in mid power image (I/b).
Image Source: Rideg, Orsolya, Angéla Oszter, Evelin Makk, Endre Kálmán, Kornélia Farkas, Tamás Tornóczky, and Krisztina Kovács. “Wide Spectrum Analysis of Human Papillomavirus Genotypes in External Anogenital Warts.” Vaccines 9, no. 6 (2021). https://doi.org/10.3390/vaccines9060604. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

• Clinical Features

CA is prevalent in the early sexually active years, with two-thirds of the respective sexual partners complaining of warts. The median time between infection and development of lesions is about 5-6 months among women. Up to 20% of people with genital warts will present other STDs. Patients who develop CA usually present with painless bumps and, less frequently, with pruritus, discharge, or bleeding. Lesions are commonly multiple (multicentric) and multifocal, also affecting the perianal, vaginal, and cervical regions, but oral and laryngeal regions may also be involved. Latent illness may become active, particularly with pregnancy and immunosuppression. Lesions may regress spontaneously, remain stable, or progress in size and/or number.

CA are soft, raised masses with smooth, verrucous, or lobulated aspects that may appear pearly, filiform, fungating, or plaque-like eruptions. The surface commonly shows finger-like projections, generally non-pigmented. They mainly occur in the moist areas of the labia minora and vaginal opening, but all genital regions may be affected (fourchette, labia minora/majora, pubis, clitoris, urethral meatus, perineum, perianal region, anal canal, introitus, vagina, and ectocervix). Therefore, colposcopic examination, using acetic acid 2–5%, is crucial to detect potentially multiple involved sites. CA are perceived as disfiguring; they impact sexual lifestyle, causing anxiety, guilt, and loss of self-esteem and creating concerns about cancer risk.³⁹

• Treatment

The most common treatments are painful and nonspecific, addressing the clinically evident lesions rather than the viral cause. Various modalities include office-based treatment (cryotherapy, electrocautery, laser, and/or surgery) or home-based treatment (chemotoxic agents or immunomodulatory therapy). First-episode patients should be STD-screened. Management should include partner notification. Surgical treatments have the highest primary clearance rates, with initial cure rates up to 60–90%. They include electrosurgery, curettage, scissors excision, and laser therapy. Primary Prevention by Prophylactic Vaccine (Quadrivalent Gardasil) is available for the prevention of HPV-associated dysplasia and neoplasia, including cervical cancer, precancerous genital lesions, and genital warts associated with HPV types 6, 11, 16, and 18. There is now accumulating evidence that population-based quadrivalent HPV vaccination can result in dramatic declines in genital warts incidence and a reduction in HPV6/11 burden.⁴⁰

3.3.3.2 Extramammary Paget Disease

• Definition and Etiology

Extramammary Paget’s Disease is a rare intraepithelial adenocarcinoma that most commonly arises in apocrine gland-bearing areas, particularly the vulva, scrotum, perianal skin, and penis. The vulva is the most frequently affected site, accounting for approximately 65% of cases.⁴¹

• Epidemiology

It typically affects postmenopausal Caucasian women, with peak incidence occurring in the 6th to 7th decades of life. While it constitutes only about 1% of vulvar cancers, its clinical presentation can be deceptive, often leading to a delayed diagnosis. The disease may appear as either solitary or multifocal lesions.⁴²

• Pathogenesis and Pathophysiology

The pathogenesis involves abnormal proliferation of glandular epithelial cells within the squamous epithelium. In primary extramammary Paget’s disease, malignant Paget cells originate within the epidermis and may invade the dermis and subcutaneous tissue. The origin is thought to be from pluripotent basal epithelial cells or skin appendages. Secondary disease involves epidermal spread or direct invasion from adjacent malignancies, including rectal or urothelial adenocarcinoma. Some molecular modifications have been reported in primary disease may play a role in pathogenesis; these include, HER2 oncogene amplification, mutations in genes encoding the PIK3/AKT cascade, and amplification at chromosomes Xcent-q21 and 19, as well as loss at 10q24-qter.⁴³

• Morphological Features

Clinically, vulvar Paget’s disease may manifest as red, white, or gray eczematous plaques with crusting, ulceration, or mild elevation. Lesions are usually irregular, sharply demarcated, and frequently extend beyond visible margins, with common involvement of the labia majora and potential spread to the labia minora, clitoris, urethral meatus, inguinal folds, and perineum. Pruritus is the most frequently reported symptom. It can mimic benign dermatoses such as eczema or psoriasis, leading to delays in diagnosis.

Histologically (Figure 3.3.5), it is composed of large Paget cells with abundant pale cytoplasm and prominent nuclei, which can be arranged singly or in clusters within the epidermis. In invasive disease, dermal invasion is evident. Immunohistochemical staining is essential: Paget cells are typically positive for CK7, EMA, CEA, PAS, and mucicarmine. Negative staining for melanocytic markers (S100, HMB-45, Melan-A) helps differentiate Paget’s disease from pagetoid melanoma. Markers such as CK20 and CDX2 may suggest secondary Paget’s disease. ⁴⁴

Figure 3.3.5. Vulvar Paget disease. The large cells of Paget’s disease are seen predominantly in the basal epithelium, but percolate up the epithelium in what is known as ‘Pagetoid spread’. Negative markers of melanoma, and positive markers of Paget, such as periodic acid Schiff stain with diastase (PAS-D), and breast markers such as Gata-3, are helpful in making this diagnosis (hematoxylin and eosin, x 10 magnification).
Image Source: Preti, Mario, Elmar Joura, Pedro Vieira-Baptista, Marc Van Beurden, Federica Bevilacqua, Maaike C.G. Bleeker, Jacob Bornstein, et al. “The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-Invasive Vulvar Lesions.” International Journal of Gynecological Cancer, 2022. https://doi.org/10.1136/ijgc-2021-003262. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

• Diagnosis

Diagnosis requires histopathological confirmation through biopsy. Vulvar mapping with multiple biopsies may be necessary to assess lesion extent. Immunohistochemistry is crucial to confirm the diagnosis and rule out mimics such as melanoma or high-grade squamous intraepithelial lesions. Imaging, particularly MRI, can help assess pelvic or nodal involvement.⁴⁵[Ning et al; Preti et al]

• Differential Diagnosis

The differential diagnosis includes lichen sclerosus, candidiasis, psoriasis, dermatophytosis, seborrheic dermatitis, contact dermatitis, squamous intraepithelial lesions, pemphigus vegetans, and pagetoid melanoma. Histologic analysis with immunostaining is key for definitive distinction.⁴⁶

• Treatment

Wide local excision remains the primary treatment modality, though recurrence rates range from 15% to 70%. Mohs micrographic surgery offers better margin control and reduced recurrence rates. Topical therapies such as 5% imiquimod, photodynamic therapy, and radiotherapy have been used for patients unfit for surgery or for recurrent disease. All patients require comprehensive evaluation to exclude synchronous malignancies, including pelvic exam, cervical cytology, transvaginal ultrasound, colonoscopy, cystoscopy, mammography, and imaging of the abdomen and pelvis.⁴⁷

3.3.3.3 Carcinoma of the Vulva: Squamous Cell Carcinoma

• Definition and Classification

Vulvar squamous cell carcinoma (SCC) represents the most prevalent form of vulvar malignancy, accounting for about 90% of cases. The 2020 WHO classification distinguishes two main etiopathogenetic pathways: HPV-associated SCC is usually precede by precursor lesions such as high-grade squamous intraepithelial lesion (HSIL, formerly known as usual-type VIN). While HPV-independent SCC may be preceded by differentiated VIN (dVIN).⁴⁸

• Epidemiology

Vulvar SCC is a rare cancer, comprising roughly 5% of all gynecologic malignancies, with increasing incidence among both older and younger women depending on subtype. HPV-associated SCC is more common in younger women (average age is 60 years), whereas HPV-independent SCC typically affects older women (average age is 75 years)cand often arises in a background of persistent lichen sclerosus or chronic inflammatory dermatoses.⁴⁹

• Etiology and Pathogenesis

HPV-associated SCC is linked primarily to high-risk HPV types 16 (in more than 70% of cases), 33, and 45. Other risk factors include smoking, immunosuppression, HIV infection, history of cervical HSIL, and vulvar, perianal, and anal lesions. It arises from HSIL and demonstrates strong diffuse p16 expression and wild-type p53 staining.

HPV-independent SCC is not associated with HPV but is often linked to chronic vulvar dermatoses and differentiated vulvar intraepithelial neoplasia (dVIN). These tumors usually show TP53 mutations with p53 overexpression and absent or focal p16 staining. This subtype tends to behave more aggressively, with higher recurrence and progression rates.⁵⁰

• Morphology and Histopathology

Early vulvar SCC and VIN frequently appear as white, plaque-like lesions (leukoplakia). Approximately 25% of these lesions may exhibit pigmentation due to melanin content. As the disease advances, these lesions can evolve into either exophytic masses or ulcerative tumors. HPV-associated SCCs typically present with basaloid or warty architecture and are often multifocal. Histologically, these tumors present as poorly differentiated SCC. In contrast, HPV-independent SCCs are usually unifocal and keratinizing. These tumors tend to be well-differentiated and have a more aggressive clinical course. dVIN-associated lesions often exhibit basal atypia, parakeratosis, and irregular rete ridges. Immunohistochemistry is crucial for distinguishing these subtypes, using markers like p16 and p53.⁵¹

• Imaging and Staging

MRI plays a critical role in staging, helping define lesion margins, assess tumor size (>2 cm) and depth of stromal invasion (>1 mm), and evaluate involvement of adjacent structures such as the urethra and vagina. Lesions appear as soft tissue masses with intermediate signal intensity on T2WI and restricted diffusion on DWI. Contrast enhancement may be homogeneous or heterogeneous. Lymph node status is a key prognostic indicator, and nodal enlargement (>5 mm) is used to classify advanced FIGO Stage III disease.

MRI is also useful in delineating lymph node involvement in parailiac, inguinal, and paraaortic regions using both axial and coronal planes.⁵²

• Vulvar Carcinoma In Situ

Lesions include HSIL (HPV-associated) and dVIN (HPV-independent). HSIL is typically multifocal, arising in the introitus and labia minora, and shows full-thickness atypia with p16 overexpression. dVIN is usually unifocal, affecting older women, and shows basal atypia and TP53 mutation. dVIN is more likely to progress to invasive SCC (up to 50%) compared to HSIL (~10%).⁵³

• Management and Treatment

  • HSLI: May be treated with excision, laser ablation, or topical agents (e.g., imiquimod). Biopsy is necessary to exclude invasion.
  • dVIN: Requires surgical excision due to high malignant potential. Management of coexisting dermatoses with topical corticosteroids is also essential.
  • Invasive SCC: Wide local excision or radical vulvectomy with lymph node assessment (including sentinel lymph node biopsy) is standard. MRI is valuable for surgical planning.⁵⁴

• Surveillance and Prognosis

Prognosis is influenced by stage, nodal involvement, and subtype. HPV-associated SCCs tend to have better outcomes, while HPV-independent types carry higher risk of recurrence (12–37%) and progression. Lifelong surveillance is recommended, particularly for dVIN-associated cases.⁵⁵

• Carcinoma of the Vagina

Primary carcinoma of the vagina is rare and typically arises from a precursor lesion known as vaginal intraepithelial neoplasia (VaIN), which is similar to cervical intraepithelial neoplasia. It is mainly a squamous cell carcinoma linked to infection with high-risk human papillomavirus. A prior history of cervical or vulvar cancer is a significant risk factor. These tumors most frequently develop in the upper third of the vagina, especially along the posterior wall near the ectocervix, and commonly spread to regional iliac lymph nodes.⁵⁶

Footnotes

37. Léonard, Boris, Frederic Kridelka, Katty Delbecque, Frederic Goffin, Stéphanie Demoulin, Jean Doyen, and Philippe Delvenne. “A Clinical and Pathological Overview of Vulvar Condyloma Acuminatum, Intraepithelial Neoplasia, and Squamous Cell Carcinoma.” BioMed Research International 2014 (2014). https://doi.org/10.1155/2014/480573.
38. Leonard et al, 2014
39. Leonard et al, 2014
40. Leonard et al, 2014
41. Ning, Yan, Rennan Ling, Feiran Zhang, Guofu Zhang, and He Zhang. “Common and Uncommon Lesions of the Vulva and Vagina on Magnetic Resonance Imaging: Correlations with Pathological Findings.” BJR|Open 5, no. 1 (2023). https://doi.org/10.1259/bjro.20230002; Preti, Mario, Elmar Joura, Pedro Vieira-Baptista, Marc Van Beurden, Federica Bevilacqua, Maaike C.G. Bleeker, Jacob Bornstein, et al. “The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-Invasive Vulvar Lesions.” International Journal of Gynecological Cancer, 2022. https://doi.org/10.1136/ijgc-2021-003262. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
42. Ning et al, 2023; Preti et al, 2022.
43. Ning et al, 2023; Preti et al, 2022.
44. Ning et al, 2023; Preti et al, 2022.
45. Ning et al, 2023; Preti et al, 2022.
46. Ning et al, 2023; Preti et al, 2022.
47. Ning et al, 2023; Preti et al, 2022.
48. Kesic, Vesna, Xavier Carcopino, Mario Preti, Pedro Vieira-Baptista, Federica Bevilacqua, Jacob Bornstein, Cyrus Chargari, et al. “The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) Consensus Statement on the Management of Vaginal Intraepithelial Neoplasia.” Journal of Lower Genital Tract Disease 27, no. 2 (2023). https://doi.org/10.1097/LGT.0000000000000732. ; Ning et al, 2023; Preti et al, 2022.
49. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
50. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
51. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
52. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
53. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
54. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
55. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.
56. Kesic et al, 2023; Ning et al, 2023; Preti et al, 2022.

Image Acknowledgements

• Preti, Mario, Elmar Joura, Pedro Vieira-Baptista, Marc Van Beurden, Federica Bevilacqua, Maaike C.G. Bleeker, Jacob Bornstein, et al. “The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-Invasive Vulvar Lesions.” International Journal of Gynecological Cancer, 2022. https://doi.org/10.1136/ijgc-2021-003262. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
• Rideg, Orsolya, Angéla Oszter, Evelin Makk, Endre Kálmán, Kornélia Farkas, Tamás Tornóczky, and Krisztina Kovács. “Wide Spectrum Analysis of Human Papillomavirus Genotypes in External Anogenital Warts.” Vaccines 9, no. 6 (2021). https://doi.org/10.3390/vaccines9060604. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).