Vulvar Intraepithelial Neoplasia


Article Author:
Michael Ayala


Article Editor:
Mary Fatehi


Editors In Chief:
Amanda Oakley
Jules Lipoff
Shyam Verma


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
6/4/2019 5:17:26 PM

Introduction

Vulvar intraepithelial neoplasia, also known as VIN, is a non-invasive squamous lesion and precursor of squamous cell carcinoma (SCC) of the vulva. There is no screening test for vulvar intraepithelial neoplasia. Diagnosis of VIN is made clinically and confirmed with a biopsy.

Etiology

There are two different classifications of vulvar intraepithelial neoplasia: usual type (uVIN) that has correlations with human papillomavirus (HPV), or differentiated type (dVIN) that correlates with chronic inflammation. Classification of vulvar intraepithelial neoplasia is made on morphology and does not involve HPV testing. Differentiated type correlates with a greater potential for progression to invasive squamous cell carcinoma. The likelihood of other anogenital cancers increases with the usual type of VIN.[1] 

Epidemiology

The incidence of vulvar intraepithelial neoplasia is higher in white women, with the highest reported incidence during the fourth decade.[1] The usual type is more common at a younger age, while the differentiated type occurs more prevalently in older women.[1][2][3] HPV DNA is present in the majority of vulvar intraepithelial neoplasia and squamous cell carcinoma, and VIN is considered an HPV-associated disease.[1] The three most common types of HPV found in these lesions are 16, 18, and 33.[1] Other risk factors for VIN include multiple sexual partners, cigarette smoking, and immunocompromised states such as those found in patients with HIV infection, autoimmune diseases and organ transplants.[2][3][4]

Pathophysiology

HPV is a single-stranded DNA virus. uVIN occurs when the body fails to produce an effective immune response to high-risk HPV subtypes. The viral DNA integrates into the host cells resulting in the production of oncoproteins E6 and E7 which interfere with normal cellular function.[1] This integration allows normal tissues to evade apoptosis, deregulate cellular proliferation, and/or promote genomic instability.[3] Mutations of p53 and PTEN, as well as microsatellite instability, have also been demonstrated in HPV-independent carcinogenesis.[1][2][3] dVIN appears to be related to chronic oxidative genetic damage that promotes similar aberrant cellular function. Lichen sclerosis and lichen planus are examples of chronic, inflammatory changes to the normal epithelium that are associated with squamous cell carcinoma of the vulva.[1][2] 

Histopathology

The histological feature necessary for a diagnosis of VIN is the proliferation of atypical basal cells. The five criteria for atypia are as follows: basal layer involvement, enlarged nuclei, hyperchromasia, pleomorphic cells and increased numbers of mitotic figures.[1] In addition to atypia, uVIN and dVIN have distinctive features.

uVIN proliferation begins at the basal layer and involves partial to the full thickness of the squamous epithelium.[2] uVIN lesions exhibit basal cells with large, dark nuclei and small amounts of basophilic cytoplasm.[1] However, approaching the surface epithelium, atypical basaloid cells may mature to develop an abundant eosinophilic cytoplasm.[1] The more mature squamous cells often display a cytopathic change termed, koilocytosis.[1] There are two subtypes of uVIN described as warty or basaloid; however, both forms are premalignant and treated the same.[1]

dVIN possesses a high oncogenic potential, and its characteristics are more subtle.[2] Key features of dVIN are a thickened epidermis, parakeratosis, basal nuclear atypia and premature maturation above the basal layer. These premature cells possess eosinophilic cytoplasm, intracellular prickles, large nuclei, and prominent nucleoli.[1] The relatively high degree of differentiation often results in dVIN lesions being mistakenly diagnosed as benign.[2]

Immunohistochemistry markers can be used to differentiate between uVIN and dVIN. P53 positive and p16 negative supports dVIN while the converse supports uVIN.[1][2][3]

History and Physical

Vulvar intraepithelial neoplasia is a clinical diagnosis.[1] There is no routine screening test for VIN; however, abnormal cytology or positive high-risk HPV test used in cervical cancer screening warrants an independent visual assessment of the vulva.[1] Acetic acid alone is not recommended for diagnosis because the whitened color of observed lesions is not specific to vulvar intraepithelial neoplasia.[1] One should note the following on examination of the vulva for lesions seen: location, number, size, shape, color, and thickness.

Evaluation

uVIN and dVIN are clinically different. uVIN is commonly multifocal and elevated seen around the introitus and on labia majora.[1] dVIN lesions demonstrate poorly demarcated pink or white plaques that often associate with lichen sclerosis or lichen planus that is refractory to medical therapy.[1][3] Any observed vulvar lesions require a biopsy to define treatment appropriately.[1]

Treatment / Management

The ideal treatment of vulvar intraepithelial neoplasia involves the complete destruction of the lesion, improving symptoms, and preserving vulvar function.[1] Treatment options include medical, surgical, expectant, or preventative management.

uVIN

Cold knife surgery and loop electrosurgical excision procedure (LEEP) are the treatments of choice of uVIN. However, margin status does not predict the risk of invasive or recurrent disease.[1] The recommendations are for a 5mm peripheral margin, and 4mm deep margin.[1] An alternative treatment is CO2 laser ablation, but vaporization of the diseased tissue precludes a pathologic specimen.[1] The advantage of laser ablation is the preservation of normal anatomy with less scarring at the cost of increased risk of recurrence.[4]

dVIN

Differentiated vulvar intraepithelial neoplasia is associated with lichen sclerosis and invasive disease, such as squamous cell carcinoma of the vulva.[5] Recurrence rates for dVIN are much higher than uVIN.[6] Treatment of these lesions should include surgical excision with a scalpel, LEEP, or laser. Wide local excision is preferable as initial treatment.[7][8][9]

There are no currently approved medications for the treatment of vulvar intraepithelial neoplasia. However, many drugs have been attempted to avoid surgery. Cidofovir is an acyclic nucleoside analog with antiviral properties that promotes apoptosis of HPV-infected cells.[1] Photodynamic therapy is an option in conjunction with nonthermal light to generate oxygen-induced cellular death.[1] Imiquimod is an immune-modifying drug with both antiviral and antitumor activity that enhances innate and cell-mediated immunity against HPV.[1]  

Spontaneous regression is reported in uVIN but is adversely influenced by increasing age of the patient, clinical presentation with chronic immunosuppression and multifocal disease, and longer duration of the lesion.[1] Close surveillance of these patients is required even after spontaneous regression occurs. Women younger than 35 years have a higher rate of regression. Pregnancy has been reported to increase both spontaneous regressions as well as the progression of premalignant vulvar lesions.[2]

HPV vaccination has reduced the incidence of vulvar intraepithelial neoplasia in young women.[2] However, HPV vaccination is designed as a prophylactic measure, not as a treatment for confirmed lesions.[3]

Differential Diagnosis

Any observed lesion of the vulva requires a biopsy for diagnosis.  Benign lesions include common dermatopathology such as lichen simplex, lichen sclerosis or lichen planus.  Vulvar lesions may also result from infection such as vestibulitis, candidiasis or herpes.  Vulvar intraepithelial neoplasia is a preinvasive lesion that may appear similar to these more common changes of the skin or typical malignancies such as basal cell carcinoma, squamous cell carcinoma, Paget disease or melanoma.  Treatment without biopsy confirmation risks progression and delays the diagnosis of potential malignancy.

Prognosis

The prognosis of biopsy-confirmed vulvar intraepithelial neoplasia that receives prompt treatment is uniformly good.  There is rarely progression to invasive cancer unless treatment is declined or markedly delayed.  

Complications

The most severe complication of untreated vulvar intraepithelial neoplasia is progression to invasive carcinoma.  Malignant disease of the vulva necessitates more involved radical resection that is commonly associated with perioperative morbidity such as pain, infection, or wound dehiscence as well as altered appearance.  Complications of surgical resection are dependent on location, distribution, and size of treatable lesions.  Topical therapies may result in topical irritation, burning or ulceration.

Pearls and Other Issues

There are two types of vulvar intraepithelial neoplasia, one related to HPV infection and another related to chronic oxidative damage, uVIN, and dVIN respectfully. dVIN only accounts for a small percentage of all VIN lesions and has a higher association with invasive cancer than uVIN. The majority of uVIN are related to HPV-16 DNA; however, there are reports of other high-risk HPV subtypes in histologically-confirmed uVIN.[1][2][3] Failure of the immune system to produce an immune response against HPV allows viral DNA to become integrated into the host DNA and when functional, promotes disruption of cellular function and transformation the occurs to cause VIN. uVIN is multifocal and multicentric as opposed to dVIN that is unifocal and difficult to distinguish from benign lesions.[1] 

Enhancing Healthcare Team Outcomes

When the primary care provider, nurse practitioner and internist suspect that a patient may have vulvar intraepithelial neoplasia, a referral to a gynecologist is the recommended next step. The diagnosis is made clinically with inspection and biopsy, often utilizing immunohistochemistry. Treatment depends on lesion type, location, size, and extent of disease. Lifelong surveillance is essential since resection of individual lesions does not guarantee the prevention or invasive cancer.[1] The primary care provider and nurse practitioner should encourage HPV vaccination to reduce the incidence of uVIN and invasive vulvar cancer.[1]

Diagnosis and subsequent treatment and follow-up care are best accomplished via an interprofessional, multidisciplinary team that includes physicians, mid-level practitioners, and nursing to achieve the best possible patient outcomes. [Level V]


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Vulvar Intraepithelial Neoplasia - Questions

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A woman presents for a well-woman examination. She has had 3 normal vaginal deliveries and normal menses up to the age of 50 when she entered menopause. She has no pertinent family history and denies smoking and drinking alcohol. States that her only medical problem is hypertension and is well controlled with lisinopril 10 mg daily. Which of the following would not raise suspicion for vulvar intraepithelial neoplasm (VIN)?



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A 24-year-old woman at an annual well-woman presents to the clinic for her annual gynecological visit. The patient has a history of a chlamydia infection that resulted in pelvic inflammatory disease (PID) and one ectopic pregnancy resulting in a salpingectomy. She states that she has multiple partners of both genders and inconsistently uses protection. What would be the most beneficial preventative health option?



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A woman with HIV comes to your office for routine gynecologic surveillance. She complains of vulvar itching and on physical examination diffuse thickening of the labia is observed bilaterally. Which of the following is recommended?



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A 65-year-old woman presents to your office for an annual well-woman examination. The patient complains of persistent vulvar itching. On examination, a 2-cm x 2-cm right labial lesion is seen, and a biopsy confirms lichen sclerosis and VIN3. What is the best treatment for this patient?



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A 35-year-old woman presents to your clinic to initiate care. The patient is a chronic smoker for the past 20 years and has no intention of quitting. She admits to multiple sexual partners, but always uses condoms. Her medical history is significant for renal transplant as a child for which she is on chronic medication. Which of the following is the most appropriate screening guideline for this patient?



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A distinct Human papillomavirus (HPV) strand is established when the DNA sequence of the L1 gene of a cloned virus differs by at least 10%. Several HPV strands have been identified and associated with certain pathologies. Which of the following HPV subtype and clinical manifestation are correct?



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A 70-year-old woman presents to her healthcare provider for persistent vulvar itching for several months refractory to multiple topical creams and oral antifungal medication. She is extremely obese and diabetic. Physical exam confirms diffuse skin thickening of her labia majora bilaterally without vaginal discharge. There is a raised irregular 2 cm white lesion of the posterior fourchette and a 1 cm ulcerated "kissing" lesion of the inferior labia majora bilaterally. Which of the following is the best next action?



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There is a strong association between HPV and genitourinary diseases. Multiple subtypes have been studied, and HPV strand 16 and 18 have been showed to have high oncogenic potential. Which of the following best describes the mechanism of action of the HPV virus?



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Vulvar Intraepithelial Neoplasia - References

References

Preti M,Scurry J,Marchitelli CE,Micheletti L, Vulvar intraepithelial neoplasia. Best practice     [PubMed]
Del Pino M,Rodriguez-Carunchio L,Ordi J, Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma. Histopathology. 2013 Jan;     [PubMed]
Léonard B,Kridelka F,Delbecque K,Goffin F,Demoulin S,Doyen J,Delvenne P, A clinical and pathological overview of vulvar condyloma acuminatum, intraepithelial neoplasia, and squamous cell carcinoma. BioMed research international. 2014;     [PubMed]
Wallbillich JJ,Rhodes HE,Milbourne AM,Munsell MF,Frumovitz M,Brown J,Trimble CL,Schmeler KM, Vulvar intraepithelial neoplasia (VIN 2/3): comparing clinical outcomes and evaluating risk factors for recurrence. Gynecologic oncology. 2012 Nov;     [PubMed]
van de Nieuwenhof HP,van Kempen LC,de Hullu JA,Bekkers RL,Bulten J,Melchers WJ,Massuger LF, The etiologic role of HPV in vulvar squamous cell carcinoma fine tuned. Cancer epidemiology, biomarkers     [PubMed]
Eva LJ,Ganesan R,Chan KK,Honest H,Malik S,Luesley DM, Vulval squamous cell carcinoma occurring on a background of differentiated vulval intraepithelial neoplasia is more likely to recur: a review of 154 cases. The Journal of reproductive medicine. 2008 Jun;     [PubMed]
Jin C,Liang S, Differentiated Vulvar Intraepithelial Neoplasia: A Brief Review of Clinicopathologic Features. Archives of pathology & laboratory medicine. 2018 Dec 28     [PubMed]
Grimm D,Prieske K,Mathey S,Kuerti S,Burandt E,Schmalfeldt B,Woelber L, Superficially invasive stage IA vulvar squamous cell carcinoma-therapy and prognosis. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2019 Mar     [PubMed]
Bryan S,Barbara C,Thomas J,Olaitan A, HPV vaccine in the treatment of usual type vulval and vaginal intraepithelial neoplasia: a systematic review. BMC women's health. 2019 Jan 7     [PubMed]

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