Clinics in Dermatology (2013) 31, 362–373
Anogenital malignancies and premalignancies: Facts and controversies Zekayi Kutlubay, MD, Burhan Engin, MD, Tuba Zara, MD, Yalçın Tüzün, MD ⁎ Department of Dermatology, Cerrahpaşa Medical Faculty, Istanbul University, 34098 Istanbul, Turkey
Abstract Anogenital malignancies and premalignancies are an important personal/public health problem due to their effects on individuals' physical, mental, and sexual health. Also, due to their etiological association with human papillomavirus (HPV) infection, anogenital malignancies and premalignancies constitute an immense public health burden. In addition to HPV infection, immunosuppression, HIV infection, chronic dermatoses, such as lichen sclerosis, previous radiotherapy and chemotherapy treatments, and smoking, are the other important etiopathologic factors in the development of anogenital malignancies and premalignancies. The incidence of anal squamous cell carcinoma (SCC) has increased considerably in the past decade, mainly due to the growing number of cases in high-risk groups, such as men who have sex with men, immunosuppressed individuals, and patients with HIV infection. Also, an increase in vulvar intraepithelial neoplasia (VIN) and VIN-related invasive vulvar cancer has been noted in women younger than age 50 years due to its association with HPV infections over the past decade. SCC of the scrotum seems to be the first cancer linked to occupational exposure. Bowen's disease, Bowenoid papulosis, and erythroplasia of Queyrat are the most widely seen premalignancies of anogenital region and are all forms of squamous intraepithelial neoplasia. Histopathologically, these conditions share identical histologic features of SCC in situ, but their clinical features differ. Early diagnosis is vital to improve prognosis, especially in anogenital malignancies. Also, if a delay occurs in diagnosis, treatment options used will be associated with significant negative effects on the patient's psychological well-being and quality of life; hence, management of anogenital malignancies and premalignancies should be organized in a multidisciplinary fashion. © 2013 Elsevier Inc. All rights reserved.
Introduction Anogenital malignancies and premalignancies frequently are encountered in routine dermatology practice. They not only affect a person's physical well-being but also his or her psychological health and quality of life. Additionally, ⁎ Corresponding author. Tel.: +00 90 212 414 3120. E-mail address:
[email protected] (Y. Tüzün). 0738-081X/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.01.003
anogenital malignancies and premalignancies are a significant public health problem. An increase in the incidence of vulvar intraepithelial neoplasia (VIN), VIN-related invasive vulvar cancer, and anal squamous cell carcinoma (SCC) in the population has been noted in the past decade.1,2 Most widely known factors that play role in the etiology of anogenital malignancies are human papillomavirus (HPV) infection, immunosuppression, HIV infection, chronic dermatoses such as lichen sclerosis (LS), previous radiotherapy and chemotherapy therapies, smoking, and psoralen
Anogenital malignancies and premalignancies and ultraviolet A photochemotherapy (PUVA) therapy.3 Of these, HPV infection often but not always plays an important role in the etiology of anogenital malignancies and premalignancies.4 Most malignant cutaneous neoplasms that involve the male genitalia are squamous in origin and are associated with HPV. Less commonly, tumors arise from cutaneous adnexa, melanocytes, soft tissue, or lymphoid tissue. HPV transmission almost exclusively occurs following skin-to-skin contact with an infected partner. Sexual intercourse is not strictly necessary, and the virus also can be transmitted during sexual foreplay. HPV infection frequently is acquired in adolescents and young adults within months after their first sexual intercourse. Up to 80% of women will likely acquire genital HPV infection by the age of 50 years.5 In the United States, about 6.2 million new HPV infections occur every year among people ages 14 to 44 years and 74% occur among those ages 15 to 24 years.4 Human papillomaviruses are a large family of small double-stranded DNA viruses that infect squamous epithelium. They can be separated into high- or low-risk types depending on their oncogenic potential. Low-risk HPV types 6 (HPV-6) and 11 (HPV-11) cause benign anogenital warts or condylomata accuminata. High-risk HPV types 16, 18, 31, 33, 35, and 45 are associated with anogenital cancers and the precursor lesions (intraepithelial neoplasia [IN]), particularly of the cervix. HPV is not only a carcinogen in the cervix, but also a proportion of vulval, vaginal, penile, and anal cancers are attributable to high-risk HPV infection, with HPV-16 being the dominant player.6 Immunosuppressed patients, especially organ transplant patients receiving chronic immunosuppressive treatment and individuals with HIV infection, are at increased risk for developing multiple HPV-related benign and malignant anogenital tumors. In these patients, a decrease in cellmediated immunity leads to a failure to clear HPV infection, resulting in an increased risk for developing HPV-related disease. Rates of anal HPV infection are extremely high in HIV-positive patients, particularly in men who have sex with men (MSM). High rates of both anal intraepithelial neoplasia (AIN) and anal cancer occur in the HIV-positive population due to increased prevalence of anal infection with high-risk HPV (particularly HPV-16 and HPV-18).7 The following contribution will discuss commonly seen malignant and premalignant conditions of anogenital region.
Anogenital malignancies Carcinoma of the vulva Vulvar carcinoma represents about 4% to 5% of the genital malignancies in women.8 SCCs account for approximately 90% of the cases, whereas melanomas, adenocarcinomas, and basal cell carcinomas are much less common. Because the vulva is covered with skin, any malignancy that
363 appears elsewhere on the skin also can occur on the vulva. Melanoma is the second most frequent histologic type, but this represents less than 5% of vulvar cancers.9 Vulvar SCC is the fourth most common gynecologic type of cancer with an annual incidence of 2 to 3 per 100,000 women.10 SCC is a malignancy of old age, the risk being increased 10-fold over the age of 75 years, but also occurs in younger patients. Approximately 15% of all vulvar cancers occur in women younger than age 40 years. These young patients tend to have early microcarcinomas, which may be associated with diffuse IN of the vulva.9 There are two types of carcinoma of the vulva. The first group comprises differentiated keratinizing SCC, is the most common, and occurs primarily in older women with a history of lichen sclerosus (LS) or lichen planus (LP). This type is not associated with oncogenic HPV types and often occurs in patients with a previous history of differentiated VIN. The second group involves non-keratinizing carcinoma of the vulva, is less common, and occurs mainly in young women. This type is associated with oncogenic HPV types (HPV-16 and HPV-18) and occurs in patients with wart-like and ⁄or basaloid VIN, together referred to as “usual VIN.”3,4 Over the past decade, an increase in VIN and VIN-related invasive vulvar cancer have been noted in women younger than age 50 years due to its association with HPV infections.1,8 Increased number of sexual partners, younger age at first sexual intercourse, abnormal Papanicolaou smear, presence of genital warts, and tobacco use are other risk factors for warty or basaloid forms of vulvar SCC. The symptoms and signs of vulvar cancer may include vulvar pruritus, vaginal discharge, dysuria, localized pain, bleeding, or ulceration.11 The most common presenting sign of vulvar cancer is a vulvar lump or mass. Rarely, patients present with a large, fungating mass. Long-term pruritus, lumps, or masses on the vulva are present in most patients with invasive vulvar cancer. On physical examination, the vulvar lesion is usually raised and may be fleshy, ulcerated, leukoplakic or warty in appearance (Figure 1).1 The most common localizations of vulvar cancer are the labia (80%), the clitoris (10%), and the lower commissure (10%). Most of the tumors present unilateral, but there have also been cases with a bilateral presentation. A multicentric occurrence is also possible.8 Vulvar cancer lesions can be detected visibly or by palpation, and biopsy of suspicious masses should be performed immediately. Gross examination of the vulva should be followed by a colposcopic examination of the vulva, vagina, and cervix, as early SCC lesions are not detectable by palpation. Multiple biopsies are required for the accurate diagnosis of any lesions suspected to be vulvar SCC. A dermal punch biopsy can be used in the same manner as it is used elsewhere on the skin. If a lesion is small, excision may not only be diagnostic but also therapeutic.11 Vulvar cancer is staged surgically, using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Stage I lesions are lesions less than 2 cm in greatest
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Z. Kutlubay et al. reoccurring lesions appear locally and near the site of the primary lesion, routine close follow-up of the patients is necessary.3
Carcinoma of the penis
Fig. 1
Vulvar carcinoma seen as fleshy, ulcerated lesion.
dimension. Stage II lesions are greater than 2 cm. Stage III denotes involvement of the urethra, vagina, anus, or metastatic disease to unilateral inguinal lymph nodes. Stage IV disease denotes involvement of the upper urethra, bladder mucosa, rectal mucosa, or pelvic bone, or bilateral inguinal metastasis, or distant metastasis.12 The most important prognostic factors are the stage at the time of diagnosis and the lymph node status. Because the vulva is rich in lymphatics, metastasis to the inguinal lymph node can occur early in the process. Lymph node involvement is directly related to the depth of stromal invasion, as well as to the size of the primary lesion. Positive lymph nodes show a direct correlation to the surface spread and the depth of invasion. Depending on the FIGO stage 5year survival rates vary between 90.4% at stage I, 77.1% at stage II, 51.3% at stage III, and 18% at stage IV.8 Surgical resection is the gold standard of treatment in patients with vulvar cancer. Surgery should completely remove the cancer and identify the extent of disease to determine the stage and the need for additional therapy. The extent of disease determines the amount of surgery needed. A small primary lesion on the vulva (ie, b 2 cm) with superficial invasion has essentially no risk for lymph node metastasis. Consequently, these lesions can be treated with wide local excision.1 Radiotherapy is used as an adjuvant in patients with positive nodes and in those with inoperable tumors. It is also sometimes used as a primary treatment in tumors of the anus and urethra, to reduce their size before surgery and to try to preserve sphincter function. In women with locally advanced vulvar cancer, no significant differences in survival were found when neoadjuvant chemoradiation was compared with primary surgery. More than 80% of recurrences appear within the first 2 years after therapy, and they may be either local or distant. Because many
SCC is the most frequent carcinoma among malignant neoplasms of the penis. SCC of the penis is rare in men in developed countries, and has an estimated annual incidence of 1 per 100,00013; however, greater rates have been seen in underdeveloped countries, such as Uganda (2.8 per 100,000) and some areas of Brazil (1.5-3.7 per 100,000). The lowest incidence has been reported among Israeli Jews (0.1 per 100,000).14 Penile cancer most commonly affects men ages 50 to 70 years but 19% occur in men younger than age 40 and 7% younger than age 30 years.13 The specific etiology and pathogenesis of penile SCC is unclear. Risk factors for penile SCC are poor penile hygiene, non-circumcision, phimosis (or an unretractable foreskin), chronic inflammatory conditions, a large number of sexual partners, HPV infection, treatment with psoralen and PUVA, and smoking.4,15 Circumcision prevents most of these pathologic conditions. The most important factor is not only the foreskin itself, but the link between foreskin retention and poor hygiene; however, circumcision needs to be performed in the neonatal period in order to reduce the risk for malignant tumors. Men who are circumcised at birth are respectively 3.2 and 3 times at lower risk for penile cancer than men who were never circumcised or who were circumcised after the first year of life.13 LS is a common cause of phimosis in males and it predisposes to penile carcinoma. Also, chronic erosive and hypertrophic LP are premalignant conditions.3 DNA sequences of HPV were found in the majority of benign or malignant penile lesions: HPV-6, -11, -42, and -43 for condylomata acuminata, HPV16 for intraepithelial neoplasm Bowen's disease (BD), and HPV-16 and -18 for penile and cervical cancers.16 Tumors typically present as an ulcerated mass and can exhibit either a flat or an exophytic, papillary clinical growth pattern. The vast majority (almost 95%) of penile cancers comprises of SCC of which the usual (keratinizing) type, often referred to as “not otherwise specified,” is the most common histologic type (49%). Other subtypes of SCC include basaloid (4%), warty (6%), mixed warty-basaloid (17%), verrucous (8%), papillary (7%), other SCC mixed (7%) or sarcomatoid carcinomas (1%).17 Penile SCC initially presents either as a de novo penile lesion or may evolve from premalignant lesions. Penile SCC can originate anywhere on the penis but it arises from glans (48%), prepuce (21%), glans and prepuce (9%), prepuce glans and shaft (14%), coronal sulcus (6%), and shaft (b 2%). The presenting symptoms of penile SCC are itching, irritation, penile pain, malignant priapism, bleeding, discharge, ulceration, and discovery of a mass. A solitary lesion that is indurated and/or ulcerated and often proliferative with excessive hyperkeratosis and sometimes with a verrucous surface is found on
Anogenital malignancies and premalignancies examination. Lymphadenopathy is present in 28% to 64% of cases at presentation.3 The differential diagnoses of penile SCC includes benign condylomata acuminata, verrucous carcinoma (BuschkeLöwenstein tumor), BD, erythroplasia of Queyrat (EQ), erosive or ulcerative sexually transmitted disease, basal cell carcinoma, malignant melanoma (pigmented or amelanotic), atypical herpes simplex infection, malignant cutaneous adnexal tumors, sarcomas, Kaposi's sarcoma, pyoderma gangrenosum, and artifact.3,13,15 Diagnosis is confirmed histologically by incisional or excisional biopsy. Histologically, SCC presents as tongues of invasive atypical keratinocytes penetrating the dermis, and contains foci of aberrant and ectopic keratinization called squamous pearls.3 The treatment of carcinoma of the penis is partial or total penectomy depending on location, tumor type, and extent; however, this procedure can be associated with significant psychological and quality-of-life issues. Conservative techniques such as Mohs micrographic surgery, laser therapy, cryotherapy, and 5% 5-fluorouracil (5-FU) and 5% imiquimod creams are increasingly used to conserve tissue and minimize residual sexual dysfunction.3,4,13 Radiotherapy may be offered as an adjunct to surgery or as definitive alternative treatment.3 Neoadjuvant, adjuvant, and palliative chemotherapy are used in advanced stage disease. 13 Combination chemotherapy and radiation using bleomycinderived treatments have been successful in some cases, with response rates as high as 43%. Penile SCC has a particular tendency for lymphatic spread to the superficial and deep inguinal lymph nodes and, subsequently, to the pelvic nodes. Sentinel lymph node biopsy has been successfully used in the surgical management of penile carcinoma. Untreated patients with penile SCC usually die within 2 years of diagnosis due to complications due to uncontrollable locoregional growth or distant metastases. The prognosis correlates with the extent of tumor invasion and lymph nodes status. Lymph node status is the most important prognostic factor.14
365 PUVA, scrotal HPV infection (type 18), and previous radiotherapy treatment.3,19 Scrotal carcinomas also may occur as a result of nonspecific factors such as poor hygiene and chronic irritation. Also, SCC of scrotum can arise from previous Fournier gangrene and harmless scar of infertility procedure.20,21 Typically, scrotal carcinoma presents in the sixth decade of life presenting with itch, irritation, pain, bleeding, discharge, ulceration or the discovery of a lump, and irregular nodular and ulcerative clinical features.3,22 The diagnosis is established by biopsy. Magnetic resonance imaging is used for staging of SCC of scrotum. The staging system for scrotal carcinoma is as follows: Stage A1 lesions are localized to scrotal wall, stage A2 lesions are locally extensive tumors invading adjacent structures (testis, spermatic cord, penis, pubis, and perineum), stage B lesions are metastatic and involve lymph nodes only, stage C are metastatic and involve pelvic lymph nodes without evidence of distant spread; and stage D lesions are metastatic beyond the pelvic lymph nodes and involve distant organs.23 The primary treatment option for scrotal carcinoma is wide local excision of the primary lesion. Sentinel node biopsy and ilioinguinal or inguinal lymphadenectomy are also recommended in patients with suspected lymph node metastases. Laser therapy has been used to treat the local lesion with a possible advantage of a better cosmetic result for low stage lesions. Both chemotherapy and radiotherapy have been recommended as neoadjuvant therapy to downstage a very large lesion to achieve complete resection. To achieve a better disease-free survival, adjuvant radiotherapy in combination with chemotherapy (methotrexate, bleomycin, and cisplatinum) for four cycles is also recommended. Although patients with stage A1 disease have approximately a 75% or better chance for long-term survival, patients with stage C or D disease have poor long-term prognosis. The prognosis in SCCs depends on age of the patient; size, grade, and stage of the tumor; and the extent of surgery.20,22,23
Carcinoma of the anus Carcinoma of the scrotum Carcinoma of the scrotum is a relatively rare disorder with an overall incidence rate that varies around 1.5 per 1 million person-years in Western countries. Its most common histologic type is SCC (27%). SCC of the scrotum seems to be the first cancer linked to occupational exposure. In 1775, Percivall Pott described a relationship between soot exposure and a high incidence of scrotal cancer among chimney sweepers.18 Occupations that have been associated with an increased incidence of scrotal carcinoma include paraffin or shale oil workers, mule spinners (exposed to carcinogens in lubricating oils for the spinning jenny in the cloth industry), Persian nomads (who traveled with pots of burning charcoal between their legs), machine operators, and lathe workers. Other risk factors for SCC of the scrotum are treatment of psoriasis with arsenic, coal tar, ultraviolet B and
Anal cancer is an uncommon malignancy, with an estimated incidence in the general population between 0.8 and 1.4 cases per 100,000 people-years.24 The most frequent tumor of the anal canal and perianal skin is SCC.25 The incidence of anal SCC has increased considerably in the past decade, mainly due to the growing number of cases in highrisk groups such as MSM, immunosuppressed individuals, and women with a history of cervical dysplasia.2 In men who practice anal-receptive sexual intercourse, the incidence of anal cancer is 35 cases per 100,000 people-years.25 The incidence of anal SCC in MSM with HIV is estimated at 70 to 128 cases per 100,000 people-years.2 Risk factors for the development of anal cancer include HPV infection; immunosupression; history of anal-receptive intercourse; history of cervical, vulvar, or vaginal cancers; HIV infection; and smoking. 26 Risk groups for anal
366 carcinoma usually include individuals with HPV-16 infection and high-grade AIN. In 28% of the cases, anal carcinoma develops from AIN or chronic (peri) anal condylomata.4 HPV-6 or -11 are detected in more than 90% of anogenital condylomata acuminata and these subtypes are not associated with cancer. HPV-16 is rarely involved in condylomata that it has a well-documented association with anal carcinoma.3 AIN is often a precursor to invasive squamous anal carcinoma. It is a multifocal disease process strongly associated with HPV (usually types 6, 11, 16, and 18). Patients with HIV, those who are systemically immunocompromised such as transplant recipients and those on long-term steroids (eg, for connective tissue disorders), women with a history of genital IN, and those with extensive anogenital condylomata are at increased risk for AIN. The risk for progression of AIN to invasive anal cancer approximates 10% at 5 years.27 Common presenting symptoms include bleeding, pain, presence of a mass, and change in bowel habits. A hard mass that may be flat, raised, or polypoid is seen on examination. It is important to identify palpable inguinal lymphadenopathy at presentation due to its association with worse outcomes, higher local failure, and decreased survival. To detect distant metastases, radiological assessment is needed.3,28 The differential diagnosis includes the manifestations of IN, erosive or ulcerative sexually transmitted disease, basal cell carcinoma, Kaposi's sarcoma, hidradenitis suppurativa, Crohn's disease, pyoderma gangrenosum, and artifact.3 Anal SCC can be treated by surgery; photodynamic therapy (PDT); chemotherapy (5-FU cream, podophyllotoxin gel); topical immunomodulators (imiquimod cream); and ablative modalities such as cryotherapy, electrocoagulation, infrared treatment, and laser therapy.4
Verrucous carcinoma/giant condyloma/ Buschke–Löwenstein tumor Buschke–Löwenstein tumor (BLT) is a highly differentiated verrucous carcinoma of the anogenital region and is regarded as a distinct entity between condylomata acuminata and SCC.29 BLT represents as verrucous, low-grade, welldifferentiated squamous carcinoma.3 It is a rare, slowgrowing, large, cauliflower-like tumor with a locally destructive behavior that typically appears in the anogenital region. 30 BLTs do not metastasize and have benign histology; however, they have the potential for expansive and invasive growth. Malignant transformation occurs in up to 50% of BLT cases, with an average time to transformation of approximately 5 years.7 BLT occurs at any age after puberty, usually between the fourth and sixth decades. Males are more frequently involved and the male/female sex ratio is 3:3.31 The etiology of BLT is not known definitely but common opinion is that it is mostly associated with presence of HPV
Z. Kutlubay et al. types 6 and 11 and very rarely 16 and 18. Having numerous sexual partners, poor hygiene, depression of the immune system, HIV, smoking, and anaerobic infections are cofactors that increase the risk for developing BLT.32 BLT occurs most commonly in individuals with immunodeficiencies, including HIV infection, post-transplantation, hematologic malignancies, prolonged steroid use, diabetes, pregnancy, and in people with alcohol abuse.7 Clinically, BLT appears as a large, disfiguring, exophytic, cauliflower-like, white or yellow tumor of papillomatous and irregular surface, eventually exceeding 10 cm.2 It is located on the penis in 81% to 94% of cases, in the anorectal area in 10% to 17%, and in the urethra in 5%. In females, the location is chiefly the vulva (90%) and an anorectal location is less frequent.31 Due to the invasive and deeply infiltrative growth of this tumor, subsequent destruction of underlying tissues occurs. As a result of this, pain, bleeding, itching, and fistulae formation are seen.7 Histologic examination shows vacuolization of cells in the superficial layer of the epidermis, massive epidermal hyperplasia, hyperkeratosis, parakeratosis, and large hyperkeratotic cellular nests propagating deep into underlying stroma.32 Due to its tendency to infiltrate deeper tissue layers, a deep surgical biopsy from different points must be performed. BLT shows invasion with a pushing rather than infiltrating pattern thus results in the compression and displacement of underlying tissues.3,31 BLT does not present histologic evidence of malignancy, such as infiltration of basement membrane, lymphatic invasion, angioinvasion, and distant metastases.33 Despite this, BLT can coexist with SCC in up to 50% of patients. Bleeding, infiltration of the tumor basis, or lymph node enlargement may be signs of malignant transformation into microinvasive carcinoma or into well-differentiated keratinizing SCC, which occurs in about 30% of cases.31 There are no guidelines on the treatment for BLT, and therapy is primarily based on case reports and case series. The mainstay of treatment is local excision of the tumor with subsequent histologic examination of the resection margins. Excision must be wide and the Mohs technique is often used.31 A combination of chemo- and radiotherapy may be a good treatment option if a complete surgical excision of the BLT is not feasible.34 Other adjuvant treatment modalities used to avoid mutilating surgical interventions are laser, cryotherapy, intralesional interferon alfa, or topical imiquimod.35
Extramammary Paget's disease Extramammary Paget's disease (EMPD) is an uncommon intraepidermal adenocarcinoma that arises in areas rich in apocrine glands and involves primarily the epidermis but occasionally extends into the underlying dermis.36 EMPD generally occurs between the ages of 50 and 80 years, most frequently in White individuals. Overall, it is more common
Anogenital malignancies and premalignancies in women than men, with a reported female/male ratio of 1.4:1.37 The most common sites of EMPD are the vulvar and anogenital regions, followed by axillae, penoscrotal region, eyelids, umbilicus, and groin.38 The pathogenesis of EMPD has been debated and the proliferative neoplastic cells called Paget cells have been associated with skin adnexae (both apocrine and eccrine glands), pluripotent keratinocyte stem cells within the epidermis, and, more recently, Toker cells, which are present in both mammary and vulvar tissue. Two major types of EMPD have been described. In primary EMPD (or intraepidermal EMPD), adenocarcinoma begins in the epidermis at the sweat gland level or from primitive epidermal basal cells. Less commonly, it can become invasive, infiltrate the dermis, and from there it metastasizes to local lymph nodes and distant sites. In secondary EMPD, which occurs less frequently, epidermotropic spread of malignant cells occur from an underlying adenocarcinoma in a dermal adnexal gland or an adenocarcinoma begins in the genitourinary (GU) or gastrointestinal (GI) tract then spreads into the contiguous epidermis of the skin.38,39 The clinical manifestation of EMPD is variable. The primary lesion is a sharply bordered red patch that the color may vary from pink, light/dark red to red-brown. It may demonstrate crusting, weepy erosions, and ulcerations. Lesions are often solitary, but may be multiple, in which cases the plaques seem to be separated by areas of normal skin.37,39,40 Symptoms of EMPD include pruritus, burning paresthesia, and pain. Patients may have associated lymphadenopathy, either unilateral or bilateral. The clinical differential diagnosis for EMPD includes eczematous dermatosis, superficial fungal infection, psoriasis, BD, leukoplakia, and melanoma. The diagnosis is made on histologic grounds and supported by immunohistochemical analysis. Histologic examination shows nests of large vacuolated cells with circular nuclei and foamy pale cytoplasm in the epidermis (Paget cells). Dermal involvement signifies a poor prognosis. Hyperkeratosis, acanthosis, and parakeratosis may be seen. If the Paget cells are only located intraepidermally, or in the epithelium of the adnexa, the tumor is considered a carcinoma in situ. If there is penetration of the basement membrane, the tumor is considered an adnexal carcinoma. Immunohistochemical staining is being used to identify Paget cells and to help differentiate between primary and secondary forms of EMPD. MUC5A2 (mucin core protein) appears to be associated much more commonly with EMPD (particularly of vulvar or male genitalia location) than mammary Paget's disease (MPD) and its loss may signify a more invasive disease. Positive staining for CK7 (cytokeratin) seems to have very good sensitivity, for Paget cells in both MPD and EMPD, whereas CK20 may be more specific for EMPD. As for carcinoembryonic antigen positive staining is quite sensitive for EMPD and a negative result seems to be associated more frequently with underlying carcinomas.3,36–40 The diagnosis of EMPD warrants a thorough search for associated adnexal or visceral malignancy. Most EMPD
367 cases reflect a primary intraepithelial adenocarcinoma, which is probably derived from a pluripotent cell in the basal layer of the epidermis. Usually, secondary EMPD and the internal malignancy are anatomically associated. Secondary EMPD in penoscrotal and perianal locations are associated with adenocarcinoma of the GU and GI tracts, respectively.36–38 Treatment options for EMPD are conventional excision, Mohs micrographic surgery, radiotherapy, carbon dioxide laser therapy, PDT, and 5-FU cream.4 Local wide excision with a 1- to 3-cm margin is the best treatment choice in noninvasive EMPD. Because EMPD always extends beyond the clinically visible margin, Mohs micrographic surgery has been recommended. Compared with wide excision, lower rates of recurrence have been reported after Mohs microscopic surgery (33% versus 23%, respectively). In invasive EMPD, adjuvant therapy such as radiotherapy or systemic chemotherapy may be necessary after surgical excision.37 Radiotherapy can be used as an alternative therapy for large or inoperable tumors, especially in elderly or comorbid patients in whom surgery may be difficult.3,40 Carbon dioxide and Nd:YAG lasers have been reported useful in the treatment of EMPD that they would provide a conservative approach to eradicate the disease while preserving vulvar anatomy and sexual function. On the other hand, significant recurrence has been reported after the use of laser surgery in this condition. 39 Promising results are reported with photodynamic therapy, but larger series and longer periods of follow-up are required. In cases with limited disease, the use of topical imiquimod has been advocated with good results.3 In metastatic EMPD, most authors recommend various forms of multiple chemotherapy regimes such as 5FU, mitomycin C, cisplatin, vincristine, and epirubicin, each in combination with radiotherapy.40
Anogenital premalignancies Intraepithelial neoplasia IN is known as an intraepidermal dysplastic change or carcinoma in situ limited to epidermis. According to the location, IN is categorized as vulvar, penile, and anal intraepithelial neoplasia. Histopathologically, IN is classified as squamous and non-squamous. Oncogenic HPV types (ie, types 16, 18, 31, 33) play a role in 90% of squamous IN.4 Immunosuppressed patients (ie, patients with HIV infection and organ transplant recipients who are receiving continuous immunosuppressive treatment) are at increased risk for developing multiple HPV-related benign and malignant anogenital tumors. Due to decreased cell-mediated immunity, immunocompromised patients are at increased risk for developing and failing to clear HPV-related disease.7 VIN is defined as loss of the normal orientation and architecture of the epithelium with cellular atypia. VIN is
368 categorized according to the updated International Society for the Study of Vulvar Disease classification, based on morphologic criteria as either usual type, or the less common differentiated type (2–10% of cases), which is generally not HPV-associated. The more common usual type (HPV-induced VIN) encompasses older terms BP, Bowenoid papulosis (BP), and carcinoma in situ. Clinically, it presents as solitary or multiple, raised, well-demarcated, asymmetric lesions, ranging from bulky whitish or erythematous plaques, to verruciform, polypoid, or papular lesions either with or without pigmentation. The risk for progression to invasive disease is estimated as 10% or less in multifocal disease, but this risk is likely to be higher in immunocompromised patients, perianal disease, and in older women with a solitary plaque.3,7 BD, BP, and EQ are forms of squamous IN. Histopathologically, these conditions are all the same in that they share identical features of SCC in situ, but their clinical features are different. Penile intraepithelial neoplasia (PIN) is a term that has been used to encompass the three premalignant clinical entities of penile BD, BP, and EQ.41
Bowen's disease BD or squamous cell carcinoma in situ (SCCIS) are synonymous terms for localized neoplastic degeneration limited to the epidermis with the potential for significant lateral spread.42 It was first described by the American dermatologist John T. Bowen in 1912. The etiology of Bowen's disease of the penis (BDP) is unknown but risk factors for developing this disease include lack of circumcision, HPV infection, phimosis, balanitis, or any chronic inflammation of the penile skin.43 BD is associated with oncogenic HPV types 16 and 33.4 Histologic features of BD include full-thickness epidermal atypia with disordered architecture, abnormal mitoses, dyskeratosis, and involvement of associated pilosebaceous apparatus with an intact epidermal junction.42 The ratio of BD is approximately equal between men and women. BD occurs in adulthood, with the highest incidence in patients older than age 60 years. BD may arise anywhere on the skin. It is usually persistent and progressive, presenting as a gradually enlarging, well-demarcated, erythematous plaque with an irregular border and surface crusting or scaling. BD also may occur on mucous membranes. BD of the penis is characterized by red, sometimes slightly pigmented, scaly, moist, velvety patches and plaques of the keratinized penis.3,44 BD may be asymptomatic or associated with pain and pruritus. Compared with BP, BD evolves relatively more often into an invasive carcinoma. A delay in diagnosis of BD often is encountered because the lesion is asymptomatic. A classic clinical history is presentation of a non–steroidresponsive dermatosis.4 Malignant potential of BD increases when its existence is compounded by concomitant disease such as HPV infection, LS or LP, or in patients with poor genital hygiene and
Z. Kutlubay et al. smokers. The potential for invasive SCC to develop from BD is approximately 3% to 5% for cutaneous and 10% for genital lesions.4,41,42 The choice of treatment depends on an analysis of various factors such as lesion size, number, site, degree of functional impairment, modality availability, and cost. Follow-up at 6 to 12 months is recommended to evaluate for recurrence. Treatment options are local excision, Mohs micrographic surgery, cryotherapy, curettage with cautery⁄ electrocautery, laser therapy with carbon dioxide, argon, and Nd:YAG lasers. Cryotherapy regimens consist of two freeze–thaw cycles of 20 seconds with a thaw period at intervals of a few weeks. Other noninvasive treatment options are photodynamic therapy, topical 5-FU.14 5-FU is used clinically as a 5% cream once or twice daily for a variable period, ranging from 1 week to 3 months. Topical treatment for BD in perianal region may minimize the risk for scarring, poor wound healing, and functional impairment. For perianal BD, excision with wide margin is recommended. Surgery and destructive treatment modalities have a significant risk for scarring, deformity, and impaired function. Recent case studies have reported the successful treatment of penial BD and anogenital BD with topical imiquimod, an immune response modifier, as a 5% cream. The ideal dosing regimen is still under investigation, but the most studied regimen is imiquimod 5% cream once daily for 16 weeks.43–45
Bowenoid papulosis BP represents a multifocal IN primarily located in the anogenital region. Although the course of the disease appears to be benign, histopathologic findings reveal features of a SCC in situ.46 Additionally, the widening of spinous epidermal layer is seen with proliferation of atypical basal cells, coilocytosis, enlarged polimorfic and hyperchromatic nuclei as well as abnormal mitosis and hyper or parakeratosis with a collection of melanin of various amount.47 HPV types 16, 18, 31, and 39 play an etiologic role in BP.4 HPV types 16, 18, 31, and 33 are considered the most oncogenic. HP-16 is the most commonly detected serotype. HPV typing may be useful to identify patients at high risk. Rarely, BP may progress to true BD or SCC. Immunosuppression is thought to predispose to HPV infection. Recent observations suggest a link between BP and altered immune function in susceptible hosts. Cases of patients with BP associated with HIV, lymphopenia, and depressed cell-mediated immunity have been reported in the literature.48 BP usually presents with multiple, small, well-demarcated, grey-brown, red, pink, or skin-colored papillomatous papules or small patches on the penile shaft, glans, or foreskin, vulva, and perianal area (Figure 2).41 The papules are nonpruritic, range in size from 2 to 10 mm, and usually lack scale. Bowenoid papulosis generally occurs in sexually active men aged 20 to 40 years, equally in both sexes.47
Anogenital malignancies and premalignancies
Fig. 2 Small, well-demarcated, grey-brown, red, skin-coloured papillomatous Bowenoid papules. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
The natural course of BP is not well defined. The papules may increase, decrease, or the lesions may disappear with time; however, coexistence of BP with and transmission into invasive carcinoma have been reported.49 The risk for progression from BP to SCC is reported as 2.6%. BP may be associated with a lesser risk for squamous carcinoma than EQ and BDP.3 It is believed that BP represents a low-grade form of SCCIS, which rarely, if ever, progresses to invasive disease but may be a risk factor for cervical neoplasia in the partners of affected men.41 Treatment options for BP usually involve locally destructive or ablative therapies such as cryosurgery, electrodessication, laser vaporization (Nd:YAG, argon, and carbon dioxide lasers), and surgical excision. Scarring can be seen with these modalities. Conservative treatment for BP so far has been based on topical use of ointments and creams containing 5-FU, podophylin, retinoic acid, and cidofovir; only moderate effects have been reported.47,48 Recently, some authors reported successful clearance of BP using imiquimod cream 5%.4,47,48
Erythroplasia of Queyrat EQ is an uncommon carcinoma in situ that usually arises on the mucosa of the glans penis or prepuce of uncircumcised men with a high risk for the development of invasive penile SCC.50 EQ (BD of the glans penis) arises from the mucocutaneous epithelium of the penis. It usually affects uncircumcised men in their third to sixth decades of life and is a rare condition that account for less than 1% of malignancies in men.51 Its cause is unknown but chronic irritation, smegma, poor hygiene, genital herpes simplex, HPV, heat, friction, maceration, inflammation, phimosis,
369 smoking (tar metabolites in urine), trauma, and specific prepuce dermatoses, such as LS or LP, may be risk factors for developing EQ. 3,50 EQ has been shown to be associated with co-infection with the rare epidermodysplasia verruciformis associated HPV-8 and the genital highrisk HPV-16.3 Clinically, EQ appears as single or multiple red, shiny, slightly raised, sharply demarcated, velvety, non-healing plaques associated with scaling, crusting, and sometimes bleeding, affecting the mucosal surfaces of the penis.52 A definite diagnosis is made by a biopsy showing the typical histologic picture of intraepidermal carcinoma in situ. Early invasion should be excluded by obtaining several biopsies.49 Both EQ and BD are premalignant, but transformation of EQ into invasive SCC is more common than in BD, with an incidence ranging from 10% to 33%. Ulceration or distinct papillomatous papules within a plaque may indicate progression to invasive SCC. Several case reports of EQ metastasis to local lymph nodes have been reported.4 EQ must be diagnosed via skin biopsy of the affected area. Areas of ulceration or distinct papillomatous lesions must be histologically evaluated. Inguinal nodes should be examined. Circumcision is recommended for all patients because it eliminates the mucosal surface of the prepuce and decreases the risk for local recurrence.52 Treatments for EQ include surgical excision, Mohs micrographic surgery, cryotherapy, electrodesiccation and curettage, radiotherapy, laser ablation, PDT, oral isotretinoin, topical 5-FU and topical imiquimod. Mohs micrographic surgery may be useful because it precisely identifies tumor-free margins while allowing minimal tissue loss. Partial or total penectomy is usually an unnecessary mutilating procedure. If urethral involvement is noted, treatment may be more challenging, with higher recurrence rates.50,52
Lichen sclerosus LS is a chronic inflammatory skin disease that is characterized by atrophic white papules or plaques of skin and mucosa.53 It most frequently occurs in adult women but also has been seen in men and children.54 LS affects between 1 in 1000 and 1 in 300 individuals in the general population.55 It is more common in women than men and the ratio of female/male ranges between 6:1 and 10:1.54 LS has two main peaks in incidence: the first being before puberty for both girls and boys, and the second after menopause for women and between ages 30 to 50 years for men. This dermatosis may affect any part of the body, but it occurs mainly in the anogenital area.56 The etiology and pathogenesis of LS is unknown but may include genetic, infectious, environmental, and hormonal factors. Local irritation or trauma seems to play a role in some cases, especially in genetically predisposed individuals. It is thought to be a genetically determined autoimmune disorder. There is a strong association with autoimmune diseases such as thyroid disease, alopecia areata, vitiligo, and
370 pernicious anemia. The incidence of HLA class II antigen DQ7 is increased in LS.3,56 Clinically, LS presents as flat, ivory, or porcelain white plaques extending around the vulval and perianal skin in a figure-of-eight configuration (Figure 3). Sometimes, telangiectasias, purpura, fissures, erosions, and ulceration are associated with the primary lesion. LS is a scarring dermatosis so in women and girls, fusion of the labia minora (lips), narrowing of the vaginal introitus (vaginal opening), and burying of the clitoris can occur. LS can be asymptomatic or associated with itching, pain, local burning sensation, painful sexual intercourse, and anal or genital bleeding. Vulvar LS usually presents with progressive pruritus, dyspareunia, dysuria, or genital bleeding. Penile LS usually is preceded by pruritus but may present with sudden phimosis of previously retractable foreskin.3,56 Histologic features of LS are thinned epidermis with flattening of the rete pegs, hydropic degeneration of the basal cells, and a bandlike zone of chronic inflammatory cells below the hyalinized dermis. Inflammation and altered fibroblast function in the papillary dermis leads to fibrosis of the upper dermis3,55 LS is known to be associated with SCC. SCC occurs in 3% to 7% of patients with vulvar LS and in 2% of men with LS of the penis. Long-term follow-up is needed for patients with LS due to the increased risk for SCC.4 The aim of treatment is to control disease before occurring complications and early diagnosis of malignancy. The first treatment option for LS is the potent topical corticosteroid, clobetasol propionate. Patients should be warned that the clinical appearance does not always reverse,
Fig. 3 Flat, ivory or porcelain white plaques extending around the vulval and perianal skin, narrowing of the vaginal introitus, and atrophy of the labia are seen. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Z. Kutlubay et al. even if symptoms are relieved. It is widely reported that prepubertal LS in girls may resolve spontaneously. Currently, topical testosterone is no longer used because it is less effective than topical corticosteroid and has androgen-associated side effects (hirsutism, clitoral hypertrophy, and amenorrhoea). Topical immunomodulators (tacrolimus and pimecrolimus) can be used as steroidsparing alternatives, but they should not be used long term as their safety is still unknown.3,56
Balanitis xerotica obliterans Balanitis xerotica obliterans (BXO) was first described by Stuhmer in 1928. It is now considered to be the male genital variant of LS.57 BXO is a chronic idiopathic progressive sclerotic process known to afflict the prepuce, meatus, glans, and the anterior urethra in a circumferential manner.58 BXO has no known predilection for any racial or ethnic group. Although it may occur in patients of any age, it is most common in middle-aged men. Also it has been reported in boys. 53 Jayakumar et al. reported that epidemiologic population data analysis revealed the incidence of BXO per year to be 3.01 cases per 1000 boys under the age of 15 years and 0.322 cases per 1000 boys under the age of 5 years. The median age of boys with BXO was 9 years (range 2–15 years) and the mean was 8.9 years, but the peak incidence of BXO was noted at age 7 years.59 The etiology of male genital LS is unknown but it is thought to be multifactorial. Genetic factors, autoimmune disease, infective processes, and local trauma have been suggested. HPV types 6 or 16 have not been detected in patients with BXO.60 BXO may be asymptomatic or patients can present with itching, soreness, and phimosis. Phimosis can cause difficulty with erection and sexual intercourse and occasionally difficulty with voiding. Purpura and telangiectases of the glans, pruritus, paraesthesia (a burning sensation), dysuria, urinary retention, and renal failure are rarer complaints to ocur.60,61 BXO most commonly occurs on the glans and inner surface of the prepuce. It usually shows insidious onset but may progress over many years. Nonspecific erythematous or hypopigmented macules or papules coalesce into atrophic ivory, white, or purple-white plaques with well-defined margins. A white patch on the prepuce or glans may extend to and around the urethral meatus, frenulum, and fossa navicularis. Urethral stenosis may occur as a result of glandular erosion, ulceration, and fissures. A sclerotic white ring at the tip of the prepuce is diagnostic.53,61 Although BXO can be detected clinically, the diagnosis is based on histopathologic examination. Histopathologic changes of BXO are similar to those of nongenital LS. Histologically, it is characterized by epidermal atrophy with surface hyperkeratosis, a thickened basement membrane, and an underlying broad zone of subepidermal edema with homogenization of collagen, which becomes more sclerotic over time and a chronic lymphohistiocytic inflammatory
Anogenital malignancies and premalignancies infiltrate in the mid-dermis.59,61 Complications reported include phimosis, painful erection, meatal stenosis, dense obliterative urethral strictures, reduced urinary flow, and urinary retention.58,61 The premalignant potential of BXO is a contentious issue. The European Association of Urology classified BXO as a premalignant lesion, sporadically associated with SCC of the penis. Pietrzak et al. reported that BXO is an associated finding in 28% of patients presenting with penile carcinoma.60 Nasca et al. reported that in their review of 86 patients with penile LS, 5 (5.8%) had histologically confirmed SCC.62 No consistently effective treatment has been developed for BXO. BXO has been managed both medically and surgically. Topical corticosteroid preparations (betamethasone diproprionate 0.05% or clobetasol proprionate 0.05%) are the main stay of treatment for penile LS. Topical calcineurin inhibitors pimecrolimus and tacrolimus have been used with success but should not be used as first-line therapy. Long-term safety of calcineurin inhibitors has not been established for genital disease.61 The surgical options are circumcision, dilating or surgically correcting meatal stenosis, and various urethroplasty techniques. Uncircumcised patients usually benefit from therapeutic circumcision. Full-thickness skin grafts from eyelids to penis, plus splitthickness grafts in chronic BXO have been used with variable success. The carbon dioxide laser has been used as an alternative to incisional surgery to ablate BXO on the glans and for the dilatation of proximal strictures.57
371
Conclusions Anogenital malignancies and premalignancies are important personal/public health problems due to their impact on the physical, mental, and sexual well-being of those affected. Also, due to their etiological association with HPV infection, they constitute an immense public health burden. There is an urgent need for early diagnosis to improve prognosis in anogenital malignancies and premalignancies. Also, delays in diagnosis may result in the use of treatment options that might result in significant effects on the patient's psychological well-being and quality of life. Therefore, dermatologists and other associated specialists should have adequate information and experience about anogenital malignancies and premalignancies to avoid delays in both diagnosis and treatment. Patient self-awareness should be increased, especially in high-risk groups (those who are immunsuppressd, HIV infected, MSM, patients who have been exposed to previous radiotherapy, and those who have received PUVA therapy). A relatively recent but significant development, HPV vaccination, probably will have an important place in prohylactic measures. For the present, the effects of such vaccination, on a population-based scale, are not yet clear but will become apparent in the near future. Because PUVA treatment is a risk factor for anogenital malignancies, patients sould be trained before taking PUVA therapy. Management of anogenital malignancies and premalignancies should be organized in a multidisciplinary fashion.
Penile horn Well-defined conical lesion with hyper-keratotic features projecting as nodule above the skin surface is termed as cutaneous horn (cornu cutaneum).63 The horn is composed of compacted keratin. It usually occurs on sun-exposed skin but rarely on penis. Penile cutaneous horn is a clinical term that describes protruding hyperkeratosis with an erythematous base on penile glans.64 The lesion is premalignant or, in one-third of cases, malignant at presentation, with squamous carcinoma the underlying pathology.3 No clinical features reliably distinguish between benign and malignant lesions. In addition to SCC, other dermatologic underlying conditions are common warts, condylomatum acuminatum, angioma, keratoacanthoma, benign hyperplastic epithelium, and intraepithelial carcinoma.65 The etiology is not clear, but predisposing factors for the development of penile horn are chronic inflammation, phimosis, trauma, poor hygiene, and radiotherapy.63,65 Treatment options include wide surgical excision with careful histologic examination to exclude a focus of malignancy. Partial penectomy with or without regional lymph node dissection is appropriate option if malignancy is present in a penile cutaneous horn. Therapy with carbon dioxide or Nd:YAG laser is used for patients who refuse surgery.66
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