Bowen's disease (Squamous Cell Carcinoma In Situ; erythroplasia of Queyrat; Squamous Cell Carcinoma In Situ of the Penis)

Bowen's Disease, Squamous Cell Carcinoma In Situ, ICD-9 232._ (0, lip; 1, eyelid; 2, ear; 3, face/cheek; 4, scalp/neck; 5, trunk; 6, arm; 7, leg; 8, unspecifiedB);

BErythroplasia of Queyrat, Squamous Cell Carcinoma In Situ of the Penis, ICD-9 233.5B

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Patients often present with a history of a persistent red, scaly plaque that can be asymptomatic or pruritic. The plaque is usually solitary, but the patient may have multiple plaques depending on the extent of sun damage. These slowly growing, well-demarcated lesions are not responsive to emollients or steroid treatment. Lesions most commonly occur in persons older than 60 years and in sun-exposed areas of the body. In erythroplasia of Queyrat (squamous cell carcinoma [SCC] in situ of the penis), the history is the same but the well-demarcated erythematous plaque or patch is located on the penis and occurs more commonly in a younger population.

  • Characteristic findings on physical examination

The most common locations are the head, neck, and lower limbs (Figure 1, Figure 2). On exam, there is a well-demarcated scaly, erythematous plaque or patch. It can be pigmented or verrucous. The size varies and can range from a few millimeters to several centimeters. On the genital area, the plaque can have a velvety, moist, and shiny appearance with frequent involvement of the glans penis, prepuce, and coronal sulcus.

Figure 1.

Bowen's Disease (squamous cell carcinoma in situ) on the chest.

Figure 2.

Bowen's disease evolving from actinic keratosis.

  • Expected results of diagnostic studies

Biopsy, most commonly a shave, is used for diagnosis and to evaluate for progression to invasive SCC. On histology, the epidermis shows acanthosis, hyperkeratosis, parakeratosis, and full-thickness keratinocyte atypia. There is a loss of polarity, loss of normal maturation, and presence of mitotic figures. Keratinocytes may appear pale and enlarged with a pagetoid appearance. The epidermis may have a "windblown" appearance, but the basal layer is preserved. There can be progression down hair follicles. If dermal invasion is seen, then the lesion has become invasive with progression to an SCC.

  • Diagnosis confirmation

The differential diagnosis consists of inflammatory and other neoplastic lesions. The most common inflammatory lesions that must be considered are nummular eczema, psoriasis, and lichen simplex chronicus. The history of multiple lesions, associated symptoms (ie, pruritus, background xerosis, arthritis, psoriatic nail changes), location, and responsiveness to topical treatments (ie, steroids) will help to distinguish between Bowen's disease and the above differential. A lesion that is nonresponsive to steroid treatment should suggest the possibility of Bowen's disease and warrants a biopsy for diagnosis.

The most common neoplasms in the differential diagnosis are seborrheic keratoses, actinic keratoses, superficial basal cell carcinoma, and Paget's disease. The clinical appearance and location of the lesion should assist in making the diagnosis, but a biopsy is needed to definitively determine the diagnosis. Actinic keratosis can progress to Bowen's disease, so a presumed actinic keratosis that does not respond to repeat cryotherapy or topical chemotherapy or immunomodulators should undergo biopsy to evaluate for progression.

Who is at Risk for Developing this Disease?

The highest incidence occurs in Caucasians with Fitzpatrick skin type I or II, although it can occur in people with darker pigmentation. The incidence in Caucasians has been reported as being 1.42 per 1000 in some populations. Bowen's disease most commonly occurs in sun-exposed areas of the body. No significant difference between male:female ratios has been noted. The highest incidence of Bowen's disease occurs in people older than 60 years, although it has been seen in younger patients.

Subjects with chronic UV exposure and actinic damage are at a greater risk for the development of Bowen's disease. There is also an increased incidence of occurrence in those with chronic arsenic toxicity or immunosuppression, those who have received radiotherapy, and those who are infected with the human papillomavirus (HPV).

Erythroplasia of Queyrat most frequently occurs in men over the age of 50, although it can occur at any age. Risk factors associated with the development of erythroplasia of Queyrat are being noncircumcised and having chronic inflammation, phimosis, and HPV infection, most commonly HPV type 16.

What is the Cause of the Disease?

  • Etiology

  • Pathophysiology

Bowen's disease may evolve de novo or from a preexisting actinic keratosis.

Erythroplasia of Queyrat involves the mucocutaneous surface of the penis and is usually seen in uncircumcised males with chronic inflammation and/or viral infection leading to keratinocyte dysplasia.

Both involve the malignant transformation of the epidermal layer of the skin without invasion through the epidermal-dermal junction. If atypical keratinocytes infiltrate the dermis, then the lesion has progressed to an invasive SCC.

HPV DNA has been detected in 40% to 80% of cases of penile SCC. The most common associated HPV types reported are HPV type 8 and coinfection with types 16, 39, and 51. Erythroplasia of Queyrat has been found to have a strong association with HPV 16, which is a high-risk oncogenic virus type. In periungual Bowen's disease, HPV type 16 has been found to play an important role in carcinogenesis.

Systemic Implications and Complications

Bowen's disease carries a 3% to 8% risk of developing into an invasive SCC in nongenital areas. Genital lesions have a 10% risk of progression. The invasive tumor is believed to have a 3% to 5% risk of metastasis.

Erythroplasia of Queyrat has been found to be more aggressive than Bowen's disease, with progression to invasive SCC in up to 33% of cases; of these cases, 20% result in metastasis.

Treatment Options

Surgical treatment

Simple excision

Mohs micrographic surgery

Physical treatment

Electrodessication and curettage

Photodynamic therapy



Medical treatment

Imiquimod cream

5-Fluorouracil cream

Diclofenac cream

Optimal Therapeutic Approach for this Disease

Different treatment options can be used to successfully treat Bowen's disease and erythroplasia of Queyrat. The recommended treatments should be guided by efficacy of treatments, number of lesions, location of lesion, size of the lesion, and comorbidities of the patient with the lesion.

  • Surgical treatment

Simple excision is most commonly recommended for small, localized lesions in areas where tissue conservation is not an issue. It allows for margin examination to determine tumor clearance and assessment of the presence of evolving invasive SCC. There are no standardized margins for elliptical excision in Bowen's disease, but a 4-5 mm margin is usually recommended around the clinically evident lesion. Marginal wide excision is recommended for perianal Bowen's disease. Five-year recurrence rates have been shown to be as high as 19% with simple excision. Perianal Bowen's disease has a higher recurrence rate and can be as high as 30% with simple excision.

Mohs micrographic surgery has been routinely used to treat Bowen's disease in areas where tissue conservation is of concern, such as the face, digits, and genital area. It allows for 100% of margin evaluation to ensure successful treatment. Five-year recurrence rates of 6.3% have been reported.

Elderly patients with extensive lesions and multiple comorbidities may not be good surgical candidates and less invasive methods should be considered.

Potential risks involved with simple surgery or Mohs surgery are bleeding, pain, infection, dehiscence, scarring with possible cosmetic and functional impairment, and prolonged wound healing.

  • Physical treatment

Electrodessication and curettage is a method of physically destroying the dysplastic layer of the epidermis. Most commonly, it is performed with three cycles of curettage and electrodessication of the lesion in alternating directions. It does not allow for histologic confirmation that the lesion has been successfully treated, but it is an easy, cost-effective way of treating localized Bowen's disease. It is more commonly used when the lesions are located on the trunk and extremities. Healing seems to be faster with this method compared with cryotherapy and other treatment modalities. Cure rates of 81% to 98% have been reported for 2 to 4 years. Potential side effects are usually minimal and include pain, edema, ulceration, and cosmetic impairment.

Photodynamic therapy is another well-known treatment option for the treatment of Bowen's disease. Its use is limited by the cost and availability of the procedure. It is a treatment that should be considered when multiple or large lesions are present and in patients with poor wound healing, multiple comorbidities, and immunosuppression. It involves applying a photosensitizing agent (ie, 5-aminolevulinic acid [5-ALA] or methyl-ester 5-aminolevulinic acid [MAL]) to the affected area and activating it with a specific light source. The photosensitizing agents are preferentially taken up by proliferating cells. The light source converts it to protoporphyrin IX, leading to radical oxygen species formation and cell death. These changes occur in more actively dividing cells, thereby targeting the dysplastic cellular areas.

To perform the treatment, the area must first be lightly curetted to remove the scale and allow for better penetration of the photosensitizing agent. After hemostasis is achieved, 5-ALA or MAL is then applied and occluded for 2 to 4 hours. The areas are then exposed to either a blue light source (417nm) for activation of 5-ALA or a red light source (650nm) for activation of MAL. Multiple treatments may be indicated based on response. Recurrence rates of 17% in 5 years have been reported. Potential side effects include localized pain and burning during and after the treatment, edema, blistering, crusting, and photosensitivity.

This procedure is a noninvasive method of treatment, and the side effects are generally milder and more tolerable compared to those with other treatment options. Good cosmetic results and functionality have been reported.

Cryotherapy is a simple procedure that has been used to treat small, localized nongential lesions. Bowen's disease often evolves from an actinic keratosis, and therefore, cryotherapy is often one of the first treatments that has been performed and failed prior to diagnosis with a biopsy. Cryosurgery works at both the cellular and vascular levels to induce necrosis of the epidermis. It is often unsuccessful in treating Bowen's disease that extends down the pilosebaceous unit. To be effective commonly requires multiple freeze-thaw cycles of liquid nitrogen applied to the dysplastic areas. It is a procedure that can be performed easily in the office.

Recurrence rates as high as 34% have been reported and vary based on the length of freezing cycle. Lower recurrence rates have been seen with multiple (usually two or three) 20- to 30-second freeze-thaw cycles. It is a noninvasive, simple treatment that can be used initially in elderly patients who do not wish to undergo more involved treatment. Treatments can result in failure, ulceration, and cosmetic impairment.

Radiotherapy has been used to treat Bowen's disease. The different techniques used are external beam radiotherapy, Grenz rays, and radioactive skin patches. The procedure is expensive and requires referral to a facility that has the ability to perform it. Although this procedure offers a noninvasive method of treatment, it requires multiple weekly treatments over the course of months and it can result in a nonhealing ulceration. It is not a method that should be used for a lesion in a location with the potential for poor wound healing (ie, the lower extremities). There have been high cure rates of 94% to 100% reported, but its potential for poor wound healing has limited its use. It is an effective treatment that should be considered when other minimally invasive treatments have failed and the patient is not a surgical candidate.

  • Medical treatment

Different topical medical treatments have been used to treat Bowen's disease with varying results. Imiquimod 5% cream is a topical immune response modifier that stimulates the innate and acquired immune system, which leads to antiviral and antiproliferative effects. It is believed to cause an upregulation of proinflammatory cytokines, through Toll-like receptor 7, resulting in cellular apoptosis of dysplastic cells and upregulation of Langerhans cells, resulting in increased antigen presentation. There are many different treatment regimens performed with 5% imiquimod, varying from 3 to 7 times a week for 3 to 16 weeks.

Treatment failure has been reported as 0% to 25% in the literature. A newer formulation of imiquimod has recently been released: imiquimod 3.75% cream. It has proved to have similar efficacy as imiquimod 5% cream in the treatment of actinic keratoses with a shorter treatment regimen. The recommended treatment regimen is daily application for 2 weeks, a 2-week nontreatment period, and then an additional 2-week application cycle. Treatment of Bowen's disease with imiquimod 3.75% cream has not yet been studied but appears promising.

5-Fluorouracil (5-FU) cream is a topical chemotherapy that acts as an antimetabolite to inhibit thymidylate synthetase, an enzyme necessary for the production of DNA and RNA. Neoplastic cells are known to have an increased rate of mitosis and are therefore preferentially targeted. The disruption of metabolic activity leads to cell death and destruction of dysplastic cells. Different regimens exist for treatment and results have been variable. The 5% 5-FU cream can be applied 1 or 2 times daily for 1 to 8 weeks. More successful results with higher clearance rates (92%) have been seen with twice-daily application for 8 weeks. Unfortunately, patient tolerance is decreased with this regimen and alternate-dosing applications show lower success rates.

Potential side effects for imiquimod and 5-FU include edema, ulceration and crusting, pain, and itching. Patient compliance is the most limiting factor for its use. It should be considered in areas where surgical or physical destruction is likely to result in an open wound and the propensity for poor wound healing is a contributing factor. Also, with compliant patients who are motivated, topical treatment is recommended to avoid cosmetic or functional impairment.

Diclofenac is a topical cream that inhibits cyclooxygenase enzymes and arachodonic acid metabolites that are needed for immune surveillance and cellular apoptosis. Few studies have been done that evaluated the efficacy of this topical treatment, but there are several reports of its success. Diclofenac 3% gel has been used 1 or 2 times daily for 2-3 month courses. Potential side effects are similar to those of imiquimod and 5-FU but have been reported as being milder.

Patient Management

Patients who present with Bowen's disease should have a full body skin exam to rule out any other skin cancers. If extensive actinic damage is present, then field treatment with a topical chemotherapeutic agent or immunomodulator (ie, 5-FU or imiquimod) should be considered to try to prevent the development of new lesions. Sun protection is strongly encouraged. For localized low-risk lesions that are adequately treated, follow-up can be scheduled for 6 to 12 months. For erythroplasia of Queyrat, close follow-up (3 months initially) should be performed to monitor for early signs of recurrence or development of invasive SCC. Lymph node evaluation should be performed at each exam. If inguinal lymphadenopathy is appreciated, then computed tomography scanning of the pelvis should be performed with possible lymph node biopsy, if appropriate.

Careful consideration should be given to choosing treatment options. Although surgery will lead to scarring and potential cosmetic and functional issues, it is the most effective treatment that allows for complete removal of the neoplasm. If topical regimens are chosen, failure for resolution after treatment course or clinical progression during treatment should be classified as treatment failure and new treatment options should be performed. Lesions should be reevaluated at 3 months to assess whether treatment was successful.

It is especially important in erythroplasia of Queyrat to achieve complete clearance because of the high rate of progression to invasive SCC and metastasis. Allowing it to go untreated may result in need for penectomy for clearance.

Unusual Clinical Scenarios to Consider in Patient Management

Mohs micrographic surgery can be used to effectively treat erythroplasia of Queyrat that involves the mucosal epithelium and could potentially prevent the need for penectomy. The surgeons can work with the urologists in the operating room to clear the neoplasm with the least aggressive procedure possible.

Mohs micrographic surgery should be considered when treating Bowen's disease, as these lesions often have extensive subclinical spread. Clinically, they may appear to be well defined, but often the atypia extends past the clinical representation of the lesion.

What is the Evidence?

Neubert, T, Lehmann, P. "Bowen's disease: a review of newer treatment options". Ther Clin Risk Manag. vol. 4. 2008. pp. 1085-95.

(The authors, Neubert and Lehmann, conducted a thorough review of the existing literature on treatment options for Bowen's disease. They presented good evidence to support the use of various treatments, the reason for favoring specific treatments in certain clinical presentations, and the recurrence rates associated with the different modalities. The review successfully covered both older and newer treatment options and studies from the literature that have compared the different treatments.)

Cox, NH, Eedy, DJ, Morton, CA. "Guidelines for management of Bowen's disease". Br J Dermatol. vol. 141. 1999. pp. 633-41.

(This article presents a review of the treatment options for Bowen's disease and assesses the strength of the evidence to support the different treatment options. The authors present evidence-based guidelines for the treatment of Bowen's disease based on the recommendations of the British Association of Dermatologists.)

Arlette, JP, Trotter, MJ. "Squamous cell carcinoma in situ of the skin: history, presentation,biology, and treatment". Aust J Dermatol. vol. 45. 2004. pp. 1-11.

(The article by Arlette and Trotter gives a broad overview of the history, incidence, etiology, histology, clinical presentation, and treatment options available for squamous cell carcinoma of the skin. It clearly describes the etiology and pathophysiology of the neoplasms based on good evidence in the literature. It briefly touches on a few of the treatment options available [ie, surgery, cryotherapy, photodynamic therapy, and immunomodulators].)

Leibovitch, I, Huilgol, SC, Selva, D, Richards, S, Paver, R. "Cutaneous squamous carcinoma in situ (Bowen's disease): treatment with Mohs micrographic surgery". J Am Acad Dermatol. vol. 52. 2005. pp. 997-1002.

(The authors reported the results obtained for their prospective case series evaluating the recurrence rate of Bowen's disease when treated with Mohs micrographic surgery. The article reports a 5-year recurrence rate of 6.3% when using Mohs to treat a combination of recurrent and primary squamous cell carcinomas. They show that a subclinical spread of more than 2 cm is greater than would be expected in a large percentage (20%) of their patients, which makes Mohs surgery a favorable option for treatment.)

Schroeder, TL, Sengelmann, RD. "Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream". J Am Acad Dermatol. vol. 46. 2002. pp. 545-8.

(This case report offers a nonsurgical option for treatment of extensive erythroplasia of Queyrat. It shows that imiquimod 5% cream can be successfully used to treat the lesion that may result in scarring and functional impairment if surgery is performed. The authors perform both clinical and histologic evaluation to confirm clearance of tumor.)

Choi, JW, Choi, M, Cho, KH. "A case of erythroplasia of Queyrat treated with imiquimod 5% cream and excision". Ann Dermatol. vol. 21. 2009. pp. 419-22.

(The authors report a case of erythroplasia of Queyrat that was proved to be positive for HPV-16 and was treated with imiquimod 5% cream. The report points out the association between HPV infection and the development of squamous cell carcinoma of the penis. It also shows that successful treatment of the neoplasm may require a combination of topical immunomodulator and surgical intervention. If topical treatment is chosen, close monitoring is important and there should be no delay in surgical removal of any resistant areas.)

Westers-Attema, A, Van den Heijkant, F, Lohman, BG. "Bowen's disease: A six-year retrospective study of treatment with emphasis on resection margins". Acta Derm Venereol. vol. 94. 2014. pp. 431-5.

(A retrospective study of Bowen's disease that looks at the recommended surgical margins and complete excision rates. The data showed greater rate of complete excision with a 5mm margin versus a 3-4mm margin.)

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