Clinical Reference / Therapeutic Strategies / Non-Melanoma Skin Cancers (NMSC): Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)

Non-Melanoma Skin Cancers (NMSC): Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)


Key Points

  • Accurate and timely diagnosis is essential to guide the appropriate management of any skin cancer.
  • A skin biopsy is recommended for diagnosis and to help guide treatment.
  • Surgical excision is almost always the first-line treatment for most non-melanoma skin cancers.
  • Mohs micrographic surgery is a tissue-sparing surgical excision technique that may be used to remove clinically indistinct skin cancers or lesions on the face or other body sites.
  • Patients who are immunocompromised (HIV/AIDS, solid organ transplant or bone marrow transplant patients, patients with lymphoma and leukemia, iatrogenically immunosuppressed patients) have an increased risk of non-melanoma skin cancers, especially squamous cell carcinoma, and should be monitored very closely for the evolution of NMSCs. Other risk factors include patients receiving selective BRAFV600 inhibitors who have an increased risk of developing SCCs or keratoacanthomas (KAs). The incidence of BCC among patients who have had organ transplants is approximately 5- to 10-fold higher than in the general population.
  • Ultraviolet (UV) light plays a significant role in the pathogenesis of NMSC.
  • On a molecular level, mutations in the p53 pathway have been implicated in SCC and BCC, whereas mutations in the hedgehog signaling pathway can cause BCCs.
  • Vismodegib, a hedgehog pathway inhibitor, is a new medical therapeutic option for the treatment of advanced local or metastatic basal cell carcinoma.

Initial Evaluation: Basal Cell Carcinoma

BCC is the most common cancer in humans. Men have higher rates than women (1.5–2:1), and the median age at diagnosis is 68 years. Several forms of BCC exist, including nodular (most common), superficial (erythematous, hyperkeratotic plaques), pigmented, and morpheaform (scar-like in appearance). They most typically present as a pearly papule, plaque, or nodule, sometimes with exaggerated telangiectasias or central ulceration.

Under dermoscopy, BCCs show the presence of well focused arborizing vessels in conjunction with foci of microulceration. Features of pigmented BCCs also include large, blue-gray, ovoid nests, multiple blue-gray globules, leaf-like structures, and spoke-wheel areas.

The common histopathologic features of all types of BCCs include the presence of aggregations of basaloid keratinocytes within a fibromyxoid stroma. Retraction artifact between the basaloid nodules and stroma can aid in the diagnosis.

In general, BCCs are relatively slow-growing tumors and may develop over months to years and invade locally rather than metastasize. If left untreated, the tumor will progress to invade the subcutaneous tissue, muscle, or even bone. Perineural invasion occurs most often in aggressive or recurrent lesions.

Risk factors for the development of BCCs include exposure to UV light, arsenic and/or radiation, immunosuppression, older age, fair skin, male gender, and previous NMSC. Basal cell nevus syndrome (also known as Gorlin syndrome) is a rare genetic condition that is caused by a mutation in the human patched gene (PTCH), a regulator of the sonic hedgehog pathway. This syndrome is characterized by multiple, early-onset BCCs; keratocystic odontogenic tumors, palmoplantar pitting, macrocephaly, and bifid ribs. Other genetic syndromes that are characterized by multiple BCCs and other characteristic findings include Bazex and Rombo syndromes, xeroderma pigmentosum, and Muir-Torre syndrome.

Dermatologists who are familiar with their presentation, diagnosis, and management best manage BCCs. Failure to diagnose and correctly manage these tumors may lead to advanced disease and significant cosmetic deformity. A biopsy to confirm the diagnosis should be performed before treating any lesion.

Nodular basal cell carcinoma: Pearly papules with exaggerated telangiectasias and central ulceration within.

Superficial basal cell carcinoma: Erythematous, scaly plaques with sharply demarginated borders. This variant favors the trunk and extremities.

Pigmented basal cell carcinoma: Pearly papules/plaques with pigmentation and typical dermatoscopic findings.

Morpheaform basal cell carcinoma: Scar-like, indurated, skin-colored, erythematous, or hypopigmented papules or plaques with dermal infiltration and telangiectasias. This type tends to behave more aggressively, with extensive local destruction.

Differential Diagnosis

Actinic Keratosis

Bowen’s Disease (squamous cell carcinoma in situ): Erythematous, hyperkeratotic papules or plaques with slight induration and crusting.

Treatment: Basal Cell Carcinoma

Principles of Basal Cell Carcinoma Management

The initial evaluation of BCC includes a complete history and physical examination and biopsy of the suspicious lesion. The histologic subtype and anatomic location are important considerations in the management of BCCs and the determination of the optimal treatment. Although most subtypes are amenable to standard surgical excision, some, such as the infiltrative, morpheaform, and micronodular forms, are best treated with Mohs micrographic surgery. Superficial BCCs can be treated successfully with cryosurgery, curettage and electrodesiccation (C&E), topical imiquimod or 5-fluorouracil therapy, photodynamic therapy (PDT), or systemic therapy.

Optical coherence tomography (OCT) imaging is a new, alternative method for diagnosing BCCs noninvasively and monitoring them; however, the availability and use of this technology are limited to a few specialized centers around the world.

Initial Therapy

First-line therapy: Surgical excision

Surgical excision with a 4 mm margin of normal tissue is usually optimal. The specimen should be sent for a pathological evaluation to ensure adequacy of the excision. If the margins are positive, Mohs micrographic surgery or further resection with complete circumferential margin assessment should be performed. Surgical excision with margins has been reported to achieve 5-year disease-free rates of over 98% for BCC.

In cases when surgery is not possible (e.g., elderly persons, the debilitated, clinically indistinct margins or extensive areas) or contraindicated, radiation therapy can provide excellent results.

For superficial or small (under 1 cm) lesions of the trunk, cryosurgery and C&E provide an acceptable cure rate with good cosmetic outcomes. C&E scars may be unsightly, and so, this is not the preferred treatment for facial lesions and is not recommended for large primary BCC, morpheaform, or recurrent BCC. Complications of cryosurgery include scarring and postinflammatory pigmentary changes and should also be used with caution in cosmetically sensitive areas.

Indications for Mohs micrographic surgery:

  • BCCs ≥ 6 mm located in high-risk areas (central face, nose, lips, eyelid, eyebrows, periorbital skin, chin, mandible, ears, preauricular and postauricular areas, temples, hands, feet) or ≥ 10 mm in other areas of the face (cheeks, forehead, scalp, and neck) or tumors ≥ 20 mm on the trunk or limbs.
  • Aggressive pathological features include perineural invasion, morpheaform, basosquamous, sclerosing, mixed infiltrative, or micronodular forms in any portion of the tumor.
  • Recurrent BCCs.
  • Lesions with clinically indistinct margins.
  • Previously excised lesions in which histologic margins were positive.
  • Tumors that will require extensive reconstruction to repair the surgical defect.

Alternative Therapy

Curettage and Electrodesiccation (C&E)

  • C&E is the process of alternatively scraping away tumor tissue with a curette down to a firm layer of normal dermis and denaturing the area by electrodessication.
  • 5-year cure rate reported to be between 91% and 97% for select patients.
  • Not recommended in areas with terminal hair growth, such as the scalp, pubic or axillary region, and beard region in males, due to the high risk of the tumor extending down follicular structures.
  • If subcutaneous tissue is reached during the procedure, conversion to standard excision should be done.
  • Side effects include hypopigmentation and scarring.
  • The use of curettage alone or curettage followed by imiquimod has been reported; however, larger studies are needed to confirm the efficacy of these treatments.

Topical Imiquimod 5% Cream

Imiquimod is a Toll-like receptor 7 agonist, which induces interferon-alpha and other cytokines to promote Th1-type immunity.

  • In general, imiquimod is used for the treatment of primary superficial BCCs in low-risk sites.
  • The selection of imiquimod over surgical excision for superficial BCCs includes patient-specific factors, such as preference to avoid surgery and potential comorbidities that are associated with surgical excision.
  • Most studies on imiquimod recommend application 5 times per week for a total of 6 weeks, with histological clearance rates of 80% to 85% 12 weeks after treatment. Cure rates (no recurrence after 3 and 5 years) of between 81% to 84% have been reported.
  • Local reactions, including erythema, edema, pain, vesicles, ulceration, and eschar formation are observed frequently. Topical imiquimod can be associated with systemic effects, including fatigue and an influenza-like illness.
  • Close clinical follow-up in the following months is necessary to monitor for adequate treatment and tumor recurrence.

5-Fluorouracil (5-FU) 5% Cream or Solution

  • 5-FU is a topically applied chemotherapeutic agent that has been approved by the US FDA for the treatment of superficial BCCs. Application is daily for up to 12 weeks.
  • Local reactions including erythema, edema, pain, vesicles, ulceration, and eschar formation are observed frequently.
  • Close clinical follow-up in the following months is necessary to monitor for adequate treatment and for tumor recurrence.

Photodynamic Therapy (PDT)

  • Although it is not approved by the US FDA for the treatment of BCCs, PDT is approved for this use in some European countries and may be considered for patients with many or refractory lesions—especially for superficial BCCs and certain thin nodular BCCs when surgery is contraindicated. This treatment is not recommended for high-risk BCC.
  • Superficial BCCs respond well to PDT, with primary clearance rates of 92% to 97% at 12 weeks and a 9% recurrence rate at 12 months. Low-risk thin nodular BCCs that are treated with PDT should be monitored frequently for recurrence, because the efficacy is typically not as good.
  • The cosmetic outcome of this treatment is considered to be superior to that of surgery.
  • A topical photosensitizer (aminolevulinic acid, such as Levulan Kerastick, and methyl aminolevulinate,such as Metvix) is applied to the skin in the medical office and allowed to incubate for 30–60 minutes or up to 3 hours (depending on the photosensitizer) prior to exposure to a light source for approximately 10–15 minutes, during which destruction of the tumor cells occurs.
  • Several different light sources are currently available for the activation of the photosensitizer:
      • Aktilite: 630 nm red LED light, 37 J/cm2.
      • BLU-U: 417 nm peak emission, 10 J/ cm2.
      • RhodoLED: red LED light, 635 nm peak emission, 37 J/c cm2.
      • Other light sources that emit red light with a continuous spectrum of 570–670 nm.
      • Lasers provide an additional form of light source for activation with deeper penetration.
      • PDT using daylight has been shown to be successful in the treatment of actinic keratoses (AKs) but has not been studied for the treatment of BCCs.
  • Strict photoprotection is necessary for 48 hours after PDT to avoid excessive photosensitization.
  • Post-procedure erythema, edema, and inflammation are expected and may linger for 5–7 days after each treatment.
  • Several treatments, at 3- to 4-week intervals, may be required.
  • Before the photosensitizer is applied, skin lesionsshould be prepared by removing superficial scale and crust by curettage; other techniques include topical keratolytics, tape stripping, microdermabrasion, fractional CO2laser, microneedling, and elevation of skin temperature.
  • There are many variables that are associated with the efficacy of PDT, including irradiance, light source, photosensitizer, incubation time, skin preparation, frequency of treatments, and exposure time of light source. Therefore, close follow-up is needed to assess the efficacy and to monitor for recurrence.

Radiotherapy (RT)

  • Different techniques of RT can be used in the treatment of BCC, including electron beam radiation therapy (EBRT) and brachytherapy (BT),
  • RT should be considered for older patients (> 70 years), patients with a preference for non-surgical treatments, and poor surgical candidates  including those who receive medications that affect coagulation and platelet function and those with significant comorbidities.
  • Tumors in locations that are considered not ideal for surgery, including nasal ala, nasal tip, nasal bridge, lower eyelid, medial canthus, and helix, and large, deep, or inoperable lesions, including those that extend into the cranial cavity, may be considered for RT.
  • RT can also be used preoperatively or postoperatively as adjunctive therapy for certain BCCs or patients.
  • RT should be avoided in younger patients for whom other treatment options are available, due to the many unwanted long-term side effects of radiation, such as permanent alopecia, radiation dermatitis, and a high risk for future NMSCs.
  • RT has local control rates of 90% to 95%, making it a cosmetically and functionally suitable treatment option.
  • The appropriate dose and schedule of therapy depend on the patient, type of radiation treatment, and tumor factors.
  • A field margin of 5–10 mm beyond macroscopic disease or a surgical site is usually adequate.

Vismodegib

  • Hedgehog inhibitor for the treatment of advanced local or metastatic basal cell carcinoma.  Vismodegib has also been used for treatment and prophylaxis in patients with nevoid BCC syndrome (Gorlin syndrome).
  • Significant side effects include teratogenicity, muscle spasms and dysgeusia (often associated with significant weight loss), alopecia, asthenia, diarrhea, nausea, and fatigue.
  • Mean duration of therapy is 36 weeks.

Sonidegib

  • Another hedgehog pathway inhibitor that is also approved by the FDA for the treatment of patients with locally advanced BCC that has recurred following surgery or radiotherapy or who are not candidates for surgery or radiotherapy.
  • Similar objective response rate between 200 mg/day and 800 mg/day, but the higher dose is associated with greater adverse effects.
  • Common adverse effects include muscle spasms, dysgeusia, alopecia, nausea, weight decrease, and fatigue. Elevated creatinine is also frequently observed and is one of the most common Grade 3–4 adverse events, along with elevated lipase. 

Subsequent Therapy

  • Patient education with respect to pathogenesis and natural history of BCCs is essential. Sun protection must be stressed.
  • Monitoring for recurrence as well as new lesions during the first 2 years after diagnosis is very important. A total of 30% to 50% of patients with prior BCC will develop another BCC within 5 years.
  • Patients with a history of BCC should have a full-body skin examination every 6 months during the first 2 years. An annual full-body skin examination thereafter is indicated to identify future development of tumor recurrence and new skin cancers.

Basal Cell Nevus Syndrome (Gorlin Syndrome)

Basal cell nevus syndrome is a rare, autosomal dominant condition that is characterized by early onset BCCs. Patients may develop hundreds of BCCs over a lifetime, varying in size from a pinpoint to > 5 cm. Associated findings include palmar or plantar pits, skeletal deformities, teeth/jaw abnormalities (cysts), and, rarely, the development of tumors in other organs, in addition to skin. Significant cosmetic disfigurement may result from skin cancers and their multiple treatments, and frequent clinical evaluation is necessary for close monitoring for tumor recurrence and development of new lesions.

Initial Therapy

  1. Surgical excision of all tumors is the best therapy and is performed if possible following the guidelines for the management of routine BCCs.
  2. Genetic counseling and examination of family members are important.
  3. Strict sun protection (avoidance) must be stressed.
  4. Evaluate the patient for associated conditions, especially jaw cysts and malignancies.

Subsequent Therapy

  • PDT may be helpful for field treatment of multiple lesions and early treatment of clinically occult lesions.
  • RT is not indicated for patients with basal cell nevus syndrome and for morpheaform BCCs, which are relatively radioresistant, and radiation itself may lead to future NMSCs in this already vulnerable population.
  • Vismodegib and sonidegib may be considered for the treatment of multiple and/or aggressive BCCs; however, the age and reproductive ability of the patient should be considered prior to the start. Significant side effects including teratogenicity, muscle spasms, dysgeusia (often associated with significant weight loss), alopecia, diarrhea, nausea, and fatigue may limit the use of these drugs.

Pitfalls

  • Do not underestimate the potential for cosmetic disfigurement due to BCC. Attempts should be made to identify lesions early and to eradicate each one completely.
  • In the case of a non-healing ulcer on the skin, always exclude the diagnosis of a skin tumor.
  • Following surgical removal of skin tumors, a histopathological examination is necessary to confirm the clinical diagnosis and excision margins.
  • RT should be avoided in younger patients, patients with basal cell nevus syndrome, and those with DNA repair deficiencies, such as xeroderma pigmentosum (XP), due to an increased risk of NMSC in these patients.

Initial Evaluation

Squamous Cell Carcinoma

Predisposing factors for squamous cell carcinoma (SCC) include precursor lesions (actinic keratosis [AK], Bowen disease), UV exposure, ionizing radiation, environmental carcinogens (arsenic), immunosuppression (especially organ transplant recipients), scars, burns, human papillomavirus (HPV), and certain genodermatoses (xeroderma pigmentosum, albinism).

SCCs of the skin often have several key clinical features, including:

  • Hyperkeratotic, erythematous papules and plaques.
  • Superficial ulcerations.
  • Typical occurrence on sun-exposed areas.

SCCs carry a higher risk for metastasis than BCCs. Paresthesias, anesthesia, and pain may be signs of perineural invasion.

Dermoscopy of invasive SCC reveals linear irregular vessels, elongated vessels that resemble hairpins, dotted vessels, or a combination of these findings.

SCCs may cause local tissue destruction and have significant potential for metastasis. They can be divided into two groups: lesions with a low risk for metastases and those with a higher risk for metastases.

  • Low-risk SCCs are those that arise from AKs (not of the lower lip) in immunocompetent persons or SCCs that develop on the trunk and extremities.
  • High-risk SCCs are those with a diameter greater than 2 cm, occurring in sites of chronic ulceration or arising in scars (Marjolin ulcer), following RT, occurring on the lower lip or temple, genitalia or “H” areas on the face, lesions with histological features of perineural or perivascular invasion, absence of inflammatory infiltrate, and those that occur in immunosuppressed patients (especially renal transplant patients).

Differential Diagnosis

Actinic Keratosis

Superficial Basal Cell Carcinoma: An erythematous scaly plaque with a sharply demarginated border.

Treatment

Principles of Squamous Cell Carcinoma Management

The diagnosis of SCC is based on biopsy; a superficial biopsy may reveal only an in situ (epidermal) component and may miss the invasive component that is underlying or adjacent to the area of the biopsy. Close clinical follow-up is therefore necessary.

Initial Therapy

First-line therapy: Surgical excision

  • For lesions < 2 cm, a 4–6 mm margin is recommended.
  • For lesions ≥ 2 cm or with other high-risk features (histologic grade ≥ 2, invasion of subcutaneous tissue), a 9 mm margin is recommended.
  • Pathologic evaluation of the margins should be performed to ensure adequacy of resection.
  • Surgical excision has demonstrated cure rates with long-term follow-up (> 5 years) of 91% or higher.
  • Careful palpation of regional lymph nodes before surgery is required. If there are palpable lymph nodes or abnormal lymph nodes that are identified by imaging studies during the initial evaluation, fine needle aspiration (FNA) or biopsy is recommended to assess for metastatic disease.
  • Imaging for staging should be performed if any concern for metastasis exists.
  • Mohs micrographic surgery is recommended for high-risk squamous cell carcinoma.
  • Sentinel lymph node biopsy (SNLB) for high-risk patients can be considered; however, the criteria for selecting patients for SLNB are unclear.
  • Adjuvant chemotherapy for patients with high-risk SCC post-surgery or as a supplement to RT in non-surgical candidates can be considered. Although there are no drugs that are currently approved by the FDA specifically for the treatment of cutaneous high-risk SCC, off-label use of 5-fluorouracil/cisplatin, paclitaxel/cisplatin, or 5 fluorouracil/carboplatin has been reported with mixed results. Sustained remission is low, and the tolerability of these agents can be a challenge, particularly in older, frailer patients.
  • Targeted immunologic therapies can be considered, because they show promising results. Epidermal growth factor receptor inhibitors, such as cetuximab, have been FDA-approved for the treatment of locally or regionally advanced mucosal SCC of the head and neck and may be used off-label for cutaneous SCC. Anti-programmed cell death protein 1 inhibitors, including nivolumab and pembrolizumab, have been used for unresectable cutaneous SCC.

Alternative Therapy

  • Mohs surgery can be considered in some cases.
  • Destructive measures (curettage and electrodesiccation or cryotherapy) may be used in the treatment of low-risk SCCs, but they are not optimal, because they do not provide margins for pathologic confirmation of adequacy of resection. Retrospective and observational data with long-term follow-up (> 5 years) report cure rates of between 95% and 96%, (mostly low-risk SCC). Curettage and electrodesiccation should not be used in areas with terminal hair, such as the scalp, groin and axillary region, and the beard region in males.
  • For large high-risk lesions in patients who are not good surgical candidates, and in patients with multiple lesions, RT may be considered.
  • Adjuvant radiation may be considered for SCC with large nerve involvement or with positive margins after definitive surgery. Many studies suggest that postoperative RT for patients with perineural invasion may improve local control.
  • Superficial therapies, including imiquimod and 5-fluorouracil, should be reserved for patients with SCC in situ due to their poor penetration beyond the epidermis. SCC in situ that is treated with imiquimod has shown a clearance rate of 73%. Slightly lower clearance rates have been shown with 5-fluorouracil.
  • Patients with multiple and/or clinically aggressive lesions may require systemic retinoid therapy (acitretin, such as Soriatane) for chemoprophylaxis of future recurrence or development of primary lesions. Low doses of these agents may be given with informed consent. Therapy must be lifelong. Chronic toxicity, especially skeletal, has limited the effectiveness of the retinoids.

Subsequent Therapy

  • Close clinical follow-up, with careful examination of the surgical site, draining lymph nodes, and the rest of the patient’s exposed skin should be performed.
    • Patients with low-risk cutaneous SCC, monitoring for recurrence or new cancers should occur at least every 3 to 6 months during the first 2 years after initial diagnosis. If no recurrence or new lesions, then exams should occur every 6 to 12 months for another 3 years, then annually for life.
    • For patient with high risk SCC, monitoring for recurrence should occur every 1 to 3 months for 1 year, then every 2 to 4 months for 1 year, every 4 to 6 months for another 3 years, and then every 6 to 12 months for life.
    • For patients with regional disease, surveillance using CT with contrast may be warranted to screen for recurrence in the regional lymph node basin or distant metastatic disease.
  • Because these lesions are usually found on sun-exposed areas and because photodamage is likely an important factor in the pathogenesis of SCC, photoprotection should be emphasized.

 Prophylaxis for High-Risk SSC Patients

  • For patients with a high risk of field cancerization, topical options include 5-FU, imiquimod, ingenol mebutate, diclofenac, and topical retinoids.
  • For large areas, 5-FU is the topical treatment of choice, because other agents (e.g., imiquimod) come in small packages and can lead to cytokine release and subsequent systemic effects when used over large surface areas.
  • There are mixed results on the use of topical retinoids, with some studies showing a reduction in AKs and others showing no difference.
  • Photodynamic therapy with 5-aminolevulinic acid or methylated aminolevulinate has been used successfully for the treatment of superficial SCC and AKs, although with less efficacy than surgery. Activation with blue light was approved by the US FDA in 2001, and more recently, the use of daylight PDT has had equal results but has generated less pain.
  • Nicotinamide, an amide form of vitamin B3, enhances the repair of UV-induced DNA damage. In a randomized trial in Australia, the use of daily nicotinamide demonstrated reduction in new SCCs and AKs. Side effects are minimal, but patients must avoid combining it with niacin, which can lead to flushing.

Initial Evaluation  

Keratoacanthoma

Keratoacanthomas are rapidly-growing (within a few weeks) nodular proliferations of keratinocytes that may represent a variant of squamous cell carcinoma. In some cases, lesions are self-involuting over a period of several months. There are several distinct clinical presentations of keratoacanthomas, including solitary, multiple, and grouped. Congenital conditions that are associated with multiple keratoacanthomas include Muir-Torre syndrome, Ferguson-Smith, and Grzybowski. In addition, BRAF inhibitors and HPV infection have been reported to be associated with multiple keratoacanthomas.

KAs should be monitored closely for complete involution or, alternatively, managed with complete surgical excision or alternative therapies, as discussed previously.

 

Keratoacanthoma: Dome-shaped, crateriform hyperkeratotic nodule on sun-exposed skin.

Initial Evaluation

Bowen’s Disease (Squamous Cell Carcinoma in Situ)

The eponym “Bowen’s disease” is used to describe squamous cell carcinoma in situ on any cutaneous surface except the glans penis. It bears several clinical features:

  • Bowen’s disease may occur on sun-exposed sites, on extragenital sites where actinic lesions are rare (palms, trunks of persons with no history of sun exposure), in the genital region, and on the glans penis (erythroplasia of Queyrat or penile intraepithelial neoplasia [PIN]). In contrast to actinic keratosis, the basal cells of SCC in situ are normal.
  • Bowen’s disease of atypical and sun-protected sites may be associated with exposure to arsenic.
  • When sun-protected Bowen’s disease develops into SCC, it may be more aggressive than actinically induced Bowen’s disease.
  • When Bowen’s disease occurs in the genital area, it is often associated with infection with tumorigenic human papillomavirus (HPV) strains type 16 and 18, as is PIN. These genital SCCs are more aggressive than actinically induced SCCs.
  • Multifocal Bowen’s disease, especially of the lower extremities, is a significant problem in organ transplant recipients and other immunocompromised individuals. They must be managed with care, because progression to carcinoma and aggressive behavior of the ensuing SCCs is the rule.
  • Untreated, Bowen disease may progress to invasive squamous cell carcinoma.

Bowen’s Disease: Erythematous, hyperkeratotic plaques with slight induration and crusting.

Differential Diagnosis

Actinic Keratosis

Superficial Basal Cell Carcinoma: An erythematous scaly plaque with a sharply demarginated border.

Treatment

Principles of Squamous Cell Carcinoma In Situ Management

The diagnosis of SCC in situ requires a biopsy; clinically, these lesions may resemble actinic keratoses or squamous cell carcinoma. SCC in situ may develop de novo or from a preexisting AK; the head and neck are the most common sites. In the anogenital region, SCC in situ may display prominent erosions. In larger lesions, a partial biopsy is sometimes the most feasible option, but it carries the risk of missing an underlying or adjacent invasive component.

Initial Therapy

First-line therapy: Surgical excision

  • As with invasive SCC, complete surgical excision with 4-6 mm margins is the preferred therapy when feasible. This may require staged excision.
  • For smaller lesions of SCC in situ on the trunk (under 1 cm), curettage and electrodesiccation (C&E) in areas without terminal hair growth and with close clinical follow-up is appropriate.
  • Lesions with indistinct clinical margins or on the face, especially adjacent to the eyelids, nose, or lips, should strongly be considered for Mohs micrographic surgery as a tissue-sparing treatment and for complete excision.
  • Imiquimod 5% cream, applied 5 times a week for 6 weeks, may be attempted. The area will become erythematous and may erode.
  • In recent studies, the use of ablative fractional laser to aid in the penetration of 5-fluorouracil that is applied daily for 7 days has shown similar cure rates to topical 5-FU for 6 weeks.
  • Erythroplasia of Queyrat: topical 5-FU and imiquimod are treatment options.
  • According to prospective studies, PDT with photosensitizing agents, including ALA and MAL, has reported cure rates of between 48% and 98%.

Alternative Therapy

  • For lesions that are not easily excised and in patients who are not good surgical candidates, radiation therapy may be used.
  • Cryotherapy with thermocouple control, as done for other cutaneous carcinomas, may be curative. Recurrence rates after cryotherapy range from 1% to 13% in retrospective studies and 0% to 50% in prospective studies.
  • Retrospective studies have reported recurrence rates of between 0% to 10.5% for in situ SCC that has been treated with RT as the primary therapy; most studies report local control rates of near 100%.

Pitfalls

  • Although a small biopsy from a large lesion may reveal Bowen’s disease, invasive squamous cell carcinoma may be present in another part of the lesion. Therapies that do not involve a pathologic review may miss this and lead to inadequate therapy.
  • Bowen’s disease may occur in non-sun-exposed areas and can be confused for inflammatory skin conditions, such as psoriasis. Fixed plaques that do not respond to topical treatment should be biopsied.

For Primary Care Physicians

  • Patients at risk for skin cancer should be referred to a dermatologist for yearly routine skin exams.
  • Patients with suspicious lesions should be referred for evaluation and biopsy as soon as possible.
  • Refer patients requiring Mohs micrographic surgery or photodynamic therapy.
  • For management of patients with large, clinically aggressive, metastatic, or multiple lesions; recurrent NMSC; or for management of multiple NMSC diagnosed in the setting of immunosuppression, refer to a dermatologist.

Clinical Cases

Case 1

  • 42-year-old man with a slowly-enlarging lesion on the right infraorbital cheek
  • No prior history of skin malignancy
  • Patient is otherwise healthy
  • Skin exam: 5 x 7 mm pearly plaque with central dell and prominent telangiectasias; a full-body skin examination does not identify any other suspicious lesions
  • Biopsy reveals nodular and micronodular BCC

Initial therapy

Referral for Mohs surgery with repair (indications: histopathology, proximity to eye)

Follow-up

  • 3 months for full-body skin examination
  • Photoprotection recommended

Case 2

  • 50-year-old woman with a scaly lesion on the back of unknown duration
  • No prior history of skin malignancy
  • Patient is otherwise healthy
  • Skin exam: 8 x 8 mm sharply-demarcated pink plaque with minimal scale; a full-body skin examination does not identify any other suspicious lesions
  • Biopsy reveals superficial BCC

Initial therapy

  • The patient is offered surgical excision, photodynamic therapy, and imiquimod cream treatment and opts for imiquimod
  • Imiquimod 5% cream is applied daily to the lesion for 6 weeks
  • Follow-up evaluation at 8-12 weeks

Follow-up

  • The patient reports significant erythema, crusting, and inflammation at the site of imiquimod application, which has now subsided. There is no evidence of persistent skin cancer at the treatment site
  • A full-body skin examination is performed and does not identify any other suspicious lesions
  • Follow-up evaluation at 3-6 months for full-body skin examination
  • Photoprotection recommended

Case 3

  • 47-year-old man presents for evaluation of a new lesion on the arm that has been growing over 3 months
  • No prior history of skin cancer
  • Patient is otherwise healthy
  • Skin exam: 1.2 x 0.8 cm pearly plaque with telangiectasias on the right arm; a full-body skin examination does not reveal additional suspicious lesions
  • Biopsy reveals: nodular BCC

Initial therapy

  • Surgical excision with 3mm margins with complex linear closure; the excisional specimen is sent to pathology to determine adequacy of surgical margins
  • Follow-up in 2 weeks for suture removal and again at 3 months for full-body skin examination

Follow-up evaluation at 3 months

  • A full-body skin examination is performed, and no suspicious lesions are identified.  The surgical excision is well healed without evidence of recurrence
  • Photoprotection recommended
  • Follow-up evaluation at 3-6 months for full-body skin examination

References

Basset-Seguin, Hauschild A, Grob JJ, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open label trial. Lancet Oncol. 2015; 16(6): 725-736. doi: 10.1016/S1470-2045(15)70198-1

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