Mohs Micrographic Surgery: Evaluation and Treatment of Nonmelanoma Skin Cancer

Etiology

UV radiation is the major risk factor for developing NMSC because it creates pyrimidine dimers, which link pyrimidine nitrogenous bases, thereby compromising DNA's structural integrity and often leading to mutations.[2] UV exposure also leads to the generation of reactive oxygen species, which are toxic to DNA and induce damage over time. Mutations to specific genes can increase the risk for BCC or SCC.[2] Individuals with lighter Fitzpatrick skin types are at greater risk of DNA damage from UV radiation than those with darker Fitzpatrick skin types. Please see StatPearls' companion resource, "Sunburn", for further information on this skin type classification. This is due to melanin, the pigment in the skin, which plays a protective role against skin cancer.

Melanin helps absorb and neutralize UV radiation, thereby reducing the risk of DNA damage in skin cells.[2] Consequently, individuals with lower Fitzpatrick skin types experience more DNA mutations and a higher incidence of skin cancer. Furthermore, UV damage accumulates with age and increased lifetime sun exposure, elevating the risk of developing NMSC cancer.

Various risk factors contribute to the cumulative damage leading to NMSC. Occupational hazards are especially significant in industries, eg, agriculture and construction, where exposure to air pollutants and polycyclic aromatic hydrocarbons (PAHs) found in coal tar, tobacco smoke, and fossil fuels is strongly linked to BCC and SCC.[3] Additionally, certain environmental risk factors are associated with these cancers. Ionizing radiation is primarily associated with BCC, while arsenic exposure has a stronger correlation with SCC.[3]Moreover, underlying medical conditions, especially those involving immunodeficiency or malignancies, can also increase the risk of developing NMSC, particularly with prolonged exposure to environmental carcinogens.[1] The use of specific pharmacological agents, especially immunosuppressants, is another important risk factor, further increasing susceptibility to these skin cancers.

Epidemiology

The incidence of both BCC and SCC has been steadily increasing over time. Between 1976 and 2010, BCC rates rose from 222 to 321.2 cases per 100,000 person-years, while SCC rates jumped from 61.8 to 162.5 per 100,000 person-years. In 2019, the mortality rate for SCC was 0.8 per 100,000 person-years, while BCC had no recorded mortality in that year.[4][5][6][7]

Pathophysiology

Chronic and intense sun exposure is the primary risk factor for developing NMSC. SCC arises from UV radiation-induced DNA damage in keratinocytes within the epidermis, leading to the formation of thymidine dimers and mutations in the TP53 gene. TP53, a tumor suppressor gene, plays a crucial role in inducing apoptosis of damaged or abnormal keratinocytes.[8] Without TP53, often called the “guardian of the genome,” mutated keratinocytes can proliferate, progressing to actinic keratoses (precancerous growths) or cutaneous SCC. Similarly, BCC results from prolonged UV exposure, frequently involving mutations in the PTCH1 gene. When PTCH1 is mutated, it fails to block the smoothened (SMO) protein, allowing activation of Gli transcription factors and leading to the unchecked growth characteristic of BCC.[Sauer's Manual of Skin Diseases] This mutation drives the uncontrolled proliferation of mutated cells. Both SCC and BCC underscore the significant role of UV radiation in their pathogenesis, though each has distinct underlying genetic mechanisms.[9][10]

Histopathology

SCC exhibits distinct histopathological features based on its stage and subtype. Actinic keratoses, often considered precursors to SCC, show characteristic findings, eg, alternating parakeratosis with orthokeratosis (the "flag sign") and atypical keratinocytes limited to the lower one-third of the epidermis. In contrast, SCC in situ, or Bowen's disease, is defined by full-thickness atypia within the epidermis. Invasive SCC shares the full-thickness atypia seen in Bowen's disease but is distinguished by its extension into the dermis.[11]

BCC also presents with distinct clinical and histopathological subtypes. Common features include nests of basaloid cells with peripheral palisading, a fibromyxoid stroma, and stromal retraction from the epithelium.[12] While nodular BCC is the most common histopathologic type, more aggressive variants, eg, micronodular BCC and basosquamous carcinoma, are also histologically differentiated.[Sauer's Manual of Skin Diseases] These aggressive forms require prompt and more intensive treatment due to their higher risk of recurrence and invasion.[James WD, Elston DM, Treat JR, Rosenbach MA, Neuhaus IM. Sauer's Manual of Skin Diseases. 11th ed. Philadelphia, PA: Wolters Kluwer; 2017]

History and Physical

NMSCs show distinct clinical presentations depending on their subtype. Generally, patients may describe a slow-growing, scaly, erythematous papule that resembles a “pimple” or a “dry patch” that does not resolve. Symptoms associated with these lesions, including tenderness, spontaneous bleeding, or a waxing and waning appearance, may be reported. The classic presentation of BCC is a pink, pearly papule with surface telangiectasias and rolled borders. BCCs can be locally destructive and may ulcerate, leading to what is known as a rodent ulcer. These lesions are most often found on sun-exposed areas, with the face being particularly common. In contrast, SCC frequently appears as an erythematous, hyperkeratotic papule or nodule and may occasionally develop a prominent hyperkeratotic horn. SCC can also cause local destruction, with ulceration and significant tenderness frequently reported by patients.[13]

Additionally, the location of the lesion provides important diagnostic clues. For instance, BCC commonly arises in sun-exposed areas, eg, the face (particularly the nose and upper lip), ears, neck, scalp, and back.[14] SCC, on the other hand, is typically found on the face (especially the lower lip), ears, scalp, and dorsal upper extremities.[15] Furthermore, dermoscopy can significantly enhance diagnostic accuracy during physical examinations. Dermoscopy enables the detailed visualization of pigment and vascular structures through magnification and optimized lighting, providing insights that are not visible to the naked eye, particularly when used by experienced practitioners.[16]

Evaluation

Clinical diagnostic findings are essential for evaluating suspicious skin lesions. However, a skin biopsy is crucial for confirming a diagnosis of NMSC and identifying the specific subtype, which guides further management. Although BCC rarely metastasizes, SCC carries a higher risk of metastasis, especially when located in certain areas of the face, eg, the lips or ears. Therefore, in cases of SCC, especially those with large or advanced lesions, regional lymph nodes should be palpated to assess for possible spread. If metastasis is suspected, additional imaging may be indicated to evaluate the extent of involvement in other organs.

Treatment / Management

The primary treatment for most NMSC is surgical excision. Depending on the location and need for tissue preservation and cosmetic outcomes, Mohs micrographic surgery has become the gold standard of care for NMSC.[13] For especially large or advanced lesions that are challenging to excise, or for patients who are not surgical candidates, other therapies, eg, radiation and immunotherapy treatments, may be used either as adjuncts or as monotherapy.

Differential Diagnosis

BCC commonly presents as a pearly, pink papule with overlying telangiectasias. However, various benign and malignant skin conditions can mimic BCC. For instance, sebaceous hyperplasia appears as skin-colored, yellow, or pink papules, often with telangiectasias, and is commonly found on the faces of older patients. Superficial variants of SCC can also closely resemble BCC, as both lesions may cause erosion or ulceration, blurring their typical presentations. Molluscum contagiosum, a common poxvirus infection in children, manifests as dome-shaped pink papules with central umbilication; when irritated or lacking central umbilication, these lesions can be mistaken for BCC. Fibrous papules, benign growths of fibrous tissue, often present as pink or red papules with telangiectasias, most frequently on the face and nose. Finally, melanoma can appear in various colors—black, blue, pink, red, or white—potentially resembling a pigmented BCC. While some BCC lesions contain black pigment, they often have a translucent, glass-like surface.[17][18] When a lesion appears atypical, particularly if pigmented, a biopsy is essential to avoid missing a diagnosis of melanoma.[18]

SCC typically presents as a scaly or hyperkeratotic erythematous papule and may resemble a nonhealing wound. Actinic keratosis, a precursor to SCC, appears as a pink to erythematous, hyperkeratotic papule with a rough, sandpaper-like texture. These lesions can become more prominent and are often biopsied due to suspicion of SCC. Advanced BCC may also mimic SCC, and verruca vulgaris (ie, common warts), caused by human papillomavirus, present as hyperkeratotic papules. Verruca vulgaris is typically flesh-colored and may display thrombosed capillaries on dermoscopy, aiding in differentiation from SCC. Seborrheic keratosis, a benign lesion often tan, brown, or black, can become irritated and resemble the erythematous papules seen in SCC. In some cases, malignant lesions may arise adjacent to benign lesions (eg, seborrheic keratoses), prompting a biopsy when the presentation is atypical.[19][20]

Surgical Oncology

Appropriate use criteria for Mohs micrographic surgery were developed through a collaboration of physicians in the United States to guide clinical decision-making regarding the treatment of neoplastic disorders encountered by dermatologists. The appropriate use criteria consider factors, eg, the type of neoplasm, the location on the body, the size of the lesion, and the presence of aggressive or significant subtypes identified in pathology.

The ppropriate use criteria defines the following 3 body regions:

• Area H represents the central face (eyes, nose, mouth, and immediate surrounding areas), temples, ears, areola, hands, feet, genitals, and the gluteal cleft.
• Area M includes the malar cheeks, forehead, scalp, posterior head, entire neck, and anterior lower legs.
• Area L encompasses the rest of the body (arms, trunk, abdomen, upper legs, and posterior lower legs).

The appropriate use criteria provide a score based on the type of cancer, location, aggressive features, and size. A score of 1 to 3 indicates inappropriate use of Mohs, 4 to 6 indicates uncertain use, and 7 to 9 indicates appropriate use of Mohs.[16][21]

Radiation Oncology

While surgical excision is the preferred method of treatment for nonmelanoma skin cancer, radiation does play a significant role in the management of nonmelanoma skin cancer. Radiation can be used as adjuvant therapy for nonmelanoma skin cancer in cases of prior surgical removal with persistent positive margins that is not again amenable to reexcision, in cases of high recurrence rate (eg, perineural or lymphatic involvement), extremely large tumors, or deeply invasive tumors with involvement of bone or other deep structures.

Radiation serves as an alternative option for patients who do not want to undergo a surgical procedure. Local control rates of BCC have been reported to be between 86% and 92%, with SCC showing similar 5-year rates.[22] Many patients report good cosmetic outcomes, but radiation dermatitis is a common adverse effect of radiation and can be both symptomatic and cosmetically unpleasant for many patients.[22]

Treatment Planning

Planning the treatment for NMSC involves careful consideration of patient demographics, tumor stage, anatomical location, and the histopathologic subtypes of BCC and SCC.[12] For patients prioritizing aesthetic, functional, and medical outcomes, Mohs micrographic surgery is the preferred approach, offering precise margin control and tissue conservation.[23][24] However, the procedure’s complexity and duration may limit its availability, particularly in underserved areas. For less sensitive locations or where aesthetics is less critical, wide local excision may be a viable alternative.

Moreover, the variant and stage of the cancer are crucial in determining the treatment plan. Aggressive subtypes, including infiltrative, sclerosing, morpheiform, and micronodular BCC, require timely surgical intervention due to their invasive nature. In contrast, superficial BCC, which often involves broader, cosmetically sensitive areas, may be better managed with alternative treatments. These treatments include, but are not limited to, electrodessication and curettage, imiquimod, 5-fluorouracil, and photodynamic therapy.

For high-risk, nonresectable tumors, therapies, eg, hedgehog pathway inhibitors, including vismodegib and sonidegib, are particularly effective for advanced cases, along with potentially PD-1 inhibitors, which have shown promise in improving patient tolerance and outcomes.[23] Radiation can be an effective therapy for these tumors. The modality of radiation used is based on the tumor type and its location. The same applies to SCC, where Mohs micrographic surgery remains the gold standard, especially since SCC carries a higher risk of growth and metastasis compared to BCC.[25] While patients may still opt for wide local excision, topical agents such as the protein synthesis inhibitor 5-fluorouracil are typically reserved for the precursors to SCC, known as actinic keratoses.

Consideration of the degree of immunosuppression in patients and any possible history of inflammatory disease is also vital.[25] Moreover, the age of a patient is a critical demographic to consider, as this is often linked with other comorbidities that may not be optimal for surgical intervention.[26] Consideration of the tendency for women to have higher postsurgical survival rates, given their full medical history and risk factor profile, could also be relevant.[26]

Medical Oncology

Medical oncology plays an important role in the management of NMSC for patients who may not be candidates for surgery or radiation due to metastasis or very advanced cancers. Occasionally, a combination of surgery, radiation, and medical oncology will all play a role in managing nonmelanoma skin cancer. Patients should always be evaluated on a case-by-case basis, and the best plan should be tailored to their specific needs.

In the case of metastatic or locally advanced SCC, current guidelines recommend immunotherapy with programmed death 1 (PD-1) inhibitors, eg, cemiplimab, nivolumab, or pembrolizumab.[27] For locally advanced BCC, hedgehog inhibitors are the treatment of choice, including vismodegib and sonidegib. For metastatic BCC, vismodegib is the first-line choice. For patients who cannot tolerate a hedgehog inhibitor due to adverse effects, cemiplimab is currently the second therapy.[27]

Staging

Staging for cancers typically involves the use of the tumor, node, metastasis (TNM) classification model developed by the American Joint Committee on Cancer.[15][26] “T” is divided into 4 stages (T1 to T4) to indicate increasing depth and extension of the tumor at the original site.[26] “N” indicates lymph node involvement, and “M” indicates metastasis and illustrates the extent of spread throughout the whole body.[26] N and M categories each include at least 2 levels (0 and 1) to indicate the presence or absence of cancer spread.[28]

Furthermore, BCC can be staged and evaluated by employing the European Association of Dermato-Oncology classification [28], which categorizes BCC into the following 5 practical patterns:

1. Common BCCs that are low-risk
2. BCCs considered difficult to treat for a variety of reasons (eg, numerous BCCs to be treated, location, or patient comorbidities)
3. Large or destructive tumors, which are less functionally significant or outside critical areas
4. Metastatic or very large or destructive tumors in critical or functionally significant areas (eg, nose, periorificial regions)
5. Deeply invasive tumors or those that encompass a higher percentage of body surface area (BSA), affecting extracutaneous tissues [29] 

Additionally, cutaneous SCC can be staged using the Brigham and Women’s Hospital staging system.[7][30] This staging tool stages tumors from T1 to T3 and assesses overall risk.[26] Tumors classified as T2b and T3 are considered high-risk due to their association with over a 20% risk of nodal metastasis.[24] Factors considered by the Brigham and Women’s Hospital system include a tumor diameter of ≥2 cm, poor histologic tumor differentiation at a cellular level, perineural invasion of ≥0.1 mm, and tumor invasion beyond subcutaneous fat.[7]

Prognosis

SCC accounts for approximately 20% of all skin cancers in the United States.[31] Treatment of SCC with Mohs micrographic surgery is highly effective, with reports indicating a 5-year cure rate of approximately 99%, even for aggressive subtypes.[32] BCC is the most common skin cancer, and with proper therapy, including Mohs micrographic surgery, 5-year cure rates are also very high at about 97% to 98%.[33] This underscores the prognostic advantages of Mohs micrographic surgery, particularly given evidence directly comparing it to surgical excision. For instance, a study by van Loo et al reveals a significant difference in recurrence over 10 years, with surgical excision showing a 12.2% recurrence rate compared to only 4.4% with Mohs micrographic surgery.[34] Additional prognostic factors to consider include patient comorbidities, extent of risk factor exposure, age, gender, and postoperative care.[26]

Complications

Complications from Mohs micrographic surgery are rare but align with the common risks associated with surgery. One primary concern is bleeding, particularly since many procedures are performed on the face, where major arteries are located. Due to the vascular anatomy of this area, surgeons must exercise extra caution to avoid injuring these vessels and to minimize bleeding risks.[35] A postoperative concern of bleeding includes the formation of a hematoma. Hematomas can present as a swelling mass at the site of surgery and may include sensations of pressure and pain. Hematomas can be emergencies if they involve the eye, which can lead to blindness, or the neck, which may occlude the patient's airway. Early-presenting hematomas can be aspirated using a 16- or 18-gauge needle. Older hematomas may become thick and adherent to surrounding tissue and thus cannot be aspirated; these will usually again become liquefactive and can be aspirated at a later date (about 2 weeks postoperatively).[36]

Infection is another potential complication when the skin's barrier is breached. However, infection rates associated with Mohs surgery are low, with national rates in the United States being less than 2%.[37] Special precautions may be necessary for high-risk patients to further decrease the likelihood of infection.

Nerve damage is a recognized risk in dermatologic surgery, often presenting as temporary numbness or tingling in the area surrounding the excised site. In most cases, sensation returns within 6 to 8 months as cutaneous nerves regenerate. Surgeons must also be cautious of "danger zones" on the face and neck where nerves and arteries are more vulnerable. These zones include areas associated with the 5 branches of the facial nerve. Another commonly referenced area is Erb's point in the lateral neck, which is at risk for injury to the spinal accessory nerve. This landmark is located by drawing a line between the mastoid process and the angle of the jaw, then measuring 6 cm inferior to the midpoint.[38]