The gold standard remains surgical excision with or without histologic incision margin control, although Mohs surgery offers many advantages. If excision is impossible or incomplete, radiotherapy is an alternative. Topical therapies can be used for superficial low-risk basal cell carcinoma, and systemic therapies can be used for unresectable exceptions.
Basal cell carcinoma is by far the most common malignant skin tumor in humans. Due to changes in recreational behavior and increased UV exposure, the incidence has increased sharply in virtually all countries in recent years. Data from Holland, for example, show a sixfold increase in the incidence of new basal cell carcinomas during the last 35 years [1]. Basal cell carcinoma virtually never metastasizes, but can cause significant morbidity due to invasive and destructive growth if inadequately treated.
Diagnostics and risk stratification
The diagnosis of basal cell carcinoma is usually easy to make clinically if the typical aspect of nodular skin-colored tumor with pearly shiny surface, telangiectasia in the peripheral area and central ulceration are present. Dermoscopic criteria help in confirming the diagnosis. However, certain histologic subtypes are much more difficult to diagnose clinically, particularly cirrhotic basal cell carcinoma, which may present as an inconspicuous scar-like indentation, or trunk skin basal cell carcinoma, which, as a superficial scaling plaque, can easily be mistaken for inflammatory skin disease (Fig. 1). In most cases, therefore, a biopsy must be performed to confirm the diagnosis, although a relatively small shave or punch biopsy is often sufficient to make the diagnosis. Determination of the histologic subtype of basal cell carcinoma is also quite critical for risk stratification and thus for treatment planning [2,3].
The classification of basal cell carcinomas into different risk groups is decisive for the prognosis regarding recurrence as well as for the best possible choice of therapy. The current NCCN guidelines only distinguish basal cell carcinomas with low and with high risk for recurrence (Table 1) [4]. In addition to localization in the H-zone of the face, poor clinical demarcation, and certain patient factors such as immunosuppression or prior radiotherapy, the histologic growth pattern is most important: tumors with an invasive histologic pattern (cirrhotic basal cell carcinomas, micronodular or basosquamous types) are characterized by a significantly greater extension than clinically apparent. In addition, recurrent basal cell carcinomas that have already been pre-treated tend to recur much more frequently.
Standard treatment: surgical excision
The standard treatment for all types of basal cell carcinoma remains surgical excision with a safety margin of 4-5 mm beyond the clinically visible limit of the tumor. For high-risk tumors, this should absolutely be done with complete incision margin control. Other treatment modalities, such as cryotherapy or topical therapies, are indicated only for low-risk superficial basal cell carcinoma.
For the majority of the most common type of basal cell carcinoma, nodular basal cell carcinoma, a spindle-shaped excision with a 4-5 mm safety margin is sufficient, and the defect can usually be closed directly. There is no agreement in the literature about the exact safety distance. However, studies have shown that with 4-5 mm distance from the clinically visible tumor margin, cure can be achieved in 95% of cases [Q]. Thus, in many cases, this treatment is the simplest option for the patient and quite acceptable in terms of recurrence rates.
If a tumor is excised incompletely, 26-41% of cases later recur within two to five years [5]. This rate is higher if the tumor was marginal at the base of the excisate. In case of recurrence, it is not uncommon to find a histologically more aggressive, infiltrative form. Thus, it is highly recommended to perform a post-excision for margin-forming tumor portions after standard excision even of low-risk basal cell carcinomas. This is especially true in facial tumors when the tumor is marginal at the base and in younger patients.
Excision by Mohs surgery
For all high-risk basal cell carcinomas, surgical excision should absolutely be performed with gap-free, histologic incision margin control. Classic Mohs surgery is best suited for this purpose. It was described in the 1930s by the American surgeon Frederic Mohs and has since become the standard treatment procedure for many types of epithelial tumors both in the United States and in numerous European centers. In Mohs surgery, the excisate is histologically embedded using a special procedure so that the entire incision margin and the base of the excisate can be assessed in a histological specimen. After the preparation is made using the cryofixation method, it is evaluated by the dermatosurgeon. Border-forming tumor parts can thus be precisely localized and targeted re-excised on the same day. Only after histologically documented complete tumor freedom is the defect closed in the final step, which in most cases is performed with a flapplasty or full-thickness skin graft.
This procedure can reduce recurrence rates, which are 5% with standard excision for nodular basal cell carcinoma, to 1-2%. The difference in cure rates is even more pronounced for recurrent tumors or histologically invasive forms: While recurrent basal cell carcinomas recur in about 17% of cases after ordinary excision, this rate can be reduced to about 5% using Mohs surgery [6]. Another advantage of this method, in addition to the lower recurrence rates and rapid feasibility, is that excision defects are significantly smaller due to the smaller safety margin. This difference comes into play particularly in invasive tumor forms, where standard excision safety distances of up to 15 mm must be selected to achieve comparable recurrence rates. In many cases, the smaller excision defects provide better functional and esthetic results for the patient. Moreover, surgical coverage procedures are less expensive and can be performed on an outpatient basis [7]. Apart from the criteria for high-risk basal cell carcinomas, Mohs surgery is also indicated as the first-choice therapy in all cases where flap surgery or skin grafting is necessary to close the defect or where surgery should be performed in the most tissue-sparing way possible. (Tab.2). However, due to the special interaction of excision, histological processing with evaluation by the dermatosurgeon and surgical coverage of the defect, the method can only be performed in certain centers and by dermatosurgeons who can demonstrate appropriate training.*.
Other forms of therapy
If excision of a basal cell carcinoma is not possible in a patient or is refused by the patient, radiotherapy is really the only alternative for high-risk basal cell carcinomas. This can also be used as first-line therapy for tumors that already show bone or cartilage invasion, as adjuvant therapy when primary surgical excision was not complete and post-excision is no longer possible, or in cases that histologically show perineural invasion. Cure rates with radiotherapy are approximately 90% for nodular basal cell carcinomas; unfortunately, infiltrative tumors show more frequent recurrences after radiotherapy. These recurrences then often have a more aggressive growth pattern. Radiotherapy is also not indicated in patients under 60 years of age due to possible late effects such as skin atrophy, telangiectasia, and secondary carcinomas. Also contraindicated is radiotherapy to previously irradiated sites and in patients with genetic syndromes with clustered basal cell carcinomas and immunosuppressed patients.
Cryotherapy is an excellent, simple treatment option for low-risk basal cell carcinoma, especially in elderly patients. Treatment can usually be performed without anesthesia in one session with two freeze-thaw cycles followed by a wound healing period of a few weeks. In low-risk tumors, this can achieve recurrence rates of 8-40%. Disadvantages include the occasional hypopigmented, somewhat atrophic scars and the lack of histologic treatment control.
Topical treatments
For superficial basal cell carcinomas from the low-risk tumor group, various treatment options exist with topical procedures. Immunotherapy with imiquimod is particularly well established here. This drug is approved for the treatment of superficial basal cell carcinoma with a diameter of <2 cm in the neck, trunk, and extremities (excl. hands and feet) when surgical excision is not indicated and follow-up is secured. The cream is applied five times a week for 6-12 weeks. Occasionally, a strong inflammatory local reaction is seen, which correlates with a higher response rate. Cure rates are about 80% with this procedure, and recurrences usually occur early.
An elegant alternative is photodynamic therapy (PDT), which can be performed in just two sessions. It is also indicated only for superficial basal cell carcinomas that are not amenable to surgical excision. Lesions are usually curetted before treatment and then treated twice at seven-day intervals. With this, healing rates of up to 87% can be achieved, with excellent cosmetic results. These topical treatments are also particularly suitable for patients with a large number of basal cell carcinomas, e.g. patients with genetic syndrome (Gorlin Goltz) and immunosuppressed patients.
There are too few clinical data for other topical treatment methods such as 5-FU in cream form or ablation with CO2 laser, so they cannot be recommended without reservation. Curettage of basal cell carcinoma followed by electrodesiccation has been widely advocated in the United States and results in acceptable recurrence rates of 3-18%. However, the cosmetic result is often not satisfactory and the therapy has never fully caught on in Europe.
Systemic treatment
Systemic therapies for basal cell carcinoma have also been available since 2013. These are the hedgehog pathway inhibitors vismodegib and sonidegib. These lead to cell death and thus tumor regression by binding to the Smoothened receptor. However, there are relatively few cases in which these systemic therapies are indicated. They can be used for locally advanced basal cell carcinoma with an extent that precludes surgical removal and for the extremely rare cases of metastatic basal cell carcinoma. They are occasionally a welcome adjunct to therapy in patients with genetic syndromes (Gorlin Goltz syndrome) [8], which are associated with numerous basal cell carcinomas. Response rates of up to 48% can be achieved by taking one capsule daily, as well as a decrease in tumor mass in about two-thirds of cases [9]. However, the therapies are associated with sometimes severe side effects (especially muscle spasms, hair loss, dysgeusia and weight loss), which severely limits their use, which usually has to take place over several years. Occasionally, a reduction in tumor mass can be achieved with these systems therapies prior to final surgical therapy.
Take-Home Messages
- Therapy of choice for all basal cell carcinomas is surgical excision with or without histologic incision margin control. Incomplete excision can lead to recurrences, which are often more aggressive histologically.
- Mohs surgery is suitable for excision, especially of high-risk basal cell carcinomas. In addition to lower recurrence rates and uncomplicated, outpatient feasibility, an advantage of this method is lower excision defects and costs.
- Radiotherapy may be an alternative for high-risk basal cell carcinoma in cases of undesirable, impossible, or incomplete excision, bone and cartilage involvement, or perineural invasion.
- Superficial low-risk basal cell carcinomas can be treated topically, such as with immunotherapy or photodynamic therapy.
- Systemic therapies are used in inoperable exceptional cases.
* For training criteria, see European Society for Micrographic Surgery (ESMS) guidelines, www.esms-mohs.eu.
Literature:
- Flohil SC, et al: Incidence, prevalence and future trends of primary basal cell carcinoma in the Netherlands. Acta Derm Venereol 2011; 91: 24-30.
- Telfer NR, Colver GB, Morton CA: Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008; 159: 35-48.
- Trakatelli M, et al: Update of the European guidelines for basal cell carcinoma management. Eur J Dermatol 2014; 24: 312-329.
- Bichakjian CK, et al: Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2016; 14: 574-597.
- Breuninger H, Dietz K: Prediction of subclinical tumor infiltration in basal cell carcinoma. J Dermatol Surg Oncol 1991; 17: 574-578.
- van Loo E, et al: Surgical excision versus Mohs’ micrographic surgery for basal cell carcinoma of the face: A randomised clinical trial with 10 year follow-up. Eur J Cancer 2014; 50: 3011-3020.
- Hoorens I, et al: Mohs micrographic surgery for basal cell carcinoma: evaluation of the indication criteria and predictive factors for extensive subclinical spread. Br J Dermatol 2016; 174: 847-852.
- Rehefeldt-Erne S, et al: Nevoid basal cell carcinoma syndrome: Report from the Zurich Nevoid Basal Cell Carcinoma Syndrome Cohort. Dermatology 2016; 232: 285-292.
- Sekulic A, et al: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171-2179.
DERMATOLOGIE PRAXIS 2018; 28(4): 14-17
