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Summary

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

A multitude of surgical and non-surgical therapies are available to treat malignant epithelial tumors of the skin. The article summarizes the current treatment options for basal cell carcinoma, squamous cell carcinoma and keratoacanthoma. Moreover, the possibilities of primary and secondary prevention for high-risk patients are reviewed. The decision about the best therapeutic option depends on location, age, and general health of the patient as well as the risk of tumor recurrence.


Therapy of squamous cell carcinoma (SCC)

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

Squamous cell carcinoma in situ (keratinocytic intraepithelial neoplasia [KIN], actinic keratosis)

Even though the clinical diagnosis is no challenge to dermatologists, when in doubt a biopsy should be performed to rule out invasive carcinoma. As in about 10 % of patients with SCC in situ (KIN) progression to an invasive SCC occurs, there is consensus in Germany that KIN should be treated. This particularly applies to patients with field cancerization, a history of multiple invasive SCC, immunosuppression or lesions in anatomic sites on the head with a high risk of recurrence (Figure 1). In addition, comorbidities, tendency for bleeding, the life situation of the patient and, when applicable, previous therapy should be considered in the differential therapeutic decision-making. The numerous established treatment methods that are available will briefly be presented. Even when employing therapies that do not foresee histologic confirmation of the diagnosis, as, for example, in the treatment of field cancerization, it is prudent to histologically examine a representative lesion. For details on the differential therapy of KIN and especially comparative studies on different therapeutic modalities, a recently updated S1 guideline of the German Society of Dermatology with comprehensive references is available (http://www.awmf.org/uploads/tx_szleitlinien/013–041l_S1_Aktinische_Keratose_2012–1.pdf). A treatment algorithm that cannot be evidence-based in all details due to the lack of comparative therapy studies is presented in Figure 2.

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Figure 1. Anatomical high-risk regions of the face. The gray-shaded regions of the face are associated with an increased risk of recurrence of malignant epithelial tumors (with the kind permission of Dr. M. Feoktistova, Medical Faculty of Mannheim).

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Figure 2. Algorithm for the treatment of squamous cell carcinoma in situ (KIN). No comparative therapy studies are available for numerous therapies, or no differences in efficacy of treatment have been demonstrated.

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Modalities for the treatment of KIN

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

Ablative therapy modalities for KIN

Surgical excision, curettage and laser therapy

An excision of KIN is most appropriate when clinical uncertainty remains with respect to possible invasion by the lesion or when rapid definitive therapy is desired. Predominantly superficial shave excisions or curettages with or without electrodesiccation are performed. Controlled studies on these therapy techniques do not exist. For the treatment of individual KIN but also for field cancerization in the event of therapy resistance to drug therapy, ablative laser systems (CO2 lasers) also can be considered. With the CO2 laser complete remission in about 90 % with a recurrence rate of about 15 % after 3–6 months can be achieved [1].

Cryosurgery

Cryosurgery (cryotherapy) is perhaps the most frequently employed method for the treatment of KIN of the free skin. Liquid nitrogen (–195 °C) serves as cryogen to freeze the skin. Rapid therapy with freezing for about 3–6 seconds is possible by using a cryospray device or cryocontact therapy with a pre-cooled probe or one with liquid nitrogen flowing through it. The response rate is 67–99 %. Cosmetic disadvantages are the increased risk of scarring and the possible development of hypo- or hyperpigmentation. The advantage of cryosurgery is that it is generally employed without local anesthesia, although local anesthesia is recommended for extensive interventions.

Photodynamic therapy (PDT)

PDT is a further established non-invasive method for the treatment of KIN. After the application of special photosensitizers for PDT of the skin (5-aminolevulinic acid [5-ALA] or 5-ALA-methyl-ester in an oil-in-water emulsion or an adhesive tape have become established), there is first an accumulation and metabolism of 5-ALA or MAL to protoporphyrin IX, especially in the tumor cells. During irradiation with light of the wavelengths 580–720 nm, singlet oxygen, a key mediator of the cytotoxic effect of PDT, is produced. PDT (with MAL or ALA) shows good results in the treatment of KIN and is an important therapy form for field cancerization leading to scar-free healing. Side effects of PDT in the treated area include erythema, pain during irradiation, edema, sterile pustules (Figure 3), erosions and rarely hyperpigmentation. In PDT of KIN, a dose of 75 J/cm2 (2 times at an interval of one week) is employed.

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Figure 3. Side effects of PDT therapy in the treatment of field cancerization. (a) Actinic keratoses on the left temple before PDT with 5-ALA. (b) Extensive sterile pustules 10 days after therapy. Complete healing within 3 weeks.

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Topical drug therapy of KIN

5-fluorouracil

5-fluorouracil (5-FU) is a pyrimidine analog that inhibits the synthesis of nucleic acids and thus has a cytotoxic action on the rapidly proliferating dysplastic keratinocytes of the treated KIN. Topical therapy with a 5 % 5-FU ointment (twice daily over 2–4 weeks) has long been employed. Treatment is continued until the development of an inflammatory reaction and initial erosion of the lesions. The combination of 0.5 % 5-FU in combination with 10 % salicylic acid is efficacious and licensed in Germany for the treatment of hyperkeratotic KIN. The treatment is performed over 6–12 weeks; follow-up is required after 6 months.

Imiquimod

Imiquimod is a TLR-7 agonist and after binding to the receptor results in addition to a direct cytotoxic effect particularly in an increased cell-mediated immune response [2]. There is activation of plasmacytoid dendritic cells with antiviral and anti-tumoral effects. Imiquimod 5 % cream (3 times weekly over 8 hours each time over 4 weeks) is licensed for the treatment of KIN. If residual lesions remain after a 4-week treatment-free interval, the treatment can be continued over another 4 weeks. During therapy pain, erythema, pruritus, erosions and ulcerations may develop; the patient must correspondingly be informed before initiation of therapy (Figure 4). Flu-like systemic side effects (joint or muscle pain, headache and fever) are observed more rarely. Follow-up should be performed after 6 months.

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Figure 4. (a) Treatment of field cancerization on the forehead of a 78-year-old woman. (b) Topical therapy with 5 % imiquimod cream (3 times weekly). Nine days after initiation of therapy erythema and crusts have developed in the involved area.

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Diclofenac

Diclofenac is a non-steroidal anti-inflammatory drug, more specifically an aryl acetic acid derivative that inhibits cyclooxygenase (COX) 1 and 2. Studies on the pathogenesis of malignant epithelial skin tumors showed that then induction of COX 2 in the skin has pro-tumor effects. Consequently, inhibition of COX for treatment of KIN is reasonable. Diclofenac is available as a 3 % hyaluronic acid gel for the treatment of KIN (twice daily over 90 days). Local irritation (pruritus, erythema) may occur as with other topical approaches, but also type IV sensitizations may develop. Therapy success should be assessed after 6–12 months.

Ingenol mebutate

Ingenol mebutate is a therapeutic agent originally discovered by alternative medicine in Australia. The pure substance extracted from a petty spurge plant (Euphorbia peplus) is a hydrophobic macrocyclic diterpene ester. Ingenol mebutate leads to direct necrosis of neoplastic keratinocytes with subsequent neutrophilic antibody-dependent cellular toxicity of tumor cells. In preclinical trials in the mouse model even clinically asymptomatic lesions of p53-mutant cell clones heal [3]. The high clinical efficacy of ingenol mebutate gel (0.015 % in the face and scalp for 3 days; 0.05 % on trunk and limbs for 2 days) has recently been proven [4]. Side effects include erythema, scaling, pruritus, pustule formation or pain at the application site with a maximum after about 7 days. Ingenol mebutate gel has been licensed in the USA since January 2012 for the treatment of KIN.

Peculiarities of therapy of KIN in special locations

Actinic cheilitis

In every case of actinic cheilitis, invasive growth should be excluded histologically before initiating therapy. For treatment both surgical as well as topical therapeutic options are available; the selection depends on the extent of the lesion (Figure 5). Small lesions of cheilitis can first be treated with topical methods or, alternatively, with cryosurgery according to the principles of KIN of the free skin. In the event of therapy resistance, laser therapy (CO2 lasers) or excision should be performed. For extensive lesions topical measures can be tried first. If there is no healing within 6 months, ablative techniques, for example CO2 laser therapy, should be employed, that lead to compete healing in almost 100 % of cases [5]. For a lower thermal impact on surrounding tissue and for better wound healing, the use of the superpulse mode is advantageous [6]. Laser therapy as a relatively bloodless modality is less of a burden on the patient in comparison to conventional surgery. Complications of this form of therapy are postoperative pain, edema, scarring and paresthesias. In vermilionectomy (according to Langenbeck and von Bruns) largely UV-protected oral mucous membrane is mobilized for closure of the lip skin; it also results in complete remission. The advantage of this method is the possibility of complete histological examination of the tissue, while despite improved surgical techniques distinctly higher peri- and postoperative morbidity (wound dehiscence, hematoma formation, paresthesias, scarring, loss of lip contour) must be taken into consideration [6].

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Figure 5. Algorithm for the treatment of actinic cheilitis.

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Erythroplasia of Queyrat and leukoplakia

Erythroplasia of Queyrat and leukoplakia should obligatorily be confirmed histologically due to the higher risk of progression to mucosal carcinomas. The selection of treatment methods depends on anatomic peculiarities. In anatomic locations with a low risk of functional or aesthetic impairment, treatment should be surgical (primary excision) or ablative (Figure 2). In contrast, when functional or aesthetic impairment of the patient must be feared, topical drug therapy with imiquimod [7] or 5-FU ointment [8] should be initiated first. In treatment failure over more than 3 months, ablative laser therapy or excision then should be performed. Close follow-up is necessary particularly for topical drug therapy to monitor the success of therapy, initially in three-month intervals.

Invasive squamous cell carcinoma (SCC)

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

After histological diagnosis of an invasive SCC, the tumor must be classified as a high- or low-risk tumor for planning therapy. As the present UICC or AJCC classification for stratifying the risk of metastasis are hardly reliable for estimating the risk of invasive SCC of the skin, the risk should be assessed on the basis of tumor size (>2 cm diameter), tumor penetration depth (<2 mm, no risk; >2 mm, moderate risk; >6 mm, high risk) and the histological classification after complete excision (desmoplasia, dedifferentiation). Further, the location of the tumor around the ear (Figure 6) and long-term immunosuppression should be included in the individual risk assessment of the patient [9].

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Figure 6. Cutaneous metastasis at the angle of the jaw following surgical excision of a high-risk SCC of the skin 18 months before presentation. The slightly hypopigmented free skin graft can be recognized in the preauricular area. This patient refused further therapy.

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The therapy of choice of an invasive SCC is excision with histological control of margins (Figure 7). For low-risk tumors safety margins of 4 mm are recommended, while high-risk tumors should be treated with micrographically controlled excision (MCS) with 1 cm safety margins, if possible, but never less than 6 mm. In MCS the lateral and basal margins are completely examined histologically after appropriate mapping. With this technique, topographic identification of clinically undiscovered latent extensions of the tumor is possible while at the same time achieving maximal sparing of tissue. Although MCS can be performed both on cryo-conserved tissue as well as on paraffin-embedded material, processing paraffin material leads to superior results. Independent of the risk criteria, MCS may be selected when maximum sparing of surrounding tissue is a priority or when due to comorbidity more radical surgery would be risky. A treatment algorithm with a recommendation for treatment of invasive SCC is illustrated in Figure 8.

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Figure 7. (a) Surgical therapy of an invasive lip cancer. (b) After complete excision in MCS closure was performed with the help of a Bernard flap. (c) Surgical result after 6 months (with the kind permission of Priv.-Doz. Dr. Jörg Faulhaber, Medical Faculty Mannheim).

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Figure 8. Algorithm for the treatment of invasive squamous cell carcinoma of the skin. No comparative studies are available for some therapies, or no significant differences in the efficacy of treatment have been demonstrated, so that the side effect profile and patient preference must be considered in the decision on treatment.

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Sentinel lymph node biopsy for invasive SCC of the skin

To date no consensus exists on the use of sentinel lymph node biopsy in the treatment of high-risk SCC of the skin. It is postulated that with SCC a more precise assessment of risk of high-risk tumors is possible. The decision on the use of this technique should be made on the basis of high-risk criteria on an individual basis and in specialized skin cancer centers in an interdisciplinary fashion (Figure 8). A complicating matter in primary SCC is the often complex lymphatic drainage situation in the head and neck region [10].

Primary radiotherapy of SCC

The simple (even if logistically time-consuming) performance and the low rate of complications make radiotherapy a suitable alternative therapeutic procedure particularly for multi-morbid patients with a high surgical risk. A retrospective study on 106 patients treated primarily with radiotherapy found a complete remission in 92.7 % after 5 and 78.6 % after 15 years [11]. A total dose of about 50–70 Gy was employed. Due to the success of radiotherapy in combination with EGFR inhibitors in SCC of the oropharynx/ larynx (head and neck SCC [HNSCC]) [12], combination therapy can also be considered [13].

Adjuvant radiotherapy in SCC

It is controversial if adjuvant radiotherapy is necessary in high-risk SCC following total excision. Randomized studies of this issue are lacking. From retrospective studies with 9 and 74 patients who were each treated only surgically or surgically with adjuvant radiotherapy due to high-risk SCC with perineural invasion, no advantage was seen in the group with additional adjuvant radiotherapy [14, 15].

SCC with regional or distant metastases

In the event that SCC metastasizes, the metastases develop in most cases within the first two years after diagnosis [16]. The great majority of SCC of the head metastasize to the locoregional lymph nodes (LN) of the parotid gland or several locoregional lymph node stations. Close follow-up of high-risk SCC in three-month intervals in the first two years after the diagnosis is therefore important. As most patients with SCC with locoregional or distant metastases are over 70 years, individualized therapeutic decisions are the rule with interdisciplinary procedures (radial LN dissection, radiotherapy, but also multimodal treatment strategies) being employed. To date larger studies comparing therapeutic approaches to metastatic SCC are lacking.

The available treatments of metastatic SCC of the skin are all palliative. Due to the heterogeneous patient collective of usually multi-morbid patients, the use of systemic therapeutic agents is predominantly extrapolated from SCC of the oropharynx/ larynx (HNSCC). To date chemotherapeutic agents (methotrexate [MTX], cisplatin, 5-FU, taxanes, gemcitabine) have been employed. A short-term response between 20–40 % is seen with MTX or up to 50–80 % with polychemotherapy. The chemotherapy regimen must be selected in dependence on the individual comorbidities of the often multi-morbid patient collective. More aggressive polychemotherapy often can not be performed for treatment of metastatic SCC of the skin due to the therapy-associated toxicity.

In recent times in skin cancer centers, targeted therapies have also been utilized, particularly blockade of EGFR or kinase inhibitors. These in combination with radio- or chemotherapy have been able to improve total survival in HNSCC [12, 17]. Two groups of anti-EGF medications have been employed: monoclonal antibodies towards the extracellular domain of the EGF receptor and the ATP-competitive tyrosine kinase inhibitors that block the EGFR signaling pathway intracellularly. Cetuximab is the prototype of the first group. There have been case reports of successful combination therapies with cetuximab and COX 2 inhibitors [18] or radiotherapy [13, 19]. Gefitinib and erlotinib are examples of available medications for oral administration from the second group of kinase inhibitors. In all EGF inhibitors group-specific side effects encompassing acneiform exanthems, hair alterations, paronychia and xerosis of the skin occur. The side effects, particularly cutaneous toxicity of these therapeutic agents can usually be well controlled [20].

Therapy of basal cell carcinoma (BCC)

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

The treatment of choice for BCC is surgery. Before the therapy decision for a BCC is made, the tumor should be categorized. Both the growth pattern of the BCC according to clinical or even better histological criteria [21] as well as local anatomic factors should be considered in planning therapy. The problematic locations of BCC on eyelids, lips, nose and ear (“H zone” or “mask zone”), but also the size of the tumor or presence of a recurrence should impact the type of surgical procedure in the direction of risk-adapted histological processing (Table 1). In the event of incomplete excision all possibilities of surgical re-excision should be utilized first, perhaps in an interdisciplinary approach with other specialties (particularly ENT, maxillomandibular surgery, ophthalmology). An algorithm on decision-making in BCC is shown in Figure 9.

Table 1.  Surgical therapy of basal cell carcinoma (BCC; with histological control) with respect to tumor type, location and risk of recurrence (adapted from the current guideline for BCC of the skin).
Recommended histological methodIndication
Micrographically controlled surgery (MCS)Problematic locations (Figure 1); infiltrating, ulcerated and sclerodermiform growth pattern; recurrent tumors
Tumor-adapted safety margins, conventional histologySmall tumors in every location, larger tumors on the trunk and limbs
Horizontal excision, conventional histologyMultifocal superficial BCC on the trunk and limbs
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Figure 9. Algorithm for the treatment of basal cell carcinoma (BCC). For therapy of 2nd or 3rd choice no comparative studies are available.

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Surgical therapy of high-risk BCC

BCC with a high risk of recurrence should be removed with MCS. When employing MCs the recurrence rate is between 1 % and 5.6 %[22]. Even economically micrographically controlled surgery is superior to single-step simple excision of high-risk BCC, when the costs of re-excision of the incompletely excised BCC are taken into consideration [23]. When MCS is contraindicated due to comorbidity, alternatively simple excision and radiotherapy are alternatives. On an individual basis in multi-morbid patients even cryosurgery or topical drug approaches combined with three-month follow-up intervals can be considered (Figure 9).

Therapy alternatives in low-risk BCC

In general, BCC in the face with a diameter <1 cm or tumors on the rest of the body with a diameter <2 cm are considered low-risk tumors. As in SCC, for the selection of the therapeutic approach in BCC individual patient factors are significant and must be taken into consideration by the treating dermatologist. In low-risk BCC, particularly superficial BCC, along with topical drug therapy, other less time-consuming and more economical destructive procedures are employed. These cause less impairment than the generally preferable surgical therapy (Figure 9). These include curettage/ electrodesiccation, cryotherapy and PDT. In an older retrospective study (2,314 patients) a justifiably low recurrence rate of 8.5 % was seen after curettage along with electrodesiccation of BCC [24]. A retrospective study on cryotherapy of BCC with 395 patients revealed a recurrence rate of 9 % with two freeze cycles, independent of the type of device employed [25]. The major disadvantage of these two methods is the lack of histological control.

Drug therapy of BCC

When surgical excision or destruction is not possible due to one of the above mentioned risk criteria or due to patient preference, good evidence exists for the efficacy of non-surgical therapy modalities for the various growth patterns of BCC. These include topical treatment with imiquimod cream or also 5-FU cream and PDT. All methods possess a higher risk of recurrence in comparison to surgical treatment. If drug therapy is chosen, dermatologic follow-up in 3–6-month intervals is of utmost importance.

Topical treatment with imiquimod (5 times weekly over 6 weeks) has proven useful particularly for multiple superficial BCC, while results in nodular BCC reveal distinctly lower healing rates limiting the indication. PDT is an effective treatment option for superficial – and in a more limited sense – for nodular BCC, but with a higher risk of recurrence. An advantage of PDT is a superior cosmetic outcome in comparison to surgical procedures.

Radiotherapy of BCC

A randomized study on 347 patients with untreated BCC proved the efficacy of primary radiotherapy (total dose 40–60 Gy, single doses between 2 and 5 Gy) with a justifiable recurrence rate of 7.5 %[26]. One disadvantage of radiotherapy is the induction of secondary tumors in the radiation field after a latency of 15–25 years [27]. Radiotherapy should be preferred in primarily inoperable BCC or in patients with comorbidities that make surgery a risk. Basal cell nevus syndrome (BCNS) is an absolute contraindication for radiotherapy.

Treatment of unresectable, locally advanced or metastatic BCC

Due to the frequency of BCC in combination with the advanced age distribution of the patients, inevitably locally advanced tumors will develop that represent an interdisciplinary challenge. To date no reliable statistics on the frequency of such tumors in multi-morbid patients exist. For the rare metastatic tumors (< 0.1 %) no generally accepted recommendations exist as of yet; usually multimodal therapy analogous to metastatic SCC (radiotherapy, chemotherapy) has been performed. When radiotherapy cannot achieve tumor control, smoothened (Smo) inhibitors are a new alternative for the indication of locally advanced or metastatic BCC (Figure 9).

Inhibitors of the sonic hedgehog signaling pathway with Smo inhibitors

Since the end or the 20th century – as a result of the knowledge on the molecular pathogenesis of BCC – various small molecule inhibitors of the sonic hedgehog signaling pathway have been identified. Various companies have pursued the development of medications for inhibition of Smo, hyperactive in BCC, in the past decade [28]. Vismodegib is the first inhibitor of this class licensed for locally advanced and metastatic BCC in 2012 in the USA [29] (Figure 10). For patients with basal cell nevus syndrome (BCNS; Gorlin-Goltz syndrome) long-term oral therapy with vismodegib is possible. Inhibiting the development of new BCC as well as inducing regression of existing BCC can be achieved with vismodegib therapy in over 50 % of patients with BCNS [30]. The most common side effects of treatment with vismodegib are alopecia, dysgeusia and muscle cramps [31]; in a randomized study on patients with BCNS, they prevented long-term therapy in more than 50 % of the patients [30].

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Figure 10. Therapy of locally advanced BCC of the nose (ulcus terebrans) and the right lateral angle of the eye in an 88-year-old woman with a Smo inhibitor (vismodegib). The patient refused surgical treatment as well as radiotherapy. (a) Before therapy. (b) After therapy with vismodegib 150 mg daily over 3 months.

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Therapy of keratoacanthoma (KA)

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

In view of the self-healing tendency of KA, surgical therapy is in general not necessary. Nonetheless, as the prediction of the further growth or resolution is very difficult and due to the often disfiguring atrophic scars after healing, excisional biopsy is frequently selected as primary therapy. Histological analysis also allows for a definitive separation from a highly differentiated SCC. When the histological diagnosis of KA is definite and secure or when the tumor is already in the stage of involution, close follow-up of spontaneous healing is justifiable (Figure 11) [32]. As alternatives to surgical or “wait-and-see” therapy, intralesional therapy with MTX, 5-FU, bleomycin or interferon-α can be considered [33]. The healing rates in all studies were > 98.5 %. Topical therapy forms with imiquimod or 5-FU have been reported in small case series, but the high spontaneous healing tendency must be kept in mind. Controlled prospective, randomized studies on the treatment of KA are still lacking; the greatest experience is reported with intralesional MTX or intralesional 5-FU.

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Figure 11. Close follow-up of spontaneous regression of a keratoacanthoma (KA) at the medial angle of the left eye. (a) KA at the time of diagnosis. (b) Two weeks later partial regression. (c) Ten weeks after the diagnosis complete healing leaving an atrophic scar.

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Intralesional therapy of KA

For treatment with MTX usually 1–4 injections at intervals of 1–6 weeks are needed for tumor regression. Using a 30 gauge needle 0.3–2 ml MTX (concentration 12.5 or 25 mg/ml) one quadrant at a time until the endpoint of paling of the tumor in all quadrants is achieved. The mean dose in a retrospective analysis was 17.6 mg per injection with a total dose of 33.8 mg [34]. 5-FU is injected weekly in a dose of 40 mg, treatment duration appears, however, to be longer in comparison to MTX with up to 8 weeks.

Larger, rapidly proliferating KA

For larger, rapidly proliferating KA, a surgical approach is recommended. When surgical risk is high, alternative conservative techniques such as radiotherapy (total dose of 20–40 Gy [single dose 2–4 Gy] can be performed with a high rate of healing [35].

Prevention of malignant epithelial skin tumors

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA

A great clinical problem is the development of further, independent tumors in high-risk patients. The strategy in these patients consists largely of close follow-up and early therapy, if possible in the stage of KIN (“watch and cut “ strategy). Among these high-risk patients are, on the one hand, patients with field cancerization of intensely UV-exposed body regions (face, hands, scalp in patients with androgenetic alopecia), on the other, chronically immunosuppressed patients (especially those with organ transplants). This patients group is possibly particularly endangered due to significance of HPV, calcineurin inhibitors [36], but also azathioprine in the tumor promotion of SCC, so that an interdisciplinary discussion of modification of immunosuppressive medication (switching to mTOR inhibitors such as everolimus in patients with organ transplants) should take place [37]. In addition to tight follow-up of these high-risk patients at three-month intervals, several options for secondary prevention are available today.

UV protection

Consistent use of sunscreens can significantly reduce the development of new KIN in immunocompetent [38, 39] and chronically immunosuppressed patients [40]. Therefore permanent very high sun protection (sun protection factor [SPF] > 50) in combination with adequate textile UV protection (particularly a broad-brimmed hat) should be recommended to patients with KIN or invasive tumors for long-term prophylaxis of malignant epithelial tumors.

Chemoprevention of malignant epithelial skin tumors

Therapy with retinoids

Retinoids are a class of naturally occurring or synthetically produced derivatives of vitamin A. Retinoids activate retinoid acid receptors (RAR) and/or retinoid X receptors (RXR) in the cell nucleus. They exhibit numerous effects on proliferation, differentiation, cell cycle and cell death of keratinocytes. Due to these experimental findings, retinoids have been studied intensively for prevention of malignant epithelial skin tumors. While topical application of retinoids is without effect [41], systemic retinoids have been effective in several studies on long-term chemoprevention of KIN in patients with a moderate risk (>10 KIN and maximally 2 invasive SCC), even if side effects (cheilitis, xerosis cutis) strongly limit long-term use. In high-risk patients (immunosuppressed, genodermatoses such as xeroderma pigmentosum or BCNS) systemic retinoids are likewise effective, especially in patients who already have had more than 5 SCC [42]. Generally, secondary prevention with systemic retinoids should be considered in the following patient groups:

  • • 
    in chronically immunosuppressed patients (following organ transplantation, non-Hodgkin lymphomas, CLL, HIV),
  • • 
    in genodermatoses (xeroderma pigmentosum, BCNS, Bazex syndrome, Rombo syndrome, epidermodysplasia verruciformis),
  • • 
    in patients with more than 5 invasive malignant epithelial skin tumors within one year.

In addition, acitretin appears to inhibit the development of highly differentiated SCC/KA in patients with melanoma being treated with BRAF inhibitors; larger studies are still needed on this issue [43]. As acitretin is not licensed for chemoprevention, an individualized decision on this long-term therapy should be sought in specialized skin cancer outpatient departments.

Secondary prevention of SCC in field cancerization

Field cancerization is a particular challenge in immunocompetent and immunosuppressed high-risk patients. No larger controlled studies on topical drug therapy with 5-FU, imiquimod, diclofenac or ingenol mebutate for proactive therapy of field cancerization in high-risk patients exist as of yet. In small randomized studies cyclical treatment with 5-ALA-PDT was capable of reducing the development of new KIN. The prophylactic effect is, nonetheless, hardly still evident after 9 months, so that possibly regular repetition of therapy may be required [44]. Altogether, there is a great need for randomized, controlled studies for this indication.

Prevention of HPV-associated malignant epithelial skin tumors

Malignant epithelial tumors in the anogenital region as well as on the mucous membranes of the head and neck region, particularly on the tonsils, are frequently associated with high-risk HPV viruses. Presently, two different licensed vaccines on the basis of “virus-like particles” (VLP) are available against the viral capsid protein L1. These VLP are not infectious, as they contain no DNA, but activate the immune system of the vaccinated person to produce specific protective antibodies. The quadrivalent vaccine (Gardasil®) is effective against the most common high-risk HPV (16, 18) and HPV 6 and 11, the inducers of condylomata acuminata, while the bivalent vaccine (Cervarix®) includes only HPV 16 and 18 [45]. By vaccinating young girls, HPV 16/18-associated cervical intraepithelial neoplasia (CIN) can be prevented in over 70 % of cases. In the high-risk collective of homosexual men, HPV immunization can likewise reduce the development of HPV-related anal intraepithelial neoplasia (AIN) [46].

For the therapy of already existing intraepithelial neoplasia of the vulva (VIN), the first successfully employed peptide-based vaccination strategy already exists. In this approach synthetic peptides directed against the oncogenic E6 and E7 proteins are employed [47]. Due to the years of latency until development of tumors, evaluation of clinical results of prophylactic or therapeutic vaccinations will require a long time. It remains to be hoped that such innovative therapy approaches will also allow for treatment of other high-risk HPV-associated malignant epithelial tumors.

References

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA
  • 1
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    Göppner D, Nekwasil S, Franke I, Gollnick H, Leverkus M. Successful combination therapy of a locally advanced squamous cell carcinoma of the skin with cetuximab and gamma-irradiation. J Dtsch Dermatol Ges 2010; 8: 8268.
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  • 17
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  • 18
    Jalili A, Pinc A, Pieczkowski F, Karlhofer FM, Stingl G, Wagner SN. Combination of an EGFR blocker and a COX-2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges 2008; 6: 10669.
  • 19
    Balermpas P, Keller C, Hambek M, Wagenblast J, Seitz O, Rodel C, Weiss C. Reirradiation with cetuximab in locoregional recurrent and inoperable squamous cell carcinoma of the head and neck: feasibility and first efficacy results. Int J Radiat Oncol Biol Phys 2012; 83: e377–e383.
  • 20
    Gutzmer R, Becker JC, Enk A, Garbe C, Hauschild A, Leverkus M, Reimer G, Treudler R, Tsianakas A, Ulrich C, Wollenberg A, Homey B. Management of cutaneous side effects of EGFR inhibitors: recommendations from a German expert panel for the primary treating physician. J Dtsch Dermatol Ges 2011; 9: 195203.
  • 21
    Leverkus M. Maligne epitheliale Tumoren: Teil I. Pathophysiologie und Klinik. J Dtsch Dermatol Ges 2012; 10: 45773.
  • 22
    Rowe DE, Carroll RJ, Day CL, Jr. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989; 15: 31528.
  • 23
    Bialy TL, Whalen J, Veledar E, Lafreniere D, Spiro J, Chartier T, Chen SC. Mohs micrographic surgery vs traditional surgical excision: a cost comparison analysis. Arch Dermatol 2004; 140: 73642.
  • 24
    Silverman MK, Kopf AW, Grin CM, Bart RS, Levenstein MJ. Recurrence rates of treated basal cell carcinomas. Part 2: Curettage-electrodesiccation. J Dermatol Surg Oncol 1991; 17: 7206.
  • 25
    Bernardeau K, Derancourt C, Cambie M, Salmon-Ehr V, Morel M, Cavenelle F, Leonard F, Kalis B, Bernard P. [Cryosurgery of basal cell carcinoma: a study of 358 patients]. Ann Dermatol Venereol 2000; 127: 1759.
  • 26
    Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P, Benhamou E, Guillaume JC, Chalon R, Petit JY, Sancho-Garnier H, Prade M, Bouzy J, Chassagne D. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer 1997; 76: 1006.
  • 27
    Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 2000; 136: 100711.
  • 28
    Göppner D, Leverkus M. Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer 2011; 2011: 650258.
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  • 30
    Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, Coppola C, Chanana AM, Marji J, Bickers DR, Epstein EH, Jr. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366: 21808.
  • 31
    Kudchadkar R, Lewis K, Gonzalez R. Advances in the treatment of Basal cell carcinoma: Hedgehog inhibitors. Semin Oncol 2012; 39: 13944.
  • 32
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  • 33
    Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin cancer: a practical review. J Am Acad Dermatol 2010; 63: 689702.
  • 34
    Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol 2007; 56: 98993.
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    Donahue B, Cooper JS, Rush S. Treatment of aggressive keratoacanthomas by radiotherapy. J Am Acad Dermatol 1990; 23: 48993.
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    McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol 1999; 140: 65660.
  • 43
    Anforth R, Blumetti TC, Mohd AA, Fernandez-Penas P. Systemic retinoid therapy for chemoprevention of nonmelanoma skin cancer in a patient treated with vemurafenib. J Clin Oncol 2012; 30: e165–e167.
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    Apalla Z, Sotiriou E, Chovarda E, Lefaki I, Devliotou-Panagiotidou D, Ioannides D. Skin cancer: preventive photodynamic therapy in patients with face and scalp cancerization. A randomized placebo-controlled study. Br J Dermatol 2010; 162: 1715.
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    Gross G, Gissmann L, Hillemanns P, Ikenberg H, Kaufmann AM, Petry KU, Pfister H, Schneede P, Schneider A, Smola S. [Prevention of HPV-associated neoplasias by vaccination – short version of the German S3 (level 3) guideline]. Dtsch Med Wochenschr 2010; 135: 10836.
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Fragen zur Zertifizierung durch die DDA

  1. Top of page
  2. Summary
  3. Therapy of squamous cell carcinoma (SCC)
  4. Modalities for the treatment of KIN
  5. Invasive squamous cell carcinoma (SCC)
  6. Therapy of basal cell carcinoma (BCC)
  7. Therapy of keratoacanthoma (KA)
  8. Prevention of malignant epithelial skin tumors
  9. References
  10. Fragen zur Zertifizierung durch die DDA
  • 1
    Welche Aussage ist richtig? Basalzellkarzinome in Hochrisikolokalisationen…
    • a. 
      sollten kürettiert werden.
    • b. 
      sollten mittels mikrographisch-kontrollierter Chirurgie (MKC) entfernt werden.
    • c. 
      sollten durch photodynamische Therapie (PDT) behandelt werden.
    • d. 
      sollten mit Imiquimod-Creme therapiert werden.
    • e. 
      können rezidivfrei mit der MKC exzidiert werden.
  • 2
    Für die Differenzialtherapie des Plattenepithelkarzinoms (PEK) in situ (KIN) gilt:
    • a. 
      Bei der Behandlung mit PDT können Erosionen, Pusteln, Krusten und Erythem entstehen.
    • b. 
      Bei der Kryotherapie entstehen selten Hypopigmentierungen.
    • c. 
      Die Therapie der Cheilitis actinica muss operativ erfolgen.
    • d. 
      Es sollte eine Sentinel-Lymphknoten-Biopsie erwogen werden.
    • e. 
      Bei KIN Grad III muss anders als bei KIN I oder II therapiert werden.
  • 3
    Bei einer 52-jährigen nierentransplantierten Patientin (Phototyp I–II) und mehreren epithelialen Hauttumoren in der Eigenanamnese…
    • a. 
      muss zwingend eine HPV-Impfung gegen Hochrisiko-HPV erfolgen.
    • b. 
      wäre eine Desensibilisierung durch UVB-Lichttherapie angezeigt.
    • c. 
      sind ausschliefllich dreimonatige dermatologische Kontrolluntersuchungen und ein konsequenter Sonnenschutz zu empfehlen.
    • d. 
      sollte eine Chemoprophylaxe mit systemischen Retinoiden durchgeführt werden.
    • e. 
      wären topische Retinoide zur Sekundärprophylaxe epithelialer Tumoren geeignet.
  • 4
    Bei einem Patienten mit Leberzirrhose wegen chronisch-aktiver Hepatitis C und 5 rasch proliferierenden Keratoakanthomen (KA)…
    • a. 
      gibt es keine Alternative zur chirurgischen Exzision.
    • b. 
      wäre eine Therapie mit intraläsionalem Methotrexat die Therapie der ersten Wahl.
    • c. 
      ist die Radiotherapie kontraindiziert.
    • d. 
      kann die Spontanregression unter engmaschiger dermatologischer Kontrolle abgewartet werden.
    • e. 
      wäre eine Laserbehandlung die Therapie der ersten Wahl.
  • 5
    Bei einem Rezidiv eines Basalzellkarzinoms (BZK) an der Ohrhelix (Z. n. zweimaliger Kürettage und Elektrodesikkation)…
    • a. 
      sollte eine erneute operative Behandlung mittels Kürettage und Elektrodesikkation erfolgen.
    • b. 
      wäre eine konventionelle einzeitige Exzision zu empfehlen.
    • c. 
      liegt eine Indikation zur mikrographisch-kontrollierten Chirurgie vor.
    • d. 
      wäre eine Umstellung auf eine topischen Therapie mit 5 % Imiquimod-Creme 5 x pro Woche über 6 Wochen sinnvoll.
    • e. 
      würden 2–3 Zyklen einer Kryochirurgie zur Behandlung ausreichen.
  • 6
    Welche Aussage ist falsch? Eine Radiotherapie kann bei folgenden Entitäten erwogen werden…
    • a. 
      bei einem inoperablen präaurikulären PEK mit Beteiligung der Orbita.
    • b. 
      bei einem R1-resezierten BZK vom sklerodermiformen Typ der Wange.
    • c. 
      bei einem rasch proliferierenden 5 cm groflen Keratoakanthom am Handrücken.
    • d. 
      bei einem infiltrativen BZK der Oberlippe bei einem Patienten mit Basalzellnävus-Syndrom.
    • e. 
      bei einem vollständig entfernten PEK, Tumordicke 7 mm und perineuraler Invasion an der Stirn einer 70-jährigen immunsupprimierten Patientin.
  • 7
    Welche Aussage zur Rezidivprophylaxe von PEK der Haut trifft nicht zu?
    • a. 
      Retinoide (z. B. Acitretin) können zur Rezidivprophylaxe von PEK und KA bei einer Therapie mit BRAF-Inhibitoren eingesetzt werden.
    • b. 
      Retinoide können zur Rezidivprophylaxe bei chronisch immunsupprimierten Patienten eingesetzt werden.
    • c. 
      Durch eine HPV-Impfung kann die Inzidenz analer intraepithelialer Neoplasien (AIN) reduziert werden.
    • d. 
      Konsequenter UV-Schutz führt zu einem Rückgang neuentstehender KIN.
    • e. 
      Topische Retinoide reduzieren die Häufigkeit des Neuauftretens von KIN.
  • 8
    Welche Aussage zu BZK trifft zu?
    • a. 
      Zur Therapie lokal fortgeschrittener inoperabler BZK ist die Radiotherapie indiziert.
    • b. 
      Zur Therapie lokal fortgeschrittener inoperabler BZK können Sonic-Hedgehog-Inhibitoren der Klasse der Smo-Inhibitoren nicht eingesetzt werden.
    • c. 
      Zur Therapie von Patienten mit Basalzellnävus-Syndrom (BCNS) sind Smo-Inhibitoren kontraindiziert.
    • d. 
      Typische Nebenwirkungen von Smo-Inhibitoren sind Hypertrichose und pustulöse Exantheme.
    • e. 
      Sklerodermiforme BZK können mit topischen Therapien gut therapiert werden.
  • 9
    Welche Aussage zum fortgeschrittenen PEK der Haut trifft nicht zu?
    • a. 
      Alle derzeitig zur Verfügung stehenden Therapeutika werden in palliativer Absicht gegeben.
    • b. 
      Eine adjuvante Radiotherapie der Lymphknotenstationen kann die Prognose des Hochrisiko-PEK der Haut nicht verbessern.
    • c. 
      Zur Therapie des metastasierten PEK der Haut sind zahlreiche randomisierte Studien durchgeführt worden.
    • d. 
      Extrapolation der Studienergebnisse des HNSCC (head and neck squamous cell carcinoma) für das PEK der Haut lassen vermuten, dass eine Kombinationstherapie von EGF-Inhibitoren mit der Radiotherapie oder Chemotherapie eine Prognoseverbesserung quoad vitam erreichen können.
    • e. 
      Tumorgröfle, Eindringtiefe und wenige histologische Kriterien (Differenzierung, Desmoplasie, perineurale Invasion) erlauben eine adäquate Abschätzung des Metastasierungsrisikos des PEK der Haut.
  • 10
    Welche Aussage trifft nicht zu? Topische Behandlungsoptionen für KIN sind…
    • a. 
      5 % 5-FU-Salbe
    • b. 
      Ingenolmebutat-Gel
    • c. 
      Diclofenac/Hyaluronsäure-Gel
    • d. 
      5 % Imiquimod-Creme
    • e. 
      Bleomycin-Salbe

Liebe Leserinnen und Leser,

der Einsendeschluss an die DDA für diese Ausgabe ist der 19. Februar 2013.

Die richtige Lösung zum Thema –Opportunistische filamentöse Mykosen: Aspergillose, Mukormykose, Phäohypho- und Hyalohyphomykose” in Heft 9 (September 2012) ist: 1e, 2b, 3b, 4e, 5e, 6c, 7b, 8c, 9b, 10a.

Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.