main topic Wien Med Wochenschr (2013) 163:347–353 DOI 10.1007/s10354-013-0193-5
Advanced basal cell carcinoma Uwe Wollina, Georgi Tchernev
Received: 10 February 2013 / Accepted: 13 March 2013 / Published online: 16 April 2013 © Springer-Verlag Wien 2013
Summary Basal cell carcinoma (BCC) is the most common skin malignancy worldwide. Ultraviolet light exposure is the best known exogenous factor in BCC development. This is also the target for primary prevention. Advanced BCC include locally advanced tumors and metastatic tumors. Prognosis is worse compared to stage I and II BCCs. Mohs or micrographically controlled surgery is the gold standard of treatment. In patients with tumors that cannot be completely removed radiotherapy was the only alternative in the past. More recently new drugs for targeted therapy of signaling pathways like sonic hedgehog or epidermal growth factor receptor became available. More small molecules are under investigation. Since the complete response rates are limited, future research has to evaluate their combination with surgery.
dem Begriff der fortgeschrittenen BCC werden lokal ausgedehnte Tumore und metastasierende Tumore zusammengefaßt. Ihre Prognose ist deutlich schlechter als bei den Stadien I und II. Mohs- oder mikrographischkontrollierte Chirurgie gilt als Goldstandard in der Behandlung. Bei Patienten, wo eine komplette Exzision des Tumors unmöglich war, blieb in der Vergangenheit nur die Strahlentherapie als Alternative. In jüngerer Zeit gibt es Medikamente für eine zielgerichtete Behandlung mit Beeinflussung von Signalkaskaden wie Sonic hedgehog oder epidermalem Wachstumsfaktor-Rezeptor. Weitere kleine Moleküle werden geprüft. Da bislang die kompletten Remissionsraten unter dieser Therapie limitiert sind, gilt es ihre bestmögliche Kombination mit der Chirurgie zu bestimmen.
Keywords: Basal cell carcinoma, Ultraviolet-light exposure, Sonic hedgehog, Epidermal growth factor, Surgery
Schlüsselwörter: Basalzellkarzinom, UltraviolettExposition, Sonic hedgehog, Epidermaler Wachstumsfaktor, Chirurgie
Das fortgeschrittene Basalzellkarzinom
Basal cell carcinoma
Zusammenfassung Das Basalzellkarzinom (BCC) ist weltweit der häufigste maligne Tumor. Die Exposition gegenüber ultravioletter Strahlung gilt als bekanntester exogener Faktor in der BCC-Entwicklung. Hierauf zielen auch alle primären Präventionsmaßnahmen. Unter
Basal cell carcinoma (BCC) is the most common type of skin cancer worldwide. The highest incidence is found among Australians with a European background (884 per 100,000 person-year) [1]. The incidence in Germany is estimated as 80 per 100,000 person-year [2]. In the last 3 decades, a worldwide increase of BCC incidence was noted including countries such as Brazil, India, or China [3–6]. Although BCC is a locally invasive and destructive malignancy, metastatic spread is rare and mostly seen in advanced and often neglected BCC with a frequency ≤ 0.5 % [7]. Typical BCC is a slowly growing tumor occurring preferentially but not exclusively in sun exposed areas. Sun exposure (ultraviolet radiation) is the most important occupational risk factor for BCC. BCC has
U. Wollina, MD () Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany e-mail:
[email protected] G. Tchernev, MD, PhD Policlinic for Dermatology and Venereology, University Hospital Lozenetz, Academic Educational Hospital of the Saint Kliment Ohridski University, Koiak street 1, 1407 Sofia, Bulgaria
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Advanced basal cell carcinoma
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been a tumor of the elderly for many generations. Recently, an increase of BCC in young adults—in particular, females—has been linked to artificial tanning (sun beds) [8, 9]. Additional risk factors include burns, arsenics, chronic wounds, HIV infection and AIDS, organ transplantation, ionizing radiation, and other immunosuppressive conditions [10]. Some rare genetic conditions are responsible for BCC during childhood and adolescence, like Gorlin-Goltz or basal cell nevus syndrome, Bazex-Dupré-Christol syndrome, Rombo syndrome, cartilage-hair dysplasia, albinism, and xeroderma pigmentosum [11]. Primary prevention of BCC aims to reduce ultraviolet radiation (UVR) exposure. Avoidance of midday sun exposure, protective clothes, and sun blocker are recommended. Direct evidence for the prevention of BCC by regular use of sun blockers is missing in contrast to actinic keratoses [12, 13]. Chemoprevention of BCC with topical tretinoin 0.1 % has not been successful [14]. Systemic retinoids like isotretinoin or acitretin have been used in high-risk transplant patients [15]. Because of their teratogeneity and other adverse effects, their applicability and long-term use is limited. Celecoxib, a cylooxygenase-2 inhibitor, was used for prevention of nonmelanoma skin cancer in middle aged adults with actinic damage. The drug was given in a daily dosage of 200 mg p.o. for 9 months. Eleven months after initiating the study, the number of BCCs was reduced. Adverse effects were similar in placebo and verum group [16].
Table 1. Staging of basal cell carcinoma Stage I
Tumors 2 cm, aggressive histopathologic subtype, with perivascular or perineural infiltration, history of radiation exposure, or previous treatment failure [41, 42] (Fig. 1). The majority of advanced BCC belong to stage III. If these tumors are 5 cm in diameter or larger they are called giant BBCs (Fig. 2). The overall cure rate drops to about 60 with 40 % of patients developing recurrences or metastatic spread within 2 years of follow-up [43]. The first treatment option is surgery including Mohs or micrographically controlled procedures.
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In about 5 % of patients a skull invasion develops. Mohs surgery or microgaphically controlled surgery is the first step. Invasive tumors may need craniectomy and dural resection. Here the interdisciplinary approach of dermatosurgery, plastic surgery, and neurosurgery is most promising, both for tumor removal as well as reconstructive surgery [44, 45]. For large skin defects tissue expansion is a useful tool. Self-fillings osmotic expanders are safe alternatives to classical tissue expanders in dermatosurgery and plastic surgery [44]. Adjuvant radiotherapy is recommended when complete excision is impossible and for tumors with perineural or perivascular invasion [43]. The five-year survival rate is 50 % [22]. Periocular advanced BCCs bear a significant risk of orbital invasion. Characteristic clinical signs are globe displacement, decreased orbital mobility, and bone infiltration. However, one-third of patients with orbital infiltration lack clinical symptoms [46]. BCCs are among the leading causes for orbital exenteration [41, 42]. In such cases a complete surgical removal is sometimes impossible. Therefore, a combination with radiotherapy is used. The nose is a predilection site for BCC. In case of advanced tumors, infiltration of cartilage and bone occurs. Other serious complications include intranasal invasion of the cribriform plate, orbital invasion, and intracranial spread [47]. Although Mohs or micrographically controlled surgery remains the cornerstone of treatment, adjuvant radiotherapy or chemotherapy may be necessary. Auricular advanced BCC tend to infiltrate deep into the subcutaneous tissue, the parotid gland, facial nerve, and bone. Adjuvant therapy after surgery may become necessary. Adjuvant chemotherapy for advanced BCC has not been investigated in randomized controlled trials Advanced basal cell carcinoma
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Fig. 2 Giant BCCs. a Giant BCC of the elbow in an 80-year-old woman. b Giant BBC of the temporal region in an 86-year-old woman, development over more than 15 years. c Ill defined
(RCTs). Therefore, the available evidence is limited. Cisplatin based neoadjuvant chemotherapy achieved complete response rates
