Uncommon clinical presentation in a Bulgarian patient

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1 Wien Med Wochenschr DOI /s Uncommon clinical presentation in a Bulgarian patient Georgi Tchernev Ivan Pidakev Ilia Lozev Torello Lotti Uwe Wollina Received: 29 December 2016 / Accepted: 25 January 2017 Springer-Verlag Wien 2017 Summary Basal cell carcinoma is the most frequent cutaneous neoplasm, with slowly progressive nature and locally invasive behavior. Despite the low metastatic potential, local tissue destruction and disfigurement caused by the tumor can be large if not eradicated in time by early diagnosis and treatment. Both genetic predisposition and exposure to environmental risks are involved in the pathogenesis of the malignant transformation in BCC. The total number of nonmelanocytic skin cancers is a risk factor for recurrence of previous tumor, on the one hand, as well as for the formation of new ones, on the other. It is still unclear what environmental and genetic factors contribute to the development of multiple nonsyndromic BCCs. We present a man with multi- Professor G. Tchernev ( ) Department of Dermatology and Dermatologic Surgery, Medical Institute of Ministry of Interior (MVR), Generel Skobelev 79, 1606 Sofia, Bulgaria georgi_tchernev@yahoo.de I.Pidakev,PhD Assoc.Prof.I.Lozev,MD Department of General, Vascular and Abdominal Surgery, Medical Institute of Ministry of Interior, Generel Skobelev 79, 1606 Sofia, Bulgaria I. Pidakev, PhD ipidakev@abv.bg Assoc.Prof.I.Lozev,MD ilialozev@gbg.bg Prof. Dr. Hon.-Prof. T. Lotti, MD University of Rome G. Marconi, Rome, Italy professor@torellolotti.it Prof. Dr. U. Wollina Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, Dresden, Germany wollina-uw@khdf.de ple sporadic, nonsyndromic BCCs, with a history of even more lesions, removed earlier, as we discuss the potential triggering risk factors and pathogenic mechanisms of malignant transformation and the further appropriate therapeutic options. The early detection and eradication of these tumors are of importance for treatment effectiveness and quality of life because although rarely metastatic, BCCs could have an aggressive course and behavior which can lead to severe disfiguration and destruction. eywords Multiple basal cell carcinoma Nonmelanoma skin cancer BCC Introduction Basal cell carcinoma (BCC) is the most frequent cutaneous neoplasm, with slowly progressive nature and locally invasive behavior [1]. Despite the low metastatic potential, local tissue destruction and disfigurement caused by the tumor can be enormous if not completely eradicated by early diagnosis and treatment [1, 2]. Although BCC can be manifested in several subtypes with variable clinical presentation and histological appearance, variations in tumor numbers and rate of tumor accrual have also been reported [3]. Both genetic predisposition and exposure to environmental risks are involved in the pathogenesis of the malignant transformation in BCC [2, 3]. A mutation in Patched, a tumor suppressor gene, has been established as a major responsible factor for the development of BCC [1, 4]. It seems that not only fairskinned people are at risk. Disturbance of multiple lines of tumor defense appears to be important for the malignant transformation and further spread, including impairment of deoxyribonucleic acid (DNA) repair, immunosurveillance, and cellular growth regulation [1]. Ultraviolet light (UV) exposure is a major

2 Fig. 1 a,b Clinical manifestation of ulcerative basal cell carcinoma, located on the left lower limb in 82-year-old patient, with medical history for multiple BCCs. c,d Intraoperative findings. Surgical excision of the same lesion. e,f Full-thickness mesh graft 4 weeks later factor contributing to all of the facettes mentioned above [2]. An increased risk of new BCCs is seen in patients who already had such a tumor [4]. Aberrant activation of the Hedgehog pathway is the major pathway in the pathogenesis of sporadic BCC as well as in multiple BCC-related nevus syndrome (BCCNS) with loss of function of PTCH1 in most cases, but sometimes mutations of SMO or SUFU [4]. Despite the lower BCC-induced mortality, compared to other cutaneous tumors, the considerable morbidity is still an unsolved problem [2]. We present a male patient with multiple sporadic, nonsyndromic BCCs, with a history of even more lesions, removed earlier, as we discuss the potential triggering risk factors and pathogenic mechanisms of malignant transformation and the further appropriate therapeutic options. Case report An 82-year-old man was admitted to the dermatological unit for surgical removal of multiple cutaneous tumors with several years of duration. According to patient s history, multiple skin cancers, histologically verified as BCCs, had been already removed several years ago; the last surgical procedure was 2 years ago.

3 Fig. 2 a Clinical manifestation of the second ulcerative BCC, located on the right lower limb of the same patient.b e Intraoperative findings of the surgical excision of the same lesion Fig. 3 a d Clinical manifestation of the third BCC, located on the forehead, with subsequent surgical removal Arterial hypertension, diabetes, and prostate hyperplasia controlled with medications were reported for the medical history. The patient had a positive history for high-risk professional exposure to radioactivity when he was younger and several severe sun burns. No family history for dermatological diseases was reported. Multiple cutaneous tumors were established by the dermatological examination in this fair-skinned, blueeyed patient. The total body examination revealed actinic and age amendments on the skin, as well as multiple cicatrices from the former surgical interventions and also at least 11 new cutaneous tumors with similar clinical appearance. Two ulcerations were observed, one measuring approximately 5 4 cm in diameter, located on his right lower limb, and a second one, measuring approximately 3 3 cm, was located on the left lower limb. Both showed pearl-like edges, bleeding surface, and irregular borders (Figs. 1 and 2). Five cutaneous tumor lesions were noted on his back and shoulder (Fig. 4), two on his thorax, and one on his forehead (Fig. 3). All of the lesions demonstrated similar clinical signs irregular borders with pearl-like edges, some of them with erosive surface, covered with brownish crusts. Telangiectasias were established around almost all of the lesions. All of the lesions were clinically and dermatoscopically suspicious for BCC in different stages of invasion. Onestage surgical excision of eight of the tumors was performed under local anesthesia (Figs. 1, 2, 3, and4); the surgical removal of the three remaining lesions was planned for the second stage. Vacuum therapy was applied once daily to the pretibial postsurgical

4 Fig. 4 a d Clinical manifestation of the multiple BCC, located on the back and shoulder, with similar clinical appearance and their subsequent surgical removal defect to optimize the granulation processes. Fullthickness skin transplantation was done 4 weeks later (Fig. 1a, b). The postsurgical period was unremarkable without complications and the patient was satisfied with the result. Histologpathology confirmed the diagnosis of BCCs with adenomatous and mucinous differentiation and one tumor was classified as morphea-like. The laboratory blood tests and imaging diagnostic procedures did not revealed any abnormalities nor signs for systemic involvement. Discussion Recent reports show that the number of patients who develop more than one BCC is increasing [4 6]. The total number of nonmelanocytic skin cancers is a risk factor for recurrence of previous tumor, on the one hand, and for the formation of new ones, on the other [6]. In the same manner, multiple BCCs (mbccs) in one patient increases the risk of recurrence and they often develop new BCCs with similar or different histological appearance [5, 6]. A retrospective study from Bulgaria, performed by Troyanova et al. (1993), covering 2620 cases (1335 males and 1285 females) with nonmelanoma skin cancers registered in the Bulgarian National Cancer Registry showed an increased risk for occurrence of second primary cancers of head and neck, thyroid, lung, larynx, bladder, colon, as well as cutaneous malignant melanoma, non-hodgkin s lymphoma, and leukemia among patients with primary removed nonmelanoma skin cancers [7]. The evaluation of BCCs within the cohort also showed a higher risk for second primary tumors of head and neck, bladder, larynx, lung, and colon as well as non-hodgkin s lymphoma and cutaneous malignant melanoma [7]. The association of nonmelanoma cutaneous neoplasms, including BCC to subsequent increased risk for appearance of second primary cutaneous and visceral tumors has been confirmed by other studies [4 8]. These patients should be monitored by a regular tumor follow-up. Some studies concluded that different factors mediate the numbers of BCC/year in males and females, while the individual factors contributing to the risk is modest [9]. Investigation of clinical risk factors associated with patients with mbcc revealed that positive family history in parents or siblings is a strong risk factor for occurrence of mbccs [10]. Sunburns

5 (as reported in our patient) after the age of 60 significantly increase the risks for mbccs, especially in men (this seems to be due to professional differences between men and women), while sun-sensitive skin per se was not a significant risk nor were fair eye color or hair color [10]. The controversial data on the significance of skin type suggest that BCC development is multifactorial. Genetic background plays a role, since the hedgehog (Hh) signaling pathway is aberrantly activated in the majority of sporadic, nonsyndromicbccs,aswellasinsyndromeswithmultiple BCCs, as in Gorlin Goltz syndrome (PTCH1 or SUFU variants) [11]. Furthermore, BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk of occurrence of specific cutaneous lesions in young individuals, including atypical Spitz tumors, uveal melanoma, malignant mesothelioma, cutaneous melanoma, clear cell renal cell carcinoma, and BCC, with more than one type of primary cancer [11]. Despite the autosomal dominant manner of inheritance, the proportion of BAP1-TPDS caused by a de novo pathogenic mutation is unknown [11]. However, the incomplete penetrance determines variations in numbers and type of BAP1-related tumors among different members of the same family [11]. Conclusions The contribution of various environmental and genetic factors in the development of sporadic mbccs is debatable. Nevertheless, occupational exposure to UV-light is a significant factor [12]. In the presented case, fair-skinned but negative family history, multiple sporadic BCCs developed starting when he was middle aged. The early detection and eradication of these tumors is of a great importance for treatment effectiveness and quality of life because although rarely metastatic, BCCs could have an aggressive course and behavior which can lead to severe disfiguration and destruction [1]. The best therapeutic option is early, complete excision and long-term follow-up and monitoring of the patient, regarding the high risk of recurrence and de novo development of nonmelanoma skin cancers [1]. Hedgehog pathway inhibitor therapy with vismodegib or sonedigib could be used in locally advanced inoperable cases and metastatic basal cell carcinoma [13, 14]. Conflict of interest G.Tchernev,I.Pidakev,I.Lozev,T.Lotti, and U. Wollina declare that they have no competing interests. References 1. Hallaji Z, Rahimi H, Mirshams-Shahshahani M. Comparison of risk factors of single basal cell carcinoma with multiple basal cell carcinomas. Indian J Dermatol. 2011;56(4): Lear W, Dahlke E, Murray CA. Basal cell carcinoma: review of epidemiology, pathogenesis, and associated risk factors. JCutanMedSurg. 2007;11(1): Madan V, Hoban P, Strange RC, Fryer AA, Lear JT. Genetics and risk factors for basal cell carcinoma. Br J Dermatol. 2006;154(Suppl1): Marghoob A, opf AW, Bart RS, Sanfilippo L, Silverman M, LeeP,LevyE,VossaertA,YadavS,AbadirM.Riskofanother basal cell carcinoma developing after treatment of a basal cellcarcinoma. JAmAcadDermatol. 1993;28(1): Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanomaskincancer. ArchDermatol. 2000;136: Chen J, Ruczinski I, Jorgensen TJ, Yenokyan G, Yao Y, Alani R, et al. Nonmelanoma skin cancer and risk for subsequent malignancy. JNatlCancerInst. 2008;100: Troyanova P, Danon S, Ivanova T. Nonmelanoma skin cancersandriskofsubsequentmalignancies: acancerregistrybasedstudyinbulgaria. Neoplasma. 2002;49: LeviF,RandimbisonL,MaspoliM,TeVC,LaVecchiaC.High incidence of second basal cell skin cancers. Int J Cancer. 2006;119: Ramachandran S, Fryer AA, Lovatt TJ, Smith AG, Lear JT, JonesPW, StrangeRC. Combinedeffectsof gender, skintype and polymorphic genes on clinical phenotype: use of rate of increase in numbers of basal cell carcinomas as a model system. CancerLett. 2003;189(2): Wallberg P, aaman T, Lindberg M. Multiple basal cell carcinoma. A clinical evaluation of risk factors. Acta Derm Venereol. 1998;78: Sekulic A, Von Hoff D. Hedgehog pathway inhibition. Cell. 2016;164(5): Bauer A, Diepgen TL, Schmitt J. Is occupational solar ultravioletirradiationarelevantriskfactor for basalcellcarcinoma? A systematic review and meta-analysis of the epidemiologicalliterature. BrJDermatol. 2011;165(3): Jacobsen AA, Aldahan AS, Hughes OB, Shah VV, Strasswimmer J. Hedgehog pathway inhibitor therapy for locally advancedandmetastaticbasalcellcarcinoma: asystematic review and pooled analysis of interventional studies. JAMA Dermatol. 2016;152(7): Ramelyte E, Amann VC, Dummer R. Sonidegib for the treatment of advanced basal cell carcinoma. Expert Opin Pharmacother. 2016;17(14): I. Pidakev, Specialistfor GeneralSurgery Assoc. Prof. I. Lozev, Specialist for General and Vascular Surgery Prof. Dr. Hon.-Prof. T. Lotti, MD (Hon)-Professor and Chair ofdermatology