- Email: [email protected]
Age distribution of biopsied junctional nevi—Unna's concept versus a dual concept of nevogenesis
1096 Letters
J AM ACAD DERMATOL DECEMBER 2007
can have difficulties in establishing an ascertained identification. Identification of Fusarium spp has been greatly improved by the use of molecular genotyping.2 Indeed, more than 1000 species, varieties, and formae speciales have been described in the genus Fusarium, and species determination remains truly problematic, and the species Fusarium solani defined on morphology represents actually a complex of about 50 phylogenetic species, termed Fusarium solani species complex.3 Therefore molecular analysis is now highly recommended to achieve a reliable identification. Precise identification is important for both epidemiologic and therapeutic purposes since some new antifungal agents display a variable activity against Fusarium, depending on the species,4 although no difference in antifungal susceptibility has been documented within Fusarium solani species complex.5 Claude Bachmeyer, MD Service de Me´decine Interne, CHU Tenon (AP-HP), Paris, France Funding sources: None. Conflict of interest: None declared. Correspondence to: Claude Bachmeyer, MD, Service de Me´decine Interne, CHU Tenon (AP-HP), 4 rue de la Chine, 75020 Paris, France E-mail: [email protected] REFERENCES 1. Nakamura Y, Xu X, Saito Y, Tateishi T, Takahashi T, Kawachi Y, et al. Deep cutaneous infection by Fusarium solani in a healthy child: successful treatment with local heat therapy. J Am Acad Dermatol 2007;56:873-7. 2. Healy M, Reece K, Walton D, Huong J, Frye S, Raad II, et al. Use of the Diversi Lab System for species and strain differentiation of Fusarium species isolates. J Clin Microbiol 2005;43:5278-80. 3. Zhang N, O’Donnell K, Sutton DA, Nalim FA, Summerbell RC, Padhye AA, et al. Members of the Fusarium solani species complex that cause infections in both humans and plants are common in the environment. J Clin Microbiol 2006;44:2186-90. 4. Lewis RE, Wiederhold NP, Klepser ME. In vitro pharmacodynamics of amphotericin B, itraconazole, and voriconazole against Aspergillus, Fusarium, and Scedosporium spp. Antimicrob Agents Chemother 2005;49:945-51. 5. Azor M, Gene´ J, Cano J, Guarro J. Universal in vitro antifungal resistance of genetic clades of the Fusarium solani species complex. Antimicrob Agents Chemother 2007;51:1500-3. doi:10.1016/j.jaad.2007.08.025
Age distribution of biopsied junctional nevi— Unna’s concept versus a dual concept of nevogenesis To the Editor: We read with interest the article by Westhafer et al1 in the May 2007 issue of the Journal,
in which the authors present the results of a retrospective study investigating patient age and location of biopsied junctional nevi. On the basis of their findings, the authors conclude that junctional nevi are common in all ages with a similar distribution in the young and the elderly. In addition, they noted that junctional nevi were more common on skin that was not chronically sun exposed. These findings led the authors to question Unna’s concept of nevogenesis, which suggests that nevi begin as junctional nevi in childhood, mature into compound nevi, and finally end up as dermal nevi in adulthood. We agree that Unna’s unifying concept cannot adequately explain the authors’ findings or the many new insights into nevogenesis that we have acquired over the past decade. Unfortunately, the authors do not sufficiently address some of these points. First, the authors question Unna’s concept of nevogenesis but fail to provide a reasonable or alternative theory that could explain the results of their study. Second, the authors conclude that junctional nevi are common in all ages, but they do not address the observation that the peak incidence of junctional nevi in their series occurred during midlife, whereas the incidence in children and the elderly was found to be relatively low. Third, such study design carries a general risk of selection bias, which may not reflect reality. On the basis of dermoscopic studies on the agerelated dermoscopic patterns of nonexcised acquired nevi, we know today that nevi developing before puberty exhibit mostly a dermoscopic globular and/or homogeneous pattern, whereas nevi seen at or after puberty tend to harbor a reticular pattern.2 These dermoscopic features correspond to specific underlying histopathologic correlates. The globular/ homogeneous patterned nevi tend to be seen in small congenital melanocytic nevi, compound nevi, or dermal nevi. On the other hand, reticular pattern nevi tend to be seen in junctional nevi. These striking age-related differences in the dermoscopic pattern of acquired nevi in vivo along with their different epidemiologic, clinical, and histopathologic features led us recently to propose a dual concept of nevogenesis,2 which might explain some of the findings by Westhafer et al. This dual concept states that dermoscopically globular nevi (i.e., congenital melanocytic nevi, compound nevi, and dermal nevi) develop via an ‘‘endogenous’’ pathway involving mutations in c-kit, c-met, or N-ras, which may cause melanoblast migration arrest in the dermis.3 These nevi commonly persist throughout life and rarely regress. In contrast, reticular nevi (ie, junctional nevi) represent true ‘‘acquired’’ nevi, which develop in response to exogenous factors, such as intermittent
J AM ACAD DERMATOL
Letters 1097
VOLUME 57, NUMBER 6
ultraviolet exposure (ie, ‘‘exogenous’’ pathway). Previous studies have indeed shown a steady increase followed by a decrease in the number of nevi before and after midlife, respectively. Today, many researchers are of the opinion that intermittent rather than long-term sun exposure is the key factor in the development and disappearance of nevi. It is theorized that intermittent ultraviolet exposure may cause BRAF mutations in melanocytic stem cells at the dermoepidermal junction. This in turn may cause the mutated stem cell to proliferate and form a nevus; however, if the host’s cell-cycle checkpoint regulators are functioning normally, the cells would eventually enter senescence.4 Furthermore, it has been observed by many researchers that these true ‘‘acquired’’ nevi often undergo spontaneous regression later in life. These observations explain not only the high prevalence of junctional nevi on skin sites that are not chronically sun exposed found in the study by Westhafer et al,1 but also explain the peak incidence of junctional nevi they observed during midlife. In sum, the results reported by Westhafer et al can be plausibly explained in the view of our dual concept of nevogenesis.2 Finally, we agree with the authors that our current concept of nevus classification requires revision and we have proposed therefore a new classification of nevi based on dermoscopy.5 Iris Zalaudek, MD,a Ashfaq A. Marghoob, MD,b Alon Scope, MD,b Rainer Hofmann-Wellenhof, MD,a Gerardo Ferrara, MD,c and Giuseppe Argenziano, MDd Department of Dermatology, Medical University of Graz; Austria,a Memorial Sloan-Kettering Cancer Center, New York; New York,b Pathologic Anatomy Unit, Gaetano Rummo General Hospital, Benevento; Italy,c Department of Dermatology, Second University of Naples; Italyd Dr. Zalaudek is currently supported by the Elise Richter Program of the Austrian Science Fund (Project number: V9-B05) Conflict of interest: None declared. Correspondence to: Iris Zalaudek, MD, Department of Dermatology, Medical University of Graz; Auenbruggerplatz 8, 8036 Graz; Austria E-mail: [email protected]
REFERENCES 1. Westhafer J, Gildea J, Klepeiss S, Clarke L, Helm K. Age distribution of biopsied junctional nevi. J Am Acad Dermatol 2007;56:825-7.
2. Zalaudek I, Hofmann-Wellenhof R, Soyer HP, Ferrara G, Argenziano G. Naevogenesis: new thoughts based on dermoscopy. Br J Dermatol 2006;154:793-4. 3. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127:179-82. 4. Michaloglou C, Vredeveld LC, Soengas MS, Denoyell C, Kuliman T, Van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005; 7051:720-4. 5. Argenziano G, Zalaudek I, Ferrara G, Hofmann-Wellenhof R, Soyer HP. Proposal of a new classification system for melanocytic naevi. Br J Dermatol 2007;157:217-27. doi:10.1016/j.jaad.2007.08.028
Transdermal delivery of Clostridium botulinum toxin type A by pulsed current iontophoresis To the Editor: In a pilot study recently published in the Journal, Kavanagh and Shams1 reported that botulinum neurotoxin (BoNT) could be delivered in humans by iontophoresis to treat palmar hyperhydrosis with obvious advantages over the use of injection. Although the authors observed significant clinical effects, no data are yet available demonstrating the actual transdermal passage of BoNT. Herein we demonstrate that iontophoresis allowed the delivery of BoNT type A (BoNT/A) through living rat skin. We used a Food and Drug Administration (FDA)eapproved pulsed current iontophoresis drug delivery system (FDA approval No. K042590, October 14, 2004, Transderm Ionto System, Mattioli Engineering, McLean, Va). Experiments were performed according to Principles of Laboratory Animal Care in compliance with the Commission for Animal Experiments of the University of Firenze. Experiments were performed on male Wistar rats (Harlan, Udine, Italy), age 6 to 8 months, weight 350 6 50 g. Pulsed current iontophoresis was performed for 10 minutes following a standard procedure.2 Forty units per milliliter of BoNT/A (Vistabex, Allergan Inc, Irvine, Calif) was applied on all selected skin areas. In each experiment, one of the areas was treated with iontophoresis; on the other area, selected as the control area, no electric treatment was performed. Full-thickness biopsy specimens were obtained from treated and control areas soon after application of iontophoresis. Biopsy specimens were soaked and washed several times with phosphate-buffered saline solution, fixed, embedded, and frozen. Sections were stained with hematoxylin-eosin solution. Immunohistochemical reaction was performed by using a monoclonal antibody against BoNT/A (US Biological, Swampscott, Mass), and a biotin/avidin
J AM ACAD DERMATOL DECEMBER 2007
can have difficulties in establishing an ascertained identification. Identification of Fusarium spp has been greatly improved by the use of molecular genotyping.2 Indeed, more than 1000 species, varieties, and formae speciales have been described in the genus Fusarium, and species determination remains truly problematic, and the species Fusarium solani defined on morphology represents actually a complex of about 50 phylogenetic species, termed Fusarium solani species complex.3 Therefore molecular analysis is now highly recommended to achieve a reliable identification. Precise identification is important for both epidemiologic and therapeutic purposes since some new antifungal agents display a variable activity against Fusarium, depending on the species,4 although no difference in antifungal susceptibility has been documented within Fusarium solani species complex.5 Claude Bachmeyer, MD Service de Me´decine Interne, CHU Tenon (AP-HP), Paris, France Funding sources: None. Conflict of interest: None declared. Correspondence to: Claude Bachmeyer, MD, Service de Me´decine Interne, CHU Tenon (AP-HP), 4 rue de la Chine, 75020 Paris, France E-mail: [email protected] REFERENCES 1. Nakamura Y, Xu X, Saito Y, Tateishi T, Takahashi T, Kawachi Y, et al. Deep cutaneous infection by Fusarium solani in a healthy child: successful treatment with local heat therapy. J Am Acad Dermatol 2007;56:873-7. 2. Healy M, Reece K, Walton D, Huong J, Frye S, Raad II, et al. Use of the Diversi Lab System for species and strain differentiation of Fusarium species isolates. J Clin Microbiol 2005;43:5278-80. 3. Zhang N, O’Donnell K, Sutton DA, Nalim FA, Summerbell RC, Padhye AA, et al. Members of the Fusarium solani species complex that cause infections in both humans and plants are common in the environment. J Clin Microbiol 2006;44:2186-90. 4. Lewis RE, Wiederhold NP, Klepser ME. In vitro pharmacodynamics of amphotericin B, itraconazole, and voriconazole against Aspergillus, Fusarium, and Scedosporium spp. Antimicrob Agents Chemother 2005;49:945-51. 5. Azor M, Gene´ J, Cano J, Guarro J. Universal in vitro antifungal resistance of genetic clades of the Fusarium solani species complex. Antimicrob Agents Chemother 2007;51:1500-3. doi:10.1016/j.jaad.2007.08.025
Age distribution of biopsied junctional nevi— Unna’s concept versus a dual concept of nevogenesis To the Editor: We read with interest the article by Westhafer et al1 in the May 2007 issue of the Journal,
in which the authors present the results of a retrospective study investigating patient age and location of biopsied junctional nevi. On the basis of their findings, the authors conclude that junctional nevi are common in all ages with a similar distribution in the young and the elderly. In addition, they noted that junctional nevi were more common on skin that was not chronically sun exposed. These findings led the authors to question Unna’s concept of nevogenesis, which suggests that nevi begin as junctional nevi in childhood, mature into compound nevi, and finally end up as dermal nevi in adulthood. We agree that Unna’s unifying concept cannot adequately explain the authors’ findings or the many new insights into nevogenesis that we have acquired over the past decade. Unfortunately, the authors do not sufficiently address some of these points. First, the authors question Unna’s concept of nevogenesis but fail to provide a reasonable or alternative theory that could explain the results of their study. Second, the authors conclude that junctional nevi are common in all ages, but they do not address the observation that the peak incidence of junctional nevi in their series occurred during midlife, whereas the incidence in children and the elderly was found to be relatively low. Third, such study design carries a general risk of selection bias, which may not reflect reality. On the basis of dermoscopic studies on the agerelated dermoscopic patterns of nonexcised acquired nevi, we know today that nevi developing before puberty exhibit mostly a dermoscopic globular and/or homogeneous pattern, whereas nevi seen at or after puberty tend to harbor a reticular pattern.2 These dermoscopic features correspond to specific underlying histopathologic correlates. The globular/ homogeneous patterned nevi tend to be seen in small congenital melanocytic nevi, compound nevi, or dermal nevi. On the other hand, reticular pattern nevi tend to be seen in junctional nevi. These striking age-related differences in the dermoscopic pattern of acquired nevi in vivo along with their different epidemiologic, clinical, and histopathologic features led us recently to propose a dual concept of nevogenesis,2 which might explain some of the findings by Westhafer et al. This dual concept states that dermoscopically globular nevi (i.e., congenital melanocytic nevi, compound nevi, and dermal nevi) develop via an ‘‘endogenous’’ pathway involving mutations in c-kit, c-met, or N-ras, which may cause melanoblast migration arrest in the dermis.3 These nevi commonly persist throughout life and rarely regress. In contrast, reticular nevi (ie, junctional nevi) represent true ‘‘acquired’’ nevi, which develop in response to exogenous factors, such as intermittent
J AM ACAD DERMATOL
Letters 1097
VOLUME 57, NUMBER 6
ultraviolet exposure (ie, ‘‘exogenous’’ pathway). Previous studies have indeed shown a steady increase followed by a decrease in the number of nevi before and after midlife, respectively. Today, many researchers are of the opinion that intermittent rather than long-term sun exposure is the key factor in the development and disappearance of nevi. It is theorized that intermittent ultraviolet exposure may cause BRAF mutations in melanocytic stem cells at the dermoepidermal junction. This in turn may cause the mutated stem cell to proliferate and form a nevus; however, if the host’s cell-cycle checkpoint regulators are functioning normally, the cells would eventually enter senescence.4 Furthermore, it has been observed by many researchers that these true ‘‘acquired’’ nevi often undergo spontaneous regression later in life. These observations explain not only the high prevalence of junctional nevi on skin sites that are not chronically sun exposed found in the study by Westhafer et al,1 but also explain the peak incidence of junctional nevi they observed during midlife. In sum, the results reported by Westhafer et al can be plausibly explained in the view of our dual concept of nevogenesis.2 Finally, we agree with the authors that our current concept of nevus classification requires revision and we have proposed therefore a new classification of nevi based on dermoscopy.5 Iris Zalaudek, MD,a Ashfaq A. Marghoob, MD,b Alon Scope, MD,b Rainer Hofmann-Wellenhof, MD,a Gerardo Ferrara, MD,c and Giuseppe Argenziano, MDd Department of Dermatology, Medical University of Graz; Austria,a Memorial Sloan-Kettering Cancer Center, New York; New York,b Pathologic Anatomy Unit, Gaetano Rummo General Hospital, Benevento; Italy,c Department of Dermatology, Second University of Naples; Italyd Dr. Zalaudek is currently supported by the Elise Richter Program of the Austrian Science Fund (Project number: V9-B05) Conflict of interest: None declared. Correspondence to: Iris Zalaudek, MD, Department of Dermatology, Medical University of Graz; Auenbruggerplatz 8, 8036 Graz; Austria E-mail: [email protected]
REFERENCES 1. Westhafer J, Gildea J, Klepeiss S, Clarke L, Helm K. Age distribution of biopsied junctional nevi. J Am Acad Dermatol 2007;56:825-7.
2. Zalaudek I, Hofmann-Wellenhof R, Soyer HP, Ferrara G, Argenziano G. Naevogenesis: new thoughts based on dermoscopy. Br J Dermatol 2006;154:793-4. 3. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127:179-82. 4. Michaloglou C, Vredeveld LC, Soengas MS, Denoyell C, Kuliman T, Van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005; 7051:720-4. 5. Argenziano G, Zalaudek I, Ferrara G, Hofmann-Wellenhof R, Soyer HP. Proposal of a new classification system for melanocytic naevi. Br J Dermatol 2007;157:217-27. doi:10.1016/j.jaad.2007.08.028
Transdermal delivery of Clostridium botulinum toxin type A by pulsed current iontophoresis To the Editor: In a pilot study recently published in the Journal, Kavanagh and Shams1 reported that botulinum neurotoxin (BoNT) could be delivered in humans by iontophoresis to treat palmar hyperhydrosis with obvious advantages over the use of injection. Although the authors observed significant clinical effects, no data are yet available demonstrating the actual transdermal passage of BoNT. Herein we demonstrate that iontophoresis allowed the delivery of BoNT type A (BoNT/A) through living rat skin. We used a Food and Drug Administration (FDA)eapproved pulsed current iontophoresis drug delivery system (FDA approval No. K042590, October 14, 2004, Transderm Ionto System, Mattioli Engineering, McLean, Va). Experiments were performed according to Principles of Laboratory Animal Care in compliance with the Commission for Animal Experiments of the University of Firenze. Experiments were performed on male Wistar rats (Harlan, Udine, Italy), age 6 to 8 months, weight 350 6 50 g. Pulsed current iontophoresis was performed for 10 minutes following a standard procedure.2 Forty units per milliliter of BoNT/A (Vistabex, Allergan Inc, Irvine, Calif) was applied on all selected skin areas. In each experiment, one of the areas was treated with iontophoresis; on the other area, selected as the control area, no electric treatment was performed. Full-thickness biopsy specimens were obtained from treated and control areas soon after application of iontophoresis. Biopsy specimens were soaked and washed several times with phosphate-buffered saline solution, fixed, embedded, and frozen. Sections were stained with hematoxylin-eosin solution. Immunohistochemical reaction was performed by using a monoclonal antibody against BoNT/A (US Biological, Swampscott, Mass), and a biotin/avidin