Squamous cell carcinoma arising from a localized vulval lesion of Hailey-Hailey disease after tacrolimus therapy
2010; Elsevier BV; Volume: 203; Issue: 3 Linguagem: Inglês
10.1016/j.ajog.2010.06.041
ISSN1097-6868
AutoresV. von Felbert, Monika Hampl, Carolina Talhari, Rainer Engers, Mosaad Megahed,
Tópico(s)Genital Health and Disease
ResumoHailey-Hailey disease (HHD) is a rare, autosomal dominant intraepidermal blistering disorder characterized by recurrent vesicles and erosions affecting mostly the intertriginous areas. We report a case of HHD affecting exclusively the vulva from which an invasive squamous cell carcinoma developed after tacrolimus therapy. Hailey-Hailey disease (HHD) is a rare, autosomal dominant intraepidermal blistering disorder characterized by recurrent vesicles and erosions affecting mostly the intertriginous areas. We report a case of HHD affecting exclusively the vulva from which an invasive squamous cell carcinoma developed after tacrolimus therapy. A 44-year-old female patient was seen in February 2004 with a 6 month history of vulval erosion. Past medical history included a dysgerminoma of the ovary with peritoneal involvement at the age of 12 years. After laparotomy with tumor resection, she had been treated with radiotherapy of the right pelvis (Co60, 4.000 Ra) and chemotherapy (methotrexate, cyclophosphamide, and dactinomycin) every 2 months for 1 year. The vulva was not irradiated. At the age of 15 years, she was diagnosed to have primary amenorrhea because of ovarian failure (high luteinizing hormone level); since then she has been treated with estrogen.Case ReportAt presentation, physical examination revealed an ulceration within a well-defined whitish plaque-like lesion of the left labia minora, which was clinically diagnosed as herpetic infection (Figure 1, A). There was no involvement of other regions of the body in particular neck, axillae, groins, and nails were normal. A biopsy of the lesion revealed parakeratosis and dyskeratotic acantholytic cells with a suprabasal cleft; cells of the central layer of the epidermis showed partial separation from adjacent cells giving the appearance of a dilapidated brick wall (Figure 1, B). Direct immunofluorescence was negative.Based on the clinical and histological examination, a diagnosis of Hailey-Hailey disease (HHD) of the vulva was made. She had no family history of HHD. Herpetic, candidal, and bacterial infections were excluded.Treatment with topical tacrolimus 0.1% ointment once daily improved the HHD lesions (treatment period 2004: 7-8 months; period without tacrolimus therapy: 7 months; treatment period 2005: 2 months). However, over several months, a small scar-like lesion on the left labia minora developed, which was initially thought to be a wound-healing disturbance after the biopsy (Figure 1, C). This lesion gradually increased in size and hardened.In June 2005, 1 year after diagnosis of HHD, the patient represented with a protruding tumour on the left side of the labia minora involving also the left paraclitoral region (Figure 2, A). Examination of the vagina, uterine cervix, inguinal lymph nodes, and perianal region showed no abnormalities. Cervical smears displayed no signs of malignancy. Routine laboratory investigations were within the normal ranges. Histological examination of a biopsy of the tumor showed a p53 immunoreactive, invasive squamous cell carcinoma (SCC) in which strands and masses of immature squamous cells with dyskeratosis infiltrated deeply into the dermis (Figure 2, B). Additionally, HHD was again present in the form of epidermal acantholysis on the edge of the section (Figure 2, C).FIGURE 2Protruding tumor on the left side of the labia minoraShow full captionA, Protruding tumor on the left side of the labia minora involving also the left paraclitoral region. B, Histological examination revealed a p53 immunoreactive, invasive SCC (p53 immunostaining). C, Epidermal acantholysis at the edge of the section (hematoxylin-eosin, original magnification, ×40).von Felbert. Squamous cell carcinoma from a vulval lesion of Hailey-Hailey. Am J Obstet Gynecol 2010.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Polymerase chain reaction (PCR) amplification of the major capsid protein gene using the general primers GP5 and GP61Snijders P.J. van den Brule A.J. Schrijnemakers H.F. Snow G. Meijer C.J. Walboomers J.M. The use of general primers in the polymerase chain reaction permits the detection of a broad spectrum of human papillomavirus genotypes.J Gen Virol. 1990; 71: 173-181Crossref PubMed Scopus (341) Google Scholar and PCR enzyme-linked immunosorbent assay with probes specific for human papillomavirus (HPV) 6, 11, 16, 18, 31, and 332Merkelbach-Bruse S. Jacob C. Tietze L. Schröder W. Rath W. Füzesi L. Consensus polymerase chain reaction and enzyme-linked immunosorbent assay for human papillomavirus detection and typing in cervical specimens.Diagn Mol Pathol. 1999; 8: 32-38Crossref PubMed Scopus (13) Google Scholar did not detect HPV infection. Cycle sequencing of the PCR product with sequence comparison (basic local alignment search tool analysis) vs National Center for Biotechnology Information database (Bethesda, MD) nonredundant was negative. Moreover, p16INKa immunostaining was negative. Thus, no HPV infection was detectable.Screening for metastasis by chest radiography, abdominal sonography, and whole-body computer tomography showed no abnormalities. The patient was referred to the Department of Gynecology at which she was treated with vulvectomy and bilateral inguinal lymphadenectomy. The tumor was classified as pT1bpN0pM0 G2. Since 2005 she is tumor free.CommentWe report a case of SCC arising from a localized vulval lesion of HHD. Solitary vulval involvement in HHD is rare.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar When involving the vulva, the disease usually presents with pruritus or pain in association with a persistent eruption.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar Moreover, vulval HHD may clinically present as leukoplakia, condyloma, lichenified white papules, and syringoma,3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar causing difficulties and delay in diagnosis. Often herpetic, candidal, or bacterial infections are initially suspected.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google ScholarSCC arising in vulval lesions of HHD is a very rare event.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar The previously reported cases of SCC arising in HHD occurred in older women (51, 61, and 70 years).3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar, 4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar Our patient was diagnosed at the age of 45 years. Histologically the SCC was localized adjacent to the HHD lesion.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar Vulval SCC generally occurs in women with preexisting vulvar intraepithelial neoplasia (VIN), and epidemiological studies have shown links to HPV.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar Ochiai et al4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar reported the occurrence of HPV types 16 and 39 in vulvar carcinoma with concomitant VIN III and HHD.Our patient presented a single vulval lesion, which showed histologically HHD adjacent to SCC and no VIN. Moreover, we could not detect HPV infection. Therefore, SCC apparently can develop from the preexisting chronic vulval disease HHD.Most patients reporting with HHD of the vulva were treated with topical steroids.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar, 6Holst V.A. Fair K.P. Wilson B.B. Patterson J.W. Squamous cell carcinoma arising in Hailey-Hailey disease.J Am Acad Dermatol. 2000; 43: 368-371Abstract Full Text Full Text PDF PubMed Google Scholar Recent studies also described macrolide immunosuppressant (eg, primecrolimus cream 1%) as effective and well tolerated in chronic vulvar disease (lichen sclerosus).7Oskay T. Serzer H.K. Genc C. Kutluay L. Pimecrolimus 1% cream in the treatment of vulvar lichen sclerosus in postmenopausal women.Int J Dermatol. 2007; 46: 527-532Crossref PubMed Scopus (32) Google Scholar Therefore, we initiated a treatment with tacrolimus cream 0.1% initially once daily together for 9-10 months. Fischer and Bradford8Fischer G. Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma.J Reprod Med. 2007; 52: 329-331PubMed Google Scholar described the development on SCC of the vulva with long-lasting lichen sclerosus treated with topical corticosteroids and pimecrolimus 1%.A study on mouse skin in a cancer model reported an acceleration of carcinogenesis after topical application of tacrolimus.9Niwa Y. Terashima T. Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.Br J Dermatol. 2003; 149: 960-967Crossref PubMed Scopus (115) Google Scholar The authors suggest a risk of potentiating SCC after a prolonged use of macrolide immunosuppressant.8Fischer G. Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma.J Reprod Med. 2007; 52: 329-331PubMed Google Scholar, 9Niwa Y. Terashima T. Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.Br J Dermatol. 2003; 149: 960-967Crossref PubMed Scopus (115) Google Scholar Becker et al10Becker J.C. Houben R. Vetter C.S. Bröcker E.B. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.BMC Cancer. 2006; 6: 7Crossref PubMed Scopus (107) Google Scholar have hypothesized that tacrolimus might have an impact on canonical signaling pathways such as mitogen-activated protein kinase (MAPK). In a patient with oral lichen planus developing an SCC after topical application of tacrolimus, they described an inhibitory effect of tacrolimus on p53 and Bax expression and stimulation of the extracellularly regulated kinase 1/2 MAPK pathway.10Becker J.C. Houben R. Vetter C.S. Bröcker E.B. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.BMC Cancer. 2006; 6: 7Crossref PubMed Scopus (107) Google ScholarThe present SCC showed strong cytoplasmic p53 immunoreactivity, supporting the hypothesis that the cause of the tumor development is more likely to be seen in the underlying HHD. But it appears also possible that tacrolimus therapy in our case promoted the development of SCC from the HHD lesion.In summary, this case report highlights the importance of a careful follow-up of patients with chronic inflammatory vulval conditions, regardless of age. A 44-year-old female patient was seen in February 2004 with a 6 month history of vulval erosion. Past medical history included a dysgerminoma of the ovary with peritoneal involvement at the age of 12 years. After laparotomy with tumor resection, she had been treated with radiotherapy of the right pelvis (Co60, 4.000 Ra) and chemotherapy (methotrexate, cyclophosphamide, and dactinomycin) every 2 months for 1 year. The vulva was not irradiated. At the age of 15 years, she was diagnosed to have primary amenorrhea because of ovarian failure (high luteinizing hormone level); since then she has been treated with estrogen. Case ReportAt presentation, physical examination revealed an ulceration within a well-defined whitish plaque-like lesion of the left labia minora, which was clinically diagnosed as herpetic infection (Figure 1, A). There was no involvement of other regions of the body in particular neck, axillae, groins, and nails were normal. A biopsy of the lesion revealed parakeratosis and dyskeratotic acantholytic cells with a suprabasal cleft; cells of the central layer of the epidermis showed partial separation from adjacent cells giving the appearance of a dilapidated brick wall (Figure 1, B). Direct immunofluorescence was negative.Based on the clinical and histological examination, a diagnosis of Hailey-Hailey disease (HHD) of the vulva was made. She had no family history of HHD. Herpetic, candidal, and bacterial infections were excluded.Treatment with topical tacrolimus 0.1% ointment once daily improved the HHD lesions (treatment period 2004: 7-8 months; period without tacrolimus therapy: 7 months; treatment period 2005: 2 months). However, over several months, a small scar-like lesion on the left labia minora developed, which was initially thought to be a wound-healing disturbance after the biopsy (Figure 1, C). This lesion gradually increased in size and hardened.In June 2005, 1 year after diagnosis of HHD, the patient represented with a protruding tumour on the left side of the labia minora involving also the left paraclitoral region (Figure 2, A). Examination of the vagina, uterine cervix, inguinal lymph nodes, and perianal region showed no abnormalities. Cervical smears displayed no signs of malignancy. Routine laboratory investigations were within the normal ranges. Histological examination of a biopsy of the tumor showed a p53 immunoreactive, invasive squamous cell carcinoma (SCC) in which strands and masses of immature squamous cells with dyskeratosis infiltrated deeply into the dermis (Figure 2, B). Additionally, HHD was again present in the form of epidermal acantholysis on the edge of the section (Figure 2, C).Polymerase chain reaction (PCR) amplification of the major capsid protein gene using the general primers GP5 and GP61Snijders P.J. van den Brule A.J. Schrijnemakers H.F. Snow G. Meijer C.J. Walboomers J.M. The use of general primers in the polymerase chain reaction permits the detection of a broad spectrum of human papillomavirus genotypes.J Gen Virol. 1990; 71: 173-181Crossref PubMed Scopus (341) Google Scholar and PCR enzyme-linked immunosorbent assay with probes specific for human papillomavirus (HPV) 6, 11, 16, 18, 31, and 332Merkelbach-Bruse S. Jacob C. Tietze L. Schröder W. Rath W. Füzesi L. Consensus polymerase chain reaction and enzyme-linked immunosorbent assay for human papillomavirus detection and typing in cervical specimens.Diagn Mol Pathol. 1999; 8: 32-38Crossref PubMed Scopus (13) Google Scholar did not detect HPV infection. Cycle sequencing of the PCR product with sequence comparison (basic local alignment search tool analysis) vs National Center for Biotechnology Information database (Bethesda, MD) nonredundant was negative. Moreover, p16INKa immunostaining was negative. Thus, no HPV infection was detectable.Screening for metastasis by chest radiography, abdominal sonography, and whole-body computer tomography showed no abnormalities. The patient was referred to the Department of Gynecology at which she was treated with vulvectomy and bilateral inguinal lymphadenectomy. The tumor was classified as pT1bpN0pM0 G2. Since 2005 she is tumor free. At presentation, physical examination revealed an ulceration within a well-defined whitish plaque-like lesion of the left labia minora, which was clinically diagnosed as herpetic infection (Figure 1, A). There was no involvement of other regions of the body in particular neck, axillae, groins, and nails were normal. A biopsy of the lesion revealed parakeratosis and dyskeratotic acantholytic cells with a suprabasal cleft; cells of the central layer of the epidermis showed partial separation from adjacent cells giving the appearance of a dilapidated brick wall (Figure 1, B). Direct immunofluorescence was negative. Based on the clinical and histological examination, a diagnosis of Hailey-Hailey disease (HHD) of the vulva was made. She had no family history of HHD. Herpetic, candidal, and bacterial infections were excluded. Treatment with topical tacrolimus 0.1% ointment once daily improved the HHD lesions (treatment period 2004: 7-8 months; period without tacrolimus therapy: 7 months; treatment period 2005: 2 months). However, over several months, a small scar-like lesion on the left labia minora developed, which was initially thought to be a wound-healing disturbance after the biopsy (Figure 1, C). This lesion gradually increased in size and hardened. In June 2005, 1 year after diagnosis of HHD, the patient represented with a protruding tumour on the left side of the labia minora involving also the left paraclitoral region (Figure 2, A). Examination of the vagina, uterine cervix, inguinal lymph nodes, and perianal region showed no abnormalities. Cervical smears displayed no signs of malignancy. Routine laboratory investigations were within the normal ranges. Histological examination of a biopsy of the tumor showed a p53 immunoreactive, invasive squamous cell carcinoma (SCC) in which strands and masses of immature squamous cells with dyskeratosis infiltrated deeply into the dermis (Figure 2, B). Additionally, HHD was again present in the form of epidermal acantholysis on the edge of the section (Figure 2, C). Polymerase chain reaction (PCR) amplification of the major capsid protein gene using the general primers GP5 and GP61Snijders P.J. van den Brule A.J. Schrijnemakers H.F. Snow G. Meijer C.J. Walboomers J.M. The use of general primers in the polymerase chain reaction permits the detection of a broad spectrum of human papillomavirus genotypes.J Gen Virol. 1990; 71: 173-181Crossref PubMed Scopus (341) Google Scholar and PCR enzyme-linked immunosorbent assay with probes specific for human papillomavirus (HPV) 6, 11, 16, 18, 31, and 332Merkelbach-Bruse S. Jacob C. Tietze L. Schröder W. Rath W. Füzesi L. Consensus polymerase chain reaction and enzyme-linked immunosorbent assay for human papillomavirus detection and typing in cervical specimens.Diagn Mol Pathol. 1999; 8: 32-38Crossref PubMed Scopus (13) Google Scholar did not detect HPV infection. Cycle sequencing of the PCR product with sequence comparison (basic local alignment search tool analysis) vs National Center for Biotechnology Information database (Bethesda, MD) nonredundant was negative. Moreover, p16INKa immunostaining was negative. Thus, no HPV infection was detectable. Screening for metastasis by chest radiography, abdominal sonography, and whole-body computer tomography showed no abnormalities. The patient was referred to the Department of Gynecology at which she was treated with vulvectomy and bilateral inguinal lymphadenectomy. The tumor was classified as pT1bpN0pM0 G2. Since 2005 she is tumor free. CommentWe report a case of SCC arising from a localized vulval lesion of HHD. Solitary vulval involvement in HHD is rare.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar When involving the vulva, the disease usually presents with pruritus or pain in association with a persistent eruption.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar Moreover, vulval HHD may clinically present as leukoplakia, condyloma, lichenified white papules, and syringoma,3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar causing difficulties and delay in diagnosis. Often herpetic, candidal, or bacterial infections are initially suspected.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google ScholarSCC arising in vulval lesions of HHD is a very rare event.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar The previously reported cases of SCC arising in HHD occurred in older women (51, 61, and 70 years).3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar, 4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar Our patient was diagnosed at the age of 45 years. Histologically the SCC was localized adjacent to the HHD lesion.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar Vulval SCC generally occurs in women with preexisting vulvar intraepithelial neoplasia (VIN), and epidemiological studies have shown links to HPV.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar Ochiai et al4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar reported the occurrence of HPV types 16 and 39 in vulvar carcinoma with concomitant VIN III and HHD.Our patient presented a single vulval lesion, which showed histologically HHD adjacent to SCC and no VIN. Moreover, we could not detect HPV infection. Therefore, SCC apparently can develop from the preexisting chronic vulval disease HHD.Most patients reporting with HHD of the vulva were treated with topical steroids.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar, 6Holst V.A. Fair K.P. Wilson B.B. Patterson J.W. Squamous cell carcinoma arising in Hailey-Hailey disease.J Am Acad Dermatol. 2000; 43: 368-371Abstract Full Text Full Text PDF PubMed Google Scholar Recent studies also described macrolide immunosuppressant (eg, primecrolimus cream 1%) as effective and well tolerated in chronic vulvar disease (lichen sclerosus).7Oskay T. Serzer H.K. Genc C. Kutluay L. Pimecrolimus 1% cream in the treatment of vulvar lichen sclerosus in postmenopausal women.Int J Dermatol. 2007; 46: 527-532Crossref PubMed Scopus (32) Google Scholar Therefore, we initiated a treatment with tacrolimus cream 0.1% initially once daily together for 9-10 months. Fischer and Bradford8Fischer G. Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma.J Reprod Med. 2007; 52: 329-331PubMed Google Scholar described the development on SCC of the vulva with long-lasting lichen sclerosus treated with topical corticosteroids and pimecrolimus 1%.A study on mouse skin in a cancer model reported an acceleration of carcinogenesis after topical application of tacrolimus.9Niwa Y. Terashima T. Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.Br J Dermatol. 2003; 149: 960-967Crossref PubMed Scopus (115) Google Scholar The authors suggest a risk of potentiating SCC after a prolonged use of macrolide immunosuppressant.8Fischer G. Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma.J Reprod Med. 2007; 52: 329-331PubMed Google Scholar, 9Niwa Y. Terashima T. Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.Br J Dermatol. 2003; 149: 960-967Crossref PubMed Scopus (115) Google Scholar Becker et al10Becker J.C. Houben R. Vetter C.S. Bröcker E.B. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.BMC Cancer. 2006; 6: 7Crossref PubMed Scopus (107) Google Scholar have hypothesized that tacrolimus might have an impact on canonical signaling pathways such as mitogen-activated protein kinase (MAPK). In a patient with oral lichen planus developing an SCC after topical application of tacrolimus, they described an inhibitory effect of tacrolimus on p53 and Bax expression and stimulation of the extracellularly regulated kinase 1/2 MAPK pathway.10Becker J.C. Houben R. Vetter C.S. Bröcker E.B. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.BMC Cancer. 2006; 6: 7Crossref PubMed Scopus (107) Google ScholarThe present SCC showed strong cytoplasmic p53 immunoreactivity, supporting the hypothesis that the cause of the tumor development is more likely to be seen in the underlying HHD. But it appears also possible that tacrolimus therapy in our case promoted the development of SCC from the HHD lesion.In summary, this case report highlights the importance of a careful follow-up of patients with chronic inflammatory vulval conditions, regardless of age. We report a case of SCC arising from a localized vulval lesion of HHD. Solitary vulval involvement in HHD is rare.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar When involving the vulva, the disease usually presents with pruritus or pain in association with a persistent eruption.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar Moreover, vulval HHD may clinically present as leukoplakia, condyloma, lichenified white papules, and syringoma,3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar causing difficulties and delay in diagnosis. Often herpetic, candidal, or bacterial infections are initially suspected.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar SCC arising in vulval lesions of HHD is a very rare event.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar The previously reported cases of SCC arising in HHD occurred in older women (51, 61, and 70 years).3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar, 4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar Our patient was diagnosed at the age of 45 years. Histologically the SCC was localized adjacent to the HHD lesion.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar Vulval SCC generally occurs in women with preexisting vulvar intraepithelial neoplasia (VIN), and epidemiological studies have shown links to HPV.4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar Ochiai et al4Ochiai T. Honda A. Morishima T. Sata T. Sakamoto H. Satoh K. Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease.Br J Dermatol. 1999; 140: 509-513Crossref PubMed Scopus (12) Google Scholar reported the occurrence of HPV types 16 and 39 in vulvar carcinoma with concomitant VIN III and HHD. Our patient presented a single vulval lesion, which showed histologically HHD adjacent to SCC and no VIN. Moreover, we could not detect HPV infection. Therefore, SCC apparently can develop from the preexisting chronic vulval disease HHD. Most patients reporting with HHD of the vulva were treated with topical steroids.3Wieselthier J.S. Pincus S.H. Hailey-Hailey disease of the vulva.Arch Dermatol. 1993; 129: 1344-1345Crossref PubMed Scopus (28) Google Scholar, 5Cockayne S.E. Rassl D.M. Thomas S.E. Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.Br J Dermatol. 2000; 142: 540-542Crossref PubMed Scopus (31) Google Scholar, 6Holst V.A. Fair K.P. Wilson B.B. Patterson J.W. Squamous cell carcinoma arising in Hailey-Hailey disease.J Am Acad Dermatol. 2000; 43: 368-371Abstract Full Text Full Text PDF PubMed Google Scholar Recent studies also described macrolide immunosuppressant (eg, primecrolimus cream 1%) as effective and well tolerated in chronic vulvar disease (lichen sclerosus).7Oskay T. Serzer H.K. Genc C. Kutluay L. Pimecrolimus 1% cream in the treatment of vulvar lichen sclerosus in postmenopausal women.Int J Dermatol. 2007; 46: 527-532Crossref PubMed Scopus (32) Google Scholar Therefore, we initiated a treatment with tacrolimus cream 0.1% initially once daily together for 9-10 months. Fischer and Bradford8Fischer G. Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma.J Reprod Med. 2007; 52: 329-331PubMed Google Scholar described the development on SCC of the vulva with long-lasting lichen sclerosus treated with topical corticosteroids and pimecrolimus 1%. A study on mouse skin in a cancer model reported an acceleration of carcinogenesis after topical application of tacrolimus.9Niwa Y. Terashima T. Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.Br J Dermatol. 2003; 149: 960-967Crossref PubMed Scopus (115) Google Scholar The authors suggest a risk of potentiating SCC after a prolonged use of macrolide immunosuppressant.8Fischer G. Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma.J Reprod Med. 2007; 52: 329-331PubMed Google Scholar, 9Niwa Y. Terashima T. Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin.Br J Dermatol. 2003; 149: 960-967Crossref PubMed Scopus (115) Google Scholar Becker et al10Becker J.C. Houben R. Vetter C.S. Bröcker E.B. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.BMC Cancer. 2006; 6: 7Crossref PubMed Scopus (107) Google Scholar have hypothesized that tacrolimus might have an impact on canonical signaling pathways such as mitogen-activated protein kinase (MAPK). In a patient with oral lichen planus developing an SCC after topical application of tacrolimus, they described an inhibitory effect of tacrolimus on p53 and Bax expression and stimulation of the extracellularly regulated kinase 1/2 MAPK pathway.10Becker J.C. Houben R. Vetter C.S. Bröcker E.B. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.BMC Cancer. 2006; 6: 7Crossref PubMed Scopus (107) Google Scholar The present SCC showed strong cytoplasmic p53 immunoreactivity, supporting the hypothesis that the cause of the tumor development is more likely to be seen in the underlying HHD. But it appears also possible that tacrolimus therapy in our case promoted the development of SCC from the HHD lesion. In summary, this case report highlights the importance of a careful follow-up of patients with chronic inflammatory vulval conditions, regardless of age. We thank K. Nolte (Aachen, Germany) for providing the immunostainings.
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