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Squamous cell carcinoma arising in Hailey-Hailey disease
Squamous cell carcinoma arising in Hailey-Hailey disease Valerie A. Holst, MD,a Kevaghn P. Fair, DO,a Barbara B. Wilson, MD,b and James W. Patterson, MDa,b Charlottesville, Virginia Hailey-Hailey disease is a recurrent, autosomal dominant vesiculobullous dermatotis with a predilection for intertrigenous areas. We report what we believe to be the first case of squamous cell carcinoma arising de novo in a skin lesion of Hailey-Hailey disease. The occurrence of malignant neoplasms arising in the skin lesions of Hailey-Hailey disease and other acantholytic dermatoses is reviewed. (J Am Acad Dermatol 2000; 43:368-71.)
H
ailey-Hailey (HH) disease is a recurrent, vesiculobullous dermatotis first described in 1939 as familial benign chronic pemphigus.1 The disease has a predilection for the neck and intertriginous areas such as axillae, scrotum, perineum, and vulva. Additional sites that may be affected include lumbosacral region, upper chest and back, inframammary region, and occasionally shoulder and face.2,3 Frequently, symptoms are exacerbated in the summer and in conditions of increased heat, sweating, and rubbing.3,4 Onset of HH generally occurs in the third to fourth decade. However, presentation and diagnosis may even be delayed until late middle age.3 HH disease is regarded as an autosomal dominant disease with variable penetrance, although sporadic cases with a negative family history account for approximately a third to a half of the cases in some studies.3-5 The HH disease gene region appears to be localized to chromosome 3q21q24 and does not appear to be allelic to Darier’s disease, which has been mapped to chromosome 12q23-q24.1.6-11 The diagnosis of HH disease requires differentiation from other acantholytic dermatoses, including the focal acantholytic changes that may occur inci-
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Pathologya and Dermatology,b University of Virginia Health Sciences Center. Reprint requests: James W. Patterson, MD, Old Medical School, Room 3888, University of Virginia Health Science Center, Charlottesville, VA 22908-0214. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/100542 doi:10.1067/mjd.2000.100542
368
dentally in both benign and malignant tumors.12-14 Although overlap may occur, the clinical and histologic features facilitate distinction among the various entities. Interestingly, the occurrence of benign and malignant neoplasms arising in the principal lesions of acantholytic dermatoses is rare.3,15-16 To our knowledge only 1 case of squamous cell carcinoma arising in a skin lesion of HH disease has been reported.17 However, this occurred after chronic application of arsphenamine. We describe the first case of squamous cell carcinoma arising de novo in a skin lesion of HH disease.
CASE REPORT A 51-year-old white female was referred for evaluation and treatment of vulvar burning and itching, dyspareunia, and a vulvar rash, as well as a lesion on the back. The vulvar rash and symptoms had been present intermittently for 5 years and had not responded to treatment with topical steroids, antifungals, or testosterone cream. The symptoms were worse during warm weather. There was no family history of similar complaints. During that same visit, a lesion that was described as an irritated, rough, nonhealing patch was noted on the left lower back, just superior and lateral to the natal cleft. Physical examination of the vulva revealed welldefined erythematous plaques on the labia majora, which were covered with macerated epidermis resembling “wet tissue paper.” No distinct vesicles were observed (Fig 1). Potassium hydroxide examination of the scrapings from both the labia majora and vaginal wall were negative for fungal organisms. A vulvar biopsy was performed. Examination of the back revealed a 2 × 5-cm irregular area of macular hyperpigmentation with a shallow ulceration on the left lower back, which, accord-
Holst et al 369
J AM ACAD DERMATOL VOLUME 43, NUMBER 2, PART 2
B
A
Fig 1. A, Well-delineated slightly elevated region of vulvar erythema is noted. B, Focal maceration is identified.
ing to the patient, had been preceded by a cluster of blisters. In addition, there were a few 2- to 3-mm vesicles on erythematous bases on the lower back. The ulcerated lesion was excised and sent for histopathologic examination. Perilesional vulvar skin was biopsied and sent for immunofluorescent studies. In addition, there was a 9 × 6-mm crusted papule resembling an irritated seborrheic keratosis that was removed from the left upper back and sent for histopathologic examination. The remainder of the skin examination was unremarkable.
HISTOPATHOLOGY Microscopic examination of the lesion excised from the lower back demonstrated ulceration of the epidermis and invasion of the dermis by well-differentiated nests of malignant squamous epithelium (Fig 2, A). The epidermis lateral to the ulcer was moderately hyperplastic, with prominent suprabasilar clefting and widespread partial acantholysis producing a distinctive “dilapidated brick wall” appearance (Fig 2, B). Villi were created by remnant dermal papillae protruding into the cleft. The acantholytic keratinocytes had well-preserved nuclei and cytoplasm, seldom forming corps ronds or grains. Features of a melanocytic lesion were not identified. The vulvar biopsy specimen showed acantholytic changes that were identical to those observed in the back excision (Fig 2, C); however, no dysplasia or malignancy was present. Subsequent biopsy specimens of the vulva and of an additional vesicular lesion on the lower back showed similar acantholytic histology. Direct immunofluorescent microscopy performed on the vulvar lesion was uniformly negative for reactivity to IgG, IgM, IgA, C3, and fibrin antibodies. The histologic features, as well as the negative immunofluorescence studies are most compatible with HH disease.
The nodule removed from the upper back proved to be a seborrheic keratosis. Interestingly, focal acantholytic changes were identified toward 1 edge of this lesion (Fig 2, D).
DISCUSSION We report the first case of squamous cell carcinoma arising de novo in a lesion of HH disease. The clinical and histologic features of this patient are most compatible with the diagnosis of HH disease.3-4,18 Although generally arising in adolescence and early adulthood, this patient’s age is well within the range for HH.3,4 Despite a negative family history, sporadic cases of HH disease account for at least a third of patients. The back and vulva, as in this patient, are frequent sites of skin involvement in HH disease. In fact, the vulvar skin lesions of HH are known to mimic candidiasis, as occurred in this case.19 Dyspareunia is associated with vaginal involvement and was a presenting symptom in our patient.20-21 Several other acantholytic dermatoses were considered in the differential diagnosis. The dyskeratosis and prominent vertical parakeratosis, of Darier’s disease were absent, and corps ronds and grains were rare. The distribution and chronic nature of the lesions make Grover’s disease highly unlikely. Acantholytic dermatosis of the genitocrural region is excluded by the presence of back lesions.22-24 In addition, pemphigus was discounted by the lack of adnexal involvement and negative direct immunofluorescence studies. Interestingly, the patient reported here developed squamous cell carcinoma in a skin lesion of HH disease. To our knowledge, this is only the third report of malignancy arising in a lesion of HH disease. The first case reported by Bitar and Giroux15 in
370 Holst et al
J AM ACAD DERMATOL AUGUST 2000
A
B
C
D Fig 2. A, Lower back lesion contained ulcerated, invasive squamous cell carcinoma. B, “Dilapidated brick wall” appearance was noted lateral to ulcer. C, Vulvar lesion also demonstrated acantholytic changes similar to back. D, In addition, focal acantholytic changes were present in upper back seborrheic keratosis.
1970 was a basal cell carcinoma that had developed in an irradiated site 9 years after radiation therapy for skin lesions of HH disease. The second case reported in 1988 occurred in a 65-year-old man at the
penoscrotal junction at a site to which arsphenamine had been chronically applied.17 No predisposing risk factors for the development of squamous cell carcinoma, such as sun exposure, irradiation, or contact
J AM ACAD DERMATOL VOLUME 43, NUMBER 2, PART 2
with carcinogenic agents could be identified in our patient. A search of the surgical pathology files at our institution from 1983 to the present produced no cases of carcinoma in any patients with HH disease or in any other acantholytic dermatoses. Malignancies arising within a primary skin lesion of other acantholytic dermatoses are also rare. Squamous cell carcinoma or basal cell carcinoma has been reported in pemphigus vulgaris and Darier’s disease. The majority of these cases were associated with a predisposing risk factor such as sun exposure, irradiation, or drug.25-30 To our knowledge, carcinoma arising in skin lesions of acantholytic dermatosis of the genitocrural region has not occurred.22-24 Grover’s disease is known to present in association with internal malignancies, particularly hematologic malignancies and solid tumors of the genitourinary tract.31-32 However, carcinoma arising in a skin lesion of Grover’s disease has not been described, probably in part because of the transient nature of the disease. In conclusion, we report what we believe to be the first case of squamous cell carcinoma arising de novo in a skin lesion of a patient with HH disease. The true incidence of cancers arising in the lesions of this disorder is uncertain; however, clinicians need to be aware of the possibility of the rare occurrence of malignancies. We gratefully acknowledge M. Catherine Slusher, MD, for clinical information and materials provided for this report. REFERENCES 1. Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol Syphilol 1939;39:679-85. 2. Michel B. Commentary: Hailey-Hailey disease. Arch Dermatol 1982;118:781-3. 3. Galimberti RL, Kowalczuk AM, Bianchi O, Bonino MV, Garcia AG. Chronic benign familial pemphigus. Int J Dermatol 1988;27: 495-500. 4. Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992;126:275-82. 5. Palmer DD, Perry HO. Benign familial chronic pemphigus. Arch Dermatol 1962;86:493-502. 6. Peluso AM, Bonifas JM, Ikeda S, Hu Z, Devries S,Waldman F, et al. Narrowing of the Hailey-Hailey disease gene region on chromosome 3q and identification of one kindred with a deletion in this region. Genomics 1995;30:77-80. 7. Richard G, Korge BP, Wright AR, Mazzanti C, Harth W, Annicchiarico-Petruzzelli M, et al. Hailey-Hailey disease maps to a 5 cM interval on chromosome 3q21-q24. J Invest Dermatol 1995;105:357-60. 8. Welsh EA, Ikeda S, Peluso AM, Bonifas JM, Bare JW, Woodley DT, et al. Hailey-Hailey disease is not allelic to Darier’s disease. J Invest Dermatol 1994;102:992-3. 9. Bashir R, Munro CS, Mason S, Stephenson A, Res JL, Strachan T. Localisation of a gene for Darier’s disease. Hum Mol Genet 1993;2:1937-9.
Holst et al 371
10. Buxton RS. Yet another skin defect, Darier’s disease, maps to chromosome 12q. Hum Mol Genet 1993;2:1763-4. 11. Craddock N, Dawson E, Burge S, Parfitt L, Mant B, Roberts Q, et al. The gene for Darier’s disease maps to chromosome 12q23q24.1. Hum Mol Genet 1993;2:1941-3. 12. Ackerman AB. Focal acantholytic dyskeratosis. Arch Dermatol 1972;106:702-6. 13. Botet MV, Sanchez JL. Vesiculation of focal acantholytic dyskeratosis in acral lentiginous malignant melanoma. J Dermatol Surg Oncol 1979;5:798-800. 14. Lambert WC, Bilinski DL, Khan MY, Brodkin RH. Trichoepithelioma in a systematized epidermal nevus with acantholytic dyskeratosis. Arch Dermatol 1984;120:227-30. 15. Bitar A, Giroux JM. Treatment of benign familial pemphigus (Hailey-Hailey) by skin grafting. Br J Dermatol 1970;83:402-4. 16. King DT, Hirose FM, King LA. Simultaneous occurrence of familial benign chronic pemphigus (Hailey-Hailey disease) and syringoma on the vulva. Arch Dermatol 1978;114:801. 17. Chun SI, Whang KC, Su WPD. Squamous cell carcinoma arising in Hailey-Hailey disease. J Cutan Pathol 1988;15:234-7. 18. Wieselthier JS, Pincus SH. Hailey-Hailey disease of the vulva. Arch Dermatol 1993;129:1344-5. 19. Misra R, Raman M, Singh N, Agarwal N. Hailey-Hailey disease masquerading as candidiasis. Int J Gynecol Obstet 1993;42:512. 20. Brandrup F, Petri J, Aegidius J. Acantholytic lesions in the vagina. Br J Dermatol 1990;123:691-2. 21. Vaclavinkova V, Neumann E. Vaginal involvement in familial benign chronic pemphigus (morbus Hailey-Hailey). Acta Derm Venereol 1982;62:80-1. 22. Cooper PH. Acantholytic dermatosis localized to the vulvocrural area. J Cutan Pathol 1989;16:81-4. 23. Wong KT, Wong KK. A case of acantholytic dermatosis of the vulva with features of pemphigus vegetans. J Cutan Pathol 1994;21:453-6. 24. Wong TY, Mihm MC. Acantholytic dermatosis localized to genitalia and crural areas of male patients: a report of three cases. J Cutan Pathol 1994;24:27-32. 25. Mahomed Y, Mandel MA, Cramer SF, Michel B. Squamous cell carcinoma arising in pemphigus vulgaris during immunosuppressive therapy. Cancer 1980;46:1374-7. 26. Hamadah I, Grande DJ.The use of Mohs surgery in facial tumors in a patient with Darier’s disease. J Dermatol Surg Oncol 1991; 17:950-3. 27. Latour DL, Amonette RA, Bale GF. Darier’s disease associated with cutaneous malignancies. J Dermatol Surg Oncol 1981;7: 408-12. 28. Rapini RP, Koranda FC. Darier’s disease and basal-cell carcinoma. J Dermatol Surg Oncol 1982;8:634. 29. Orihuela E, Tyring SK, Pow-Sang M, Dozier S, Cirelli R, Arany I, et al. Development of Human Papillomavirus type 16 associated squamous cell carcinoma of the scrotum in a patient with Darier’s disease treated with systemic isotretinoin. J Urol 1995; 153:1940-3. 30. Downs AMR, Ward KA, Peachey RDG. Subungual squamous cell carcinoma in Darier’s disease. Clin Exp Derm 1997;22:277-9. 31. Guana AL, Cohen PR. Transient acantholytic dermatosis in oncology patients. J Clin Oncol 1994;12:1703-9. 32. Parsons, JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol 1996;35:65366.
H
ailey-Hailey (HH) disease is a recurrent, vesiculobullous dermatotis first described in 1939 as familial benign chronic pemphigus.1 The disease has a predilection for the neck and intertriginous areas such as axillae, scrotum, perineum, and vulva. Additional sites that may be affected include lumbosacral region, upper chest and back, inframammary region, and occasionally shoulder and face.2,3 Frequently, symptoms are exacerbated in the summer and in conditions of increased heat, sweating, and rubbing.3,4 Onset of HH generally occurs in the third to fourth decade. However, presentation and diagnosis may even be delayed until late middle age.3 HH disease is regarded as an autosomal dominant disease with variable penetrance, although sporadic cases with a negative family history account for approximately a third to a half of the cases in some studies.3-5 The HH disease gene region appears to be localized to chromosome 3q21q24 and does not appear to be allelic to Darier’s disease, which has been mapped to chromosome 12q23-q24.1.6-11 The diagnosis of HH disease requires differentiation from other acantholytic dermatoses, including the focal acantholytic changes that may occur inci-
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Pathologya and Dermatology,b University of Virginia Health Sciences Center. Reprint requests: James W. Patterson, MD, Old Medical School, Room 3888, University of Virginia Health Science Center, Charlottesville, VA 22908-0214. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/100542 doi:10.1067/mjd.2000.100542
368
dentally in both benign and malignant tumors.12-14 Although overlap may occur, the clinical and histologic features facilitate distinction among the various entities. Interestingly, the occurrence of benign and malignant neoplasms arising in the principal lesions of acantholytic dermatoses is rare.3,15-16 To our knowledge only 1 case of squamous cell carcinoma arising in a skin lesion of HH disease has been reported.17 However, this occurred after chronic application of arsphenamine. We describe the first case of squamous cell carcinoma arising de novo in a skin lesion of HH disease.
CASE REPORT A 51-year-old white female was referred for evaluation and treatment of vulvar burning and itching, dyspareunia, and a vulvar rash, as well as a lesion on the back. The vulvar rash and symptoms had been present intermittently for 5 years and had not responded to treatment with topical steroids, antifungals, or testosterone cream. The symptoms were worse during warm weather. There was no family history of similar complaints. During that same visit, a lesion that was described as an irritated, rough, nonhealing patch was noted on the left lower back, just superior and lateral to the natal cleft. Physical examination of the vulva revealed welldefined erythematous plaques on the labia majora, which were covered with macerated epidermis resembling “wet tissue paper.” No distinct vesicles were observed (Fig 1). Potassium hydroxide examination of the scrapings from both the labia majora and vaginal wall were negative for fungal organisms. A vulvar biopsy was performed. Examination of the back revealed a 2 × 5-cm irregular area of macular hyperpigmentation with a shallow ulceration on the left lower back, which, accord-
Holst et al 369
J AM ACAD DERMATOL VOLUME 43, NUMBER 2, PART 2
B
A
Fig 1. A, Well-delineated slightly elevated region of vulvar erythema is noted. B, Focal maceration is identified.
ing to the patient, had been preceded by a cluster of blisters. In addition, there were a few 2- to 3-mm vesicles on erythematous bases on the lower back. The ulcerated lesion was excised and sent for histopathologic examination. Perilesional vulvar skin was biopsied and sent for immunofluorescent studies. In addition, there was a 9 × 6-mm crusted papule resembling an irritated seborrheic keratosis that was removed from the left upper back and sent for histopathologic examination. The remainder of the skin examination was unremarkable.
HISTOPATHOLOGY Microscopic examination of the lesion excised from the lower back demonstrated ulceration of the epidermis and invasion of the dermis by well-differentiated nests of malignant squamous epithelium (Fig 2, A). The epidermis lateral to the ulcer was moderately hyperplastic, with prominent suprabasilar clefting and widespread partial acantholysis producing a distinctive “dilapidated brick wall” appearance (Fig 2, B). Villi were created by remnant dermal papillae protruding into the cleft. The acantholytic keratinocytes had well-preserved nuclei and cytoplasm, seldom forming corps ronds or grains. Features of a melanocytic lesion were not identified. The vulvar biopsy specimen showed acantholytic changes that were identical to those observed in the back excision (Fig 2, C); however, no dysplasia or malignancy was present. Subsequent biopsy specimens of the vulva and of an additional vesicular lesion on the lower back showed similar acantholytic histology. Direct immunofluorescent microscopy performed on the vulvar lesion was uniformly negative for reactivity to IgG, IgM, IgA, C3, and fibrin antibodies. The histologic features, as well as the negative immunofluorescence studies are most compatible with HH disease.
The nodule removed from the upper back proved to be a seborrheic keratosis. Interestingly, focal acantholytic changes were identified toward 1 edge of this lesion (Fig 2, D).
DISCUSSION We report the first case of squamous cell carcinoma arising de novo in a lesion of HH disease. The clinical and histologic features of this patient are most compatible with the diagnosis of HH disease.3-4,18 Although generally arising in adolescence and early adulthood, this patient’s age is well within the range for HH.3,4 Despite a negative family history, sporadic cases of HH disease account for at least a third of patients. The back and vulva, as in this patient, are frequent sites of skin involvement in HH disease. In fact, the vulvar skin lesions of HH are known to mimic candidiasis, as occurred in this case.19 Dyspareunia is associated with vaginal involvement and was a presenting symptom in our patient.20-21 Several other acantholytic dermatoses were considered in the differential diagnosis. The dyskeratosis and prominent vertical parakeratosis, of Darier’s disease were absent, and corps ronds and grains were rare. The distribution and chronic nature of the lesions make Grover’s disease highly unlikely. Acantholytic dermatosis of the genitocrural region is excluded by the presence of back lesions.22-24 In addition, pemphigus was discounted by the lack of adnexal involvement and negative direct immunofluorescence studies. Interestingly, the patient reported here developed squamous cell carcinoma in a skin lesion of HH disease. To our knowledge, this is only the third report of malignancy arising in a lesion of HH disease. The first case reported by Bitar and Giroux15 in
370 Holst et al
J AM ACAD DERMATOL AUGUST 2000
A
B
C
D Fig 2. A, Lower back lesion contained ulcerated, invasive squamous cell carcinoma. B, “Dilapidated brick wall” appearance was noted lateral to ulcer. C, Vulvar lesion also demonstrated acantholytic changes similar to back. D, In addition, focal acantholytic changes were present in upper back seborrheic keratosis.
1970 was a basal cell carcinoma that had developed in an irradiated site 9 years after radiation therapy for skin lesions of HH disease. The second case reported in 1988 occurred in a 65-year-old man at the
penoscrotal junction at a site to which arsphenamine had been chronically applied.17 No predisposing risk factors for the development of squamous cell carcinoma, such as sun exposure, irradiation, or contact
J AM ACAD DERMATOL VOLUME 43, NUMBER 2, PART 2
with carcinogenic agents could be identified in our patient. A search of the surgical pathology files at our institution from 1983 to the present produced no cases of carcinoma in any patients with HH disease or in any other acantholytic dermatoses. Malignancies arising within a primary skin lesion of other acantholytic dermatoses are also rare. Squamous cell carcinoma or basal cell carcinoma has been reported in pemphigus vulgaris and Darier’s disease. The majority of these cases were associated with a predisposing risk factor such as sun exposure, irradiation, or drug.25-30 To our knowledge, carcinoma arising in skin lesions of acantholytic dermatosis of the genitocrural region has not occurred.22-24 Grover’s disease is known to present in association with internal malignancies, particularly hematologic malignancies and solid tumors of the genitourinary tract.31-32 However, carcinoma arising in a skin lesion of Grover’s disease has not been described, probably in part because of the transient nature of the disease. In conclusion, we report what we believe to be the first case of squamous cell carcinoma arising de novo in a skin lesion of a patient with HH disease. The true incidence of cancers arising in the lesions of this disorder is uncertain; however, clinicians need to be aware of the possibility of the rare occurrence of malignancies. We gratefully acknowledge M. Catherine Slusher, MD, for clinical information and materials provided for this report. REFERENCES 1. Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol Syphilol 1939;39:679-85. 2. Michel B. Commentary: Hailey-Hailey disease. Arch Dermatol 1982;118:781-3. 3. Galimberti RL, Kowalczuk AM, Bianchi O, Bonino MV, Garcia AG. Chronic benign familial pemphigus. Int J Dermatol 1988;27: 495-500. 4. Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992;126:275-82. 5. Palmer DD, Perry HO. Benign familial chronic pemphigus. Arch Dermatol 1962;86:493-502. 6. Peluso AM, Bonifas JM, Ikeda S, Hu Z, Devries S,Waldman F, et al. Narrowing of the Hailey-Hailey disease gene region on chromosome 3q and identification of one kindred with a deletion in this region. Genomics 1995;30:77-80. 7. Richard G, Korge BP, Wright AR, Mazzanti C, Harth W, Annicchiarico-Petruzzelli M, et al. Hailey-Hailey disease maps to a 5 cM interval on chromosome 3q21-q24. J Invest Dermatol 1995;105:357-60. 8. Welsh EA, Ikeda S, Peluso AM, Bonifas JM, Bare JW, Woodley DT, et al. Hailey-Hailey disease is not allelic to Darier’s disease. J Invest Dermatol 1994;102:992-3. 9. Bashir R, Munro CS, Mason S, Stephenson A, Res JL, Strachan T. Localisation of a gene for Darier’s disease. Hum Mol Genet 1993;2:1937-9.
Holst et al 371
10. Buxton RS. Yet another skin defect, Darier’s disease, maps to chromosome 12q. Hum Mol Genet 1993;2:1763-4. 11. Craddock N, Dawson E, Burge S, Parfitt L, Mant B, Roberts Q, et al. The gene for Darier’s disease maps to chromosome 12q23q24.1. Hum Mol Genet 1993;2:1941-3. 12. Ackerman AB. Focal acantholytic dyskeratosis. Arch Dermatol 1972;106:702-6. 13. Botet MV, Sanchez JL. Vesiculation of focal acantholytic dyskeratosis in acral lentiginous malignant melanoma. J Dermatol Surg Oncol 1979;5:798-800. 14. Lambert WC, Bilinski DL, Khan MY, Brodkin RH. Trichoepithelioma in a systematized epidermal nevus with acantholytic dyskeratosis. Arch Dermatol 1984;120:227-30. 15. Bitar A, Giroux JM. Treatment of benign familial pemphigus (Hailey-Hailey) by skin grafting. Br J Dermatol 1970;83:402-4. 16. King DT, Hirose FM, King LA. Simultaneous occurrence of familial benign chronic pemphigus (Hailey-Hailey disease) and syringoma on the vulva. Arch Dermatol 1978;114:801. 17. Chun SI, Whang KC, Su WPD. Squamous cell carcinoma arising in Hailey-Hailey disease. J Cutan Pathol 1988;15:234-7. 18. Wieselthier JS, Pincus SH. Hailey-Hailey disease of the vulva. Arch Dermatol 1993;129:1344-5. 19. Misra R, Raman M, Singh N, Agarwal N. Hailey-Hailey disease masquerading as candidiasis. Int J Gynecol Obstet 1993;42:512. 20. Brandrup F, Petri J, Aegidius J. Acantholytic lesions in the vagina. Br J Dermatol 1990;123:691-2. 21. Vaclavinkova V, Neumann E. Vaginal involvement in familial benign chronic pemphigus (morbus Hailey-Hailey). Acta Derm Venereol 1982;62:80-1. 22. Cooper PH. Acantholytic dermatosis localized to the vulvocrural area. J Cutan Pathol 1989;16:81-4. 23. Wong KT, Wong KK. A case of acantholytic dermatosis of the vulva with features of pemphigus vegetans. J Cutan Pathol 1994;21:453-6. 24. Wong TY, Mihm MC. Acantholytic dermatosis localized to genitalia and crural areas of male patients: a report of three cases. J Cutan Pathol 1994;24:27-32. 25. Mahomed Y, Mandel MA, Cramer SF, Michel B. Squamous cell carcinoma arising in pemphigus vulgaris during immunosuppressive therapy. Cancer 1980;46:1374-7. 26. Hamadah I, Grande DJ.The use of Mohs surgery in facial tumors in a patient with Darier’s disease. J Dermatol Surg Oncol 1991; 17:950-3. 27. Latour DL, Amonette RA, Bale GF. Darier’s disease associated with cutaneous malignancies. J Dermatol Surg Oncol 1981;7: 408-12. 28. Rapini RP, Koranda FC. Darier’s disease and basal-cell carcinoma. J Dermatol Surg Oncol 1982;8:634. 29. Orihuela E, Tyring SK, Pow-Sang M, Dozier S, Cirelli R, Arany I, et al. Development of Human Papillomavirus type 16 associated squamous cell carcinoma of the scrotum in a patient with Darier’s disease treated with systemic isotretinoin. J Urol 1995; 153:1940-3. 30. Downs AMR, Ward KA, Peachey RDG. Subungual squamous cell carcinoma in Darier’s disease. Clin Exp Derm 1997;22:277-9. 31. Guana AL, Cohen PR. Transient acantholytic dermatosis in oncology patients. J Clin Oncol 1994;12:1703-9. 32. Parsons, JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol 1996;35:65366.