February 2011February 21, 2011

Two Patients With Hailey-Hailey Disease, Multiple Primary Melanomas, and Other Cancers

Author Affiliations

Author Affiliations: Department of Dermatology, Eastern Virginia Medical School, Norfolk (Dr Mohr); and Departments of Pathology, Division of Dermatopathology (Drs Erdag and Patterson), Surgery, Division of Surgical Oncology (Drs Shada and Slingluff), and Medicine, Division of Hematology and Oncology (Dr Williams), University of Virginia Health System, Charlottesville.


Copyright 2011 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2011

Arch Dermatol. 2011;147(2):211-215. doi:10.1001/archdermatol.2010.445

Background  Hailey-Hailey Disease (HHD) is an autosomal dominant skin disorder that is characterized by erythematous and sometimes vesicular, weeping plaques of intertriginous regions. Squamous cell carcinoma and basal cell carcinoma arising in lesions of HHD have been described in the literature. To our knowledge, there are no reports of melanoma or noncutaneous malignant neoplasms associated with HHD.

Observations  We discuss the mechanisms of oncogenicity, including genetic, environmental, and iatrogenic factors, in 2 patients with HHD, multiple primary melanomas, and other cancers. Patient 1 had a mucoepidermoid carcinoma of the parotid gland. Patient 2 had a history of acute monoblastic leukemia and malignant peripheral nerve sheath tumor as well as radiologic evidence of an acoustic neurilemmoma.

Conclusions  The cause of the cancers in these 2 patients is likely multifactorial. We describe the patients to draw attention to the possible association between HHD and cancer. Additional research should be performed to determine whether patients with HHD have an increased incidence of cancer.

Hailey-Hailey disease (HHD), also termed familial benign chronic pemphigus, is a rare autosomal dominant skin disease that was first described in 1939 by the Hailey brothers.1 The disease typically occurs between the second and fourth decades of life and presents with blisters, erythema, and malodorous plaques in intertriginous locations.2 Longitudinal white bands of the fingernails may be a helpful diagnostic clue.2 Exacerbating factors include friction, heat, sweating, UV radiation, and superinfection.2 Family history is often of help in diagnosis; however, up to one-third of cases represent sporadic mutations with no family history.3 Histologically, HHD is characterized by extensive epidermal suprabasilar acantholysis, which may have the appearance of a “dilapidated brick wall.” In 2000, Hu et al4 and Sudbrak et al5 identified the ATP2C1 gene, which is located on chromosome 3q21-q24. More than 80 mutations in this gene have been reported in HHD.6 The ATP2C1 gene encodes for the human secretory pathway Ca2+/Mn2+ ATPase (hSPCA1) protein associated with the Golgi apparatus and is expressed abundantly in keratinocytes.6

Malignant melanoma of the skin is increasingly common, and patients with 1 melanoma have an increased risk of a second primary melanoma, but a diagnosis of 3 or more distinct primary melanomas is uncommon.7 We describe 2 patients with HHD, multiple primary melanomas, and other cancers. To our knowledge, the literature contains no prior reports of melanoma or noncutaneous malignant neoplasms associated with HHD. We discuss possible mechanisms of oncogenicity in these patients with HHD.


A 67-year-old man with Fitzpatrick type III skin presented to the surgical oncology clinic for treatment of multiple primary melanomas. His first melanoma, which occurred when he was 46 years old, was treated with wide excision. More recently, over a 1-year period, he was diagnosed as having 5 additional primary melanomas on his trunk and upper extremities. Three of the 5 melanomas were Clark level IV, with Breslow depths of 3.45, 4.03, and 5.12 mm; 1 was Clark level III, with a Breslow depth of 0.91 mm; and 1 was Clark level II, with a Breslow depth of 0.28 mm. The latter specimen also contained a separate dermal nodule of melanoma, which was believed to be a metastasis. Most of this patient's specimens have shown concurrent histologic features of HHD and melanoma, as shown in Figure 1. Fine-needle aspiration of a left axillary mass revealed metastatic melanoma, which was surgically resected. The results of other staging were negative at that time, and the patient has been enrolled in an experimental melanoma vaccine trial.

Figure 1
Image not available

Melanoma on the upper part of the left side of the back of patient 1. A, An asymmetrical 5 × 4-cm pink and tan patch with a central pink papule. B and C, Biopsy specimens revealing melanoma with epithelioid and spindle cell morphological features and extensive epidermal acantholysis giving a “dilapidated brick wall” appearance consistent with Hailey-Hailey disease (hematoxylin-eosin, original magnification ×100 [B]; S-100 protein, original magnification ×200 [C]).

The patient reported significant sun exposure during his life, rare sunscreen use during his youth, and approximately 12 blistering sunburns before the age of 20 years. He had no family history of melanoma. His maternal grandmother, mother, sister, and nephew had HHD.

His medical history was remarkable for HHD, asthma, osteoarthritis, benign colon polyps, benign prostatic hypertrophy, vertigo, nephrolithiasis, hypertension, and gastroesophageal reflux. Also, at the age of 64 years, he was diagnosed as having a high-grade mucoepidermoid carcinoma of the left parotid gland, with metastasis to the left cervical lymph nodes, which was treated with a combination of left total parotidectomy, left superior cervical lymph node dissection, carboplatin, paclitaxel, and local irradiation with a dose of 6600 rad (to convert to grays, multiply by 0.01). His postoperative course was complicated by episodes of gustatory hyperhidrosis.


A 35-year-old man with Fitzpatrick skin type II presented to the surgical oncology clinic for treatment of his first melanoma, on the right side of the upper part of his back. The melanoma, which was at least a modified Clark level III with a Breslow depth of at least 0.83 mm, extended to the base of the biopsy specimen. Sentinel nodes of the right axilla were negative for metastasis. The patient subsequently noted a papule on the plantar aspect of his left foot. Because of the atypical clinical appearance of the lesion, it was initially treated as a callus and a plantar wart (Figure 2). Ultimately, it was diagnosed as an acral lentiginous melanoma, which was at least Clark level IV, with a Breslow depth of at least 8 mm. Wide resection was performed, and a sentinel lymph node biopsy revealed 2 positive nodes in the left groin. Also, a third melanoma, which was Clark level II, with a Breslow depth of 0.33 mm (Figure 3A), was diagnosed on the right arm. A metastatic workup was negative for distant disease.

Figure 2
Image not available

Melanoma on the left foot of patient 2. A, An atypical-appearing melanoma on the plantar surface of the left foot. B, Ulcerated tumor with a dermal infiltrate of pleomorphic spindled melanocytes, confirmed with Melan-A stain (not shown) (hematoxylin-eosin, original magnification ×100).

Figure 3
Image not available

Histopathologic features in case 2. Biopsy specimens from patient 2 revealing superficial spreading melanoma, predominately in situ (A), and basal cell carcinoma and Hailey-Hailey disease (B) (hematoxylin-eosin, original magnification ×100).

The patient had HHD, numerous dysplastic nevi, and a history of approximately 12 basal cell carcinomas of the arms and back (Figure 3B). He had a history of significant sun exposure with minimal sunscreen use as a youth. He also reported experiencing approximately 6 blistering sunburns before he was 20 years old. His mother had numerous atypical nevi and a melanoma. His father and paternal aunt had HHD. There was no family history of neural tumors.

The patient's medical history was notable for several malignant neoplasms. At the age of 19 years, he developed leukemia. Initially, his leukemia was of an indeterminate type; therefore, while awaiting final typing, he was treated with 2 doses of vincristine sulfate and 7 days of prednisone. After additional testing, he was diagnosed as having acute monoblastic leukemia, M5 subtype, which was treated with cytarabine and daunorubicin hydrochloride. Subsequently, he received 1200-rad total-body irradiation and high-dose cyclophosphamide and methotrexate therapy in preparation for an allogeneic stem cell transplant, which was donated by his HLA-matched sister. After transplantation, he was placed on a regimen of cyclosporine for approximately 5 months. He has had no recurrence of leukemia or other hematologic disorder.

At the age of 30 years, he developed a malignant peripheral nerve sheath tumor of the cervical spine, which was resected and treated with 4860 rad of localized radiation therapy. More recently, a mass of the right cerebellopontine angle was noted on magnetic resonance imaging; this finding was suggestive of a vestibular schwannoma.


Both patients described herein were diagnosed as having HHD, multiple primary melanomas, and at least 1 other type of cancer. The mechanism underlying carcinogenesis in these patients is likely multifactorial. Contributing factors include skin type and excessive exposure to UV radiation. We discuss the possible genetic and iatrogenic mechanisms of oncogenicity in these 2 patients.

Although there are reports of cutaneous malignant neoplasms arising in HHD, to our knowledge there are no reports of melanoma arising in patients with HHD. There are 4 reports of squamous cell carcinoma and 2 reports of basal cell carcinoma arising in lesions of HHD.3,814 Presumably, the impaired epidermal barrier may allow infection with oncogenic strains of human papillomavirus, thus promoting the development of squamous cell carcinoma. Human papillomavirus was detected in 1 case of HHD-associated squamous cell carcinoma.14

Based on the findings of molecular studies of HHD, there are additional data to suggest that, in theory, patients with HHD may be predisposed to neoplasia. In 2007, Okunade et al15 demonstrated that a heterozygous mutation of the ATP2C1 gene in mice leads to an increased incidence of squamous cell tumors in aged adult mice. They suggested that this mutation leads to Golgi stress, increased apoptosis, and a genetic predisposition to cancer. Also, cancer transformation is commonly associated with rearrangement of calcium channels, leading to cellular proliferation and impaired apoptosis.16 Therefore, it is possible that the aberrant calcium signaling in HHD may promote an oncogenic environment. Cialfi et al17 demonstrated that HHD keratinocytes undergo oxidative stress, which may contribute to DNA damage. They also found downregulation of Notch1 and Itch in HHD keratinocytes. It has been reported that Notch1 may act as a transforming oncogene in human melanocytes; therefore, in terms of Notch1 levels, patients with HHD should, in theory, be at decreased risk for advanced melanomas.18 Decreased Notch1 levels may not be a sufficient protective factor, as suggested by the multiple advanced melanomas in our 2 patients.

Alternatively, the chemotherapy and localized radiation therapy that patient 1 received for his mucoepidermoid carcinoma may have placed him at risk for the development of secondary malignant neoplasms. The same holds true for patient 2; it is likely that the chemotherapy, total-body irradiation, and immunosuppression after his stem cell transplantation made him more susceptible to developing secondary malignant neoplasms. For survivors of childhood cancer, the risk of developing a second cancer can be up to 35 times greater than in the general population, occurring at an incidence of 4%.19 Melanoma after childhood cancer has been reported after treatment of primary hematologic malignant neoplasms.20 Guérin et al21 found a trend toward increased risk of melanoma as a second malignant neoplasm after treatment with a combination of alkylating agents and mitotic spindle inhibitors, although these data were not statistically significant. Patient 2 was treated with cyclophosphamide, an alkylating agent, and 2 doses of vincristine, a mitotic spindle inhibitor. Interestingly, carboplatin and paclitaxel, the chemotherapy agents that were used to treat mucoepidermoid carcinoma in case 1, have been investigated as a possible treatment for metastatic melanoma.22

Total-body irradiation, as was used in case 2, has been associated with a 2.7- to 4.4-fold higher risk of second neoplasms, with a positive dose relationship.23 The latency period from time of radiation treatment to the development of the second neoplasm may be up to 50 years after exposure.24 Guérin et al21 demonstrated that the risk of melanoma was found to be linked to the local radiation dose, with an increased risk noted specifically for local radiation doses of more than 1500 rad. Patient 1 received a dose of 6600 rad to the left parotid gland and cervical field, while patient 2 received 1200 rad of total-body irradiation plus 4860 rad to a cervical spine field. A considerable number of secondary malignant neoplasms that occur after radiotherapy do not occur within the irradiated field.25

A genetic basis for disease could also be considered in patient 2, given his multiple atypical-appearing nevi and the family history of melanoma in his mother. Four melanoma-susceptibility genes have been characterized, including cyclin-dependent kinase inhibitor 2A (CDKN2A, also called p16), alternate reading frame (ARF, also called p14), cyclin-dependent kinase 4 (CDK4), and melanocortin 1 receptor (MC1R).26 Approximately 20% to 40% of families with melanoma carry a mutation in p16/ARF, and only 1% to 2% of families carry a mutation of CDK4 or ARF -only genes.26 Genetic studies have not been performed in these cases but will be considered in the future.

Some familial melanoma syndromes are associated with other cancers, including pancreatic cancer and neural tumors. The melanoma–neural system tumor syndrome is a familial syndrome that is composed of multiple primary melanomas as well as tumors of neural origin, including acoustic neurilemmomas, meningiomas, astrocytomas, medulloblastomas, glioblastoma multiforme, and others.27 Mutations involving ARF alone28 or a region of chromosome 9p21 encompassing CDKN2A, CDKN2B (also called p15), and ARF genes29 have been identified in the melanoma–neural system tumor syndrome. With the personal history of both a malignant peripheral nerve sheath tumor and radiographic evidence of an acoustic neurilemmoma in patient 2, strong consideration should be given to the melanoma–neural system tumor syndrome.

We have described 2 patients with a diagnosis of HHD, multiple primary melanomas, and other cancers. We hope to draw awareness to this association of HHD and cancer, and if similar cases are recognized, then additional genetic and molecular studies may be performed to elucidate the mechanism of carcinogenicity in this patient population.

Back to top
Article Information

Correspondence: Melinda R. Mohr, MD, Department of Dermatology, Eastern Virginia Medical School, 721 Fairfax Ave, Ste 200, Norfolk, VA 23507 (melinda.mohr@gmail.com).

Accepted for Publication: May 24, 2010.

Author Contributions: All authors had full access to all the data in the report and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mohr, Erdag, and Shada. Acquisition of data: Mohr, Erdag, Shada, and Slingluff. Analysis and interpretation of data: Mohr, Erdag, Shada, Williams, Slingluff, and Patterson. Drafting of the manuscript: Mohr, Erdag, and Shada. Critical revision of the manuscript for important intellectual content: Mohr, Erdag, Shada, Williams, Slingluff, and Patterson. Administrative, technical, or material support: Patterson. Study supervision: Slingluff and Patterson.

Financial Disclosure: None reported.

Hailey  HHailey  H Report of 13 cases in 4 generations of a family and report of 9 additional cases in 4 generations of a family. Arch Derm Syphilol 1939;39679- 685Article
Burge  SM Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol 1992;126 (3) 275- 282
Holst  VAFair  KPWilson  BBPatterson  JW Squamous cell carcinoma arising in Hailey-Hailey disease. J Am Acad Dermatol 2000;43 (2, pt 2) 368- 371
Hu  ZBonifas  JMBeech  J  et al.  Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet 2000;24 (1) 61- 65
Sudbrak  RBrown  JDobson-Stone  C  et al.  Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Hum Mol Genet 2000;9 (7) 1131- 1140
Szigeti  RKellermayer  R Hailey-Hailey disease and calcium: lessons from yeast. J Invest Dermatol 2004;123 (6) 1195- 1196
Slingluff  CL  JrVollmer  RTSeigler  HF Multiple primary melanoma: incidence and risk factors in 283 patients. Surgery 1993;113 (3) 330- 339
Chun  SIWhang  KCSu  WP Squamous cell carcinoma arising in Hailey-Hailey disease. J Cutan Pathol 1988;15 (4) 234- 237
Cockayne  SERassl  DMThomas  SE Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva. Br J Dermatol 2000;142 (3) 540- 542
Hirai  ANaka  WKitamura  K  et al.  A case of squamous cell carcinoma developed in the lesion of Hailey-Hailey's disease [in Japanese]. Rinsyo Derma (Tokyo) 1983;25205- 210
Inaba  YMihara  ITanioka  S Squamous cell carcinoma and Bowen's carcinoma arising in the lesion of Hailey-Hailey disease [in Japanese]. Jpn J Clin Dermatol 1991;45557- 560
Bitar  AGiroux  JM Treatment of benign familial pemphigus (Hailey-Hailey) by skin grafting. Br J Dermatol 1970;83 (3) 402- 404
Furue  MSeki  YOohara  KIshibashi  Y Basal cell epithelioma arising in a patient with Hailey-Hailey's disease. Int J Dermatol 1987;26 (7) 461- 462
Ochiai  THonda  AMorishima  TSata  TSakamoto  HSatoh  K Human papillomavirus types 16 and 39 in a vulval carcinoma occurring in a woman with Hailey-Hailey disease. Br J Dermatol 1999;140 (3) 509- 513
Okunade  GWMiller  MLAzhar  M Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. J Biol Chem 2007;282 (36) 26517- 26527
Capiod  TShuba  YSkryma  RPrevarskaya  N Calcium signalling and cancer cell growth. Subcell Biochem 2007;45405- 427
Cialfi  SOliviero  CCeccarelli  S Complex multipathways alterations and oxidative stress are associated with Hailey-Hailey disease. Br J Dermatol 2010;162 (3) 518- 526
Pinnix  CCLee  JTLiu  ZJ Active Notch1 confers a transformed phenotype to primary human melanocytes. Cancer Res 2009;69 (13) 5312- 5320
Jazbec  JTodorovski  LJereb  B Classification tree analysis of second neoplasms in survivors of childhood cancer. BMC Cancer 2007;727
Corpron  CBlack  CRoss  M  et al.  Melanoma as a second malignant neoplasm after childhood cancer. Am J Surg 1996;172 (5) 459- 462
Guérin  SDupuy  AAnderson  H  et al.  Radiation dose as a risk factor for malignant melanoma following childhood cancer. Eur J Cancer 2003;39 (16) 2379- 2386
Rao  RDHoltan  SGIngle  JN Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer 2006;106 (2) 375- 382
Curtis  RERowlings  PADeeg  HJ Solid cancers after bone marrow transplantation. N Engl J Med 1997;336 (13) 897- 904
Preston  DLShimizu  YPierce  DASuyama  AMabuchi  K Studies of mortality of atomic bomb survivors: report 13: solid cancer and noncancer disease mortality: 1950-1997. Radiat Res 2003;160 (4) 381- 407
Paulino  ACFowler  BZ Secondary neoplasms after radiotherapy for a childhood solid tumor. Pediatr Hematol Oncol 2005;22 (2) 89- 101
Pho  LGrossman  DLeachman  SA Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Curr Opin Oncol 2006;18 (2) 173- 179
Azizi  EFriedman  JPavlotsky  F Familial cutaneous malignant melanoma and tumors of the nervous system: a hereditary cancer syndrome. Cancer 1995;76 (9) 1571- 1578
Randerson-Moor  JAHarland  MWilliams  S A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet 2001;10 (1) 55- 62
Bahuau  MVidaud  DKujas  M Familial aggregation of malignant melanoma/dysplastic naevi and tumours of the nervous system: an original syndrome of tumour proneness. Ann Genet 1997;40 (2) 78- 91