Takahide Kaneko

Papillon-Lefèvre Syndrome and Malignant Melanoma

Papillon-Lefèvre syndrome (PLS) is a rare autosomal-recessive genodermatosis characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis. The development of malignant cutaneous neoplasms within the hyperkeratotic lesions of the syndrome is quite rare. Here, we report on a 51-year-old Japanese woman with PLS associated with recurrent malignant melanoma (MM). Mutation analysis of the cathepsin C gene revealed that the proband was homozygous for a missense mutation, c.415G→A, which is predicted to result in the amino acid substitution p.G139R. Including our case, 4 families have been described as having PLS with MM, 3 of which are Japanese, implying a high incidence of melanoma development in Japanese PLS patients. We suggest that hereditary palmoplantar keratoderma (PPK) in Japanese patients might be predisposed to MM. A literature review revealed that in 18 cases of MM-associated PPK, 13 (76%) were Japanese, suggesting a high incidence of MM in Japanese PPK patients. This tendency might be attributable to the high frequency of acral lentiginous melanoma in Japanese subjects, in contrast to a lower frequency of this subtype in Caucasians.

Significance of sentinel node biopsy in the management of squamous cell carcinoma arising from recessive dystrophic epidermolysis bullosa

The most life‐threatening complication developing in patients with recessive dystrophic epidermolysis bullosa (RDEB) is squamous cell carcinoma (SCC). To improve patient prognosis, early detection of regional lymph node metastasis is required. Herein, we report a patient diagnosed with non‐Hallopeau–Siemens RDEB who developed SCC on the left foot with inguinal lymph node swelling. Use of the sentinel node biopsy (SNB) technique favorably minimized defective damage to the inguinal region in this case. Genetic analysis identified one novel COL7A1 mutation, a maternal c.238G > C (p.A80P) and one previously reported mutation, a paternal c.3631C > T (p.Q1211X). A published work review demonstrated that no COL7A1 mutations specific for SCC development in RDEB have previously been identified. It remains unclear if SNB in combination with gene diagnosis is beneficial for the management of SCC in RDEB patients, however, because of the limited number of case reports. To address this issue, COL7A1 mutational analysis should be performed in as many cases of RDEB as possible.

A Case of Photocontact Urticaria Induced by Photodynamic Therapy with Topical 5-Aminolaevulinic Acid

Photodynamic therapy (PDT) with topical application of 5‐aminolaevulinic acid (ALA) is a promising new treatment option for the management of various cutaneous malignancies. Generally, topical ALA‐based PDT has relatively insignificant adverse effects of transient character; these include itching, stinging or burning pain and slight to moderate erythema. We describe the first case of photocontact urticaria induced by topical ALA‐based PDT for the treatment of unilesional mycosis fungoides. Although the first treatment session resulted merely in mild erythema, the second PDT caused marked urticaria corresponding to the PDT‐applied area with an intolerable stinging sensation. A photopatch test demonstrated that black light and visible light irradiation after topical ALA provoked an urticarial reaction in the patients uninvolved skin. These observations suggested an allergic pathogenesis for the wheal formation induced by PDT with topical ALA in this case. Photocontact urticaria should be considered as a possible adverse effect in ALA‐based PDT.

Successful treatment of lymphadenosis benigna cutis with topical photodynamic therapy with delta-aminolevulinic acid.

Background: Photodynamic therapy (PDT) using topical δ-aminolevulinic acid (ALA) has been used for nonmelanoma skin cancers, including malignant cutaneous T-cell lymphomas. Moreover, PDT has been tried for benign inflammatory or infectious skin lesions. Objective: To evaluate the effects of ALA-PDT on skin lesions of lymphadenosis benigna cutis (LABC). Patients and Methods: Two 16-year-old females with solitary and infiltrated nodules were treated 5 times with topical ALA-PDT. Results: Both patients responded well and showed dramatic clinical and histopathological improvement without visible scars. Conclusion: The results confirm that topical ALA-PDT is an effective and safe modality for the treatment of LABC, and that such treatment may be cosmetically beneficial.

Interferon-gamma down-regulates expression of the 230-kDa bullous pemphigoid antigen gene (BPAG1) in epidermal keratinocytes via novel chimeric sequences of ISRE and GAS.

Abstract:  The 230‐kDa bullous pemphigoid antigen (BPAG1) is an integral component of hemidesmosomes. We have previously reported that interferon‐γ (IFNγ) inhibits the transcription of the BPAG1 gene ( 1 ). Here we investigated the target sequences of IFNγ‐signal transduction pathway in the BPAG1 promoter in epidermal keratinocytes. Transient transfections with 5′‐deletion constructs of BPAG1 promoter‐luciferase reporter gene plasmids in cultured normal human epidermal keratinocytes (NHEK) allowed us to narrow the DNA region containing IFNγ inhibitory element (IGIE) to between −1 and −89, upstream from the transcription initiation site (+1). Homology search in this region identified a chimeric sequence, consisting of IFN‐stimulated responsive element (ISRE) with a partial 7‐bp sequence of IFNγ activation site (GAS), as identified in the guanylate‐binding protein (GBP) gene, inserted at its center. Functional analysis of IGIE, inserted in front of the heterologous thymidine kinase promoter, indicated that IGIE acts as a down‐regulatory element of the promoter through IFNγ‐dependent signal pathway. Transient transfection studies with BPAG1 promoter‐reporter gene constructs containing mutated IGIE (with TT to GG transversions in the region of 5′ISRE, GAS, and 3′ISRE) demonstrated that disruption of the ISRE sequences, but not GAS, markedly suppressed the BPAG1 basal promoter activity and resulted in attenuated IFNγ response in keratinocytes. Our findings provide novel insight into the mechanism of IFNγ regulation in keratinocyte differentiation and proliferation.

Transcriptional regulation of the 230‐kDa bullous pemphigoid antigen gene expression by interferon regulatory factor 1 and interferon regulatory factor 2 in normal human epidermal keratinocytes

Abstract:  Interferon regulatory factors (IRFs) are a family of transcriptional factors induced by interferon‐γ (IFN‐γ). Recent studies have indicated that the deregulation of IRF system in keratinocytes is responsible, at least in part, for aberrant proliferation and the differentiation of the psoriatic epidermis. Previously, we reported that the expression of 230‐kDa bullous pemphigoid antigen (BPAG1) gene, which is strictly restricted to basal keratinocytes, is transcriptionally suppressed by IFN‐γ, but the contribution of IRFs in such suppression is still unclear. In this study, we investigated the role of IRFs in the regulation of BPAG1 gene expression. Computer analysis identified IRF1 and IRF2 consensus sequences between −135 and −123 on BPAG1 promoter region. Transient transfection studies with BPAG1 promoter‐luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down‐regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. Several sets of gel retardation assays with the BPAG1–IRF binding sequence as a probe indicated that IRF1 and IRF2 could bind to the BPAG1–IRF sequence, but some other protein(s), which was induced by IFN‐γ stimulation and possessed binding activity to IRF consensus sequence, showed preferential binding to the BPAG1–IRF sequence. Our results suggest that IFN‐γ–IRF system is involved in BPAG1 gene regulation in type‐1 helper T‐cell inflammatory skin conditions, such as psoriasis vulgaris.

Dermoscopy of eccrine poroma with calcification.

BACKGROUND Eccrine poromas are relatively common slow-growing benign solitary adnexal tumors originating from the intraepidermal portion of the eccrine sweat duct (acrosyringium). Dystrophic calcification is rarely found in lesions of eccrine poroma, and only 2 cases of eccrine poroma with calcification have been reported thus far. In the present report, we describe another case of eccrine poroma with calcification occurring in the palm of the hand. Also, we show dermoscopic features of this case. MAIN OBSERVATIONS A 73-year-old man with hemiparesis, who had a 10-year history of tumor on his right palm, which was occasionally injured by a walking crutch, causing bleeding and ulceration. Physical examination revealed a pigmented dome-shaped tumor. Dermoscopic analysis revealed glomerular vessels, multiple pink-white structureless areas, and lacunae. Histological examination revealed that the tumor was composed of cords of tumor cells extending from the epidermis into the dermis. These were uniformly cuboidal cells with round, basophilic nuclei and dense vascular stromas with telangiectasia. The tumor showed cystic structures and calcification. The patient was diagnosed with Pinkus-type eccrine poroma on the basis of histological findings. CONCLUSIONS Although cutaneous neoplasms commonly associated with calcification are of follicular origin, it is known that dystrophic calcification may be triggered also in tumors of eccrine origin by multiple factors, including mechanical injury. Dermoscopy may be helpful in establishing clinical diagnosis of calcified eccrine poromas.

Q‐switched ruby laser therapy and long‐term follow‐up evaluation of small to medium‐sized congenital melanocytic naevi

Congenital melanocytic naevi (CMN) are defined as a tissue malformation of the neuroectoderm that presents at birth or within the first few months of life. CMN are generally classified according to their current size at detection, or their predicted size at adulthood: small (< 150 mm in diameter), medium (150–200 mm) or large (> 200 mm). Although the development of malignant melanomas arising in small and intermediate CMN is rare, there is a significant risk of malignant degeneration associated with large CMN, particularly those that arise on the torso in the so-called bathing-trunk distribution, where the risk is estimated to be about 2.5–5%. Medium-sized CMN are difficult to treat, especially if the lesions occur on the visible areas of the body such as the face or limbs. The Q-switched ruby laser (QSRL) has been successfully used to treat various benign pigmented lesions. Long-term follow-up is needed for the assessment of recurrence, delayed scarring and malignant transformation. In this study, we treated patients with small to mediumsized CMN using early serial QSRL. Hirosaki University School of Medicine and Hospital granted ethics approval for this study, and all patients provided informed consent for the procedure. In total, 18 patients (7 male, 11 female, mean ± SD age 5.5 ± 3.6 years, range 4 months to 14 years) were enrolled. All the patients had Fitzpatrick skin types III and IV. The sites of involvement in 9, 1, 6 and 3 cases were the face (n = 9 cases), legs (n = 6), arms (n = 3) and chest (n = 1) (Table 1). Irradiation was carried out every 3 months. Each patient received 2–44 treatments (mean of 18.7). Examinations were carried out for > 3 years, and the CMN lesions did not completely disappear in any case. However, 11 patients had slight improvement in the colour of the lesions, 1 patient had partial hypopigmentation remaining, 5 patients had receding of pigmentation, but the affected skin returned to its original colour within 1 month from the final treatment, and 1 patient (patient 18, Fig. 1) had recurrence (Table 1). After treatment ended, none of the patients had hypertrophic scarring, and the skin texture remained unchanged. A typical case of CMN recurrence during long-term follow-up was that of a 6-year-old boy with a CMN on his left upper arm (Fig. 1a). On histological examination, the lesion was identified as a compound naevus showing no evidence of malignancy or dysplastic changes (Fig. 2a). The patient received 5 treatments with normal-mode ruby laser and 10 with QSRL, after which the lesion significantly improved in colour and cosmetic appearance (Fig. 1b). There was no partial hypopigmentation or textural change. Initially, we assumed that using the normal-mode laser and the QSRL in combination had been effective. However, at the age of 21 years, the patient returned to our clinic because the skin lesion had recurred (Fig. 1c). We suggested further QSRL therapy, but he preferred to undergo excision. The histological findings of the excised lesion showed a marked decrease in the number of junctional melanocytes and nests in the papillary and reticular dermis, but many naevus cells remained in the deep dermis (Fig. 2b,c).

Juvenile myelomonocytic leukemia presenting multiple painful erythematous lesions diagnosed as Sweet's syndrome

Dear Editor, Juvenile myelomonocytic leukemia (JMML) is a rare hematological disorder of infants and young children, and is characterized by proliferation of neutrophilic and monocytic lineages. Clinical features of JMML include hepatosplenomegaly, lymphadenopathy, recurrent infections and bleeding. Several cases have been reported to have skin infiltration of JMML although almost 30% patients show macularpapular skin rash as leukemids. Recently, even chilblain-like lesions were reported as skin manifestation of JMML. This report indicates for the first time that Sweet’s syndrome could be a manifestation of JMML. A 3-year-old boy presented with a 1-year history of febrile recurrent skin eruption. Physical examination showed multiple, painful, erythematous plaques and nodules up to 2 cm in diameter on his face and lower extremities (Fig. 1a,b,c). We also found multiple postinflammatory pigmentations. A skin biopsy from erythema on his leg demonstrated a diffuse dermal infiltration of neutrophils and lymphocytes, including leukocytoclasts (Fig. 1d,e). Careful examination of several specimens could not detect presence of atypical leukocytes and monoclonality of infiltrating cells. At this point, clinical and histological findings were compatible with Sweet’s syndrome although Sweet’s syndrome occurring in a 3-year-old boy was atypical. Because Sweet’s syndrome is known to be associated with hematological malignancies, we then performed additional detailed examinations. Laboratory investigations showed leukocytosis (26 430/ mm with 19% monocytes, 2% metamyelocytes, 4% blast cells), thrombocytopenia (3.7 × 10/mm) and a high level of hemoglobin F. Bone marrow aspiration showed mild myeloid hyperplasia with 10% of monocytoid blast cells. Philadelphia chromosome, bcr-abl rearrangement, monosomy 7 and trisomy 8 were absent. Final diagnosis of JMML was confirmed by hypersensitivity of myeloid progenitors in addition to granulocyte macrophage colony-stimulating factor. After the final diagnosis of JMML, we examined the skin specimens immunohistochemically, but the results showed no monoclonal growth of infiltrating cells that were positive for lysozyme and CD68. Administration of 6-mercaptopurine was given at 30 mg/day, resulting in partial remission. Subsequently, cord blood stem cell transplantation was performed, and this graft was received. Unfortunately, the patient died of renal dysfunction and infection 4 months after the cord blood stem cell transplantation. During the course of treatment, we could not see any eruptions of Sweet’s syndrome. Sweet’s syndrome is an acute inflammatory dermatosis characterized by dermal infiltrate of neutrophils and variable leukocytoclasis, and typically affects middle-aged women. Although Sweet’s syndrome shows typically multiple, painful, reddish, indurated erythema found in our case, atypical clinical features including bullous lesions, pustular dermatosis of the hands and subcutaneous types have been highlighted recently. It is well known that the cases with Sweet’s syndrome often have associated hematological malignancies and most are acute myeloid leukemia. The presence of leukemic cells within skin lesions of Sweet’s syndrome has been reported in several cases. In these cases, it is occasionally difficult to distinguish between nonspecific and specific lesions because the natures and the numbers of infiltrating leukemic cells in the skin are variable depending on origins of leukemic cells, disease conditions and treatments

A novel H1 domain mutation in the keratin 2 gene in a Japanese family with ichthyosis bullosa of Siemens.

Ichthyosis bullosa of Siemens (IBS) is a rare autosomal dominant skin disorder characterized by blister formation in the upper suprabasal layers of the epidermis. Clinical features of the disease, which include blistering after mechanical trauma, lichenified hyperkeratosis over the flexural areas of the limbs, and superficial peeling of the skin, are similar to those of epidermolytic hyperkeratosis/bullous congenital ichthyosiform erythroderma (EHK/BCIE). This clinical resemblance makes diagnosis difficult. Recent molecular studies have identified mutations in the keratin 2 (K2) gene (KRT2; this new designation is used throughout this report according to the current nomenclature for mammalian keratins) in patients with IBS, in contrast to the keratin 1 or 10 mutations that have been detected in patients with EHK/BCIE, enabling us to differentiate between IBS and EHK/BCIE. Thus far, 29 missense mutations that result in amino acid substitutions in K2 have been identified in patients with IBS; all such mutations reside in the helix initiation or termination motifs of K2. Here, we describe a novel mutation in the H1 region of K2 in a Japanese family with IBS.