R. Caputo

Amicrobial pustular dermatosis of cutaneous folds associated with autoimmune disorders: a new entity?

BACKGROUNDnAn unclassified amicrobial pustular dermatosis particularly affecting the main cutaneous folds, external auditory canals and scalp and coexisting with systemic lupus erythematosus has been recently described.nnnOBJECTIVEnWe studied 3 young females bearing such cutaneous manifestations in association with subacute cutaneous lupus erythematosus, celiac disease and various serum autoantibodies, respectively, in order to further characterize this possibly new entity.nnnMETHODSnVarious routine and immunological laboratory tests, histopathologic and direct immunofluorescence examinations and in vitro studies of neutrophil function were performed in each patient.nnnRESULTSnWe reported our findings and compared our cases with the few others appearing in the literature. We documented an impaired neutrophil chemotaxis in 2 subjects, but neutrophil dysfunction does not seem to be one of the verifying criteria.nnnCONCLUSIONSnAll of these cases may represent a distinctive form in the clinicopathological spectrum of neutrophilic dermatoses (ND) because of the typical distribution and the close link with different autoimmune disorders. Cimetidine in combination with ascorbic acid can be indicated as an effective and safe alternative to the classic medications of ND, although the action of both drugs remains unexplained.

Sclerodermic Linear Lupus Panniculitis: Report of Two Cases

Lupus erythematosus panniculitis is a rare disease characterized by deep subcutaneous nodules, most commonly localized on the upper limbs and face. Unique clinical presentations, such as linear configuration or ‘overlap’ forms between lupus erythematosus panniculitis and localized scleroderma have been reported. We present here the clinical characteristics, course and laboratory findings of 2 patients having linear lupus erythematosus panniculitis with localized scleroderma-like changes. The 2 patients (of the 14 patients with lupus erythematosus panniculitis seen by us since 1990) were females with a young age at the onset of disease (median, 25 years). In 1 case, evolution into systemic lupus erythematosus with severe renal involvement occurred whereas the other patient, who had a spontaneous abortion and exhibited anticardiolipin antibodies, should be followed and screened for the emergence of antiphospholipid syndrome. Thus, the clinical behavior of this variant seems to be more aggressive, as compared with the usual course of lupus erythematosus panniculitis, which is considered to be a benign disease, although some reports have suggested that its prognosis is not always favorable. The linear distribution could be the clinical hallmark of such a unique, ‘sclerodermic’ subset of lupus erythematosus panniculitis.

Indeterminate cell histiocytosis in association with later occurrence of acute myeloblastic leukaemia

Indeterminate cell histiocytosis (ICH) is a proliferation of indeterminate CD1a+, CD68+, S100+ and CD207− dermal dendritic cells. We describe a 39‐year‐old man who developed diffuse ICH and, 6u2003years later, acute myeloblastic leukaemia (AML). He was treated with cyclophosphamide, etoposide and vinblastine until 2003. In August 2004, he presented dyspnoea, hyperpyrexia and infiltration of the lung parenchyma, compatible with an AML invasion, and died after a course of induction chemotherapy. Cytomorphology and immunophenotype analyses suggested an ICH clonal evolution. The leukaemogenic role of etoposide is discussed. ICH has previously been reported in association with B‐cell malignancy, but only one case has shown systemic progression.

Uncommon Clinical Presentations of Juvenile Xanthogranuloma

Two unusual clinical presentations of juvenile xanthogranuloma (JXG), the most common non-Langerhans cell histiocytosis, are described: a flat ‘plaque-like’ and a ‘paired’ form. This report confirms the great variability of JXG. Besides representing a dermatological curiosity, the recognition of these atypical forms of presentation should facilitate the clinical diagnosis of the disorder.

Widespread idiopathic pyoderma gangrenosum evolved from ulcerative to vegetative type: a 10-year history with a recent response to infliximab

Pyoderma gangrenosum (PG) is an infrequent neutrophilic dermatosis, which commonly presents with a limited number of ulcerative, pustular, bullous or vegetative lesions associated with an underlying systemic disorder. We report a 34‐year‐old man with ulcerative PG that was exceptionally widespread and not associated with any other condition. Moreover, it was resistant to steroid treatment and, after prolonged use of ciclosporin, it unexpectedly developed a vegetative pattern, further supporting the hypothesis that the different forms of PG are part of a single clinical spectrum. Finally, dramatic improvement of the condition occurred after treatment with infliximab, an antitumour necrosis factor‐α monoclonal antibody; however, this produced circulating autoantibodies. Although this has not had any clinical consequence to date, accurate follow‐up in patients treated with infliximab is essential to monitor the onset of a possible autoimmune disorder induced by the drug.

Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma and Castleman disease

SIR, Paraneoplastic pemphigus (PNP) is an autoimmune blistering and erosive mucocutaneous disease associated with neoplasia, most commonly of lymphoreticular origin, first described by Anhalt et al. An alternative term, paraneoplastic autoimmune multiorgan syndrome, has since been proposed to define a condition in which patients, in addition to severe, often fatal pulmonary involvement and deposition of autoantibodies in different organs, may display lesions that resemble pemphigoid, erythema multiforme, graft-versus-host-disease and lichen planus as well as classic pemphigus. We report a patient with a lichen planus-like mucocutaneous variant of PNP associated with follicular dendritic cell (FDC) sarcoma and Castleman disease (CD), emphasizing in particular the rarity of PNP in association with such a type of sarcoma. A 53-year-old woman had painful persistent oral erosions accompanied by dry cough, dysphagia and weight loss since December 2002. She had been given topical and systemic corticosteroids at another hospital, with no improvement. In June 2003, when the patient was referred to our institute, she presented with extensive erosions of the oral mucosa (Fig. 1a), tongue and conjunctiva and a 3-week history of lichenoid papules symmetrically distributed on the trunk (Fig. 1b) and extremities. Laboratory examinations revealed mild anaemia (haemoglobin 10Æ7 g dL; normal 12–16) and positive antinuclear antibodies with speckled pattern at a titre of 1 : 160. Histology from a papular area showed a lichenoid interface dermatitis with numerous necrotic keratinocytes (Fig. 2a). Direct immunofluorescence disclosed intercellular deposits of IgG throughout the epidermis, whereas indirect immunofluorescence demonstrated IgG autoantibodies directed to the intercellular substance of stratified epithelium, namely monkey oesophagus, and also of rat bladder transitional cell epithelium. An immunoprecipitation analysis, carried out as reported, identified a complex of three antigens: proteins of 210 and 190 kDa that could represent desmoplakin II ⁄envoplakin and periplakin, respectively, and the as yet uncharacterized 170-kDa antigen (Fig. 2b). A specific enzyme-linked immunosorbent assay, using recombinant desmoglein (Dsg) 1 and Dsg3 proteins, did not detect antibodies to either Dsg1 or Dsg3. A diagnosis of PNP was made and a search for an underlying neoplasm revealed, on abdominal computed tomographic scans, a 9 · 5 · 8 cm soft tissue mass in the right retroperitoneal area. The mass was excised and pathological examination showed histological features of FDC sarcoma in association with residual foci of CD of the hyaline-vascular type. On immunohistochemistry, the tumour cells of the sarcoma had a CD21+, CD35+, nerve growth factor receptor-positive, actinpositive phenotype. Within 3 weeks after resection of the tumour the mucocutaneous manifestations continued to deteriorate and therapy was initiated with intravenous methylprednisolone 80 mg daily and azathioprine 100 mg daily for 15 days, but this was ineffective. Pulsed intravenous methylprednisolone 250 mg daily for 5 days, and subsequently, a cycle of high-dose intravenous immunoglobulins 0Æ6 g kg daily for five consecutive days resulted in moderate clinical improvement. However, she developed ingravescent dyspnoea: respiratory function tests disclosed restrictive pulmonary changes, whereas positron emission tomography of the chest showed features suggestive of secondary lung involvement by sarcoma. She died of respiratory failure in April 2004. In our patient, the association of PNP with FDC sarcoma, a rare malignant neoplasm of follicular dendritic cells, is unique. Notably, the FDC sarcoma arose from CD, as seen in only one previously reported case. Although there is no firm evidence a

Immunohistochemical expression of apoptotic markers in drug-induced erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease, which is almost always associated with drug intake. In contrast, erythema multiforme (EM) is a disorder regarded as only rarely caused by drugs. Keratinocyte apoptosis has been shown to play an important part in the pathogenesis of SJS and TEN, whilst its role in EM remains controversial. To determine the expression of apoptosis-associated molecules Fas, Fas ligand (FasL), Bcl-2 and Bax in the above disorders, an immunohistochemical analysis was performed. We studied both lesional skin from thirty patients having drug-induced EM and 5 cases classified within the SJS/TEN spectrum and normal skin samples. We found a keratinocyte overexpression of Fas antigen, an important molecule mediating apoptosis, not only in SJS and TEN but also in EM. Another noteworthy finding was the strong expression of Bcl-2, a protein known as blocking apoptosis, along the basal layer and in the dermal infiltrate both in SJS/TEN and in EM. Taken together, these findings suggest that Fas-dependent keratinocyte apoptosis may play a part in the pathogenesis of both SJS/TEN and EM. Fas-mediated cell death may be partially suppressed by the Bcl-2 protein.

Chemotherapeutic experience in indeterminate cell histiocytosis

SIR, Indeterminate cell histiocytosis (ICH) is a rare disorder of cells morphologically and phenotypically resembling Langerhans cells but lacking Birbeck granules. Two clinical subsets have been described, namely disseminated disease presenting with multiple, asymptomatic cutaneous papules and nodules in the absence of systemic involvement and a localized form consisting of solitary skin lesions. Although some patients who have developed leukaemia have been reported, the majority of cases have an indolent, often self-limited course, requiring no aggressive treatments. We present the cases of two adult males who had widespread and relapsing ICH. Despite the absence of visceral involvement, several chemotherapy regimens were necessary for their treatment. Patient 1. In July 2000, a 32-year-old man presented with a few months’ history of generalized, asymptomatic reddishbrown papules and nodules; the lesions first appeared on the face and slowly but progressively increased in size and number to involve the trunk and limbs (Fig. 1). Laboratory investigations disclosed an erythrocyte sedimentation rate of 40 mm in the first hour and a moderate leucocytosis with neutrophilia. The skin histology showed a diffuse, monomorphous infiltrate of histiocytes with eosinophilic cytoplasm and round or kidney-shaped nuclei throughout the entire dermis; histiocytes, singly or clustered in aggregates, within the epidermis as well as scattered lymphocytes in a perivascular distribution into the dermis were also seen. Immunohistochemistry demonstrated that the proliferating cells had a CD1a+, S-100+, CD68 (KP1)+, MAC 387+, HLADR+, Factor XIIIa– phenotype. Electron microscopy specimens were characterized by proliferating histiocytes having an indented nucleus and abundant cytoplasm, with lysosomes, phagosomes and a well-developed endoplasmic reticulum. Birbeck granules were absent. A diagnosis of ICH was made and an adequate staging failed to disclose visceral involvement. The patient was treated with oral cyclophosphamide 100 mg daily for 6 months; regression of the skin lesions began by the end of the first month and continued over the following 5 months. However, a widespread papulonodular eruption unresponsive to cyclophosphamide developed and the patient was given intravenous etoposide 170 mg m of body surface daily for four consecutive days every 4 weeks. Initially, the patient’s condition improved, but later the disease progressed despite continued therapy, and etoposide was discontinued. In April 2002, the patient was treated with four weekly courses of 0Æ1 mg kg of intravenous vinblastine sulphate and intramuscular methylprednisolone 20 mg. Within 1 month, marked improvement in the lesions was noted and the treatment schedule was changed to every 2 weeks for 3 months, and then every 4 weeks for 6 months, until complete resolution. Within 6 months, a relapse unresponsive to vinblastine occurred; in February 2004, the patient received a single course of 2-chlorodeoxyadenosine 0Æ1 mg kg )1 day by continuous intravenous infusion for 7 days, inducing complete remission. At the time of writing this report in July 2004, the patient was free of lesions, without recurrences. Patient 2. A 36-year-old man was seen with a 2-year history of an asymptomatic, symmetrical, flesh-coloured papulonodular eruption of the extremities and trunk in May1998 (Fig. 2). Histological, immunohistochemical and ultrastructural findings were consistent with ICH. Extracutaneous disease was excluded. The patient responded satisfactorily to oral cyclophosphamide and was then lost to follow-up. In December 2000, he was referred because of a relapse but cyclophosphamide was ineffective. In contrast, intravenous etoposide for 1 year induced complete remission. In February 2003, the patient was given a combination of vinblastine and methylprednisolone for lesions resistant to etoposide. Vinblastine was administered for 1 year, leading to pronounced involution of the skin lesions. At the time of writing this report, he remained free of lesions without therapy. Fig 1. Patient 1: Reddish-brown papulonodular eruption involving the trunk and upper limbs.

Lupus erythematosus with antiphospholipid syndrome and erythema multiforme-like lesions

The occurrence of erythema multiforme (EM) in patients with lupus erythematosus (LE) has been described previously as a coincidental association. In contrast, LE with EM‐like lesions and a peculiar immunological pattern, including positive rheumatoid factor, antinuclear antibodies and a serum antibody against an extract of human tissues recently recognized as similar to Ro (SSA), constitutes an established entity named Rowells syndrome. We describe a woman with LE and long‐standing widespread vesiculobullous and necrotic haemorrhagic EM‐like lesions in combination with Ro (SSA) and scl‐70 antibodies and the typical laboratory findings of the antiphospholipid syndrome (APS), namely lupus anticoagulant, anticardiolipin antibodies and prolonged activated partial thromboplastin time. This case could conceivably be consistent with a diagnosis of Rowells syndrome, if the latter is regarded as a clinicopathological spectrum. However, the coexistence of LE, persistent EM‐like disease and incomplete APS may also fulfil the diagnostic criteria for the ‘multiple autoimmune syndromes’. We speculate that the laboratory markers of APS play a pivotal part in such an unusual clinical presentation.

Ichthyosis congenita type IV: a new case resembling diffuse cutaneous mastocytosis

The wide phenotypical heterogeneity within the ichthyosis congenita group of diseases is well known. We report a case of a very rare and unusual autosomal recessive ichthyosis congenita, type IV, according to the ultrastructural classification. Our case presented the triad clue for the diagnosis, characterized by follicular hyperkeratosis, prematurity and perinatal complications, but the clinical diagnosis was further complicated by hypereosinophilia and a strongly positive Dariers sign suggesting diffuse cutaneous mastocytosis. The diagnosis was provided only by electron microscopy, which showed the pathognomonic markers of ichthyosis congenita type IV, namely a large number of membrane structures in the stratum corneum and stratum granulosum. As a consequence, correct genetic counselling for the parents was carried out, and they were informed about the benign course of the disease after the complications of the perinatal period. This case is a further example of the reliability of ultrastructural markers in the diagnosis of inherited keratinization disorders, especially those with an unusual clinical appearance.