Pamela Vezzoli

Drug-induced lupus: an update on its dermatologic aspects.

Drug-induced lupus erythematosus (DILE) is defined as an entity characterized by clinical manifestations and immunopathological serum findings similar to those of idiopathic lupus but which is temporally related to continuous drug exposure and resolves after discontinuation of the offending drug. Similar to idiopathic lupus, DILE can be divided into systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Based on the literature review and retrospective analysis of our case series, we focused on the dermatological aspects of DILE. The cutaneous features of drug-induced SLE are protean, including particularly purpura, erythema nodosum and photosensitivity as well as the skin lesions characterizing both urticarial and necrotizing vasculitis. The typical laboratory profile of systemic DILE consists of positive antinuclear antibodies (ANA) and antihistone antibodies, the latter being regarded as the serum marker of this subset. The drugs most frequently implicated in the development of systemic DILE are hydralazine, procainamide, isoniazid and minocycline. Drug-induced SCLE usually presents with annular polycyclic or papulosquamous cutaneous manifestations as in the idiopathic form, but blisters or targetoid lesions mimicking erythema multiforme cannot rarely be associated. The clinical presentation is often generalized, with involvement of the lower legs that are usually spared in idiopathic SCLE. ANA and anti-Ro/SSA antibodies are usually present, whereas antihistone antibodies are uncommonly found. Drugs associated with SCLE include particularly calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine and the recently reported tumour necrosis factor (TNF)-α antagonists. Drug-induced CCLE is very rarely described in the literature and usually refers to fluorouracile agents or TNF-α antagonists. The picture is characterized by the occurrence of classic discoid lesions, but aspects of lupus tumidus can occasionally develop. ANA are demonstrated in around two-thirds of the cases. Management of DILE is based on the withdrawal of the offending drug. Topical and/or systemic corticosteroids and other immunosuppressive agents should be reserved for resistant cases.

Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy derived from precursors of plasmacytoid dendritic cells. We analyzed 21 cases with array-based comparative genomic hybridization (aCGH). Complete or partial chromosomal losses largely outnumbered the gains, with common deleted regions involving 9p21.3 (CDKN2A/CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2 (IKZF1) regions. CDKN2A/CDKN2B deletion was confirmed by FISH. This scenario argues for disruption of cell cycle at G(1)/S transition, representing a genetic landmark of BPDCN, and possibly contributing to its pathogenesis. Statistical analysis of overall survival in our series highlighted an association of poor outcome with biallelic loss of locus 9p21.3. We suggest that, in the absence of reliable parameters for predicting prognosis in BPDCN other than age, tumor stage, and/or clinical presentation, simple methods, such as FISH for CDKN2A/CDKN2B, could help to identify the most aggressive cases.

Cutaneous extranodal NK/T-cell lymphoma: a clinicopathologic study of 5 patients with array-based comparative genomic hybridization

Extranodal natural killer/T-cell (ENK/T) lymphoma is a rare neoplasm, subcategorized into ENK/T-nasal (ENK/T-N) and ENK/T-nasal type (ENK/T-NT) lymphomas. ENK/T-NT lymphoma with initial presentation in the skin is known as primary cutaneous ENK/T-NT (PC-ENK/T-NT) lymphoma. The aim of this study was to investigate pathogenesis, genomic alterations, and prognosis of cutaneous ENK/T lymphomas to provide further insights into clinicopathologic features and genetic mechanism of lymphomagenesis. A retrospective case study of 5 white patients affected by ENK/T lymphoma (4 PC-ENK/T-NT and 1 ENK/T-N with cutaneous involvement) was performed. Most of the cases presented with multiple nodules and ulcerations localized on the extremities. A considerable percentage had disease in advanced stage with a 12-month survival rate of 40%. Genomic alterations were detected by array-based comparative genomic hybridization that showed gains of 1q, 7q and loss of 17p in the cases of PC-ENK/T-NT lymphomas and gain of 7q and loss of 9p, 12p, 12q in the case of ENK/T-N lymphoma. In conclusion, ENK/T lymphoma is a very aggressive entity, and, in our cases, the exclusively cutaneous presentation was not associated with a better prognosis. The results of our array comparative genomic hybridization analysis could be useful to better define the different ENK/T lymphoma subgroups with cutaneous involvement.

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

Rationale and efficacy for the use of rituximab in paraneoplastic pemphigus.

Paraneoplastic pemphigus (PNP) is a life-threatening, autoimmune, blistering-skin disease, associated with various neoplasms, particularly lymphoproliferative disorders. It is characterized by polymorphic cutaneous manifestations, severe mucosal erosions and internal organ involvement, and marked by unique histopathological features and a complex autoantigenic profile. To define this condition, the encompassing term ‘paraneoplastic autoimmune multiorgan syndrome’ has also been suggested. Although a number of immunosuppressive treatments have been used in PNP, its mortality rate remains high. The anti-CD20 monoclonal antibody, rituximab, was successfully administered to two patients with PNP and CD20+ follicular lymphoma in 2001. Since then, good responses to rituximab by different refractory autoimmune disorders have been reported, but further controlled trials are warranted to evaluate the effectiveness and safety of this agent as a second-line treatment for PNP.

Cetuximab-induced acneiform eruption and the response to isotretinoin

Sir, Epidermal growth factor receptor (EGFR) is commonly over-expressed in tumours. Its main function is to promote the growth and division of cells by the activation of various intracellular signalling pathways. The monoclonal human-murine chimeric antibody cetuximab is a member of a new family of anti-neoplastic agents that specifically targets and locks on to the EGFR, causing receptor internalization and preventing ligand-mediated receptor activation (1). Clinical trials with cetuximab, as a single therapeutic agent or in combination with other drugs, have demonstrated significant activity in several EFGR-expressing tumours, notably in patients previously resistant to chemotherapy (2). Unlike conventional cytotoxic agents, cetuximab does not cause myelosuppression, neuropathy, significant constitutional symptoms, or alopecia (3). In contrast, cutaneous side-effects are common, the most frequent of which is an acneiform eruption, usually observed within 1–3 weeks after the onset of treatment (4–7). The question of whether this disorder is responsive to classical anti-acne treatments, remain poorly elucidated. We report here typical acneiform eruption in 2 patients with metastatic colorectal cancer treated with cetuximab and their responses to antibiotics and isotretinoin, respectively.

Elephantoid oedema of the eyelids

We describe a male patient with rosacea who had a 2‐year history of persistent bilateral oedema of the eyelids, leading to an elephantoid condition with blepharoptosis. An upper eyelid blepharoplasty was performed, but swelling progressively recurred over a few months. Based on the case history, clinical appearance and histological findings, rosaceous lymphoedema was considered to be the diagnosis. The latter is a bilateral, solid oedema of the mid‐third of the face, regarded as a rare complication of rosacea. It is thought to occur as a result of chronic inflammation and lymphatic stasis, but its exact aethiopathogenesis remains elusive. Predominant eyelid involvement, causing severe visual impairment as in our patient, is unique.

Primary cutaneous T-cell lymphoma expressing FOXP3: A case report supporting the existence of malignancies of regulatory T cells

Regulatory T (Treg) cells, which represent 5% to 10% of peripheral T cells, regulate the activities of T-cell subsets by performing immunosuppressive functions and thus preventing the development of autoimmune responses. The majority of Treg cells are CD4+, CD25+, and FOXP3+. Recently, it has been demonstrated that the tumor cells in adult T-cell leukemia lymphomas can function as Treg, raising the question of whether any variant of primary cutaneous T-cell lymphoma may also express a regulatory phenotype. We describe an extraordinary case of primary cutaneous T-cell lymphoma clinically characterized by protean cutaneous manifestations and histologically showing a pattern consistent with epidermotropic pleomorphic medium-/large-cell primary cutaneous T-cell lymphoma. The majority of neoplastic cells were CD4+ CD25+ T cells and strongly expressed FOXP3. With this background, the current case, characterized by an aggressive course requiring polychemotherapy, may support the existence of lymphoproliferative malignancies of Treg cells.

Cutaneous T-Cell/Histiocyte-Rich B-Cell Lymphoma: A Case Report and Review of the Literature

Background: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) primarily presenting on the skin is an extremely rare entity with only sporadic cases reported in the literature. Methods: We here report an extraordinary case of primary cutaneous THRLBCL with self-healing and 24 months of follow-up. Results: The lesion was a dermohypodermal/subcutaneous circumscribed ulcerated nodosity. Histological examination with immunohistochemical, molecular analysis and comparative genomic hybridization were performed. A complete staging was negative for secondary involvement. Conclusion: Our case is remarkable because it is the second well-documented primary cutaneous THRLBCL in which we observed a complete self-regression of skin lesions without recurrences or dissemination of the disease. According to the literature, we highlight that the tumoral microenvironment, in our case, could play a relevant role in stopping lymphoma growth. Furthermore, this case supports the observation that THRLBCL primarily presenting on the skin shows an overall good prognosis.

Cutaneous Lymphoid Hyperplasia Associated with Leishmania panamensis Infection

Cutaneous leishmaniasis (CL) is an infection caused by protozoa from the genus Leishmania. The disease is transmitted by sandflies. Reservoirs are dogs, mice, wild rodents and, more rarely, humans. CL is clinically characterized by a single, polymorphous lesion, usually localized on the face or limbs. Nowadays, CL is more frequently seen among travellers returning from tropical and subtropical countries (1). Cutaneous lymphoid hyperplasia (CLH), also known as pseudolymphoma, is a reactive proliferation, probably secondary to persistent antigenic stimulation. We present here a case of CLH associated with L. panamensis infection.