Paraneoplastic pemphigus with bronchiolitis obliterans in a child

Paraneoplastic pemphigus (PNP) is a rare blistering autoimmune disease associated with an underlying neoplasm, mucous membrane erosions, and occasionally bronchiolitis obliterans. Most cases have been reported in adults and the number of childhood cases in the current literature is limited. We describe a young patient with PNP who was initially misdiagnosed as having recurrent Stevens-Johnson syndrome. This patient had an underlying inflammatory myofibroblastic tumor and subsequently developed fatal progressive bronchiolitis obliterans.     

Paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a life-threatening autoimmune blistering skin disease. Clinically, it is characterized by severe mucosal erosions and various cutaneous lesions associated with lymphoproliferative neoplasmas. Suprabasal acantholysis and clefts with scattered necrotic keratinocytes are the unique histopathological features. PNP patient sera recognize multiple antigens, which have been identified as the plakin protein family that includes desmoplakin, bullous pemphigoid antigen I (BPAG1), envoplakin and periplakin, and desmogleins 1 and 3. Castleman's tumor, non-Hodgkin's lymphoma, thymoma, follicular dendritic cell sarcoma and chronic lymphocytic leukemia are the commonly associated neoplasmas in PNP. We have also demonstrated that the autoantibodies reacting to epidermal proteins are directly produced by the cells in the associated tumors. Bronchiolitis obliterans is frequently found in PNP and may cause respiratory failure and death. In our experience, the early detection and removal of the tumor and i.v. administration of immunoglobulin are critical for the treatment of PNP.     

Fatal Paraneoplastic Pemphigus After Removal of Castleman's Disease in a Child

Paraneoplastic pemphigus (PNP) is seen most frequently in the setting of Castleman's disease (CD) in childhood. We report herein a 10-year-old girl with PNP appearing a few weeks after resection of a recurrent CD. Despite improvement in skin and mucosal lesions with prednisolone and azathioprine, she had severe bronchiolitis obliterans and died from respiratory failure a few months later.     

Paraneoplastic pemphigus resembling linear IgA bullous dermatosis

A 69-year-old Chinese man presented in 2001 with a blistering eruption over the upper and lower limbs associated with oral ulceration for 1 month. He had stage IIIA follicular small cell cleaved non-Hodgkin's lymphoma diagnosed 5 years previously, and had received several lines of palliative chemotherapy, including two courses of chlorambucil, six cycles of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP), and two four-cycle courses of rituximab, with disease stabilization at the time of presentation. Examination revealed erythematous, annular plaques with raised, urticarial borders studded with tense bullae and vesicles over the thighs. Some lesions were arciform and annular, with vesicles arranged in a ring at the border (Fig. 1). There was involvement of the feet with desquamation at the tips of the toes (Fig. 2). Severe erosions with hemorrhagic crusts on the lips, tongue, and buccal mucosa were seen. Herpes simplex virus serology was negative. A biopsy specimen from a vesicle on the left thigh showed suprabasal acantholysis (Fig. 3), some apoptotic keratinocytes (Fig. 4), satellite cell necrosis in the epidermis, and a superficial perivascular infiltrate of lymphocytes and eosinophils. Direct immunofluorescence showed intercellular immunoglobulin G (IgG) and C3 within the epidermis and along the basement membrane zone. Indirect immunofluorescence on monkey esophagus was positive for anti-intercellular antibody at a titre of 1/160 and positive on rat bladder at a titre of 1/80. A presumptive diagnosis of paraneoplastic pemphigus was made. This was later confirmed by the presence of antibodies against envoplakin (210 kDa), periplakin (190 kDa), and desmoglein 1 on immunoprecipitation studies. He was started on prednisolone 60 mg/day (1 mg/kg/day), with complete resolution of skin lesions within 1 week, but persistence of oral ulcers. Cyclophosphamide was added at a low dose of 1 mg/kg/day as he had baseline leukopenia. Cyclosporine was later added to a maximum of 4 mg/kg/day with only mild improvement of the oral lesions. He declined rituximab therapy. He died 2 months later from fulminant pneumonia.     

Therapy of paraneoplastic pemphigus with Rituximab: a case report and review of literature

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease with poor prognosis when associated with malignant neoplasm. We report the case of a patient with PNP associated with a CD20+ non-Hodgkin follicular lymphoma who was treated with Rituximab plus corticosteroids and short courses of cyclosporin. One and a half years after Rituximab therapy, oral ulcerations had cleared and oral methylprednisolone was slowly tapered down without further recurrences. In the course of the disease, the patient developed sepsis due to Listeria monocytogenes and viral infections by human herpes virus 1 and 3. At the end-stage of the disease she developed a cutaneous infection from Mycobacterium chelonae. The patient died 2 years and 7 months after the onset of PNP. Rituximab may be useful for PNP therapy, but further studies are necessary to confirm this hypothesis.     

IgA pemphigus with paraneoplastic pemphigus‐like clinical features showing IgA antibodies to desmoglein 1/3 and desmocollin 3, and IgG and IgA antibodies to the basement membrane zone

A 79‐year‐old Japanese woman presented with severe recalcitrant erosions on her oral mucosa, resembling paraneoplastic pemphigus. Using indirect immunofluorescence, we detected IgA antibodies against the cell surface, and both IgG and IgA antibodies against the basement membrane zone. Immunoblotting showed that the IgG antibodies reacted weakly with bullous pemphigoid 230 and periplakin, whereas the IgA antibodies did not react with any antigen. IgA antibodies to both desmoglein (Dsg)1 and Dsg3 were detected by ELISA. IgA antibodies to desmocollin (Dsc)3 were also detected by using cDNAs for human Dsc1–3 transfected into COS‐7 cells. Despite treatment with oral prednisolone, high‐dose intravenous immunoglobulin and double‐filtration plasmapheresis, the skin lesions remained active, and the patient died from bronchiolitis obliterans‐like respiratory failure. Despite extensive investigations and postmortem examination, no underlying neoplasms were found. The complex immunopathological findings probably played an important role in the development of the patient's unusual clinical features.     

Paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a life-threatening autoimmune mucocutaneous blistering disease associated with malignancy, particularly lymphoproliferative neoplasms. Clinically, it is characterized by severe and intractable mucositis and polymorphous cutaneous eruptions, ranging from blisters to lichenoid lesions. The histologic features are also diverse according to the morphology of the clinical lesions, ranging from suprabasal acantholysis to interface changes with necrotic keratinocytes. PNP is characterized by the production of autoantibodies against the plakin family proteins as well as the desmoglein 1 and 3, which are target antigens of ordinary pemphigus. Thus, indirect immunofluorescence on substrates other than skin is useful in the diagnosis of PNP. The presence of anti-desmoglein antibodies have been demonstrated by enzyme-linked immunosorbent assay. The gold standard for the diagnosis of PNP however, is the detection of the characteristic circulating autoantibodies against 210-kDa envoplakin and 190-kDa periplakin by immunoblotting or immunoprecipitation. It is now accepted that both humoral and cellular immunities are involved in the pathogenesis of PNP. Anti-desmoglein 3 antibodies are known to play a pathogenic role in the initiation of acantholytic blister formation. Autoreactive CD8 + cytotoxic T cells induced by antitumor immune response are also involved in the development of mucocutaneous manifestations and bronchiolotis obliterans. The prognosis of PNP depends on the nature of the underlying neoplasm, with high mortality rate due to sepsis or multi-organ failure, particularly bronchiolitis obliterans. Although the combined use of immunosup-pressive agents and rituximab has been administered in treating PNP, to date, there are no consistently effective treatments for PNP.     

Two courses of rituximab (anti-CD20 monoclonal antibody) for recalcitrant pemphigus vulgaris

Background Pemphigus vulgaris (PV) is a severe autoimmune blistering disease involving the skin and mucous membranes. The response to therapy varies greatly amongst patients and treatment may be challenging. Rituximab is a chimeric monoclonal antibody that selectively targets cell surface antigen CD20, thus depleting mature B cells in vivo. Methods We report the results of rituximab treatment in two patients with severe PV. In both patients, high‐dose oral prednisolone and adjuvant therapy with intravenous immunoglobulins and mycophenolate mofetil failed to control disease activity. Consequently, the patients were treated with two courses of four weekly intravenous infusions of rituximab (375 mg/m²) with a 6‐month interval. Results Clinical improvement was already noticeable 3–6 weeks after the first infusion. After the second course, complete remission was achieved. Oral prednisolone was reduced and treatment with mycophenolate mofetil was continued. The patients remained in full remission 6 months after the last rituximab infusion. Conclusion These cases suggest that two courses rather than a single course of rituximab may be a preferable mode of treatment. Rituximab should be considered as a promising treatment option for recalcitrant PV.     

Two unusual cases of toxic epidermal necrolysis

Two cases of toxic epidermal necrolysis (TEN) are presented. A 27-year-old woman presented with peripherally located targetoid plaques, papules, blisters and lip erosions which began 9 days after 'recreational' use of 'speed' (dexamphetamine and ephedrine) consistent with erythema multiforme major. Three days later she developed widespread lesions with large areas of blistering affecting 40% of body surface area. The diagnosis was revised to TEN. Intravenous cyclosporin led to rapid prevention of new blister formation. A 71-year-old woman, 3 months after commencing amiodarone, developed extensive erythema, blistering and erosions affecting 50% of body surface area, with a maculopapular rash affecting the limbs and extremities consistent with a diagnosis of TEN. She developed septicaemia following bilateral pneumonia with pleural effusions and died 7 days after admission.     

Paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a distinct autoimmune blistering disease that can affect multiple organs other than the skin. It occurs in association with certain neoplasms, among which lymphoproliferative diseases are most commonly associated. The clinical presentation of PNP consists typically of painful, severe oral erosions that may be accompanied by a generalised cutaneous eruption and systemic involvement. The eruption may be of different morphology, consisting of lesions that resemble pemphigus, pemphigoid, erythema multiforme or graft versus host disease, as well as lesions resembling lichen planus. Similarly, the histological findings also show considerable variability. PNP is characterised by the presence of autoantibodies against various antigens: desmoplakin I (250 kd), bullous pemphigoid antigen I (230 kd), desmoplakin II (210 kd), envoplakin (210 kd), periplakin (190 kd), plectin (500 kd) and a 170‐kd protein. This 170‐kd protein has recently been identified as alpha‐2‐macroglobulin‐like‐1, a broad range protease inhibitor expressed in stratified epithelia and other tissue damaged in PNP. The prognosis of PNP is poor and the disease is often fatal. Immunosuppressive agents are often required to decrease blistering, and treating the underlying malignancy with chemotherapy may control autoantibody production. The prognosis is better when PNP is associated with benign tumours and these should be surgically excised when possible.     

Paraneoplastic pemphigus. A report of two cases associated with chronic B-cell lymphocytic leukaemia

Paraneoplastic pemphigus (PNP) is an autoimmune blistering and erosive mucocutaneous disease associated with neoplasia. Clinical manifestations are polymorphous, and include erythema, bullae, erythema multiforme-like lesions and severe mucous membrane involvement. PNP manifesting as lichenoid dermatitis has recently been observed. We describe two Italian men with fatal PNP featuring typical PNP autoantigens associated with chronic B-cell lymphocytic leukaemia. The first patient presented with an extensive blistering eruption, several erythema multiforme-like lesions and severe mucosal involvement. The second patient presented with a lichenoid dermatitis, then developed bullae, and died with an erythrodermic and exfoliative dermatosis resembling pemphigus foliaceus. Our patients represent two Italian cases of well-documented PNP. In patient 2, the sequence of clinical presentations was unique, and strongly supports the hypothesis of epitope spreading through chronic lichenoid inflammation of the dermo-epidermal junction exposing new self antigens, leading to the humoral response characteristic of PNP.     

Sweet's syndrome associated with cellulitis

A 38-year-old woman developed an acute, painful cutaneous eruption on her lower legs, neck, chest and fingers while receiving a number of oral and intravenous antibiotics for left leg cellulitis caused by trauma. Clinically and histopathologically, she was diagnosed with Sweet's syndrome with typical pseudovesicular skin changes in conjunction with erythema nodosum-like lesions on her lower legs. She responded quickly to oral prednisolone. We propose Staphylococcal cellulitis as a cause of Sweet's syndrome.     

Paraneoplastic pemphigus associated with CD20-positive follicular non-Hodgkin's lymphoma treated with rituximab: a third case resistant to rituximab therapy

Paraneoplastic pemphigus is an IgG-mediated disease characterized clinically by a polymorphous blistering eruption with severe mucosal involvement associated with an underlying or occult malignancy. It is associated with high mortality, and response to treatment is generally poor. Potent immunosuppression is often necessary to control progression of the disease. Three case reports have documented successful treatment of paraneoplastic pemphigus with rituximab, an anti-CD20 monoclonal antibody. However, two previous reports have noted that rituximab was unsuccessful in halting progression of PNP. We report a third case of paraneoplastic pemphigus associated with follicular non-Hodgkin's lymphoma in which rituximab was not effective. Whether rituximab is an effective and novel treatment for paraneoplastic pemphigus remains undecided.     

Cutaneous B‐cell lymphomas – pathogenesis,diagnostic workup,and therapy

Cutaneous B‐cell lymphomas (CBCLs) comprise a group of mature lymphoproliferative B‐cell disorders that primarily affect the skin. Characterized by great biological and clinical variability among its various subtypes, CBCLs fundamentally differ from primary nodal or systemic B‐cell lymphomas. Given their uncomplicated course and excellent prognosis, lymphoma classifications rank primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) as indolent CBCLs. By contrast, diffuse large B‐cell lymphoma, leg type (DLBCL‐LT) in particular, represent more aggressive lymphoma variants associated with a poorer prognosis. Therapeutic decisions and diagnostic procedures are based on the exact histological and immunohistochemical classification as well as the exclusion of systemic involvement and thus differentiation from nodal and systemic lymphomas. In this context, the diagnostic workup should also include molecular biology methods. Primary therapeutic options for indolent CBCL lesions include surgery and radiation therapy, as well as systemic treatment with rituximab (anti‐CD20 antibody) in case of dissemination. More aggressive CBCLs usually require a combination of rituximab and polychemotherapy, primarily the CHOP regimen or modifications thereof. Given that the pathogenesis and biology of CBCLs has not been conclusively elucidated, and given the limited therapeutic armamentarium available, there is great need for comprehensive research, especially with respect to DLBCL‐LT.     

Entero‐Behçet's disease coexisting with long‐term epilepsy and schizophrenia‐like symptoms

Entero‐Behçet's disease coexisting with long‐term epilepsy and schizophrenia‐like symptoms is presented. A 43‐year‐old woman presented with repeatedly occurring aphthous stomatitis for several years. She had been treated for absence seizures, epilepsy and schizophrenia since she was 9 years old. She presented with multiple aphthous stomatitis on her gingiva, erythema nodosum‐like symptoms on the right lateral aspect of her leg and genital ulcers on her perianal area. She also showed polyarthritis. Laboratory examinations revealed elevated C‐reactive protein, elevated neutrophil counts, decreased serum Fe and elevated serum Cu. Histological examination showed perivascular neutrophil and mononuclear cell infiltrates and eosinophilic change of the vessel wall in the lobules of subcutaneous fat tissue. Six weeks after the oral prednisolone therapy, she showed resolution of aphthous stomatitis, folliculitis‐like eruption and genital ulcer. She experienced severe abdominal pain after the start of treatment of Behçet's disease. Plain computed tomography revealed edematous change in the appendix, and ascending and transverse colon. These results led to the diagnosis of entero‐Behçet's disease acute exaggeration. Treatment with infliximab (300 mg/once) was started. Eight weeks after the start of infliximab, her abdominal pain disappeared and C‐reactive protein decreased, followed by the successful change to adalimumab infusion therapy.     

Staphylococcal scalded skin syndrome complicating acute generalized pustular psoriasis

A 60-year-old woman with psoriasis vulgaris treated with oral cyclosporin and acitretin developed an acute generalized pustular eruption with erythema and associated fever consistent with acute generalized pustular psoriasis. She was admitted to hospital and, despite intravenous fluid replacement, developed acute renal failure. In addition, she developed staphylococcal septicaemia. After transfer to the intensive care unit because of deteriorating renal function, a sudden onset of widespread flaccid blistering (Nikolsky sign positive) and superficial erosions was noted. Histology of a biopsied blister revealed subcorneal splitting of the epidermis consistent with staphylococcal scalded skin syndrome. The patient was treated with intravenous dicloxacillin and the blistering gradually improved over 10 days.     

伴发滤泡树突状细胞肉瘤的副肿瘤天疱疮1例报告

讨论成功救治的1例滤泡树突状细胞肉瘤伴发的副肿瘤天疱疮患者。女,56岁,因口腔溃疡1个月,全身皮疹10天入院。临床表现为口唇溃疡,躯干、四肢扁平苔藓样和多形红斑样皮疹,皮损组织病理见表皮内泡,孤立坏死角质形成细胞,基底细胞空泡化和真皮大量淋巴细胞浸润等副肿瘤天疱疮表现。患者血清行鼠膀胱为底物的IIF为阳性,表皮浸出物为底物免疫印迹试验发现190、210KD阳性条带。PET／CT检查示腹膜后肿物,彻底手术切除并经组织病理证实为滤泡树突状细胞肉瘤。按照我国自行总结的治疗方案,术前、术中及术后均给予静脉点滴免疫球蛋白,给予糖皮质激素治疗,手术后患者皮疹逐渐好转,术后两个月时复查躯干四肢皮损基本消退,术后半年口腔溃疡大部分愈合,无皮疹复发。     

Paraneoplastic pemphigus in association with a retroperitoneal Castleman's disease presenting with a lichen planus pemphigoides-like eruption. A case report and review of literature

A 50-year-old man presented with severe mucosal erosions of the lips, oral cavity and perianal area, a lichen planus-like eruption on the trunk and extremities and scaly plaques of the palms and soles. The clinical impression was of Stevens--Johnson syndrome, or paraneoplastic pemphigus (PNP). Histopathology revealed vacuolar interface and lichenoid dermatitis with dyskeratosis and suprabasal acantholytic vesiculation. Direct immunofluorescence showed deposition of IgG in the intercellular space and linear deposition of C3 along the basal membrane zone. Indirect immunofluorescence revealed circulating IgG with intercellular staining of the epithelium of rat urinary bladder. Western blotting demonstrated bands of 250- and 230-kDa antigens. The clinical, histological and immunological features were consistent with the lichen planus pemphigoides variant of PNP. A retroperitoneal hyaline-vascular Castleman's disease was detected and excised. The skin lesions worsened initially after tumour resection but improved gradually, leaving extensive melanosis after cyclosporin and mycophenolate mofetil treatment.     

A case of lichen planus pemphigoides with autoantibodies to the NC16a and C‐terminal domains of BP180 and to desmoglein‐1

Lichen planus pemphigoides (LPP) is a rare autoimmune blistering disease that occurs in association with lichen planus (LP). This report describes a 59‐year‐old Japanese female patient with LPP. The patient first showed LP lesions on her hands, and subsequently developed bullae on her extremities and erosions of the oral mucosa. The patient's serum was positive for IgG autoantibodies against the BP180 NC16a domain, the BP180 C‐terminal domain and desmoglein‐1. However, a serum sampled one and a half years before the diagnosis of LPP was negative for autoantibodies against BP180 NC16a and BP180 C‐terminal domains. These findings strongly suggest that the damage to the basal cells in the LP lesions exposed a sequestered antigen or formed neoantigens, leading to the production of pathogenic autoantibodies for LPP. Most of the previous cases of LPP have produced autoantibodies to the NC16a domain of BP180. This is the first case in which autoantibodies to the C‐terminal domain of BP180 were detected. The oral mucosal symptoms in this case may have been caused by autoantibodies to the BP180 C‐terminal domain.     

A Case of Paraneoplastic Pemphigus as a Preceding Manifestation of Underlying Follicular Lymphoma Treated with R-CHOP

Paraneoplastic pemphigus is a rare, life-threatening disorder associated with an underlying neoplasm, which presents with painful stomatitis and polymorphous skin lesions. Successful diagnosis of paraneoplastic pemphigus can lead to the diagnosis and treatment of the underlying malignancy. However, involvement of the respiratory system is typically unresponsive to treatment. Herein, we report the case of a 44-year-old female diagnosed with paraneoplastic pemphigus with underlying follicular lymphoma treated with a chemotherapy regimen including rituximab. Her skin lesions and underlying lymphoma responded to treatment, but bronchiolitis obliterans continued to progress and resulted in fatal respiratory failure.