Paraneoplastic Autoimmune Multiorgan Syndrome Research Articles

Pemphigus and cancer: A single-center experience over 30 years in Morocco

Background: The aim of this study was to investigate the association between pemphigus and cancer and to analyze the characteristics of pemphigus in which a neoplasm occurs. Materials and Methods: This was a retrospective, descriptive study conducted at the Dermatology Department of Ibn Sina Hospital in Rabat from January 1993 to December 2022, including all pemphigus cases in which cancer was diagnosed before, during, or after the onset of pemphigus. Results: Among 302 pemphigus cases, 13 patients presented an associated cancer (4,3%). Only one patient had a paraneoplastic pemphigus. There was an increased incidence of various solid cancers (11/13) in deep pemphigus types yet without temporal relationship. When hematological malignancy occurred (3/13), it was mainly non-lymphoproliferative and preceded deep pemphigus types with good prognosis. Patient comorbidities and immunosuppressive treatments did not influence the onset of cancer. Conclusion: Our manuscript suggests an increased incidence of solid cancers in deep pemphigus subtypes, independently of the timeline of the latter onset. These pemphigus cases carry a good prognosis. Key words: Pemphigus, Cancer, Paraneoplastic pemphigus, Paraneoplastic autoimmune multiorgan syndrome

DP21 Thymoma and the skin: manifestations of multiorgan autoimmunity

Abstract We present three patients who developed distinct cutaneous manifestations of thymoma: a rare mediastinal tumour. A 25-year-old man was treated for myasthenic crisis. Past medical history included thymectomy in 2016. Admission imaging confirmed recurrence of thymoma. He developed a red–brown macular rash affecting the trunk, back and thighs. Biopsy showed a florid lichenoid dermatitis consistent with graft-versus-host disease (GVHD). After resolution with steroids and mycophenolate mofetil, he subsequently developed a Stevens–Johnson syndrome/toxic epidermal necrolysis-like eruption with erythroderma and epidermal loss. Unfortunately, he developed multiorgan failure and died shortly afterward. A 43-year-old man presented to the emergency dermatology clinic with a 4-month history of a blistering rash affecting the chest and limbs. His previous medical history was significant for thymoma in 2008 and a recurrence in 2013. Skin biopsy demonstrated changes suggestive of bullous pemphigoid, and repeat computed tomography confirmed the recurrence of thymoma. Enzyme-linked immunosorbent assay testing was positive for bullous pemphigoid 180. He has responded well to prednisolone and doxycycline. A 51-year-old woman was reviewed in 2020 and 2021 with pruritic hyperpigmented patches affecting the face, trunk and limbs. Her past medical history included several relapses of thymoma with occurrence in 2002 and relapses in 2007, 2008, 2011, 2015 and 2021. Skin biopsy in June 2021 showed features of cutaneous GVHD. She received ruxolitinib and tapering steroids for thymoma-associated multiorgan autoimmunity (TAMA)-like GVHD and has had a remarkable improvement in her skin disease. Thymoma is described as a rare neoplasm, and up to 34% of thymomas are thought to be accompanied by symptoms of autoimmunity. The most frequently described syndromes include myasthenia gravis, pure red blood cell aplasia and hypogammaglobulinaemia. Other reported presentations include panencephalitis, enterocolitis and autoimmune hepatitis. Thymoma and cutaneous autoimmune presentations have been previously described, often in association with two rare syndromes: TAMA and paraneoplastic autoimmune multiorgan syndrome (PAMS). Both conditions demonstrate variability in clinical phenotype, driven by the activation of humoral and cellular immune responses. Clinically, patients may present with a spectrum of skin disease, including GVHD-like exanthems, lichen planus-like disease and pemphigus-like and pemphigoid-like lesions. Our case series demonstrates the heterogeneous cutaneous manifestations of thymoma-induced autoimmunity. We also describe two extremely rare phenomena accompanying thymomas: TAMA and PAMS. We also suggest that there is much crossover between these syndromes and previous definitions may require further review. This case series also highlights the importance of the wider multidisciplinary team in managing these patients and the complexities of their disease.

Indolent T-lymphoblastic proliferation: A systematic review of the literature analyzing the epidemiologic, clinical, and pathologic features of 45 cases.

An indolent T-lymphoblastic proliferation (iT-LBP) is a rare benign disorder characterized by an abnormal expansion of immature T-cells, which morphologically can mimic malignancy. Since the first case was described in 1999, dozens more have been reported in the literature. However, the epidemiologic, clinical, pathologic, and biologic features of this disease have not been well described. Here, we retrospectively reviewed all known cases reported in the literature to better understand this entity. A PubMed search up to January 2022 highlighted 25 papers describing cases/case series of iT-LBP, one of which was a case presentation in a slide workshop. Except for 9 of the cases in one of the papers, where it was evident that the number of CD3+/TdT+ cells were too few to conform with a diagnosis of iT-LBP, all papers and all the cases reported were included in the study amounting to a total of 45 cases. Clinicopathologic characteristics were analyzed using descriptive statistics and frequencies. Our analysis highlighted the previously known association with Castleman disease and Castleman-like features and underlined its association with dendritic cell proliferations in general, as well as uncovering high frequency of concurrence with hepatocellular carcinoma and autoimmune diseases, most notably myasthenia gravis, paraneoplastic pemphigus and paraneoplastic autoimmune multiorgan syndrome. Furthermore, the co-expression of CD4 and CD8 and high prevalence of extranodal disease and recurrences were other less well described features that were revealed.

Severe Airflow Obstruction From Constrictive (Obliterative) Bronchiolitis in Paraneoplastic Autoimmune Multiorgan Syndrome

Paraneoplastic autoimmune multiorgan syndrome (PAMS), also known as “paraneoplastic pemphigus,” is a rare life-threatening autoimmune disease triggered by an underlying neoplasm. It is characterized by painful erosive stomatitis and a polymorphous mucocutaneous eruption.1 A subset of patients with PAMS manifest pulmonary involvement characterized by progressive airflow obstruction related to constrictive (obliterative) bronchiolitis (also known as bronchiolitis obliterans).2

Paraneoplastic autoimmune multiorgan syndrome (PAMS)

Originally described by Anhalt as paraneoplastic pemphigus in 1990, paraneoplastic autoimmune multiorgan syndrome (PAMS) is a potentially lethal blistering disease, characterized by polymorphous clinical features, including mucocutaneous erosions, blisters, lichenoid papules, and erythema. Several autoantibodies have been detected in serum of PAMS patients, including anti-plakins, anti-alpha-2-macroglobulin like 1, and anti-desmogleins autoantibodies. The mortality rate of PAMS is up to 50%. This is due on the one hand to the poor response to treatments and on the other hand to the delay in the diagnosis and to the prognosis of the underlying neoplasia.

Paraneoplastic autoimmune dermatoses

Paraneoplastic skin manifestations associated with malignancies are extremely polymorphous. Clinicians should be familiar with paraneoplastic dermatoses to establish an early diagnosis of the underlying neoplasm. Lack of familiarity with cutaneous clues for internal malignancies may delay diagnosis and treatment of cancer. In this review, we describe several paraneoplastic autoimmune dermatoses, including paraneoplastic autoimmune multiorgan syndrome, paraneoplastic bullous pemphigoid, and paraneoplastic dermatomyositis.

Paraneoplastic Autoimmune Multiorgan Syndrome: A Retrospective Study from a Tertiary Care Center in South India.

Background:Paraneoplastic autoimmune multiorgan syndrome (PAMS), first described as paraneoplastic pemphigus (PNP) is a heterogeneous autoimmune syndrome with a diverse spectrum of clinical and immunopathological features associated with an internal neoplasm.Materials and Methods:The details of the patients diagnosed with PAMS/PNP from an Indian tertiary center between January 2010 to December 2019 were retrieved from the hospital database. The clinical manifestations, histopathological features, immunofluorescence findings, and other relevant clinical details were obtained.Results:There were eight patients (4 males, 4 females) with PAMS, age ranging from 8 to 46 years (mean 31 years), of whom two were 8-year-old children. The mucocutaneous manifestations were polymorphic and all had recalcitrant oral mucosal involvement. The most common mucosal presentation was pemphigus-like (5/8), and the cutaneous presentation was lichen planus-like (5/8). Castleman's disease (5/8) was the commonest neoplasm followed by thymoma (2/8). Interface dermatitis was seen in all biopsies and three different patterns of direct immunofluorescence were seen, which were intercellular “fish-net” fluorescence in the epidermis (2/8), granular/linear deposition along the basement membrane (4/8) and a combination of both patterns (1/8). Indirect immunofluorescence done on rat bladder in 3 patients showed intercellular “fish-net” fluorescence. Desmoglein levels were not elevated in any of our patients. The follow-up period ranged from 1 to 112.5 months (mean, 23.6 months) with a mortality rate of 12.5%.Conclusion:In our study, Castleman's disease was the most common associated malignancy, and the mucocutaneous and histopathological findings were heterogeneous. Timely diagnosis and early intervention improved the outcome in our patients.

Paraneoplastic autoimmune multiorgan syndrome.

Originally described by Anhalt as paraneoplastic pemphigus in 1990, paraneoplastic autoimmune multiorgan syndrome (PAMS) is a potentially lethal blistering disease, characterized by polymorphous clinical features, including mucocutaneous erosions, blisters, lichenoid papules, and erythemas. Several autoantibodies have been detected in serum of PAMS patients, including antiplakins, anti-alpha-2-macroglobulin like 1, and antidesmogleins autoantibodies. The mortality rate of PAMS is up to 90%. This is due on the one hand to the poor response to treatments and on the other hand to the delay in the diagnosis and to the prognosis of the underlying neoplasia.

Autoimmune mucocutaneous blistering diseases in the south of Italy: a 25-year retrospective study on 169 patients.

Autoimmune mucocutaneous blistering diseases (AMBDs) represent a heterogeneous group of organ-specific and potentially life-threatening diseases. We sought to determine the relationship between clinical remission and therapeutic regimens with clinical type and phenotype of AMBDs, as well as clinical outcomes achieved based on different therapeutic regimens. A retrospective single-center study on 169 AMBDs patients, including pemphigus vulgaris (PV), mucous membrane pemphigoid (MMP), paraneoplastic autoimmune multiorgan syndrome (PAMS), and lichen planus pemphigoides (LPP), was performed from 1994 to 2019 in an oral medicine tertiary center, where we collected sociodemographic data, clinical type and phenotype, prescribed therapies, and related outcomes. The mean age of AMBDs patients was 55.0±16.4years. They were followed for a mean of 8.4±5.8years. The majority of these patients (62.1%) were successfully managed with conventional immunosuppressive therapy (CIST) alone. However, 37.9% of patients required additional biological treatments, either because they were non-responders or developed severe side effects from CIST, or because of the rapid and severe progression of the disease. Overall, complete clinical remission was achieved in 92.3% of patients. A statistically significant difference was noted between the frequency distribution of AMBDs patients among different therapeutic regimens (P=.002), of different clinical phenotype and type of AMBDs patients and clinical remission (P=.012 and P=.005, respectively). No difference was reported regarding clinical outcomes and different therapeutic regimens. AMBDs' management may be challenging, nonetheless CIST and biologic regimens introduced, when needed as reliable alternatives to CIST, result in a very high percentage of CCR.

Features and Risk Factors for Paraneoplastic Autoimmune Multiorgan Syndrome in 145 Chinese Patients.

Paraneoplastic autoimmune multiorgan syndrome is a complex and deadly disease. We retrospectively reviewed the clinical features and risk factors for para-neoplastic autoimmune multiorgan syndrome in 145 Chinese patients. The most common neoplasm was Castleman disease (56%), and patients with Castle-man disease tended to be younger (≤42 years old: 83% vs. 29%) and to have a greater proportions of lichen planus-like lesions (47% vs. 27%) and bronchiolitis obliterans (49% vs. 29%), compared to other neoplasm-associated patients. Among all 145 patients in the study, the survival rates were 84% at 1 year, 65% at 3 years, and 54% at 5 years. Kaplan-Meier curve analysis revealed that mortality was associated with older age (>42 years), neoplasm type, labial lesions, and larger skin lesion area (>17.5% of the body surface area). However, only older age and larger skin lesion area were independent factors associated with mortality in multivariate analysis. We suggest that patients with Castleman disease and paraneoplastic autoimmune multiorgan syndrome have many unique characteristics and the underlying risk factors for death require further exploration.

Follicular Dendritic Cell Sarcoma With Indolent T-Lymphoblastic Proliferation Is Associated With Paraneoplastic Autoimmune Multiorgan Syndrome.

Nonclonal expansions of immature T cells outside of the thymus, termed indolent T-lymphoblastic proliferation (iT-LBP), have been identified in rare lymphoproliferative disorders. We report that iT-LBP is a frequent finding in cases of follicular dendritic cell sarcoma (FDCS), and shows an association with paraneoplastic autoimmune multiorgan syndrome (PAMS). We studied 31 cases of FDCS by paraffin immunohistochemistry using antibodies to CD21, CD23, CD35, clusterin, CXCL13, podoplanin, CD3, CD4, CD8, CD20, CD1a, and TdT. Chart review was performed to characterize the clinical behavior including evidence of autoimmune disease. FDCS occurred in a wide variety of nodal and extranodal sites. Fourteen of 31 (45%) cases contained immature TdT-positive T cells; in 5 cases these cells were numerous and present throughout the tumor. Four of these 5 patients with numerous immature T cells developed autoimmune disease, clinically categorized as PAMS and/or myasthenia gravis. PAMS persisted after tumor resection, causing severe morbidity and mortality. These findings suggest that the neoplastic follicular dendritic cells can recruit or foster the proliferation of immature T cells and that these cells may play a role in mediating PAMS. Recognition of iT-LBP in FDCS is important to avoid misdiagnosis as thymoma or T-lymphoblastic lymphoma, and may predict serious autoimmune complications in some patients.

Paraneoplastic autoimmune multiorgan syndrome (PAMS): Beyond the single phenotype of paraneoplastic pemphigus.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is characterized by a heterogenous group of signs and symptoms including severe desquamative stomatitis, a polymorphous cutaneous eruption, humoral immunity against plakin proteins, contribution of cell-mediated autoimmunity and commonly a progressive respiratory failure. Autoantibodies in PAMS target a wide array of antigens including plakins, cadherins, alpha-2-macroglobulin like 1 (A2ML1), BP180, plakophilin-3, and several neuromuscular antigens. Originally described as paraneoplastic pemphigus in 1990 due to some of its clinical and immunologic similarities to classic pemphigus (pemphigus vulgaris and pemphigus foliaceus), PAMS is a multiorganopathy with several distinct features from these classic forms of pemphigus. Epidemiologically, PAMS is associated with underlying neoplasia and has a differing HLA-II allele predisposition compared to classic forms of pemphigus. Clinically, lesion morphology is polymorphous, and lesion distribution fundamentally differs from that seen in classic pemphigus. PAMS has a significantly higher mortality rate and a poorer response to treatments typically effective in pemphigus. Histologically, PAMS is characterized by the presence of interface dermatitis, vacuolar changes, and dyskeratotic keratinocytes which are not seen in classic pemphigus. PAMS demonstrates not only intercellular IgG as seen in classic pemphigus, but the presence of linear basement membrane zone deposition. Antibodies against desmoglein 3 (Dsg3) map to a broader array of epitopes than in pemphigus vulgaris and there is a higher prevalence of complement binding anti-Dsg3 IgG autoantibodies in PAMS. Autoantibodies can in rare cases be absent in the more cell-mediated form of PAMS. Considering these numerable differences, we review the entity of PAMS, and provide similarities and differences to classic forms of pemphigus.

Paraneoplastic autoimmune multi-organ syndrome is a distinct entity from traditional pemphigus subtypes.

Paraneoplastic autoimmune multi-organ syndrome is a distinct entity from traditional pemphigus subtypes.

Authors' reply: Paraneoplastic autoimmune multi-organ syndrome is a distinct entity from traditional pemphigus subtypes.

Authors' reply: Paraneoplastic autoimmune multi-organ syndrome is a distinct entity from traditional pemphigus subtypes.

Paraneoplastic pemphigus: a short review

Paraneoplastic pemphigus (PNP) is a fatal autoimmune blistering disease associated with an underlying malignancy. It is a newly recognized blistering disease, which was first recognized in 1990 by Dr Anhalt who described an atypical pemphigus with associated neoplasia. In 2001, Nguyen proposed the term paraneoplastic autoimmune multiorgan syndrome because of the recognition that the condition affects multiple organ systems. PNP presents most frequently between 45 and 70 years old, but it also occurs in children and adolescents. A wide variety of lesions (florid oral mucosal lesions, a generalized polymorphous cutaneous eruption, and pulmonary involvement) may occur in patients with PNP. The earliest and most consistent finding is severe stomatitis. There is a spectrum of at least five clinical variants with different morphology. Similarly, the histological findings are very variable. Investigations to diagnose PNP should include checking for systemic complications (to identify tumor), skin biopsies (for histopathological and immunofluorescence studies), and serum immunological studies. PNP is characterized by the presence of autoantibodies against antigens such as desmoplakin I (250 kD), bullous pemphigoid aniygen I (230 kD), desmoplakin II (210 kD), envoplakin (210 kD), periplakin (190 kD), plectin (500 kD), and a 170 kD protein. Unlike other forms of pemphigus, PNP can affect other types of epithelia, such as gastrointestinal and respiratory tract. Treatment of PNP is difficult, and the best outcomes have been reported with benign neoplasms that have been surgically excised. The first-line treatment is high-dose corticosteroids with the addition of steroid-sparing agents. Treatment failures are often managed with rituximab with or without concomitant intravenous immunoglobulin. In general, the prognosis is poor, not only because of eventual progression of malignant tumors but also because treatment with aggressive immunosuppression therapy often results in infectious complications, which is unfortunately at this time the most common cause of death in PNP.

High-dose-rate intraluminal brachytherapy for paraneoplastic autoimmune multiorgan syndrome.

Paraneoplastic autoimmune multiorgan syndrome (PAMS), also known as paraneoplasic pemphigus, involves the skin, internal organs and mucosa. PAMS-associated mortality may occur as a result of autoantibody formation against internal tumors and their infiltration into organs other than the skin lesions that characterize PAMS. The most common symptoms of PAMS include pain associated with continuous oral ulceration and resistance to pharmacological treatment. The present study reports the case of a 42-year-old female patient who was admitted with an 8-month history of erosive skin lesions within the trunk region, oral mucosa and vaginal mucosa. The patient was diagnosed with PAMS based on computed tomography scans and histological analyses of the lesions. The lymphoid hyperplasia in the retroperitoneum and lesions in the vaginal mucosa and trunk area were improved following pharmacological treatment and resection of the lymph node showing hyperplasia. However, the oral lesion was treated with intraluminal brachytherapy due to its resistance to long-term pharmacological treatment. The majority of the lesions were improved following treatment, in the absence of any severe side effects. In addition, neither worsening nor progression of the oral lesion was observed during the 4-year follow-up period.

Paraneoplastic autoimmune multi-organ syndrome and oral mucosa involvement: an intriguing disorder

Paraneoplastic autoimmune multi-organ syndrome and oral mucosa involvement: an intriguing disorder

A Systematic Review of Patients with Mucocutaneous and Respiratory Complications in Paraneoplastic Autoimmune Multiorgan Syndrome: Castleman's Disease is the Predominant Malignancy.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a rare disorder that manifests with severe mucocutaneous blistering and erosions accompanied by underlying malignancy. Constrictive bronchiolitis (CB) can occur in a subset of patients. We sought to characterize the particular group of PAMS patients with CB by comparing the underlying tumor in these patients versus all reported PAMS patients. We performed a systematic review of the Medline/Pubmed and compared the incidence of the most frequent tumor type in the CB cohort with the previously reported incidences of tumors in all documented PAMS patients. There is an increased occurrence of Castleman's tumor in patients with mucocutaneous and pulmonary complications of PAMS OR 3.86, 95% CI [2.2-6.7]. As PAMS is a syndrome with a heterogeneous presentation and autoantibody profile, the particular pathogenic pathway seen in Castleman's tumor may provide additional insight into the antigenic sites involved in PAMS-related CB.

Diagnostic imaging in paraneoplastic autoimmune multiorgan syndrome: retrospective single site study and literature review of 225 patients.

The utility of diagnostic imaging in paraneoplastic autoimmune multiorgan syndrome (PAMS) is unknown. We examined the role of diagnostic imaging in patients with PAMS evaluated at our tertiary referral center (at Mayo Clinic, Rochester, MN, USA) and in the English literature between January 1, 1996, and August 31, 2012. We included 17 patients from our institution and 208 patients from the literature review. Of these 225 patients, 113 (50.2%) were not known to have a malignancy diagnosis at the time of PAMS diagnosis. Of the 123 patients from our institution and from the literature reported to undergo imaging studies, conventional computed tomography (CT) was the predominant imaging modality (n=110; 89.4%); 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT was also used, albeit infrequently (n=12; 9.8%). When CT was included in imaging to identify or confirm the presence of a malignancy, imaging was successful in all patients who ultimately were diagnosed with an associated malignancy. At our institution, a relatively high percentage (n=7; 41%) of patients had 18F-FDG PET/CT, which not only identified all tumors found on CT but also facilitated staging of lymphoma and guided biopsy procedures. Diagnostic imaging is frequently utilized in PAMS with unknown malignancy. Both conventional CT and 18F-FDG PET/CT are likely to detect the typical underlying neoplasms. Relative to conventional CT, 18F-FDG PET/CT may provide additional useful information regarding prognosis for the likely underlying malignancies, although there is a paucity of reports describing the use of this modality for this purpose.

Paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus) with unusual manifestations and without detectable autoantibodies

We describe a patient with paraneoplastic autoimmune multiorgan syndrome (PAMS) secondary to a lymphoblastic T- cell lymphoma who presented with a lichenoid dermatitis and vitiligo, later developing bronchiolitis obliterans and autoimmune hepatitis. Notably, he had no detectable autoantibodies. The development of vitiligo and autoimmune hepatic involvement probably indicate a role for cytotoxic T- cell lymphocytes in the pathogenesis of this syndrome.