Paraneoplastic pemphigus and Castleman’s disease: a case report and a revision of the literature

Paraneoplastic pemphigus (PNP) is a mucocutaneous autoimmune disorder, firstly described by Dr Anhalt in 1990 [1]. It is characterized by mucocutaneous manifestations associated with an underlying tumor that usually is suspected because of the refractoriness of mucocutaneous lesions to treatment.

The diagnosis is made by Mimouni’s criteria, which include:

The clinical picture is characterized by polymorphic mucocutaneous manifestations such as oral lesions, conjunctivitis, genital ulcers, skin eruption, so it may mimic other pathologies such as herpes simplex virus infection, Stevens-Johnson syndrome, lichen planus pemphigoids, lupus erythematosus, Behcet’s disease or other pemphigus. The clinical picture can be also characterized by a pulmonary epithelial involvement often leading to life-threatening bronchiolitis obliterans (BO).

In adults, the coexisting tumors are mostly non‐Hodgkin’s lymphoma (42%) and chronic lymphocytic leukemia (29%), while in paediatric patients PNP is most commonly associated with Castleman’s Disease (CD) [2, 3].

CD is a rare lymphoproliferative disorder that includes a group of heterogeneous hematologic disorders with a spectrum of characteristic, but nonspecific histopathologic features. This disease encompasses two entities, unicentric CD (UCD), which involves a single enlarged lymph node or region of lymph nodes, and multicentric CD (MCD) which involves multiple lymph node stations. MCD is in turn divided in idiopathic MCD (iMCD), POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes)—associated MDC (POEMS-MCD) and HHV-8 associated MCD (HHV8-MCD) [4]. When present, symptoms and signs are aspecific, such as linfoadenophaty, abdominal pain, anemia, fever, fatigue, weight loss and diagnosis is made by clinical picture and histological examination. It is unclear why CD is related to the pathogenesis of PNP. One hypothesis is that Castleman's tumors' proteins function as antigens and induce the production of autoantibodies cross-reacting with skin antigens. On the other side, secreted autoantibody from Castleman's tumors, which reacts against epidermal proteins, could be an essential factor in the pathogenesis of paraneoplastic pemphigus [5, 6].

Aim of this study is to present a case report and explore the relationship between PNP and CD in pediatric patients, focusing on clinical manifestations, histopathological findings, treatment and outcome to find elements for an early diagnosis.

We report a clinical case and perform a literature review of PNP and CD in children between 1990 and 2022. The clinical manifestations, pathological findings, treatment and outcome are reported and analyzed.

This scoping review has been performed according to the PRISMA Extension guide for Scoping Reviews. An electronic search was undertaken on PubMed database on October 12th, 2022. To avoid missing results that may be of note for our revision study, constructing our search in PubMed, we used all of the important concepts from our basic clinical question, avoiding unnecessary filters. So, the terms “Castelman’s disease” and “Paraneoplastic Pemphigus” have been used as Mesh Terms.

Studies were identified as eligible for this scoping review if they met the following inclusion criteria:

The exclusion criteria were:

To reduce errors and bias, two researchers independently analyzed titles and abstracts to exclude distinctly irrelevant articles. Finally, the eligibility of the articles was confirmed by evaluating the full text. Disagreements regarding inclusion/exclusion were settled by discussion between the researchers.

Afterwards, data were compiled in a Microsoft Excel spreadsheet to calculate frequencies and percentages of the problems.

In childhood, CD is the neoplasm most frequently associated with PNP [2]. The presence of PNP was identified as an independent unfavorable survival risk factor for patient with CD [24].

Our case report involved a previously health adolescent girl with refractory oral manifestations since two years before CD diagnosis.

Analyzing the literature, PNP onset is more frequent in otherwise healthy adolescence, without gender difference. In all patients, the first manifestation is oral ulcers refractory to conventional therapies. Skin involvement is present in almost all patients, especially as lichenoid rash.

Almost half of patients (56%) experienced systemic symptoms, in particular fever, dyspnoea, cough, weight loss, due to reduced intake of food secondary to oral pain. In our case report, no systemic symptoms had been referred.

From a histological point of view, CD is classified into three subtypes: hyaline vascular, plasma cell and mixed. In pediatric population is registered that the unicentric CD usually corresponds to the hyaline vascular variant, and the multicentric disease corresponds to the plasma cell variant. Stroma-rich hyaline-vascular CD appears to be a distinctive histological variant of the CD usually associated with paraneoplastic pemphigus [25‐27]. In addition, our results are consistent with reported literature; in fact, almost all patients had unicentric HV CD (89%, 17 of 19).

It is unclear why CD is related to the pathogenesis of PNP. One hypothesis is that Castleman's tumors' proteins function as antigens and induce the production of autoantibodies that then cross-reacted with skin antigens from the plakin and cadherin family expressed in keratinocytes, particularly envoplakin (210 kD) and periplakin (190 kD). On the other side, secreted autoantibody from Castleman's tumours, which reacts against epidermal proteins, could be an essential factor in the pathogenesis of PNP [5, 6, 28, 29].

This is still to be clearly demonstrated as a few reports have shown paraneoplastic pemphigus with negative autoantibodies, suggesting the role of cytotoxic T-cells [30].

The increased risk of paraneoplastic pemphigus in stroma-rich hyaline vascular variant of CD can be explained by two possible mechanisms: the hyalinised vessels express plakin protein, which could incite antibody production against epidermal plakin; in a similar way, myoid cells could potentially act as antigen presenting cells activating immune response against plakin and desmoglein [29].

In our study main tumour, localizations were retroperitoneal and intrathoracic.

In literature the mainstay PNP treatment is the resection of the underlying neoplasm which lead to an improvement or remission of mucocutaneous lesions, along with reduction in antibody titers [31].

In our review, almost all patients underwent complete surgical resection of the tumour, except one patient and case index, who underwent partial resection. Most worrying in PNP associated with CD is BO, a diffuse segmental constrictive bronchiolitis. Its pathogenesis is not clear: in addition to autoantibody-mediated injury, CD8 + T-lymphocytes may have an important role in the progression of bronchiolitis. Pulmonary involvement persisted also after tumour resection and BO gradually progresses to respiratory failure and death [10, 11].

In our review, all patients received corticosteroids with poor response. Immunosuppressant, IVIG, rituximab, tocilizumab, daclizumab, plasmapheresis were also used like adjuvant therapies for treating severe mucocutaneous lesions and BO [7‐23, 31‐33]. Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described.. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD [32].

The outcome was survival in 11 of 18 patients, death in 7 patients. BO seems an important prognostic factor: among the 11 survivors, 4 had BO (36%) and 6 (55%) did not, whereas in the mortality group, all patients had BO and respiratory failure was the cause of death.

Among survivors affected by BO two patient underwent lung transplantation with success, so lung transplantation must be considered in patient with BO [33].

PNP should be always considered when investigating atypical mucocutaneous lesions such as pemphigus non-responding to conventional treatment. Screening for associated diseases may be mandatory in case of suspicious, in order to promptly obtain a diagnosis and start an adequate therapy. In childhood most patients have an unicentric CD that responds well to surgery; multicentric forms are rarely observed and require systemic therapy. In conclusion, treatment of CD in pediatric patients is not yet uniform and needs further studies and experimental trials.