Paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus): How and why should we recognize atypical cases early?

Paraneoplastic autoimmune multiorgan syndrome (PAMS), originally described by Anhalt et al.1 in 1990 as paraneoplastic pemphigus, is a rare and often fatal autoimmune bullous disease of the skin and mucous membranes, almost always associated with confirmed or occult benign and malignant neoplasms. The disease is clinically distinguished by recalcitrant and severe mucositis and polymorphic cutaneous lesions and is most commonly associated with lymphoproliferative disorders.2 PAMS results from autoantibodies produced against various epidermal proteins involved in cell adhesion. Autoantibody diversity is also responsible for the broad clinical spectrum of the disease. In this issue of JEADV, Zaheri et al.3 in a Dutch cohort of 24 patients, report few atypical PAMS cases that do not fully meet the diagnostic criteria defined by Anhalt et al.1 Atypical presentations of the disease can easily cause difficulty in diagnosis. It should be kept in mind that timely diagnosis can be lifesaving in PAMS since delayed and/or misdiagnosis may increase morbidity and mortality. Can any diagnostic criteria identify all individuals with that disease? The answer to this question would be no. PAMS is a heterogeneous autoimmune syndrome that can present with a wide variety of clinical and immunopathological features. No single clinical, laboratory, and/ or pathological feature could serve as the ‘gold standard’ to support the diagnosis. Naturally, the original diagnostic criteria of Anhalt et al.1 cannot recognize all PAMS patients, as presented in the study of Zaheri et al.3 Not surprisingly, a better understanding of disease pathogenesis and the development of new diagnostic tools have led to a reexamination of existing diagnostic criteria and some proposals.4,5 No matter how high sensitivity and specificity a diagnostic tool has been developed,5 it is unusual to expect it to recognize all PAMS cases. Therefore, as Zaheri et al.3 noted, limiting the PAMS diagnosis to specific criteria would not be reasonable. Clinical suspicion is fundamental in the diagnosis of PAMS. Mucosal lesions are usually the first manifestations that precede skin lesions for days/months. Polymorphic cutaneous lesions may resemble lichen planus, erythema multiforme, and toxic epidermal necrolysis. In some cases, PAMS cannot be distinguished from other autoimmune bullous diseases such as pemphigus vulgaris, bullous pemphigoid and mucous membrane pemphigoid. PAMP should be considered in patients with chronic, persistent mucosal erosion, which was detected in all but one patient (96%) in the study of Zaheri et al.3 The presence of polymorphic cutaneous lesions, especially a lymphoproliferative disorder, increases the likelihood of diagnosing PAMP. PAMP diagnosis may even precede an underlying malignancy, allowing its early detection. A comprehensive study for occult neoplasm should be performed in patients with clinical symptoms of PAMS but no known neoplasm. If the result is negative and clinical suspicion persists, this study should be repeated at short intervals. The neoplastic disease is discovered after the diagnosis in almost 30% of all PAMP patients.2 Therefore, successful and early diagnosis of PAMP may lead to diagnosis and even treatment of the underlying neoplastic diseases.