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Hi, I’m Matt Binnicker, the Director of Clinical Virology and Vice Chair of Practice in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Did you know paraneoplastic pemphigus (PNP) is a rare and potentially fatal mucocutaneous blistering disease that is often associated with an underlying malignancy? In this month’s “Hot Topic” my colleague, Dr. Julia Lehman, will discuss the specialized tissue and serum testing that are required to establish the diagnosis, and therefore, a guided approach to the clinical management of PNP. I hope you enjoy this month’s Hot Topic, and I want to personally thank you for allowing Mayo Clinic the opportunity to be a partner in your patients’ health care.
Hello, I’m Dr. Julia Lehman, Director of the Mayo Clinic Immunodermatology Laboratory and dermatologist/dermatopathologist at Mayo Clinic. I’d like to talk to you today about paraneoplastic pemphigus, or PNP.
I have no disclosures to report.
Paraneoplastic pemphigus, or PNP, is a rare but often fatal autoimmune blistering disease, with five-year mortality rates approaching 40%. PNP also goes by the name paraneoplastic autoimmune multiorgan syndrome, or PAMS, out of recognition that this process may affect visceral organs as well, most notably the lungs.
In almost all reported cases, PNP is associated with the presence of an underlying malignancy, which may have preexisted the diagnosis of PNP in two-thirds of cases but may herald the presence of new malignancy in the remaining third. Typically, patients develop severe ulcerative stomatitis and may have skin lesions ranging from fragile erosions, to tense blisters, to lichenoid papules and plaques, to targetoid lesions mimicking those of erythema multiforme major/Stevens-Johnson syndrome.
It’s important to know that the malignancies most frequently associated with PNP are not those typically screened for with routine malignancy surveillance. Specifically, in adults, the most commonly associated diagnoses are hematologic malignancies and occasionally sarcomas and other solid-organ malignancies. In children, the most commonly associated cancer is Castleman disease.
Accurate diagnosis of PNP is essential, particularly due to the need to recognize any underlying malignancy but also to acknowledge the increased risk of death due to infection or bronchiolitis obliterans, a pulmonary complication of PNP that can also be fatal.
If PNP is in the differential diagnosis for a patient, it is very important to make an accurate diagnosis for prognostic and therapeutic reasons. So how does one go about making a diagnosis of PNP? When this diagnosis is being considered, it is our standard practice to obtain a lesional skin biopsy for routine microscopy, as well as a perilesional skin biopsy for direct immunofluorescence. Importantly, the specimen for direct immunofluorescence must be put into a special medium such as Michel’s medium or Zeus medium. We also draw serum for enzyme-linked immunosorbent assay (ELISA) studies for desmogleins 1 and 3 antibodies, as well as for indirect immunofluorescence studies using monkey esophagus and human salt-split skin. We can also perform a specialized serum indirect immunofluorescence assay using rat bladder substrate, and this confers higher diagnostic sensitivity than standard substrates.
On histopathology, the most frequent finding is acantholysis, or separation of keratinocytes. Keratinocyte necrosis and lichenoid inflammation may also be seen, and in some cases, subepidermal separation may be present. It’s important to note that no single finding is observed universally in PNP.
When present, desmoglein 1 and 3 autoantibodies may suggest a diagnosis of PNP, although additional studies and clinical correlation is required to distinguish PNP from other forms of pemphigus.
On direct immunofluorescence, intercellular deposition of IgG and/or C3 is seen in the majority of cases, and linear deposition may also be a feature. In our experience, a lichenoid tissue reaction, as characterized by the presence of cytoid bodies with multiple conjugates and shaggy deposition of fibrinogen along the basement membrane zone, is also common.
Indirect immunofluorescence using monkey esophagus substrate reveals the presence of autoantibodies deposited on the cell surface in three-quarters of cases. Though rare, the concomitant finding of intercellular and linear deposition is highly suggestive of PNP.
Indirect immunofluorescence using rat bladder epithelium substrate is a more sensitive and specific test, and it is positive in about 80% of cases of PNP.
Ultimately, as there is no single pathognomonic feature of PNP, accurate diagnosis requires careful correlation of clinical information, histopathologic findings, direct immunofluorescence features, and results of serum studies. Our immunodermatologists would be happy to discuss cases with you, if you are uncertain about a patient’s diagnosis.
Thank you very much for watching this Hot Topic on PNP. Hot Topics on other immunobullous diseases are forthcoming.