T he concept of paraneoplastic pemphigus (PNP) is expanding. Since the initial description by Anhalt et al in 1990, many clinical variations on the initial theme of recalcitrant mucocutaneous erosions, typically associated with a lymphoproliferative malignancy, have been reported. Additionally, there have recent reports of paraneoplastic pemphigus associatedwith other malignancies such as uterine carcinoma and hepatocellular carcinoma. It has also become apparent that the cutaneous lesions may be polymorphous, resembling bullous pemphigoid, erythema multiforme, graft-versus-host disease, and lichen planus. Dr Grando has espoused the term ‘‘paraneoplastic autoimmune multiorgan syndrome’’ (PAMS) because of the heterogeneous features that may be distinguished from the classic manifestations of paraneoplastic pemphigus. Indeed, according to Dr Grando, it is important to recognize this syndrome, both because of its high mortality rate and the fact that antibodies directed toward other organ systems may complicate the condition. The kidney, muscles, heart, lung, mucous membranes, and skin may be targeted. An example is the case of a child initially diagnosed with Stevens-Johnson syndrome, but subsequently found to have paraneoplastic pemphigus associated with an inflammatory myofibroblastic tumor and fatal progressive bronchiolitis obliterans. The mortality rate in PAMS approximates 90%, and the disorder is mostly recalcitrant to the standard panel of immunosuppressive agents used in the primary blistering diseases. Although it seems logical that treating the underlying malignancy might alleviate the mucocutaneous manifestations, according to Dr Grando this is not necessarily the case. Although the underlying pathogenesis of paraneoplastic pemphigus is an enigma, it appears that there may be a different underlying inherited predisposition compared to pemphigus vulgaris. According to Martel et al, pemphigus is a group of autoimmune blistering diseases caused by autoantibodies directed against keratinocyte adhesion molecules. Pemphigus vulgaris and pemphigus foliaceous, in which autoantibodies bind, respectively, to desmoglein 3 and desmoglein 1, are strongly associated with HLA-class DR4 and DR14 alleles. In paraneoplastic pemphigus, autoantibodies target proteins of the plakin family in addition to desmogleins 1 and 3. In this study, these authors observed a significant association of paraneoplastic pemphigus with the HLA-DRB1*03 allele in 61.5% of patients, whereas DRB1*04 and DRB1*14 alleles appear not to be involved in paraneoplastic pemphigus susceptibility. Nguyen et al examined three patients manifesting the lichen planus pemphigoides-like subtype of paraneoplastic pemphigus, by a variety of immunohistochemical techniques. They found that in addition to the known paraneoplastic pemphigus antigenic complex, epithelial targets recognized by PNP antibodies included 240, 150, 130, 95, 80, 70, 66, and 40/42-kd proteins, but excluded desmoglien 1 and desmoglein 3. In addition to skin, and the epithelium lining the upper digestive and respiratory tract mucosae, deposits of autoantibodies were found in kidney, urinary bladder, and smooth, as well as striated muscle. Autoreactive cellular cytotoxicity was mediated by CD8+ cytotoxic T lymphocytes, CD56+ natural killer cells, and CD68+ monocytes and macrophages. Inducible nitric oxide synthase was visualized both in activated effectors of cellular cytotoxicity and their targets. Keratin-14 positive basal epithelial cells sloughed from the large airways and obstructed small airways. The authors concluded that the paraneoplastic disease of epithelial adhesion known as paraneoplastic pemphigus in fact represents only one manifestation of a heterogeneous autoimmune
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Jul 1, 2011
Supriya S Venugopal + 1
Open Access