Paraneoplastic Pemphigus (PnP)

  • Rare
  • M>F
  • 2/3 have an underlying neoplasm
  • 1/3 unknown, but cancer can be diagnosed years after
  • #1 is lymphoproliferative
  • 40% nonHodgkin lymphoma (NHL)
  • 30% chronic lymphocytic leukemia (CLL)
  • 10% Castleman’s (#1 seen in children)
  • 6% malignant or benign thymomas
  • 6% sarcomas
  • 6% Waldenstrom’s macroglobuline mia
  • Others rarely

Tumor antigens cross-react with epithelial antigen→ cellular immunity (T cells and IL-6 release) and humoral immunity (antibodies) → skin lesions

Antibodies are IgG (rarely IgA) against the plakin family mainly (intermediate filament attachment to hemi or desmosomes): Dsg3, Dsg1, plectin, epiplakin, desmoplakin I, desmoplakin II, bullous pemphigoid antigen 1, envoplakin, periplakin, alpha-2-macroglobulin-like-1

Mucosal involvement
  • Key feature = severe intractable stomatitis extends onto vermilion lip (earliest sign and most persistent)
  • ± Severe pseudomembranous conjunctivitis → leads to scarring
  • Rare involvement of other mucosa (e.g. esophageal, nasopharyngeal, anogenital)
Cutaneous features are polymorphous
  • Can look like lichen planus, erythema multiforme, bullous pemphigus, pemphigus vulgaris, erythroderma
Extracutaneous features/complications
  • Bronchiolitis obliterans (BO), #1 cause of death (1/3 of patients die of BO)
  • Infection, sepsis, malnutrition due to pain
  • Prognosis = 75-90% chance of mortality, usually within 2 years, possibly worse prognosis if EM-like lesions, especially if together with keratinocyte necrosis of path and severe mucosal involvement
  • NB: PnP is the only pemphigus to attached epithelia other than squamous

H & E (lesional):
  • Variable suprabasal acantholysis, keratinocyte necrosis / dyskeratosis, vacuolar interphase, bandlike lymphocytic infiltrate, may share features of pemphigus vulgaris, erythema multiforme, lichen planus depending on clinical morphology
DIF (perilesional):
  • IgG / C3 ± IgA / IgM intercellular pattern, rarely along DEJ
Demonstration of circulating antibodies as as with pemphigus foliaceous (see subtab) if IIF → rat bladder is the substrate of choice
Work up for bronchiolitis obliterans:
  • CXR / CT lung / PFT
Work up for underlying malignancy:
  • CBC + smear
  • LDH
  • SPEP + Immuno-fixation
  • Flow cytometry
  • PET-CT

  1. Treatment of occult neoplasm → improvement or full resolution within 6-18 months if curative (e.g. Castelman). Skin lesions resolve more rapidly vs. stomatitis that is usually refractory. NB: Tx of underlying malignancy often does NOT halt progression of PnP, especially if not curative.
  2. Corticosteroid – prednisone (0.5- 1.0 mg/kg) for acute relief and tapered over few months
  3. Steroid sparing drugs (case by case depending on if underlying cancer)
    • Mycophenolate mofetil
    • Cyclophosphamide
    • Azathioprine
    • Plasmapheresis
    • Rituximab
    • IVIG
    • Daclizumab / basiliximab
    • Tocilizumab

NB: topical pain control ± antibiotics to consider

Mucosa
  • Other pemphigus and pemphigoid
  • EM / SJS / TEN viral/chemotherapy/
  • Lichenoid Stomatitis
  • Graft vs. host disease
Skin
  • EM / SJS / TEN
  • Other pemphigus / pemphigoid
  • Lichen planus / lichenoid eruptions