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Page 4 of 9 Wu et al. J Cancer Metastasis Treat 2020;6:40 I http://dx.doi.org/10.20517/2394-4722.2020.77

A B

Figure 3. Direct immunofluorescence showed clearly positive staining for IgG in the basement membrane zone (A), and a faint positive
IgA staining (B)

DISCUSSION
BP is an autoimmune blistering disorder that is caused by autoantibodies against hemidesmosomal protein
[1]
BP180 and BP230 at the skin basement membrane . The causes of BP in oncologic patients could be
[2,3]
idiopathic, paraneoplastic , secondary to cancer therapy or related to another medication. With the
widespread use of immunotherapy in cancer management, BP has become a well-established cutaneous
toxicity associated with immunotherapy. The cause of BP in our case is most likely nivolumab, as the patient
denied a history of BP, and as his other medications were generally tolerated for years. The timing of his
renal cancer diagnosis (5 years prior) and nivolumab initiation (9 months prior) makes the paraneoplastic
phenomenon highly unlikely.

Here, we summarise a list of selected case reports of immunotherapy induced BP by literature review in
Table 1. Most reported immunotherapy-induced BP involving either skin or mucous membrane only Table 1;
[4]
combination of cutaneous BP and mucous membrane pemphigoid (MMP) is rare . Cutaneous BP typically
presents with pruritic blisters that arise on erythematous or urticarial plaques. Gradually, the bullous
[5]
lesion can erode and leave haemorrhagic crust . MMP usually presents with oral erosions, blistering or
desquamative gingivitis, which are associated with significant morbidity and severe complications, such
as tissue destruction, fibrosis and loss of function (e.g., laryngeal stenosis). In addition, MMP could be
initially indistinguishable from a gingivitis due to poor oral hygiene practices . Thus, oncologists should
[6]
be aware of cutaneous BP and MMP in all patients who have been treated with immunotherapy.

Onset of BP post-initiation of immunotherapy varies from weeks to several months [Table 1]. Previous
evidence showed that the median number of weeks of immunotherapy prior to onset of BP was 17 (range
[7]
of 3 to 91) . However, delayed cases have been reported, even several months after discontinuation of
[8,9]
immunotherapy .
Diagnostic workup usually includes skin biopsy for histology and immunofluorescence staining.
[10]
Histopathology normally shows subepidermal clefting with an eosinophilic inflammatory infiltration .
DIF characteristically shows linear deposits of IgG and/or C3 along the epidermal basement membrane
zone. Indirect immunofluorescence (IIF) or enzyme-linked immunosorbent assays will confirm the deposit
of autoantibodies specific for BP230 (also known as BPAG1) and/or BP180 (also known as BPAG2; collagen
XVII) [6,11] . Several cases have been reported with raised serum anti-BP180 associated with immunotherapy-
induced BP as well . Interestingly, in one case, it was demonstrated that immunotherapy-induced BP
[12]