History
A 78-year-old male with angiosarcoma of the scalp developed a pruritic rash 14 months after initiating pembrolizumab therapy. Examination revealed pink papules coalescing into plaques involving the back, chest, bilateral arms, and thighs (Fig 1, A). On the bilateral lower legs, there were multiple 1-2 cm well-circumscribed ulcers and few intact bullae (Fig 1, B).
Fig 1.
Biopsy revealed irregular acanthosis with patchy hypergranulosis and orthokeratotic hyperkeratosis as well as a moderate lichenoid infiltrate with scattered eosinophils (Fig 2, A-D). Direct immunofluorescence demonstrated heavy IgG staining at the dermal-epidermal junction. Serum submitted for indirect immunofluorescence demonstrated anti-BP180 and anti-BP230 levels >200RU/mL (reference <20RU/mL).
Fig 2.
Question 1: What diagnosis best matches this patient’s clinical presentation?
-
A.
Lichen planus (LP)
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B.
Bullous pemphigoid (BP)
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C.
Bullous LP
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D.
LP pemphigoides (LPP)
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E.
Pemphigus vulgaris
Answer:
-
A.
Lichen planus – Incorrect. LP would not present with bullae and is not associated with elevated serum BP antibodies.
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b.
Bullous pemphigoid – Incorrect. BP would not present with lichenified papules and plaques and does not typically demonstrate lichenoid inflammation on histology.
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C.
Bullous LP – Incorrect. In bullous LP, bullae typically only appear in areas affected by LP. Bullous LP is not associated with elevated serum BP antibodies.
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D.
LP pemphigoides – Correct. This patient has lichenified well-circumscribed pink papules coalescing into plaques consistent with LP. He also has bullae and ulcers on the lower legs, some of which are separate from areas affected by LP. This presentation is suggestive of LPP, a cutaneous condition characterized by subepidermal inflammation leading to overlapping clinical signs of LP and BP.1 Diagnosis of LPP is supported by histology showing lichenoid inflammation, direct immunofluorescence with IgG deposits in the basement membrane zone, and elevated serum BP antibodies. Immunotherapy, including programmed cell-death protein 1 (PD-1)/programmed cell-death ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, frequently causes cutaneous immune-related adverse events and rarely cause LPP.
-
E.
Pemphigus vulgaris – Incorrect. Pemphigus vulgaris is typically characterized by painful bullae and mucosal involvement and is not associated with elevated serum BP antibodies.
Question 2: Which of the following drugs has been most frequently associated with this condition?
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A.
Pembrolizumab
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B.
Vemurafenib
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C.
Cobimetinib
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D.
Talimogene laherparepvec
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E.
Encorafenib
Answer:
-
A.
Pembrolizumab – Correct. Pembrolizumab is a humanized IgG4 monoclonal antibody that targets lymphocyte PD-1 receptors. The normal PD-1/PD-L1 interaction between lymphocytes and tumor cells downregulates the body’s typical immune response, allowing tumor growth.1 Anti-PD-1/PD-L1 therapies block immune checkpoint pathways, promoting antitumor immune response. Cutaneous immune-related adverse events associated with PD-1/PD-L1 inhibitors are common; while pembrolizumab-associated LPP is rare, it has been reported in several patients.1,2
-
B.
Vemurafenib – Incorrect. Vemurafenib is a potent oral small-molecule BRAF inhibitor that may be used to treat advanced melanoma demonstrating appropriate somatic BRAF mutations. BRAF inhibitor medications have not been associated with LPP or similar autoimmune blistering disorders.
-
C.
Cobimetinib – Incorrect. Cobimetinib is an oral small-molecule selective inhibitor of the MEK (mitogen-activated protein kinase-1) pathway. While cobimetinib can be used to treat advanced melanoma, MEK inhibitor medications have not been associated with LPP or similar disorders.
-
D.
Talimogene laherparepvec – Incorrect. Talimogene laherparepvec is an injectable modified oncolytic herpesvirus which may be used in the treatment of advanced melanoma but has not been associated with LPP or other blistering disorders.
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E.
Encorafenib – Incorrect. Encorafenib is an oral small-molecule BRAF inhibitor. Like vemurafenib, this agent has not been associated with LPP or similar disorders.
Question 3: What is the best management for this patient?
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A.
Stop pembrolizumab. Treat with topical and oral steroids and acitretin. Rechallenge with pembrolizumab if needed
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B.
Stop pembrolizumab. Treat with topical and oral steroids and acitretin. Switch to the cytotoxic chemotherapeutic agent if needed
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C.
Continue pembrolizumab. Treat with topical and oral steroids and acitretin
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D.
Continue pembrolizumab. Treat with narrowband ultraviolet B (UVB) therapy
Answer:
-
A.
Stop pembrolizumab. Treat with topical and oral steroids and acitretin. Rechallenge with pembrolizumab if needed – Correct. We requested that the primary oncology team pause pembrolizumab therapy. We treated the patient with triamcinolone acetate 0.1% ointment twice daily, 0.05% clobetasol propionate ointment as needed, acitretin 10 milligrams daily, and high-dose prednisone (60 milligrams daily). Two weeks later, the patient’s rash had significantly improved, and there were no new affected areas. We increased the acitretin to 25 milligrams daily and tapered prednisone to 5 to 10 milligrams daily with continued control of his cutaneous LPP. Four months after stopping pembrolizumab, his angiosarcoma demonstrated progression. Thus, he resumed pembrolizumab; with continued acitretin and topical steroids, he experienced no subsequent flare in LPP despite resuming immunotherapy. His angiosarcoma burden stabilized with resumption of therapy. This case offers an approach that supports resuming immunotherapy in the setting of progressive malignancy for patients with LPP.
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B.
Stop pembrolizumab. Treat with topical and oral steroids and acitretin. Switch to the cytotoxic chemotherapeutic agent if needed – Incorrect. Switching to alternative systemic cancer therapy, such as cytotoxic chemotherapeutic agents, is unnecessary before first attempting a rechallenge of pembrolizumab. The patient had previously responded to pembrolizumab, and it is unclear how he would respond to an alternative therapy.
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C.
Continue pembrolizumab. Treat with topical and oral steroids and acitretin – Incorrect. Given the severity of the patient’s cutaneous eruption, temporary cessation of pembrolizumab is preferred.
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D.
Continue pembrolizumab. Treat with narrowband ultraviolet B (UVB) therapy – Incorrect. Given the severity of the patient’s cutaneous eruption, temporary cessation of pembrolizumab is preferred. UVB therapy is not indicated for LPP and may actually trigger the condition.3
Conflicts of interest
None disclosed.
Footnotes
Funding sources: None.
IRB approval status: Not applicable.
Statement on any prior presentation: There has been no prior presentation.
Consent for the publication of all patient photographs and medical information was provided by the authors at the time of article submission to the journal stating that all patients gave consent for their photographs and medical information to be published in print and online and with the understanding that this information may be publicly available.
References
- 1.Schmidgen M.I., Butsch F., Schadmand-Fischer S., et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges. 2017;15(7):742–745. doi: 10.1111/ddg.13272. [DOI] [PubMed] [Google Scholar]
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- 3.Mandy Chan W.M., Lee J.S., Thiam Theng C.S., Chua S.H., Boon Oon H.H. Narrowband UVB-induced lichen planus pemphigoides. Dermatol Rep. 2011;3(3):e43. doi: 10.4081/dr.2011.e43. [DOI] [PMC free article] [PubMed] [Google Scholar]