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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 40-43

Lichen planus pemphigoides versus bullous pemphigoid: A diagnostic dilemma of cutaneous adverse event in a case of nonsmall cell lung cancer treated with durvalumab


Department of Dermatology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India

Date of Submission15-Mar-2020
Date of Decision01-Aug-2020
Date of Acceptance28-Jan-2021
Date of Web Publication25-Jun-2021

Correspondence Address:
Sunanda Arun Mahajan
Department of Dermatology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_11_20

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  Abstract 


Monoclonal antibodies targeting the immune checkpoint pathways including programmed cell death 1 and programmed cell death ligand-1 have been used in several malignancies. Dermatological toxicities ranging from more common pruritus to rare autoimmune bullous reactions and lichenoid eruptions are an emerging consequence. We report a case of a 74-year-old male diagnosed with nonsmall cell lung carcinoma. He was treated with injection durvalumab following which he developed an itchy, erythematous to hyperpigmented, papular eruption over body. It was diagnosed as a lichenoid drug eruption based on clinicohistopathological correlation and was treated with topical corticosteroids and emollients. Following this, he presented with tense bullae all over the body including the areas of previous lichenoid eruption, associated with pruritus. The histopathology, immunofluorescence, and serology were diagnostic of bullous pemphigoid. However, considering the history, lichen planus pemphigoides (LPP) was the closest differential diagnosis. We treated him with systemic corticosteroids and tetracycline with resolution of the lesions in few weeks and was advised against the continuation of durvalumab therapy. In this article, we have highlighted this adverse event as well as a way to differentiate between LPP and bullous pemphigoid.

Keywords: Bullous pemphigoid, durvalumab, lichen planus pemphigoides, lichenoid eruption


How to cite this article:
Bhoite KS, Mahajan SA, Saini SA. Lichen planus pemphigoides versus bullous pemphigoid: A diagnostic dilemma of cutaneous adverse event in a case of nonsmall cell lung cancer treated with durvalumab. Indian J Drugs Dermatol 2021;7:40-3

How to cite this URL:
Bhoite KS, Mahajan SA, Saini SA. Lichen planus pemphigoides versus bullous pemphigoid: A diagnostic dilemma of cutaneous adverse event in a case of nonsmall cell lung cancer treated with durvalumab. Indian J Drugs Dermatol [serial online] 2021 [cited 2021 Nov 27];7:40-3. Available from: https://www.ijdd.in/text.asp?2021/7/1/40/319347




  Introduction Top


Many advanced cancers have adopted pathways to evade immune detection and clearance; one pathway involves overexpression of programmed cell death ligand-1 (PD-L1). PD-L1 binds to programmed cell death 1 (PD-1) on T-cells and suppresses their activity. By blocking this interaction, the host immune response can be improved, potentially augmenting the antitumor response and reversing the T-cell suppression. All these agents have shown good activity in lung cancer and other solid tumors. These inhibitors are generally well tolerated, though some of the most common immune-related adverse events (irAE) are cutaneous rash or pruritus. Here, the goal was to highlight a severe cutaneous adverse event secondary to one of these drugs along with its clinical course, biopsy findings, and management.


  Case Report Top


A 74-year-old male diagnosed with nonsmall cell lung cancer (NSCLC) was treated with chemoradiotherapy for 5 months followed by immunotherapy in the form of three doses of injection durvalumab at 2 weekly intervals. After the third dose, he complained of multiple pruritic, hyperpigmented papules associated with scaling over bilateral lower and upper extremities and trunk with bilateral pitting pedal edema up to middle one-third of the legs [Figure 1]. Lichenoid eruption secondary to durvalumab was suspected and a biopsy was done from a leg papule. Histopathology showed hyperplastic epidermis with lichenoid band of infiltrate obscuring the dermoepidermal junction (DEJ) and necrotic keratinocytes, confirming the diagnosis of lichenoid drug eruption [Figure 2] and [Figure 3]. He was treated with oral antihistaminics, topical corticosteroids, and emollients; and the lesions healed with postinflammatory hyperpigmentation.
Figure 1: Multiple violaceous to hyperpigmented papules and plaques present over the forearm, dorsa of hands, thighs, legs, and feet associated with scaling

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Figure 2: Hyperplastic epidermis with acanthosis and lymphohistiocytic infiltrate at the interface suggestive of lichenoid eruption

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Figure 3: Higher magnification shows necrotic keratinocytes

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A month later, he presented with erythematous pruritic plaques over the upper and lower extremities and trunk followed by the development of tense bullae. These lesions involved the normal skin as well as areas of postinflammatory hyperpigmentation secondary to the previous lichenoid eruption [Figure 4]. Skin biopsy was done from a vesicle and a perilesional sample was sent for direct immunofluorescence (DIF). Bullous pemphigoid and lichen planus pemphigoides (LPP) were the two differential diagnoses that were considered. Histopathology showed a subepidermal split with dermal inflammatory infiltrate composed of mainly eosinophils and neutrophils which was suggestive of bullous pemphigoid [Figure 5] and [Figure 6]. DIF showed a linear staining of the basement membrane zone with immunoglobulin G (IgG), IgA, and C3 which was diagnostic of bullous pemphigoid [Figure 7]. On serology, the BPAg 180 level was >200 and BPAg 230 level was 45,971, i.e., both were positive. On the basis of these findings, we concluded the diagnosis as bullous pemphigoid.
Figure 4: Multiple tense bullae over a mildly erythematous base present over the neck, arms, forearms, and thighs. Postinflammatory hyperpigmentation over the thighs, legs, and forearms with fine scaling over lesions of previous lichenoid eruption

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Figure 5: Sub-epidermal split with dermal inflammatory infiltrate composed of mainly eosinophils and neutrophils which was suggestive of bullous pemphigoid

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Figure 6: On higher magnification, the blister fluid was composed of plasma and cells such as eosinophils and neutrophils

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Figure 7: Direct immunofluorescence showed a linear staining of the basement membrane zone with immunoglobulin G, immunoglobulin A, and C3 which was diagnostic of bullous pemphigoid

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He was treated with tablet tetracycline 250 mg QID and tablet prednisolone 40 mg per day, tapered eventually over 5 months with topical antiobiotics and emollients. The lesions healed with postinflammatory hyperpigmentation. The immunotherapy was stopped and at present, the patient is off steroids and lesion-free for 2 months.


  Discussion Top


PD-1 is an inhibitory molecule found on the surface of T-cells that maintains immune tolerance to self-antigens. Numerous malignant tumors express PD-L1, which acts to inhibit antitumor T-cell function, allowing cancers to evade the host immune response. Blockade of PD-L1 has been shown to improve the immune function of tumor-specific T-cells and increases tumor lysis. The immune checkpoint monoclonal antibody, durvalumab (IgG1), is an antagonist antibody to PD-1, which can relieve inhibition of tumor-specific T-cells, restoring effective antitumor immunity, approved by the US Food and Drug Administration for the treatment of advanced melanoma and NSCLC.[1]

The most common irAE with anti-PD-1 therapy being mucocutaneous includes dermatitis which could be lichenoid, psoriasiform, moribilliform, urticarial, eczematous, or bullous.[2]

With the reactivation of the immune T-cells, there is an aberrant targeting of dermal antigens due to cross-reactivity, which generates inflammation. There is unmasking of the T-cell response that is mainly responsible for the lichenoid eruption. In addition, the immunotherapy may unmask or amplify a preexisting response as the T-cells are not cancer antigen specific. The time lapse could be 3 days to 13 months from the onset of therapy.[3]

The exact mechanism of immunotherapy-related bullous pemphigoid is not yet established. BP180 has been shown to be expressed in melanoma and NSCLC which raises the possibility of production of antibodies against tumor cell antigens that also target the skin.[3] There is an altered regulation of T-cells targeting collagen XVII or BP180.[2] Bullous pemphigoid is known to occur after treatment with immune checkpoint blocking antibodies.[4]

Another possibility which we considered in our case was LPP, which is also known to occur as a cutaneous adverse event after anti-PD1 antibody treatment. This is not a coincidence of lichen planus and bullous pemphigoid but rather a distinct disease entity. Drug-induced LPP presents as pruritic violaceous papules over distal extremities, followed by development of tense dome-shaped blisters on involved as well as uninvolved skin, 4–6 weeks later, though it can occur simultaneously as well.[5],[6] Certain drugs are known to destroy the basement membrane causing the exposure of the hidden antigens, against which antibodies are formed resulting in subepidermal blisters. These anti-PD1 antibodies are known to induce an inflammatory reaction at the DEJ clinically presenting as a lichenoid reaction which can expose the antigens at the DEJ resulting in antibody-induced blistering.[5]

It can be a difficult to diagnose situation sometimes, considering the potential clinical, histological, and immunological overlap between bullous lichen planus, LPP, and bullous pemphigoid, which happened in our case. Hence, a clinicopathological and immunological correlation is necessary to confirm one particular diagnosis and to check exactly under which entity the case would fit into [Table 1].[7],[8],[9]
Table 1: Clinical, histological, and immunological differences between bullous lichen planus, lichen planus pemphigoides, and bullous pemphigoid

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In our case, there was a dilemma whether to label the blistering phenomenon as bullous pemphigoid or LPP. Our patient gave a history of erythematous plaques prior to the development of blisters which were generalized in distribution and without any mucosal involvement. Furthermore, when the blisters developed, the lichenoid lesions had settled leaving behind patches of postinflammatory hyperpigmentation. On serology, antibodies against both antigens BP230 and BP180 were detected. DIF of the perilesional skin showed the deposition of IgA along with C3 and IgG. Considering the points discussed above [Table 1], we concluded the diagnosis to be bullous pemphigoid developing sequentially after a lichenoid drug eruption secondary to durvalumab therapy. Furthermore, the other confirmatory tests for LPP such as epitope mapping and electrophoresis for antigens of 200kda and 130kda could not be done due to unavailability. The above-mentioned conditions are close differential diagnoses of each other, and hence, it is the dermatologist's decision based on the combination of all the features.


  Conclusion Top


There is a wide range of adverse cutaneous morphologies seen with PD-1/PD-L1 inhibitors. Here, we have highlighted a combination of two such reactions in a single patient. We have also highlighted the differentiation between LPP and blood pressure on clinical, histological, and immunological grounds. Many such patients need to be evaluated to know the wide range of presentations of cutaneous adverse events. Depending on the severity, these can be treated with topical or systemic corticosteroids with or without discontinuation of immunotherapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to thank the Department of Dermatology, Seth G. S. Medical College and KEM Hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shi VJ, Rodic N, Gettinger S, Leventhal JS, Neckman JP, Girardi M, et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti–programmed cell death 1 and anti–programmed cell death ligand 1 immunotherapy. JAMA Dermatol 2016;152:1128-36.  Back to cited text no. 1
    
2.
Shen J, Chang J, Mendenhall M, Cherry G, Goldman JW, Kulkarni RP. Diverse cutaneous adverse eruptions caused by anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies: Clinical features and management Ther Adv Med Oncol 2018;10:1-9.  Back to cited text no. 2
    
3.
Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham J, Page DB, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res 2016;4:383-9.  Back to cited text no. 3
    
4.
Kang S, Amagai M, Bruckner AL, Enk AH, Margolis DJ, McMicheal AJ, et al. Bullous pemphigoid. In: Fitzpatrick's Dermatology. 9th ed., Vol. 1. New York: McGraw-Hill Education; 2019. p. 946.  Back to cited text no. 4
    
5.
Laureano A, Rafael M, Marques Pinto G, Cardoso J. Lichen planus pemphigoides possibly induced by hormone therapy. Eur J Dermatol 2013;23:903-4.  Back to cited text no. 5
    
6.
Onprasert W, Chanprapaph K. Lichen planus pemphigoides induced by enalapril: A case report and a review of literature. Case Rep Dermatol 2017;9:217-24.  Back to cited text no. 6
    
7.
Schmidgen MI, Butsch F, Schadmand-Fischer S, Steinbrink K, Grabbe S, Weidenthaler-Barth B, et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges 2017;15:742-5.  Back to cited text no. 7
    
8.
Hübner F, Langan EA, Recke A. Lichen planus pemphigoides: From lichenoid inflammation to autoantibody-mediated blistering. Front Immunol 2019;10:1389.  Back to cited text no. 8
    
9.
Griffiths CE, Barker J, Bleiker T, Chalmers R, Creamer D. Immuno bullous diseases: Very rare pemphigoid disorders. In: Rook's Textbook of Dermatology. 9th ed., Vol. 2. UK: Wiley Blackwell; 2016. p. 50, 49.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1]



 

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