>Citation : Elinkichari D, Tantot J and Dalle S. (2024) Pembrolizumab-Induced Lichen Planus in a Patient with Metastatic Pulmonary Giant Cell Carcinoma: A Case Report and Literature Review. J Case Rep Med Hist 4(5): doi https://doi.org/10.54289/JCRMH2400121

>Copyright : © 2024 Elinkichari D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Case Report | Open Access | Full Text

Dorsaf Elinkichari*,1, Juliet Tantot2 and Stéphane Dalle1

1Service de Dermatologie, CHU Lyon Sud, Pierre bénite, Lyon, France
2Service d’Anatomopathologie, CHU Lyon Sud, Pierre bénite, Lyon, France

*Corresponding author: Dorsaf Elinkichari, Service de Dermatologie, CHU Lyon Sud, Pierre bénite, Lyon, France

Abstract


Ιmmune checkpoint inhibitors (ICIs) have revolutionized the management of advanced cancers. Nevertheless, the oncologic response is often achieved at the cost of immune-related adverse events (irAEs). We present a case of an immune-mediated lichen planus (LP) and a literature review of similar cases.
A 60-year-old man, who is being treated with pembrolizumab for a pulmonary giant cell carcinoma since April 2022, presented in November 2022 with a pruritic eruption that appeared two weeks ago. Examination showed bright purple confluent scaly papules on wrists, proximity of limbs, back and buttocks and palmar keratoderma made of violaceus papules covered with reticular white striae. Histological examination revealed an epidermal hyperplasia, vacuolization of the basal layer, necrotic keratinocytes and a band-like subepidermal lymphocytic infiltrate with many eosinophils. The diagnosis of an immune-related LP was retained. Pembrolizumab was withheld because of the severity and the extension of the lesions. Superpotent topical steroids were prescribed with a significant improvement of the rash within 3 weeks.
Immune-mediated lichenoid euptions represent one of the most frequent dermatologic irAEs. In our patient, the onset seven months after the initiation of ICIs, the infiltrate rich in eosinophils, and the rapidly diffused character are indications of an immuno-mediated LP.
Keywords: Lichen planus; Pembrolizumab; Anti-PD1; Immunotherapy; Drug reactions
Abbreviations: ICI: Ιmmune checkpoint inhibitors, LP: lichen planus

Introduction


Ιmmune checkpoint inhibitors (ICIs) have revolutionized the management of advanced cancers in dermatology as well as in other disciplines [1]. Pembrolizumab is one of the most frequently used ICIs, with a growing list of approved indications including non-small-cell lung cancers, metastatic melanoma, and advanced squamous cell cancer. It is an anti-Programmed Death protein 1 (Anti-PD-1) agent. Blocking the inhibitory signals of cytotoxic T cells, ICIs allow the upregulation of the antitumor immune response [2]. Nevertheless, the immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ. Dermatologic irAEs (dirAEs) are among the most common and are observed in about 40% of all treated patients. These include maculopapular, psoriasiform, lichenoid, vitiligoid and eczematous rashes, auto-immune bullous disorders, pruritus, hair, nail and mucosal changes, as well as a few severe life-threatening drug reactions [3].
Herein we describe a case of an immune-mediated lichenoid eruption in a patient being treated with pembrolizumab for a pulmonary giant cell carcinoma.

Case Report


A 60-year-old Caucasian man, with a history of hypothyroidism supplemented for years, and who is being treated with pembrolizumab for a stage IV pulmonary giant cell carcinoma since April 2022, presented in November 2022 with a pruritic eruption that appeared two weeks ago. The eruption started with confluent papules of the wrists then extended to the limbs and the trunk. The patient did not have any other relevant history. Skin examination showed polygonal, bright purple, confluent, and scaly papules on wrists, proximity of limbs, back and buttocks and palmar keratoderma made of violaceus and confluent papules covered with reticular fine whitish streaks (Figure A). These lesions were symmetrically distributed. Mucosal and nail examination was normal. The standard biological tests were within normal values. The patient had no history of unprotected sexual intercourse, and staining for syphilis antibodies was negative. Differential diagnosis included lichen planus (LP) and lichenoid drug eruption. Light microscopic evaluation of skin biopsy of the back revealed histological features of LP: Hypergranulosis, vacuolization of the basal layer with apoptotic keratinocytes, and a band-like subepidermal lymphocytic infiltrate. The presence of numerous eosinophils did not rule out the diagnosis of a lichenoid drug reaction (Figure B). The diagnosis of a grade 3 immune-related lichenoid eruption was then retained. A multidisciplinary consultation meeting led to anti-PD-1 therapy withdrawal because of the severity and the extension of the lesions. Superpotent topical steroids were prescribed with a significant improvement of the pruritus and the rash within three weeks. Given the stability of the cancerous disease, checkpoint inhibitors were not reintroduced. At the fourth month follow-up, all skin lesions have healed.

Figure 1: Bright purple confluent scaly papules on wrists (A.1), back and buttocks (A.2), Palmar keratoderma (A.3)

Figure 2: Hematoxylin Eosin Coloration X 10 showing epidermal hyperplasia, vacuolization of the basal layer, band-like subepidermal lymphocytic infiltrate (B.1) Hematoxylin Eosin Coloration X 20 showing rich lymphocytic and eosinophilic infiltrate (B.2).

Discussion


LP is a T cell‐mediated, inflammatory skin condition that affects between 0.5 and 1% of the population. Classic LP typically presents as a symmetrically distributed pruritic, polygonal, violaceous papules. It is suggested that the pathogenicity of LP involves the autoimmune-mediated lysis of basal keratinocytes by CD8 + lymphocytes. Yet, definitive etiological triggers are still unknown. An association between LP and the following has been observed : chronic active hepatitis (hepatitis C particularly); primary biliary cirrhosis; complication of hepatitis B vaccination; viral and bacterial antigens; medications; trauma (Koebner phenomenon); metal ions; and some autoimmune diseases such as autoimmune thyroiditis, alopecia areata, vitiligo, and autoimmune polyendocrinopathy [4].

Lichenoid eruptions are among the most frequent manifestations of anti-PD-1 cutaneous toxicity. PD-1 is a membrane receptor. Its activation is responsible for self-tolerance during immune response. Increased expression of PD-L1 and PD-L2 by tumour cells thus leads to inhibition of T cells and tolerance toward malignant cells. Blockade of this pathway is transforming the prognosis of many cancers. However, the inhibition of the same pathway may lead to disruption of loss of self-tolerance and induce immune mediated diseases [2]. T cell-mediated autoimmune response secondary to PD-1 inhibition induces cell apoptosis, including basal layer keratinocytes apoptosis, and plays an important role in the pathogenesis of lichenoid reactions.

According to a recent study, LP or lichenoid eruption is 10.7-fold more likely to develop in patients treated with nivolumab or pembrolizumab than the general population [5]. Although lichenoid reactions have emerged as an important dirAEs, immune-induced LP have been infrequently described in the literature. So far, 26 cases of LP and 21 cases of LP pemphigoid induced by anti-PD1 have been reported, with the first description appearing in 2016 [6,7]. Among LP cases, 14 patients had a classic form (Cutaneous LP: 7 cases; cutaneo-mucosal LP: 7 cases), seven patients had bullous LP, four patients had hypertrophic LP mimicking early invasive squamous cell carcinomas, one patient had LP pilaris, and one patient had erosive LP [6-12]. The patient with LP pilaris also had lesions of classic cutaneous LP [13]. Delay of onset from the beginning of treatment ranged from two weeks to 18 months [11,12]. A delay of seven months was observed in our patient. This latency period is of particular interest as cutaneous toxicities can present even after withdrawal of ICIs [3]. In the majority of the reported cases, as in our patients, lesions were clinically and histologically indistinguishable from classic LP. However, a consistent chronology, an infiltrate rich in eosinophils and an eruptive and rapidly diffused character may be indicators of an immuno-mediated LP.

The majority of patients were treated with either oral or topical corticosteroids. Hydroxychloroquine was prescribed, in association with oral prednisone and topical steroids, in one of the patients presenting with a hypertrophic LP, with a complete resolution [14]. In the patient with LP pilaris, anti-inflammatory dose of doxycycline initially slowed the progression. However, control of infammation has been obtained only with systemic steroids and hydroxychloroquine, with a remaining scarring alopecia [13]. Withdrawal of anti-PD-1 treatment was considered in seven patients. Pembrolizumab was temporarly suspended in two patients [15,16]. Cases of LP associated with anti-PD1 are summarized in Table A.

In conclusion, immunotherapy is increasingly becoming the standard treatment for many malignancies. ICIs are actually reshaping the prognosis of many cancers. These new treatments are bringing new hope to patients, but also a whole new spectrum of toxicities for clinicians to manage. Immune-induced LP represents one of the most frequent dirAEs. Several variants have been reported in the literature such as hypertrophic LP, bullous LP, and LP pilaris. However, immune-related classic cutaneous LP is the most frequently described. Treatment is based on topical steroids. Systemic steroids are often proposed in severe reactions. Withdrawal of ICIs may be indicated in refractory cases, in the framework of a multidisciplinary consultation meeting.

  Table A: Reported cases of LP associated with anti-PD1

Age (Years) Sexe History of LP before ICIs Variant of LP Treatment Primary disease Delay from start of treatment to onset of symptoms Management
Wakade et al., 2016 [17] 71 Female Unspecified Bullous LP Pembrolizumab non-small-cell lung cancer 1 month Topical steroids Acitretin 0.2 mg/kg/d
49 Female Unspecified Bullous LP Pembrolizumab Metastatic melanoma 3 weeks Withdrawal of ICIs Bolus IV methylprednisone followed by systemic steroids Acitretin 0.2 mg/kg/d
86 Male Unspecified Bullous LP Pembrolizumab non-small-cell lung cancer 15 weeks Topical steroids ICIs discontinued (Stable malignancy/Respiratory failure)
Komori et al., 2016 [18] 67 Female Unspecified Classic cutaneous LP Nivolumab + Radiotherapy Breast cancer with hepatic metastasis Unspecified Withdrawal of nivolumab Topical steroids
Hofmann et al., 2016 [16] 87 Male Unspecified Classic mucosal LP Pembrolizumab Metastatic melanoma 48 weeks Topical steroids Systemic steroids ICIs temporarily suspended
69 Male Unspecified Classic cutaneo-mucosal LP Pembrolizumab> Metastatic melanoma 49 weeks Topical steroid Systemic steroids Withdrawal of ICIs
79 Male Unspecified Classic cutaneo-mucosal LP Pembrolizumab Metastatic melanoma 49 weeks Withdrawal of ICIs Topical steroids Systemic steroids
65 Female Unspecified Classic cutaneo-mucosal LP Pembrolizumab Metastatic melanoma 43 weeks Topical steroids Topical pimecrolimus Mouthwash steroids
74 Male Unspecified Classic cutaneo-mucosal LP Pembrolizumab Metastatic melanoma 49 weeks Topical steroids Mouthwash steroids
46 Male Unspecified Classic cutaneous LP Pembrolizumab Metastatic melanoma 24 weeks Topical steroid Levocetirizine 5 mg/d
80 Male Unspecified Classic cutaneous LP Pembrolizumab Metastatic melanoma 21 weeks Topical steroids Levocetirizine 5 mg/d
Komori et al., 2017 [19] 67 Female Unspecified Erosive LP Nivolumab + Radiotherapy Breast cancer with hepatic and lymph node metastasis 5 months Topical steroids Systemic steroids
Massey et al., 2017 [20] 70 Female Unspecified Hypertrophic LP Pembrolizumab Squamous-cell lung cancer 3 months Topical steroids
Zhao et al., 2018 [15] 67 Man No Bullous LP Pembrolizumab Metastatic melanoma 12 months Topical steroids Systemic steroids ICIs temporarily suspended
Biolo et al., 2018 [21] 77 Man Unspecified Linear bullous LP Nivolumab Metastatic renal carcinoma 8 months Topical steroids Systemic steroids
Maarouf et al., 2018 [22] 51 Man Yes Hypertrophic LP Nivolumab Non-small-cell lung cancer, stage IV 2 weeks Topical steroids
Fontecilla et al., 2018 [23] 79 Man Yes Hypertrophic LP Pembrolizumab Non-small-cell lung cancer, stage IV 6 weeks Systemic steroids
Denny et al., 2018 [24] 46 Man No Classic cutaneous LP Pembrolizumab Metastatic melanoma 6 months Topical steroids Systemic steroids
Coscarat et al., 2020 [13] 78 Female No Hypertrophic LP Pembrolizumab lung adenocarcinoma 6 months Topical steroids Systemic steroids Hydroxychloroquine
Economopoulou et al., 2020 [9] 66 Male Yes Classic cutaneo-mucosal LP Nivolumab metastatic oral cavity cancer 8 months Topical steroids
De Lorenzi et al., 2020 [8] 68 Male No Bullous LP Nivolumab Metastatic clear cell renal cell carcinoma 3 months Systemic steroids Withdrawal of ICIs
Yilmaz et al., 2020 [10] 27 Female No Classic cutaneous LP Nivolumab Metastatic renal clear cell carcinoma 5 months Topical steroids
Ferguson et al., 2020 [11] 73 Female Unspecified Classic cutaneo-mucosal LP Nivolumab Metastatic renal clear cell carcinoma 18 months Topical steroids Betamethasone mouthwashes Systemic steroids Withdrawal of ICIs
Uthayakumar et al., 2021 [14] 62 Female Unspecified LP pilaris + Classic cutaneous LP Pembrolizumab Metastatic melanoma 9 months Topical steroids Topical tacrolimus Doxycycline 100 mg: Initially slowed the progression Hydroxychloroquine Systemic steroids
Hanamie et al., 2022 [12] 74 Female Unspecified Classic cutaneous LP Nivolumab Non small cell lung cancer 6 weeks Topical steroids
81 Male Unspecified Bullous LP Pembrolizumab Non small cell lung cancer 6 months Topical steroids Oral antihistamine
Our case 60 Male No Classic cutaneous LP Pembrolizumab Pulmonary giant cell carcinoma 7 months Topical steroids Withdrawal of ICIs

Acknowledgments: Dorsaf Elinkichari is the guarantor of the content of the manuscript, including the data and analysis. Juliet Tantot contributed to acquisition of data, and interpretation of information. Stéphane Dalle revised data critically for important intellectual content, and gave final approval of the version to be submitted.
Informed consent: The patient has given informed consent to the publication of his case details.
Funding: None
Conflict of Interest: None of the authors have a conflict of interest to disclose

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