Severe overlap of morphea and lichen sclerosus after anti-PD-L1 immunotherapy in small cell lung cancer

Abstract

Dear Editors,

The anti-PD-L1 immune checkpoint inhibitor (ICI) atezolizumab is a treatment standard for small cell lung cancer (SCLC). Although cutaneous treatment-related adverse events (TRAE) are very common, sclerodermiform eruptions represent a very rare phenomenon.

A 65-year-old female patient with metastatic SCLC presented to our clinic in a reduced general condition due to cutaneous eruptions following the initiation of a palliatively intended combined immune-chemotherapy with carboplatin (AUC5 d1), etoposide (100 mg/m² d1–3), and atezolizumab (1,200 mg d1). After four cycles of combinatory treatment Q3W, she had received four additional cycles of atezolizumab monotherapy Q3W. The patient did not report pre-existing comorbidities, allergies, or prior medication. She exhibited extensive indurations paired with erosions, fibrinous coating, and crusts, predominantly on the thighs and the lower abdominal area (Figure 1). Simultaneously, a severe pruritus and pain were debilitating. Sclerotic skin involvement led to a major restriction in everyday mobility and limited the ability to breathe. A Dermatological Life Quality Index (DLQI) score of 23 and Eastern Cooperative Oncology Group (ECOG) performance status score of two, reflected a pronounced and emotionally burdensome situation. Previous topical glucocorticosteroid treatment was sine effectu.

On presentation to the clinic, systemic oncological treatment was discontinued. Laboratory studies revealed mild anemia (hemoglobin of 10.9 g/dl) and leukocytosis (17.2 × 10⁹ cells/l) with elevated absolute levels of neutrophils, monocytes, and eosinophils with normal erythrocyte and platelet counts. Skin biopsies confirmed extensive sclerosis in the upper and middle dermis and marked subepidermal edema (Figure 2a,b). Masson-Goldner trichrome staining confirmed extensive dermal collagenous fibrosis (Figure 2c,d). Clinically, a morphea overlapping lichen sclerosus et atrophicans was diagnosed. Prominent lesional eosinophilic granulocytes confirmed the suspicion of TRAE. Systemic sclerosis manifestations were excluded. Interestingly, radiographic imaging revealed a complete remission (CR) of the SCLC.

We started intravenous prednisolone treatment up to 2 mg/kg body weight (BW) daily with a dose of over 100 mg prednisolone equivalent for a total of 11 days with tapering attempts in between, and methotrexate 15 mg SC once a week. Physiotherapy, antipruritic and multimodal pain management were initiated. The patient received psycho-oncological support.

Due to a refractory skin condition, extracorporeal photopheresis (ECP) was performed four times with a biweekly schedule. In addition, UVB 311 nm phototherapy was administered with a total dose of 2.89 J/m². This treatment gradually improved her skin condition, although superinfections occurred repeatedly. These were mostly controlled by topical antiseptic treatment. However, she suddenly developed septic shock with severe hypotension, syncope, elevated inflammatory parameters, and acute kidney injury. Meropenem 500 mg intravenously was started three times daily. As with the skin ulcers, blood cultures showed Staphylococcus lugdunensis, and the therapy was changed to cefazolin 2 g IV three times daily for 16 days in accordance with the resistogram. As the skin condition remained poorly controlled, combination therapy with methotrexate and ECP was recommended. However, due to increasing side effects and discomfort, the patient decided to discontinue treatment and asked to be discharged home. Just two weeks later, she succumbed to another superinfection of the TRAE sites.

Cutaneous events are among the most common TRAEs associated with checkpoint inhibitors. They are usually very mild and comparatively easy to treat, including both localized and generalized lichenoid and Morphea-like eruptions.^1-3 In contrast to anti-CTLA-4 ICIs, anti-PD-1 ICIs and even anti-PD-L1 ICIs have been associated with sclerodermiform eruptions.⁴ A possible explanation for this is the induction of a profibrotic type 2 macrophage polarization. One explanation could be the induction of a profibrotic type 2 macrophage polarization.⁵ However, the sclerodermiform eruptions presented here resembled severe morphea overlapping lichen sclerosus et atrophicans, a very rare phenomenon not yet described as a TRAE after atezolizumab. Severe TRAE has been associated with a favorable treatment outcome in NSCLC.⁶ Interestingly, the patient experienced a CR of SCLC. However, the cutaneous TRAE was so severe that the patient succumbed to the complications despite various treatment strategies.

Summarizing, we describe a unique case that highlights the opportunities, risks, and cutaneous complications associated with ICI therapy. This case vividly illustrates that, although life-threatening cutaneous TRAE caused by ICI are rare, their onset must be taken seriously, closely monitored, and treated with a comprehensive multimodal approach at an early stage.

G.G. has received honoraria from BMS, Almirall Hermal, Janssen-Cilag, and Mylan, and has received travel expenses from MSD. J.K. has received honoraria from Bristol-Myers Squibb and Sanofi Genzyme, as well as travel support from SUN Pharma and Pierre Fabre, all outside the submitted work. C.G. is a member of the advisory boards of BMS, Immunocore, MSD, Novartis, Pierre-Fabre, Sanofi, SUN Pharma, and Sysmex. C.G. has received honoraria from BMS, GSK, Immunocore, MSD, Novartis, Pierre-Fabre, Sanofi, SUN Pharma, and Sysmex. Additionally, C.G. has received travel expenses from BMS, Pierre-Fabre, and SUN Pharma and is an unpaid board member of DeCOG (ADO), the Hiege Stiftung, and the Roggenbuck-Stiftung. Furthermore, C.G. is the founder of Dermagnostix and Dermagnostix R&D. All other authors have declared no conflicts of interest.