Anogenital lichen sclerosus et atrophicus lesions in a case series of cancer patients on immunotherapy

Abstract

Lichenoid reactions are one of the most frequently observed toxicities with anticancer agents and, recently, a rapid emergence of immunotherapies in oncology has hastened the need to better characterize their unique toxicity profiles, particularly for less common skin toxicities, including anogenital lichen sclerosus et atrophicus (LSA). This case series describes four patients with advanced cancer (one melanoma, two lung cancers, and one kidney tumor) developing LSA lesions while receiving an immunotherapy. Medical records from 2017 to 2020 were retrospectively reviewed. Two patients received pembrolizumab, anti-programmed cell death-1 (PD-1), one nivolumab, anti-programmed cell death-1 (PD-1), and one ipilimumab, an immune checkpoint inhibitor. LSA emerged after a median of 3 months (range, 2–4 months) from starting immunotherapy. All LSA cases were grade 2. Three cases occurred on the penis and one case on the anus. All patients improved after a specific treatment for LSA, and no LSA-related antineoplastic treatment interruption/life-threatening condition were reported. To date, this is the first case series of LSA lesions associated with immunotherapy. Early LSA recognition and management is helpful in cancer patients on immunotherapy allowing a long survival and treatment response.

Introduction

Cutaneous adverse effects are one of the most frequent toxicity observed in association with anticancer agents. In the last decade, a rapid emergence of the immune checkpoint inhibitors led to the growing number of skin-related toxicities that are immune-related adverse events in approximately 20% of cases on treatment with anti-programmed cell death-1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) and 40% to 50% of patients treated with combined PD-1/cytotoxic T-lymphocyte antigen-4 (CTLA-4) blockade [1]. Skin adverse events are characterized by a wide spectrum of clinical manifestations and different intensity which can be dose-limiting or leading to therapy discontinuation.

In general, lichenoid reactions occur in approximately 15% of patients treated with immunotherapy [2, 3]. The etiopathogenesis of lichen sclerosus is not fully understood, even genetic and autoimmune factors may have a strong influence on its development [4]. In 10–21% of cases, lichen sclerosus is associated with other autoimmune diseases including pernicious anemia, alopecia areata, thyroid disease, morphea, and vitiligo [5]. A relationship with infections, hormonal disorders, and chronic irritation of the genitals is also suggested.

Specifically, lichen sclerosus et atrophicus (LSA), described originally by Hallopeau, in 1887 is an inflammatory disorder of unknown etiology affecting skin and mucosa, especially the genital area [6]. LSA is rarely associated to anticancer therapies. In this report, we describe one of the largest series of patients diagnosed with immunotherapy-related LSA reported to date.

Materials and methods

We identified cancer patients who developed LSA from February 2017 to January 2020. Clinical and laboratory data used in the diagnosis and management of malignancy and LSA were recorded and reviewed.

The diagnosis of LSA is based on clinical signs and symptoms, and a confirmatory biopsy is not always necessary when the typical clinical features are present [7].

Dermoscopy was included as part of the clinical inspection to support diagnosis, as well as to avoid unnecessary invasive investigations and for monitoring the response to treatment [8].

Descriptive statistics of quantitative variables were calculated. The study was approved by the Institutional Review Board of IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.

Results

Four patients with a diagnosis of malignancy (1 melanoma, 2 lung cancers and 1 kidney carcinoma) associated with LSA were identified (Table 1). They were all males with a median age of 70 years (range, 48–76 years). Two patients received the anti-programmed cell death-1 (PD-1) monoclonal antibody pembrolizumab as first-line therapy, one patient the anti-PD-1 (PD-1) monoclonal antibody nivolumab as second-line therapy, and one patient the immune checkpoint inhibitor ipilimumab as first-line therapy. We observed LSA after a median of 3 months (range, 2–4 months) from starting immunotherapy. All LSA cases were grade 2. Three cases occurred on the penis and one case on the anus.

Table 1.

Main characteristics of patients with genital Lichen Sclerosus et Atrophicus (LSA)

Ptid	Sex	Age (yrs)	Primary site of tumor	Tumor Stage	Type of IT	PFS (mo)	OS (mo)	Time from starting IT to LSA (mo)	LSA site	Initial Grade# of LSA	Final Grade of LSA§	Time to LSA resolution§ (mo)	Other skin comorbidities
1	M	76	Lung	IV	Nivolumab	21	36	2	Penis	2	0&	1	No
2	M	48	Melanoma	IV	Ipilimumab	34	49	3	Anal region	2	0&	7	Vitiligo
3	M	76	Lung	IV	Pembrolizumab	5	12	3	Penis	2	1&&	12	No
4	M	64	Kidney	IV	Pembrolizumab	13	31	4	Penis	2	1&&	16	Psoriasis

IT immunotherapy; LSA Lichen Sclerosus et Atrophicus; M male; mo months; N number; OS overall survival; PFS progression-free survival; pt patient; yrs years

* From diagnosis of LSA years

^#According to Common Terminology Criteria for Adverse Events (CTCAE) Version 5

^§After specific treatment for LSA; ^& complete; ^&& partial responses of LSA

Clinically, main LSA features were: grayish-white discoloration and post-inflammatory hpo/hyperpigmentation of gland, purpura, architectural change with coronal adhesions, paraphimosis. Itching was present in all patients. Sexual symptoms were present on one case and urinary symptoms on one case.

Characteristic dermoscopic patterns to aid clinical diagnosis were always present (Fig. 1).

Fig. 1.

Clinical and dermoscopic presentation of genital Lichen Sclerosus et Atrophicus in two patients receiving novel targeted therapies. Clinically (A) lichenoid balanoposthitis with white discoloration, ulceration and paraphimosis and dermoscopically (B) (tenfold magnification) patchy white areas associated to ulceration and dotted vessels. Gray-blue dots with a characteristic peppered arrangement are present (patient number 1). Clinical (C) Lichen Sclerosus et Atrophicus with post-inflammatory hypopigmentation netted of penis and dermoscopic (D) features of whitish structureless areas (patient number 4)

Treatment consisted of topical clobetasol propionate 0.05% ointment, 0.5 g (1 fingertip unit) once at night for 1–3 months in patients. After the third month, the same ointment was applied at the same dose; alternate days for 1 month, twice weekly until the last clinical follow-up. A soap substitute, emollients, barrier preparation was also prescribed.

All patients presented a clinical improvement after LSA treatment achieving a complete remission in 2 (50%) patients, and a partial response in 2 (50%) patients. Median progression-free survival and overall survival of immunotherapy were 17 months (range, 5–34) and 33.5 months (range, 12–49), respectively. No antineoplastic treatment interruption and no life-threatening condition due to LSA were observed.

Discussion

Considering the rarity of LSA, this is one of the largest case series of patients presenting with this condition in association with immunotherapies. In particular, our results suggest that LSA can manifest late in the natural tumor course of the malignant tumor but within approximately 3 months of starting an immunotherapy.

Although the pathogenesis of lichen sclerosus is not been fully elucidated, it is increasingly considered as an autoimmune disease because of high prevalence of organ-specific autoantibodies such as extracellular-matrix-protein-1 and the upregulation of pro-inflammatory cytokines with activation and maintenance of a T-helper type 1 (Th1) response. This immune dysregulation might explain the association between LSA and ipilimumab that can rise activated T-cells and humoral immunity and between LSA and anti-PD1 drugs that can prevent the deactivation of T-lymphocytes, promoting self-reactive T-cells [4]. Moreover, all patients included in this study had an immunogenic tumor (melanoma, kidney, and lung cancers) in which immunosuppression and angiogenesis work hand-in-hand. Interestingly, two (50%) cases presented a history of other immune-mediated skin comorbidities, as previously shown [5]. However, no other autoimmune toxicities were reported in our case series.

These findings point more and more toward LSA as an autoimmune-induced disease in cancer patients. In our experience, we underlined the association between immunotherapy and genital and extragenital lichen sclerosus, as previously shown only in single cases of patients affected with different types of tumors, mainly treated with nivolumab, pembrolizumab, and ipilimumab [2, 9, 10]. However, the incidence of LSA was reported in only 0.5% of overall cancer patients receiving checkpoint inhibitors during the time of this study at our Institute.

Interestingly, in our patients developing LSA on immunotherapy, we observed a long treatment response and overall survival, despite most cases were metastatic malignancies. Likely, the appearance of LSA lesions as well as certain other cutaneous manifestations (e.g. vitiligo-like depigmentation during immunotherapy for melanoma) may be a positive prognostic indicator for the response to antineoplastic therapy due to the overactivation of the immune system.

The main limitations of this study were its sample size, retrospective design, single institution setting, and the heterogeneity of antineoplastic agents. Furthermore, there is the lack of histological diagnosis in most cases, even because a confirmatory genital biopsy, although ideal, is not always practical and is not always essential when the clinical features are typical [11].

In conclusion, early recognition and management of LSA is helpful in cancer patients, mainly those receiving immunotherapy, allowing a long survival and a lasting response to treatments. Thus, dermatologists play an important role on the care teams of patients with cancer through frequent skin toxicity evaluations. Particular attention to identify these uncommon drug-related skin lesions, adequate symptomatic control and specific LSA treatment may also ameliorate efficacy of antineoplastic treatment by minimizing the need for dose reduction and drug suspension. A multidisciplinary approach will be increasingly important especially with the explosive development of numerous immune checkpoint inhibitors, both as monotherapy or combination therapy, which can drive precision medicine across different clinical specialties.

Abbreviations

IT

Immunotherapy

LSA

Lichen Sclerosus et Atrophicus

M

Male

mo

Months

N

Number

OS

Overall survival

PFS

Progression-free survival

pt

Patient

yrs

Years

Author contributions

Study concept and design: Conteduca, Medri. Acquisition, analysis, or interpretation of data: Conteduca, Medri, Mazzoni, De Giorgi, Stanganelli. Drafting of the manuscript: Conteduca, Medri. Study supervision: Stanganelli. Manuscript review and approval: all authors.

Funding

No funding was required in the preparation of this manuscript.

Declarations

Conflict of interest

V. Conteduca received speaker honoraria or travel support from Astellas, Janssen-Cilag, and Sanofi-Aventis. V. Conteduca received consulting fee from Bayer and is an advisory board member of Janssen, Astellas, AstraZeneca, and Merck. U. De Giorgi reports grants from AstraZeneca; personal fees from Astellas, Bayer, Novartis, Merck Sharp & Dohme, and Pharmamar; grants and personal fees from Sanofi; grants and non-financial support from Roche; and personal fees and non-financial support from Janssen-Cilag, Pfizer, Bristol Myers Squibb, and Ipsen. No potential conflicts of interest were disclosed by the other authors.