Research

JAMA Dermatology | Original Investigation

Clinical and Histologic Features of Lichenoid Mucocutaneous

Eruptions Due to Anti–Programmed Cell Death 1
and Anti–Programmed Cell Death Ligand 1 Immunotherapy
Veronica J. Shi, MD; Nemanja Rodic, MD, PhD; Scott Gettinger, MD; Jonathan S. Leventhal, MD;
Julia P. Neckman, MD; Michael Girardi, MD; Marcus Bosenberg, MD, PhD; Jennifer N. Choi, MD

CME Quiz at
IMPORTANCE Antagonist antibodies to programmed cell death 1 (PD-1) and programmed cell jamanetworkcme.com and
CME Questions page 1180
death ligand 1 (PD-L1) have shown remarkable activity in multiple tumor types. Recent US
Food and Drug Administration approval of such agents for advanced melanoma, non–small
cell lung cancer, and renal cell carcinoma has hastened the need to better characterize their
unique toxicity profiles.

OBJECTIVE To provide a clinical and pathologic description of the lichenoid mucocutaneous

adverse effects seen in patients receiving anti–PD-1/PD-L1 treatment.

DESIGN, SETTING, AND PARTICIPANTS Patients with advanced cancer who were referred to
dermatology at Yale–New Haven Hospital, a tertiary care hospital, after developing cutaneous
adverse effects while receiving an anti–PD-1 or PD-L1 antibody therapy either as monotherapy
or in combination with another agent were identified. Medical records from 2010 to 2015 and
available skin biopsy specimens were retrospectively reviewed.

MAIN OUTCOMES AND MEASURES Patient demographic characteristics, concurrent

medications, therapeutic regimen, type of disease, previous oncologic therapies, clinical
morphology of cutaneous lesions, treatment of rash, peripheral blood eosinophil count,
tumor response, and skin histologic characteristics if biopsies were available.

RESULTS Patients were 13 men and 7 women, with a mean (range) age of 64 (46-86) years.
The majority of cases (16 [80%]) had a clinical morphology consisting of erythematous
papules with scale in a variety of distributions. Biopsies were available from 17 patients; 16
(94%) showed features of lichenoid interface dermatitis. Eighteen patients were treated with
topical corticosteroids, and only 1 patient required discontinuation of anti–PD-1/PD-L1
therapy. Only 4 of 20 patients (20%) developed peripheral eosinophilia. Sixteen patients
(80%) were concurrently taking medications that have been previously reported to cause
lichenoid drug eruptions.

CONCLUSIONS AND RELEVANCE Papular and nodular eruptions with scale, as well as mucosal
Author Affiliations: Department of
erosions, with lichenoid features on histologic analysis were a distinct finding seen with Dermatology, Yale School of
anti–PD-1/PD-L1 therapies and were generally manageable with topical steroids. Concurrent Medicine, New Haven, Connecticut
medications may play a role in the development of this cutaneous adverse effect. (Shi, Rodic, Leventhal, Neckman,
Girardi, Bosenberg); Department of
Pathology, Yale School of Medicine,
New Haven, Connecticut (Rodic,
Bosenberg); Section of Medical
Oncology, Department of Internal
Medicine, Yale School of Medicine,
New Haven, Connecticut (Gettinger);
Department of Dermatology,
Northwestern University Feinberg
School of Medicine, Chicago, Illinois
(Choi).
Corresponding Author: Jennifer N.
Choi, MD, Northwestern University
Feinberg School of Medicine,
Department of Dermatology, 676 N
JAMA Dermatol. 2016;152(10):1128-1136. doi:10.1001/jamadermatol.2016.2226 St Clair, Ste 1600, Chicago, IL 60611
Published online July 13, 2016. ([email protected]).

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 Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs Original Investigation Research

I
mmunotherapy represents the next generation of antican-
cer therapy. Within the last several years, numerous im- Key Points
muno-oncology agents have emerged as effective treat-
Question What are the features of the cutaneous adverse effects
ment options for patients with cancer. One immune target associated with anti–programmed cell death 1 and
of particular interest is programmed cell death 1 (PD-1), an anti–programmed cell death ligand 1 therapy?
inhibitory molecule found on the surface of T cells that
Findings In this case series of 20 patients, the clinical morphology
maintains immune tolerance to self-antigens.1 Numerous
of cutaneous eruptions consisted of erythematous papules with
malignant tumors express programmed cell death ligand 1 (PD- scale, with skin histologic analysis predominantly showing
L1), which acts to inhibit antitumor T-cell function,2 allowing lichenoid interface changes.
cancers to evade the host immune response. Blockade of PD-L1
Meaning There is a distinct cutaneous lichenoid eruption
has been shown to improve immune function of tumor-
associated with anti–programmed cell death 1 and
specific T cells and increase tumor lysis.3 anti–programmed cell death ligand 1 therapy.
Nivolumab and pembrolizumab are IgG4 antagonist anti-
bodies to PD-1, which can relieve inhibition of tumor-specific
T cells, restoring effective antitumor immunity. Both have been opsy, and for those patients without biopsy, eosinophil count
approved by the US Food and Drug Administration (FDA) for was recorded at the time of presentation of cutaneous toxic
the treatment of advanced melanoma and non–small-cell lung effect. Tumor response was determined from documenta-
cancer (NSCLC). Nivolumab was also recently FDA approved tion from the patients’ treating oncologists and was charac-
for the treatment of metastatic renal cell carcinoma and re- terized on the basis of RECIST (Response Evaluation Criteria
lapsed or refractory classical Hodgkin lymphoma. Toxicity of in Solid Tumors) criteria. Time to disease progression was cal-
anti–PD-1 therapies is primarily related to autoimmunity un- culated from the first dose of anti–PD-1/PD-L1 treatment to pro-
masked by releasing self-protective PD-1 inhibition. Com- gression, which was determined by imaging. Any other irAEs
pared with ipilimumab, an antagonist antibody to another that were documented were recorded. The histopathologic
immune inhibitory molecule, cytotoxic T lymphocyte– features of available biopsy specimens were reviewed by 2
associated protein 4, anti–PD-1 therapy is better tolerated, with dermatopathologists (N.R., M.B.) and tabulated. For each avail-
less severe autoimmune adverse effects.4 Two of the most com- able case, light microscopic examination of tissue sections pre-
mon immune-related adverse events (irAEs) with anti–PD-1 pared with hematoxylin-eosin staining was performed. In
therapy are the mucocutaneous adverse effects of rash and pru- addition, for 3 of the cases (numbers 2, 5, and 9), a panel of
ritus. Antibodies targeting the ligand PD-L1 (eg, atezoli- immunoperoxidase stains, including stains for CD3, CD4, CD8,
zumab and durvalumab) are still under active investigation in and CD20, was performed.
clinical trials and show similar dermatologic adverse effects.
Given that these immunotherapeutic agents have only
emerged recently, their toxicity profiles are still being fully char-
acterized. In this study, we aim to characterize the clinical and
Results
histopathologic features of cutaneous eruptions that developed A total of 20 patients were included in this study (13 men and
in a series of patients receiving anti–PD-1 or anti–PD-L1 therapy. 7 women). Ten patients were treated with nivolumab alone,
while 4 were treated with nivolumab in combination with ipi-
limumab. One patient was treated with nivolumab in combi-
nation with bevacizumab, and 1 patient was initially treated
Methods with nivolumab in addition to erlotinib and then continued tak-
With the approval of the Yale University Institutional Review ing nivolumab alone. Two patients were treated with pem-
Board, cases were collected based on a consecutive list of pa- brolizumab alone, 1 patient was treated with the anti–PD-L1
tients from Yale–New Haven Hospital who were sent to the Yale agent atezolizumab alone, and 1 patient received atezoli-
Oncodermatology Clinic for a dermatology consultation. Data zumab in combination with carboplatin and paclitaxel. Twelve
for the cases were collected retrospectively, and informed con- patients (60%) had received prior systemic therapy for their
sent was waived due to the retrospective nature of the study. cancer, with 3 of 20 patients having received prior immune
Patients were included if they were receiving treatment with checkpoint inhibitors. One of these patients had already had
either an anti–PD-1 or anti–PD-L1 agent alone, or if they were a previous course of nivolumab and ipilimumab combination
receiving an anti–PD-1 or anti–PD-L1 agent in combination with therapy, while 2 patients had therapy with ipilimumab. Table 1
other therapy, and if they were referred for dermatologic evalu- summarizes the characteristics of the included patients.
ation of rash. Data for patients evaluated between 2010 and The time of onset to cutaneous eruption was variable, with
2015 were collected, and included demographic characteris- a mean (range) time of 4 months (3 days to 12.8 months). The
tics, concurrent medications, therapeutic regimen, type of dis- majority of cases (16 [80%]) had a clinical morphology con-
ease, previous oncologic therapies, clinical morphology and sisting of erythematous papules with scale, in either a focal dis-
distribution of cutaneous lesions, treatment of rash, periph- tribution such as localized lesions on an extremity, neck, or
eral blood eosinophil count, and tumor response. Concurrent chest (11 [55%]) (patient number 4) (Figure 1A), or in a more
medications at the time of presentation were recorded. The pe- generalized distribution of coalescing larger plaques on the
ripheral blood eosinophil count was recorded at the time of bi- trunk and extremities (9 [45%]). Other clinical morphologies

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 1130
Table 1. Clinical and Histologic Profile of 20 Patients With Cutaneous Adverse Effects While Receiving Anti–Programmed Cell Death 1 and Anti–Programmed Cell Death Ligand 1 Treatment
Time
to Treatment
Cancer Oncologic Rash, Anatomic Held for Tumor PFS,
No./Sex Type Agent Prior Therapy mo Morphology Distribution Pruritus Rash Treatment of Rash Response mo Other irAE Histologic Pattern
1/M Lung Nivolumab None 12.8 Grover Trunk Yes No Triamcinolone CR 33.7a None Lichenoid, spongiotic
disease
2/F Lung Nivolumab Carboplatin + gemcitabine, 1.8 Papular Extremities Yes No Clobetasol PR 38.0 None Lichenoid (CD3+, CD4+, CD8+,
pemetrexed CD20−)
Research Original Investigation

3/M Lung Nivolumab Carboplatin 1.2 Papulopustular Trunk No No Clobetasol, PD 1.7 None Lichenoid, spongiotic
+ pemetrexed minocycline
4/F Lung Nivolumab None 4.6 Papular Trunk, extremities Yes No Topical steroidsb PR 8.9 Autoimmune NA
diabetes
b
5/M RCC Nivolumab HD IL-2, bevacizumab 2.0 Papular Generalized No No Topical steroids PR 9.5 None Lichenoid (CD3+, CD4+, CD8+,
CD20−)

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6/F RCC Nivolumab None 1.6 Papular, Palms, soles, mouth Yes Yes Clobetasol, PUVA SD 10.4 Hypothy- Lichenoid
palmoplantar roidism, colitis
b
7/M MM Nivolumab HD IL-2 13.0 Papular Chest (shawl-like) No No None PR 75.0 None Lichenoid, spongiotic
8/M Lung Nivolumab Carboplatin 0.8 Papular Lower back, left Yes No Triamcinolone CR 32.3 Possible Lichenoid, spongiotic
+ gemcitabine upper arm pneumonitis
9/F Lung Nivolumab Vinorelbine and 10.2 Mucositis Mouth No Yes Clobetasol, PR 55.6b None Lichenoid, spongiotic (CD3+,
cisplatin + cetuximab, Valacyclovir CD4+, CD8+, CD20−)
cetuximab, gemcitabine,

JAMA Dermatology October 2016 Volume 152, Number 10 (Reprinted)

erlotinib, docetaxel +
retaspimycin hydrochloride
10/M MM Nivolumab None 0.5 Erosive lichen Penis, mouth Yes No Clobetasol SD 4.2b None Lichenoid
planus
c
11/M MM Pembrolizumab High-dose interferon, Papular Extremities, trunk Yes No Clobetasol PD 3.9 LFT elevation NA
ipilimumab
12/M MM Pembrolizumab Ipilimumab 2.1 Hypertrophic Lower extremities Yes Yes Clobetasol, PR 3.5b LFT elevation Lichenoid
plaques Prednisone
13/M MM Nivolumab None 0.1 Papular Generalized Yes No Topical steroidsb PR 39.5b None Lichenoid
+ ipilimumab (3 d)
14/M MM Nivolumab Interferon, previous course 2.8 Papular, Extremities, trunk Yes No Triamcinolone PD 2.8 None Lichenoid, spongiotic
+ ipilimumab of nivolumab annular,
+ ipilimumab inflammation
of seborrheic
keratoses

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15/M Lung Nivolumab None 2.5, Papular, Left forearm, Yes No Triamcinolone PR 10.5b None Lichenoid, spongiotic
+ ipilimumab 6.0 lichenoid left upper thigh
keratosis
16/M Lung Nivolumab None 4.5 Papular Back, extensor arms, Yes No Triamcinolone PR 10.7 Adrenal NA
+ ipilimumab upper chest insufficiency,
acute
interstitial
nephritis
17/F Lung Nivolumab Carboplatin 1.5 Papular Face, neck, left arm No No Triamcinolone PD 2.0 None Lichenoid, spongiotic
+ bevacizumab + pemetrexed
+ bevacizumab

(continued)

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Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs
 Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs Original Investigation Research

were variable, ranging from keratotic plaques resembling hy-

This patient had 2 acute cutaneous eruptions that appeared to be temporally related to erlotinib administration.
pertrophic lichen planus (patient 12) (Figure 1B) to discrete pap-

Vacuolar interface dermatitis

ules on the trunk that looked typical of Grover disease, or tran-
sient acantholytic dermatosis (patient number 1). Of note, 2
Table 1. Clinical and Histologic Profile of 20 Patients With Cutaneous Adverse Effects While Receiving Anti–Programmed Cell Death 1 and Anti–Programmed Cell Death Ligand 1 Treatment (continued)

patients (numbers 6 and 19) (Figure 1D and E) had papules

Histologic Pattern
and plaques limited to a striking palmoplantar distribution with

Exacerbation within 5 d of an existing rash patient had developed while taking ipilimumab.
additional oral mucosal lesions. Four patients (numbers 6, 9,

Lichenoid

Lichenoid
10, 19) developed oral lesions that varied in appearance in-
volving the tongue, buccal mucosa, lips, and/or gingivae. One
patient (number 6) developed 1- to 2-mm whitish flat-topped
low thyrotropin
LFT elevation,

papules with apparent Wickham striae on the bilateral buccal

Other irAE

mucosae extending onto the lateral commissures, whereas the

None

None

other patients developed erosions resembling oral lichen pla-

nus. Other unique presentations included inflammation of ex-
isting seborrheic keratoses (patient 14) (Figure 1C) and ero-
b
35.9

16.7

6.6
Tumor PFS,
Response mo

sive lesions on the penis, clinically resembling erosive genital

lichen planus (patient 10) (Figure 1F).
Specific strength of topical steroids unknown.

Most patients (15 [75%]) were noted to experience pruritus

PR

PR

PR

with the lesions. The most common treatment was topical cor-
Treatment of Rash

ticosteroids.Onepatient(number18)whodeveloped2acuteerup-
tions that appeared temporally related to erlotinib administra-
Clobetasol,
Prednisone

Clobetasol

tion required oral prednisone treatment. The 2 patients who

NBUVB

developed palmoplantar lesions (numbers 6 and 19) were treated

with phototherapy, 1 with psoralen and UV-A, and the other with
Treatment

narrow-band UV-B, with improvement. Five patients (25%) re-

Held for
Rash

quired dose delay of the oncologic agent due to cutaneous adverse

Yes

Yes
No

effects. Eosinophil counts were substantially elevated in only 4

Pruritus

patients (20%) at the time of cutaneous eruptions. The majority

Yes

Yes

Yes

of patients (16 [80%]) were taking concurrent medications that

b

d
c

have been previously reported to cause lichenoid drug eruptions.

Abbreviations: CR, complete response; HD IL-2, high dose interleukin 2; irAE, immune-related adverse effect; LFT,
Palms, arms, mouth

Table 2 lists the concurrent medications at the time of presenta-

Extremities, trunk

progression of disease; PFS, progression-free survival; PR, partial response; PUVA, psoralen and UV-A therapy;

tion and the absolute eosinophil counts in patients at time of bi-

liver function test; MM, metastatic melanoma; NA, not applicable; NBUVB, narrow-band UV-B therapy; PD,
Distribution

Generalized

opsy or at time of presentation of cutaneous eruption if biopsy

Anatomic

was not performed.

Tumor response, time to progression, and development of
any other irAEs were also assessed (Table 1). Of 6 patients with
Morphology

melanoma, 3 had a partial response, 1 had stable disease, and

Papular,
Papular

Papular
palmar

2 had progression of disease. Of 11 patients with NSCLC, 2 pa-

tients had complete response, 7 had a partial response, and 2 had
progression of disease. Of 3 patients with renal cell carcinoma,
Rash,
Time

2.3d
1.9,

8.3

3.1
mo

2 patients had a partial response, and 1 patient had stable dis-

to

ease. The mean progression-free survival (PFS) was 20.1 months,

with a wide range between 1.7 and 75.0 months. This large range
was due to prolonged PFS (mean, 26.9 [range, 3.5-75.0] months)
in those patients who experienced tumor response, compared
Prior Therapy

with a much shorter PFS (4.2 [range, 1.7-10.4] months) in patients

who had either stable disease or progression.
Sunitinib
Erlotinib

Response ongoing at time of data collection.

RCC, renal cell carcinoma; SD, stable disease.

Histologic analysis was available from 17 of the 20 pa-

None

tients. Nearly all cases (16 of 17 [94%]) showed features of li-

chenoid interface dermatitis (Figure 2A-C). In addition, many
erlotinib, then

Atezolizumab

Atezolizumab
Nivolumab +

+ paclitaxel

carboplatin

of the cases also showed features of spongiotic dermatitis (8

nivolumab
Oncologic

of 17 [47%]). One case, the patient (number 18) who de-

Agent

alone

and

veloped an acute eruption in temporal association with erlo-

tinib administration, showed evidence of vacuolar interface
Cancer

Lung

Lung
No./Sex Type

changes. Of the 3 biopsies for which ancillary immunostain-

RCC

ing was performed, all showed intradermal and intraepithe-

20/M

lial lymphocytes that were CD3 positive (Figure 2D). Intrader-

18/F

19/F

mal lymphocytes were CD4 positive, while intraepithelial

a

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 Research Original Investigation Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs

Figure 1. Cutaneous Eruptions Consisting of Erythematous Papules With Scale Due to Anti–Programmed Cell Death 1 and Anti–Programmed Cell
Death Ligand 1 Therapy

A Scaly papules on the chest B Hypertrophic scaly papules and plaques C Inflammation around seborrheic keratoses
on the leg and scaly papules on the back

D Pseudovesiculated papules on the palm E Papules and plaques on the palm F Erosions on the penis

A, Small number of discrete scaly papules on the chest (patient number 4). D, Coalescent pseudovesiculated papules on the palm (patient number 6).
B, Hypertrophic scaly papules and plaques on the lower extremity (patient E, Scaly, discrete papules and plaques on the palm (patient number 19).
number 12). C, Inflammation of and around existing seborrheic keratoses, in F, Numerous erosions on the penis, resembling erosive lichen planus (patient
addition to new-onset scaly papules, on the back (patient number 14). number 10).

lymphocytes were CD8 positive; CD20 stains had negative re- tibody therapy, including pruritus (25%) and rash (16%).12 These
sults (Figure 2E-G). Table 1 summarizes the histopathological adverse effects are usually manageable and do not generally re-
features of each skin biopsy. quire discontinuation of therapy.
Whereas “rash” has been commonly reported as an adverse
effect in many oncologic trials evaluating treatment with anti–
PD-1/PD-L1 antibodies, further details about the specific nature
Discussion of these cutaneous eruptions are often not completely described.
Cutaneous adverse effects associated with treatment with anti– Our study aimed to characterize both the clinical and histologi-
PD-1 antibodies most commonly include rash (4%-27% of pa- cal features of cutaneous adverse effects associated with anti–
tients), pruritus (2%-23%), and less frequently vitiligo (5%-11%),7-11 PD-1/PD-L1 therapy. Clinically, the eruption seen with use of these
with comparable incidences seen with pembrolizumab and niv- agents consisted of erythematous scaly papules or plaques that
olumab use. Similar adverse effects are seen with anti–PD-L1 an- were usually pruritic. The distribution of lesions varied, with

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 Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs Original Investigation Research

Table 2. Concurrent Medications and Peripheral Eosinophil Counts

Concurrent Medications
Not Reported to Cause Lichenoid Reported to Cause Lichenoid Serum Eosinophils
Patient No. Drug Eruptions Drug Eruptions5,6(p616) (Absolute Count, Cells/μL)
1 Brimonidine, cholecalciferol, Clopidogrel, metformin, 1050a
coenzyme Q10, iron, metoprolol, simvastatin,
loperamide, tetrahydrozoline, aspirin
nitroglycerin
2 Coumadin, amiodarone Aspirin, metformin 104
3 Rosuvastatin, zolpidem … 504a
4 Insulin … 0
5 Chlorthalidine Lorazepam, amlodipine, 212
atenolol
6 Montelukast, diphenhydramine Tiotropium, metoprolol, 252
hydrochlorothiazide
7 Levothyroxine, tamsulosin Hydrochlorothiazide 747a
8 Ipratropium-albuterol, Tiotropium, alprazolam, 138
oxycontin, oxycodone- aspirin
acetaminophen,
fluticasone/salmeterol,
rosuvastatin, fenofibrate
9 … Ibuprofen 84
10 Prochlorperazine, sertraline, Omeprazole, allopurinol, 72
mirtazapine atorvastatin, naproxen
11 Nitroglycerin Aspirin, atorvastatin, glipizide, 930a
lisinopril, metformin,
metoprolol
12 Celecoxib, levetiracetam, … 135
phenobarbital, vitamin B12
13 Vitamin D … 310
14 Zolpidem Aspirin, ibuprofen, omeprazole 126
15 Cholecalciferol, rivaroxaban, Atorvastatin, colchicine 304
famotidine, moxifloxacin
16 Albuterol, famotidine, Aspirin, lorazepam, 150
hydrocortisone, hydroxyzine, omeprazole
zolpidem, levetiracetam
17 Mirtazapine, morphine Lorazepam 66
18 Eszopiclone Sertraline 208
19 Levothyroxine, bupropion Omeprazole, sertraline 159
SI conversion factor: To convert
20 Acetaminophen, bupropion, Atorvastatin, metoprolol, 0
eosinophils to billions per liter,
tadalafil, digoxin, omeprazole, tiotropium
fluticasone-salmeterol, multiply by 0.001.
morphine, ondansetron, a
Peripheral eosinophilia, defined as
prochlorperazine, rivaroxaban greater than 500 cells/μL.

either a small number of discrete papules or plaques on a limited matitis on histologic analysis in 3 patients receiving pembroli-
area of the body or a generalized distribution of larger plaques zumab as treatment for melanoma.14 Clinically, the patients pre-
with a predilection for the trunk. There was also a wide range in sented with papular lesions as well, primarily on the trunk and
time to cutaneous presentation after initiation of anti–PD-1/PD- extremities, between 4 and 9 weeks after starting treatment with
L1 therapy, from 3 days to 13 months. For those patients with de- pembrolizumab. Two of these patients had previously received
layed eruptions up to 1 year into therapy, no other identifiable immunotherapy with ipilimumab. All 3 cases showed a CD3-
triggers were noted. In a recent publication, cutaneous adverse positive lymphocytic infiltrate, with a more prominent CD4 com-
effects with onset up to 60 weeks after treatment initiation with ponent than CD8; 10% of the T cells expressed PD-1. Tumor re-
anti–PD-1 therapy have been described.13 sponse was noted in 2 of the 3 patients, and consisted of 1 partial
Although the clinical morphology varied, a striking finding and 1 complete response. All 3 patients had relatively mild adverse
wasthatthehistologicfeatureswereremarkablyconsistentamong effects, and oncologic treatment was not discontinued. In another
the patients. Nearly all of the cases for which biopsies were per- recent case series of 5 patients treated with anti–PD-1/PD-L1
formed in our study (16 [94%]) showed lichenoid interface agents, histologic examination revealed lichenoid dermatitis with
changes. Three biopsies for which immunohistochemical stain- greater histiocytic infiltrates, increased spongiosis, and increased
ing was available showed that the lichenoid infiltrate was com- epidermal necrosis, compared with biopsies of non–drug-related
posed of predominantly CD4-positive T cells within the dermis, lichen planus and lichen planus–like keratoses.15 Our results are
with a few CD8-positive intraepithelial lymphocytes. In addition, consistent with these, showing a cutaneous lichenoid eruption
many showed concurrent features of spongiotic dermatitis, an that is unique to anti–PD-1/PD-L1 therapy.
atypical finding when lichenoid interface changes are appreciated. Another noteworthy finding was that most cutaneous
A previous case series reported similar findings of lichenoid der- eruptions were mild and were managed adequately with

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 Research Original Investigation Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs

Figure 2. Photomicrographs Showing Lichenoid Interface Dermatitis

A H&E, ×4

B H&E, ×10 C H&E, ×20 D CD3-positive

E CD4-positive F CD8-positive G CD20-negative

A-C, Hematoxylin-eosin (H&E) staining, original magnification ×4, ×10, and ×20, respectively. Staining of lymphocytic infiltrate revealed the following
immunoprofile: D, CD3-positive (both intradermal and intraepithelial lymphocytes); E, CD4-positive (intradermal lymphocytes); F, CD8-positive (intraepithelial
lymphocytes); and G, CD20-negative.

topical corticosteroids. Only 1 patient (number 12) developed ous lesions. Most patients did not need to discontinue or
hypertrophic plaques on the extremities that did not substan- interrupt oncologic therapy, even when presenting with mu-
tially improve with administration of topical steroids or oral cosal lesions.
prednisone, and required complete discontinuation of anti– Several patients in this study were being treated with
PD-1 therapy due to the severity of his cutaneous lesions. Only anti–PD-1 or anti–PD-L1 therapy with other concurrent medi-
4 other patients required doses to be held, including 2 who de- cations. While ipilimumab also causes a cutaneous eruption
veloped oral lesions, but these patients were able to restart on- consisting of erythematous papules coalescing into thin
cologic treatment, with eventual resolution of their cutane- plaques, it is usually associated with a concurrent increase in

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 Lichenoid Mucocutaneous Eruptions With Anti–PD-1 and Anti–PD-L1 Drugs Original Investigation Research

peripheral blood eosinophil levels.16 Eosinophilia was not medications, and the fact that anti–PD-1/PD-L1 therapy was the
seen in the majority of patients in our series or in the 4 patients only new medication for these patients suggests that it may be
who specifically received ipilimumab. Furthermore, the the drug culprit. An alternative explanation may be that the ad-
lichenoid changes on histologic analysis of the patients in our ministration of an anti–PD-1 or PD-L1 therapeutic agent may have
series are distinct from the superficial, perivascular CD4- unmasked an immune response to a medication that was pre-
predominant infiltrate with eosinophils that has been previ- viously tolerated, resulting in these lichenoid eruptions. Inter-
ously described in ipilimumab-related eruptions. Lichenoid estingly, 1 patient (number 18) seemed to develop acute rashes
eruptions have not previously been reported with use of ipili- that were temporally related to erlotinib administration, even
mumab, bevacizumab, epidermal growth factor receptor though she had previously tolerated a course of erlotinib with-
inhibitors such as erlotinib, or traditional cytotoxic chemo- out such dermatologic adverse effects 2 years prior, possibly rep-
therapies such as carboplatin or paclitaxel. Thus, it seems resenting an activation of the immune system by anti–PD-1
likely that these lichenoid eruptions are associated with anti– therapy to mount a more exuberant inflammatory response.
PD-1 therapy. In addition, the clinical appearance and lichen- There is evidence that development of cutaneous adverse
oid changes on histologic analysis are consistently seen effects during anti–PD-1 therapy is associated with longer PFS,19
among both anti–PD-1 agents, nivolumab and pembroli- tumor response,20 and overall survival.21 In our group, 5 of 6
zumab, in addition to anti–PD-L1 agents, supporting the idea patients (83%) with NSCLC treated with anti–PD-1 or PD-L1
that this cutaneous reaction may be a direct, on-target effect monotherapy showed a response, compared with the typical
on the PD-1/PD-L1 pathway rather than a nonspecific hyper- response rates of 14% to 20% with nivolumab7,22 and 19%
sensitivity reaction. with pembrolizumab.23 Six of 20 patients (30%) developed
The mechanism through which anti–PD-1/PD-L1–induced other definitive irAEs that were associated with therapy. Four
drug eruptions occur remains to be elucidated. The PD-1 path- of these 6 patients showed a response to therapy, which may
way has been implicated to play an important role in the induc- suggest a possible association between irAE development
tion and/or maintenance of tolerance. Subsequent work has and clinical response. Given the small number of patients,
examined the mechanisms by which PD-1 and its ligands can con- definitive conclusions about the association of cutaneous
trol self-reactive T-cell responses.17 Perhaps the focal distribu- adverse effects with tumor response in this group cannot be
tion seen in some of our patients suggests an underlying “un- drawn, but further research into this area is intriguing.
masking” of an immune response to a preexisting antigen that
is localized to a specific site in the body. Only once there is block-
ade of the PD-1 pathway does the body now produce an inflam-
matory response to this antigen. These findings may have impli-
Conclusions
cations for the pathogenesis of lichen planus, a T-cell–mediated There appears to be a range of clinical presentations and distri-
disease that bears a clinical resemblance to the lesions seen in butions of the cutaneous adverse effects seen with anti–PD-1/PD-
our patients. Lichen planus can also affect the oral mucosa, and L1 agents, but the eruption is typically papular in morphology with
blockade of the PD-1/PD-L1 pathway significantly increases the associated scale. The lichenoid pattern on histologic analysis is
proliferation of peripheral blood T cells in oral lichen planus, sug- a remarkably consistent finding and appears to be a distinct fea-
gesting an inhibitory role of PD-1.18 Histologically, lichen planus ture compared with cutaneous reactions seen with other immu-
also shows a similar lichenoid interface dermatitis, with a dense, notherapies. Notably, the eruptions are usually relatively mild and
bandlike lymphohistiocytic infiltrate at the dermal-epidermal can be typically adequately managed with topical corticosteroids.
junction. Interestingly, the majority (16 of 20 [80%]) of patients Future investigation is needed to determine whether there is an
in this series were also receiving concurrent medications that association between cutaneous adverse effects or other irAEs and
have been reported in the literature to cause lichenoid drug re- tumor response. This series of patients adds further characteriza-
actions (Table 2). These patients had all previously tolerated these tion to the emerging toxicity profiles of anti–PD-1/PD-L1 therapies.

ARTICLE INFORMATION Administrative, technical, or material support: 3. Blank C, Kuball J, Voelkl S, et al. Blockade of
Accepted for Publication: May 22, 2016. Gettinger, Neckman, Girardi, Bosenberg, Choi. PD-L1 (B7-H1) augments human tumor-specific T
Study supervision: Leventhal, Bosenberg, Choi. cell responses in vitro. Int J Cancer. 2006;119(2):
Published Online: July 13, 2016.
Conflict of Interest Disclosures: Drs Gettinger and 317-327.
doi:10.1001/jamadermatol.2016.2226.
Choi have served as advisory board members for 4. Weide B, Di Giacomo AM, Fonsatti E, Zitvogel L.
Author Contributions: Drs Shi and Choi had full
Bristol-Meyers Squibb. No other disclosures are Immunologic correlates in the course of treatment
access to all of the data in the study and take
reported. with immunomodulating antibodies. Semin Oncol.
responsibility for the integrity of the data and the
accuracy of the data analysis. 2015;42(3):448-458.
REFERENCES
Study concept and design: Gettinger, Bosenberg, Choi. 5. Gorouhi F, Davari P, Fazel N. Cutaneous and
Acquisition, analysis, or interpretation of data: All 1. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of
mucosal lichen planus: a comprehensive review of
authors. the PD-1 immunoinhibitory receptor by a novel B7
clinical subtypes, risk factors, diagnosis, and
Drafting of the manuscript: Shi, Gettinger, family member leads to negative regulation of lym-
prognosis. Scientific World Journal. 2014;2014:
Neckman, Choi. phocyte activation. J Exp Med. 2000;192(7):1027-1034.
742826.
Critical revision of the manuscript for important 2. Brown JA, Dorfman DM, Ma FR, et al. Blockade
6. Litt JZ. Litt’s Drug Eruption Reference Manual. 14th
intellectual content: Shi, Rodic, Gettinger, of programmed death-1 ligands on dendritic cells
ed. London, England: Informa Healthcare; 2008.
Leventhal, Girardi, Bosenberg, Choi. enhances T cell activation and cytokine production.
Statistical analysis: Shi. J Immunol. 2003;170(3):1257-1266.

jamadermatology.com (Reprinted) JAMA Dermatology October 2016 Volume 152, Number 10 1135

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NOTABLE NOTES

Defining “Lichen”
From Greek Mycology to Modern Dermatology
Daniel Zaghi, MD, MS; John Randall Griffin, MD

The term lichen is frequently used in modern dermatology. Hip-

Figure. Lichen Lividus
pocrates (460-371 BC), who was among the first to use the term lichen,
described it as “an eruption of a papulae,” a definition still given in the
Merriam Webster dictionary.1 Near to the first century AD, the Roman phy-
sician, Aulus Cornelius Celsus, characterized lichen as a “papulae,” and
an eroding blistering eruption. The Roman naturalist and philosopher,
Gaius Plinius Secundus (AD 23-79), better known as Pliny the Elder, char-
acterized lichen as “synonymous with the impetigo of the Latins.”2 Ap-
proximately 100 years later, Galen of Pergamon (AD 129-217) was the first
to associate lichen with pruritus by describing lichen as “a roughness of
the skin, attended with much itching.”3
Over 1000 years later the English physician, Robert Willan (1757-1812),
who is widely regarded as the founder of modern dermatology, described Considered a likely precursor to lichen planus. Robert Willan. On Cutaneous
Diseases. London, England: J. Johnson; 1796.
lichen as Greek in origin and a “genera of papule.” Willan further character-
ized lichen as “an extensive eruption of papulae affecting adults, connected
with internal disorder; recurrent; non-contagious.” Interestingly, Willan also
enumerated 7 variants of lichen: lichen pilaris, lichen circumscriptus, lichen Hebra’s taxonomy of lichen ruber has not been completely forgotten; mod-
agrius, lichen lividus, lichen tropicus, lichen simplex, and lichen urticatus.3 ern descriptions of a “lichen ruber planus” as synonymous with lichen pla-
Lichenlividus,depictedinWilan’s1796publication“OnCutaneousDiseases” nus are still infrequently reported in the literature.3
(Figure), is a likely precursor to lichen planus.1
Author Affiliations: Division of Dermatology, Baylor University Medical Center,
Ferdinand Ritter von Hebra (1816-1880), who used the principles of pa- Dallas, Texas.
thology to classify lesions, provided our modern description of lichen.1 This
Corresponding Author: Daniel Zaghi, MD, MS, Division of Dermatology, Baylor
approach, along with a highly regarded lecture series starting in 1844, gar- University Medical Center, 3900 Junius St, Ste 145, Dallas, TX 75246
nered him the title, “Mr Dermatology.1 Hebra discounted Willan’s descrip- ([email protected]).
tion of lichen, instead favoring that of Hippocrates and Galen. Hebra also 1. Crissey JT, Parish LC, Holubar K. Historical Atlas of Dermatology and
described an eruption termed lichen ruber, which most closely resembles Dermatologists. Boca Raton, FL: Parthenon Pub Group; 2002.
our modern lichen planus. Hebra’s account of lichen ruber stood largely in- 2. Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25(4):593-619.
tact until English dermatologist Erasmus Wilson replaced the term with 3. Sepić J, Ristić S, Perković O, et al. A case of lichen ruber planus in a patient
lichen planus in 1869 to reflect the flat nature of the papules.2 However, with familial multiple sclerosis. J Int Med Res. 2010;38(5):1856-1860.

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