Introduction
The programmed cell death-1 pathway is a key regulatory immune checkpoint that promotes
self-tolerance by suppressing Th1 lymphocytes. Pembrolizumab and nivolumab are anti–programmed
cell death-1 monoclonal antibodies that mediate antitumor responses by reversing tumor
suppression of T cells.
1
Heterogeneous dermatologic immune-related adverse effects have been reported in patients
receiving programmed cell death-1 inhibitors, including lichenoid, maculopapular,
and immunobullous reactions.
2
Toxicity of programmed cell death-1 inhibition is attributed to autoimmunity through
reversal of self-protective programmed cell death-1 inhibitory mechanisms. Cutaneous
immune adverse effects may be associated with improved prognosis.
3
Recently, eruptive skin neoplasms in sun-exposed areas have been associated with anti–programmed
cell death-1 therapy; however, the clinical significance remains unclear.
4
,
5
We report 2 patients receiving programmed cell death-1 inhibitor monotherapy who developed
eruptive cutaneous squamous cell carcinomas (SCCs).
Case report
A 77-year-old white man with Lynch syndrome underwent pembrolizumab immunotherapy
for simultaneous recurrent rectal and gastric adenocarcinomas. His dermatologic history
was significant for multiple actinic keratoses, 2 cutaneous SCCs, and a keratoacanthoma.
After the third cycle of pembrolizumab, he presented with multiple pruritic verrucous
papules with surrounding erythema on the forearms and lower extremities. Biopsy revealed
inflamed seborrheic keratoses with an underlying lichenoid infiltrate containing CD3+,
CD4+, and programmed cell death-1–positive lymphocytes. The patient was treated with
topical steroids and many of the lesions desquamated. After 5 months of pembrolizumab,
the patient developed 5 new keratotic lesions located on the bilateral aspect of the
forearms, dorsal aspect of the left hand, and scalp. Biopsies revealed cutaneous SCC
with programmed cell death-1–positive lymphocytic tumor infiltrates (Fig 1). These
tumors were excised by an unaffiliated dermatologist and the patient did not develop
additional cutaneous SCCs in a year of follow-up. A similar presentation occurred
in an 82-year-old woman receiving nivolumab every 3 weeks for metastatic melanoma.
This patient had no history of skin cancer other than the melanoma. After 1 month
of immunotherapy, she developed vitiligo on her forearms (Fig 2, A). After 8 months
of nivolumab, she suddenly developed 6 similar keratotic tumors on the bilateral aspect
of her lower extremities (Fig 2, B). Biopsies of 3 lesions revealed cutaneous SCCs. Histology
revealed tumor surrounded and infiltrated with programmed cell death-1–positive lymphocytes.
The patient continued receiving nivolumab, and cutaneous SCCs were treated with topical
clobetasol. Three of the cutaneous SCCs resolved after 2 months and the remaining
tumors appeared inflamed and decreased in size. Both patients' internal malignancies
demonstrated excellent responses to anti–programmed cell death-1 therapy.
Fig 1
Histology of eruptive squamous cell carcinoma. Shave biopsy of keratotic lesion on
arm in patient with Lynch syndrome, demonstrating (A) squamous cell carcinoma with
numerous horn pearls (eosinophilic parakeratotic keratinization) and (B) programmed
cell death-1–positive tumor-infiltrating lymphocytes surrounding and infiltrating
the tumor periphery. Similar histologic findings were observed in the second patient
with metastatic melanoma. (Hematoxylin-eosin stain; original magnification: ×10.)
Fig 2
Vitiligo and eruptive squamous cell carcinoma in an 82-year-old woman with metastatic
melanoma. A, Vitiligo on the upper extremity of patient 2 after 1 month of treatment
with nivolumab. B, Eruption of keratotic tumor on her lower extremity after 8 months
of immunotherapy.
Discussion
Programmed cell death ligand-1 is overexpressed in cutaneous SCCs, and programmed
cell death-1 inhibitors have demonstrated efficacy in patients with unresectable or
recurrent cutaneous SCCs.
6
Eruption of cutaneous SCCs in the setting of programmed cell death-1 inhibition is
therefore paradoxic. Two previous cases of programmed cell death-1 inhibitor–associated
eruptive cutaneous SCCs have been described. Lee et al
5
reported cutaneous SCCs on the dorsal aspect of the forearms and hands after 4 months
of nivolumab and ipilimumab therapy in a patient with metastatic melanoma. Histopathology
revealed a lymphocytic lichenoid infiltrate and the lesions were largely responsive
to topical corticosteroids. Immunotherapy was not resumed because metastatic lesions
remained stable or improved after the eruptive cutaneous lesions. Similarly, Haraszti
et al
4
reported 10 invasive cutaneous SCCs on the temple, upper extremities, and lower extremities
after 4 months of therapy with pembrolizumab and SD-101 injections peritumorally for
metastatic melanoma. No adverse cutaneous effects occurred when pembrolizumab therapy
was used alone. To our knowledge, we are the first to report cutaneous SCC eruptions
associated with programmed cell death-1 inhibitor monotherapy.
Eruptive keratoacanthomas have also been documented as rare cutaneous adverse events
of programmed cell death-1 inhibition. Similar to reported eruptive cutaneous SCCs,
keratoacanthomas occurred in photodamaged regions after 1 to 18 months of anti–programmed
cell death-1 therapy. Effective treatment modalities included intralesional and topical
corticosteroids, 5-fluorouracil, imiquimod, cryotherapy, and curettage.
5
,
7
,
8
In some cases, keratoacanthomas resolved without intervention within 6 to 8 weeks
despite continuation of programmed cell death-1 inhibitors.
7
Lichenoid infiltration patterns occurred in eruptive cutaneous SCCs and keratoacanthomas,
suggesting that immunoactivating anti–programmed cell death-1 antibodies may induce
inflammatory responses potentiating aberrant keratinocyte proliferation in predisposed
individuals. Tumor and tumor-infiltrating cells of both keratoacanthomas and cutaneous
SCCs exhibit similar programmed cell death ligand-1 expression profiles, with high
densities of cytotoxic T cells.
9
Therefore, eruptions of keratoacanthomas and cutaneous SCCs in the setting of programmed
cell death-1 inhibition may occur through shared immunomediated mechanisms, but additional
studies are needed to elucidate this phenomenon.
Although many documented eruptions of cutaneous SCCs or keratoacanthomas associated
with programmed cell death-1 inhibitors occurred in patients with metastatic melanoma,
to our knowledge we are the first to report this association in the context of Lynch
syndrome. Anti–programmed cell death-1 agents are efficacious in Lynch syndrome because
tumors with aberrant mismatch-repair function are more sensitive to programmed cell
death-1 blockade than mismatch-repair–proficient tumors.
10
Mismatch-repair–deficient tumors express programmed cell death-1 in the microenvironment,
presumably inducing programmed cell death-1–dependent immunoevasion to facilitate
tumor survival.
10
Genomic instability yields mutation-associated neoantigens in mismatch-repair deficiency,
and higher mutational loads have been correlated with potent anti–programmed cell
death-1 responses.
10
Additionally, deficient mismatch-repair tumors have dense infiltrates of CD8+ T cells,
enabling durable immunoresponses to anti–programmed cell death-1 therapy.
10
Because programmed cell death-1 inhibitors are efficacious through immunomodulation,
tumors with mismatch-repair deficiencies and high mutational burdens may predispose
individuals to immunorelated dermatologic toxicities associated with programmed cell
death-1 inhibitors, although further study is necessary to substantiate this association.
Additional immunorelated cutaneous effects have been reported in patients receiving
programmed cell death-1 inhibitors with various latency periods, indicating a role
for both acute and delayed immunoreactions.
2
Programmed cell death-1–associated immunorelated cutaneous lesions tend to occur in
combination, consistent with clinical courses observed in this report.
2
After programmed cell death-1 inhibitors were initiated, eruptive inflammatory seborrheic
keratoses with rapid resolution preceded the onset of cutaneous SCCs in the first
patient, and vitiligo developed before cutaneous SCC onset in the second patient.
These events may be attributed to autoimmunity through reversal of programmed cell
death-1 inhibitory mechanisms. Both patients' internal malignancies were particularly
responsive to anti–programmed cell death-1 therapy. Increased progression-free intervals
have been associated with immunorelated cutaneous adverse effects of programmed cell
death-1 inhibitors, including hypopigmentation and keratoses.
3
In summary, we report 2 cases of eruptive cutaneous SCCs as immunorelated dermatologic
events associated with programmed cell death-1 inhibitor monotherapy. The cutaneous
SCCs were preceded by skin reactions (to seborrheic keratoses in one patient and to
melanocytes in the other) several months before the SCCs. Additional studies analyzing
the relative contribution of epigenetics, immuno-microenvironments, and antigen-specific
immunoresponses may further elucidate the pathogenesis and clinical significance of
immunorelated dermatologic lesions in patients receiving programmed cell death-1 inhibitors.