Unresectable cutaneous squamous cell carcinomas (SCCs) can be difficult to treat: only about 30% of patients respond to any type of current treatment.1 Substantial progress has recently been made in the development of immunotherapy for the treatment of cancer. In particular, checkpoint blockade using antibodies that impede immune inhibitory pathways, such as programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1), represents a novel strategy.
We report herein a case of dramatic response of a biopsy-proven cutaneous SCC to an immunotherapeutic agent, pembrolizumab, a PD-1 inhibitor. Pembrolizumab is a first-in-class drug recently approved by the US Food and Drug Administration (FDA) for unresectable melanoma.2 Squamous cell carcinomas may be particularly amenable to immunotherapy because they are enriched in patients with immunosuppression.3 Preclinical studies have shown that transgenic mice overexpressing PD-L1 in keratinocytes show accelerated SCC formation.4 Hence, blockade of the PD-1/PD-L1 pathway may control SCCs.
A man in his 70s presented with 4-month history of a growing mass on the right temple accompanied by right temporal fossa pain and right ear discomfort. Biopsy of the lesion revealed a moderately to poorly differentiated epithelial proliferation with focal keratinization consistent with cutaneous SCC. Immunohistochemical stains confirmed the diagnosis, showing positive expression of CK5/6 and p63. A computed tomographic scan of the facial bones showed a 1.6 × 1.6-cm mass in the right temporal fossa.
The patient underwent a wide local resection and total parotidectomy with facial nerve sacrifice and right modified radical neck dissection. There was tumor involvement of the main trunk of facial nerve on pathologic analysis, but the surgical margins were negative. None of the 28 lymph nodes were positive for tumor. Due to the high-risk features of his cutaneous SCC, he received 6 months of treatment with cetuximab (250 mg/m2) and concurrent irradiation (60 Gy total). He experienced extensive cutaneous adverse effects during cetuximab treatment but remained without disease for 1 year.
At 1 year, magnetic resonance imaging (MRI) showed a new enhancing mass on the right supraorbital and infraorbital regions consistent with recurrence, which was thought to be either spread of disease along cranial nerve V1 or hematologic metastasis. He underwent right orbital exenteration, and pathological analysis confirmed recurrence of the cutaneous SCC. During the surgery, the tumor appeared to extend up the poststyloid area into the skull base, very close to basilar vascular structures, and was therefore deemed unresectable.
The patient was monitored with interval scans without evidence of disease progression until approximately 14 months after his prior surgery when an MRI showed extensive tumor involvement of the soft tissue to the right of the Meckel cave, cisternal segment of cranial nerve V, and dura of the right middle fossa (Figure 1). Immunohistochemical staining of a specimen from the patient’s cutaneous SCC lesions was strongly positive for PD-L1 (Figure 2), suggesting that blockade of the PD-1/PD-L1 pathway might be a therapeutic option.
A, Coronal MRI with contrast shows an abnormal enhancing soft tissue mass to the right of the Meckel cave measuring 1.4 × 1.8 cm (arrowhead). B, Axial MRI with contrast shows the same mass (arrowhead). There was enhancement within the cisternal segment of cranial nerve V, Meckel cave, and right middle fossa dura consistent with tumor involvement. C and D, After treatment with 3 cycles of a programmed cell death protein 1 (PD-1) inhibitor, the coronal (C) and axial (D) MRIs with contrast show reduction of soft tissue bulk consistent with treatment response (arrowheads). In addition, there was reduced enhancement within the right facial nerve at the genu and descending segment consistent with response to treatment. There was also reduced enhancement within the cisternal segment of cranial nerve V, Meckel cave, and right middle fossa dural-based thickening, which indicates markedly regressed tumor involvement.
A, Biopsy specimen of the patient’s unresectable cutaneous squamous cell carcinoma (SCC) prior to treatment with pembrolizumab. B, Immunostaining of another SCC biopsy specimen shows a strong signal on the tumor cells (original magnification ×200 for both images).
After considering several factors—adaptive immunotherapy in the form of PD-1 inhibitors had recently been approved by the FDA for metastatic melanoma and was now commercially available; early data in head and neck squamous cells showed potential efficacy5,6; and no good treatment options were available that would preserve quality of life—the patient decided to pursue an off-label trial of pembrolizumab (intravenous infusions, 2 mg/kg every 3 weeks). He tolerated the treatment with adverse effects of mild fatigue, chills, malaise, arthralgias, and weight loss. After 2 cycles, dramatic tumor response was observed (Figure 2). After 6 cycles, the patient was still progression free.
A recent retrospective study of patients with unresectable cutaneous SCC showed that only 30% responded to therapy of any kind, and overall survival of such patients was only 10.9 months.1,3 Hence, unresectable cutaneous SCCs represent an unmet medical need. This case highlights the potential for immunotherapy in the form of PD-1/PD-L1 inhibition to address this need, a finding that requires further investigation through clinical trials.
Corresponding Author: Anne Lynn S. Chang, MD, Department of Dermatology, Stanford University School of Medicine, 450 Broadway St, Pavilion C, Second Floor, MC 5334, Redwood City, CA 94063 (firstname.lastname@example.org).
Published Online: September 30, 2015. doi:10.1001/jamadermatol.2015.2705.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We are indebted to Gary Gold, MD, for assistance in retrieving and interpreting radiologic images. He received no compensation for his contributions.
Chang ALS, Kim J, Luciano R, Sullivan-Chang L, Colevas AD. A Case Report of Unresectable Cutaneous Squamous Cell Carcinoma Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor. JAMA Dermatol. 2016;152(1):106-108. doi:10.1001/jamadermatol.2015.2705