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Immunotherapy in Squamous Cell Skin Carcinoma: A Game Changer?

(A) Left temporal cutaneous lesion prior to immunotherapy. (B) Left temporal cutaneous lesion after 7 cycles of immunotherapy.

(A) Left temporal cutaneous lesion prior to immunotherapy. (B) Left temporal cutaneous lesion after 7 cycles of immunotherapy.


A 74-year-old white male was diagnosed with squamous cell carcinoma in 2013. Six months after Mohs surgery, he underwent a left superficial parotidectomy, left neck dissection, and excision of the left postauricular lymph node after confirmation of lymphatic spread. Pathology from the left parietal scalp lesion revealed multifocal invasive squamous cell carcinoma. Extranodal tumor extension was noted in a postauricular lymph node and left parotid gland, and he was diagnosed with stage IV squamous cell carcinoma.

Despite receiving adjuvant radiation therapy from December 2013 to March 2014 to the right neck and scalp, a skin graft after 5 months was confirmed to have squamous cell carcinoma. Positron emission tomography-computed tomography showed metastatic disease at the level of cricoarytenoid cartilage and bilateral parotid glands. Cetuximab was discontinued, as he had an anaphylaxis episode after the first dose, and he later underwent localized radiation to his left temple.

He returned after a year with multiple cutaneous nodular masses over the left face and neck, with a large ulcerated necrotic area over the left temporal region (Figure). Due to the lack of further chemotherapy options, he was started on pembrolizumab.

Anti-programmed death ligand 1 testing from the tumor showed a staining distribution of 1%-24% and a staining intensity of 1+, with a low positive result. Next-generation sequencing assay showed genomic alterations in AKT3 E17K, ERBB2 S310F, FBXW7 R441W, NF2 R198, PDGFRA E289K, EP300 Q589, EPHB1 R364Q, LRP1B P1337S, MCL1 123K, RB1 W99, RUNX1T1 E238K, SMARCA4 R1189Q, S767F, TP53 P152S, splice site 560-1G>A, and S95F, with at least 5 potential therapies for these targetable mutations.


Squamous and basal cell skin cancer are the most common cancers in the US. The overall prognosis of cutaneous squamous cell carcinoma is excellent, except for patients with high-risk features like nodal metastasis. The recurrence rate of squamous cell carcinoma after primary treatment is around 3.7%, and definitive treatment guidelines do not exist due to the rarity of this condition.

Since the 2011 Food and Drug Administration approval of immunotherapy for melanoma, several studies are testing the clinical efficacy in other cancers. Pembrolizumab has been shown to be efficacious in patients with head and neck squamous cell lung cancer, with a reasonable side-effect profile despite poor performance status. Three recently published case reports reported the use of immunotherapy in metastatic or heavily pretreated patients.123

The next-generation sequencing assay of our patient’s tumor detected a high mutational burden with several targetable mutations and 1%-24% programmed death ligand 1 expression. Rizvi et al4 reported an association of durable clinical benefit, objective response, and progression-free survival to higher mutational burden in lung cancer. It is intriguing if the response seen in our patient could be attributed to the same hypothesis.

While our patient had near-complete response after 7 cycles of pembrolizumab therapy, the duration of immunotherapy and subsequent treatment strategy are uncertain. Furthermore, the clinical benefit of therapies targeted toward detectable mutations and the exact sequence of their use is unclear at this time.

There is definitely an unmet need for prospective clinical studies to further evaluate the therapeutic potential of immunotherapy in metastatic nonmelanoma skin cancer. The question remains whether the future of oncological therapies should not be based on histology but rather on the genetic make-up or mutational milieu of the cancer.

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-Sravanthi Ravulapati, MD, Cerena Leung, MD, Nishant Poddar, MD, Yifan Tu, MD, PhD

This article originally appeared in the May 2017 issue of The American Journal of Medicine.

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