Radiation Recall Dermatitis Following Treatment With Pembrolizumab: A Case Report and Review of the Literature

Abstract

Radiation recall dermatitis is an inflammatory reaction of the skin that may infrequently occur in areas of the skin that have been previously treated with radiation therapy. This is thought to be due to a triggering agent administered after radiation therapy which leads to an acute inflammatory reaction, manifesting as a skin rash. We present the case of a 58-year-old male with recurrent invasive squamous cell carcinoma of the tongue, previously treated with chemotherapy and radiation therapy, who presented with progression of his disease. He was treated with pembrolizumab and subsequently developed a new-onset facial rash over the previously treated radiation field. The distribution of the rash was suggestive of radiation recall dermatitis. A biopsy showed dermal necrosis without evidence of dermatitis, vasculitis, or infectious process. This case highlights the incidence of a rare complication of immune checkpoint inhibitor therapy and emphasizes the need for careful monitoring for radiation recall dermatitis.

Introduction

Radiation recall dermatitis (RRD) is an inflammatory reaction of the skin that may infrequently occur in areas of the skin that have been previously treated with radiation therapy. This is thought to be due to a triggering agent administered after radiation therapy which leads to an acute inflammatory reaction, which may manifest as a skin rash. The rash may vary from mild erythema of the skin to more severe necrosis with desquamation. This phenomenon was initially found to be induced by actinomycin-D ¹ ; however, it has also been shown to occur with other chemotherapeutic agents. Taxanes and anthracyclines specifically have been shown to have a higher incidence of RRD. ² Herein, we describe a case of pembrolizumab-induced RRD.

Case Presentation

A 58-year-old male with a 45-pack year smoking history presented to the hospital with complaints of worsening dysphagia for the past 4 weeks. He also complained of difficulty speaking, pain in his tongue, decreased oral intake, and 40 lb weight loss. On presentation to the emergency room, the patient was hemodynamically stable and afebrile. Physical examination was significant for left-tongue firmness and tenderness to palpation over the left tongue. A fixed level 1B lymph node was identified. A computed tomography (CT) scan of the soft tissue of the neck showed an ill-defined hypodense lesion involving the anterior root of the tongue measuring 2.6 × 3.3 × 2.3 cm³.

The patient was evaluated by the ear, nose, and throat (ENT) service. A biopsy of the tongue mass was obtained which showed moderately differentiated invasive squamous cell carcinoma. A positron emission tomography (PET) scan revealed an anterior, left-sided tongue mass with a max standardized uptake value (SUV) of 21.2 with bilateral cervical lymphadenopathy suspected to be consistent with metastatic disease. A multidisciplinary meeting was had with ENT, medical oncology, and radiation oncology. The patient was recommended to undergo total glossectomy with mandible resection given involvement of the majority of the tongue and the gingiva. However, the patient wished to omit extensive surgery and proceed with definitive chemoradiation therapy. He underwent G-tube placement with dental extractions.

The patient received concurrent chemoradiotherapy, treating gross disease to 6996 cGy and bilateral neck (Levels 1b-IV and VII) to 6105 cGy in 33 fractions with radiosensitizing weekly Cisplatin. The patient completed 7 cycles of Cisplatin therapy. A repeat PET scan 3 months later demonstrated new pulmonary lesions. A biopsy of the pulmonary nodule showed moderately differentiated squamous cell carcinoma with similar morphologic features as the tongue biopsy sample. Programmed death ligand-1 (PDL-1) testing showed 80% positivity and the decision was made to start the patient on immunotherapy with pembrolizumab. Six days after starting immunotherapy, the patient presented to the hospital with a new-onset facial rash and associated pain (Figure 1-3). Examination revealed a bilateral rash over the cheeks with a thick layer of necrotic tissue and scabbing along with scabbed lesions of the nose (Image 1-2). There was also a flat erythematous rash over the neck and the upper chest which extended to where the radiation therapy mask and treatment field ended without any evidence of skin changes or rash along the rest of the body. A biopsy of the rash showed a small focus of epidermal and dermal necrosis with adjacent serous crust. There was no evidence of interface dermatitis, vasculitis, or infectious process that would account for the necrosis. The patient was suspected to have RRD, and he was treated with topical triamcinolone, oral prednisone, and doxycycline. A timeline of our patient’s clinical course from initial presentation to diagnosis is shown in Figure 4.

Image 1-2.

Bilateral necrotic facial rash with involvement of the neck and the clavicle with underlying erythema.

Figure 1.

Planning CT scan showing upper and lip in Axial view. The planning CT images show contouring which corresponds to different radiation dose levels.

Figure 3.

Dosimetry image showing dose distribution of radiation therapy at 1.2 cm depth (500-7000 cGy).

Figure 4.

Timeline of events from the patient’s initial presentation to the hospital to the development of the bilateral facial rash.

Discussion

We present a case of severe RRD characterized by erythema and necrosis of the skin that occurred 6 days after administration of pembrolizumab, and 3 months after completion of radiation therapy. The incidence of RRD has been documented mainly with the use of chemotherapeutic agents. ³ In fact, the incidence of radiation recall reactions triggered by chemotherapeutic drugs is 8.8%. ⁴ An observational study by Kodym et al ⁵ found the highest frequency of radiation recall reactions with taxanes and anthracyclines.

The pathophysiologic mechanism behind RRD is still poorly understood and multiple theories have been proposed to explain this phenomenon. It has been hypothesized that stem cells in the area of irradiation may have increased sensitivity to subsequent chemotherapy, leading to a cutaneous reaction. ⁶ Another theory suggests RRD is an idiosyncratic drug hypersensitivity reaction caused by radiation induced inflammatory cytokines. ³

Immune checkpoint inhibitors (ICIs) are known to cause inflammatory adverse reactions including myelitis, pneumonitis, and nephritis. RRD has been less commonly reported with the use of ICIs and the specific incidence has been difficult to determine due to the rarity of the disease. The clinical presentation ranges from a mild rash with erythema to a more severe desquamating rash with skin necrosis. Our patient presented with a severe localized erythematous rash over the irradiated area with areas of necrosis. A punch biopsy of the area showed dermal necrosis with adjacent serous crust. Stevens-Johnson’s syndrome has also been reported as a cutaneous reaction after treatment with radiation and Nivolumab. ⁷ Also with Nivolumab, Yigit et al ¹ reported a case of an erythematous plaque-like lesion that developed 4 weeks after initiation of Nivolumab and corresponded with the previously irradiated area. This rash was not observed on subsequent cycles and regressed after treatment with topical steroid therapy. ¹

Another case of RRD after pembrolizumab is reported by Wang et al ⁸ where the patient developed a confluent erythematous rash with superficial edema limited to the previously irradiated supraclavicular area 3 days after the start of immunotherapy. This was the first case of concomitant RRD along with lung involvement, characterized as radiation recall pneumonitis. The patient was treated with prednisolone over a 6-week course and had rapid resolution of his symptoms.

The treatment of RRD is based on the severity of symptoms. It remains difficult to predict which patients will develop RRD, and therefore patients receiving treatment with a triggering agent should be monitored closely for development of a rash. In mild disease, the disease may regress spontaneously, and patients may be managed with close observation. In cases of more severe RRD, with necrosis or desquamation of the skin, treatment includes a combination of topical and systemic steroids, ⁹ and potentially withdrawing the offending agent. Careful consideration should be had with regards to re-challenging a patient who has had a radiation recall reaction.

The use of immune therapy has become more widespread in the field of oncology. Pembrolizumab is becoming an increasingly used ICI. Radiation recall is a poorly understood inflammatory response that is unpredictable, however, can have devastating consequences. Our case highlights the incidence of a rarely seen phenomenon observed with the immune checkpoint inhibitor, pembrolizumab, and emphasizes the need for careful monitoring for radiation recall.