New Drug and Possible New Toxicity – Squamous Cell Carcinoma Following Imatinib in Patients with Gastrointestinal Stromal Tumors

Case Series

Case Report 1. The first patient case is of a 90-year-old woman who initially presented to the hospital after routine laboratory studies for anemia. Upper gastrointestinal endoscopy showed 4×5 cm mass with central cavitation. Endoscopic ultrasound (EUS) revealed a mass in the cardia which measured 32 mm in the long axis and 17 mm in luminal diameter. Computed tomography of the chest showed a large hiatal hernia with marked thickening of the distal esophagus. There was an 11 mm enlarged lymph node adjacent to the gastroesophageal junction below the diaphragm, which was suspicious for lymph node metastasis. Pathology reports of the lesion were positive for c-KIT and negative for S100, smooth muscle actin and desmin, compatible with GIST. No mitotic activity or tumor necrosis was identified in that limited biopsy sample. She was transfused with 1 unit of packed red blood cells and given 200 mg intravenous iron sucrose prior to discharge.

The patient had been administered 400 mg/day imatinib mesylate (Gleevec®, Novartis) for her GIST for 2 years. While her GIST was well-controlled, a small superficial mass emerged on her left anterior shoulder (Figure 1A). It rapidly developed into a 3-cm, ulcerated, reddish nodule with an erythematous halo within 1 month (Figure 1B). Excisional biopsy was performed and the specimen was sent for histopathologic analysis (Figure 1C). Histopathology showed dermal lobules of moderately atypical squamous cells with frequent mitoses and small focal areas of keratinization. There were areas with glandular differentiation and mucin deposition highlighted with Mucicarmine stain.

Computed tomography appeared grossly unchanged, with no metastatic disease, swollen lymph nodes or visceral involvements. Immunohistochemistry showed that tumor cells were strongly positive for p63 and cytokeratin 7. The clinical and histopathological findings led to the diagnosis of SCC with moderate to poor glandular differentiation. Additional resection with 2-cm margin from the postoperative scar was performed.

Following the initial excision of SCC in our patient, three more suspicious growths appeared on her arms and back. Her dermatological surgeon biopsied the lesions and histopathologic evaluation confirmed the diagnosis of SCC. Imatinib was stopped due to the accelerated growth of SCC in this patient. Uneventful excisions of all the SCC lesions were performed and the patient has been regularly followed-up for her GIST and SCC.

Case Report 2. The second case involves a 61-year-old woman, with past medical history remarkable for rheumatoid arthritis, who presented to our institution with a rash 2 cm from the anal verge. Upon further questioning, the patient reported that she had experienced leakage of a small amount of stool and also passing of a small amount of bright red blood in her stool over the past many months. On physical examination, a palpable mass was present just proximal to the anal verge. Imaging and a rectal EUS with fine-needle aspiration biopsies were obtained and pathology was consistent with rectal GIST.

The patient underwent neoadjuvant treatment with 400 mg/day imatinib (Gleevec®, Novartis), followed by a successful rectal resection of the tumor. After 1 year, the patient underwent a follow-up examination and post-surgical imaging was ordered. This showed possible residual disease. Therefore, it was decided to restart imatinib postoperatively on a dose of 400 mg daily.

On 4 months of imatinib therapy, the patient developed mouth sores, worsening fatigue and appetite, as well as facial swelling, thought to be due to imatinib. The medication was reduced to 200 mg daily due to these side-effects.

On 9 months of imatinib therapy, the patient developed ill-marginated, erythematous, rough papule following imatinib on both of her legs (calves) (Figure 2). Skin biopsy of one of the lesions showed aggregates of pleomorphic keratinocytes with nuclear atypia, hyperkeratosis and dyskeratosis in the epidermis. These lesions were consistent with actinic keratosis, which is widely accepted as a precursor to SCC formation.

On 1 year of imatinib treatment, the cutaneous lesion in our patient had progressed to SCC. Imatinib was discontinued immediately and the SCC was managed successfully with surgical resection. However, unfortunately, we were unable to collect the complete data regarding SCC of this patient.