Scrotal erythema and cutaneous ulceration post lenvatinib therapy in a patient with renal cell cancer

Dear Editor,

Tyrosine kinase inhibitors, including those with antiangiogenic properties, are increasingly being used for treating many tumoral conditions. With their expanding use, the reported adverse effects are also increasing. Cutaneous toxicities are commonly reported and need attention to help mitigate these adverse effects without affecting chemotherapy regimens. We report a case of lenvatinib-induced scrotal erythema and cutaneous ulceration in a patient with renal cell cancer (RCC), which is infrequently reported, and review the existing literature on tyrosine kinase inhibitors induced scrotal erythema, a unique adverse effect of this class of drugs.

A 61-year-old man, known case of metastatic RCC, presented to us with multiple round-oval, painful ulcers with yellowish slough, perilesional erythema over the medial thigh, and scrotal erythema 6 weeks after starting lenvatinib (24 mg daily) [Figure 1a]. Other concomitant medications included paracetamol (650 mg) for pain and pantoprazole (40 mg) for 3 months. There was no history of any other medication intake prior to the onset. Based on the temporal association, a diagnosis of lenvatinib-induced ulceration was made. The diagnosis was based on clinical findings including temporality, characteristic distribution, and morphology which were consistent with previous literature. The rest of the cutaneous sites and mucosae were normal. Investigations revealed anaemia (haemoglobin- 9 g/dL) with elevated serum creatinine (1.72 mg/dl). The Common Terminology Criteria for Adverse Events (CTCAE) grading for ulcers was grade 2 based on the combined surface area of ulcers between 1-2 cm and partial thickness skin loss.¹ The patient was treated with prostaglandin ointment and emollients. Lenvatinib treatment was continued in view of grade 2 reaction and emergent need for chemotherapy, weighing the risk-benefit. The ulceration improved over 3-4 weeks with topical therapy [Figure 1b].

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Figure 1a:

Multiple round-oval ulcers with yellowish slough, perilesional erythema over the medial thigh, and scrotal erythema.

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Figure 1b:

The lesions healed with scarring after 3 weeks of topical therapy.

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Lenvatinib is a multiple tyrosine kinase inhibitor approved by the US Food and Drug Administration for hepatocellular carcinoma (HCC), RCC, thyroid cancer and endometrial cancer. The reported cutaneous toxicities include palmoplantar erythrodysesthesia, stomatitis, cutaneous ulcerations, and psoriasiform eruptions.² These cutaneous toxicities are also observed with other tyrosine kinase inhibitors and are referred to as “class effect”. Cutaneous ulcers with lenvatinib occur most commonly over the proximal lower extremities and the perineum after a median latency of 7 weeks.³ Previously reported cases included patients with HCC and thyroid cancer treated with lenvatinib. The ulcers involved the perineum and inner thighs in all except one patient, where the subclavicular area was involved.³ The mechanism proposed is an anti-angiogenic effect due to inhibition of platelet-derived growth factor (PDGF), leading to impaired healing.³ Treatment includes prostaglandin ointments and cessation of the drug, depending on the risk-benefit analysis.

The first reported case also had scrotal erythema, which is an infrequent side effect (incidence - 1.83%) reported with multiple tyrosine kinase inhibitors like sorafenib, sunitinib, cabozanitinib, and pazopanib.⁴ However, to the best of our knowledge, scrotal erythema has not been reported with lenvatinib. Scrotal erythema presents as well-defined erythematous pruritic plaques over the scrotum. It usually occurs after 5 weeks of treatment, affecting friction-prone areas like the inguinal folds and scrotum. The mechanism has been postulated due to increased circulating and tissue levels of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 alpha, leading to increased vascular permeability and neovascularisation.⁵ Diagnosis is clinical and treatment includes barrier creams and ointments. Prostaglandin creams (PGE1) have been used previously in a case of lenvatinib ulceration; the mechanism is thought to be due to its established vasodilatory and cytoprotective properties, which enhance local blood flow and promote tissue repair.⁶ They have also been used in chronic burn wounds and ischemic ulcers of limbs.⁷ To conclude, scrotal erythema and cutaneous ulceration with lenvatinib is an infrequent adverse effect that needs early recognition to avoid unnecessary workup.