Immune checkpoint inhibitors have transformed cancer care across many solid malignancies. However, these immunotherapies also cause unpredictable immune-related adverse events. While tyrosine kinase inhibitors typically cause palmoplantar toxicities, clinicians now encounter hand-foot skin reaction during pembrolizumab therapy. Early recognition ensures prompt treatment and preserves patient quality of life.

Understanding Hand-Foot Skin Reaction Versus Classical Hand-Foot Syndrome

Dermatologists and oncologists must distinguish two distinct cutaneous patterns affecting the hands and feet during systemic cancer therapy. Traditionally, cytotoxic agents such as capecitabine, infusional 5-fluorouracil, and pegylated liposomal doxorubicin cause classic hand-foot syndrome, termed palmar-plantar erythrodysesthesia. This classical condition manifests as diffuse, symmetric erythema accompanied by prominent edema and tingling paresthesias across the entire palmoplantar surface.

In contrast, hand-foot skin reaction displays distinctive clinical and anatomical hallmarks. Tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors typically trigger this reaction. Specifically, lesions concentrate over areas subjected to repeated mechanical pressure and frictional stress. Patients present with localized, tender, well-demarcated erythematous plaques topped by thick hyperkeratosis. Over time, these calluses can blister, erode, or form deep painful fissures. Histologically, while chemotherapy-induced toxicities demonstrate diffuse epidermal necrosis, this reaction shows pronounced hyperkeratosis, focal parakeratosis, and superficial keratinocyte degeneration.

Case Breakdown: Pembrolizumab-Induced Grade 3 Toxicity

A recent case report details a 79-year-old man with advanced lung adenocarcinoma receiving pembrolizumab monotherapy. Although checkpoint inhibitors rarely trigger localized hyperkeratotic palmoplantar lesions, this patient developed severe grade 3 toxicity during treatment.

Initially, the patient experienced localized erythema, coarse desquamation, and painful hyperkeratotic plaques across weight-bearing zones of his palms and soles. Subsequently, the cutaneous lesions progressed into painful vesiculobullous eruptions that severely restricted walking and daily activities. Because mechanical friction directly amplifies these skin changes, lesions clustered along heel borders and metatarsal heads. To confirm the diagnosis, physicians performed skin biopsies. Histopathology revealed prominent epidermal hyperkeratosis, subepidermal inflammatory infiltrates, and basal keratinocyte vacuolization. These microscopic findings verified drug-induced dermatologic injury rather than infectious dermatoses. Consequently, treating oncologists discontinued pembrolizumab infusions immediately to protect the patient from debilitating complications.

Immunopathogenesis of Checkpoint Inhibitor Cutaneous Toxicities

Understanding the immunological mechanism helps clinicians anticipate and manage checkpoint-mediated skin eruptions. Pembrolizumab binds the PD-1 receptor on T lymphocytes, thereby blocking inhibitory pathways and boosting antitumor immune surveillance. Unfortunately, this disinhibition simultaneously unleashes autoreactive cytotoxic T cells against self-antigens located in healthy cutaneous tissue.

Furthermore, mechanical shear stress continuously injures capillary networks in palmoplantar skin. In normal physiology, rapid cellular renewal repairs minor subclinical friction injuries. However, when PD-1 blockade impairs immune tolerance, pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 flood the traumatized dermal-epidermal junction. Consequently, keratinocytes undergo abnormal differentiation and focal apoptosis, triggering hyperkeratosis and blistering. Moreover, epidermal growth factor signaling pathways interact with these cytotoxic pathways, accelerating palmoplantar desquamation. Therefore, the combination of repetitive mechanical microtrauma and exuberant immune activation produces the severe localized clinical picture.

Diagnostic Assessment and Severity Grading for Oncology Teams

Oncologists must perform regular, systematic physical examinations of palmoplantar surfaces during every treatment cycle. Specifically, clinicians utilize the Common Terminology Criteria for Adverse Events to assess functional severity and guide therapeutic interventions.

Grade 1 toxicity involves minimal erythema, light hyperkeratosis, or painless peeling that does not interfere with daily activities. Therefore, patients require only preventive measures and topical symptomatic care without interrupting cancer therapy. In grade 2 toxicity, painful hyperkeratotic lesions limit instrumental activities of daily living, such as cooking, writing, or driving. Thus, temporary treatment delays may become necessary alongside escalated topical regimens. Grade 3 toxicity denotes severe, debilitating skin changes with extensive blisters, intractable pain, and profound compromise of self-care. At this stage, physicians must immediately withhold pembrolizumab. Additionally, clinicians should collect skin swabs to rule out secondary bacterial or viral superinfections before initiating high-potency immunosuppressive therapies.

Management Protocols: From Topical Keratolytics to Systemic Steroids

Successful resolution of severe immune-related dermatologic toxicities demands a structured multidisciplinary strategy involving oncologists and dermatologists. For the reported 79-year-old patient, clinicians implemented an intensive combined medical protocol.

First, physicians permanently discontinued the offending PD-1 inhibitor to prevent progressive tissue necrosis. Next, the care team prescribed systemic corticosteroids, starting with oral prednisone at 1 milligram per kilogram daily, tapered gradually over several weeks. Systemic corticosteroids rapidly dampen autoreactive lymphocyte infiltration within the upper dermis. Simultaneously, the patient applied high-potency topical corticosteroids twice daily to suppress localized superficial inflammation. In addition, the team introduced topical salicylic acid ointment as an effective keratolytic agent. Salicylic acid softens stubborn hyperkeratotic crusts and facilitates stratum corneum desquamation. Clinicians also advised protective footwear, soft cotton socks, and thick emollient creams. Remarkably, the patient achieved marked symptom relief within several weeks and experienced complete skin resolution after approximately two months.

Clinical Recommendations for Indian Oncologists and Dermatologists

The increasing adoption of immunotherapy across tertiary oncology centers in India requires increased vigilance for atypical toxicities. Because patients often travel significant distances between immunotherapy infusions, early patient education regarding hand and foot symptoms remains vital.

Furthermore, many Indian patients walk barefoot or wear thin-soled open sandals, which substantially increases palmoplantar mechanical friction and pressure. Consequently, oncologists should routinely instruct patients to wear well-cushioned footwear, apply generous urea-based emollients, and avoid heavy manual labor during treatment cycles. Moreover, doctors must establish streamlined referral pathways between medical oncology and dermatology departments. Prompt interdepartmental collaboration facilitates rapid punch biopsies, accurate grading, and timely immunosuppressive therapy. When healthcare teams address symptoms at grade 1, they frequently avoid permanent drug discontinuations. Ultimately, proactive toxicity management protects patient functional independence while preserving life-saving anticancer regimens.

Frequently Asked Questions

How does hand-foot skin reaction differ from cytotoxic hand-foot syndrome?

While both conditions affect palmoplantar skin, hand-foot skin reaction presents primarily with localized, painful hyperkeratosis and blisters over pressure points. In contrast, classical hand-foot syndrome presents with diffuse, symmetric erythema, tingling, and edema across entire palms and soles. Furthermore, cytotoxic chemotherapies typically cause the classical syndrome, whereas targeted kinase inhibitors and rare immunotherapy reactions cause the localized hyperkeratotic pattern.

What initial steps should clinicians take when grade 3 toxicity develops?

Clinicians must immediately withhold pembrolizumab or the offending checkpoint inhibitor when grade 3 toxicity appears. In addition, physicians should promptly prescribe systemic corticosteroids, typically oral prednisone at 1 milligram per kilogram daily. Concurrently, doctors ought to recommend high-potency topical corticosteroids and keratolytic agents like salicylic acid. Finally, clinicians must arrange a dermatologic consult for diagnostic biopsy and infection exclusion.

Can patients safely restart pembrolizumab after severe skin lesions resolve?

Restarting pembrolizumab depends on the peak severity and initial therapeutic response. For manageable grade 2 toxicities, clinicians can carefully resume immunotherapy once symptoms diminish to grade 1 with low steroid doses. However, severe grade 3 skin toxicities involving blistering or ulceration often require permanent discontinuation. Therefore, oncologists and dermatologists must collaboratively evaluate risk versus benefit before considering rechallenge.

Disclaimer: This content is for informational and educational purposes only... Refer to the latest local and national guidelines for clinical practice.

References

1. Ambrogio F et al. Pembrolizumab-related hand and foot skin reaction. Dermatol Reports. 2026 Oct 05. doi: 10.4081/dr.2026.10184. PMID: 42831863.
2. Lacouture ME, Sibaud V, Gerber PA, et al. Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(2):157-170.
3. Sibaud V. Dermatologic toxicity of immune checkpoint inhibitors: Clinical presentation, pathogenesis, and management. Am J Clin Dermatol. 2018;19(3):345-361.