Vincristine-Induced Acrocyanosis and Erythema Pernio

Abstract

Introduction:

Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy.

Case Description:

A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient’s oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient’s symptoms and the appearance of his feet had markedly improved.

Discussion:

Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient’s history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Introduction

Acrocyanosis and erythema pernio are dermatologic manifestations of an underlying vasospastic disorder. Primary care clinicians evaluating a patient with a vasospastic disorder must consider whether the disorder is primary or secondary; a secondary vasospastic disorder can carry a poor prognosis and lead to loss of tissue. ¹ Acrocyanosis is a painless discoloration of the skin, and erythema pernio (also called chilblains) results from an inflammatory process that causes erythema and edema of the skin. Both conditions most commonly involve distal body parts such as the hands and feet. ² Medication-induced vasospastic syndromes, including those caused by antineoplastic agents, are documented in the medical literature. For example, the antineoplastic agent vincristine has been associated with Raynaud phenomenon.^3,4 This article presents a case of unilateral acrocyanosis of the right foot and pernio erythema of the toes on both feet after a patient completed therapy for Ewing sarcoma that included repeated administration of vincristine.

Case Description

A 22-year-old man was evaluated in the primary care clinic for discomfort and red lesions that had involved the toes of both feet for several weeks. The toe discomfort was a hypersensitivity, which was worst over the red lesions. He was not aware of any recent trauma or injury. He also reported that both feet felt cooler and that his right foot had a blue-purple discoloration for the past several months. He did not have associated numbness, weakness, or fever, and he could bear weight without pain.

His past medical history was notable for localized Ewing sarcoma of the right femur. He had completed therapy 1 month earlier with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide in accordance with the Children’s Oncology Group protocol AEWS1031 (ClinicalTrials.gov identifier: NCT01231906). ⁵ The primary tumor was located in the right femoral diaphysis. Local control for the primary tumor consisted of wide local excision and reconstruction with a vascularized fibular allograft harvested from the right fibula. The patient had internal fixation hardware at the site of tumor resection. Expected toxicities of the treatment included chemotherapy-induced myelosuppression, which had resolved. No unexpected or severe toxicities had been apparent during the therapy for Ewing sarcoma. The patient attended regularly scheduled follow-up appointments with the oncology team, but he did not discuss his current symptoms during those appointments.

On examination his right foot appeared dark blue and felt cool. Toes on both feet had multiple erythematous papules that were not painful on palpation (Figure 1). The dorsalis pedis pulse and the posterior tibial pulse were 2+ bilaterally. The patient had intact motor and sensory function in both lower extremities, and he did not have any gait disturbance.

Figure 1.

Photographs of patient’s feet. Left, Acrocyanosis and erythema pernio of the right foot. Right, Erythema pernio of the left foot.

The differential diagnosis included arterial occlusion, venous thrombosis, musculoskeletal injury, and a vasospastic process. The next day, to rule out an acute process, lower-extremity arterial and venous ultrasonography and the ankle-brachial index test with transcutaneous oximetry were performed, and the findings were normal. In addition, radiography of the right ankle and foot did not show abnormalities.

The case was discussed with the patient’s oncology team, and in light of the unremarkable results from the diagnostic testing, the conclusion was that the appropriate diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Over the preceding 10 months, the patient had received a cumulative vincristine dose of 36 mg; vincristine was identified as the most likely cause of the acrocyanosis and erythema pernio because of the drug’s adverse effect profile. ⁶ Supportive care recommendations included wearing warm socks and footwear, avoiding cold temperatures, and continuing to exercise to promote circulation to the feet.

The patient returned for follow-up 2 weeks later with marked improvement in symptoms and appearance after adhering to the recommended supportive care measures. The symptoms were expected to continue to improve over time with cessation of vincristine, and the patient was advised to continue regular follow-up with his oncology team.

Discussion

Patients often present to primary care clinicians for evaluation of dermatologic problems. Primary care clinicians must be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes of these manifestations, including pharmacologic agents.

The diagnosis of acrocyanosis and erythema pernio is made on clinical examination. Acrocyanosis is characterized by blue discoloration, usually affecting the entire hand or foot, that worsens with cold temperatures. ² Erythema pernio (also called chilblains), is characterized by localized erythema and swelling, usually of the digits. ² While these dermatologic changes can be benign or idiopathic, the possibility of a medication-induced or other secondary cause must be ruled out.

Acrocyanosis can be a sign of an underlying cancer diagnosis, especially in elderly patients, but it can also be a sign of vasculitis, infection (eg, chikungunya), hematologic disorder (eg, cold agglutinin disease), genetic disease, eating disorder, or vascular disorder.^2,7 These underlying causes are more likely if the acrocyanosis is unilateral, painful, or associated with tissue damage. ⁸ Erythema pernio can be a sign of systemic lupus or a particular syndrome if occurring in infancy (eg, Nakajo-Nishimura syndrome or Singleton Merten syndrome). Erythema pernio can result from poor peripheral circulation due to cold exposure or, as in the present case, medication. ²

Criteria that support a diagnosis of erythema pernio are findings of localized erythema and swelling of acral sites that worsen with cool environments and during winter months and then improve with rewarming and drying of the area (Table 1). In contrast, secondary erythema pernio, such as pernio lupus erythematosus, persists despite the environmental temperature and usually is associated with other general symptoms indicative of associated autoimmune connective tissue or malignant disease. If the diagnosis of erythema pernio is not clear, skin biopsy should be pursued to clarify the diagnosis, and if systemic disease is suspected, the following laboratory studies should be considered: complete blood cell count, peripheral blood smear, serum protein electrophoresis with immunofixation, cold agglutinins, and antinuclear antibody. ⁹

Table 1.

Clinical Features of Primary Erythema Pernio and Secondary Erythema Pernio.

Feature	Primary erythema pernio	Secondary erythema pernio
Redness and swelling	Localized to acral sites; lasts >24 h	Not localized; not involving only acral sites
Severity in relation to environmental conditions	Worse in cool environments and in winter	Independent of warm or cool environments and seasons
Skin biopsy findings	Dermal edema; superficial and deep perivascular lymphocytic infiltrate	Evidence of vasculitis, pernio lupus erythematosus, or other secondary disease
Response to conservative therapy a	Good	Poor
Systemic clinical signs and symptoms	Absent	Present

Source: Data from Cappel and Wetter. ⁹

a

Conservative therapy includes warming and drying of affected areas, use of topical corticosteroids, and use of topical calcium channel blockers.

The only pertinent history for the patient described above was Ewing sarcoma (recently in remission), which prompted consideration of medication-induced vasospastic changes. The patient’s right foot was affected more than the left. This was likely an exacerbation of the symptoms from recent major surgery on the right leg, including femoral resection and fibular harvest. Nonetheless, a vascular disorder was primarily considered because of the risk of irreversible tissue damage; imaging was performed to rule this out. The case was discussed with the oncology team because of concern for medication-induced changes, and the team concluded that the patient’s problems were most likely related to adverse effects of vincristine, a vital component of his therapy for Ewing sarcoma. With this information and normal imaging findings, supportive treatment was initiated, which resulted in marked improvement in both the acrocyanosis and the erythema pernio.

Vincristine is an antineoplastic agent that is commonly used to treat various cancers. As a mitotic inhibitor, vincristine interferes with axonal microtubule formation during mitosis, which results in a characteristic adverse effect profile that includes peripheral neuropathy and, rarely, manifestations of Raynaud phenomenon.^{3,4,6,10 -12} Peripheral neuropathy, with pain, abnormal sensation, and loss of motor function, is 1 of the most common, dose-limiting adverse effects of vincristine. Vasospastic effects are less common but have been reported. ¹³ The proposed mechanism of action for the vasospastic adverse effect is the promotion of distal artery and arteriole constriction. ³

Treatment should include protection against cold exposure. Warm socks should be worn at all times, and other protective clothing should be worn when outside. Medications (eg, nifedipine) can be used to improve circulation. ² As in the patient described above, symptoms should improve (they rarely worsen) with cessation of the offending medication. ³

Vincristine is metabolized by the cytochrome P450 isozymes 3A4 (CYP3A4) and 3A5 (CYP3A5), and variants can affect the pharmacokinetics of vincristine. Ongoing research is evaluating the use of pharmacogenomics to predict adverse drug reactions to antineoplastic agents such as vincristine, and several studies have identified genes that may increase the risk of adverse reactions, although no data are specifically for vincristine-induced vasospastic changes such as those in the patient described above.^12,14,15 At this time, pharmacogenomics are not routinely used to adjust vincristine dosing for patients with Ewing sarcoma, and more research is needed in this area to accurately assess the risks and benefits of doing so in the context of a life-threatening illness.

The following genes have been associated with vincristine-induced peripheral neuropathy: CEP72, FIG4, NDRG1, GARS, FGD4, SEPTIN9, and ETAA1. Genetic variants of MTNR1B, RAB7A, and SNU13 were associated with the pharmacokinetics of vincristine. ¹⁵ Although vincristine is metabolized by CYP3A4 and CYP3A5, only CYP3A4 variants (not CYP3A5 variants) were associated with vincristine-induced peripheral neuropathy. ¹² Pharmacogenomics tests for CYP3A4 are clinically available, but more research is needed before CYP3A4 testing is used routinely to determine the risk of vincristine adverse effects.

While vincristine is known to induce Raynaud phenomenon, our clinical case is 1 of the first documented reports of acrocyanosis and erythema pernio manifestations secondary to administration of this chemotherapeutic drug. A limitation of the case is that the patient had surgery on the severely affected leg, which may have led to a more robust presentation or confounded the clinical picture. In summary, primary care providers should consider the possibility of medication-induced, dermatologic vasospastic changes, especially if patients have recently been treated with vinca alkaloids, including vincristine and vinblastine.