Introduction
Serpentine supravenous hyperpigmentation (SSH) is the term used by Hrushesky to describe a benign exaggeration of skin pigmentation along the venous network used for intravenous infusion of 5-fluorouracil [ 1 ]. Subsequently, this phenomenon has been observed in patients treated with other chemotherapeutic agents. Melphalan is an alkylating agent used to treat multiple myeloma, malignant lymphoma and lymphoblastic and myeloblastic leukemia.
Our case illustrates a rare form of drug adverse reaction due to an unhabitual chemotherapeutic agent complicated by thrombosis.
Case report
A 54-year-old man, followed for kappa light-chain multiple myeloma, presented—one day after peripheral intravenous administration of melphalan as part of conditioning for autologous hematopoietic stem cell transplantation—with a cutaneous eruption of the right forearm consisting of linear serpentine hyperpigmented lesions following the underlying superficial venous network ( Fig. 1 ). The lesions were non-inflammatory, painless, non-itchy. There were no other associated findings and the patient’s general condition was stable.
Ten days later, the eruption was complicated by pain over the hyperpigmented areas. A venous Doppler ultrasound revealed thrombosis of the corresponding superficial venous network.
The patient was treated with oral anticoagulation and alcohol-based dressings, with a favorable outcome.
The clinical and pharmacological findings were consistent with the diagnosis of a complicated SSH.
Discussion
Anticancer chemotherapeutic agents can be responsible for skin pigmentation disorders through stimulation of melanogenesis or toxic mechanisms [ 2 ]. Pigmentation may also affect mucous membranes and skin appendages [ 3 ].
SSH describes increased skin pigmentation overlying the superficial venous network through which chemotherapy is administered. This morphological pattern has also been described as a supravenous hyperpigmented eruption.
The pathophysiology of SSH is not fully understood and is likely multifactorial. Several mechanisms have been proposed; intravenous chemotherapy can cause endothelial damage and drug leakage into the skin, leading to melanocyte injury and abnormal melanin deposition. These mechanisms, combined with oxidative stress, inflammation, and local vascular changes, contribute to chemotherapy-induced cutaneous hyperpigmentation.
Hypersensitivity mechanisms may also explain the occurrence of lesions at sites distant from the infusion area [ 4 ].
The clinical presentation is variable. In some patients, lesions initially appear as erythematous streaks located directly over the injected veins and subsequently evolve into linear hyperpigmented patches. In other cases, patients may present only with delayed pigmentary changes that develop weeks or months after treatment initiation, without a preceding inflammatory phase.
Locations of SSH were mostly in the forearm near the site of injection (85%), although two cases reported SSH on the trunk. Onset of a supravenous cutaneous drug reaction ranged from thirty minutes up to six months after the initial infusion. Duration of SSH ranged from a few days to greater than a year after the chemotherapy was stopped, often leaving residual hyperpigmentation.
SSH is most commonly associated with chemotherapy infusions. The agent most frequently reported in the literature is the antimetabolite 5-fluorouracil. However, a wide range of chemotherapeutic drugs have been implicated, including taxanes such as docetaxel, vinca alkaloids such as vinorelbine and vincristine, alkylating agents such as carboplatin and oxaliplatin, antitumor antibiotics such as actinomycin and bleomycin, anthracyclines such as epirubicin and proteasome inhibitors such as bortezomib [ 5 ].
Combinations of these agents have also been associated with SSH. In addition, rare cases have been reported with non-chemotherapeutic drugs, including multidrug regimens containing minocycline.
Over the past decades, topical 5-FU has gained widespread use in dermatology and oncodermatology, particularly for the management of actinic keratoses, field cancerization, Bowen disease, and selected superficial basal cell carcinomas.
Reported adverse effects of topical 5-FU include erythema, irritation, erosions, and ulceration at the application site [ 6 ]. Rare distant cutaneous reactions, such as painful scrotal dermatitis, have also been described [ 7 ]. Moreover, clinically significant systemic absorption may occur, particularly under occlusion or in the presence of a disrupted skin barrier, and severe systemic toxicities including neutropenia have been reported [ 8 ]. Despite these local, distant, and systemic adverse effects, no cases of serpentine supravenous hyperpigmentation have been reported following topical 5-FU administration, supporting the hypothesis that direct venous exposure may play a key role in its pathogenesis.
Although not life threatening, pigmentary changes in patients treated with targeted anticancer agents can negatively affect patients’ Health-Related Quality of Life (HRQoL) and impair psychosocial functioning and activities of daily living. Furthermore, they often result in dose reductions, interruptions, or even discontinuation of therapy, which may lead to suboptimal management of the cancer itself and result in poorer outcomes [ 9 ].
Management of SSH is primarily supportive, including symptomatic management with topical corticosteroids or vasodilators, venous washing with normal saline to reduce local toxicity and prevent SSH and switching from peripheral to central venous access when necessary.
If complications such as thrombophlebitis are suspected, Doppler ultrasound evaluation may be performed before starting an oral anticoagulation.
Importantly, chemotherapy can usually be continued, as SSH is not associated with severe systemic toxicity.
Physicians must learn to promptly recognise this rare side effect of this commonly used chemotherapeutic agent so that timely action is taken without much delay in treatment and without any dose modifications.
Further studies and case reports are needed to improve understanding of SSH. Future research should aim to better characterize the time of onset, duration of lesions, histopathological features, treatment approaches and outcomes, more implicated drugs and possible complications.
Acknowledgements
The authors express their gratitude to everyone who contributed to this work.
Contributor Information
Sofia Gueroum, Dermatology and venereology department, Ibn Rochd University Hospital Center, Hassan II University, 8 Rue Lahcen El Arjoun, Casablanca 20100, Morocco.
Bouchra Baghad, Dermatology and venereology department, Ibn Rochd University Hospital Center, Hassan II University, 8 Rue Lahcen El Arjoun, Casablanca 20100, Morocco.
Fatima Zahra Benhayoun, Dermatology and venereology department, Ibn Rochd University Hospital Center, Hassan II University, 8 Rue Lahcen El Arjoun, Casablanca 20100, Morocco.
Hanane Rachadi, Dermatology and venereology department, Ibn Rochd University Hospital Center, Hassan II University, 8 Rue Lahcen El Arjoun, Casablanca 20100, Morocco.
Soumiya Chiheb, Dermatology and venereology department, Ibn Rochd University Hospital Center, Hassan II University, 8 Rue Lahcen El Arjoun, Casablanca 20100, Morocco.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Funding
There were no sources of funding.
Ethical approval
No approval is required.
Consent
Patient consent was obtained.
Guarantor
Sofia Gueroum.
References
1. Hrushesky WJ. Serpentine supravenous fluorouracil hyperpigmentation. JAMA. 1976;236:138–1386. 10.1001/jama.1976.03270020012002
2. Lebrun-Vignes B, Valeyrie-Allanore L. Toxidermies. Rev Med Interne 2015;36:256–70. 10.1016/j.revmed.2014.10.004
3. Sibaud V, Fricain JC, Baran R. et al. Anomalies pigmentaires induites par les traitements anticancéreux. Première partie: les chimiothérapies. Ann Dermatol Venereol 2013;140:183–96. 10.1016/j.annder.2012.12.012
4. Narayan S, Goel V, Redhu P. et al. Serpentine supra-venous hyperpigmentation “badge of courage” in fight against cancer: a brief review. Gulf J Oncol 2022;1:83–7.
5. Dai J, Belum VR, Wu S. et al. Pigmentary changes in patients treated with targeted anticancer agents: a systematic review and meta-analysis. J Am Acad Dermatol 2017;77:902–910.e2. 10.1016/j.jaad.2017.06.044
6. Pujol RM, Rocamora V, Lopez-Pousa A. et al. Persistent supravenous erythematous eruption: a rare local complication of intravenous 5-fluorouracil therapy. J Am Acad Dermatol 1998;39:839–42. 10.1016/S0190-9622(98)70361-5
7. Yi JZ, Himes RS, Smith RJ. et al. Painful scrotal dermatitis secondary to topical 5-fluorouracil. Dermatol Online J 2021;27. 10.5070/D327654060
8. Cohen PR. Topical application of 5-fluorouracil 5 percent cream associated with severe neutropenia: discussion of a case and review of systemic reactions after topical treatment with 5-fluorouracil. Dermatol Online J 2018;24:13030/qt974797j7. 10.5070/D3244039360
9. Shan J, Obiakor BC, Cheng J. et al. Serpentine supravenous hyperpigmentation induced by chemotherapy: a systematic review. Arch Dermatol Res 2024;316:215. 10.1007/s00403-024-03057-2