Atypical Bilateral Hyperpigmented Macules on the Lower Legs Possibly due to Cyclophosphamide

Chemotherapeutic agents, such as rituximab, cyclophosphamide, hydroxydaunorubicin, and vincristine sulfate, induce various cutaneous adverse events. Indeed, alopecia, erythematous rash, etc., are common cutaneous adverse events due to chemotherapeutic agents, but hyperpigmentation is extremely rare [1]. Drug-induced hyperpigmentation accounts for 10–20% of all cases of acquired hyperpigmentation, and its pathogenesis is not fully understood, but several mechanisms have been proposed, including hypersecretion of melanocyte-stimulating hormone, post-inflammatory hyperpigmentation, and a direct toxic effect on melanocytes leading to increased melanin production [2]. In this report, we present a case of atypical bilateral hyperpigmented macules consisting of black dots in the follicles, suggesting the relationship between skin pigmentation and hair follicles on the lower legs, possibly due to direct stimulation of the hair follicles by cyclophosphamide.

A 65-year-old Japanese man visited an outpatient clinic with a 4-month history of symmetrical hyperpigmentation on the bilateral lower legs that developed 3 weeks after the initial administration of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisolone (R-CHOP) regimens for diffuse large B-cell lymphoma in the department of hematology. He had no medical history and no oral medications that could cause hyperpigmentation. On his initial visit, a physical examination revealed xerotic skin exhibiting brownish discoloration with black scales on both lower legs (Fig. 1a, b). In addition, diffuse pigmented macules were distributed on the nail beds and tongues. Dermoscopic findings revealed brownish unstructured areas and black dots consistent with follicles (Fig. 1c). A biopsy specimen from his lower leg showed an increased melanin in the basal and stratum corneum. Moreover, melanin incontinence was widely found in the upper dermis (Fig. 1d). We diagnosed him as having bilateral hyperpigmented macules on the lower legs possibly due to cyclophosphamide. Three months after discontinuation of R-CHOP due to the resistance, keratotic black macules were flattened and partially disappeared. Instead of R-CHOP therapy, CHASER (rituximab, cyclophosphamide, etoposide, and cytarabine) therapy was started, and black papules with dermoscopic findings similar to the previous one flared up again (Fig. 2a, b), suggesting the possible relationship between cyclophosphamide and bilateral hyperpigmented macules. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543124).

Cutaneous pigmentation could be induced by cytotoxic drugs, such as bleomycin, hydroxydaunorubicin, and cyclophosphamide. Cyclophosphamide is known to cause nail pigmentation but rarely causes cutaneous pigmentation [3]. In fact, at least 10 cases of cutaneous hyperpigmentation caused by cyclophosphamide have been reported in PubMed using the words “CHOP therapy,” “cyclophosphamide,” and “hyperpigmentation” [2‒4]. In previous reports, cyclophosphamide-induced cutaneous pigmentation was located on sun-exposed or traumatized sites [4]. In contrast, the pigmented lesion in our present case was distributed only on the lower legs. One of the possible reasons for this atypical distribution in our case is that the lower legs are prone to edema and vasodilation, and local concentrations of cytotoxic drugs are likely to be increased. In fact, local vasodilation due to curettage increases the concentration of the drug in the skin, resulting in a high degree of tissue toxicity of bleomycin, which may cause the hyperpigmentation consistent with scratch scars [5]. Taken together, cyclophosphamide might accumulate in lower legs due to edema, leading to develop the unusual distribution of hyperpigmentation in our present case, though the exact underlying mechanism is still unknown.

Although the mechanism by which cyclophosphamide causes hyperpigmentation is unknown, Slominsky et al. [6] explained that cyclophosphamide can target hair follicles in mouse experiments, causing abnormal transfer of pigment granules to ectopic hair bulb sites, extrafollicular melanin incontinence. In addition, cyclophosphamide-induced hyperpigmentation is histologically characterized by pigment incontinence in the superficial dermis [7] and necrotic keratinocytes in the epidermis [3]. Since melanocyte-stimulating hormone is expected to be associated with generalized hyperpigmentation, and since the hyperpigmentation is limited to the hair follicles on the lower legs, we thought that melanocyte-stimulating hormone was not considered as a cause of hyperpigmentation in our cases. Since histopathological findings suggested that inflammatory cell infiltration of the dermis was minimal, the pigmentation of our case was not considered post-inflammatory hyperpigmentation. Moreover, since the common chemotherapy agent for CHOP and CHACE is cyclophosphamide, and since the onset of hyperpigmentation in CHASE was recurrent, we thought that the causative agent was cyclophosphamide. Notably, the dermoscope in our present case showed black dots consistent with follicles, suggesting the possible relationship between cutaneous pigmentation and hair follicles. In addition, our present case showed pigment incontinence, necrotic keratinocytes, and basal hypermelanosis. Taken together, we considered it was consistent with cyclophosphamide-induced hyperpigmentation. This report presents only a single case, but further cases may provide fundamental insights into the mechanism of cyclophosphamide-induced hyperpigmentation.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The protocol for this human study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine, Sendai, Japan (permit no. 2021-1-1213).

The authors have no conflicts of interest to declare.

The authors received no funding.

Jun Yamamoto and Taku Fujimura treated the patient, acquired the clinical data, and wrote the manuscript. Taku Fujimura and Yoshihide Asano analyzed histopathological findings and supervised the study.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.