An unusual case of erythema dyschromicum perstans related to ribociclib therapy for invasive breast carcinoma

Dear Editor, A 48-year-old Indian female presented with an 8-month history of progressive, nonpruritic generalized pigmented dermatosis, which started over the lower limbs and subsequently spread to involve her trunk, buttocks, and upper limbs. The patient was started on letrozole and ribociclib on December 8, 2020, for invasive breast carcinoma, approximately 2 months before the onset of her rashes. Besides her history of invasive breast cancer, she had no other comorbidities and was not taking any other regular medications or cosmeceuticals. Physical examination showed multiple hyperpigmented, brown to slate-gray, small, and large patches distributed over the upper arms, forearms, thighs, lower limbs, and buttocks [Figure 1]. There was a white lacy patch seen over the right buccal mucosa, with no nail abnormalities observed on further examination. The clinical differential diagnoses include erythema dyschromicum perstans, lichen planus pigmentosus (LPP), and drug-induced LPP.Figure 1: Clinical image of confluent hyperpigmented brown patches over the thighs and lower legs.A skin punch biopsy was performed over the patient’s right thigh lesional skin; histopathological examination showed vacuolar interface dermatitis with focal spongiosis, and dermal pigmentary incontinence with mild peri-adnexal and perivascular lymphocytic infiltrate [Supplementary Figure 1]. Direct immunofluorescence was negative.Supplementary Figure 1: Photomicrographs showing histopathological changes. Skin biopsy showed basal vacuolar alteration, apoptotic keratinocytes in the epidermis, with lymphocytic exocytosis and pigmentary incontinence in the superficial dermis (H and E, ×200).Given the slate gray pigmentation and histological findings, a provisional diagnosis of erythema dyschromia perstans (EDP) related to ribociclib was established. After discussion with her oncologist, ribociclib was stopped and switched to palbociclib, and letrozole was continued for the treatment of breast cancer. The patient was prescribed with emollients and topical mometasone furoate cream. On follow-up with her oncologist, her cutaneous pigmentation had improved at 3 months after cessation of ribociclib. EDP is an acquired macular pigmentary disorder of unknown etiology. It is characterized by the presence of symmetrically distributed gray macules over the trunk, neck, face, and upper limbs.[1] It commonly occurs in Asian and Latino patients with darker skin phototypes (Fitzpatrick III-IV), and it can affect patients of any gender or age group. The histological features of EDP are similar to other inflammatory dermatoses, including lichenoid reactions. Active or early lesions can show basal vacuolar degeneration, superficial dermal edema, and perivascular lymphocytic infiltrate. Inactive lesions can demonstrate pigmentary incontinence in the dermis with melanophages.[1] Direct immunofluorescence may show colloid immunoglobulin M deposits.[2] Clinicopathological correlation is required to establish a prompt diagnosis and identification of the causative drug. Although the exact pathophysiology of EDP remains unknown, postulated mechanisms of disease include hyperproduction of melanin from epidermal melanocytes, melanin–drug binding leading to reduced drug clearance from dermal melanocytes, and synthesis of pigments such as lipofuscin.[3,4] The onset of EDP had been reported to the following medications: ethambutol, fluoxetine, chlorothalonil, omeprazole, and osimertinib.[1] The reported drug-induced latency period for EDP ranged from 2 to 12 months.[5] Ribociclib is a selective cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the endocrine-based therapy for hormone-positive, human epidermal growth factor 2-negative breast cancer.[6] The main dermatological side effects reported with the use of CDK 4/6 inhibitors include alopecia, stomatitis, leukocytoclastic vasculitis, Stevens–Johnson syndrome, and subacute lupus erythematosus.[7-10] However, pigmentary changes caused by CDK 4/6 therapies are rarely reported. There had only been one other case of CDK4/6-induced EDP reported, with the onset of hyperpigmentation occurring at 2 months after commencement of ribociclib for treatment of breast cancer.[6] In our case, the patient developed an eruption of brown to slate-gray hyperpigmented macules, 2 months after starting ribociclib therapy. The diagnosis of EDP is supported by predominantly truncal and limb involvement of pigmentation and relatively stable clinical course. While LPP is a possible differential diagnosis, it is less likely in this case given the generalized distribution of nonpruritic rashes without facial involvement, the lack of a waxing and waning course which is commonly seen in LPP, and the negative direct immunofluorescence. Therefore, the clinical features and histopathological findings are consistent with a diagnosis of ribociclib-induced EDP. Ribociclib was considered a likely drug culprit based on the temporal relationship between drug initiation and onset of hyperpigmentation, and resolution of hyperpigmentation with cessation of ribociclib. A Naranjo score was performed to aid in the determination of drug causality (probable causality) [Supplementary Table 1].Supplementary Table 1: Naranjo scoring system was used in determining drug causality in our patient[ 11 ]Management of drug-induced EDP involves prompt identification and withdrawal of the culprit medication. Topical treatment with corticosteroids, hydroquinone, calcineurin inhibitors, and tretinoin cream has been attempted with variable success. Systemic treatment with dapsone, minocycline, clofazimine, macrolide antibiotics, and pentoxifylline had also been disappointing, with 55% of cases resistant to treatment or developing worsening rashes. Narrow-band ultraviolet B phototherapy had been reported to be useful for EDP.[12] In conclusion, our patient presented with EDP induced by CDK 4/6 inhibitor, ribociclib, which is uncommon and rarely reported in the literature. Although uncommon, the prominent pigmentation of EDP can be distressing for patients, which warrants increased awareness. Further studies are required to understand its underlying pathophysiology and guide appropriate treatment options. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.