When a Patient Presents With Hyperpigmented Bands on the Fingernails and Toenails

Editor’s Note: This piece is adapted with permission from the original, which appeared in The Dermatologist.

An 83-year-old woman presented to our clinic with discoloration on her fingernails and toenails. One year prior, the patient received a diagnosis of  invasive ductal carcinoma in the right breast. She underwent a right modified mastectomy and then received chemotherapy and localized radiotherapy. She reported that the nail pigmentation started 3 months after beginning a chemotherapy regimen of doxorubicin, dexamethasone, and cyclophosphamide. She did not report any prior nail abnormalities, history of recent trauma, or nail loss. She also reported no accompanying pain or discomfort.

During examination, we observed multiple, brown-bluish, pigmented, horizontal nail bands ranging from poorly demarcated to well-demarcated in all fingernails and toenails. We did not detect any mucosal or skin involvement. Further investigation in the form of detailed history, physical examination, and blood tests showed no metabolic, endocrinologic, autoimmune, or infectious disorders.

Key Questions to Consider

1. What in this patient’s history stands out as a potential etiology of this concern?
2. What physical findings in particular provide clues to the etiology?
3. What dermatoscopic findings might one expect in this case?

Answering the Key Diagnostic Questions

1. Chemotherapy, with onset of the nail concerns 3 months after treatment began.
2. Multiple versus single nail involvement, morphologic pattern of pigmentation, and accompanying symptoms or lesions provide some clues to the etiology behind the melanocyte activation.
3. Dermatoscopic findings for the longitudinal form of drug-induced melanonychia include a diffuse gray coloration of the nail plate and the presence of thin, longitudinal gray lines with regular thickness, spacing, coloration, and the absence of parallelism disruption.¹⁵

Understanding Chemotherapy-Induced Transverse Melanonychia

Chemotherapy-induced transverse melanonychia (also known as horizontal melanonychia or transverse hyperpigmented nail bands) is a rare, benign nail pigmentation disorder characterized by transverse hyperpigmented bands that can involve both fingernails and toenails. Activation of melanocytes by various causative factors leads to an increase in melanin production in the nail matrix.¹ Melanonychia refers to a darkening of the nail that may present with different morphologic patterns, including longitudinal, diffuse, and transverse patterns.¹

Clinical Presentation, Dermatoscopy, and Histology

Hypo- and hyperpigmented nail changes can be seen after uses of various causative drugs, including some chemotherapeutics, antiretrovirals, antimalarials, and metals. Beau lines, true leukonychia, apparent leukonychia (such as Muehrcke lines), and melanonychia are the most common nail pigmentation anomalies reported after common medical therapies.²

Melanonychia, or dark brown-black hyperpigmentation on the nail plate, is described in 3 morphologic patterns: longitudinal melanonychia (also known as melanonychia striata) extending proximally from the nail matrix or cuticle to the distal free edge of the nail plate; diffuse melanonychia, which involves the entire nail plate; and transverse melanonychia, with bands lying across the width of the nail plate.¹ Although longitudinal melanonychia is more commonly reported, diffuse and transverse melanonychias are rarely reported.

The etiology of melanonychia is discussed as melanocytic hyperplasia and melanocyte activation. Melanocyte hyperplasia can occur as inherited or acquired (sun-induced) and presents with longitudinal streaking or total nail pigmentation, commonly as a nevus or melanoma. Melanocyte activation or stimulation of dormant melanocytes in the nail matrix can occur from trauma; inflammation; some nonmelanocytic tumors; and other systemic conditions, including autoimmune diseases, nutritional deficiencies, and HIV (Table 1 below). Iatrogenic factors, such as chemotherapeutics, phototherapy, and radiation therapies, can also cause melanocyte activation.^3,4 Although trauma, inflammation, and tumors mostly present with a longitudinal pattern and single (or few) nail involvement,⁵ systemic conditions and iatrogenic causes present with entire fingernail and toenail involvement and multiple streaks in a longitudinal or transverse pattern on the nail plate. They can also be accompanied by mucosal or skin hyperpigmentation.⁶ Multiple or single nail involvement, morphologic pattern of pigmentation, and accompanying symptoms or lesions provide some clues to the etiology behind the melanocyte activation. Patients with darker skin types (Fitzpatrick types III–VI) are more susceptible to melanonychia when exposed to the discussed causative factors. In the evaluation of melanonychia, one should also rule out exogenous pigmentation and pregnancy.

Drug-induced melanonychia is a benign condition that should not require stopping the causative medication.⁷ It is commonly seen with chemotherapeutic agents (cyclophosphamide, doxorubicin, hydroxyurea, busulfan, taxanes, capecitabine, cisplatin, bleomycin, daunorubicin, dacarbazine, 5-fluorouracil, methotrexate, imatinib) and less commonly with antiretrovirals (zidovudine, lamivudine), antimalarials (amodiaquine, chloroquine, mepacrine, quinacrine) and metals (arsenic, thallium, mercury). The pattern of pigmentation varies with the causative drug and can be seen in 1 or more patterns.^8,9 Although most drugs present with longitudinal pigmentation, clofazimine, infliximab, psoralens, phenytoin, fluconazole, cyclins, ketoconazole, phenothiazines, and sulfonamides are reported with diffuse pigmentation. Limited cases have been reported of transverse melanonychia; causative drugs include hydroxyurea,^6,10-22 imatinib,^13,14 and etoposide.⁷ Transverse melanonychia has only been reported with medication use, whereas longitudinal and diffuse melanonychia have been reported with other causes. Drug-induced melanonychia outgrows partially or completely after cessation of the causative drug. Total resolution of pigmentation varies, from 6 to 8 weeks to several months and years.

Dermatoscopic findings for the longitudinal form of drug-induced melanonychia include a diffuse gray coloration of the nail plate and the presence of thin, longitudinal gray lines with regular thickness, spacing, coloration, and the absence of parallelism disruption.¹⁵ The gray color indicates melanocyte activation rather than melanocytic hyperplasia, which is characterized by a brown color.¹⁶

Histologically, melanocytes lie dormant or quiescent in both the nail matrix and nail bed. Stimulants cause melanocyte activation and the transferring of melanin-rich melanosomes to the differentiating matrix cells through dendrites. These matrix cells migrate distally and finally become nail plate onychocytes, resulting in visible pigmentation in the nail plate. An increase in the number of melanocytes or mitosis is not observed and the matrix cells have normal cytologic architecture.¹ Histopathologic examination does not provide a clue about the etiology of melanocyte activation in melanonychia but can distinguish melanocytic activation from melanocytic hyperplasia.¹⁷

Differential Diagnosis and Management Pearls

Several conditions must be excluded for differential diagnosis, including hemosiderosis, hyperbilirubinemia, Addison disease, Cushing syndrome, vitamin B12 deficiency, HIV, hyperthyroidism, porphyria, and alkaptonuria.

Drug-induced nail hyperpigmentation resolves shortly after discontinuation of the responsible drug. After ruling out nail malignancies and other causes of nail hyperpigmentation, observation, and reassurance during and after chemotherapy are key in the management of drug-induced melanonychia. No additional examination or treatment are required.

Important Considerations in This Patient

In this case, our patient received chemotherapy a year ago and lesions first started 3 months after initiation of chemotherapy. Other possible causes of transverse melanonychia, such as trauma, inflammation, and systemic conditions, were ruled out with further investigation. Our patient also had a history of local radiotherapy for breast cancer. Radiotherapy-related melanonychia has been reported in mycosis fungoides and arthritis cases,^3,4 but they were all whole-body radiotherapies involving hands. Our patient had a history of only localized radiotherapy for breast cancer.

Reports exist regarding drug-induced transverse melanonychia due to hydroxyurea, imatinib, and etoposide therapies. In our case, the patient had a history of cyclophosphamide and doxorubicin therapies. Reports of cyclophosphamide-induced melanonychia characterize it as diffuse, black, longitudinal, or dark gray pigmentation of the proximal nail plate.¹⁸ Doxorubicin-induced transverse melanonychia descriptions include alternating bands of dark brown and white lines.¹⁸ In this case, our patient presented with transverse hyperpigmented bands in all fingernails and toenails. Drug-induced nail pigmentation can also be accompanied by mucosal hyperpigmentation,¹⁴ but in our case, there was no mucosal involvement.

Transverse melanonychia has not been reported under dermatoscopic examination before. Dermatoscopic examination of the patient’s left middle fingernail showed gray-bluish discoloration of the distal two-thirds, with shiny white horizontal bands on a bluish background. No evidence of nail dystrophy was noted. Gray-blue discoloration is consistent with melanocytic activation and other drug-induced hyperpigmentation descriptions; however, the shiny white appearance of the bands was unique.

In Conclusion

Nail evaluation by specialists before and after chemotherapy can enrich current literature on the pathophysiology and patterns of drug-induced nail abnormalities.

Dr. Ozer is a dermatopathology research fellow with Rao Dermatology in New York.

Dr. Khan is a resident in the Brown University Dermatology Residency program.

Dr. Farabi is a dermatology resident in New York.

Dr. Safai is a Professor and Chairman of the Department of Dermatology of New York Medical College.

Dr. Atak is a dermatology resident in New York.

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