Case
Awhite man in his early 40s with a medical history of chronic lymphocytic leukemia (Rai stage 0) reported a 6-month history of a growing mass in his right axilla and weight loss. Physical examination revealed palpable right axillary lymphadenopathy. The patient was an active smoker (1 pack per day) with an unremarkable family history. A positron emission tomography scan showed a hypermetabolic right axillary lymph node that measured 5 × 5 cm as well as multiple liver lesions, the largest of which measured 8 cm. The results of a core needle biopsy specimen from the right axillary lymph node were consistent with malignant neoplasm, with immunohistochemistry staining positive for S100, HMB-45, and MART-1. He began pembrolizumab therapy.
After starting treatment, the patient began to notice slowly worsening painless, nonpruritic, diffuse dark gray skin, nail beds, and eye discoloration (Figure). The results of laboratory studies revealed normal electrolytes, normal kidney function, mild elevation of liver function, and mild anemia with a hemoglobin level of 12 g/dL (for SI unit conversion, multiply by 10.0 to convert to liters). Computed tomography of the chest, abdomen, and pelvis showed worsening hepatic metastases and right axillary adenopathy.
What Is Your Diagnosis?
- Hemochromatosis
- Diffuse melanosis cutis
- Addison disease
- Hyperpigmentation due to sun exposure
Discussion
Diagnosis
B. Diffuse melanosis cutis
Diffuse melanosis cutis (DMC) is a rare condition characterized by the hyperpigmentation of skin and mucous membranes caused by increased melanin deposition in patients with malignant melanoma. According to a systematic review,1 fewer than 100 cases have been reported. Diffuse melanosis cutis presents more commonly in males (60% of cases) and white patients (95% of cases), with a median age at the time of diagnosis of about 50 years.1 This condition is also associated with melanuria in about 77% of cases.1 Usually, DMC is seen 12 months after an initial diagnosis of metastatic melanoma. Patients present with progressive and diffuse blue-gray hyperpigmentation of the skin and mucous membranes, leading to darkening of the skin, hair, peritoneal fluid, sputum, urine, and sometimes the internal organs.2
Histopathologic findings include deposition of perivascular histiocytes filled with melanin and free pigment in the dermal connective tissue. The underlying pathogenesis for this condition is not fully understood. According to one hypothesis, when metastatic melanoma undergoes lysis by ischemia, immunological responses, or oncologic treatments, cells release melanin precursors into the bloodstream that undergo auto-oxidation, become ingested by histiocytes, and are then deposited in the dermis.3 Another hypothesis suggests that tumor cells release melanocyte peptide growth factors such as α melanocyte-stimulating hormone, which might be responsible for DMC. The role immunotherapy played in the manifestation of DMC in this case is unclear. One case series of patients who developed DMC after immunotherapy initiation concluded that DMC may be a negative predictor of response to anti–PD-1 (programmed cell death 1) treatment.4 In particular, it remains unclear whether immunotherapy promotes DMC development or just cannot control DMC that would inevitably develop.
The discoloration of DMC is most prominently noted in sun-exposed areas, progressing in a cephalocaudal direction.2 Diffuse melanosis cutis is an ominous sign that is associated with a worse prognosis, with a median survival of 4 to 6 months after diagnosis.1,5 According to case reports,5,6 novel therapies that target a BRAF mutation and immunotherapies have shown a considerable survival benefit.
Based on the results of the biopsy specimen, the patient was diagnosed with metastatic melanoma. Metastatic melanoma should be one of the differential diagnoses in patients presenting with unusual skin discoloration and/or dark-colored bodily secretions. Given this patient’s short survival after his initial presentation, prognosis should be discussed at the time of diagnosis. Other differential diagnoses include hemochromatosis, most notably the hereditary form, which demonstrates skin hyperpigmentation in most cases. Elevated liver function levels are more likely related to worsening hepatic metastases. In this case, hemochromatosis is less likely given the patient’s unremarkable family history and the absence of other clinical features of hemochromatosis, including arthropathy or diabetes. Addison disease, also known as primary adrenal insufficiency, can cause generalized brown hyperpigmentation. However, the absence of other features of adrenal insufficiency such as hypotension, hypoglycemia, and electrolyte abnormalities makes this diagnosis less likely. Hyperpigmentation due to sun exposure would be limited to sun-exposed areas and would not cause hyperpigmentation of nail beds and eyes, as is seen in this case.
This patient’s treatment was changed to the combination of pembrolizumab and talimogene laherparepvec injection. However, the disease progressed and the patient declined further treatment. He was transitioned to hospice care and died 6 months after DMC onset.
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Article Information
Published Online: May 23, 2019. doi:10.1001/jamaoncol.2019.0524
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient’s family for granting permission to publish this information. We also thank Donald Miller, MD, for his support and Sarah Mudra for manuscript editing. They received no compensation for their contributions.
References
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