An immunocompromised patient with cutaneous coccidioidomycosis and treatment-related hyperpigmentation caused diagnostic challenges.
A 70-year-old US woman was referred for dermatological review for a history of progressive pruritic, inflammatory papules and pustules on both cheeks and her central forehead.
She had stage IV medullary thyroid cancer and was being treated with the multikinase inhibitor vandetanib. She had undergone thyroidectomy and radiation therapy.
She has not experienced any previous facial trauma and her only other reported symptoms were occasional diarrhea and night sweats.
Over the four months prior to referral, she had received a 10-day course of prednisolone, oral antibiotics (cephalexin and levofloxacin), an antiviral (acyclovir) and topical agents (clindamycin, clotrimazole), with brief or no improvement.
The inflammatory lesions improved while she was taking oral prednisolone but worsened following discontinuation.
Her first dermatology visit was eight months after lesion onset, and she was started on a one-month course of doxycycline (100mg twice daily) and topical metronidazole (0.75% twice daily) for a working diagnosis of rosacea.
She experienced no clinical improvement from standard rosacea therapies, so a punch biopsy was performed on a representative pustule on the left glabella.
The histopathology led to the diagnosis of cutaneous coccidioidomycosis.
Coccidioidomycosis is caused by Coccidioides spp. fungi in dust and soil, which thrive in arid and semi-arid conditions, sandy alkaline soil and dry deserts.
The fungi are endemic to the southwestern US, where they become aerolised and develop into spherules in the lungs when inhaled. When the spherules rupture, they release endospores which travel to other organs.
Histopathology may reveal granulomatous dermatitis, eosinophilic inflammation, micro-abscesses, perivascular inflammation and gummatous necrosis. Coccidioidomycosis shows refractile spherules containing endospores, which can be identified using certain stains.
Coccidioidomycosis causes nonspecific symptoms such as fever, cough, dyspnoea, fatigue, arthralgias, myalgias and cutaneous lesions.
The differential diagnosis spans rosacea, discoid lupus, psoriasis, granuloma faciale, sarcoidosis and other disseminated fungal or mycobacterial infections such as tuberculosis, paracoccidioidomycosis and blastomycosis.
Serologic testing of the patient was inconclusive, yielding negative IgM and indeterminate IgG results, but additional confirmatory testing was deemed unnecessary due to the histopathologic findings and the patient’s residence in an endemic region.
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Chest imaging showed a new 1.3 x1.3cm pulmonary nodule in the left lower lobe, alongside preexisting stable subcentimetre nodules that were not biopsied.
Given the patient’s oncologic history, it was unclear whether the new nodule represented metastatic disease or pulmonary coccidioidomycosis, and in the absence of definitive pathology, empiric antifungal therapy was initiated.
After two weeks of oral fluconazole (400mg daily), the papules and pustules showed substantial improvement. However, blue-grey hyperpigmentation persisted at sites of prior papulopustules and intensified after three months of continued treatment.
Vandetanib has previously been linked to drug-induced hyperpigmentation, specifically blue-grey discoloration. Emerging evidence suggests concurrent use of vandetanib and doxycycline may have a synergistic effect, increasing the hyperpigmentation risk.
Discussion with infectious disease and oncology specialists led to the recommendation for the patient to continue vandetanib and concurrent indefinite fluconazole treatment.
While immunocompetent patients typically need between six and 12 months of therapy, immunocompromised patients with disseminated coccidioidomycosis often require lifelong treatment.
The risk of disseminated disease increases greatly in immunocompromised patients; only 1% of immunocompetent patients will develop disseminated coccidioidomycosis compared to 30-50% of immunosuppressed patients.
The immunocompromised also face a 50% mortality rate with disseminated disease and coccidioidomycosis may relapse during immunosuppressive treatment after antifungal discontinuation.
The patient was originally from Iran and had recently relocated to the endemic region, meaning no early-life endemic exposure may have contributed to the increased susceptibility created by her immunosuppression.
“This case highlights diagnostic challenges in endemic fungal infections and rare drug-associated hyperpigmentation,” the report’s authors wrote.
“Lesions mimic other dermatologic conditions, requiring histologic confirmation.”
