What is the likely diagnosis and next steps for a patient with a persistent skin lesion, who has not responded to long-term antifungal therapy, with biopsy results showing hyperkeratosis, orthokeratosis, neutrophils in the stratum corneum, and lymphocytic infiltration, and a negative PAS stain for fungal elements?

Likely Diagnosis: Psoriasis

The clinical presentation—persistent skin lesion unresponsive to antifungal therapy, negative fungal culture, negative PAS stain, and biopsy showing hyperkeratosis, orthokeratosis, neutrophils in the stratum corneum with retained granular layer—strongly suggests psoriasis rather than a fungal infection. 1

Why This Is Not a Fungal Infection

The histopathologic findings definitively exclude dermatophytosis:

• Negative PAS stain rules out fungal infection when combined with the clinical context 2, 1
• Retained granular layer is inconsistent with dermatophytosis, which typically shows loss or thinning of the granular layer 1
• Four weeks of negative fungal culture with no growth effectively excludes fungal etiology 2
• While neutrophils in the stratum corneum can occur in dermatophytosis, they are more commonly found within compact orthokeratosis or parakeratosis in fungal infections (62% and 31.8% respectively), not with the constellation of findings described here 1

Most Likely Diagnosis: Psoriasis

The histopathologic pattern is classic for psoriasis:

• Hyperkeratosis with orthokeratosis (psoriasis can show orthokeratosis, especially in treated or chronic lesions) 1
• Neutrophils in the stratum corneum forming Munro microabscesses is pathognomonic for psoriasis 3
• Lymphocytic infiltration is characteristic of the inflammatory component 3
• Retained granular layer can occur in psoriasis variants, particularly when orthokeratotic 1

Differential Diagnoses to Consider

Other Non-Fungal Conditions:

• Seborrheic dermatitis: Can present with similar scaling but typically shows parakeratosis with plasma cells 4
• Atopic dermatitis: Would show more spongiosis and eosinophils 4
• Hyperkeratosis lenticularis perstans (Flegel's disease): Shows alternating parakeratosis with neutrophils and orthokeratosis, with lichenoid infiltrate 3
• Drug eruption: Particularly in patients on immunosuppressive therapy, though less likely with this histology 4

In Immunocompromised Patients (if applicable):

• Cutaneous manifestations of disseminated fungal infections (Aspergillus, Mucor, Fusarium): Present as papules, nodules, or ulcers with necrosis and angioinvasion 2, 4
• Nocardia infection: Manifests as painless subcutaneous nodules or "cold" abscesses 4

Next Steps for Definitive Diagnosis

Immediate Actions:

1. Repeat biopsy with immunohistochemistry if diagnosis remains uncertain, requesting specific stains to differentiate psoriasis from other inflammatory dermatoses 2

2. Clinical re-examination focusing on:

   • Distribution pattern (extensor surfaces, scalp, nails suggest psoriasis)
   • Presence of Auspitz sign (pinpoint bleeding when scale removed)
   • Nail changes (pitting, oil spots, onycholysis)
   • Joint symptoms (psoriatic arthritis) 4

3. Discontinue antifungal therapy immediately since fungal infection is excluded 2, 1

If Immunocompromised Status Is Present:

1. Obtain tissue culture for bacteria, atypical mycobacteria, and other fungi beyond dermatophytes (Aspergillus, Mucor, Fusarium) using Grocott's methenamine silver or calcofluor white staining 2

2. Consider surgical excision or deep tissue biopsy if lesion shows signs of necrosis, ulceration, or rapid progression to exclude invasive fungal infection 2, 5

Treatment Recommendation

Initiate psoriasis-directed therapy with topical corticosteroids as first-line treatment, given the histopathologic confirmation and exclusion of fungal etiology 6. For localized disease, high-potency topical corticosteroids should be applied for 2-4 weeks with clinical re-evaluation 6. If widespread or refractory, consider systemic therapy or phototherapy 6.

Common Pitfalls to Avoid:

• Do not continue antifungal therapy based solely on clinical appearance when histopathology and cultures are negative 2, 1
• Do not assume parakeratosis is required for psoriasis—orthokeratotic variants exist 1
• In immunocompromised patients, do not delay aggressive tissue sampling if there is any concern for invasive fungal infection, as mortality remains high 2
• Compact orthokeratosis alone justifies PAS-D staining in suspected dermatophytosis, but when negative with retained granular layer, strongly favors non-fungal etiology 1