What is the differential diagnosis for a patient presenting with papules?

Differential Diagnosis of Papules

The differential diagnosis for papules is extensive and must be systematically approached based on distribution, morphology, associated symptoms, and patient demographics, with key categories including inflammatory/papulosquamous disorders, infectious etiologies, drug reactions, and malignancy-associated lesions.

Primary Inflammatory and Papulosquamous Disorders

The most common papulosquamous diseases presenting with papules include:

• Psoriasis vulgaris: Presents with erythematous papules and plaques with silvery scale, often on extensor surfaces. Can progress to erythrodermic forms covering >95% body surface area. 1
• Lichen planus: Characterized by violaceous, polygonal, flat-topped papules with Wickham striae, typically on flexor surfaces and oral mucosa. Histologically shows lichenoid lymphocytic infiltrate at the dermoepidermal junction. 2
• Pityriasis rosea: Papulosquamous eruption that commonly presents in annular configurations. 3, 4
• Seborrheic dermatitis: Greasy scale in scalp and body folds, typically with less pruritus than atopic dermatitis. Can present with papular lesions. 1, 3

Atopic and Contact Dermatitis

• Atopic dermatitis: Intensely pruritic papules with eczematous changes including oozing and crusting. Distribution varies by age. Must be distinguished from severe psoriasis (which has less pruritus and lacks eczematous change). 1
• Contact dermatitis (irritant or allergic): Atypical or localized distribution is the key distinguishing feature. Consider patch testing if topical therapy fails. 1

Infectious Etiologies

Parasitic

• Scabies: Inguinal, axillary, and genital papules. In infants, look for palmoplantar vesicles and burrows. 1
• Cutaneous leishmaniasis: Papulonodular lesions that may be pleomorphic and nonulcerative, especially in immunocompromised patients. Multiple small circumferential papules can form after treatment initiation. Differential includes cutaneous fungal and mycobacterial infections, pyoderma gangrenosum, and sarcoidosis. 1

Fungal

• Tinea corporis: Annular papulosquamous lesions without eczematous change. Confirm with skin scraping for microscopy and culture. 1
• Cutaneous mold infections (Aspergillus, Mucormycosis, Fusarium): Present as papules, nodules, or ulcers in immunocompromised patients. Skin biopsy essential for diagnosis. 1

Bacterial

• Nocardia: Subcutaneous nodules or abscesses, frequently painless and "cold to the touch." Consider in immunocompromised patients. 1

Viral

• Herpes zoster: Early lesions are erythematous macules that rapidly evolve to papules then vesicles in dermatomal distribution. Prodromal pain typically precedes rash by 24-72 hours. Atypical presentations may show nonspecific papules without vesicular appearance. 1, 5

Drug-Induced and Immunotherapy-Related

• Checkpoint inhibitor-related rash: Macules/papules occur in 24% with ipilimumab, 15% with anti-PD-1 agents, and 40% with combination therapy. Grade based on body surface area coverage (<10%, 10-30%, >30%). 1
• Drug reactions: Rule out DRESS syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis in severe cases with systemic symptoms. 1

Autoimmune and Connective Tissue Disease

• Dermatomyositis: Vacuolar interface dermatitis with perivascular lymphocytic infiltrate and mucin deposition. Direct immunofluorescence is negative (unlike lupus, which is positive). 2
• Lupus erythematosus: Interface dermatitis with positive direct immunofluorescence on perilesional skin distinguishes from dermatomyositis. 2

Malignancy-Associated Papules

• Cutaneous T-cell lymphoma: Lack of classic eczematous changes (no oozing/crusting). Atypical lymphocytes on biopsy, flow cytometry, and Sézary cell count needed. Can mimic severe atopic dermatitis or erythrodermic psoriasis. 1
• Facial papules: May represent cutaneous signs of internal malignancy. Skin biopsy necessary to distinguish from benign lesions. 6

Other Important Considerations

• Pityriasis rubra pilaris: Difficult to distinguish from psoriasis; look for "skip" areas and significant palmoplantar keratoderma. 1
• Sarcoidosis: Included in differential for cutaneous leishmaniasis and other granulomatous conditions. 1
• Secondary syphilis: Classic papulosquamous disease that must be considered. 4

Critical Diagnostic Approach

When evaluating papules, immediately rule out infectious causes (perform KOH prep, skin scraping), drug reactions, and life-threatening conditions before considering chronic inflammatory disorders. 1, 7

Key diagnostic steps include:

• Detailed distribution assessment (localized vs. generalized, dermatomal vs. random) 1, 2
• Presence or absence of scale, pruritus, and eczematous changes 1
• Skin biopsy with direct immunofluorescence when diagnosis unclear 1, 2
• Consider HIV testing, complete blood count, comprehensive metabolic panel in appropriate clinical contexts 1, 2

Common Pitfalls

• Assuming all papulosquamous lesions are psoriasis: Always consider tinea corporis (perform KOH), contact dermatitis, and drug reactions. 1, 7
• Missing secondary infection: Purulence is not typical of most papular conditions unless secondarily infected with Staphylococcus or Streptococcus. 1
• Overlooking immunocompromised status: Atypical, multifocal, pleomorphic presentations increase with immunosuppression. 1
• Failing to biopsy atypical presentations: When topical therapy fails or presentation is unusual, biopsy to exclude cutaneous T-cell lymphoma, drug reactions, or infectious etiologies. 1