Diffuse Darkening of All Nail Beds: Differential Diagnosis and Work-Up
When all nail beds are diffusely darkened, systemic causes—including medications, endocrine disorders, and ethnic pigmentation—are far more likely than subungual melanoma, which typically affects a single digit. 1, 2
Key Distinguishing Feature: Number of Nails Involved
The most critical diagnostic clue is that subungual melanoma almost always involves a single digit, whereas diffuse involvement of all nails points strongly toward systemic or benign causes. 2
Differential Diagnoses for Diffuse Nail Darkening
Systemic and Benign Causes (Most Likely)
- Ethnic melanonychia: The most common cause in dark-skinned individuals, representing physiologic melanocytic activation 2
- Medications: Antibiotics and cytostatics frequently cause generalized nail pigmentation 1
- Endocrine disorders: Including pregnancy, which can activate nail matrix melanocytes 2
- Systemic diseases: Psoriasis, atopic dermatitis, lichen planus, and alopecia areata tend to affect numerous or all nails 1
- Metabolic conditions: Alkaptonuria, hemochromatosis, porphyria 2
- Syndromes: Peutz-Jeghers syndrome, Laugier-Hunziker syndrome, graft-versus-host disease 2
- Chronic trauma: Repetitive injury can activate melanocytes across multiple digits 2
Infectious and Non-Melanocytic Causes
- Onychomycosis: Fungal infections can cause non-continuous darkening 1, 3
- Bacterial infections: Pyocyanic superinfection of loosened nails 3
Clinical Red Flags That Suggest Melanoma (Unlikely with All Nails Involved)
While melanoma is improbable when all nails are affected, you must still evaluate for these high-risk features in any individual nail:
- Hutchinson sign: Periungual pigment spread onto cuticle or lateral/proximal nail folds 2, 4
- Bandwidth >3 mm with proximal widening 2
- Abrupt onset after middle age (>50 years) 2
- Rapid growth or darkening of a melanonychia band 2
- Pigment variegation with blurry lateral borders 2
- Nail plate dystrophy, ulceration, bleeding, or nodule formation 5, 6
- Personal or family history of melanoma 2
Recommended Work-Up Algorithm
Step 1: Comprehensive History
- Medication review: Specifically antibiotics, chemotherapy agents 1
- Ethnicity and family history: Ethnic melanonychia is common in dark-skinned populations 2
- Timing: Abrupt onset suggests melanoma; gradual onset favors benign causes 2
- Systemic symptoms: Endocrine, dermatologic, or metabolic disease 1, 2
Step 2: Physical Examination
- Document all nails: Photograph and measure any suspicious bands 7, 6
- Assess for Hutchinson sign on each digit 2, 4
- Examine skin and mucosa: Look for associated dermatologic conditions or syndromic features 1
- Palpate for nodules or ulceration beneath the nail plate 5
Step 3: Dermoscopy
- Perform dermoscopy on any nail with irregular features, as this enhances diagnostic accuracy 8, 1
- Look for patterns suggesting melanoma versus benign activation 1, 9
Step 4: Biopsy (Only If High-Risk Features Present)
Biopsy is NOT indicated for diffuse involvement of all nails unless specific high-risk features are present in an individual nail. 2 Most investigators advocate a wait-and-see approach for benign-appearing melanonychia, especially in children. 2
If biopsy is warranted for a suspicious individual nail:
- Remove the nail plate sufficiently to expose the underlying lesion 8, 5, 7, 6
- Sample the nail matrix adequately, as melanoma arises here 5, 7, 6
- Excisional biopsy is preferred when feasible, encompassing the entire lesion 5, 7, 6
- Incisional biopsy is acceptable for larger lesions, but must include adequate matrix sampling 5, 6
- Only practitioners skilled in nail apparatus biopsy should perform these procedures 8, 5, 7, 6
Step 5: Pathology Requirements (If Biopsy Performed)
The pathology report must include:
- Breslow thickness measurement 7, 6
- Presence or absence of ulceration 7, 6
- Margins of excision status 7, 6
- Clark level 7, 6
Critical Pitfalls to Avoid
- Do not biopsy all nails: Diffuse involvement strongly suggests systemic causes, not melanoma 1, 2
- Avoid superficial sampling: Shave or punch biopsies may underestimate Breslow thickness and are contraindicated 8, 7
- Do not delay biopsy if a single nail has high-risk features: Diagnosis of nail unit malignancies is often significantly delayed due to initial misdiagnosis 5
- Never perform partial removal of a melanocytic lesion: This creates pseudomelanoma and diagnostic confusion 8
Follow-Up Strategy
Prolonged follow-up is mandatory for early detection of possible malignant changes, even in benign-appearing cases. 2 Patients should be taught self-examination and advised to return immediately if any nail develops rapid growth, darkening, or Hutchinson sign. 8, 2