What are the benign, inflammatory, infectious, and systemic causes, and recommended work‑up, for a papular lesion on the lip that is not due to human papillomavirus infection or malignancy?

Differential Diagnosis of Lip Papules (Non-HPV, Non-Malignant)

Most Common Benign Causes

The most common non-HPV, non-malignant causes of lip papules include mucoceles, pyogenic granuloma, calibre-persistent labial artery, and angiolymphoid hyperplasia with eosinophilia. 1, 2, 3, 4

Mucoceles

• Present as soft, fluctuant, translucent papules or nodules, typically on the lower lip 1
• Often have a dark punctum suggesting a blocked duct opening or small area of hemorrhage 5
• Result from trauma to minor salivary glands causing mucus extravasation 1
• Painless unless secondarily infected 5

Pyogenic Granuloma

• Appears as a sessile or pedunculated, erythematous, exophytic papule or nodule with smooth or lobulated surface 3
• Bleeds easily with minor trauma 3
• Represents a reactional response to constant minor trauma or hormonal changes 3
• Can occur on lips, though gingiva is more common 3

Calibre-Persistent Labial Artery (CPLA)

• Presents as an asymptomatic papule on the lower lip, though can involve upper lip 2
• Represents a primary arterial branch penetrating submucosal tissue without division or diameter decrease 2
• Often misdiagnosed as varix, hemangioma, venous lake, or fibroma 2
• Critical pitfall: Excisional biopsy without prior diagnosis carries risk of profuse bleeding 2

Angiolymphoid Hyperplasia with Eosinophilia (ALHE)

• Multiple, well-delimited, erythematous papules with smooth surface 4
• Predominantly affects head and neck region in middle-aged women 4
• Lesions can be pruritic or painful and do not spontaneously resolve 4
• Represents an angioproliferative process with inflammatory infiltrate 4

Diagnostic Algorithm

Initial Clinical Assessment (2-3 Week Observation Period)

Observe lesions that are <5mm, soft consistency, normal coloration, and stable appearance for 2-3 weeks before intervention. 1, 5

• Maintain good oral hygiene and avoid local trauma during observation 1, 5
• Document size, color, texture, and any associated symptoms 5

Red Flag Features Requiring Immediate Biopsy

Any of the following mandate biopsy within 2 weeks: 1, 5

• Progressive growth over observation period 1, 5
• Development of ulceration or spontaneous bleeding 1, 5
• Change from soft to indurated or fixed consistency 1
• Development of pain or functional impairment 1

Diagnostic Testing Based on Clinical Suspicion

For suspected vascular lesions (CPLA, hemangioma):

• Use Doppler ultrasonography as first-line noninvasive diagnostic tool 2
• Avoid excisional biopsy until vascular nature is excluded to prevent hemorrhage 2

For suspected inflammatory/reactive lesions (pyogenic granuloma, ALHE):

• Excisional biopsy is both diagnostic and therapeutic 3, 4
• Laboratory workup for ALHE should include complete blood count with differential and IgE levels 4

For suspected mucoceles:

• Clinical diagnosis is often sufficient for typical presentations 1
• Biopsy if atypical features or diagnostic uncertainty 5

Treatment Approach

Mucoceles

• Surgical excision is definitive treatment 1
• Remove involved minor salivary glands to prevent recurrence 1

Pyogenic Granuloma

• Surgical excision is the safest method for both diagnosis and treatment 3
• Must excise down to periosteum if gingival to prevent recurrence 3

Calibre-Persistent Labial Artery

• Conservative management if asymptomatic and diagnosis confirmed by Doppler 2
• Surgical excision only if symptomatic, with careful hemostasis 2

Angiolymphoid Hyperplasia with Eosinophilia

• Surgical excision is preferred treatment, though recurrence may occur if incomplete 4
• Alternative options include laser therapy (pulsed dye, CO2), intralesional corticosteroids, or cryotherapy 4
• Mohs micrographic surgery with excision of abnormal vessels at base reduces recurrence 4

Critical Pitfalls to Avoid

Performing excisional biopsy on vascular lesions without prior imaging leads to profuse bleeding. 2

Delayed biopsy of lesions with red flag features can result in delayed diagnosis of squamous cell carcinoma. 1, 5

Over-treatment of benign lesions causes unnecessary morbidity and scarring. 1, 5

Incomplete excision of pyogenic granuloma or ALHE results in high recurrence rates. 3, 4

Referral Indications

Refer to oral surgery or dermatology when: 5

• Lesions persist beyond 2-3 week observation period 5
• Any red flag features present 1, 5
• Diagnostic uncertainty exists 5
• Vascular lesion suspected requiring specialized imaging or surgical expertise 2
• Functional impairment present 5

Follow-Up Protocol

Re-evaluate all observed lesions at 2-3 weeks. 1, 5

Any change in size, color, or texture during observation warrants immediate biopsy. 1, 5

Post-excision monitoring for recurrence, particularly for ALHE and pyogenic granuloma. 3, 4