Abstract
This case series study of patients with granulomatous cheilitis at a tertiary referral center seeks to better describe the demographic characteristics, presenting features, associated disorders, and response to treatment of granulomatous cheilitis.
Granulomatous cheilitis (GC) is a rare disorder characterized by noncaseating granulomatous inflammation of the lips in the absence of systemic disease, eg, Crohn disease (CD) or sarcoidosis.1 A subtype of orofacial granulomatosis, the term GC was proposed in 1985 by Wiesenfeld and colleagues to encompass the spectrum of idiopathic, noncaseating granulomatous diseases of the face and mouth.2 When GC is found with lingua plicata (fissured tongue) and facial palsy, it is referred to as Melkersson-Rosenthal syndrome. Granulomatous cheilitis can have a chronic disfiguring course that is exceedingly difficult to manage.3
There are few published case-series studies describing responses to specific treatments for GC.4 This review of cases at a tertiary referral center seeks to better describe the demographic characteristics, presenting features, associated disorders, and response to treatment of GC.
Methods
The study was reviewed and approved by the University of Pennsylvania Institutional Review Board. Informed consent was waived because deidentified data were used.
This was an observational case-series study using patient records from the electronic medical records database of the University of Pennsylvania (Epic Systems). We conducted an unstructured search using PennSeek to identify all patients’ records from 2000 to 2019 that contained the terms granulomatous cheilitis, cheilitis granulomatosa, Melkersson-Rosenthal, or orofacial granulomatosis. Only patients with a lip biopsy result demonstrating noncaseating granulomatous inflammation were included in the analysis.
To assess response to GC treatment, the primary end point was improvement in lip symptoms (eg, edema, erythema, tenderness), based on clinical examination by a physician. A list of treatments, including start and end dates, was extracted from each patient’s medical record. The treatment response level, as indicated in the clinical notes, was recorded by treatment type, and graded as either complete response (CR), partial response (PR), or no response (NR). For patients who received concurrent, multiple treatments, the response was noted for each treatment type. For treatments that produced a CR or PR, the time to response was calculated from treatment initiation to the clinical encounter at which a physician recorded the response.
Results
We identified 19 patients whose records included results of a lip biopsy that demonstrated noncaseating granulomatous inflammation. All patients underwent chest imaging to rule out sarcoidosis. To rule out CD, 7 of 9 patients underwent colonoscopy; 2 declined. Nine of the patients had GC (Table 1). The mean (SD) age of patients with GC at presentation was 46.6 (16.3) years, 7 of 9 (78%) were female, and their chief concern was painless upper-lip edema (Table 1). Of the 10 patients excluded for other diagnoses, 2 were diagnosed with CD, 2 with sarcoidosis, 4 with allergic contact dermatitis, and 2 were undiagnosed owing to insufficient workup.
Table 1. Demographic and Clinical Characteristics of Patients With Granulomatous Cheilitis.
| Characteristic | Patients (N = 9) |
|---|---|
| Age, mean (SD) [range], y | 46.6 (16.3) [21-76] |
| Sex, female to male ratio | 7:2 |
| Race, ratio to total | |
| African American | 0:9 |
| Asian | 2:9 |
| White | 6:9 |
| Hispanic | 0:9 |
| Other | 1:9 |
| Clinical presentation, ratio to total | |
| Pattern of disease | |
| Upper lip | 5:9 |
| Lower lip | 2:9 |
| Both lips | 2:9 |
| Progression | |
| Relapsing remitting | 5:9 |
| Persistent | 4:9 |
| Features | |
| Pain | 1:9 |
| Pruritus | 0:9 |
| Erythema | 4:9 |
| Gingival edema | 5:9 |
| Ulceration of oral mucosa | 2:9 |
| Facial palsy | 1:9 |
| Lingua plicata | 0:9 |
| Chin or cheek edema | 1:9 |
| Diagnostic tests, abnormal to normal ratio | |
| ACE | 0:5 |
| ESR | 0:4 |
| Other diagnostic tests, abnormal to normal ratio | |
| CXRa | 1:8 |
| Colonoscopy | 0:7 |
| Patch testingb | 3:0 |
| Length of follow-up, mean (SD) [range], mo | 33.2 (38.8) [1-112] |
Abbreviations: ACD, allergic contact dermatitis; ACE, angiotensin-converting enzyme; CXR, chest radiography; ESR, erythrocyte sedimentation rate; GC, granulomatous cheilitis.
This patient had cystic lung disease considered unrelated to GC.
Three patients with GC received patch testing and had positive results for allergy to ethylenediamine, gallates, glutaraldehyde, and thiuram mix; however, these were not considered clinically relevant based on failure of avoidance to improve symptoms. Other patients with noncaseating granulomatous lip inflammation who were diagnosed with allergic contact dermatitis based on improvement after allergen avoidance were excluded by this causative disorder.
Of the 9 patients with GC, serial intralesional triamcinolone (ILK) was administered to 6 patients (Table 2). Although ILK administration was followed by a response in 5 patients, recurrences were common after initial injection. Of the 6 patients treated with ILK, 2 achieved a CR; 1 had recurrence after 35 months; and 1 had sustained resolution at 22 months. One patient with GC and comorbid unilateral facial palsy consistent with Melkersson-Rosenthal syndrome achieved CR with a 2-week taper of oral prednisone; all symptoms improved with therapy. One patient experienced spontaneous CR, ie, without treatment. Two patients with GC did not respond to treatment: 1 had no response to topical clobetasol and the other, to ILK, prednisone, hydroxychloroquine, and adalimumab.
Table 2. Treatments and Responses in 9 Patients With Granulomatous Cheilitis.
| Treatment | No. of patients | Treatment duration, mean (range), mo | Response, No. | Time to response, mean, mo | ||
|---|---|---|---|---|---|---|
| NRa | PRb | CRc | ||||
| Adalimumab | 1 | 41.7 | 1 | 0 | 0 | NA |
| Cetirizine | 2 | 10.1 | 2 | 0 | 0 | NA |
| Doxycycline | 3 | 14.4 (4.3-33.9) | 1 | 2 | 0 | 2.1 |
| Hydroxychloroquine | 2 | 8.3 | 1 | 1 | 0 | 3.7 |
| Intralesional triamcinolone | 6 | 36.9 (6.1-121.1) | 1 | 3 | 2 | 1.7 |
| Prednisone | 3 | 0.7 (0.3-1.5) | 2 | 0 | 1 | 0.5 |
| Topical clobetasol | 1 | 1.0 | 1 | 0 | 0 | NA |
| Debulking surgery | 1 | NA | 0 | 1 | 0 | NA |
| No treatment | 1 | 3.5 | 0 | 0 | 1 | 1.5 |
Abbreviations: CR, complete response; NA, not applicable; NR, no response; PR, partial response.
No response was defined by the terms: no response, recurrence, poor, weak, worsened, and/or no change.
Partial response was defined by the terms: favorable response, responding, decreased swelling, controlled, improved, much improved, greatly improved, and/or markedly better.
Complete response was described by the terms: improved completely, no ongoing symptoms, not active, controlled with no recurrence, cleared, asymptomatic, resolved, largely resolved, complete control, clinical remission, and/or normal.
Discussion
A rare, poorly understood disorder, GC presents with painless orofacial swelling and noncaseating granulomatous inflammation on histopathological examination. To the best of our knowledge, only 3 case-series studies of more than 5 patients with GC have been published to date.5 We describe the clinical features and therapeutic outcomes of 9 patients with GC. Diseases including allergic contact dermatitis, CD, and sarcoidosis must be considered and excluded prior to diagnosing GC. In this cohort of 9 patients, all received chest imaging to rule out sarcoidosis, and 7 underwent colonoscopy to rule out CD. Patch testing and ophthalmologic examination may also be useful in evaluating allergic contact dermatitis and sarcoidosis, respectively.
Only limited conclusions can be drawn from this small case series. However, for this rare disease, we know of no other higher-level primary studies.5 Reliance on clinician documentation for response grading and variable therapeutic approach across patients also limits our ability to evaluate specific treatments.
The treatment of GC remains challenging. In the present data, only half of patients with GC eventually had a durable (>6 months) CR. However, most required several months of therapy to achieve response. In some patients, GC relapse occurred after years of remission. Patients should be counseled that GC is characterized by partial responses and periodic worsening, and may require long-term therapy. Additional investigations into novel therapies may improve future outcomes for this condition.
References
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