|Year : 2020 | Volume
| Issue : 1 | Page : 12-16
Granulomatous cheilitis: Report of three cases and systematic review of cases and case series reported from India
Yugal Kishore Sharma, Shivanti Chauhan, Kirti Deo, Prachi Agrawal
Department of Dermatology, Dr. D. Y. Patil Medical College and Hospital, DPU, Pune, Maharashtra, India
|Date of Submission||19-Jul-2018|
|Date of Decision||23-Sep-2018|
|Date of Acceptance||21-Nov-2018|
|Date of Web Publication||06-Jan-2020|
172, New Mohan Puri, Meerut - 250 001, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Granulomatous cheilitis (GC) is a rare idiopathic inflammatory disorder characterized by chronic persistent swelling of the lips. Despite a lingering controversy, it remains linked to orofacial granulomatosis and Melkersson–Rosenthal syndrome (MRS). Aim: To systematically review all cases of GC reported hereto from India with the three being reported now, analyzing patients'/disease characteristics, associated diseases, and treatment protocol. Materials and Methods: Using biomedical search engines such as PubMed, Scopus, and Google Scholar, a systemic review of cases/case series reported from India (1994–2018) was undertaken, and data on patients'/disease characteristics, association with other diseases, and treatment extracted discussed and analyzed without subjecting to statistical analysis due to the small population size. Results: The mean age at presentation of these cases (n, 73: Single, 39: Participants of 6 series, 31 plus presently reported, 3) was 29.36 years and at onset was 26.62 years. There was female preponderance of 1.8. Complete triad of MRS was recorded in 8 (10.95%), and oligosymptomatic forms were as follows: GC + facial palsy, 5 (6.85%); GC + fissured tongue, 4 (5.48%); and facial palsy + fissured tongue, 1 (1.37%). Monosymptomatic GC was seen in 55 (75.34%) and upper lip involvement in 29 (39.72%). Conditions associated with GC included Down syndrome, rosacea, granulomatous vulvitis, and pregnancy. None of the cases were associated with Crohn disease and sarcoidosis. Intralesional triamcinolone acetonide (33, 45.21%) was the most common modality of treatment. Conclusion: Cases of GC from India over the past quarter of a century were reported rarely and showed female preponderance. This chronically recurrent entity with variable severity lacks larger studies and randomized controlled trials for optimum treatment.
Keywords: Granulomatous cheilitis, Melkersson–Rosenthal syndrome, orofacial granulomatosis
|How to cite this article:|
Sharma YK, Chauhan S, Deo K, Agrawal P. Granulomatous cheilitis: Report of three cases and systematic review of cases and case series reported from India. Clin Dermatol Rev 2020;4:12-6
|How to cite this URL:|
Sharma YK, Chauhan S, Deo K, Agrawal P. Granulomatous cheilitis: Report of three cases and systematic review of cases and case series reported from India. Clin Dermatol Rev [serial online] 2020 [cited 2020 Jan 27];4:12-6. Available from: http://www.cdriadvlkn.org/text.asp?2020/4/1/12/275242
| Introduction|| |
Granulomatous cheilitis (GC), also called Miescher cheilitis, who first (Meischer, 1945) described it as a rare idiopathic inflammatory disorder characterized by chronic painless swelling of the lips. It remains linked, despite a lingering controversy, to orofacial granulomatosis (OFG) as well as Melkersson–Rosenthal syndrome (MRS). OFG was first described by Wiesenfeld et al. as idiopathic persistent and/or recurrent labial enlargement, oral ulcers, and a variety of orofacial features in the absence of any identifiable systemic conditions. Melkersson (1928) linked concurrent relapsing facial palsy and transient facial edema. Addition of fissured tongue (Rosenthal, 1931) in three individuals belonging to two families completed the triad of recurrent orofacial edema, relapsing facial nerve palsy, and fissuring of the tongue (lingua plicata) which later became eponymous with Rosenthal and Melkersson. GC also continues to be regarded as a monosymptomatic form of MRS ever since such first reference by Mart in 1959. However, a possibility of GC and MRS being separate diseases too exists.
A literature search during workup of our recent cases of GC [Table 1] lead us to conduct a systematic review of its cases, and case series in English literature reported hereto from India and presented the same herein incorporating relevant details of the three cases of ours, reported presently [Table 2].,,,,,
|Table 1: Details of the findings of the three cases of granulomatous cheilitis being reported now|
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|Table 2: Case series of cases of granulomatous cheilitis reported from India|
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| Materials and Methods|| |
A search of the available literature on GC and MRS from PubMed, Scopus, Google Scholar, and other biomedical search engines was done. Keywords such as GC, MRS, and OFG were used. Patients of all age groups were included in the study. Cases with chronic macrocheilia due to other causes such as tuberculosis, leprosy, sarcoidosis, Ascher's syndrome, multiple endocrine neoplasia type IIb (MEN-IIb), and non-Hodgkin lymphoma were excluded from the study. A total of 70 cases – 39 single and 31 participants of 6 series (n, 2 to 13 cases) were reported– from India since 1994. The extracted data regarding patients'/disease characteristics, association with other diseases, and treatment were further analyzed, and systematic review was done as detailed below.
| Results|| |
Over the past 24 years, on an average, three (3.04) cases of GC/MRS were reported annually from India with a female preponderance of 1.8:1. Their mean age at presentation was 29.36 (youngest 8; oldest 65) years and at onset was 26.62 years (youngest 3 months; oldest 64 years).,, The complete triad of MRS was seen in 8 (10.95%) cases. Oligosymptomatic forms seen were as follows: GC with facial palsy in 5 (6.85%), GC with fissured tongue in 4 (5.48%), and facial palsy with fissured tongue in 1 (1.37%) case. Monosymptomatic GC was the most common (55, 75.34%) form. Lip involvement was of upper in 29 (39.72%); lower, 12 (16.44%); and both, 23 (31.51%). Gingiva was involved in 16 (21.91%); cheeks, 8 (10.95%); and buccal mucosae, vulva, and periorbital, 1 (1.37%) each. Facial palsy was seen in 14 (19.18%) and fissured tongue, 13 (17.80%) cases.
Out of the 73 cases, histopathological examination was done in 68 (93.15%) patients; 60 (82.19%) revealed granulomatous infiltration while 8 (10.96%) showed no granulomas.
The associated conditions reported included Down syndrome in two, a 30-year-old man and a 13-year-old girl;, rosacea, one; and granulomatous vulvitis, one. Two cases aged 25 and 32 years who were pregnant , had onset during the 4th month of pregnancy. Neither Crohn's disease nor sarcoidosis was associated.
Injection triamcinolone acetonide was the treatment modality administered most commonly in 33 (45.21%); others being systemic steroids (9, 12.32%), topical steroids (3, 4.11%), clofazimine (8, 10.96%), metronidazole (7, 9.58%), minocycline (7, 9.58%), doxycycline (2, 2.74%), dapsone (2, 2.74%), azithromycin (1, 1.37%), co-trimoxazole (1, 1.37%), acyclovir (1, 1.37%), gingivectomy (7, 9.58%), cheiloplasty (1, 1.37%), and physiotherapy (2, 2.74%). Biological immunomodulators were not tried in any case.
All three of our cases [Table 1] of GC presented with persistent painless swelling of the lips [Figure 1]a-e], had no gastrointestinal/respiratory complaints, and were negative to patch test with standard metals, bakery, and dental allergens. Mantoux test, slit-skin smear, chest X-ray, and histopathological examination alone and/or with special stains, angiotensin-converting enzyme assay, and patch tests excluded fungal infections, tuberculosis, leprosy, sarcoidosis, and contact dermatitis. Skin histopathology [Figure 2]a-c; case 1] in all three of our patients showed identical noncaseating epithelioid cell granulomas with congested capillaries within a fibrocollagenous stroma.
|Figure 1: Case 1: (a) Erythematous swelling of lips, cheeks, and chin with perioral crusting and fissuring. (b) Reduction in swelling at 2 months. Case 2: (c) Erythematous swelling of the upper lip. (d) Reduction in swelling at 6 weeks. Case 3: (e) Erythematous swelling involving upper lip and philtrum|
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|Figure 2: Case 1: (a) Stratified squamous epithelium with atrophy at places with dense inflammatory infiltrate in the underlying connective tissue (H and E, ×10). (b and c) Multiple focal collections of epithelioid cells along with multinucleated giant cells (H and E, ×40)|
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| Discussion|| |
GC is a distinct clinicopathologic entity of unknown origin; none of the possible hypotheses – genetic, infections, dietary, and contact allergens – have been proven as etiopathogenetic. Genetic evidence, scanty as yet, comprises: first; autosomal dominant inheritance pattern and detection – on chromosomal analysis of peripheral blood lymphocyte culture – of 9p trisomy in a Belgian child and an unbalanced product of a balanced 9p/21p translocation in her mother, both of them having MRS, and second, FATP1 mutation, identified through exome sequencing, causing MRS in a Han Chinese family. Some of the triggers suggested include carbonated drinks, chocolate, cinnamon, beer, benzoates, cinnamaldehyde, monosodium glutamate, food additives, and dental materials such as amalgam, mercury, cobalt, gold, and zinc., Allergy to gluten-rich diet was found in one of the cases in an Indian study.
The clinical presentation of OFG or its subset GC may sometimes, like sarcoidosis, be a consequence of granulomatous proliferation of any organ or part of the body such as facial, labial, mucosal, and gingival. GC has also been reported to precede, follow, or be concurrent with an extraintestinal form of Crohn's disease; the mucosal damage characteristics of both conditions can, at least in part, be due to increased tumor necrosis factor-α. In a systematic review of 173 Italian children with OFG, Crohn disease was present concurrently in 70 (40.4%). None of the Indian studies reported association with Crohn's disease or sarcoidosis.
Odontogenic infection, especially with Peptostreptococcus spp., Eubacterium spp., and Streptococcus spp., has been found associated with GC in several reports that describe remission after treatment of the infection. Other infective causes include Mycobacterium tuberculosis and Mycobacterium leprae.
Mean age at presentation of the cases in this systematic analysis was 29.36, range: 8–64, years. The mean ages recorded in different overseas studies have been 20 (UK), 25 (Denmark), 33.2, and 33.8 (US), years.
The female preponderance was observed in both the above-mentioned studies from the US., However, the UK  study recorded no gender preponderance, while only a slight male preponderance of 1.1 existed in the Denmark study.
GC represents a monosymptomatic form of MRS. In a study of 36 cases (Greene and Rogers), 42% had orofacial involvement as GC at presentation. Worsaae et al. reported labial swelling in 87.8% (6); upper lip-to-lower lip ratio being 1.1:1. Wiesenfeld et al. reported facial swelling in 47% (28) and labial swelling in 68% (41): upper in 45% (27) and lower in 50% (30). Zimmer et al. reported facial swelling in 50% (21) and labial in 74% (31). Among the Indian studies, upper lip involvement was most frequent (29, 39.72%), followed by both lips (23, 31.51%). The disease can also affect other oral and facial regions, including face, oral mucosa, gums, tongue, pharynx, and larynx; patients may report pain/burning, especially with associated erythema, fissures, erosions, or scaling of the lips. One Indian case had concurrent granulomatous vulvitis; another rosacea; and two others, Down syndrome., Two pregnant Indian ladies had onset of GC during the 4th month of pregnancy.,
Facial palsy has been reported as 19% and 47% in two studies from the US , and 13% from the UK. Among the Indian cases, 14 (19.18%) had facial palsy.
Fissured tongue present in 13 (17.80%) of the cases from India has been reported in 50% cases of a US  based study and barely 2% in a UK  based one.
Nonnecrotizing granulomas are not always present in the histopathological sections of GC; in general, corroboration of clinical diagnosis, especially in the early stages, is based on the findings of nonnecrotizing dermal granulomas, edema, lymphangiectasia, and perivascular lymphocytic infiltration. The differential diagnosis should include diseases that involve facial edema, conditions caused by granulomas, and generally, all chronic forms of macrocheilia such as tuberculosis, leprosy, sarcoidosis, Ascher's syndrome, MEN-IIb, and non-Hodgkin lymphoma.
No placebo-controlled studies exist to evaluate the effectiveness of the various treatments due to the rare occurrence of GC. Intralesional triamcinolone acetonide has been most commonly used with/without clofazimine or dapsone. It was also the most commonly used modality in the cases of our systematic review (33, 45.21%). Other therapeutic approaches used have included antimicrobial/anti-inflammatory agents such as erythromycin, tetracycline, minocycline, and metronidazole; anti-allergic agents such as tranilast; and immune modulators such as thalidomide, etanercept, and infliximab.,, Recalcitrant cases can be treated with reduction gingivectomy and cheiloplasty, as was done in some of the Indian cases. Although the clinical course and therapeutic response of these patients of GC is often unpredictable, spontaneous remissions and recurrences are not uncommon.
| Conclusion|| |
Despite being a distinct clinicopathologic entity, GC remains a rare, often difficult-to-diagnose condition due to its wide spectrum of presentation that requires a more vigilant examination and thorough investigation. The cases reported from India revealed female preponderance of 1.8, and the mean age at presentation was 29.36 years and at onset was 26.62 years. GC (monosymptomatic form) was the sole manifestation in 75.34% cases; the upper lip was the most common site (39.72%). The most common treatment modality in this systematic analysis was intralesional steroids, followed by systemic steroids without any standard dosage regimen/treatment protocol. According to our systematic review, the management of this idiopathic condition is usually symptomatic and lacks consensus. The aim of this analysis was to create a clearer picture of the clinical presentation and epidemiology of this uncommon chronically recurrent condition in our country so as to underline the need for evolving standard treatment protocol with larger studies and longer follow-up.
Declaration of patient consent
The informed consent was obtained for participation in the study and publication of data and images for research and educational purposes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]