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Granulomatous cheilitis: Back to the Future


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By Warren R. Heymann, MD, FAAD
June 1, 2022
Vol. 4, No. 22

I opened my dermatology practice in 1985 — looking retrospectively, life was then both simpler and more complicated. It was the pre-computer era when patients paid their fee at the time of their visit, utilizing a peg-board system. The ledger would balance at the end of the day; patients would take their receipt and submit it to their insurance company for reimbursement (no kidding!). Medically, managing diseases such as severe psoriasis to achieve a PASI 100 was a pipe dream compared to our current biologic reality. Today, for uncommon, recalcitrant disorders such as granulomatous cheilitis (GC) our first-line treatments are intralesional steroid injections, antibiotics, and methotrexate — just as in 1985. Appropriately, Back to the Future was released that year.

In 1985 Weisenfeld et al conceptualized “oro-facial granulomatosis (OFG)” encompassing granulomatous cheilitis (GC) and the Melkersson-Rosenthal syndrome (MR). The following is an excerpt from their abstract:

A study of 60 patients with oro-facial granulomatosis has been conducted and the clinical presentation of this disorder defined. It encompasses the previously recognised clinical entities of Melkersson-Rosenthal syndrome and cheilitis granulomatosa. The pathological features of the disease are lymphoedema and the presence of multiple non-caseating giant cell granulomata. These granulomata are histologically indistinguishable from those found in both gastrointestinal Crohn's disease and systemic sarcoidosis. Within this series of patients, nine had evidence suggestive of gastrointestinal Crohn’s disease, and in six this was confirmed. A diagnosis of sarcoidosis was made in a further two patients. The relationship of oro-facial granulomatosis to these systemic granulomatous diseases is not yet clear. (1)

OFG most commonly affects the lips, presenting as a nontender and persistent swelling involving one or both lips. Intraoral sites can also be affected. The tongue may display fissures, edema, paresthesia, erosions, or cause dysgeusia. Gingivae can develop swelling, erythema, pain, or erosions. The buccal mucosa often appears cobblestoned. According to Basal et al: “Delay in diagnosis and evaluation of OFG may cause indurated, swollen lips that may compromise cosmetic face value, speaking, and eating functions, and other possible systemic granulomatous disorders can be missed…OFG is an entity of exclusion. The exact etiology of OFG is still unclear and is multifactorial. It may be a manifestation of Crohn’s disease (oral lesions may manifest as an extraintestinal site of disease involvement and may precede the gastrointestinal lesions in as many as 30% of the cases), tuberculosis, sarcoidosis, leprosy, systemic fungal infections, foreign-body reactions, and genetic predisposition. Tooth-associated infections, allergy to dental materials such as amalgam fillings, hygiene products, food additives, or contact allergens have been reported as causative agents. Food preservatives containing benzoates, cinnamon, chocolate as well as products containing glitter (lip gloss), perfumes, and flavorings, have been proposed as potential triggers for OFG.” (2) COVID-19 has been reported to trigger a recurrence of MR in a 51-year-old woman whose disease had been in remission for 4 years. (3)

Illustration for DWII on granulomatous cheilitis
Histological analysis is useful, notably for incomplete forms of OFG such as GC, to exclude other granulomatous disorders including cutaneous tuberculosis, leishmaniasis, and leprosy (especially in endemic regions). Histopathologic features demonstrate subepithelial edema, an increased number of dilated lymphatic vessels, granulomatous infiltration and non- necrotic, non- caseous granulomas, with or without multinucleated giant cells, perivascular mononuclear infiltration, and occasional focal fibrosis. Edema is due to lymphatic and vascular destruction by granulomas. These pathological findings are not always observed, and their absence should not exclude the diagnosis of OFG. In their series of 39 OFG patients, in those who were biopsied, 73.5% displayed non- caseous granulomas. In the remaining 26.5%, non-diagnostic chronic inflammation granulomas were observed. (4)

Treating GC is essential because of attendant functional impairment and profound emotional distress. Due to the relative rarity of the disorder, controlled clinical trials have not been performed. Corticosteroid therapy (topical, intralesional, and occasionally systemic) remains the initial treatment for GC. (5) Durgin et al administered intralesional triamcinolone (ILK) to 6 patients with GC. 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 complete response; 1 had recurrence after 35 months; and 1 had sustained resolution at 22 months. (6) Other anti-inflammatory, immunomodulatory, or immunosuppressive treatments including topical tacrolimus, or oral clofazimine, thalidomide, dapsone, doxycycline, azithromycin, methotrexate, mycophenolate mofetil, azathioprine, and tumor necrosis factor inhibitors have yielded inconsistent results. JAK inhibitors have yet to be reported for OFG therapy but are in the offing. (6,7)

Advances in therapy will be based on comprehending the pathogenesis of OFG. Sorting out the precise contributing roles of genetic predisposition, immunology of the predominant Th-1 response, allergens, microbial influences, role of UV radiation, and relationship to Crohn disease is a monumental challenge. Therapeutically, we are still driving a DeLorean. It is high time to switch to a Tesla.

Point to Remember: The physical and emotional impact of granulomatous cheilitis is profound. The diagnosis remains one of exclusion (most notably ruling out Crohn disease and sarcoidosis). Steroids remain first-line therapy. Advances in therapy will require further research into the pathogenesis of this enigmatic disease.

Our expert’s viewpoint

Misha Rosenbach, MD, FAAD
Associate Professor of Dermatology at the Hospital of the University of Pennsylvania

It is always a genuine pleasure to be asked to add commentary to one of Warren’s DWI&I pieces, but as always, it’s a challenge to add to his contributions or compare with his eloquent summary of the topic. In order to expand and further contextualize this piece, let me start with the caveat that I am a ‘lumper,’ often questioning, say, why do we separate 6+ subtypes of entities such as pigmented purpuric dermatoses or pityriasis rubra pilaris if doing so fails to impact our approach to patient workup or treatment? Similarly with granulomatous inflammation of the face, I would argue that there are several overlapping Venn diagrams at play where different entities share some common features, and for the clinician, there are some valuable pearls to keep in mind.

First: I think it’s helpful to consider that Melkersson Rosenthal (the “triad that’s never the triad”), granulomatous cheilitis, and oral facial granulomatosis are very similar if not the same entity. For all patients with this pattern of inflammation, it’s important to rule out sarcoidosis (rare) and Crohn disease (extremely common). Finding Crohn disease impacts the patients, of course, but also makes it easier on the treating dermatologist — there is much more data to guide treatment for IBD than for OFG. Remember that Crohn disease can occur anywhere along the GI track, “from the mouth to the anus” (and beyond, with perianal and groin involvement such as skin tags, cobblestoning, genital swelling, and knife-cut ulcers — but also can occur beyond the lips, with facial swelling, as in OFG).

Second: There are some simple adjunctive nonpharmacological interventions that may benefit many patients. As Warren points out, the inflammation here may be deep, and can be missed on superficial biopsy, and is often perivascular or perilymphatic. This leads to physical obstruction of the drainage of the face. Patients may benefit from physical therapy, occupational therapy, lymphatic massage, and special fitted “compression masks” to remove / limit edema that develops overnight. Even if you successfully treat patients’ inflammation, often there is residual damage, impaired drainage, and/or scarring. The resultant edema can be improved with physical modalities (and, occasionally, surgical correction). Additionally, Warren briefly mentions the potential for allergic reactions to trigger inflammation; while I personally remain unconvinced of the strength of this association, it is simple and very low risk to advise patients to avoid common allergic triggers (benzoates, cinnamates), and/or to get contact allergy testing.

Third: We have limited data to guide any therapeutic choice. Balance your treatment with the severity of the disease, patient comorbidities and the patients’ perception of the disease severity and impact, and the safety and side effect profile of various options. However, whatever agent you choose, keep in mind that granulomatous inflammation is slow to develop, and slow to resolve — often taking 3 months to show an initial response and 6 months to see full efficacy from a new treatment. Another caveat is dosing — many treatment approaches involve repurposed agents used off-label. Dermatologists are often comfortable with these agents based on their dosing for psoriasis; however, granulomatous diseases often require higher dosing regimens (the dosing for adalimumab for Crohn Disease is different than that for psoriasis, for example). Treatment is used to stop the inflammation — but, as stated above, there may be residual scarring, impaired drainage, and edema. This doesn’t often require systemic anti-inflammatory treatment but may benefit from local therapy as previously discussed.

Finally: This discussion highlights where dermatology has been, and, hopefully, where it’s headed. In 2022 we have access to amazing science which can help unlock the similarities and differences between various entities. Our field should be prepared to modernize and update our thinking about different diseases — including considering when it’s appropriate to lump them together under one broader all-encompassing term. The objective is helping patients, and different names for the same disease sometimes can hinder achieving that goal.

  1. Wiesenfeld D, Ferguson MM, Mitchell DN, MacDonald DG, Scully C, Cochran K, Russell RI. Oro-facial granulomatosis--a clinical and pathological analysis. Q J Med. 1985 Jan;54(213):101-13. PMID: 3975343.

  2. Bansal S, Garg A, Khurana R, Bansal A. Primary orofacial granulomatous involvement of lip and gingiva only: A diagnostic challenge. J Indian Soc Periodontol. 2020 Nov-Dec;24(6):575-578. doi: 10.4103/jisp.jisp_18_20. Epub 2020 Nov 14. PMID: 33424177; PMCID: PMC7781253.

  3. Taşlıdere B, Mehmetaj L, Özcan AB, Gülen B, Taşlıdere N. Melkersson-Rosenthal Syndrome Induced by COVID-19. Am J Emerg Med. 2021 Mar;41:262.e5-262.e7. doi: 10.1016/j.ajem.2020.08.018. Epub 2020 Aug 15. PMID: 32829989; PMCID: PMC7428670.

  4. Galdiero MR, Maio F, Arcoleo F, Boni E, Bonzano L, Brussino L, Cancian M, Cremonte L, Del Giacco SR, De Paulis A, Detoraki A, Firinu D, Lamacchia D, Loffredo S, Nettis E, Parente R, Parronchi P, Pellacani G, Petraroli A, Rolla G, Senter R, Triggiani M, Vitiello G, Spadaro G, Bova M. Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature. Allergy. 2021 Jul;76(7):2189-2200. doi: 10.1111/all.14799. Epub 2021 May 15. PMID: 33641182.

  5. Jamil RT, Agrawal M, Gharbi A, Sonthalia S. Cheilitis Granulomatosa. 2021 Apr 29. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29261927.

  6. Durgin JS, Rodriguez O, Sollecito T, Tanaka T, English JC 3rd, Shields BE, Rosenbach M. Diagnosis, Clinical Features, and Management of Patients With Granulomatous Cheilitis. JAMA Dermatol. 2021 Jan 1;157(1):112-114. doi: 10.1001/jamadermatol.2020.4383. PMID: 33175085; PMCID: PMC7658797.

  7. Kreuter A, Koushk-Jalali B, Oellig F, Tigges C. Low response of granulomatous cheilitis to currently established treatments. J Eur Acad Dermatol Venereol. 2021 Jul;35(7):e453-e454. doi: 10.1111/jdv.17208. Epub 2021 Mar 16. PMID: 33651435.



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