INTRODUCTION — Granuloma faciale is a benign and chronic inflammatory dermatosis that presents as single or multiple red-brown or violaceous papules, plaques, or nodules that range from several millimeters to several centimeters in diameter (picture 1A-E). The most common site for granuloma faciale is the face. Treatment can be challenging.
The clinical features, diagnosis, and treatment of granuloma faciale will be reviewed here.
EPIDEMIOLOGY — Granuloma faciale is rare. However, the exact incidence and prevalence are unknown. Middle-aged White adults are the most common population in which granuloma faciale is reported, and males are more likely to be affected than females. In a French retrospective analysis of 66 patients with granuloma faciale, 41 patients were men and 25 were women, giving a sex ratio of 1.7:1 . All patients were adults and the mean age was 53 years (range 20 to 85 years). Granuloma faciale rarely occurs in children .
PATHOGENESIS — The name "granuloma faciale" is a misnomer because granuloma formation is not a histologic feature of this disorder . Rather, vasculitis is a common histologic finding, suggesting that granuloma faciale may be a localized form of cutaneous small vessel vasculitis [1,3,4].
The factors that contribute to the development of granuloma faciale are unknown. Hypersensitivity reactions, actinic exposure, infection, trauma, and radiation are examples of proposed contributors; however, roles for these factors are unproven [4,5].
Several studies have attempted to elucidate the pathogenesis of granuloma faciale [6-9]. Potentially relevant immunofluorescence and immunohistochemical findings include:
●Deposition of immunoglobulins and complement around vessels has been detected in granuloma faciale, suggesting that an immune complex-mediated mechanism resulting in vascular damage may play a role . However, not all granuloma faciale specimens exhibit this finding [4,10]. (See 'Histopathology' below.)
●Evidence for high interleukin-5 (IL-5) production and clonal expansion of CD4+ T cells was detected in a study that analyzed specimens from two patients with granuloma faciale . IL-5 may play a role in eosinophil recruitment, and eosinophils are usually present in the inflammatory infiltrate of granuloma faciale.
CLINICAL FEATURES — Granuloma faciale most commonly manifests as a single red-brown or violaceous papule, plaque, or nodule on the face (picture 1A-E) [1,4,11,12]. The lesions usually range from several millimeters to several centimeters in diameter. The surface of granuloma faciale tends to be smooth with prominent follicular orifices and telangiectasia.
Granuloma faciale usually is asymptomatic. Pruritus occasionally is present and ulceration is rare . Lesions of granuloma faciale tend to persist once they appear; spontaneous resolution is uncommon .
Although the majority of granuloma faciale presents as a solitary skin lesion on the face, multiple skin lesions and extrafacial involvement (with or without concomitant facial involvement) also may occur [14-21]. In a retrospective analysis of 66 patients with granuloma faciale, 25 patients (38 percent) had multiple lesions, six patients (6 percent) had extrafacial involvement alone, and one patient (1.5 percent) had both facial and extrafacial involvement . Among the patients with facial lesions, the most common sites were the forehead, cheeks, and nose.
Rhinophyma-like granuloma faciale and keloidal granuloma faciale are rare clinical variants. In rhinophyma-like granuloma faciale, the inflammatory process results in significant distortion of the nasal contour [22,23]. Keloidal granuloma faciale presents with firm, sharply circumscribed plaques or nodules [5,24,25].
ASSOCIATED DISORDERS — There are multiple case reports that associate granuloma faciale with eosinophilic angiocentric fibrosis, a rare, benign, chronic, and progressive fibrosing disorder that affects mucosal surfaces [26-32]. Eosinophilic angiocentric fibrosis usually involves the sinonasal tract and upper respiratory airways. This disease can result in nasal masses, epistaxis, breathing difficulties, epiphora, and proptosis . Eosinophilic angiocentric fibrosis and granuloma faciale both demonstrate eosinophil-rich infiltrates, microvascular inflammation, progressive fibrosis, and similar subpopulations of cytotoxic, regulatory, and helper T cells, suggesting that these two disorders may represent the same pathologic process but in distinct anatomic sites .
The development of granuloma faciale in a patient with rheumatoid arthritis and Sjögren syndrome has been reported, raising questions about whether pathogenic pathways are shared between these diseases . Simultaneous regression of granuloma faciale during treatment of prostate adenocarcinoma during hormonal treatment for prostate cancer in another patient led other authors to postulate whether tumor-secreted substances may function as antigenic stimulants for the inflammatory process in granuloma faciale . Data are insufficient to draw conclusions about a relationship between granuloma faciale and these diseases.
HISTOPATHOLOGY — The histology of granuloma faciale is characterized by a diffuse, polymorphous, inflammatory infiltrate involving primarily the upper half of the dermis (picture 2) [1,4]. Occasionally inflammation extends into the deep reticular dermis and subcutaneous tissue. The inflammatory infiltrate consists of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells (picture 3). In some cases, eosinophils are few in number or absent .
A thin zone of uninvolved papillary dermis separating the epidermis from the inflammatory infiltrate is frequently, but not always present in tissue specimens from granuloma faciale (picture 4). The term "Grenz zone" Is used to refer to this finding. In a retrospective study of 73 skin specimens from 66 patients with granuloma faciale, a Grenz zone was identified in 54 specimens (74 percent) . Dermal fibrosis, often presenting as concentric fibrosis around blood vessels, is another common finding [1,4].
The theory that granuloma faciale represents a form of cutaneous small vessel vasculitis is supported by the frequent histologic finding of vascular damage (picture 5A-B). Specimens often exhibit perivascular inflammatory infiltrates penetrating vessel walls. Leukocytoclasis (karyorrhexis), extravasated red blood cells, and hemosiderin deposits also may be seen [1,4]. However, necrotizing vasculitis with fibrinoid necrosis of vessel walls is seen in only a minority of patients. Among the 73 specimens examined in the retrospective study mentioned above, only five (7 percent) exhibited necrotizing vasculitis .
Direct immunofluorescence studies of granuloma faciale have yielded variable findings [4,6,10,37]. Some analyses have identified deposition of immunoglobulins and complement in vessel walls [6,37], while others have not found this to be a consistent finding [1,4,10]. Immunoglobulin deposition at the basement membrane zone is an additional inconsistent finding [1,4,10,37].
DIAGNOSIS — The clinical features of granuloma faciale overlap with other skin diseases. Thus, the diagnosis of granuloma faciale is made based upon correlation of the clinical and histologic findings . (See 'Differential diagnosis' below.)
Clinical evaluation — Clinical findings that strongly support a diagnosis of granuloma faciale are the presence of one or more persistent, asymptomatic, smooth, red-brown or violaceous papules, plaques, or nodules with follicular prominence, especially when located on the face. Findings of significant scale, ulceration, or significant pruritus should raise suspicion for other skin disorders.
Diascopy (examination while applying pressure to a skin lesion with a glass slide) may demonstrate an "apple jelly" appearance, thereby limiting differentiation from true granulomatous disorders, such as lupus vulgaris and sarcoidosis . (See "Cutaneous manifestations of sarcoidosis", section on 'Examination and biopsy' and "Cutaneous manifestations of tuberculosis", section on 'Lupus vulgaris'.)
Skin biopsy — A skin biopsy is necessary to confirm the diagnosis. The biopsy specimen should contain the full thickness of the skin. We typically perform a punch biopsy that extends into the superficial subcutaneous fat. (See "Skin biopsy techniques", section on 'Punch biopsy'.)
Histologic findings that strongly support a diagnosis of granuloma faciale include:
●Mixed dermal inflammatory infiltrate (neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells)
●Grenz zone (present in most patients)
Other histologic features of granuloma faciale are described separately. (See 'Histopathology' above.)
Dermoscopy — The utility of dermoscopy as a diagnostic tool for granuloma faciale remains to be determined. One case report described the following dermoscopic findings: pink background; white striations; and prominent, follicular orifices . Another case report documented whitish-grayish, structureless areas; branching vessels; and orthogonal, whitish streaks . Amorphous, yellow or yellow-brown areas corresponding to hemosiderin deposition may also be observed .
DIFFERENTIAL DIAGNOSIS — Misdiagnosis of granuloma faciale is common [1,13]. Among 66 patients with granuloma faciale reviewed in a retrospective study, the clinical diagnosis prior to a biopsy was granuloma faciale in only 10 patients (15 percent) .
Examples of the skin disorders most commonly confused with granuloma faciale include cutaneous sarcoidosis, cutaneous lymphoma, pseudolymphoma, cutaneous lupus erythematosus, erythema elevatum diutinum, and immunoglobulin G4 (IgG4)-related disease . Skin biopsy distinguishes granuloma faciale from these other disorders:
●Cutaneous sarcoidosis – Cutaneous sarcoidosis may present as a wide variety of skin findings, including red-brown or violaceous papules, plaques, or nodules (picture 6A-B). In particular, the lupus pernio variant is characterized by violaceous or erythematous papules, plaques, or nodules on the central face (picture 7A-B). In contrast to granuloma faciale, noncaseating granulomas are detected on histologic examination . (See "Cutaneous manifestations of sarcoidosis".)
●Cutaneous lymphoma – The nodules or plaques of B-cell lymphomas or primary cutaneous anaplastic large cell lymphoma may resemble granuloma faciale (picture 8). A skin biopsy demonstrates an abnormal lymphocytic infiltrate consistent with cutaneous lymphoma.
●Pseudolymphoma – Pseudolymphoma (also known as cutaneous lymphoid hyperplasia) is a benign inflammatory disorder that presents with clinical and/or histologic findings similar to cutaneous lymphoma . Affected patients present with solitary or multiple erythematous to violaceous plaques or nodules (picture 9). Biopsy reveals lymphocyte accumulation in the skin . Possible triggers include drugs, insect bites, trauma, infection, and other factors. (See "Cutaneous T cell pseudolymphomas" and "Cutaneous B cell pseudolymphomas".)
●Cutaneous lupus erythematosus – Discoid lupus erythematosus often presents as erythematous scaly plaques with follicular plugging that evolve into atrophic, disfiguring scars (picture 10A-B). The head is a common site for involvement. Tumid lupus erythematosus (also known as lupus erythematosus tumidus) is characterized by erythematous non-scaly, edematous papules or plaques on areas of sun-exposed skin (picture 11). Unlike granuloma faciale, the inflammatory infiltrate in discoid and tumid lupus erythematosus is lymphocytic, rather than mixed. (See "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus' and "Overview of cutaneous lupus erythematosus", section on 'Lupus erythematosus tumidus'.)
●Erythema elevatum diutinum – Extrafacial granuloma faciale may be difficult to distinguish from erythema elevatum diutinum (EED), a form of leukocytoclastic vasculitis characterized by the development of erythematous, violaceous, or brown papules, plaques, or nodules. In contrast to granuloma faciale, which most frequently involves the face, the extremities and buttocks are typical sites for EED. Although both EED and granuloma faciale demonstrate inflammatory infiltrates containing neutrophils and eosinophils, as well as vasculitis and fibrosis on histopathologic examination, some histologic features may help to distinguish these diseases. A study that compared histologic findings from nine patients with EED and 41 patients with granuloma faciale found that granuloma faciale specimens were more likely to exhibit a dense inflammatory infiltrate, a predominance of eosinophils, and the presence of plasma cells . In addition, granulomas were detected in two specimens of EED, but were not detected in any of the specimens of granuloma faciale . (See "Erythema elevatum diutinum".)
●IgG4-related disease – IgG4-related disease presents with masses in internal organs, elevated serum IgG4, and, occasionally, cutaneous involvement . Given that granuloma faciale and IgG4-related disease both demonstrate plasmacellular infiltrates, eosinophils, storiform fibrosis, and obliterative vasculitis, a pathogenic relationship has been proposed . The histopathologic criteria for IgG4-related disease include dense plasmacellular infiltrate with IgG4/IgG ratio greater than 40 percent, fibrosis, and obliterative venulitis . When utilizing a threshold of 50 IgG4-positive plasma cells per high power field, up to 20 percent of patients with granuloma faciale meet the histopathologic criteria for diagnosis of IgG4-related disease [44-46]. Along with systemic evaluation in equivocal cases, the more stringent criterion (based on international consensus) of 200 IgG4-positive plasma cells per high power field permits distinction of IgG4-related disease from granuloma faciale . (See "Pathogenesis and clinical manifestations of IgG4-related disease".)
Other disorders that may clinically resemble granuloma faciale are basal cell carcinoma, granulomatous rosacea, Jessner's lymphocytic infiltration of the skin (picture 12A-B), fixed drug eruption (picture 13A-B), polymorphous light eruption (picture 14), and mastocytoma (picture 15).
TREATMENT — Although granuloma faciale is a benign and usually asymptomatic disorder, the chronic course and resulting cosmetic disfigurement drive most patients to seek treatment. A systematic review of articles documenting treatment of granuloma faciale between 2000 and 2016 identified topical and intralesional corticosteroids, topical tacrolimus, dapsone, laser therapy, and cryotherapy as the most frequently reported treatments .
However, because of a lack of high-quality data on the efficacy of treatments and the variable and unpredictable response of granuloma faciale to individual treatments, the best approach to the management of this condition remains unclear. Our approach to the treatment of granuloma faciale is reviewed here.
First-line therapy — Common first-line therapies for granuloma faciale are topical tacrolimus, cryotherapy, and topical or intralesional corticosteroid therapy. Although all of these therapies have been reported to be effective in some patients, none of the treatments have been evaluated in high-quality studies.
Given the common location of granuloma faciale on the face, topical tacrolimus is our preferred initial treatment because of the potential for side effects of dyspigmentation or scarring after cryotherapy and the risk for cutaneous atrophy from local corticosteroid treatment. Consideration for patient preference and treatment cost also may influence the selection of treatment.
Topical tacrolimus — Multiple case reports document improvement in granuloma faciale during treatment with topical tacrolimus, including patients who failed to respond to local corticosteroids or other treatments [8,40,48-56]. We typically instruct adults with granuloma faciale to apply topical tacrolimus 0.1% ointment twice daily to the affected area. We expect to see at least partial improvement within the first three months.
In most reports, marked clinical improvement or resolution occurred within two to six months of twice daily treatment. Both disease remissions lasting for at least six months to three years and disease recurrences have been reported following cessation of topical tacrolimus treatment [48,49,54,56]. Randomized trials and long-term follow-up studies will be useful for confirming the efficacy of topical tacrolimus. Treatment of granuloma faciale with this agent generally has been well tolerated [48,49,51].
It is possible that topical pimecrolimus, a related drug, also may have benefit for granuloma faciale. Dramatic improvement in granuloma faciale during treatment with topical pimecrolimus (twice daily for two months) has been documented in a case report .
Cryotherapy — Cryotherapy may be beneficial for granuloma faciale. In an uncontrolled prospective study, nine adults with granuloma faciale on the face were treated with spray or contact cryotherapy at baseline and after one, three, and six months, as needed . Spray treatments consisted of one or two 20- to 30-second freeze-thaw cycles with liquid nitrogen; contact cryotherapy involved one to three 15- to 20-second freeze-thaw cycles. One month after the first treatment, two patients achieved complete clearance. By the end of the third month, seven patients had cleared, and by the end of the sixth month all patients had cleared. Two patients experienced mild postinflammatory hypopigmentation that resolved within four months. No recurrences were observed during a follow-up period of 24 months.
Cryotherapy for granuloma faciale should be performed only by clinicians trained in the procedure. Potential adverse effects include transient or permanent dyspigmentation and scarring. Although studies documenting efficacy have described freeze times ranging from 15 to 30 seconds [20,58,59], consideration for the treatment site and concern for adverse effects influence the duration of freezing. We typically administer one freeze-thaw cycle and repeat treatment every four to six weeks. If a significant clinical response is not achieved after three to four treatments we discontinue this treatment.
Cryotherapy has also been combined with intralesional corticosteroid therapy; however, data are insufficient to determine whether combination treatment is superior to cryotherapy alone. The efficacy of this combination was reviewed in a case series of nine patients treated for facial granuloma faciale with one 20- to 30-second cycle of liquid nitrogen immediately followed by the injection of triamcinolone (5 mg/mL) intralesionally . The treatment was repeated every three weeks for several courses as needed. All patients achieved near-clearance of lesions and the only side effect reported was mild pain. No recurrences were observed during a follow-up period of six months to six years (mean 1.7 years). Of note, six of the nine patients in the series had a preceding history of an inadequate response to intralesional corticosteroid monotherapy. Case reports also document clinical improvement in granuloma faciale following combination cryotherapy and intralesional corticosteroid therapy [12,20].
Local corticosteroids — Local corticosteroid therapy is a common treatment for granuloma faciale [11,21,60]. Data are insufficient for a definitive recommendation on the best regimen for local corticosteroid treatment for granuloma faciale. The discomfort associated with intralesional corticosteroid injection is usually well tolerated but may be a deterrent for some patients. When treating with intralesional corticosteroid therapy, we utilize a 3 mg/mL concentration of triamcinolone acetonide. Injections may be repeated every four to six weeks. If there is no evidence of response after three injections, we usually discontinue this treatment.
When treating with a topical corticosteroid, we typically prescribe a high-potency (group 2 or group 3) topical corticosteroid and instruct the patient to apply the corticosteroid to the affected area twice daily for two weeks. Subsequently, we transition to twice-daily application of a low-potency topical corticosteroid (group 5 or 6) (table 1). If improvement is not evident within two to three months, we discontinue topical corticosteroid treatment.
The potential for benefit from local corticosteroid therapy is supported by a retrospective study of 38 patients with granuloma faciale that included several patients treated with topical or intralesional corticosteroid therapy . Responses to these treatments ranged from mild improvement to complete resolution . In addition, in a case report, a patient who failed to respond to two months of oral dapsone (100 mg per day) experienced substantial improvement after one month of high-potency topical corticosteroid therapy . Another report described improvement in granuloma faciale in two patients after intralesional corticosteroid treatment . However, there are also multiple reports of patients who have required other therapies for granuloma faciale following failure of local corticosteroid treatment [25,55,59,61].
Cutaneous atrophy is a potential adverse effect of topical and intralesional corticosteroid therapy. Close clinical follow-up is necessary to monitor for the development of atrophy. During treatment with a topical corticosteroid we reevaluate the treatment site approximately once per month.
Other therapies — Limited data suggest that other therapies can be effective for some patients.
Pulsed dye laser — A beneficial effect of 585 or 595 nm pulsed dye laser therapy on granuloma faciale is suggested by case reports and small case series [2,50,61-64]. As an example, in a series of four patients treated with a 595 nm pulsed dye laser sessions after failing cryotherapy, two achieved significant cosmetic improvement and two did not respond to laser treatment . In another series in which two patients were treated with pulsed dye laser and two had a topical corticosteroid treatment added to pulsed dye laser treatment after an initial slow response, three patients had excellent responses (complete flattening and bleaching of treated areas) and one had a partial response . Patients in this series received a total of three to eight treatments.
Side effects experienced by patients treated with pulsed dye laser therapy granuloma faciale include pain and transient dyspigmentation. Scarring is a potential complication.
Dapsone — Multiple case reports document clinical improvement in granuloma faciale during treatment with oral dapsone (25 to 200 mg per day) with or without intralesional corticosteroid therapy [26,66-69]. Several months of treatment may be necessary to achieve a satisfactory response. Because of the potential for serious adverse effects (table 2), we generally reserve dapsone treatment for patients who have failed to respond to first-line therapies or for patients for whom the extent of disease makes local treatment impractical.
Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for hematologic complications from dapsone. Screening for G6PD deficiency should be performed prior to initiating dapsone therapy. Topical dapsone may be an option for patients unable to tolerate systemic therapy. Five percent gel twice daily for nine months reportedly produced near complete resolution in single patient . (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'.)
Other — There are fewer reports to support the efficacy of other treatments. Intralesional rituximab appeared to improve granuloma faciale in a small case series . Systemic treatment with clofazimine (300 mg per day) , antimalarials , and colchicine (1 mg/day)  have been effective in individual patients. In addition, case reports document successful treatment of granuloma faciale with carbon dioxide (CO2) lasers, including a patient with the rhinophyma-like variant [22,74]. Of note, the development of keloidal granuloma faciale has been reported in a patient following CO2 laser treatment for a melanocytic nevus . Treatment successes with a potassium-titanyl-phosphate (KTP) laser , dermabrasion , excisional surgery , or topical psoralen plus ultraviolet A (PUVA) photochemotherapy  also are reported.
PROGNOSIS — Granuloma faciale generally persists indefinitely without treatment. Spontaneous resolution is uncommon .
SUMMARY AND RECOMMENDATIONS
●Granuloma faciale is a rare, idiopathic inflammatory disorder of the skin that manifests as red-brown or violaceous papules, plaques, or nodules. Granuloma faciale usually occurs in middle-aged adults. Granuloma faciale in children is rare. (See 'Epidemiology' above.)
●The most common location presentation of granuloma faciale is a single plaque or nodule on the face. Granuloma faciale also can present with multiple lesions and can occur on other skin areas. (See 'Clinical features' above.)
●The diagnosis of granuloma faciale is made based upon review of both the clinical and histologic findings. Histologic examination reveals a mixed inflammatory infiltrate in the dermis with neutrophils and eosinophils. A thin zone of uninvolved papillary dermis (Grenz zone) is often present. (See 'Diagnosis' above.)
●The treatment of granuloma faciale can be challenging. Responses to treatment are variable and unpredictable and data on the treatment efficacy are limited. Treatments have included topical and intralesional medications, systemic medications, laser treatment, surgery, and psoralen plus ultraviolet A (PUVA) photochemotherapy. (See 'Treatment' above.)
●For patients with granuloma faciale, we suggest topical tacrolimus as initial treatment based upon multiple case reports that suggest efficacy and the well-tolerated nature of this treatment (Grade 2C). Alternative options for first-line therapy are cryotherapy and topical or intralesional corticosteroid therapy. (See 'First-line therapy' above.)
●Granuloma faciale exhibits a chronic course. Spontaneous resolution is uncommon. (See 'Prognosis' above.)