Facial granulomaL92.2

Colcott-Fox 1895; Wigley 1945; Pedace and Perry 1966

Rare, chronic, usually benign, inflammatory skin disease(dermatologically accentuated systemic disease) of unknown etiology, with a distinct clinical (in an early stage peau d`orange aspect of the surface) and histologic aspect, characterized in an early stage by a histoeosinophilia, although inconstant, but usually formative, as well as signs of a leukocytoclastic vasculitis. This early inflammation is overlaid over time by increasing fibrosis, clinically recognizable by a consistency proliferation of plaques (nodules).

Rare! In large dermatological centers this diagnosis is made 1-2x per year.

Preferably in whites.

Men are significantly more often affected than women. In one "medium-sized" study (n=11) the ratio was about 80%, in another 60% in favor of men.

Ultimately unknown. In the past, the disease was (erroneously) classified as a granulomatous disease. However, the vasculitic phenomena with leukocytoclasia, which can be detected in the early stage of the disease by fine tissue analysis, rather point to a vasculitic genesis.

The concordant occurrence with sino-nasal localized eosinophilic angiocentric fibrosis suggests a close pathogenetic relationship of both diseases (see below). It is increasingly considered to classify granuloma faciale as a cutaneous manifestation of an IgG4-associated disease.

Associated infections (streptococcal infections, syphilis, viral infections -hepatitis virus, HIV, tumor diseases (prostate carcinoma, lymphoma, multiple myeloma etc.) as well as autoimmune diseases (rheumatoid arthritis, celiac disease, Crohn's disease, uveitis) have been observed.

Possible at any age, preferentially affecting adults between 40-60 years of age; less commonly, children may also be affected.

V.a. face, preferentially on nose, chin, forehead, temples and cheeks, also on capillitium.

About 10-20% of cases are extrafacial: upper and lower extremities, capillitium, trunk (see Fign.).

Involvement of the oral mucosa is rare (see also the rhino-nasal involvement pattern of eosinophilic angiocentric fibrosis.

Roundish to oval, 0.5-2.0 cm in size, usually solitary but also several or numerous, slightly raised, firm, asymptomatic, red or brown-red, with longer persistence also brown-yellowish, scale-free plaques with dilated follicular orifices. This results in an "orange peel-like" surface aspect at an early stage of the disease. This is no longer detectable in later, long-term plaques or nodules. In these cases, a surface smooth, follicle-free surface relief may present. Occasionally, more severe fibrosis is also observed, so that keloid-like nodular structures may appear (Verma R et al. 2005).

Rare are large-area, 5.0- 7.0 cm, bizarrely configured, firm plaques that prove markedly resistant to therapy. Diascopically, a yellow-brownish intrinsic infiltrate is characteristic. The rare coincidental occurrence with other (IgG4-associated) diseases is possible:

• Eosinophilic angiocentric fibrosis: Inflammatory pseudotumorous mucosal affection interpreted as a monotopic sinonasal variant of IgG4-associated autoimmune disease. Since it can occur coincidentally with granuloma faciale, a close pathogenetic association of both entities can be assumed especially since their histologic substrate has a high degree of commonality.
• Retroperitoneal fibrosis

In very rare cases, granuloma faciale has been implicated as a precursor of severe vasculitides such as:

• Wegener's granulomatosis(granulomatosis with polyangiitis)
• Churg-Strauss syndrome(eosinophilic granulomatosis with polyangiitis) (single case reports).

In the early stage, the signs of leukocytoclastic vasculitis can be detected with perivascular oriented neutrophilic granulocytes and nuclear dust and fibrin in the vessel walls. Eosinophilic leukocytes are encountered to varying degrees. Fibrinoid vascular occlusions are also observed in early phases.

In clinically "full-blown" lesions, a dense, diffuse infiltrate is found in the upper and middle dermis. Vascular orientation is usually not (or no longer) detectable. Epidermis and skin appendages remain uninvolved. The infiltrate-free border strip is typical. The infiltrate consists of lymphocytes, neutrophilic leukocytes and nuclear dust, eosinophilic leukocytes, histiocytes and plasma cells. In addition, proliferation of fibrocytes.

Late stage onion-skin-like fibrosis may impose; storiform patterns are also possible. Eosinophilia is largely absent. An accentuated plasma cellular component is often found. Occasionally, granulomatous tissue reaction with histiocyte- and granulocyte-rich infiltrates is also observed.

Schematizingly, the following algorithm can be established:

No groundbreaking fluorescence pattern. Deposits of immunoglobulins (especially IgG), complement (C3/C4) and fibrinogen were detected at the dermo-epidermal junction zone, but in the vessel walls and around vessels of the middle dermis.

Clinical Differentials:

• Drug reaction, fixed: Rarely occurring in the facial region; short history; succulent foci without follicular accentuation; tendency to blister.
• Lymphadenosis cutis benigna: Clinically and anamnestically very similar; almost always solitary; follicular accentuation is possible; color is not red but brown; diascopic: intrinsic infiltrate.
• B-cell lymphoma of the skin (see primary cutaneous B-cell lymphoma)
• Lupus erythematosus (CDLE): Usually years-long disease career, atrophic surface epithelium; scarring in older foci; painful when brushed with fingernail. Histology and IF are diagnostic.
• Sarcoidosis: Brown plaques with smooth surface; no follicular emphasis; usually multiple. Histology definitely excludes granuloma eosinophilicum faciei.
• Tuberculosis cutis luposa: Rare at capillitium; acral localization is typical; atrophic surface epithelium, no follicular accentuation; brown-red color, typical yellow-brown intrinsic filtrate.
• Erythema elevatum diutinum: Rare; usually extensor on the extremities; rarely occurring on the face; polycyclic, nodular, blue-red or red-brown, succulent, extensive plaques. Possible stabbing pain, burning and itching.

Histological differential diagnoses:

• Leukocytoclastic vasculitis of other etiology: Mostly vigorouserythrocyte extravasation; no prominent eosinophilia; infiltrate is overall less marked.
• Erythema elevatum diutinum: Considered by some authors to be a variant of granuloma (eosinophilicum) faciei. Histologically indistinguishable.
• Eosinophilic cellulitis (Wells syndrome): Dense, perivascular and interstitial infiltrates; almost exclusively eosinophilic and (few) neutrophilic granulocytes. Polygonally circumscribed, eosinophilic flame figures in the dermis. No signs of vasculitis.
• Lymphadenosis cutis benigna (cutaneous pseudolymphoma): Dense mature-cell dermal infiltrate of lymphocytes, plasma cells, reticulum cells; only occasional eosinophilic leukocytes. Formation of lymphoid follicles with germinal center cells. No signs of vasculitis.

Because of benignity and chronicity of the disease, the therapeutic risk should be weighed. Therapy trial with DADPS (e.g. dapsone fatol): 100-200 mg/day for 4 months (therapy success only moderate!). Caveat. Determine glucose-6-phosphate dehydrogenase before starting therapy. If necessary, intralesional glucocorticoid injection with triamcinolone acetonide crystal suspension(Volon A 10 mg, diluted 1:3-1:5 with local anesthetics, e.g. scandicaine).

In case of therapy resistance, or in case of only solitary lesions excision in toto, dermabrasion in case of flat foci, CO ₂ -laser, argon laser, cryosurgery or cauterization (see also Fig.).

Positive therapeutic effects (single case reports) have been reported with locally applied tacrolimus or pimecrolimus (occlusive at times) and topical dapsone (Topical Dapsone as 5% Gel/Aczone; Allergan Inc, Irvine, CA) (Lindhaus C et al. 2018).

The rare large-area or large-nodule variants of granuloma faciale can persist for years, growing slowly. They prove to be markedly resistant to therapy. In these cases, irradiation with fast electrons is an alternative.

Chronic course, spontaneous healing under scarring atrophy is possible especially in infantile granuloma faciale.

There is a close etiopathogenetic relationship to erythema elevatum diutinum. Both cases are vasculitic processes. The histological substrate (factor: eosinophilia) is decisive for differential diagnosis. The clinical aspect of the punctate surface (orange peel-like) arises from the pressure of the dermal infiltrate. This leads to an interfollicular protrusion of the surface. With simultaneous preservation of the follicle, it pulls inward like a wick, resulting in these "follicular impressions." Important differential diagnostic feature to differentiate from malignant (follicle-destroying) processes.

However, tissue eosinophilia is not a constant feature of granuloma (eosinophilicum) faciale. While it is often predominant in the early phase of granuloma faciale, it may be completely absent in the late stage in favor of a plasma cell component.

Additionally, and thus misleadingly, the term "eosinophilic granuloma" is occupied by a variant of Langerhans cell histiocytosis. To avoid this misunderstanding, the term"granuloma faciale" is increasingly used, alternatively granuloma faciale with eosinophilia.

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