Non-infectious Granulomatous Disorders, Including Foreign Body Reactions

When histiocytes form granulomas within the skin, the cutaneous disorders are referred to as granulomatous. This group of disorders is further divided into infectious (e.g. mycobacterial infections, dimorphic fungal infections) and non-infectious (e.g. sarcoidosis, granuloma annulare). This chapter focuses on the latter category.

Sarcoidosis

Disorder of unknown etiology in which granulomas develop in one or more organs, most commonly the lung, skin, liver, and spleen.

Cutaneous manifestations occur in >30% of patients and may be the first and/or only sign of the disease ( Table 78.1 ).

Table 78.1

Clinical features of the major granulomatous dermatitides.

AEGCG, annular elastolytic giant cell granuloma; IGD, interstitial granulomatous dermatitis; PNGD, palisaded neutrophilic and granulomatous dermatitis.

Courtesy, Clifton R. White, Jr., MD.

	Sarcoidosis ^∗	Classic granuloma annulare ^{^}	Necrobiosis lipoidica	IGD/PNGD	Cutaneous Crohn disease	Rheumatoid nodule (see Fig. 37.2 )
Average age (years)	25–35, 45–65	<30	30	40–70	35	40–50
Sex predilection	Female	Female	Female	IGD: Female	Female	Male ^†
Racial/ethnic predilection in United States	African-American	None	None	Caucasian	Ashkenazi Jews	None
Sites	Symmetric on face, neck, upper trunk, extremities	Hands, feet, extensor aspects of extremities	Anterior and lateral aspects of shins	IGD: lateral trunk, medial arms/thighs; PNGD: elbows, fingers	Anogenital region, buttocks, lower > upper extremities	Juxta-articular areas, especially elbows, hands, ankles, feet
Appearance	Protean; most commonly red-brown or violaceous papules and plaques; occasionally violaceous or annular	Papules coalescing into annular plaques	Plaques with elevated borders, telangiectasias centrally	IGD: erythematous papules and plaques, sometimes annular; PNGD: umbilicated papules	Dusky erythema, lymphedema, ulceration, vegetating plaques	Skin-colored, firm, mobile subcutaneous nodules
Size of lesions	0.2 to >5 cm	1- to 3-mm papules, annular plaques usually <6 cm	3 to >10 cm	IGD: 5 mm to > 2 cm; PNGD: 1–4 mm	Variable	1–3 cm
No. of lesions	Variable	1–10	1–10	1 to >20	1–5	1–10
Associations	Systemic manifestations of sarcoidosis; can be drug-induced (e.g. IFN, TNF inhibitors) or reaction pattern to underlying lymphoma	Possible diabetes mellitus, thyroid disease, or hyperlipidemia; rare reports of HIV infection, malignancy	Diabetes mellitus	Medications, e.g. statins, TNF inhibitors; autoimmune disease, e.g. rheumatoid arthritis	Intestinal Crohn disease	Rheumatoid arthritis
Special clinical characteristics	Occasional central atrophy and hypopigmentation; develop within scars and tattoos	Central hyperpigmentation	Yellow-brown atrophic centers, ulceration	“Rope sign” (linear cords)	Draining sinuses and fistulas	Occasional ulceration, especially at sites of trauma

∗ Clinical variants include lupus pernio and subcutaneous (Darier–Roussy), psoriasiform, ichthyosiform, angiolupoid, and ulcerative sarcoidosis.

^ Clinical variants include generalized/disseminated, micropapular, nodular, perforating, subcutaneous, and patch granuloma annulare.

† Although rheumatoid arthritis has a female:male ratio of 2–3:1.

The classic lesion is a red-brown papule or plaque with a yellowish color on compression (diascopy), most commonly on the face ( Figs 78.1 and 78.2 ; see Fig. 45.1A ).
Variants:
- –
  Lupus pernio – purple to red-brown papules and plaques of the nose, ears, and cheeks; may be beaded along the nasal rim ( Fig. 78.2C ); associated with chronic pulmonary sarcoidosis (75% of patients), upper respiratory tract sarcoidosis (50%), and cysts within the distal phalanges
- –
  Darier–Roussy sarcoidosis (subcutaneous variant) – painless, firm, mobile nodules or plaques
- –
  Löfgren syndrome – hilar adenopathy, fever, migrating polyarthritis, and acute iritis; erythema nodosum is the primary skin finding (see Table 83.2 ); often spontaneously remits
- –
  Heerfordt syndrome – parotid gland enlargement, uveitis, fever, cranial nerve palsies

Once the diagnosis of cutaneous sarcoidosis is established, evaluation for systemic involvement is necessary ( Table 78.2 )

Table 78.2

Initial systemic evaluation of a patient with cutaneous sarcoidosis.

ACE, angiotensin converting enzyme; DLCO, diffusing capacity for carbon monoxide; PET, positron emission tomography; PFTs, pulmonary function tests; QFT-GIT, Quantiferon-gold TB In-Tube test.

In ALL patients:

CXR (PA and lateral) ^∗
PFTs with DLCO
Ophthalmologic examination
CBC, LFTs, BUN/Cr, TSH, serum calcium, serum 25-hydroxy- and 1,25-dihydroxy-vitamin D levels, ACE level
TST or IFN-gamma release assay (e.g. QFT-GIT) ^∗∗
ECG ^∗∗∗

Based upon findings from thorough history, review of systems, physical examination:

Heart palpitations, syncopal or pre-syncopal episodes, abnormal ECG: refer to cardiology (further cardiac imaging will be performed, e.g. cardiac MRI or PET)
Extensive facial involvement (e.g. lupus pernio, multiple nasal/perinasal lesions): refer to otolaryngology (evaluation for sinus and/or upper airway involvement)
Cough, chest pain, dyspnea, velcro rales in lung base, abnormal CXR or PFTs: refer to pulmonology
Neuropathy (e.g. peripheral, cranial, small fiber): refer to neurology

Items in bold should be repeated annually.

∗ High resolution chest CT scan is more sensitive than CXR and should be ordered if any suspicious findings on CXR or if normal CXR but high clinical suspicion for pulmonary involvement.

∗∗ To exclude tuberculosis, which can present with similar radiographic signs.

∗∗∗ Any abnormalities should prompt referral to cardiology.

DDx of classic papule/plaque: other entities in this chapter, granulomatous rosacea and perioral dermatitis, dimorphic fungal infections, cutaneous tuberculosis; in young children, consider Blau syndrome (see Ch. 37 ).
Rx of cutaneous lesions: CS (topical, intralesional); oral medications include minocycline, antimalarials, methotrexate, tacrolimus, TNF inhibitors, thalidomide, and JAK inhibitors.

Granuloma Annulare

May be a delayed-type hypersensitivity reaction to an unknown antigen; by history can follow an arthropod bite, trauma.
Common clinical variants (see Table 78.1 ) – localized, often acral ( Fig. 78.3 ); subcutaneous on hands, shins, and scalp in children; generalized ( Fig. 78.4 ).
Less common variants are perforating, often on the hands ( Fig. 78.5 ), patch type on the trunk, and micropapular ( Fig. 78.6 ).
Generalized granuloma annulare, also referred to as disseminated, is more likely to be associated with diabetes mellitus (see Table 45.10 ) or lipid abnormalities (e.g. hypercholesterolemia) compared to other variants; atypical presentations seen in HIV-infected patients.
DDx: other entities in this chapter (see Table 78.1 ), tinea, interstitial granulomatous dermatitis, inflammatory morphea.
Rx: spontaneous resolution may occur; first-line – CS (topical including under occlusion, intralesional); second-line – cryosurgery, niacinamide +/− tetracycline, antimalarials, retinoids, PUVA/UVA1/excimer laser and apremilast.