Sarcoidosis is a multisystem disease which may involve any organ of the body but most commonly affects the lungs, lymph nodes (mediastinal and peripheral), skin, liver, spleen, and eyes.^{23.24.25. and 26.} Central nervous system involvement is uncommon. ²⁷ There is an increased incidence of sarcoidosis in people of Irish and Afro-Caribbean origin. ²⁸ Cutaneous sarcoidosis is rare in Asia. ²⁹

Between 10% and 35% of patients with systemic sarcoidosis have cutaneous lesions.^{30.31. and 32.} Although sarcoidosis is usually a multiorgan disease, chronic cutaneous lesions may be the only manifestation. ³³ The skin lesions may be specific, showing a granulomatous histology, or non-specific. The most common non-specific skin lesion is erythema nodosum, which is said to occur in 3–25% of cases. ³⁰ Sarcoidosis of the knees is frequently associated with erythema nodosum. ³⁴ An erythema nodosum-like eruption with the histological changes of sarcoidosis has also been described. ³⁵ Sarcoidosis predominantly affects adults; skin lesions are rarely seen in children.^{36.37.38. and 39.} There are reports of its occurrence in monozygotic twins. ⁴⁰ Children presenting before the age of 4 years, usually have the triad of rash, uveitis, and arthritis,^{41. and 42.} without apparent pulmonary involvement. ⁴² This early-onset sarcoidosis (OMIM 609464) is caused by mutations in the NOD2/CARD15 gene on chromosome 16q12, similar to Blau’s syndrome (see below). Vasculitis may also occur in this group. ⁴²

A diversity of clinical forms of cutaneous sarcoidosis occurs. These forms include:

This miscellaneous group represents rare cutaneous manifestations of sarcoidosis. Lupus pernio may resolve with fibrosis and scarring and is often associated with involvement of the upper respiratory tract and lungs. ⁷⁶ Oral, eyelid, and scrotal lesions have been reported.^{77.78. and 79.} The majority of skin lesions resolve without scarring. Hypopigmented macules without underlying granulomas have been described, particularly in patients of African descent. ⁸⁰ Other rare presentations have included leonine facies, ⁸¹ faint erythema, ⁸² palmar erythema, ⁸³ vasculitis, ⁴² alopecia,^{84. and 85.} and lesions confined to the vulva. ⁸⁶ Sarcoidosis may follow the use of interferon therapy (IFN-α) for melanoma⁸⁷ or hepatitis C.^{88.89.90.91.92.93. and 94.} Sometimes the lesions are limited to injection site scars in these patients. ⁹⁵ It may also occur in patients with hepatitis C unrelated to treatment. ⁹⁶ It has also followed BCG vaccination. ⁹⁷

It is generally considered that the presence of cutaneous lesions in association with systemic involvement is an indicator of more severe disease. Skin lesions may occur in scars^{98.99.100. and 101.} following trauma (including surgery, desensitizing injection sites, and venepuncture),^{102.103. and 104.} cosmetic tattoos,^{105. and 106.} radiation, and chronic infection. In some cases these lesions may be the first manifestation of sarcoidosis.^{107. and 108.} Other cases do not appear to be related to systemic sarcoidosis and may be a sarcoidal reaction to a foreign body. ¹⁰⁹

Various systemic diseases have been reported in association with cutaneous sarcoidosis. The association in many of these conditions is probably fortuitous. They include B-cell chronic lymphocytic leukemia, ¹¹⁰ cutaneous lymphoma,^{111. and 112.} pyoderma gangrenosum, ¹¹³ hypoparathyroidism, ¹¹⁴ cryptococcal infection, ¹¹⁵ dermatomyositis, ¹¹⁶ primary biliary cirrhosis, ¹¹⁷ autoimmune thyroiditis and/or vitiligo,^{118.119. and 120.} polycythemia vera, ¹²¹ Wegener’s granulomatosis, ¹²² and HIV infection. ¹²³ In cases of HIV infection, sarcoidosis may develop after the commencement of highly active antiretroviral therapy (HAART) and the restoration of some immune function.^{123. and 124.} The term ‘immune restoration disease’ has been used for this circumstance. Subcutaneous granulomas and granulomatous tenosynovitis have been reported in an organ transplant recipient. ¹²⁵

The etiology of sarcoidosis remains controversial although an infectious origin has long been suspected.^{126. and 127.} The main candidate is a cell-wall-deficient form of an acid-fast bacillus, similar, if not identical to, Mycobacterium tuberculosis. ¹²⁸ In one study, DNA sequences coding for the mycobacterial 65 kDa antigen were found in 11 of 35 cases of sarcoidosis, ¹²⁹ while in a more recent study, using only cutaneous specimens, mycobacterial DNA was demonstrated by PCR in 16 of 20 cases. ¹³⁰ Non-tuberculous (atypical) mycobacteria constitute the largest group of the species identified in this study. ¹³⁰ Other findings supportive of a mycobacterial etiology are the beneficial effects of long-term tetracyclines¹³¹ and the activation of a case following concurrent M. marinum infection of the skin. ¹³² In a study of 35 patients with sarcoidosis in 2005, M. tuberculosis rRNA was not detected in any case. ¹³³ Based on these results the authors concluded that this organism cannot be considered as the etiological agent of the disease. ¹³³ Another study concluded that there was no role for human herpesvirus type 8 (HHV-8) in the etiology, despite earlier reports suggesting a role. ¹³⁴

Several studies have reported increased T-helper (Th)-1 cytokines with increased levels of tumor necrosis factor (TNF)-α in patients with sarcoidosis. ¹³⁵

The exact relationship of Blau’s syndrome (OMIM 186580) to sarcoidosis is becoming clearer. It is characterized by the familial presentation of a sarcoid-like granulomatous disease involving the skin, uveal tract and joints, but not the lung. ¹³⁶ Camptodactyly is another defining sign. ¹³⁷ Ichthyosis has been reported in one case. ¹³⁸ Onset is in childhood and the mode of inheritance is autosomal dominant. It shares with early-onset sarcoidosis mutations in the NOD2/CARD15 gene which maps to chromosome 16q12.139.^{140. and 141.} Some patients with Crohn’s disease also have mutations in this gene.

For limited cutaneous sarcoidosis, parenteral therapies have been the mainstay of therapy but systemic therapy has been used for severe cutaneous disease, particularly if there is an aesthetic impact. ¹⁴² Therapies that have been used include corticosteroids, hydroxychloroquine, chloroquine, allopurinol, methotrexate, isotretinoin, mepacrine, ¹⁴³ tacrolimus, ¹⁴⁴ thalidomide, ¹⁴² and various inhibitors of TNF-α such as adalimumab^{145. and 146.} and infliximab.^{135. and 147.} The various therapies used to treat cutaneous sarcoidosis have recently been reviewed. ¹⁴⁸

A number of foreign substances and materials when introduced into the skin may induce a granulomatous dermatitis which histologically resembles sarcoidosis. They are listed in Table 7.1.

Following some kind of trauma, silica may contaminate a wound in the form of dirt, sand, rock, or glass (including windshield glass from motor vehicles). ¹⁷⁰ Papules and nodules arise in the area of trauma. The granulomas seen in the dermal reaction contain varying numbers of Langhans or foreign body giant cells, some of which may contain clear colorless particles. These may be difficult to see with routine microscopy but are birefringent in polarized light. The differentiation from true sarcoidosis may be difficult, since granulomas sometimes develop in scars in sarcoidosis and the granulomas can contain bi­refringent calcite crystals. A sarcoidal reaction to identifiable foreign material does not exclude sarcoidosis. It has been suggested that particulate foreign material may serve as a nidus for granuloma formation in sarcoidosis. ¹⁷¹ Silica-rich birefringent particles have also been described in lesions without a history of injury or silica exposure. ¹⁷² Energy-dispersive X-ray analysis techniques using scanning electron microscopy can be used to identify elements present in the crystalline material. ¹⁷³ The granulomas are thought to develop as a response to colloidal silica particles and not as a result of a hypersensitivity reaction. ¹⁷⁴

A granulomatous dermatitis may occur in response to pigments used in tattooing (see p. 389).^{175. and 176.} The skin lesions are sometimes limited to certain areas of a tattoo where a particular pigment has been used. ¹⁷⁶ Two patterns are seen, a foreign body type and a sarcoid type. ¹⁷⁷ In the latter form there are aggregates of epithelioid histiocytes and giant cells with a sparse perigranulomatous round cell infiltrate. The histiocytes and giant cells contain pigment particles. True sarcoidosis has also been reported in tattoos, in some cases associated with pulmonary hilar lymphadenopathy. Some of these cases may represent a generalized sarcoid-like reaction to tattoo pigments rather than true sarcoidosis.^{178. and 179.} Other granulomatous complications of tattoos include tuberculosis cutis and leprosy. ¹⁸⁰

Sarcoidal granulomas may occur as a rare complication of ear piercing. It is not always a consequence of the trauma/scarring but may represent a contact allergy to nickel and other metals. ¹⁸¹

Zirconium compounds used in under-arm deodorants and other skin preparations have been associated with a granulomatous skin reaction in sensitized individuals.^{182. and 183.} Histologically, the lesions are identical to sarcoidosis. Usually no birefringent material is seen in polarized light. In one case of a reaction to an aluminum–zirconium complex, foreign body granulomas and birefringent particles were seen as well as tuberculoid type granulomas. ¹⁸⁴ Ophthalmic drops containing sodium bisulfite have been implicated in the formation of pigmented papules on the face. The papules were caused by sarcoidal granulomas with brown-black pigment in foreign body giant cells. ¹⁸⁵

Sarcoidal granulomas have been reported at the injection sites of interferon, both interferon β-1b used in the treatment of multiple sclerosis, ¹⁸⁶ and interferon α-2a used in the treatment of hepatitis C. ¹⁸⁷

In the past, cutaneous granulomatous lesions with histology similar to sarcoidosis have been reported in persons exposed to beryllium compounds in industry.^{188. and 189.} Other foreign bodies capable of inducing sarcoidal granulomas include acrylic and nylon fibers, wheat stubble, and sea urchin spines.^{190.191. and 192.} Sea urchin spines can produce all types of granuloma, not only sarcoidal ones. The nature of the granulomatous reaction that followed the use of hydroxyurea is uncertain. It may have been sarcoidosis itself. ¹⁹³

Occasionally, keratin from ruptured cysts or hair follicles can induce sarcoidal granulomas rather than the more usual foreign body type of reaction.

Typical tuberculoid granulomas can be seen in the dermal inflammatory reaction of late primary inoculation tuberculosis, late miliary tuberculosis, tuberculosis cutis orificialis, tuberculosis verrucosa cutis (‘prosector’s wart’), scrofuloderma, and lupus vulgaris. ¹⁹⁵ Cutaneous tuberculosis is discussed in detail with the bacterial infections (see p. 556). A similar pattern of inflammation can be seen after BCG vaccination and immunotherapy.^{196. and 197.}

The tuberculids are a heterogeneous group of cutaneous disorders associated with tuberculous infections elsewhere in the body or in other parts of the skin (see p. 559). They include lichen scrofulosorum, papulonecrotic tuberculid, and erythema induratum-nodular vasculitis. Although it has previously been thought that organisms are not found in tuberculids, recent PCR studies have demonstrated mycobacterial DNA in some cases (see p. 559). ²⁰⁰

In lichen scrofulosorum there is a superficial inflammatory reaction about hair follicles and sweat ducts which may include tuberculoid granulomas. Acid-fast organisms are not usually seen or cultured from the lesions. ²⁰¹ Caseation is rare. ²⁰²

Histopathological studies of papulonecrotic tuberculid have shown a subacute or granulomatous vasculitis and dermal coagulative necrosis with, in some cases, a surrounding palisading histiocytic reaction resembling granuloma annulare. ²⁰³ Acid-fast bacilli are not found in the lesions. Tuberculoid granulomas were not described in one study²⁰⁴ but have been recorded in others. ¹⁹⁵

In erythema induratum-nodular vasculitis there is a lobular panniculitis, although tuberculoid granulomas usually extend into the deep dermis (see p. 463).

Tuberculoid granulomas are seen in the tuberculoid (TT), borderline tuberculoid (BT), and borderline (BB) groups of the classification of leprosy introduced by Ridley and Jopling. ²⁰⁵ Leprosy is considered further on page 562.

This condition was first reported in the English literature in 2002 under the title ‘fatal bacteria granuloma after trauma: a new entity’. ²⁰⁷The cases were reported from rural China. They were characterized by spreading, dark-red plaques that followed slight trauma to the face. The patients had severe headache and clouding of consciousness during the later stages of the disease. All patients died within 1.5– 4 years.

Electron microscopy demonstrated two types of bacteria: one was an anaerobic actinomycete, which was sensitive to lincomycin (a forerunner of clindamycin); the other organism seen was a Staphylococcus. The unknown actinomycete was regarded as the probable causative agent. ²⁰⁷ A recent paper has reported finding Propionibacterium acnes, which seems unusual. ²⁰⁸

Some lesions of late secondary syphilis and nodular lesions of tertiary syphilis show a superficial and deep dermal inflammatory reaction in which there are tuberculoid granulomas (see p. 575). ²⁰⁹ Plasma cells are generally but not always prominent in the inflammatory infiltrate and there may be swelling of endothelial cells.^{210. and 211.} One recent study has found that a plasma cell infiltrate and endothelial swelling, traditionally associated with syphilis of the skin, are in fact infrequently seen in biopsies. ²¹² Organisms are rarely demonstrable in these lesions.

In chronic cutaneous leishmaniasis (see p. 635) and leishmaniasis recidivans, tuberculoid granulomas are present in the upper and lower dermis. ²¹³ The overlying epidermal changes are variable. Occasionally the granulomas extend to the basal layer of the epidermis as in tuberculoid leprosy. ²¹⁴ Necrosis is not usually seen in the granulomas. ²¹⁵ Leishmaniae are usually scarce but may be found in histiocytes or, rarely, free in the dermis. The organisms have sometimes been mistaken for Histoplasma capsulatum but differ from the latter in having a kinetoplast.

Rosacea is characterized by persistent erythema and telangiectasia, predominantly of the cheeks but also affecting the chin, nose, and forehead (see p. 434). The lacrimal and salivary glands were affected in one case. ²¹⁶ In the papular form, papules and papulopustules are superimposed on this background. Tuberculoid granulomas are seen in the granulomatous form. Granulomatous rosacea has been reported in children as well as adults, and in association with infection with the human immunodeficiency virus (HIV).^{217.218. and 219.} Granulomatous rosacea can be found in most clinical variants of rosacea. ²²⁰ A rosacea-like granulomatous eruption developed in an adult patient using tacrolimus ointment in the treatment of atopic dermatitis. ²²¹ Granulomas may be a response to Demodex organisms or lipids.^{222. and 223.} Granulomas have also been described in the lesions of pyoderma faciale, thought to be an extreme form of rosacea. ²²⁴

Thirty cases of this unusual granulomatous condition of the face have been reported from a single center in France.^{227. and 228.} All cases occurred in children, with a mean age of 3.8 years. The children presented with one or several acquired painless nodules on the face, lasting for at least one month. There was no response to antibiotics and no infectious agent was demonstrated. It was suggested that the disease might belong to the spectrum of childhood rosacea. ²²⁸ A granulomatous response to an embryological residue was also considered. ²²⁸

Perioral dermatitis is regarded by some as a distinct entity²²⁹ and by others as a variant of rosacea. ²³⁰ The histological changes seen in perioral dermatitis and acne rosacea overlap, and clinical features are often more important in separating these two conditions. ²³¹

Red papules, papulovesicles, or papulopustules on a background of erythema are arranged symmetrically on the chin and nasolabial folds with a characteristic clear zone around the lips. ²³² Lesions may occur less commonly on the lower aspect of the cheeks and on the forehead. ²³³ A periocular variant has also been described.^{234. and 235.} Perioral dermatitis chiefly affects young women, but it has also been reported in children.^{236.237.238. and 239.} In a recent review of patients with lip and perioral area dermatitis, Nedorost has presented a useful table with the distinguishing features between a rosacea-type of perioral dermatitis, a steroid-induced type, and disease due to irritants, allergic/photo­allergic contact reactions, and atopic cheilitis. ²⁴⁰ She suggests that an extended patch test series may be useful in making a diagnosis. ²⁴⁰ Inhaled corticosteroids may also induce the disease. ²⁴¹

Granulomatous perioral dermatitis of childhood is particularly seen in children of Afro-Caribbean descent. This form has been given the acronym FACE – facial Afro-Caribbean childhood eruption.^{242.243. and 244.} This term is no longer used because of its rare occurrence in non-black children. The term childhood granulomatous periorificial dermatitis is now preferred.^{245. and 246.} Subtle clinical differences exist between this condition and perioral dermatitis and granulomatous rosacea, although it may still be a variant of one of these conditions. It has also been proposed as a childhood variant of lupus miliaris disseminatus faciei (see below). ²⁴⁷ It is benign, self-limited, and typically resolves within a year of onset without scarring. ²⁴⁵ Extrafacial lesions may occur.^{245. and 248.} Its resolution seems to be hastened with the use of systemic antibiotics²⁴⁸ or with tacrolimus. ²⁴⁹

In many cases perioral dermatitis appears to be related to the application of one or more cosmetic preparations which may act by occlusion. ²⁵⁰ The use of strong topical corticosteroids, particularly fluorinated ones, may also have an etiological role.^{251.252. and 253.} Various types of toothpaste have been implicated.^{254. and 255.} Perioral dermatitis has been reported in renal transplant recipients maintained on oral corticosteroids and azathioprine. ²⁵⁶ It has also been associated with the wearing of the veil by Arab women. ²⁵⁷

Its relative rarity in patients with seborrheic dermatitis treated with corticosteroids has led to the postulate that perioral dermatitis may develop under fusiform-bacteria-rich conditions, rather than Malassezia-rich conditions as in the case of seborrheic dermatitis. ²⁵⁸

Topical metronidazole, erythromycin, and oral tetracyclines have been used as conventional treatments. Liquid nitrogen, benzoyl peroxide, and oral isotretinoin are other therapies. Recently, topical pimecrolimus has been used successfully. ²⁵⁹ Its efficacy has been confirmed by a randomized, vehicle-controlled study of 1% pimecrolimus cream. It was found to rapidly improve clinical symptoms, being most effective in corticosteroid-induced perioral dermatitis. ²⁶⁰

Although the cause of lupus miliaris disseminatus faciei is unknown, it may be related to rosacea.^{262. and 263.} It has also been called acne agminata and acnitis. ²⁶⁴ It is characterized by yellowish brown papules distributed over the central part of the face, including the eyebrows and eyelids. When widespread facial lesions are present, the appearances may mimic sarcoidosis. ²⁶⁵ Occasionally lesions occur elsewhere, including the axillae.^{266. and 267.} The lesions last for months and heal with scarring. ²⁶⁸ This condition occurs in both sexes, predominantly in adolescents and young adults and rarely in the elderly.^{269. and 270.} It has been suggested that as the currently used name is confusing, a new title should be substituted – FIGURE (facial idiopathic granulomas with regressive evolution). ²⁷¹

Studies using PCR techniques have failed to demonstrate the DNA of M. tuberculosis in lesional skin. ²⁷²

Successful treatment with the 1450 nm diode laser has been reported recently. ²⁷³

Non-caseating granulomas of tuberculoid type may be found, rarely, in the dermis and subcutis in Crohn’s disease (see p. 493). The term metastatic Crohn’s disease is often used for the presence of multiple cutaneous lesions. ²⁷⁸ Granulomas are not uncommon in the wall of perianal sinuses and fistulas. A granulomatous cheilitis has also been reported (see p. 188). ²⁷⁹ It is important to exclude Crohn’s disease in cases of apparent Melkersson–Rosenthal syndrome. ²⁸⁰

There is even a report of cutaneous granulomas developing in a patient with histologically proven ulcerative colitis. ²⁸¹

Granuloma annulare is a dermatosis, usually self-limited, of unknown etiology and characterized by necrobiotic (collagenolytic) dermal papules that often assume an annular configuration. ²⁸⁴ Either the skin or the subcutis, or both, may be involved. The clinical variants of granuloma annulare include localized, generalized, perforating, ²⁸⁵ and subcutaneous or deep forms.^{286. and 287.} Rare types include a follicular pustulous variant, ²⁸⁸ an acute-onset, painful acral form, ²⁸⁹ and a patch form, ²⁹⁰ although the latter cases are probably examples of the interstitial granulomatous form of drug reaction (see p. 192). The linear variant reported some years ago would now be regarded as a variant of interstitial granulomatous dermatitis (see p. 191). ²⁹¹ Classic granuloma annulare was preceded in one case by the development of a severe linear form along Blaschko’s lines. ²⁹²

In the localized form, one or more erythematous or skin-colored papules are found. Grouped papules tend to form annular or arciform plaques. The hands, feet, arms, and legs are the sites of predilection in some 80% of cases. ²⁹³ A papular umbilicated form has been described in children in which grouped umbilicated flesh-colored papules are limited to the dorsum of the hands and fingers. ²⁹⁴ The generalized form accounts for approximately 15% of cases.^{284. and 295.} Multiple macules, papules, or nodules are distributed over the trunk and limbs. ²⁹⁶ Rarely, there may be confluent erythematous patches or plaques.^{297. and 298.} The appearances may even simulate mycosis fungoides. ²⁹⁹ It has been reported as a side effect of allopurinol³⁰⁰ and of amlodipine. ³⁰¹ Lesions in perforating granuloma annulare are grouped papules, some of which have a central umbilication with scale. ³⁰² The extremities are the most common site. The generalized form may also have perforating lesions. ³⁰³ A high incidence of perforating granuloma annulare has been reported in Hawaii. ³⁰⁴ It is rare in infants and young children. ³⁰⁵ In subcutaneous (or deep) granuloma annulare, deep dermal or subcutaneous nodules are found on the lower legs, hands, head, and buttocks.^{306. and 307.} These lesions are associated with superficial papules in 25% of cases. ³⁰⁸ This group also includes those lesions described as pseudorheumatoid nodules, palisading subcutaneous granuloma, and benign rheumatoid nodules.^{309.310. and 311.} Although arthritis does not usually occur in children with these nodular lesions, IgM rheumatoid factor has been found in serum in some cases.^{312. and 313.} There is a report of one case occurring in association with juvenile rheumatoid arthritis. ³¹¹ Computed tomography (CT) scan changes of this variant have been described. ³¹⁴ Rarely, the changes may involve deeper soft tissues and produce a destructive arthritis and limb deformity. ³¹⁵ Pseudorheumatoid nodules have also been reported in adults. A recent series of 14 cases all involved females and most involved the small joints of the hand. ³¹⁶ Granuloma annulare was present at the periphery of the nodules in eight cases. ³¹⁶ The authors suggested the term juxta-articular nodular granuloma annulare for these cases. ³¹⁶

Granuloma annulare has been reported as a seasonal eruption on the elbows or hands^{317. and 318.} and from unusual sites such as the penis,^{319.320.321. and 322.} palms, ³²³ about the eyes,^{324.325.326. and 327.} and ear.^{328. and 329.} There has been one case of cutaneous granuloma annulare associated with histologically similar intra-abdominal visceral lesions in a male with insulin-dependent diabetes. ³³⁰

Females are affected more than twice as commonly as males. The localized and deep forms are more common in children and young adults.^{307. and 331.} The deep (subcutaneous) form has been reported as a congenital lesion. ³³² Generalized granuloma annulare occurs most frequently in middle-aged to elderly adults. Most cases of granuloma annulare are sporadic but familial cases have occasionally been reported. ³³³ Patients with the generalized form of the disease show a significantly higher frequency of HLA-BW35 compared with controls and with those who have the localized form of the disease. ³³⁴

Lesions of granuloma annulare have a tendency to regress spontaneously; however, about 40% of cases recur. ²⁹³ Resolution of lesions subject to biopsy, but not other lesions has been reported. ³³⁵ Spontaneous regression of localized lesions in children occurred, in one series, from 6 months to 7 years, with a mean of 2.5 years. ³³⁶ In the generalized form, the clinical course is chronic with infrequent spontaneous resolution and poor response to therapy. ²⁹⁶ Non-perforating lesions are usually asymptomatic. ³³⁷

Although the etiology and pathogenesis of the skin lesions in granuloma annulare remain uncertain, possible triggering events include insect bites, trauma, the presence of viral warts, drugs, erythema multiforme, and exposure to sunlight.^{301.338.339. and 340.} Lesions have occurred in the scars of herpes zoster, localized or generalized,^{341.342.343.344.345. and 346.} in a saphenectomy scar, ³⁴⁷ in a Becker’s nevus, ³⁴⁸ and at the sites of tuberculin skin tests. ³⁴⁹ The possible link between both the localized and generalized forms and diabetes mellitus remains controversial. There is more convincing evidence of this association with the generalized form than with the localized form although there may be a weak association with nodular as opposed to the annular type of localized lesion.^{350.351. and 352.} Significantly lower serum insulin levels have been found in children with multiple lesions of granuloma annulare. ³⁵³ A case-control study failed to find any association between granuloma annulare and type 2 diabetes mellitus. ³⁵⁴ Reported cases of the concurrence of these two diseases may represent the chance association of two not uncommon conditions. ³⁵⁵ It has been reported in association with sarcoidosis, ³⁵⁶ Alagille syndrome, ³⁵⁷ toxic adenoma of the thyroid, ³⁵⁸ autoimmune thyroiditis,^{359. and 360.} uveitis, ³⁶¹ hepatitis B³⁶² and C infection, ³⁶³ parvovirus B19 infection, ³⁶⁴ BCG, ³⁶⁵ hepatitis B, ³⁶⁶ and antitetanus vaccination,^{367. and 368.} waxing-induced pseudofolliculitis, ³⁶⁹ tuberculosis,^{370. and 371.} tattoos, ³⁷² granulomatous mycosis fungoides, ³⁷³ a monoclonal gammopathy, ³⁷⁴ hypercalcemia, ³⁷⁵ myelodysplastic syndrome, ³⁷⁶ chronic myelomonocytic leukemia, ³⁷⁷ Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, gastrointestinal stromal tumor, ³⁷⁸ and metastatic adenocarcinoma.^{379.380.381.382.383.384.385.386.387. and 388.} In these conditions, the clinical presentation may be atypical. ³⁸⁹ Localized, generalized, and perforating forms of granuloma annulare have been reported in patients with AIDS; the generalized form is the most common clinical pattern.^{390.391.392.393.394.395.396.397.398. and 399.} It may, rarely, be the presenting complaint in AIDS. ⁴⁰⁰Bartonella infection has not been detected in lesions of granuloma annulare. ⁴⁰¹ Interstitial granuloma annulare has been reported in borreliosis, ⁴⁰² but it may represent a pattern related to the Borrelia infection itself.

It has been suggested that the underlying cause of the necrobiotic granulomas is an immunoglobulin-mediated vasculitis. ⁴⁰³ In a recent study, neutrophils and neutrophil fragments were commonly present in early lesions but a true vasculitis was rare. Direct immunofluorescence studies did not demonstrate immune deposits in vessel walls. ⁴⁰⁴ Other studies have stressed the importance of cell-mediated immune mechanisms with a delayed hypersensitivity reaction of T helper (Th) 1 type against as yet undefined antigens.^{405. and 406.} This is supported by the finding of increased levels of interleukin (IL)-18, interferon gamma, and IL-2 in lesional skin. ⁴⁰⁷ Collagen synthesis is increased in the lesions of granuloma annulare, probably representing a reparative phenomenon. ⁴⁰⁸

Necrobiosis lipoidica was originally called ‘necrobiosis lipoidica diabeticorum’ but, although some cases are associated with diabetes mellitus,^{443. and 444.} it is not peculiar to diabetes. ⁴⁴⁵ In one series only 11% of patients with necrobiosis lipoidica had diabetes mellitus at presentation, while a further 11% developed impaired glucose tolerance/diabetes in the succeeding 15 years. ⁴⁴⁶ The incidence in diabetics is low – approximately 3 cases per 1000. ⁴⁴³ It is even lower in childhood diabetes. ⁴⁴⁷

The legs, particularly the shins, are overwhelmingly the commonest site of involvement, but lesions may also occur on the forearms, hands, and trunk. Unusual sites include the nipple, penis, surgical scars, and a lymphedematous arm.^{448.449.450.451.452. and 453.} Three-quarters of cases are bilateral at presentation and many more become bilateral later. Lesions may be single but are more often multiple. Diffuse disease is rare. ⁴⁵⁴ Females are affected more than males in a ratio of 3 to 1. The average age of onset in one series was 34 years, but the condition may be seen in children.^{455. and 456.} It has occurred in monozygotic twins, but not until adult life. ⁴⁵⁷

The earliest lesions are red papules which enlarge radially to become patches or plaques with an atrophic, slightly depressed, shiny yellow-brown center and a well-defined raised red to purplish edge. Nodules are uncommon. ⁴⁵⁸ Some lesions resolve spontaneously but many are persistent and chronic and may ulcerate;^{459.460. and 461.} this occurred in 13% of cases in one series. ⁴⁶² Rarely, squamous cell carcinoma may arise in long-standing lesions.^{463.464.465.466.467. and 468.} The simultaneous occurrence of necrobiosis lipoidica with granuloma annulare^{469. and 470.} and with sarcoidosis has been reported.^{471. and 472.} It has also been associated with autoimmune thyroid disease, scleroderma, rheumatoid arthritis, and jejunoileal bypass surgery. ⁴⁷³ The case reported in association with light-chain-restricted plasma cellular infiltrates^{473. and 474.} has been questioned by others as not representing necrobiosis lipoidica. ⁴⁷⁵

The association of these lesions with diabetes has already been referred to but the role of this metabolic disorder in the development of the cutaneous lesions is not understood. Diabetic vascular changes may be important: in some early lesions a necrotizing vasculitis has been described. ⁴⁷⁶ Lesions show increased blood flow, refuting the hypothesis that the disease is a manifestation of ischemic disease. ⁴⁷⁷ The finding in areas of sclerotic collagen of Glut-1, a protein responsible for glucose transport across epithelial and endothelial barrier tissue, raises the possibility that a disturbance in glucose transport by fibroblasts may contribute to the histological findings. ⁴⁷⁸ Adults and children with insulin-dependent diabetes mellitus and necrobiosis lipoidica are at high risk for diabetic nephropathy and retinopathy. ⁴⁷⁹ The recent detection of spirochetal organisms in patients with this disease from central Europe, by focus floating microscopy, points to an involvement of B. burgdorferi or other strains in the development of this disease. ⁴⁸⁰

Necrobiotic xanthogranuloma is a rare condition characterized by the presence of violaceous to red, partly xanthomatous plaques and nodules; there is a predilection for the periorbital area. A paraproteinemia is often present. The clinical course is chronic. It is discussed further in Chapter 40, page 958.

Skin manifestations, including rheumatoid nodules, are relatively common in rheumatoid arthritis.^{498. and 499.} These nodules occur in approximately 20% of patients, usually in the vicinity of joints. Sited primarily in the subcutaneous tissue, they may involve the deep and even the superficial dermis. They vary from millimeters to centimeters in size and consist of fibrous white masses in which there are creamy yellow irregular areas of necrobiosis. Old lesions may have clefts and cystic spaces in these regions. It is most probable that rheumatoid nodules result from a vasculitic process; however, even in very early lesions such a change may be difficult to demonstrate. ⁵⁰⁰ Nodules usually persist for months to years. Rarely, similar lesions occur in systemic lupus erythematosus.^{501.502. and 503.}

Multiple small nodules may develop on the hands, feet, and ears during methotrexate therapy. ⁵⁰⁴ This event is known as ‘accelerated rheumatoid nodulosis’. The term rheumatoid nodulosis has also been used for the presence of subcutaneous rheumatoid nodules with recurrent articular symptoms but no significant synovitis. The rheumatoid factor is often negative.^{505. and 506.} The distinction of this entity from juxta-articular pseudorheumatoid nodules is problematic. ⁵⁰⁶

With the decline in the prevalence of rheumatic fever in developed countries, rheumatic nodules are now rarely seen or biopsied. Consequently, most histological studies are found in the older literature. ⁵¹¹ Nodules are more common in children than adults and are usually associated with acute rheumatic carditis. They are usually asymptomatic and are distributed symmetrically over bony prominences, particularly at the elbows. ⁵¹² Their size ranges from a few millimeters to 2–3 centimeters in diameter. The lesions, unlike rheumatoid nodules, last for only a short time and eventually involute. ⁵¹¹

Purified bovine collagen is currently being used, in the form of intracutaneous injections, to treat certain forms of superficial scarring (see p. 394). In some persons this results in a granulomatous reaction resembling granuloma annulare. There are irregular foci of eosinophilic necrobiosis surrounded by a palisading rim of multinucleate and mononuclear histiocytes, with lymphocytes and plasma cells. ⁵¹⁴

Areas of necrobiosis associated with a granulomatous reaction have also been described, rarely, in association with Trichophyton rubrum, and with the presence of splinters of wood and suture material (Fig. 7.18).^{515.516. and 517.} Necrobiotic areas are also seen in cutaneous berylliosis. Changes which superficially resemble necrobiotic granulomas are also seen in injection sites of drugs of abuse. ⁵¹⁸

Necrobiotic palisaded granulomas have been reported at the sites of injection of hepatitis B vaccine and of disodium clodronate.^{519. and 520.}

Children with ataxia telangiectasia may present with erythematous plaques which on histopathological examination show necrobiotic granulomas. As with other immunodeficiency diseases, granulomas of other types are often present. Tuberculoid and sarcoidal granulomas have also been reported in ataxia telangiectasia. ⁵²¹

Necrobiotic granulomas have also been reported in parvovirus B19 infection. ³⁶⁴ There is some resemblance to the lesions of granuloma annulare. At other times the pattern is more like interstitial granulomatous dermatitis.

The extravascular granulomas of Churg–Strauss (allergic) granulomatosis and of Wegener’s granulomatosis may have necrobiotic features. They are mentioned here for completeness, but they are considered further in Chapter 8, pages 239–241. Necrobiotic granulomas are a rare manifestation of systemic lymphoma. ²⁰

Finally, Crohn’s disease of so-called metastatic type may have necrobiotic granulomas. ⁵²²

In chromomycosis the characteristic organisms are round to oval thick-walled brown cells about 6–12 µm in diameter (sclerotic bodies, Medlar bodies). Intracellular septation may be seen. Single organisms or small groups are found within multinucleate giant cells, within microabscesses, suppurative granulomas, or surface crust. Tuberculoid granulomas are occasionally seen in the dermal infiltrate. ⁵²³ In phaeohyphomycosis, which is clinically distinct from chromomy­cosis, there are hyphal and yeast forms in suppurative granulomas. Species identification requires culture of the organism. Chromomy­cosis and phaeohyphomycosis are discussed further in Chapter 25, pages 596–598.

The causative organism, Sporothrix schenckii, is present in the lesions of primary cutaneous sporotrichosis (see p. 598) in the yeast form; it is only rarely found in its hyphal form. The formation of sporothrix asteroids by the encasement of individual yeast cells by a deposit of immune complexes and fibrin is an occasional finding. These asteroids are seen infrequently in sporotrichotic lesions in some parts of the world, but are comparatively common in those seen in Australia and South Africa. ⁵²⁴ The yeast cells are small, round to oval structures, some of which show budding. They may be found within giant cells or in suppurative granulomas. They are difficult to see and may require PAS stains for recognition. The asteroids are found only in microabscesses and the centers of suppurative granulomas. They can be recognized in these locations on careful study of hematoxylin and eosin preparations. Generally, organisms are few in sporotrichosis.

Tuberculoid or suppurative granulomas may be seen in infections caused by non-tuberculous mycobacteria, including M. marinum and M. chelonae (see p. 559). In M. marinum infections, caseation is not usually seen. Organisms are sparse; when found, they are usually within histiocytes. Organisms may be moderately plentiful in M. chelonae infections. They are frequently seen in and about round to oval clear spaces in the center of suppurative foci.

Rarely these infections may present with a lichenoid as well as a granulomatous dermatitis. ⁵²⁵

In the disseminated form of blastomycosis the organisms are scarce and are found either within giant cells or free in the dermis (see p. 594). The organism (Blastomyces dermatitidis) is a thick-walled round cell, 8–15 µm in diameter. Multiple nuclei may be seen in the cell. Single broad-based buds are occasionally present on the surface. PAS or Grocott methenamine silver stains facilitate demonstration of the organism.

Most cutaneous lesions in paracoccidioidomycosis (‘South American blastomycosis’) are secondary lesions seen in the course of the disseminated form of the disease (see p. 595). The causative agent, Paracoccidioides brasiliensis, is usually found in giant cells. The organisms vary more in size than Blastomyces dermatitidis and can be larger. Also, P. brasiliensis is thin walled, lacks multiple nuclei, and often has multiple buds arranged round the mother cell.

The cutaneous lesions of coccidioidomycosis are almost always secondary to pulmonary disease (see p. 594). Areas of necrosis are sometimes present in the dermis. Sporangia of Coccidioides immitis are rounded structures, 10–80 µm in diameter, which contain multiple sporangiospores, 1–5 µm in diameter. Sporangia are usually easily identified in sections stained with hematoxylin and eosin. Spherules and sporangiospores stain with silver stains. Sporangiospores are PAS positive whereas spherules may be negative or only weakly positive. ⁵²⁶

Marked epidermal hyperplasia and epidermal, follicular and dermal abscesses are seen in blastomycosis-like pyoderma (see p. 553). There is usually severe solar elastosis. In some cases a palisading rim of histiocytes is seen surrounding the suppurative foci in the dermis. Multinucleate giant cells are occasionally present in this zone but they are not as common as in the mycoses discussed above. Bacteria, particularly Gram-positive cocci, may be seen in suppurative foci. Staphylococcus aureus is often isolated from tissue samples but not from the skin surface.

In mycetomas, nocardiosis, and actinomycosis, foci of suppuration may become surrounded by a histiocytic rim to form suppurative granulomas. Organisms are present within the suppurative foci. These conditions are discussed in Chapter 25, pages 600–602.

Suppurative granulomas and zones of necrosis surrounded by a palisade of epithelioid cells may be seen in the skin, at the site of injury, in cat-scratch disease (see p. 570). A variable number of lymphocytes, plasma cells, histiocytes, and eosinophils are present in the adjacent tissues. ⁵²⁷

The cutaneous lesions of lymphogranuloma venereum do not have a specific histopathological appearance (see p. 571). The characteristic suppurative and centrally necrotic granulomas are found in the regional lymph nodes. ⁵²⁷

Superficial granulomatous pyoderma is a variant of pyoderma gangrenosum (see p. 237) which has a more indolent course than classic pyoderma gangrenosum.^{528. and 529.} One group has suggested that this condition would be better called ‘pathergic granulomatous cutaneous ulceration’. ⁵³⁰ Unlike the typical pyoderma gangrenosum, there are suppurative granulomas and scattered multinucleate giant cells in the dermis associated with irregular epidermal hyperplasia, sinus formation, fibrosis, and a heavy mixed inflammatory infiltrate which includes plasma cells and eosinophils.^{529. and 531.} The histological changes mimic an infectious process but the lesions respond to corticosteroid therapy and not antibiotics.

Occasionally suppurative granulomas are seen adjacent to ruptured cysts (epidermal and dermoid cysts, in particular) and to inflamed hair follicles which rupture, liberating their contents into the dermis.

Foreign body granulomas are formed around such disparate substances as starch, ⁵³² talc, ⁵³³ tattoo material (Fig. 7.20),^{177. and 534.} cactus bristles, ⁵³⁵ wood splinters, suture material, retained epicardial pacing wires,^{536. and 537.} Bioplastique, Dermalive and Artecoll microimplants,^{538.539.540. and 541.} injected mineral oil, ⁵⁴² injected hyaluronic acid,^{543.544.545. and 546.} pencil lead, ⁵⁴⁷ bovine collagen, ⁵⁴⁸ artificial hair, ⁵⁴⁹ golf club graphite, ⁵⁵⁰ fragments of a chain saw blade, ⁵⁵¹ and insect mouth parts. ⁵⁵² Some foreign materials such as glass, zirconium, ⁵⁵³ beryllium, acrylic fibers, and tattoo pigments may induce local sarcoidal granulomas (see p. 173). Tuberculoid granulomas have been reported in one patient at the site of injection of zinc-containing insulin. ⁵⁵⁴ Granulomatous reactions have appeared suddenly to long-implanted material as a feature of the immune reconstitution syndrome associated with the use of highly active antiretroviral therapy (HAART) for HIV infection. ⁵⁵⁵ Multiple linear nodules, composed of granulomas of foreign body type, have developed along the superficial veins on both arms in an HIV-positive intravenous drug user treated with HAART. ⁵⁵⁶

Talc particles are birefringent, as are starch granules; the latter exhibit a characteristic Maltese cross birefringence in polarized light. ⁵⁵⁷ Incidentally, it is not well known that cryptococci may also be bi­refringent in polarized light. Materials used to ‘cut’ heroin and other addictive drugs and the filler materials in crushed tablets may produce cutaneous foreign body granulomas in intravenous drug abusers. ⁵⁵⁸ The elemental nature of unknown inorganic material can be determined using energy-dispersive X-ray analysis techniques if necessary. A granulomatous reaction has been recorded at the base of the penis following the injection of acyclovir (aciclovir) tablets dissolved in hydrogen peroxide, in the self-treatment of recurrent genital herpes infection. ⁵⁵⁹

Plant material may be readily identified by its characteristic structure and may be PAS positive. ⁵³⁵ It is prudent to perform stains for bacteria and fungi to exclude contaminating organisms when foreign bodies such as wood splinters or bone fragments are found. Pulse granulomas (Fig. 7.21) are rare reactions to particles of food that are characterized by clusters of small to medium-sized hyaline rings.^{560. and 561.} They may be seen around fistulae involving the gastrointestinal tract. Because the hyaline material usually involves vessel walls, cases have also been reported as (giant-cell) hyalin angiopathy (see p. 386).

A granulomatous reaction at the site of an arthropod bite may be a reaction to insect fragments or introduced epidermal elements. ⁵⁵² A florid granulomatous reaction producing an exophytic tumor has been reported following multiple bee stings used as a folk remedy. ⁵⁶²

A granulomatous reaction is sometimes seen about certain types of suture material including nylon, silk, and dacron. ⁵⁶³ Each type of suture material has a characteristic appearance and birefringence pattern in tissue sections.

Immunization with aluminum-adsorbed vaccines such as tetanus toxoid may produce an unusual foreign body reaction.^{564. and 565.} A central zone of granular debris containing aluminum and phosphate is surrounded by a rim of granular histiocytes (see p. 392). A marked lymphoid infiltrate with lymphoid follicles and eosinophils is present at the periphery. This may superficially resemble the changes of Kimura’s disease. The granulomatous reaction involving a Mantoux test site may have resulted from the implantation of epidermal keratin during the intradermal injection. ⁵⁶⁶ The foreign body granuloma that resulted from a BCG vaccination was probably due to the presence of monosodium glutamate in the vaccine. ⁵⁶⁷ Granulomatous inflammation of the penis has followed intravesical treatments with BCG. The nature of the reactions was never completely elucidated, but it was thought to be a BCG-related granulomatous reaction. ⁵⁶⁸ A granulomatous reaction of mixed foreign body and sarcoidal types has followed the use of depot formulations of leuprorelin acetate in the treatment of prostate cancer. ⁵⁶⁹

A granulomatous reaction has been reported on the eyelids following the use of aluminum salts in blepharopigmentation, a process which attempts to produce a permanent line along the eyelid margin, simulating a cosmetic eyeliner.^{570. and 571.} A similar cosmetic tattoo has been reported on the lips. ⁵⁷² Titanium alloys used in ear piercing are a rare cause of a granulomatous reaction. ⁵⁷³

Granulomas have been described in the skin at the point of entry of acupuncture, indwelling catheter, and venepuncture needles coated with silicone.^{574.575. and 576.} Particles of silicon were detected in macrophages by X-ray microanalysis. Silica granulomas of the elbow have been reported in a tennis player as a consequence of falls on a tennis court which was covered with an artificial silica/polypropylon grass surface. ⁵⁷⁷ Silicone granulomas have followed its injection into various sites for cosmetic purposes.^{578.579. and 580.} Their origin was not determined in another case. ⁵⁸¹ They are discussed further in Chapter 14, pages 394–395.

Endogenous materials include calcium deposits, urates, oxalate,^{582. and 583.} keratin, and hair.

Both metastatic and dystrophic calcification may be associated with a granulomatous foreign body reaction. This is also seen in idiopathic calcinosis of the scrotum and subepidermal calcified nodules.

A granulomatous reaction to keratin and hair shafts occurs adjacent to ruptured epidermal, pilar and dermoid cysts, pilomatrixomas, and any condition associated with rupture or destruction of a hair follicle. Granulomas have been reported as a reaction to autologous hairs incarcerated during hair transplantation. ⁵⁸⁴ A similar reaction is seen in the interdigital web spaces of barbers from implanted hair.^{585. and 586.} It is not uncommon for enlargement of a banal nevocellular nevus to be due to a granulomatous reaction following damage to a hair follicle. Fragments of keratin may or may not be found in these reactions. Occasional fine wavy eosinophilic squames may be identifiable within spaces in the dermis or within giant cells. Hair shafts are oval or rounded structures when cut in section and sometimes exhibit cortical and medullary layers: they are variably birefringent in polarized light and acid fast when stained by the Ziehl–Neelsen technique. Foreign body granulomas to keratin are also seen near squamous cell carcinomas and in recurrences. Their presence is an indication for a careful search for residual tumor. ⁵⁸⁷

Cutaneous amyloid is usually inert but in nodular amyloidosis it may occasionally provoke a foreign body giant cell reaction.

A chalazion is a solitary, usually painless lesion of the eyelid that results from a granulomatous reaction to lipid released from a blocked sebaceous gland. It is best visualized when the lid is everted. Recurrent lesions may occur in patients with seborrheic dermatitis and rosacea.

The Melkersson–Rosenthal syndrome is a rare condition of unknown etiology characterized by the triad of chronic orofacial swelling predominantly involving the lips, recurrent facial nerve palsy, and a fissured tongue (lingua plicata).588.^{589.590.591.592. and 593.} The complete triad occurs in about 25% of cases. A monosymptomatic form in which there is localized episodic swelling of the lip(s) has been called cheilitis granulomatosa of Miescher or granulomatous cheilitis.^{594.595.596. and 597.} The term ‘orofacial granulomatosis’ was introduced by Wiesenfeld and colleagues in 1985 to cover both granulomatous cheilitis and Melkersson–Rosenthal syndrome. ⁵⁸⁸ Anogenital granulomatosis has been regarded as the counterpart of orofacial granulomatosis.^{598. and 599.} Crohn’s disease and sarcoidosis need exclusion. Some of these cases were called vulvitis granulomatosa in the past.^{598. and 600.} The concomitance of granulomatous cheilitis and vulvitis is extremely rare. ⁶⁰¹

The presenting complaint is usually swelling of the lips, but adjacent areas of the cheek are frequently involved. ⁵⁹³ The initial facial swelling may last only a few days and be soft and fluctuant, but it becomes firmer and persistent with time. ⁶⁰² Facial nerve palsy, usually unilateral, occurs in 13–50% of cases.^{588. and 603.} Facial swelling has also been reported in association with syringomyelia. ⁶⁰⁴ The median age at onset was 20 years in one series, and there was an equal sex incidence. ⁵⁸⁸ Persistent unilateral orbital and eyelid edema is an extremely rare manifestation of the disease. ⁶⁰⁵

The etiology is unknown but the syndrome has been considered to be a manifestation of sarcoidosis, ⁶⁰⁶ a reaction to infection or to foreign material, such as silicates, gold, and mercury, ⁶⁰⁷ and a delayed hypersensitivity to cow’s milk protein or food additives. ⁶⁰⁸ In one case, it was worsened by the cocoa in drinking chocolate. ⁶⁰⁹Borrelia burgdorferi has been excluded as an etiological agent, ⁶¹⁰ but the DNA of Mycobacterium tuberculosis has been identified by PCR in one case. ⁶¹¹ In a further case the granulomatous cheilitis was regarded as the consequence of a tuberculid. ⁶¹² Elimination of odontogenic infections has produced remission in some cases. ⁶¹³

Occasional cases have been associated with other granulomatous skin lesions or granulomatous lymphadenopathy.^{588. and 614.} A granulomatous cheilitis may be a manifestation of Crohn’s disease.^{279.615.616. and 617.} The lip sign may predate gastrointestinal symptoms by years.^{618. and 619.} There is one report of a patient with Crohn’s disease and the full triad of lesions associated with the Melkersson–Rosenthal syndrome. ⁶²⁰

Granulomatous cheilitis has been successfully treated with clofazimine, thalidomide, and infliximab.^{616.621. and 622.} Triamcinolone injections have also been used, both alone,^{623. and 624.} and combined with dapsone.^{625. and 626.} Sometimes surgical treatment is necessary for the persistent macrocheilia that may occur with Melkersson–Rosenthal syndrome and cheilitis granulomatosa.^{627. and 628.} Amalgam removal resulted in the resolution of another case. ⁶²⁹

The elastolytic granulomas predominantly affect the exposed skin of the head, neck, and limbs. This group of granulomatous conditions includes actinic granuloma, ⁶³⁷ annular elastolytic giant cell granuloma, atypical necrobiosis lipoidica of the face and scalp, ⁶³⁸ and Miescher’s granuloma. ⁶³⁹ They are all characterized by annular lesions exhibiting a zonal histological pattern that includes a granulomatous response with giant cells at the annular rim and centrally a loss of elastic fibers or the presence of solar elastotic material. These conditions appear to form part of a spectrum. Some have used the term annular elastolytic giant cell granuloma as the group generic term,^{640. and 641.} while others have used it for cases not associated with actinic damage, and have retained the term actinic granuloma for those that do. The two entities will be considered separately in the discussion that follows. The relationship, if any, of this group to the necrobiotic granulomas is controversial. Another lesion, granuloma multiforme, is also very similar clinically and histologically to these conditions and is discussed here.

There have been several reports from South Africa of an annular eruption in ochronotic areas of the face in a group with hydroquinone-induced ochronosis.682.^{683. and 684.} The lesions clinically resemble actinic granuloma and have a zonal appearance with a peripheral hyperpigmented ochronotic zone, an elevated rim and a central hypopigmented area.

Granulomas of various types have been described in cutaneous lesions in persons with genetic and acquired immune deficiency disorders. ⁶⁸⁵ They are listed in Table 7.3. In those with non-AIDS-related immune deficiency, various granuloma types have been described in cutaneous lesions. ⁶⁸⁶ Although, as might be expected, some are associated with a variety of infectious agents to which these patients are prone, many are not. Excellent reviews of the primary immunodeficiency disorders have been published.^{687. and 688.}

In chronic granulomatous disease, despite the name, true granulomas are not common in cutaneous lesions. There are a variety of reports of suppurative granulomas with organisms, foreign body granulomas with and without organisms, and caseation necrosis.^{686.689.690.691.692.693.694. and 695.} Carriers of X-linked chronic granulomatous disease (OMIM 306400) may present with lupus erythematosus-like lesions. ⁶⁹⁶ Several types of autosomal recessive chronic granulomatous disease occur (OMIM 233700, 233710, 233690). Caseating granulomas have been described in X-linked infantile hypogammaglobulinemia (OMIM 300300). Lymphocytes in the granulomas were almost exclusively of CD8 phenotype. ⁶⁹⁷ Sarcoid-like and caseating granulomas have been reported in lesions of common variable immunodeficiency (OMIM 240500).^{698.699.700.701.702.703.704. and 705.} This disease, which has multiple phenotypes, is the most commonly diagnosed primary immunodeficiency disease in adults, after selective IgA deficiency. ⁷⁰⁶ Onset of symptoms is not until the second or third decade of life.^{706. and 707.} It results from a dysfunction of B-cell differentiation resulting from mutations in the TNFRSF13B gene on chromosome 17p11.2. ⁷⁰⁸ Tumor necrosis factor-α (TNF-α) is elevated in this condition, and specific inhibition of this cytokine has been successful in moderating the disease. ⁷⁰⁹ Cutaneous lesions in ataxia-telangiectasia (OMIM 208900) have contained necrobiotic and tuberculoid granulomas.^{521.710.711. and 712.} Sarcoid-like granulomas have also been reported in this condition and in the related Nijmegen breakage syndrome (OMIM 251260). ⁷¹³ Necrobiotic and tuberculoid granulomas have also been reported in combined immunodeficiency, an old term for a heterogeneous group of conditions. ⁷¹⁴ Sarcoidosis with typical granulomas may also be associated with combined immunodeficiency. ⁷¹⁵ There is a lower CD4⁺/CD8⁺ ratio in the sarcoidal granulomas of the immunodeficiency group than in the granulomas of sarcoidosis. ⁷¹⁶ In one case of primary acquired agammaglobulinemia, non-caseating granulomas were described. ⁷¹⁷ Two neonates with perforating neutrophilic and granulomatous dermatitis have been reported. This pattern was said to be a clue to an immunodeficiency which took the form of agammaglobulinemia. ⁷¹⁸