Sarcoidal granulomas are found in sarcoidosis and in certain types of reaction to foreign materials and squames.
The prototypic condition in this group is sarcoidosis. Sarcoidal granulomas are discrete, round to oval, and composed of epithelioid histiocytes and multinucleate giant cells which may be of either Langhans or foreign body type. Generally, the type of multinucleate histiocyte present in a granuloma is not helpful in arriving at a specific histological diagnosis. Giant cells may contain asteroid bodies, conchoidal bodies (Schaumann bodies) or crystalline particles. Typical granulomas are surrounded by a sparse rim of lymphocytes and plasma cells, and only occasional lymphocytes are present within them. Consequently, they have been described as having a 'naked' appearance. Although the granulomas may be in close proximity to one another, their confluence is not commonly found. With reticulin stains, a network of reticulin fibers is seen surrounding and permeating the histiocytic cluster.
Sarcoidal granulomas can be found in the following circumstances:
- Blau's syndrome
- foreign body reactions
- secondary syphilis
- Sezary syndrome
- herpes-zoster scars
- systemic lymphomas
- common variable immunodeficiency
Sarcoidal granulomas are exceedingly rare in secondary syphilis, Sezary syndrome, herpes-zoster scars and systemic lymphomas.
Sarcoidosis is a multisystern 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. There is an increased incidence of sarcoidosis in people of Irish and Afro-Caribbean origin.
Between 10% and 35% of patients with systemic sarcoidosis have cutaneous lesions. Although sarcoidosis is usually a multiorgan disease, chronic cutaneous lesions may be the only manifestation. 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. An erythema nodosum-like eruption with the histological changes of sarcoidosis has also been described. Sarcoidosis predominantly affects adults; skin lesions are rarely seen in children. There are reports of its occurrence in monozygotic twins.
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. Oral lesions may also occur. The majority of skin lesions resolve without scarring. Hypopigmented macules without underlying granulomas have been described, particularly in patients of African descent. Other rare presentations have included leonine facies, faint erythema palmar erythema and lesions confined to the vulva.
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 following trauma (including surgery and venepuncture), radiation and chronic infection. In some cases these lesions may be the first manifestation of sarcoidosis. Other cases do not appear to be related to systemic sarcoidosis and may be a sarcoidal reaction to a foreign body.
Various systemic diseases have been reported in association with cutaneous sarcoidosis. The association in many of these conditions is probably fortuitous. They include cutaneous lymphoma, hyperparathyroidism, autoimmune thyroiclitis and/or vitiligo, and HIV infection. In one case of HIV infection, the sarcoidosis became manifest after the commencement of highly active antiretroviral therapy (HAART) and the restoration of some immune function. The term 'immune restoration disease' has been used for this circumstance.
The etiology of sarcoidosis remains controversial although an infectious origin has long been suspected. The main candidate is a cell wall deficient form of an acid-fast bacillus, similar, if not identical to, Mycobacterium tuberculosis. In one study, DNA sequences coding for the mycobacterial antigen were found in 11 of 35 cases of sarcoidosis, while in a more recent study, using only cutaneous specimens, mycobacterial DNA was demonstrated by PCR in 16 of 20 cases. Non-tuberculous (atypical) mycobacteria constitute the largest group of the species identified in this study. Other findings supportive of a mycobacterial etiology are the beneficial effects of long-term tetracyclines and the activation of a case following concurrent M. marinum infection of the skin. A recent stud y concluded that there was no role for human herpesvirus type 8 (HHV 8) in the etiology, despite earlier reports suggesting a role.
The exact relationship of Blau's syndrome to sarcoidosis is uncertain. It is characterized by the familial presentation of a sarcoid-like granulomatous disease involving the skin, uveal tract and joints, but not the lung. Onset is in childhood and the mode of inheritance appears to be autosomal dominant. It has been regarded by some as a familial form of early-onset sarcoidosis but it is generally regarded as a unique condition.
There is a dermal infiltrate of granulomas of the type already described. Granulomas may be present only in the superficial dermis or they may extend through the whole thickness of the dermis or subcutis, depending on the type of cutaneous lesion. There is no particular localization to skin appendages or nerves. Necrosis is not usually seen in granulomas but has been reported. Small amounts of fibrinous or granular material m ay be seen in some granulomas. Fibrinoid necrosis is said to be quite common in the cutaneous lesions of black South Africans. Slight perigranulomatous fibrosis may be present but marked dermal scarring is unusual except in lupus pernio or necrotizing and ulcerating lesions.
Overlying epidermal hyperplasia occurs in verrucous lesions and hyperkeratosis occurs in the rare ichthyosiform variant. Otherwise, in most cases, the overlying epidermis is normal or atrophic.
Transepidermal elimination has been reported in sarcoidosis and the histology shows characteristic elimination channels. In some cases the round cell infiltrate surrounding the granulomas is more intense and the granulomas less discrete. The diagnosis of sarcoidosis may then become one of exclusion.
Asteroid bodies and conchoidal bodies (Schaumann bodies) may be seen in multinucleate giant cells but are not specific for sarcoidosis and may occur in other granulomatous reactions including tuberculosis. Schaumann bodies, which are shell-like calcium-impregnated protein complexes, are much more common in the granulomas of sarcoidosis than in those of tuberculosis. Birefringent material was found in the granulomas in 12 of the 50 cases studied in a recent report. Electron probe microanalysis identified calcium, phosphorus, silicon and aluminum. It is thought that the calcium salts are probably the precursors of Schaumann bodies. Another explanation for the material is that it represents foreign material inoculated during a previous episode of inapparent trauma leading to granuloma formation subsequently in a patient with sarcoidosis. Asteroid bodies are said by some to be formed from trapped collagen bundles or from components of the cytoskeleton, predominantly vimentin intermediate filaments.
Biopsies taken from Kveim-Siltzbach skin test sites, sometimes used in the past for the diagnosis of sarcoidosis, show a variety of changes ranging from poorly formed granulomas with a heavy mononuclear cell infiltrate to small granulomas with few mononuclear cells. Measurement of the serum angiotensin-converting enzyme (ACE) level has now replaced this skin test.
Immunohistochemical marker studies have shown that the T lymphocytes expressing the suppressor/cytotoxic phenotype are found predominantly in the perigranulornatous mantle whereas those expressing the helper/inducer phenotype are present throughout the granuloma. B lymphocytes are also present in the mantle zone.
Immunofluorescence studies in some cases have shown IgM at the dermoepidermal junction, IgM within blood vessel walls, and IgG within and around the granuloma. A fibrin network is present within granulomas.