Differential Diagnosis:

1- sarcoidosis

2-Giant Cell Rich Histiocytic Dermatitis

3- pyoderma gangrenosum

4- granuloma annulare

5- necrobiosis lipoidica

6-   tuberculosis and

other granulomatous skin disease. 

Granulomatous inflammation in the skin represents a chronic inflammatory tissue reaction pattern in which there is a preponderance of monocytes or their variants, namely histiocytes macrophages, epithehoid cells and giant cells. This does not include conditions where there is a primary proliferation of histiocytes such as xanthoma and benign cephalic histiocytosis. In most instances, these cells are aggregated into focal collections called granulomas although a more diffuse arrangement may be found which reflects an immunologic defect within the host. An example of this is lepromatous leprosy. Granuloma formation is usually regarded as a tissue reaction to an insoluble, non-degradable or slowly released antigen, of endogenous or exogenous origin

To arrive at a more specific diagnosis, the dermatopathologist classifies the reaction pattern according to the structural characteristics of the granulomas, the presence of other features like necrosis, necrobiosis or suppuration, the presence of organisms or foreign material. The clinical information is of utmost importance in alerting the dermatopathologist to look for some of these features. The histological subgroups are as follows, the first five being the main ones:

In this type, granulomas are well circumscribed nodules composed of epithehoid histiocytes and typically have a "naked" appearance, a term which describes the scarcity of lymphocytes surrounding and within the granulomas. The granulomas may be superficial or extend throughout the dermis or through to the subcutis. Unlike tuberculoid leprosy, they do follow the nerves or adnexal structures. The prototype of this reaction pattern is sarcoidosis. Histologically, asteroid bodies and Schaumann bodies (calcified deposits) may be seen within multinucleated giant cells but these are not pathognomonic for sarcoidosis and can be present in tuberculosis.

A number of foreign substances may induce a sarcoidal reaction. These include silica, tattoo pigments, Zirconium, Beryllium, acrylic and nylon fibres, and sea urchin spines. A golden rule of thumb when faced with a sarcoidal reaction is to examine under polarized light to detect birefringent foreign material.

In this group, the granulomas consist of collections of epithelloid histiocytes, Langerhans and foreign body giant cells, and are surrounded by a mantle of lymphocytes and plasma cells. Caseous necrosis when present, should prompt the search for acid-fast bacilli. Caseous necrosis tends to be extensive in cutaneous lesions of tuberculosis in patients who are immunosuppressed, and acid-fast bacilli are easy to find. However, it may be histologically impossible to differentiate cutaneous tuberculosis from an atypical mycobacterial infection. Caseous necrosis in the absence of demonstrable acid-fast bacilli is seen in the following conditions:

a) some forms of cutaneous tuberculosis where there is good host immunity namely, tuberculosis verrucosa cutis, lupus vulgaris.

b) tuberculids, lesions thought to be due to allergic sensitivity to tuberculous infections elsewhere in the body.

c) acne agminata, a condition suggested to represent a granulomatous reaction to damaged pilosebaceous units.

In mycobacterium marinum infection, there may be tuberculoid granulomas but usually caseous necrosis is not seen. Necrosis if present, is usually in small foci or fibrinoid. In addition, there may be elements of acute inflammation, in the form of dermal and intraepidermal abscesses (see suppurative granulomas). Like tuberculosis verrucosa cutis, pseudoepitheliomatous hyperplasia may be present and acid-fast bacilli are seldom seen on tissue sections. The definitive diagnosis therefore rests upon clinicopathological correlation and relevant pointers include a history of exposure to aquarium fish, site involved, past exposure to tuberculosis and Mantoux reaction. Tissue cultures for tuberculosis and mycobacterium marinum, in our local experience, have a disappointingly low yield.

Tuberculoid granulomas are also seen in the tuberculoid spectrum of leprosy. In tuberculoid leprosy and borderline tuberculoid leprosy, nerve involvement is prominent and granulomas tend to be elongated, following the course of nerves. Other conditions where tuberculoid granulomas may be seen are granulomatous rosacea (inflammation centered around hair follicles in the presence of vascular dilatation), some forms of tertiary syphilis (infiltrate usually includes plasma cells), chronic cutaneous leishmaniasis (Leishmaniae usually scarce) and Crohn's disease (non-caseating tuberculoid granulomas).

In this group, the granulomas consist of collections of epithelloid histiocytes in the center of which are neutrophilic abscesses. In addition, a combination of other histological changes may be seen, including pseudoepitheliomatous hyperplasia, intraepidermal and dermal microabscesses and a mixed inflammatory cell infiltrate which includes multinucleated giant cells. The main causes for this reaction pattern are deep mycoses, chromomycosis and sporotrichosis being the more common causes locally, mycobacterium marinum infection, and blastomycosis-like pyoderma (caused by Staphylococcus aureus). Other causes of suppurative granulomas are superficial variant of pyoderma gangrenosum, ruptured cysts and hair follicles, and halogenodermas. It is therefore imperative to cut multiple sections to examine for microorganisms and to perform tissue stains for fungi and mycobacteria. This is particularly important as fungal pathogens are often difficult to isolate by culture and definitive diagnosis may then depend on identification of microorganisms in biopsy material.

The term "necrobiosis" refers to areas of degenerated collagen under light microscopy. There is smudging. of collagen fibres, loss of connective tissue nuclei and an alteration in the intensity of staining. Zones of necrobiosis are surrounded by a rim of histiocytes including epithelloid cells, macrophages and multinucleated giant cells; thus the alternative term of "palisading granulomas". This granulomatous pattern is classically seen in granuloma annulare, necrobiosis lipoidica and rheumatoid nodules. Distinguishing features are:

a) mucin in necrobiotic areas - large amounts of mucin favours granuloma annular

b) extent of necrobiosis - more extensive and less well-defined in necrobiosis lipoidica. It should also be mentioned that there are histological variants of granuloma annulare where necrobiosis is minimal or absent (interstitial granuloma annulare). The deep (subcutaneous) variant of granuloma annulare is differentiated from rheumatoid nodule by its presence of mucin in necrobiotic foci.

c) inflammatory component - superficial and deep perivascular mixed inflammatory infiltrate including plasma cells, is conspicuous in necrobiosis lipoidica

d) intervening dermis - there is usually dermal fibrosis in necrobiosis lipoidica

e) vascular changes e.g. endothelial swelling, lymphocytic vasculitis - these are prominent in necrobiosis lipoidica

Foreign body granulomatous reactions may arise secondary to exogenous or endogenous material. Exogenous materials include tattoo, suture material, insect mouth parts. Some foreign materials may induce a sarcoidal reaction. The commonest endogenous cause is that of a ruptured epidermal cyst or hair follicle, releasing keratin contents.

A granulomatous reaction pattern is also seen in other conditions like actinic granuloma, granulomatous mycosis fungoides, granulomatous slack skin disease. In these cases, the presence of other histological features are diagnostic.

This histological pattern is seen in a group of systemic vasculitides. They have been included here for completeness. Histologically, they show varying degrees of granulomatous involvement, both related to vessels and extravascular. The vasculitis may or may not be necrotizing. This group includes Wegener's granulomatosis, Churg-Strauss disease, angiocentric immunoproliferative disorders (lymphomatoid granulomatosis, angiocentric T-cell lymphoma), sarcoidosis, Crohn's disease. Temporal arteritis and Takayasu's arteritis are also often considered in this group although the granulomatous inflammation is restricted to vessel walls.

In practice, it is not uncommon to see a granulomatous reaction which does not fall into any specific categories as described above and often a diagnosis of "granulomatous dermatitis" is rendered. An infectious cause would often have been looked for and special stains for microorganisms examined. The absence of identifiable organisms however, does not exclude an infectious cause and often, the definitive diagnosis depends on clinicopath9logical correlation. It is also worth remembering as in any dermatologic process, that many conditions described above show only non-specific changes in the early evolution of the inflammatory process and in the late or resolving phase, where fibrosis is present without granulomas.

Ref: 

 1- Tan Suat Hoon, Tutorial in Dermatopathology II- Granulomatous Reaction Pattern, National Skin Centre, Vol 8 No 1,

 

2-Wolgamot, Gregory M  Olerud, John E ; Shors, Andrew ; Rhim, Jonathon M; Argenyi, Zsolt B ,Giant Cell Rich Histiocytic Dermatitis/Panniculitis Associated With ThrombocytosisAmerican Journal of Dermatopathology. 29(3):296-299, June 2007