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The suppurative granuloma:
In this type of granuloma, in which there is a mixture of lymphoid and granulomatous inflammation, some of the aggregates of epithelioid cells outline a space containing neutrophiles (Fig. 3). In one or more
sites, a suppurative granuloma may contact the epidermis and the latter often shows pseudoepitheliomatous hyperplasia. In areas of contact, the wall of the granuloma may undergo fibrinoid necrosis. Necrotic debris
becomes sequestered in the hyperplastic epidermis and, eventually, is extruded to the surface (transepidermal elimination). In one or more sites, a successful host response is manifested by dermal fibrosis
(scar) and often by lichenoid patterns at the dermal-epidermal interface. The epidermis in areas of early regression shows compact hyperkeratosis, hypergranulosis, and hyperplasia and hypertrophy of cells in the
stratum malpighii. A biopsy specimen from an area of regression is unlikely to be interpreted as an infectious process. The suppurative granuloma is characteristic of many infectious processes. It is seen in some
mycobacterioses and in deep fungus infections. The suppurative quality of some granulomas, such as seen in some deep fungus infections, or in atypical acid fast infections, may express activation of the complement
cascade.
Allergic granuloma: A mixed, epithelioid histiocytic and eosinophilic infiltrate, in which the breakdown product of eosinophils imparts a bright eosinophilia to zones of necrosis, characterizes this variant.
Eosinophilic debris may condense with fibrin on the surface of some organisms, as in basidiobolus or phycomycotic infections. Intense eosinophilic deposits are characteristic of one variant of the Splendore-Hoeppli
phenomenon (20,21). Antigen-antibody complexes also contribute to eosinophilic deposits at the surface of some infectious agents and may explain the deposits at the periphery of sulfur granules (actinomycosis), or
the deposits at the surface of sporotrichum organisms (asteroid body), or other deep fungi.
The necrotizing granuloma:
This response is a relatively pure, granulomatous process, in which focal areas of fibrinoid, or caseous necrosis, are prominent (Fig. 5). The epithelioid cells form palisades with radial extensions of cytoplasm into the zones of necrosis. Multinucleated histiocytic giant cells are common. They often border zones of necrosis with their nuclei concentrated in a row near the interface with viable tissue, but absent at the interface with necrotic tissue. This "horseshoe" distribution of nuclei characterizes the Langhans cell; it may be a morphologic adaptation to accommodate secretory functions. Degree of “maturity” may explain the differences between Langhans' cells, and foreign body giant cells. Inflammatory infiltrates in the adjacent dermis adjacent to a necrotizing granuloma are dense and pleomorphic. Plasma cells are often numerous. The resolution of a necrotizing granuloma invariably results in a scar. A necrotizing granuloma may characterize some of the same infectious processes listed for suppurative granulomas.
Lupus vulgaris, tropical granulomatous diseases such as leishmaniasis, and tertiary lues may show the pattern of a necrotizing granuloma.
The infarcted granuloma:
This variant is a circumscribed, tumoral area of coagulation necrosis with epithelioid cells and giant cells in palisades at the interface between the coagulated tissue and the viable tissue. A gumma is the prototype of the infarcted granuloma. A dirofilarial granuloma also qualifies as an infarcted granuloma; in the zones of necrosis, ghost outlines of the parasite are recognizable in infarcted vessels (22). Lupus miliaris disseminatus faciei has features of an infarcted granuloma. Demodex organisms are occasionally found in the center of the zone of necrosis. Areas of necrosis in erythema induratum often have the qualities of an infarcted granuloma. The reaction in the subcutaneous fat in lymphomatoid granulomatosis has features of an infarcted granuloma.
Granulomatous angiitis:
This reaction is characterized by a necrotizing angiitis in which the perivascular infiltrates are granulomatous. Granulomatous angiitides may be seen as a cutaneous manifestation of disseminated vasculitides, such as Wegener's granulomatosis (1) and lymphomatoid granulomatosis. Perivascular granulomas with eosinophilia and eosinophilic necrosis may be a cutaneous manifestation of allergic granulomatosis (Churg-Strauss granulomatosis). A necrotizing, granulomatous angiitis is a feature of miliary tuberculosis.
Granulomatous collagenosis and elastosis (mesenchymal palisaded granulomas):
A granulomatous response is not peculiar to infectious processes. In most inflammatory processes, connective tissue is activated. The early response is characterized by lysis of collagen and proliferation of mesenchymal cells. In this lytic phase, some of the mesenchymal cells acquire histiocytic qualtities and function as collagenoclasts. In addition, histiocytes are recruited to the area of damage and also function as collagenoclasts. Collagenases are probably involved in the lytic process. A mucinous matrix occupies the defects that are produced by the lysis of collagen. In some inflammatory processes, the histiocytic (lytic) phase of connective tissue activation is dominant. This reaction defines the histologic pattern in granuloma annulare. Immobilized monocytes and activated connective tissue are prominently represented at the borders of the zones of lysis. The reaction in necrobiosis lipoidica has features of the histiocytic (lytic) phase of connective tissue activation and, in addition, contains compact aggregates of epithelioid histiocytes (pure granulomas). Abnormal crystals, such as cholesterol, urates, or calcium in connective tissue may provoke a granulomatous response in the pattern of a palisaded granuloma.
These patterns of palisaded granuloma express the cellular, lytic phase of activated connective tissue. The concept of a granulomatous response to antigen-antibody complexes may explain some of these peculiar
connective tissue diseases of the dermis. If an antigen, or an antigen-antibody complex is fixed to dermal collagen, or in the interstitium of dermal connective tissue, and is relatively insoluble, the host's
response may include the histiocytic transformation of myofibroblasts, recruitement of macrophages, and lysis of the antigenically altered collagen, or matrix. Vessels may be locally involved in the antigen-antibody
reaction. The enzymatic responses of histiocytes may liberate antigens from sites of fixation in connective tissue; the transformation of histiocytes to epithelioid cells is not a requisite for these enzymatic
functions. Histiocytes often function as collagenoclasts. Granuloma annulare is the model for mesenchymal granulomas (palisaded granulomas).
Elastica may also be antigenically, physically, or chemically altered. In inflammatory processes in actinically altered dermis, it is not uncommon to find histiocytes and giant cells with phagocytized remnants of
elastica in their cytoplasm. Actinic granuloma, granuloma multiforme, and some forms of anetoderma are examples. Granulomatous, elastolytic disorders may produce remarkable changes in the elasticity of the skin
(cutis laxa).
Lipoid granuloma:
This pattern expresses a granulomatous response to endogenous, or exogenous, lipids. Epithelioid cells surround a central, rounded, clear space. This pattern is characteristic of the lipoid granuloma. The clear space seen on routine histologic preparations marks a defect produced by the removal of lipids during the processing of tissue. The lipoid granuloma is common in the dermis in follicular diseases, such as acne rosacea, or chalazion. It may be seen in the evolution of lobular panniculitides (lipogranulomatous panniculitis). It may also be seen in foreign body reaction to exogenous lipids such as vaseline, and injections of paraffin.
Lymphohistiocytic granuloma:
This variant is characterized by diffuse infiltrates in which lymphocytes and histiocytes closely intermingle. The histiocytes do not produce the dense aggregates of an epithelioid tubercle. They have a moderate amount of cytoplasm, eccentric, oval or reniform nuclei, and distinct cell membranes. They may have vacuolated cytoplasm. They are admixed with lymphocytes, plasma cells, eosinophils, and neutrophils in varying proportions. The infiltrate may press upon the epidermis. In infectious processes, this pattern generally correlates with a heavy load of organisms, defective immunity, and a poor response to the infection. The reaction in granuloma inguinale qualifies as a neutrophilic and lymphohistiocytic granuloma. Borderline lepromatous leprosy, lepromatous leprosy and disseminated anergic cutaneous leishmaniasis are variants of lymphohistiocytic granulomas. In summary, in some infections with intracellular parasitism, such as lepromatous leprosy, leishmaniasis, granuloma inguinale, rhinoscleroma, Whipple's disease, or malakoplakia, lymphohistiocytic inflammatory infiltrations (Figs. 1 & 2) are markers for the inability of the host to control the proliferation of organisms whose pathogenicity is low. For some of the organisms, the immune status of the host impacts on the character of the immune response, producing either a granulomatous or a lymphohistiocytic response. For some infections, such as syphilis, the alterations in the character of the immune response are sequential from the primary to tertiary stage.
Metabolic histiocytoses:
histiocytic infiltrations may characterize genetic, metabolic diseases (lipid storage diseases), such as Hurler's or Hunter's disease. They may be seen in the early tissue reactions of hyperlipidemias, but such lesions eventually acquire xanthomatous qualities.
Lymphohistiocytic dysplasias:
In the expression of the inhibitory effects of lymphokines, which are secreted by dysplastic lymphocytes, some lymphoid dysplasias, such as lymphomatoid granulomatosis and Lennert's lymphoma, have lymphohistiocytic or granulomatous qualities.
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