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Granulomatous Elastolysis
Elastic tissue and elastotic material sometimes are preferentially digested by the digestive enzymes of histiocytes. In these disorders, activated histiocytes form interstitial infiltrates among collagen bundles of
the reticular dermis. In this location, they are in intimate contact with elastic fibers, or elastotic material; elastic fibers may be found extending into the cytoplasm of some of the histiocytes or multinucleated
giant cells. The process histologically may closely resemble a palisaded granuloma but, in some examples, the collagenous component appears to be relatively spared; the elastotic material appears to bear the
brunt of the injury. In some examples, such as granulomatous lax (slack) skin, the process may be relatively diffuse throughout the affected dermis. In classic granuloma annulare, the elastica seems to be somewhat
less affected than the collagenous component. In actinic granuloma, the patterns of granulomatous, interstitial inflammation are relatively confined in distribution to the upper portion of the dermis (i.e., the zone
of tissue showing solar elastosis) (S12C14aP4a-3-5). The process is centrifugal; it spreads from a central nidus in
circumferential fashion and leaves behind a trail of altered collagenous tissue which is relatively free of elastica and elastotic material. The limited distribution of the zone of elastolysis points up the close
relationship between the altered elastica and the granulomatous response; the altered elastica has apparently acquired antigenic properties.
Calderone DC, Fenske NA: The clinical spectrum of actinic elastosis. J Am Acad Dermatol 1995;32:1016-24.
Necrotizing, Palisaded Granuloma of
Collagen-Vascular Disease
(Basophilic Variant)
In the category of collagen-vascular diseases, some variants are occasionally associated with palisaded granulomas. In some examples, histiocytes form palisades about a central zone
of necrosis in which the necrotic debris is intensely basophilic; this basophilia is related to the breakdown of inflammatory cells, including neutrophils and histiocytes. The necrosis generally is more complete
than the collagenolytic and mucinous changes which characterize the usual examples of granuloma annulare. Some examples of rheumatoid nodule are characterized by central zones of basophilic necrosis. Smaller
granulomas with similar qualities may be encountered in the setting of rheumatoid disease, Wegener’s granulomatosis, and other disorders, particularly in association with circulating immune complexes (papular
rheumatoid nodules) (S12C15P5-1-3).
Higaki Y, et al: Rheumatoid papules: a report on four patients with histopathologic findings. J Am Acad Dermatol 1993;28: 406-11.
Jorrizo JL, et al: J Am Acad Dermatol 1983;9: 845-51.
Long D, et al: Interstitial granulomatous dermatitis with arthritis. J Am Acad Dermatol 1996;34 :957-61.
Verneuil L, et al: Interstitial granulomatous dermatitis with cutaneous cords and arthritis: a disorder associated with autoantibodies. J Am Acad Dermatol 2001;45: 286-91.
Sangueza OP, et al: Palisadesd neutrophilic granulomatous dermatitis in rheumatoid arthritis. J Am Acad Dermatol 2002;47: 251-7.
The palisaded granuloma of Churg-Strauss disease usually is associated with a tissue eosinophilia, and tends to be intensely eosinophilic in the zone of necrosis; it is characteristic
of an “allergic granuloma.”
Drage, LA: Evidence for pathogenic involvement of eosinophils and neutrophils in Churg-Strauss syndrome. J Am Acad Dermatol 2002;47:209-16.
Wegener’s Granulomatosis
Wegener’s granulomatosis is characterized by neutrophilic infiltrates, necrotizing vasculitis, extravascular palisaded granulomas, and by reactive fibroplasia. Some of the vascular
changes may be frankly granulomatous but, often, there are features of a leukocytoclastic angiitis in lesions of the skin. Vascular changes affect a variety of organ systems, including the kidneys, lungs, skin, and
the upper-respiratory tract. Fibrosis, including fibrous thickening of the walls of small muscular vessels, is a feature of established lesions (S12C15P5-4-6). Small vessel angiitis may be a feature. Wegener’s granulomatosi is a representative of the group of
vasculitides (i.e., small vessel angiitides) in which anti-neutrophil cytoplasmic antibodies (ANCA) are manifested. Poorly organized granulomas may be found in perivascular arrays in the skin (S12C15P5-7).
Sinus Histiocytosis with Massive Lymphadenopathy
(Rosai-Dorfman Disease)
Sinus Histiocytosis with massive lymphadenopathy is a poorly understood disease characterized by infiltrates of distinctive histiocytes with a variable admixture of inflammatory cells
including neutrophils, lymphocytes, and plasma cells (S12C16P6-1).
Intracytoplasmic inflammatory cells are a feature of the large, pale histiocytes. The histiocytes have plump, round nuclei with open chromatin patterns and a prominent central nucleolus. The disorder was first characterized as sinus histiocytosis of lymph nodes, but visceral and skin involvement were also noted (Azoury and Reed). Rosai and Dorfman provided a more complete description of the disorder. In the skin, the infiltrates tend to be interstitial in the dermis and the subcutaneous fat. The histiocytes are S100(+) and CD1a(-). The distinctive histiocytes of the infiltrates cluster in poorly organized granulomatous patterns.
Moschella SL, Cropley TG: Mononuclear phagocytic and dendritic cell systems. J Am Acad Dermatol 1990;22: 1091-7.
Inflamed Tatoos
The metallic pigments of tatoos may induce an inflammatory reaction, including a granulomatous response. In some examples, the reaction is lymphohistiocytic without the formation of
well-organized granulomas (S12C16P6-2-6).
Granuloma Faciale
The designation, “granuloma,” has application to both gross and microscopic morphology. Histologically, the designation is most appropriate for patterns in which activated histiocytes
are clustered in epithelioid patterns. It has, however, been applied to patterns in which histiocytes are numerous, but are not tightly clustered; the patterns in granuloma inguinale might be cited as an example. As
a descriptive term in clinical practice, the designation gives recognition to a lesion having tumoral, or infiltrative, qualities in combination with distinctive tinctorial qualities (tan or apple-jelly). Disorders,
which have been characterized as “granulomatous” on the basis of clinical presentation, but are not truly granulomatous histologically, tend to promote confusion in the minds of students of pathology, who are early
on in their studies.
The designation, granuloma faciale, gives recognition to clinical features. The histologic patterns are characterized by pleomorphic infiltrates with a high component of histiocytes; the histologic patterns are not
granulomatous by rigid histologic criteria. Histologically, the infiltrates are composed of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes; the histiocytes may contain hemosiderin deposits. The
infiltrates are perivascular in distribution. The process is angioplastic with the formation of an increased number of vessels in the affected areas. In addition, the newly formed vessels are associated with a
fibrous matrix, independent of the fibrous pattern of the preexisting reticular dermis (S12C17,P7-1-5). The end-result
is the formation of islands of vessels and fibrous tissue among hair follicles. Some of the histologic features of an established lesion provide evidence of alternating phases of activity and resolution. In an area
showing signs of activity, the vessels show vasculitic patterns with leukocytoclastic features. The infiltrates extend from perivascular zones into the supporting, fibrous matrix. The reaction has a cyclic quality
with episodes of acute reactions alternating with those of chronicity and repair; the acute insults are not uniform in distribution so that areas showing fibrinoid and a high component of neutrophils may abut upon
areas showing chronic inflammation and fibrosis; in acute reactions, the fibrinoid (“toxic hyalin”) is often concentrically deposited about the lumens of involved vessels; repair of the walls of vessels often is
manifested in the formation of concentric, fibrous lamellae.
Hansen’s Disease
Hansen’s disease (leprosy) is a disease in which the organism is remarkably resistant to the effects of inflammatory infiltrates. The immune response is mostly histiocytic and the
organisms are remarkably adapted to the intracellular environment provided by histiocytes. The primary immune response is cell-mediated; only in reactions do neutrophils contribute to the response, apparently in the manner of a response to circulating immune complexes.
The histologic responses varying in keeping with the polar expressions of clinical disease. The histologic spectrum ranges from pure granulomatous reaction to diffuse poorly organized
infiltrates of foamy histiocytes. The spectrum has been variously segmented both clinically and histologically. In practice the two histologic variables are to be integrated in making assignments to a segment along
the spectrum.
Indeterminate leprosy is a difficult histologic diagnosis. The distribution of the infiltrates along the vascular plexus, even into the subcutis, and a high component of histiocytes
in the perivascular infiltrates are histologic features. At the tuberculoid end of the spectrum, the patterns are epithelioid and, focally, the infiltrates tend to extend to the dermal-epidermal interface. In
contrast to the tubercles of a lesion of sarcoid, the infiltrates of tuberculoid leprosy tend to form cuffs along vessels without clearly defined tubercle-like components (S12C17P7-6). Plasma cells are also a feature of the reaction. Organisms are few in number; the demonstration of organisms
may require diligence. As the load of organisms increases, the character of the reaction changes; foamy histiocytes increasingly become a feature and the infiltrates, in addition to being perivascular, become more
extensive and interstitial as well.
Tick-Bite Granuloma
The reaction to a tick-bite basically is a lymphoid hyperplasia with both perivascular and interstitial components. The infiltrates often are pleomorphic with admixtures of
lymphocytes, histiocytes, eosinophils and plasma cells (S12C18P8-1-4). In the confluent interstitial components, reaction centers with
mantle zones (B-cell domains) commonly are a feature. In addition, the lymphoid tissue beyond the B-cell domains are T-cell domains, often with a prominent component of post-capillary venules (vessels with high
endothelial cells). Some degree of atypia with transformed lymphoid cells is an acceptable variation.
Erythema Induratum
In the category of panniculitides, lesions without demonstrable organisms, but with a striking histologic resemblance to lesions of tuberculosis, as might be seen in lesions of tuberculosis involving the lungs, have
in the past been classified as erythema induratum; this at a time when tuberculosis was prevalent. A tuberculous variant and a non-tuberculous variant of erythema induratum was proposed and the latter subtype was
later characterized as nodular vasculitis. From this beginning, the category was incorporated into the group of lobular panniculitides. The histologic definition of
tuberculous and non-tuberculous variants is complicated by the response of fat to non-specific injury; the response usually has granulomatous or lipogranulomatous qualities. There are occasional example of panniculitis which are necrotizing, granulomatous, vasculitic, and extend into the dermis. They so closely resemble tuberculosis as seen in other organ systems that, in the absence of a demonstable pathogen, they can be properly qualified as examples of “erythema induratum” (S12C19P9-1-3).
Mycobacterium fortuitum infection
In this category, the inflammatory pattern is suppuration with necrosis, or a suppurative granuloma (S12C14bP4b-1-6). The organism is a thin, branching bacillus. It stains inconsistently with common stains, including those
for the demonstration of acid fast organisms.
Smith MB, et al: Clinical and pathologic features of Mycobacterium fortuiterium infections; an emerging pathogen in patients with AIDS. Am J Clin Pathol 2001;116: 225-32.
Elastosis Perforans Serpiginosa
Elastosis perforans serpiginosa is not a representative of the category of granulomatous disease. It is a nevoid hyperelastosis characterized by invasive downgrowth of epithelium into
the dermis. In sites, just in advance of the spreading perforations, there is hyperelastosis in the upper portion of the dermis; elastic fibers of the type normally found in the reticular dermis extend into the
papillary dermis to the dermal-epidermal interface. This type of elastica is foreign to the papillary dermis; in close approximation to the epidermis, it may exert a taxic influence on the neighboring epithelium. In
practice, epithelium extends into the zone of abnormal elastica. An area of necrosis forms at the interface between the invasive epithelium and the connective tissue (or forms and then attracts the epithelium);
histiocytes have a role in the lysis of connective tissue fibers at this interface. Elastic fibers are relatively resistant to the effects of the inflammatory reaction. With destruction of the collagenous framework,
the elastic lattice collapses and is engulfed, along with the necrotic debris, by the invading epithelium (S12,C20,P10-1-7).
The elastic fibers and the necrotic debris are eventually extruded at the surface of the skin (transepidermal elimination). In this process, the dermis focally is cleared of abnormal elastica. With repair, a trail
of newly formed fibrous tissue is left behind; it is devoid of elastica; it has the qualities of a loosely vascularized scar.
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