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Clinical/Introduction
Granuloma annulare (GA) and necrobiosis lipoidica (NL) are classified as idiopathic palisading granulomatous
dermatitides, the spectrum of which encompasses the rheumatoid nodule, the rheumatic fever nodule,
spirochete-associated juxta-articular nodes and the palisading granuloma of Churg and Strauss (PGCS). Cases
of GA have been associated with systemic diseases including infections with Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), Borrelia burgdorferi, syphilis, diabetes mellitus (DM), iritis, rheumatoid
arthritis (RA), sarcoidosis, and autoimmune thyroiditis. Necrobiosis lipoidica has been described in
patients with sarcoidosis, DM, Crohn's disease, ulcerative colitis (UC), and RA, and after jejuno-ileal
bypass operation. We reported GA or NL tissue reactions in 49 patients with underlying systemic diseases
including UC, Crohn's disease, RA, iritis, systemic lupus erythematosus (SLE), polymyalgia rheumatica,
Borrelia burgdorferi, Mycoplasma pneumoniae, EBV, HIV, hepatitis C, and parvovirus infections, Wegener's
granulomatosis (WG), allergic granulomatosis of Churg and Strauss (AGCS), DM, thyroid disease, and malignant
lymphoma. While lesions of GA are found most commonly on the hands, feet, and wrists, patients with GA
tissue reactions in the setting of systemic disease manifest disease in an atypical site. For example GA
tissue reactions involving the elbow may be associated with chronic viral illness, rheumatologic diseases or
ANCA-positive vasculitic syndromes.
A recent study evaluated clinical features associated with subcutaneous granuloma annulare. This entity at
a light microscopic level closely resembles a rheumatoid nodule including the presence of large zones of
necrobiosis accompanied by striking deposits of fibrin. Subcutaneous granuloma annulare appears to be
almost an exclusive disorder of the pediatric population with mean age of presentation being 4.3 years. The
site localization is to the extremities and scalp. Nineteen percent of patients may have recurrences. In a
period of follow up that averaged 26 years no patient was known to develop systemic disease including in the
context of collagen vascular disease.
Histopathology
Granuloma annulare manifests as an interstitial histiocytopathy with mucinosis involving the dermis in a
patchy fashion with areas of spared normal dermis.
As lesions age, multinucleated histiocytes assume a significant proportion of the infiltrate. The
histiocytes initially assume a diffuse pattern of interstitial infiltration. As the collagen necrobiosis
becomes better developed, the histiocytes form a discret palisade around the altered collagen.
Common to lesions of NL is the presence of laminated degenerating collagen fibres interspersed with layers
of mononuclear cells including foamy histiocytes, multinucleated giant cells and lymphocytes; lesions are
generally pandermal and may involve the subcutis. As the lesions mature, significant dermal sclersosi can
be observed. Foci of conspicuous mesenchymal mucin deposition are not present.
In patients whose GA and NL tissue reactions are associated with systemic disease, most biopsies showed an
active vasculopathy defined by the presence of vasculitis or a thrombogenic vasculopathy. In biopsies of GA
associated with underlying disease there may also be variable tissue neutrophilia. A leukocytoclastic
vasculitis is seen primarily in those patients with ANCA positive vasculitic syndromes, inflammatory bowel
disease, hepatitis C, and collagen vascular disease. Granulomatous vasculitis occurs most commonly in
patients with diabetes mellitus, sarcoidosis, and HIV disease. A thrombotic diathesis could be seen in
patients with diabetes mellitus, collagen vascular disease, and HIV disease.
The question arises as to whether the atypical granuloma annulare tissue reaction of systemic disease is
different from so called "neutrophilic and palisaded granulomatous dermatitis" of collagen vascular disease.
This entity describes papular lesions occuring on the dorsum of the fingers and over the elbows. Rheumatoid
papules presumably represents a subgroup of this group of patients. There is interstitial histiocytic
infiltration with variable dermal neutrophilia. In summation both the histology and clinical presentation
resembles the atypical granuloma annulare tissue reaction. However it should be emphasized that this hybrid
granulomatous and neutrophilic reaction pattern is not unique to patients with collagen vascular disease
being seen in patients with hepatitis C and mixed cryoglobulinemia, inflammatory bowel disease, and ANCA
positive vasculitic syndromes.
Tissue eosinophilia in biopsies of granuloma annulare was not uncommon being identified in up to two thirds
of biopsies. It tends to occur in younger patients and a specific correlation with systemic disease has not
been established
References
- Carrington CB, Liebow A. Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med
1966;41:497-527
- Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous
dermatitis in patients with collagen vascular disease. Arch Dermatol 1994;130:1278-1283
- Crowson AN, Williams J, Nuovo GJ, Magro CM. The dermatopathological manifestations of hepatitis C
infection: a reverse transcriptase in situ polymerase chain reaction (RT-PCR) study (Abst). Lab Invest
2001;81:67A
- Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare : histopathology and direct
immunofluorescence. Arch Dermatol 1977;113:463-467
- Felner EI, Steinberg JB, Weinberg AG Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics
1997;100:965-7
- Ikeda E et al. Multiple rheumatoid papules characteristic of the early stage of rheumatoid arthritis. Eur
J Dermatol 1999;9:313-316
- Magro CM, Crowson AN. Behcet's Disease. Int J Dermatol 1995;34:159-165
- Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a
manifestation of systemic disease. Hum Pathol 1996;27:50-56
- Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of
171 cases. Arch Dermatol 1966;93:272-281
- Romero LS, Kantor GR Eosinophils are not a clue to the pathogenesis of granuloma annulare.Am J Dermatopathol
1998;20:29-34
- Smith ML, Jorizzo JL, Semble E et al. Rheumatoid papules: lesions showing features of vasculitis and
palisading. J Am Acad Dermatol 1989;2:20: 348-352
OTHER FORMS OF PALISADING GRANULOMATOUS INFLAMMATION
RHEUMATOID NODULES
Introduction
Rheumatoid nodules are a manifestation of sero-positive rheumatoid arthritis. Clinically, they manifest as
nodules located in proximity to joints. Similar lesions may occur in patients with macroscopic
polyarteritis nodosa and systemic lupus erythematosus.
Histopathology
The classic rheumatoid nodule affects the subcutaneous tissue with an extension into the overlying dermis.
The morphology is one of irregularly-shaped, broad zones of necrobiosis of connective tissue fibre elements.
The necrobiotic zones have a hypereosinophilic appearance due to the deposition of fibrin. There is a
concomitant peripheral palisading infiltrate of histiocytes. Within the necrobiotic zones, vessels showing
necrotic endothelium and occluded by fibrin thrombi are observed. Outside these palisading necrobiotic
areas, is a distinctive vascular reaction which mimics granulation tissue. In particular, one observes
glomeruloid congeries of vessels accompanied by plasmacellular infiltrates, hemosiderin deposition, and at
times, a necrotizing vasculitis. The differential diagnosis is primarily with subcutaneous granuloma
annulare, an uncommon form of granuloma annulare typically seen in children, in which biopsies show
conspicuous tissue eosinophilia. The rheumatic fever nodule also bears a striking resemblance to the
rheumatoid nodule, but is distinguished by a characteristic clinical history: it is a distinctive eruption
that occurs in children with acute rheumatic carditis. Another mimic of the rheumatoid nodule is the
post-traumatic pseudo-rheumatoid nodule, which has a similar morphology.
JUXTA ARTICULAR NODES
Introduction/Clinical
Juxta articular nodes are discrete nodose lesions seen in proximity to the joints and are a manifestation of
tertiary syphilis or Lyme disease.
Histopathology
The morphology closely mimics that of the rheumatoid nodule. In particular, one observes zones of
necrobiosis accompanied by a granulomatous infiltrate. Plasma cell infiltration is striking as would be
expected in any treponemal infection. Special stains to evaluate for spirochetes usually reveals fragmented
spiroquetal forms within the necrobiotic zones.
HISTIOCYTIC DERMAL INFILTRATES WITH EPIDERMAL ALTERATION
Palisading granulomatous drug reaction
We recently described a group of patients in whom drug therapy was associated with reproducible clinical
pattern and histomorphology for which the appellation interstitial or palisading granulomatous drug reaction
was proposed. Most had erythematous to violaceous, non-pruritic plaques, often annular, predominantly
involving inner aspects of the arms, medial thighs and intertriginous areas. The most frequent clinical
differential diagnoses included cutaneous T cell lymphoma, erythema annulare centrifigum, GA, and lupus
erythematosus. The implicated drug classes included calcium channel blockers, angiotensin converting enzyme
inhibitors, beta blockers, lipid lowering agents, antihistamines, anticonvulsants and antidepressants, with
most patients on 2 or more of these drugs, all which have been associated with pseudolymphomatous skin
infiltrates linked pathophysiologically to pertubation of immune function. Skin biopsies showed
interstitial histiocytic infiltrates with variable degeneration of collagen and elastic fibres mimicking
early lesions of granuloma annulare (GA), often in concert with a vacuolar interface dermatitis. Some cases
showed lymphoid atypia: intermediate and transformed lymphocytes with hyperchromatic convoluted nuclei
disposed interstitially within the dermis or along the dermoepidermal junction with variable
epidermotropism.
Differential Diagnosis
A very similar histomorphology is seen in the setting of id reactions to infection by microbes with
superantigen porperties (see below). Systemic connective tissue disease (CTD) syndromes, including an
unclassifiable category comprising young women with Raynaud's phenomenon, arthralgias and an acral
papulosquamous eruption held by us to be an indolent forme fruste of CTD, may look similar. Occasionally,
lesions of idiopathic GA manifest a lymphocytic interface injury pattern.
Reference
- Magro CM, Crowson AN, Schapiro BL. Interstitial and palisading granulomatous drug reaction : A distinctive
clinical and pathological entity. J Cutan Pathol 1998;25:72-78.
ID REACTIONS TO MICROBIAL PATHOGENS
WITH SUPERANTIGEN PROPERTIES
Introduction/Pathogenesis
Apart from direct infection, the major cutaneous expression of infections are immunological responses to
nonviable microbial antigens, designated as cutaneous id reactions, which manifest a histomorphology similar
to that seen at the primary infective site. Id reactions to microbial pathogens with superantigen
properties, the so-called reactive arthropathy-associated pathogens, may provoke an interstitial
histiocytopathy. Superantigens stimulate cytokine production by monocytes and T-lymphocytes via interaction
with MHC class II-expressing antigen-presenting cells and T-cells outside the traditional peptide-binding
grooves, binding to highly conserved residues on the MHC class II molecule, interacting mainly with the V--
region of the T-cell receptor to stimulate 5-30% of the T-cell repertoire, unlike usual bacterial peptides
which stimulate only 0.01-0.0001% of that repertoire.
Clinical
The majority of patients are women who manifest skin lesions which clinically resemble Sweet's syndrome,
erythema multiforme and/or erythema nodosum. Fever, arthralgia, oligoarthritis, mucosal ulcers of the mouth
and/or genital tract and uveitis are additional features in some. There is evidence of a recent prior or
concurrent infection, based on either serology or cultures, by pathogens including Cytomegalovirus,
Parvovirus B19, Streptococcus sp, mycoplasma, Klebsiella sp, and Borrelia burgdorferi.
Histopathology
Skin biopsies showed focal lymphocytic interface dermatitis, a diffuse interstitial histiocytic infiltrate,
and a mononuclear cell predominant vascular reaction which in some cases represent vasculitis by virtue of
manifesting concomitant luminal or mural fibrin deposition. The vasculitis may be either lymphocytic or
granulomatous. Eosinophils, eczematous alterations, and papillary dermal edema can be identified in a
minority of cases.
Differential Diagnosis
The differential diagnosis includes idiopathic granuloma annulare, interstitial granulomatous drug
reactions, and connective tissue disease.
References
- Dellabona P, Peccoud J, Kappler J, Marrack P, Benoist C, Mathis D. Superantigens interact with MHC class II
molecules outside of the antigen groove. Cell. 1990;62:1115-21.
- Drake CG, Kotzin BL. Superantigens: biology, immunology, and potential role in disease. J Clin Immunol
1992;12:149-62.
- Magro CM, Crowson AN. Interface and granulomatous dermatitis as a manifestation of antecedent microbial
infection : the superantigen id reaction. J Cutan Pathol 1998;25:538-44.
- Magro CM, Crowson AN, Schapiro BL. Interstitial and palisading granulomatous drug reaction : A distinctive
clinical and pathological entity. J Cutan Pathol 1998;25:72-78.
- Magro CM, Dawood MR, Crowson AN. The cutaneous manifestations of human parvovirus B19 infection. Hum
Pathol 2000;31:488-97.
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