A 54 year old man presented with fatigue and weakness and was found to be seropositive for hepatitis
C. He then developed ulcerating pustular plaques up to 11 cm in diameter on the forearms and shins. A
forearm lesion was biopsied along it's pustule-studded rolled border. The biopsy showed epidermal
hyperplasia with pustulation overlying a dermis heavily infiltrated by neutrophils with lysis of dermal
collagen and a Sweet's-like vascular reaction peripheral to the zones of maximal tissue pathergy.
Case 4 - Figure 1 - There is an ulcerative and pustular lesion of the forearm with a raised, rolled lesional edge.
Case 4 - Figure 2 - There is pseudoepitheliomatous hyperplasia of the epidermis in this biopsy from the lesional edge.
Case 4 - Figure 3 - The dermis contains neutrophilic microabscesses and there is neutrophilic dermal connective tissue lysis.
Case 4 - Figure 4 - A Sweet's-like vascular reaction is seen around blood vessels peripheral to the zone of maximal tissue pathergy.
Pyoderma gangrenosum in a patient with Hepatitis C.
Hepatitis C virus (HCV) is a hepatotropic RNA virus which enters the body through a parenteral route
to cause persistent infection
and, in 50% of patients, chronic disease. Roughly one-fifth
progress to hepatic cirrhosis and/or hepatocellular carcinoma , but serious hepatic injury can
be prevented if interferon- a
therapy is begun within three months of infection . Fatigue is the most common physical
manifestation, but HCV infection may present with a dermatosis. The skin manifestations include
, porphyria cutanea tarda , cryoglobulinemia ,
vasculitis , lichen planus , pityriasis rubra
pilaris , graft versus host disease , polyarteritis nodosa ,
urticaria , erythema nodosum , erythema multiforme , pyoderma
gangenosum (PG) , granuloma annulare , perniosis-like lesions ,
lichenoid and granulomatous interface dermatitis  and follicular-based purpura .
Clinical and Histopathologic Manifestations
The clinical spectrum of HCV-associated lesions in a recent series of 35 patients studied by
us  comprised photodistributed eruptions resembling dermatomyositis, palpable purpura,
folliculitis, violaceous perniotic acral lesions, ulcers, nodules, and urticaria. Lesions are classified
histologically by the dominant reaction pattern, namely vasculopathies of neutrophilic, lymphocytic and
pauci-inflammatory types; palisading granulomatous interstitial histiocytopathy; sterile neutrophilic
folliculitis; neutrophilic lobular panniculitis; neutrophilic dermatoses including neutrophilic
urticaria, neutrophilic eccrine hidradenitis and PG; interface dermatitis and B-cell lymphoproliferative
disease typically including marginal zone lymphoma and clonal plasmacellular infiltrates. Endothelial
enlargement and degeneration are frequently seen in all reaction categories. Tissue eosinophilia was
seen in 50% of HCV-associated dermatoses biopsied.
encompass lymphocytic vasculitis, granulomatous
vasculitis, leukocytoclastic vasculitis (LCV), Sweet's like vascular reactions, glomeruloid
neovascularization and pauci-inflammatory vasculopathy. Endothelia may manifest intranuclear
eosinophilic structures surrounded by halos resembling viral inclusions. Some LCV cases show a
concomitant neutrophilic folliculitis, while those associated with mixed cryoglobulinemia often have a
pustular LCV, a reaction pattern associated with bacterial and viral triggers. Cutaneous manifestations
of mixed cryoglobulinemia type 3 (polyclonal immunoglobulin) and type 2 (monoclonal immunoglobulins
complexed with polyclonal IgG) are well described in the setting of HCV infection. Virions have been
detected in mixed cryoprecipitates, but it has proven difficult to detect the virus in skin biopsies of
HCV- associated mixed cryoglobulinemic vasculitis.
Palisading granulomatous inflammation
in HCV patients manifests an
interstitial array of histiocytes between collagen bundles with tissue neutrophilia mimicking granuloma
annulare (GA) . A similar histology correlates to infection by microbes with superantigen
properties  of which HCV is not one . A different mechanism is likely operative.
The interstitial histiocytic infiltrates may reflect an up-regulated T-helper lymphocyte type-1 (Th1)
response, an important part of the host immune reaction to HCV that is enhanced by ribavirin, and is the
postulated mechanism by which ribavirin augments the effect of IFN-a in reducing viral
. A Th1 response, via interferon- g
elaboration, could effect tissue histiocytic infiltration.
manifests as either a cell poor or a lichenoid
pattern, the latter often with granulomatous inflammation (i.e. a lichenoid and granulomatous
dermatitis); variable tissue neutrophilia and hyalinizing vascular changes of the superficial plexus
reminiscent of porphyria cutanea tarda may co-exist.
Although lichen planus (LP) has been
associated with HCV infection, case control studies suggest there is no increased incidence of HCV
infection in patients with LP compared to those with other inflammatory dermatoses . In vitro analyses have shown a role for virus-specific cytotoxic T-lymphocytes
(CTL's) in viral clearance
. It has been suggested that CTL's might exert control over
viral load, but also contribute to the emergence of mutant viruses, so called "CTL escape variants" which
elude CTL-mediated viral killing.  A cross-reacting lymphocyte response to virally-infected
cells might be of CTL type, producing apoptosis in target cells such as keratinocytes and endothelia in
concert with upregulated fas expression as occurs in infected cells destined for apoptosis .
Sterile neutrophilic folliculitis
manifests follicular inflammation and
perifollicular vasculitis of either LCV and/or granulomatous subtypes. Neutrophilic dermolysis with a
mononuclear cell dominant vascular reaction is seen in cases of HCV-associated pyoderma gangrenosum (PG).
Neutrophilic lobular panniculitis
was seen in 2 cases in our
HCV-induced clonal lymphoproliferative disorders include clonal plasmacellular
infiltrates and marginal zone lymphoma comprising monomorphous
infiltrates of small B lymphocytes in apposition to the eccrine coil, with permeation of the interstitium
of the fat lobule and occasional admixed large lymphocytes. The neoplastic B cells show variable
co-expression of CD43 without significant with CD23 and/or CD10 expression.
In order to better define the histology of HCV-associated skin lesions and to explore a role for
direct viral infection of the skin, we studied paraffin-embedded tissue sections from skin lesions from
18 patients seropositive for HCV. Reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) was performed using a probe for HCV RNA. RT in situ PCR
analyses in 8 of 18 cases examined revealed expression of HCV DNA in a focal, weak fashion in endothelia
and in perivascular inflammatory cells in those cases showing vasculopathic changes. LCV cases showed
focal endothelial localization; in one case with co-existant necrolytic epidermal changes, the signal was
also noted in epidermal keratinocytes. Two cases of palisading granulomatous inflammation showed weak
focal endothelial cell expression, as did a case of sterile neutrophilic folliculitis with perifollicular
vasculitis and one case of panniculitis.
Viral parasitism of endothelia appears to be important in the propogation of skin lesions in the
setting of HCV infection. We postulate that parasitism by HCV can render endothelia autoantigenic
through exposure of cryptic antigens. Cross reactivity between endogenous and viral antigens may lead to
cellular and/or type II immune reactions. In our series a few of the patients in fact had depressed
complement levels. A prior study correlated neutrophilic urticaria to underlying HCV
infection , the etiologic basis of which may reflect complement activation through
circulating immune complexes comprising mixed cryoglobulins with or without admixed HCV particles.
Tropism of HCV B lymphocytes provides a mechanism for the development of low grade clonal B cell
lymphoproliferative disease by promoting B cell expansion with resultant autoantibody production;
circulating immune complexes containing monoclonal cryoglobulins may also be of pathogenetic importance.
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