—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 4 - Pyoderma Gangrenosum in a Patient with Hepatitis C

A. Neil Crowson
Regional Medical Laboratory and University of Oklahoma
Tulsa, OK


Click on each slide thumbnail image for an enlarged view
Clinical History
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.

Diagnosis
Pyoderma gangrenosum in a patient with Hepatitis C.

Discussion

Introduction
Hepatitis C virus (HCV) is a hepatotropic RNA virus which enters the body through a parenteral route to cause persistent infection [1, 2] and, in 50% of patients, chronic disease. Roughly one-fifth progress to hepatic cirrhosis and/or hepatocellular carcinoma [3], but serious hepatic injury can be prevented if interferon- a therapy is begun within three months of infection [3]. Fatigue is the most common physical manifestation, but HCV infection may present with a dermatosis. The skin manifestations include pruritus [4, 5] , porphyria cutanea tarda [6], cryoglobulinemia [7], vasculitis [8], lichen planus [9], pityriasis rubra pilaris [10], graft versus host disease [11], polyarteritis nodosa [12], urticaria [13], erythema nodosum [14], erythema multiforme [15], pyoderma gangenosum (PG) [16], granuloma annulare [17], perniosis-like lesions [18], lichenoid and granulomatous interface dermatitis [19] and follicular-based purpura [20].

Clinical and Histopathologic Manifestations
The clinical spectrum of HCV-associated lesions in a recent series of 35 patients studied by us [2] 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.

Vasculopathic lesions
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) [17]. A similar histology correlates to infection by microbes with superantigen properties [21] of which HCV is not one [22]. 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 load [22, 23] . A Th1 response, via interferon- g elaboration, could effect tissue histiocytic infiltration.

Interface dermatitis
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. [2, 19] 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 [24]. In vitro analyses have shown a role for virus-specific cytotoxic T-lymphocytes (CTL's) in viral clearance [22, 23] . 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. [25] 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 [26].

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 series. [2]

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.

Pathogenesis
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. [2]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 [24], 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.

References

  1. Pawlotsky JM, Dhumeaux D, Bagot M. Hepatitis C virus in dermatology. A review. Arch Dermatol 1995;131:1185-1193.
  2. Crowson AN, Nuovo G, Ferri C, Magro CM. The dermatopathological manifestations of hepatitis C infection: a clinical, histologic and molecular assessment of 35 cases. Hum Pathol 2003;6:573-9.
  3. Alpert E, Isselbacher KJ. Hepatitis-associated antigen and hepatoma in the U.S. Lancet 1997;2:1087.
  4. Fisher DA, Wright TL. Pruritus as a symptom of hepatitis C. J Am Acad Dermatol 1994;30:629-632.
  5. Kanazawa K, Yaoita H, Murata K, Okamoto H. Association of prurigo with hepatitis C virus infection. Arch Dermatol 1995; 131:852-853.
  6. Koester G, Feldman J, Bigler C. Hepatitis C in patients with porphyria cutanea tarda. J Am Acad Dermatol 1994;31:1054.
  7. Durand JM, Lefevre P, Harle JR et al. Cutaneous vasculitis and cryoglobinaemia type II associated with hepatitis C virus infection. Lancet 1991;337:499-500.
  8. Durand JM, Kaplanski G, Richard MA et al. Cutaneous vasculitis in a patient infected with hepatitis C virus. Detection of hepatitis C virus RNA in the skin by polymerase chain reaction. Br J Dermatol 1993;128:359-360.
  9. Mokni M, Rybojad M, Puppin D Jr et al. Lichen planus and hepatitis C virus. J Am Acad Dermatol 1991;24:792.
  10. Cecchi R, Giomi A, Tuci F et al. Pityriasis rubra pilaris, lichen planus, alopecia universalis and vitiligo in a patient with chronic viral hepatitis C. Dermatology 1994;188:239-240.
  11. Bouloc A, Pawlotsky JM, Choukroun V et al. Cutaneous chronic graft-vs-host disease and hepatitis C virus. Arch Dermatol 1995;131:853-855.
  12. Carson CW, Conn DL, Czaja AJ et al. Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa. J Rheumatol 1993;20:304-309.
  13. Reichel M, Mauro TM. Urticaria and hepatitis C. Lancet 1990;336:822-823.
  14. Domingo P, Ris J, Martinez E et al. Erythema nodosum and hepatitis C. Lancet 1990;336:1377.
  15. Antinori S, Esposito R, Aliprandi CA et al. Erythema multiforme and hepatitis C. Lancet 1991;337:428.
  16. Crowson AN, Magro CM, Mihm MC Jr. Pyoderma gangrenosum : A review. J Cutan Pathol 2003;30:97-107.
  17. 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.
  18. Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol 1997;28:478-484.
  19. Magro CM, Crowson AN. Lichenoid and granulomatous dermatitis: a novel cutaneous reaction pattern. Int J Dermatol 2000;39:126-33.
  20. Magro CM, Crowson AN. Sterile neutrophilic folliculitis with perifollicular vasculopathy: a distinctive cutaneous reaction pattern reflecting systemic disease. J Cutan Pathol 1998;25:215-221.
  21. Magro CM, Crowson AN. A distinctive cutaneous reaction pattern indicative of infection by reactive arthropathy-associated microbial pathogens: the superantigen id reaction. J Cutan Pathol 1998;25:538-544.
  22. Tam RC, Pai B, Bard J et al. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol 1999;3:376-382.
  23. Cribier B, Garnier C, Laustriat D, Heid E. Lichen planus and hepatitis C infection: an epidemiologic study. J Am Acad Dermatol 1994;31:1070-1072.
  24. Rehermann B, Chang K-M, McHutchinson R et al. Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients. J Virol 1996;70:7092-7102.
  25. Chang KM, Gruener NH, Southwood S et al. Identification of HLA-A3 and –B7 restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C. J Immunol 1999;162:1156-64.
  26. Wattre P, Bert V, Hober D. [Apoptosis and human viral infections]. Ann Biol Clin (Paris) 1996;54:189-197.
  27. Smith R, Caul EO, Burton JL. Urticaria and hepatitis C. Br J Dermatol 1997;136:980.