—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 3 - Cutaneous Crohn's Disease
with Psoriasiform Dermatitis and Endovascular Histiocytopathy

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 38 year old man with a 15 year history of Crohn's disease developed an 8 x 5 cm plaque on the right buttock that was not in continuity with diseased anal or rectal mucosa. A biopsy showed a psoriasiform pattern of epidermal hyperplasia overlying dilated dermal lymphatic spaces containing aggregates of banal histiocytes.


Case 3 - Figure 1 - There is a plaque on the left buttock, some 8x5 cm in diameter. It is not in continuity with the anal canal.
Case 3 - Figure 2 - The biopsy shows psoriasiform hyperplasia overlying markedly dilated dermal lymphatic spaces.


Case 3 - Figure 3 - The dilated lymphatic spaces contain clusters of endovascular histiocytes.
Case 3 - Figure 4 - The dilated lymphatic spaces contain clusters of endovascular histiocytes.


This is a patient of Dr Michael Wilkerson, Tulsa OK, who kindly provided clinical photographs.

Diagnosis
Cutaneous Crohn's disease with psoriasiform dermatitis and endovascular histiocytopathy.

Discussion

Introduction and Clinical Features
Skin lesions occur in 14 to 44% of patients with Crohn's disease (CD) [1, 2, 3] and include erythema nodosum (EN) [1], pyoderma gangrenosum (PG) [2, 3, 4] , bowel dermatosis-arthritis syndrome [5], periorificial pyoderma [6], pyoderma faciale [7], sterile neutrophilic folliculitis with perifollicular vasculitis [8], and so-called "metastatic" CD [8] which comprises non-necrotizing sarcoid-like granulomatous dermatitis. [2]

Pathogenesis
The pathogenetic mechanism by which skin lesions develop in CD patients is enigmatic. Animal models suggest that microbial pathogens may play a role in producing the gut and skin lesions of CD. [9, 10] Some case reports relate CD directly to infection by Mycobacterium avium subspecies paratuberculosis [10] for which antimicrobial therapy can be curative. Other implicated microbes include viruses such as paramyxovirus [11]and measles virus [12], and other bacteria such as Listeria monocytogenes, Yersinia sp. Helicobacter sp, Escherichia coli, and Chlamydia sp.. [13] Elevated levels of anti-Saccharomyces cerevisiae antibodies (ASCA's), described in sera of adult CD patients [14], dissappear with resection of the diseased bowel. In contrast to perinuclear anti-nuclear cytoplasmic antibody (pANCA), which appears to identify a subset of CD patients with a UC-like presentation, the ASCA antibodies appear not to be autoantibodies but are instead directed against oligomannosidic epitopes common to various microbial species; [3, 13] breakdown of tolerance to gut microbes is postulated. [3]

We hypothesized that the skin lesions might be due to hematogenous dissemination of colonic bacteria. [3] In this regard, the mucosal lesions of CD may reflect direct bacterial infection as enteric microflora induce persistent antigenic stimulation in the genetically susceptible host or, alternatively, persistent low-grade bacterial intracellular colonization of macrophages in the lamina propria could evoke the inflammatory cascade leading to active enteritis. [3]Held to support this concept is the identification by polymerase chain reaction (PCR) of the 16S rRNA gene, highly conserved among bacteria, in the inflammatory lesions of CD. [3, 13] Using an RT in situ PCR method to enable direct localization of the bacteria in tissue specimens, we demonstrated the presence of intracellular bacteria in the colonic lamina propria of people with active colitis, a finding that suggests that intracellular bacteria are directly associated with pathogenesis. Conversely, we failed to demonstrate consensus bacterial 16S rRNA in the corresponding skin biopsies from these patients, a finding that effectively excludes a colonic bacterid as the pathogenetic basis of skin lesions in CD and implies that there is an alternative mechanism in their propagation. [3]The cutaneous manifestations may reflect an excessive immunologic response to nonviable bacterial protein fragments or to homologous epitopes in the dermal microvasculature or stroma. This could explain, at least in part, the temporal association of the cutaneous eruptions with the exacerbation of colitis and their improvement and/or resolution with treatment.

Histopathology

In our hands, the following cutaneous lesions are most common in CD patients:

1:  Palisading granulomatous dermatitis with features of granuloma annulare and necrobiosis lipoidica - comprising superficial and deep dermal interstitial and palisading histiocytic infiltrates with variable necrobiosis, venulitis of granulomatous and/or neutrophilic subtypes, and extravascular neutrophilia

2:  Sterile neutrophilic folliculitis with perifollicular vasculopathy, - manifesting either a purely granulomatous or purely neutrophilic folliculitis, with variable follicular necrosis and perifollicular vasculitis of either leukocytoclastic and/or granulomatous subtypes in the setting of special stains negative for bacteria and fungi.

3:  Dominantly neutrophilic infiltrates (ie neutrophilic dermatoses including pyoderma gangrenosum (PG)) - comprising papillary dermal edema with neutrophilic and mononuclear cell infiltrates localized to vessels showing erythrocyte extravasation absent fibrin deposition, ie "Sweet's syndrome-like vasculopathy". Other cases are typical of PG by virtue of neutrophilic infiltration of the dermis with disintegration of the connective tissue fiber network (neutrophilic dermolysis) with a Sweet's-like vascular reaction. An important clue is the presence of scattered multinucleated giant cells in the zones of neutrophilic infiltration, a feature previously reported as being characteristic of PG lesions in patient with CD. [15] One occasionally sees pseudoepitheliomatous hyperplasia and intraepithelial pustulation. The term pyostomatitis vegetans has been applied to such lesions in continuity with diseased rectal or oral mucosa.

4:  Panniculitis - comprising infiltration of the interstices of the fat lobules by neutrophils and mononuclear cells with minimal leukocytoclasia; some cases have concomittant pandermal vasculitis of granulomatous and leukocytoclastic types with lymphocytic eccrine hidradenitis. We have also seen a septal fibrosing and neutrophilic panniculitis compatible with EN but with prominent microabscess formation.

5:  Non-folliculocentric vasculitis - usually a granulomatous vasculitis whereby the superficial vascular plexus contains thrombi unaccompanied by inflammation or a pan-dermal leukocytoclastic vasculitis.

6:  Lichenoid and granulomatous dermatitis - namely a lymphocytic interface dermatitis with a superficially disposed band-like interstitial and perivenular histiocytic infiltrate obscuring the dermoepidermal junction. The mechanism of granulomatous inflammation in patients with CD may relate to a dominant T-helper type 1 (Th1)-dominant cytokine milieu. [15, 16, 17, 18] In particular, Th-1 products include interferon (IFN)-g, a potent histiocyte chemotaxin and activator. [16]

7:  Psoriasis-like lesions - in vulva and groin comprising a psoriasiform diathesis with psoriasiform hyperplasia, spongiform pustulation, granular cell layer diminution and neutrophil-imbued parakeratosis without attenuation of the suprapapillary plates. There is an association of psoriasis with CD, both of which appear to be Th1 mediated autoimmune diseases and respond to recombinant human interleukin-11 therapy. [19] Common genetic loci implicated in psoriasis and CD may be important. [20]

8:  Classical metastatic Crohn's disease - characterized by cohesive epithelioid granulomata involving the entire sampled thickness of the dermis.

9:  Other morphological clues to diagnosis - include lymphoplasmacellular or neutrophilic eccrine hidradenitis and dilated histiocyte-filled lymphatics throughout the dermis. In our experience, this is seen in some10% of cases of CD but is also seen in skin lesions of rheumatoid arthritis [21] and is not pathognomic. The location of such lesions, namely penis, perineum and perianal skin, implies that perturbed lymphatic drainage reflects peri-rectal disease.

Conclusion
The spectrum of cutaneous lesions in CD is wide. Vasculitis, extravascular neutrophilia and granulomatous inflammation, typically in concert, are common. Although a similar inflammatory milieu is seen in the enteric biopsies of these patients, different mechanisms are likely operative in lesional propagation at skin and intestinal sites.

References

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  2. Magro CM, Crowson AN, Mihm MC. Cutaneous manifestations of gastrointestinal disease : In : Elder DE, Johnson BE, Elenitsas R, Johnson BE, Murphy GF Eds. Lever's Histopathology of the Skin. 9th Ed'n. Philadelphia :JB Lippincott Co. 2004 (in press).
  3. Crowson AN, Magro CM, Nuovo GJ, Mihm MC Jr. The cutaneous manifestations of Crohn's disease: a study of 32 cases with investigation of the role of the common bacterial sequence 16srDNA in lesional propagation. Hum Pathol (in press).
  4. Crowson AN, Magro CM, Mihm MC Jr. Pyoderma gangrenosum : A review. J Cutan Pathol 2003;30:97-107.
  5. Delaney TA, Clay CD, Randell PL. The bowel-associated dermatosis-arthritis syndrome. Australas J Dermatol 1989;30:23-27.
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