J Cutan Pathol 2001: 28: 97–100 Copyright C Munksgaard 2001

Printed in Denmark ¡ All rights reserved Journal ofCutaneous Pathology

ISSN 0303-6987

Giant cells in pyoderma gangrenosumIt has been claimed that pyoderma gangrenosum (PG) lesions may Scott Sanders1,contain granulomatous foci when associated with Crohn’s disease. Steven R. Tahan2,To test this assertion, we obtained clinical histories and archived cu- Theodore Kwan3 andtaneous biopsies from 34 PG patients. Thirteen of these patients had Cynthia M. Magro4

inflammatory bowel disease (IBD). Immunostaining with PGM1, a 1Department of Dermatology, Cornell Universitymacrophage marker, revealed well-formed giant cells with three or Medical Center, New York, New York, USA,

2Department of Pathology, Beth Israel-more nuclei in biopsies from 6 of 13 patients with IBD. Five of the 6Deaconess Medical Center, Boston,biopsies came from patients with Crohn’s disease and one from a pa-Massachusetts, USA, 3Department of Pathology,tient with ulcerative colitis. Two were peristomal. In the 21 patients Lahey Hitchcock Medical Center, Burlington,

who had PG without IBD, no giant cells were seen. Thus, PGM1π Massachusetts, USA, 4Department of Pathology,histiocytic giant cells within a PG lesion may be indicative of associ- Ohio State University, Columbus, Ohio, USAated IBD (pΩ0.006), particularly Crohn’s disease.

Sanders S, Tahan SR, Kwan T, Magro CM. Giant cells in pyodermagangrenosum. Scott Sanders, Department of Dermatology,

Cornell University Medical Center, 525 EastJ Cutan Pathol 2001; 28: 97–100. C Munksgaard 2001.68th Street, New York, NY 10021, USATel: π1 212 772 0128Fax: π1 212 746 6656

Accepted August 3, 2000

Pyoderma gangrenosum (PG) is associated with a var-iety of systemic diseases, including inflammatorybowel disease (IBD), myelodysplastic syndromes andconnective tissue diseases. Inflammatory bowel dis-ease is the most common systemic disease associ-ation,1 underlying 10 to 50% of all PG cases.1–3

In aggregate, 2 to 34% of IBD patients havedermatologic findings.4,5 One-half to 5% of ulcerativecolitis patients (UC) and 0.8 to 1.5% of Crohn’s dis-ease patients develop PG, making it the most com-mon dermatologic manifestation of UC and the sec-ond most common of Crohn’s disease after erythemanodosum.2,4,6,7 Most cases of IBD-associated PG de-velop with right sided colitis as multiple lower leglesions, sometimes with seronegative polyar-thritis.2,4,7–10

Historically, PG has been more strongly associatedwith UC than Crohn’s, though the association withCrohn’s has been increasingly appreciated.11 Indeed,PG was ‘‘once regarded as pathognomonic of idio-pathic UC,’’12 probably, in part, because the originaldescription of five PG patients included four withUC.13 That original report noted a ‘‘tuberculoid reac-

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tion’’ with chronic lesions containing ‘‘numerous for-eign-body giant cells, in aggregations and diffuselyscattered throughout the cutis.’’13 A superficial gran-ulomatous variant of PG was recently described tocontain foreign body giant cells amid pseudoepitheli-omatous hyperplasia overlying abscesses, palisadinghistiocytes, variable plasmacytosis and granulationtissue. No specific disease association has been recog-nized for this variant.14

It has been claimed that ‘‘cases of PG associatedwith Crohn’s disease may have areas of granulo-matous inflammation.’’12 However, commentatorsmore frequently note that the inflammatory reactionpattern is nonspecific,15 rendering histologic diagnosisdifficult and consistent prediction of disease associ-ations impossible. The conclusion, therefore, is that‘‘all patients presenting with pyoderma [gangrenos-um] must undergo thorough investigation of the gas-trointestinal tract and hematopoietic system and thenbe followed up carefully, even after the skin lesionshave healed.’’9

The aim of this study was to determine if the pres-ence of histiocytic giant cells within PG lesions are

Sanders et al.

associated with IBD. To assist in the identification ofsuch giant cells we used an immunohistochemical as-say for PGM1, a macrophage marker.

Material and methodsAll cases in the surgical pathology records from theBeth Israel Deaconess Medical Center and PathologyServices, Inc. diagnosed as PG from 1989 to 1997were reviewed. The prior clinical diagnosis of a der-matologist was confirmed by review of hospital rec-ords or dermatology office charts. Criteria for the di-agnosis of PG were one or more cutaneous ulcerswith erythematous or violaceous borders. The ulcerwas thought to be sterile or superinfected and was notcaused entirely by a traumatic event. Lesions did notheal with antibiotics but did respond to cortico-steroids or other immunosuppression. Patients oftenhad systemic diseases associated with PG. Clinicalrecords also provided patient age and sex, lesion loca-tion, and duration before biopsy.

Corresponding histologic slides were reviewed toconfirm the previous diagnosis. Cases diagnosed asPG revealed a common histomorphology; namely, apandermal neutrophilic infiltrate with lysis of dermalcollagen. Extravascular fibrin deposition with necrot-izing vasculitis was noted in the zones of maximumtissue damage. Along the borders of the neutrophilicinfiltrate the vessels were surrounded by a mono-nuclear cell predominant infiltrate without conspicu-ous necrosis (Figs. 1 and 2).

Ultimately, the study group consisted of 34 patientswho fulfilled both clinical and histological criteria ofPG and had formalin-fixed, paraffin-embeddedblocks available.

Four micron sections were mounted on Fisher Su-perfrost microscope slides. An automated apparatus(Ventana EBS; Ventana Medical Systems, Tuscon,Arizona, USA) was used for protease antigen retrievaland avidin biotin complex-detection16 of antibodiesbound to tissue CD68 (Clone PGM1, Dako, 1:50).Inflamed human tonsil was used as a positive control.Negative control slides did not receive primary anti-body. Sections were counterstained with Harris’shematoxylin prior to coverslipping.

Slides were reviewed without knowledge of the pa-tient’s underlying systemic disease. The presence ofPGM1π giant cells with three or more nuclei wasrecorded for each case. Fisher’s exact test was used tocompare the presence of PGM1π giant cells betweenpatients with and without IBD.

ResultsThirty-seven biopsies from 34 patients with PG wereimmunostained. There were 15 PG biopsies from 13patients with IBD. Seven of the IBD patients had

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Fig. 1. Hematoxylin and eosin stain of punch biopsy of pyodermagangrenosum associated with Crohn’s disease. Scanning powershowing a superficial and deep perivascular and interstitial lymph-ohistiocytic infiltrate atop a confluent focus of acute and chronicinflammatory cells deep within the reticular dermis.

Crohn’s and six UC, together accounting for 38% ofthe PG patients in our series. In no patient was PG apresenting symptom of gastrointestinal disease. In onepatient with UC, a colostomy ultimately cured other-wise refractory PG lesions.

Twenty-one patients had PG without known IBD.Among these were two patients with rheumatoid ar-thritis, two patients with hematologic malignancies(one with multiple myeloma another with chronicmyelogenous leukemia), one patient with a previouslyundiagnosed metastatic breast cancer, one case ofautoimmune liver disease, four patients with knowndiabetes, two patients with hypothyroidism and threepatients with prior diverticulosis.

PGM1π giant cells with three or more nuclei (Fig.3) were present in 6 of 15 PG biopsies from patientswith associated IBD. In contrast, PGM1π giant cellswere not found in the 22 biopsies of non-IBD associ-ated PG (pΩ0.006).

In the 6 cases with giant cells, 1 to 10 giant cellswere seen within a tissue profile. Five of these 6 cases

Giant cells in pyoderma gangrenosum

Fig. 2. Hematoxylin and eosin stain of a dermal infiltrate froma case of pyoderma gangrenosum. Swollen endothelial cells arepermeated by neutrophils. In the peripheral dermis, a dense infil-trate of neutrophils and their fragments surround lysed collagenbundles.

Fig. 3. PGM1 (CD68) cytoplasmic staining of a multinucleatedgiant cell amid a field of scattered inflammatory cells.

exhibited prominent epitheloid histiocytes and subtlenecrobiosis. Four biopsies exhibited focal vasculitisand two showed a granulomatous perivasculitis The3 biopsies which included a pannus all showed a lobu-

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lar and septal panniculitis. One of the 6 cases con-tained a loosely formed granuloma. In no case weresarcoidal granulomas observed. Of note, 5 of the 6patients with cutaneous giant cells had Crohn’s dis-ease; the other patient had a perirectal abcess whichhad been clinically categorized as a manifestation ofUC. Nine patients with PG and IBD (60%) lackedgiant cells.

Within our series were 2 biopsies from a patientwith superficial granulomatous PG in a mastectomyscar. These biopsies did not have multinucleated giantcells but did exhibit granulomas.

DiscussionOur results suggest that the presence of PGM1πmultinucleated giant cells within PG may be indica-tive of underlying IBD.

We suspect immunohistochemistry for PGM1 likelyimproved the sensitivity of detecting giant cells, as hasbeen documented in the detection of granulomaswithin intestinal Crohn’s disease17 PGM1 was pro-duced by immunizing mice with splenic macrophagesand is believed to react with a macrophage-specificepitope of CD68. The function of CD68 is unknown,although speculation centers on a selectin receptor ora role in endocytosis and lysosomal trafficking, par-ticularly for oxidized lipoproteins.18,19 Importantly,PGM1 is the most specific marker for macrophageswithin formalin-fixed tissues.20,21

Our findings can be interpreted several ways. First,IBD-associated PG might simply contain giant cells aspreviously observed.12 Second, although all our caseswere clinically and histologically considered to be PG,they may truly represent metastatic cutaneousCrohn’s disease (MCCD), a term introduced in 1976to describe a ‘‘granulomatous reaction occuring inflexures and separated from the affected areas of thegastrointestinal tract by normal skin.’’22 MCCD isboth rare and probably underdiagnosed, being ‘‘theleast common dermatological manifestation ofCrohn’s disease.’’23 Forty-four cases not contiguouswith the GI tract24 and a total of 75 cases25 have beenreported.

MCCD can easily be confused with PG because ofthe similarities they share. They occur in the samepatient population, most often as an ulcerated lesion,frequently on the legs, reportedly in patients withlarge intestinal involvement.6,25 The histology of bothPG and MCCD is nonspecific.15,24 When we com-pared the previously described histopathologic fea-tures of MCCD cases24 with our 6 giant cell contain-ing PG cases, there were many shared features, al-though granulomas were found with much greaterfrequency within MCCD.

A third and likely possibility is that a spectrum oflesions exists combining features of MCCD and PG.

Sanders et al.

Although granulomatous inflammation is considereda hallmark of Crohn’s disease, giant cells are presentin only 50% of mucosal Crohn’s cases, and mucosalbiopsies typically yield giant cells or granulomas witheven lower frequency.26 Not suprisingly, comparedwith intestinal Crohn’s disease, documented cases ofMCCD have a higher percentage of granulomas(94%) and giant cells (66%),24 perhaps suggesting thatdermatopathologists are reluctant to diagnose MCCDwithout these features.

In this series, the diagnosis of PG necesarily restsupon the clinical judgment of the dermatologist re-inforced by histologic findings. The use of archivalbiopsies make it impossible to know the exact locationof the biopsy site (center, edge, or periphery), a factorwhich may determine PG’s histology.1 Finally, itshould be emphasized that giant cells were not seenin 60% of PG lesions associated with IBD and in nopatient was PG a presenting feature of IBD. Despitethese acknowledged limitations, the observationsherein may have both diagnostic and etiologic impli-cations. Moreover, the presence of giant cells withinIBD-associated PG may suggest a similar patho-genesis for cutaneous and mucosal inflammation.Further studies are needed to evaluate the significanceof these observations.

AcknowledgementsWe are grateful to the following clinicians for their help in procuringclinical information: Peter Bendetson, Thomas Cooper, JeffreyDover, Nancy Egan, Gerald Gladstone, Bruce Goldstein, Julia Har-re, Richard A. Johnson, Elaine T. Kaye, Lara Kelley, Robert Ken-ney, Jeltje Koumans, Mark Lewis, Anita Licata, Brian P. O’Donnell,Barry Paul, Andrew D. Samel, Ronald Schneider, Steven Shama,Melvin Shoul, James Solomon, J. Michael Taylor, Ruth Tedaldi,Michael Terlizzi, Douglas Tom, Arthur Tong, John F. von Weiss,Janice Washburn, Martin Bram Weiss, Donna Yonkosky.

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