Pyoderma gangrenosum

Pyoderma Gangrenosum CHRISTOPHER M. DUGUID, FRANK C. POWELL, FRCPI

MBBS

yoderma gangrenosum (PC) is typified by tender, painful, rapidly enlarging cutaneous ulcers with raised, violaceous, undermined borders and a necrotic base. The area of ulceration is often surrounded by an inflammatory erythematous areola. There is frequently associated systemic disease,’ such as inflammatory bowel disease (IBD), arthropathy, benign monoclonal gammopathy, or malignancy.*

P

History Many different terms have been used to describe PG-like lesions in the last century, including “vaccinia gangrengangrenosa,” a condition that osa” and “dermatitis evolves from small pustules to large ulcerating areas with purplish borders and a purulent base. Greenbaum has reviewed the history of PG,3 described as “geometric phagedna” by Brocq, “chronic burrowing ulcer” by Meleny, “pyoderma chronicum papillare et ulcerans” by Zurhelle and Klein, and “chronic ulcerative pyoderma” by Bolog. In 1930 Brunsting et al reported their careful clinical record of the evolution of PG from discrete isolated pustules to well-developed ulcerations, one of the classic morphologic descriptions in dermatologyP Four of the five cases they observed had associated chronic ulcerative colitis (CUC), and PG was thus initially considered to be closely linked to CUC. That their original term of pyoderrrza (“infection”) gangrenosum (‘tissue gangrene”) is still used today, despite the absence of either true infec-

From the Regional Centre of Dermatology, Mater Misercordiae Hospital, Dublin, Ireland. Address correspondenceto: Frank C. Powell, FRCPl, Regional Centre of Dermatology,MaterMisercordiae Hospital, EcclesStreet,Dublin 7, Ireland. Dr. C. M. Duguid is in receipt of a scholarship from the Australasian College of Dermatologists to the Regional Centre of Dermatology sponsored by Jannsen- Cilag Ltd.

0 2993 by Elsevier Science Publishing Co., Inc.

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0738-081x/93/$6.00

tion or tissue gangrene, is a tribute to the quality of their original paper.

Clinical Manifestations The fully developed lesion of PG is characterized by undermined serpingious, violaceous, or dusky red margins, which may be studded with pustules.1,5-7 Surrounding the ulcer is a margin of intense erythema. The ulcer base is irregular and necrotic, with a mucopurulent surface. Pain, often severe, is a characteristic feature.’ PG usually evolves from a pustule with an inflammatory areola, sometimes surmounting a dusky painful nodule. Lesions appear singularly or in a group and extend rapidly, with softening, necrosis, and eventually central ulceration (Fig 1, top). New lesions often arise at sites of cutaneous trauma such as those caused by venepuncture, minor skin injuries, burns, and surgery,’ and this “pathergic phenomenon” may explain deterioration of PG following debridement or surgery, and the initiation of new lesions in graft donor sites. Progression can be relentless with the formation of large areas of necrotic tissue. Healing may result in distinctive cribriform scarring.6 The scar may remain tender and liable to breakdown with minor trauma. PG can appear at any site on the body, but most commonly occurs on the legs and is seen mainly in middle age.’ Clinical entities that may be variants of PG have been described, including malignant pyoderma,* an aggressive ulcerative disease confined mainly to the head or neck and often associated with neurologic symptoms; bullous pyoderma,9 characterized by tense, often hemorrhagic bullae, which break down to form large painful superficial ulcers, often on the limbs or trunk at sites of trauma (Fig 1, bottom; Fig 2)‘O; an eruptive pustulation seen mainly in association with acute IBD” which may represent an abortive form of PG; and superficial granuloma-

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Figure 2. Superficial bullous pyoderma gangrenosum with central ulceration and bullous borders.

Figure 1. Early pyoderma gangrenosum with pustulation showing central necrosis (top) and bulla formation (bottom) in the same patient.

tous pyoderma, l2 characterized by superficial vegetative ulcers with an indolent course.

Histology The histopathologic findings vary according to the type of PC, the age of the lesion, and the site of the biopsy.13 Biopsies taken from the advancing erythematous edge show vasculitis with endothelial swelling, fibrinoid necrosis, thrombosis, extravasation of erythrocytes, and a predominance of lymphocytes.13 Specimens taken from the undermined border demonstrate mixed, predominantly neutrophilic infiltrate and early abscess formation with epidermal necrosis centrally. Positive direct immunoflourescence, mainly vascular, is found in the erythematous zone in 61% of patients.’ The combination of lymphocytic infiltrate with vascular damage and positive immunofluorescence in the active zone of erythyma sug-

gests that an immune-mediated lymphocytic vasculitis may be a significant feature in the pathogenesis of PG. Bullous PG may show epidermal necrosis, spongiosis, intraepidermal vesiculation, intraepidermal bullae, or subcorneal abscess formation.9 Vasculitis is not a prominent feature and direct immunofluorescence is usually negative.14 Superficial granulomatous PG shows abscess formation in the upper dermis, about which there may be granuloma formation. In the surrounding area there is a mixed inflammatory infiltrate with numerous plasma cells, lymphocytes, neutrophils, and eosinophils.12

Pyoderma Gangrenosum and Malignancy The frequency of reported malignancy in PG varies. Powell et al found malignancy in 6 of 86 patients’ and Holt et al described 3 of 15 patients with multiple myeloma15; however, Prystowski et al found 1 patient in a series of 22 with leukemia,“j and Hickman and Lazarus did not find any patients with malignancy of 15 studied.” Combining these reviews, a total of 10 in 138 patients with PG had a malignancy (7.2%).

Leukemia Leukemia is the most frequently reported associated malignancy with PG, accounting for more than one third of all reports (Table 1). Acute myeloid is the most common described, usually of the myelocytic or monomyelocytic type, affecting both adults and children.*J8 In two thirds

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DUGUID PYODERMA

Table 1. Malignancies Associated With Pyoderma Gangrenosum* Malignancy Leukemias Acute myeloid Acute lymphoblastic Chronic myeloid Chronic lymphoid Hairy cell leukemia Myeloma 434 W Biclonal IgM (Waldenstrcim’s) Myeloproliferative disorders Polycythemia rubra vera Myelofibrosis Primary thrombocythemia Lymphoma Hodgkin’s Non-Hodgkin’s Cutaneous T-cell lymphoma Solid tumors Carcinoid Adrenocortical Ovary l

Number of Patients 26 1 12 2 4 19 1 1 2 14 13 2 1 2

2

Jsolntedcasesof colonic, prostatic, breast, and bronchial carcinomahave been

reported.

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GANGRENOSUM

Myeloprol ifera tive Disease Polycythemia Rubra Vera Polycythemia rubra vera (PRV) has been reported in 14 patients with PG. 23 PG appeared concurrently with or after the diagnosis of PRV in all cases. The time lapse between the two diagnoses averaged 7 years. Six of eight cases in whom follow-up was provided had malignant transformation of the PRV. The leukemia that developed was associated with a poor prognosis, patients often dying within 12 months of the appearance of the skin lesions. Thus, the onset of PG in a patient with PRV is of ominous prognostic significance.

Myelofibrosis Isolated reports of myelofibrosis and PG appear in the literature.*J9 In all but one case the PG occurred after or at the time of diagnosis of the myelofibrosis. The lesions may be of the ulcerative type or bullous in nature.‘O The appearance of PG in one patient heralded the onset of an acute leukemic stage. 24 The patient of Caughman et al also had lesions typical of Sweet’s syndrome, and they suggested the term neutrophilic dermatosisofmyeloproliferative diseasefor these overlapping syndromes.10

Thrombocythemia of cases, PG occurred prior to or concurrently with the diagnosis of the leukemia. Features suggestive of underlying leukemia include bullous PG (60% of patients had this variant), fever, anemia, low platelet count, and leukocytosis. The presence of PG in a patient with acute myeloid leukemia is an indicator of poor prognosis, as 14 patients died within 12 months.

Myeloma Chevrant-Breton et al reviewed 21 patients with PG and myeloma,2 19 of which were IgA type. Three cases of Waldenstrom’s macoglobulinemia were referred to Carsuzaa et a1.19PG usually preceded the detection of the myeloma, often by several years.20 The lesions of PG are typically ulcerative, although a case of bullous PG was described.*l The frequency of IgA myelomas (which normally accounts for 10% of all myelomas) is striking.16 According to Prystowski et al, 11% of patients with benign paraproteinemia subsequently develop myeloma, macroglobulinemia, or amyloid within a 5-year period, clearly indicating the need for follow-up.16 Treatment of myeloma or paraproteinemia has been paralleled by healing of PG lesions in some patients.*O,**

There have been two reports of an association between PG and thrombocythemia. *~5 One was of the bullous type and responded well to corticotherapy.E

Myelodysplastic Syndromes A total of seven cases of myelodysplastic syndrome have been described in patients with PG (six with refractory anemia with excess of blast cells and one with refractory anemia). Four of these had leukemic transformation, two within 1 year.*J9

Lymphoma Five patients with lymphoma and PG have been reported.26-29 Two had non-Hodgkin’s,26*27 one had Hodgkin’s disease,*s and two had cutaneous T-cell lymphoma.29 PG was of the bullous variety and responded dramatically to oral steroids in one patient.26 Two other patients had longstanding ulcerative PG when the lymphoma was diagnosed.29

Solid Tumors The association of solid tumors with internal malignancy is less frequent and includes cases of carcinoma of the colon, bladder, and prostate,’ carcinoma of the breast and bronchi,* and metastatic ovarian carcinoma.30 One pa-

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Table 3. Evaluation of Patients with Pyoderma Gangrenosum

Table 2. Differential Diagnosis of Pyoderrna Gangrenosum Infections

Vasculitis

Insect bites Halogenodermas Malignancy

Sweet’s syndrome

Early Folliculitis Furuncles Carbuncles Atypical mycobacterial infections, tuberculosis, syphilis, blastomycosis, sporotrichosis, cryptococcus, cutaneous amebiasis, herpes simplex virus, AIDS related Necrotizing Rheumatoid ulcers Wegener’s granulomatosis Bencet’s syndrome Systemic lupus erythematosus Brown recluse spider Necrotizing arachniditis Iododerma, bromoderma Cutaneous malignancies Basal cell carcinoma Squamous cell carcinoma Cutaneous T-cell lymphoma May be difficult to differentiate from bullous pyoderma gangrenosum, especially if atypical

Factitial pyoderma

tient has been reported to have with adrenocortical noma, and another, carcinoid tumor.32

carci-

Diagnosis and Evaluation Diagnosis may be difficult as there is no specific histologic or serologic marker of PG. A careful clinical history and the morphologic features of the cutaneous lesion are the main diagnostic indicators. The differential diagnoses to be considered are listed in Table 2. Skin biopsies should be taken from the border of the ulcer for histopathologic examination and microbiologic culture. Further investigations to fully evaluate the patient with PG are listed in Table 3. The possibility of an underlying malignancy needs to be considered, and those who develop bullous PG should in particular be screened for hematologic disease.

1. History and physical examination 2. Skin biopsy from border-for routine stains and specific stains for bacteria, funpi, acid-fast bacilli 3. Tissue culture-bacterial, mycobacterial, atypical mycobacterial, viral 4. Serum bromide/iodide 5. Chest x-ray 6. Gastrointestinal evaluation Liver function test Hepatitis serology 7. Complete blood count 8. Serum protein electrophoresis, immunoglobulins 9. Urinary Bence- Jones protein 10. Antibody screen 11. In selected patients, consider Bone marrow examination Gastrointestinal radiology Endoscopy

Treatment Topical treatments should maintain a clean, moist wound. These include saline soaks, silver sulfadiazine, and occlusive dressings. Because of the risk of pathergy surgical debridement or skin grafting is generally avoided. Topical and intralesional steroid therapy has been reported as effective in some cases,33but has been disappointing in our hands. Systemic steroids are the mainstay of treatment and are particularly useful in bullous PG, with rapid relief of pain and healing. Generally, high doses (60 - 120 mg/d) for prolonged periods are required. Pulse therapy with methylprednisolone has been shown to be effective in antibiotics resistant cases. l6 Dapsone sulfapyridine, (minocycline, rifampin, clofazimine, intravenous vancomycin, and mezlocillin), and cytotoxic agents such as azathioprine, cyclophosphamide, and cholorambucil have all shown to be effective in some patients, either alone or in conjunction with systemic steroids. More recently, immunosuppressive agents such as cyclosporine have shown encouraging results in the management of this disease.

References Etiology and Pathogenesis The etiology of PG is unknown. It may represent a focal cutaneous reaction in a host compromised by altered immune reactivity or systemic disease, and the fmdings of Su et al are consistent with immune-mediated vascular damage. l3 Trauma may “direct” altered immunocompetent cells to damaged skin, or alter the antigenic cutaneous signal, thus accounting for the pathergic phenomenon.

1. Powell FC, Schroeter AL, Su WPD, et al. Pyoderma gangrenosum: A review of 86 patients. Q J Med 1985;55:173-86. 2. Chevrant-Breton J, Logeais B, Pibouin renosum (pyodermite phagedkique). ereol 1989;116:577-89.

M. Pyoderrna gangAnn Dermatol Ven-

3. Greenbaum SS. Phagedaena Geometries (Brocq). Inoculation studies with viable bacteria cultured from lesions of phagedaena geometrica (Brocq) (chronic burrowing ulcer and pyoderma gangrenosum). Arch Dennatol 1941;43: 775-80.

Clinics in Dermatology 1993;11:229-133 4. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (ecthyma) gangrenosum. Clinical and experimental observations in 5 cases occurring in adults. Arch Dermatol 1930;22:655 - 80. 5. Hickman JG. Pyoderma gangrenosum. Clin Dermatol 1983;1:102-13. Schwaegerle SM, Bergfeld WF, Senitzer D, et al. Pyoderma 6. gangrenosum: A review. J Am Acad Dermatol 1988; 18:559 -68. 7. Callen JP. Pyoderma gangrenosum and related disorders. Med Clin North Am 1989;73:1247-61. 8. Perry HO, Wmkelmann RK, Muller SA, et al. Malignant pyoderma. Arch Dermatol 1968;98:561-576. 9. Perry HO, Wmkelmann RK. Bullous pyoderma gangrenosum and leukaemia. Arch Dermatol 1972;106:901-5. 10. Caughman W, Stem R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. J Am Acad Dermatol 1983;9:757-8. 11. O’Loughlin S, Perry HO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol 1978;114: 1061-4. 12. Wilson-Jones E, Winkelmann RK. Superficial granulomatous pyoderma: A localised vegetative form of pyoderma gangrenosum. J Am Acad Dermatol 1988;18:511-21. 13. Su WPD, Schroeter AL, Perry HO, et al. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Path01 1986;13:323-30. 14. Pye RJ, Choudhury C. Bullous pyoderma as a presentation of acute leukaemia. Clin Exp Dermatol 1977;2:33-8. 15. Holt PJ, Davies MG, Saunders KC, et al. Pyoderma gangrenosum: Clinical and laboratory tindings in 15 patients with special reference to polyarthritis. Medicine (Baltimore) 1980;107:114-33. 16. Prystowski JH, Kahn S, Lazarus GS. Present status of pyoderma gangrenosum: Review of 21 cases. Arch Dermatol 1989;125:57-64. 17. Hickman JG, Lazarus GS. Pyoderma gangrenosum: A reappraisal of associated systemic diseases. Br J Dermatol 1980;102:235-7. 18. Gilman AL, Cohen BA, Urbach AH, et al. Pyoderma gangrenosum as a manifestation of leukaemia in childhood. Paediatrics 1988;81:846-8. 19. Carsuzaa F, Pierre C, Dubegny M. Pyoderma gangrenosum et gammopathie a IgA association a une gastrite atrophique. Ann Dermatol Venereol 1989;116:707-13.

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20. Powell FC, Schroeter AL, Su WPD, et al. Pyoderma gangrenosum and monoclonal gammopathy. Arch Dermatol 1983;119:468-72. 21. Horton JJ, Trounce JR, MacDonald DM. Bullous pyoderma gangrenosum and multiple myeloma. Br J Dermatol 1984;110:227-30. 22. Moller H, Waldenstrom JG, Zettervall 0. Pyoderma gangrenosum (dermatitis ulcerosa) and monoclonal (&A) globulin healed after melphalan treatment. Acta Med Stand 1978;203:293-6. 23. Ho KK, Vandenber AN, Otridge BW, et al. Pyoderma gangrenosum, polycythaemia rubra vera and development of leukaemia. J Am Acad Dermatol, 1992;27:804-808. 24. Jacobs P, Palmer S, Gordon-Smith EC. Pyoderma gangrenosum in myelodysplasia and acute leukaemia. Postgrad Med J 1985;61:689-94. 25. Shepherd P, Liddell K. Pyoderma gangrenosum associated with primary thrombocythaemia. Br Med J 1982;285: 837-8. 26. Mahood JM, Sneddon IB. Pyoderma gangrenosum complicating non-Hodgkin’s lymphoma. Br J Dermatol 1980; 102:233-5. 27. Wasik F, Miklaskenska M, Birecka I, et al. Pyoderma gangrenosum et affection bulleuse rhelateurs dun processus lymphoide mallin. Bull Sot Fr Dermatol Syph 1974;Bl: 21-2. 28. Michigan Dermatological Society transactions. Pyoderma gangrenosum and Hodgkin’s lymphoma. Arch Dermatol 1974;109:269. 29. Kitahama A, Roland PY, Kerstein MD. Pyoderma gangrenosum with cutaneous T-cell lymphoma manifested as lower extremity ulcers-Case reports. Angiology 1991;42:494503. 30. Ortonne JP, Thivolet J, Chouvet 8, et al. Pyoderma gangrenosum, Cystadeno-Carcinome ovarien trait& par melphain et leucemie aigue myeloblastique. Ann Dermatol Venereol 1979;106:251-6. 31. Cole HGH, Nelson RL, Peters MS. Pyoderma gangrenosum and adrenocortical carcinoma. Cutis 1989;44:205 - 8. 32. Lee SS, Biro L, Price E. Pyoderma gangrenosum with carcinoid tumor. Cutis 1976;18:791-4. 33. Jennings JL. Pyoderma gangrenosum: Successful treatment with intralesional steroids. J Am Acad Dermatol 1980; 9:575-80.