Metastatic Crohn's Disease Presenting as Chronic Perivulvar and Perirectal Ulcerations in an Adolescent Patient

Metastatic Crohn's disease (MCD) is a rare, granulomatous, extraintestinal manifestation of Crohn's disease (CD) with multiple clinical presentations.1 As such, there is often a delay in diagnosis and consequent therapeutic intervention. We describe MCD presenting as chronic perivulvar and perirectal ulcerations in an adolescent patient without history of gastrointestinal involvement. Additional investigation revealed active colorectal CD, and appropriate treatment was subsequently initiated.A 13-year-old African-American girl presented to her primary care physician with a 6-month history of hemorrhoids, constipation, perineal and perivulvar fissures, skin tags, and weight loss. She denied any nausea, vomiting, fever, cough, or night sweats. She had been previously in good health and was on no medications. Physical examination revealed multiple erythematous, indurated, tender papules and plaques, with granulomatous vegetations and ulcerations involving the inguinal, perivulvar, perineal, and perirectal regions. A few edematous, inflamed papillomas were noted in the perirectal area. There was no evidence of sinus tract or fistula formation. Mild tenderness of the lower abdominal region was observed on palpation, but the remainder of her physical examination was unremarkable. Serum electrolytes, liver transaminases, white blood cell count, platelet count, and urinalysis were within normal limits. Abnormal laboratory values included hemoglobin 10.5 μg/dL (normal values: 12–15 μg/dL), ferritin 5.6 ng/mL (normal values: 7–140 ng/mL), and serum albumin 2.9 g/100 mL (normal values, 3.5–5.5 g/100 mL). Results of chest radiography were normal, and a tuberculin skin test result was nonreactive.On referral to pediatric gastroenterology, biopsies of friable, granulomatous, perivulvar tissue and an adjacent skin tag were performed. Histopathology of both specimens revealed ulcerated fibromembranous tissue, diffuse acute and chronic inflammation with a lymphohistiocytic infiltrate, and noncaseating granuloma formation with multinucleated giant cells consistent with MCD (Fig 1). A few of the foreign body type giant cells contained polarizable material and calcifications. PAS and Fite stain results were negative for fungi and acid-fast bacilli, respectively. Tissue culture findings for bacteria, fungi, and mycobacteria were negative. A colonoscopy with bowel wall biopsy was subsequently performed and revealed active colorectal disease without evidence of sinus tract or fistula formation. Histopathology of intestinal mucosa showed inflammation with chronic inflammatory infiltrates, fibrosis, and granuloma formation consistent with CD. Upper gastrointestinal series with small-bowel follow-through was normal.The patient was placed initially on prednisone (30 mg daily), mesalamine (250 mg three times daily), 6-mercaptopurine (75 mg daily), 3% topical tetracycline cream, and .5% hydrocortisone cream. However, over the ensuing months, her cutaneous and intestinal disease continued to worsen despite adjustments in medication dosages and frequent tissue debridements under general anesthesia. At age 15 years, a diverting ileostomy to provide bowel rest and stool diversion was performed, but with continued worsening of bowel and mucocutaneous lesions, a total colectomy (anteroposterior resection) with ileostomy was required in September 1996. Dermatology was consulted subsequently for additional evaluation of her cutaneous disease and therapeutic suggestions. Skin examination revealed tender, erythematous, edematous plaques and ulcerations of the perivulvar and perineal areas, with granulomatous vegetations of the inguinal creases (Fig 2). A recommendation was made to increase the dosing of immunosuppressive agents and to add metronidazole to the treatment regimen. Her current medications include prednisone (40 mg daily), 6-mercaptopurine (50 mg daily), mesalamine (500 mg three times daily), metronidazole (250 mg three times daily), and ferrous sulfate.The patient's medical course has been complicated by a small-bowel obstruction requiring exploratory laparotomy and adhesiolysis in November 1996, a wound infection with methicillin-resistantStaphylococcus aureus in February 1997, and severe recalcitrant iron deficiency anemia. Although her gastrointestinal disease presently is inactive, she continues to experience exacerbations of her genital disease, necessitating hospitalization for wound care, debridement, and intravenous antibiotics. She is followed routinely by pediatric gastroenterology, surgery, and dermatology.CD, or regional enteritis, is a chronic, inflammatory bowel disease characterized by sharply demarcated segments of involvement from mouth to anus. Typical histologic findings include infiltration of the lamina propria by lymphocytes, ulcerations, and crypt abscesses. Noncaseating granulomas are found in 10% to 25% of sectioned specimens.2,3 The disease, first described by Crohn in 1932, may occur at any age, but most often begins in the second to fourth decades of life with a slight female predominance. One third of cases occur before age 20. Although the most common site of gastrointestinal involvement includes small-bowel and esophagus, 12% to 25% of cases involve only the colon.3,4 Associated mucocutaneous findings occur in 22% to 75% of patients with CD. Skin manifestations of CD have been classified by Burgdorf and co-workers1 into four categories: granulomatous cutaneous disease including peristomal and perianal inflammation with sinus tract and fistula formation, as well as MCD; oral changes with aphthae-like ulcers and mucosal cobblestoning; nutritional changes including acquired zinc deficiency; and miscellaneous idiopathic markers, notably pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and necrotizing vasculitis. Of these, contiguous perianal skin lesions are the most common cutaneous findings, and ∼25% of all CD cases present initially with perianal lesions.5 In 1976, Greenstein and associates6 published a large retrospective review of 700 patients with CD and noted that cutaneous lesions occurred at an increased frequency in the setting of colonic involvement, compared with ileal involvement alone. Subsequent studies, including a 1979 review by the National Cooperative Crohn's Disease Study,7 have reported similar findings.MCD, as first described by Parks et al8 in 1965, refers to a rare granulomatous inflammation of skin noncontiguous to the gastrointestinal tract. Since this first reported case of cutaneous inframammary ulcerations in an elderly woman with known CD, there have been more than 80 documented cases in the literature. Most of these reports occurred in patients with known colonic involvement. However, 21% of cases of MCD developed simultaneously with, or preceded by several months to years, the gastrointestinal disease.9 As demonstrated in our patient, the severity of skin lesions does not always parallel the severity of bowel disease.In 1996, Lucky and colleagues9 published a retrospective review of 80 reported cases of MCD occurring between 1965 and 1995. Fourteen patients were younger than 18 years of age. Genital involvement was noted in 56% of cases, whereas nongenital sites including extremities, trunk, face and lips, and intertriginous/flexural areas constituted 44% of cases. Two thirds of children with cutaneous CD had genital involvement, compared with half of the adult cases. Clinically, the nongenital lesions presented as painful nodules, ulcerations, lichenoid papules, pustules, and/or abscesses. Genital manifestations, similar to the findings in our patient, included tender perivulvar, perineal and perirectal ulcerations, fissures, skin tags, and swelling. With such a diversity of clinical presentations, the diagnosis and appropriate treatment of metastatic CD is often delayed. This varied clinical presentation probably has led to an underestimate of the true incidence of this disease.10 Clinically, MCD should be considered in the differential diagnosis of hidradenitis suppurativa, dermatitis, intertrigo, lymphogranuloma venereum, sarcoidosis, foreign body reaction, and mycobacterial or deep fungal infections, among others.Microscopically, MCD is characterized by a noncaseating granulomatous infiltration of the dermis sometimes extending into subcutaneous fat. The granulomas are composed primarily of epithelioid cells and multinucleated giant cells with a lymphohistiocytic infiltrate, similar to the findings in primary bowel lesions. Granulomatous perivasculitis is a more common finding than true vasculitis.11 In 1981 Burgdorf et al12 suggested that immune complexes deposited in the skin could be responsible for the granulomatous reaction observed in MCD. Although nonspecific circulating immune complexes have been shown to occur in some patients with CD with extraintestinal manifestations, this has not been a consistent finding. In 1990, Shum et al13 proposed a T-lymphocyte-mediated type IV reaction to explain the extraintestinal granuloma formation and vascular damage. They propose that lymphocytes cross-react with yet unknown antigens in the skin to cause MCD and, depending on the proximity of the inflammatory reaction to a vessel, either granulomatous perivasculitis or true vasculitis is the pathologic consequence. Rook et al14 have proposed that a mycobacterium or other slow-growing bacterium is the primary event in granuloma formation. However, recent investigations by Frank and co-workers,15using polymerase chain reaction in unfixed intestinal tissue, were unable to confirm a role for mycobacterium in CD. Other research has addressed the roles of β-2 integrin,16 CD14+ monocyte populations,17 and the DNA repair gene MLH-118 in disease pathogenesis.Numerous therapies for the treatment of MCD have been suggested. Although most lesions resolve spontaneously, genital lesions appear to be particularly recalcitrant to treatment. Systemic, intralesional, and topical corticosteroids, dapsone, sulfasalazine, azathioprine, metronidazole, tetracycline, 6-mercaptopurine, and oral zinc supplementation are among the treatments purported to be of benefit. Surgical debridement, hyperbaric oxygen,19 and fecal diversion have been used in particularly resistant cases.In summary, our patient presented with MCD manifesting as chronic perivulvar and perirectal ulcerations. Although her gastrointestinal disease presently is quiescent after total colectomy and ileostomy, her cutaneous symptoms are only transiently controlled with debridement and immunosuppressive agents. MCD may present in a myriad of forms, thereby delaying both diagnosis and treatment. MCD should be considered in the differential diagnosis of any chronic granulomatous dermatoses, particularly in patients with known CD. There should be a high degree of suspicion for MCD, especially in children, when dealing with genital and/or perirectal fissures, ulcers, hemorrhoids, skin tags, swelling, or chronic genital induration and inflammation, and additional investigation for occult intestinal involvement is warranted.