Metastatic Crohn disease is a rare cutaneous disorder characterized by noncaseating, granulomatous skin lesions present at sites anatomically separate from the gastrointestinal tract. It is the least common dermatologic manifestation of Crohn disease, and the differential diagnosis includes numerous similarly appearing, granulomatous skin entities. Males and females appear to be equally affected, and children tend to present with clinical lesions different from those of adults. An integration of clinical information, microscopic findings, and ancillary studies is necessary to accurately diagnose this rare cutaneous disease. Our objective is to review the clinical features, histopathologic characteristics, suggested pathogenesis, differential diagnosis, and current therapeutic options of metastatic Crohn disease.
First described by Crohn et al,1 Crohn disease is a chronic granulomatous inflammatory bowel disorder that may involve any segment of the gastrointestinal tract. Along with the characteristic gastrointestinal findings of this disease, patients with Crohn disease may also present with extraintestinal manifestations including ocular findings, musculoskeletal pathology, and mucocutaneous manifestations.2 Mucocutaneous findings are the most frequent extraintestinal manifestation of Crohn disease; 22% to 44% of patients present with mucocutaneous changes, which may be categorized as granulomatous skin disease, oral manifestations, cutaneous changes secondary to nutritional deficiencies, and cutaneous disorders that have been associated with Crohn disease (eg, pyoderma gangrenosum, erythema nodosum, erythema multiforme, and epidermolysis bullosa acquisita).3 Included within the granulomatous cutaneous category are perianal, peristomal, and perifistular inflammatory lesions, which are contiguous with the gastrointestinal tract and are the most common cutaneous manifestations of Crohn disease.3 Parks et al4 were the first to describe the presence of sterile, noncaseating, granulomatous lesions of the skin at sites noncontiguous with the gastrointestinal tract in patients with Crohn disease. This entity is known as metastatic Crohn disease (MCD), the name first coined in 1970 by Mountain.5,6 It is characterized by cutaneous, noncaseating granulomas at sites anatomically separate from the gastrointestinal tract. It is the least common dermatologic manifestation of Crohn disease. In this article, we discuss the clinical features, histopathologic findings, theories of pathogenesis, differential diagnosis, and treatment options of this rare cutaneous entity.
Metastatic Crohn disease is defined as granulomatous lesions of the skin occurring at sites separate from the gastrointestinal tract in patients affected with Crohn disease.4,6 In adults, the age of onset of MCD ranges from approximately 29 to 39 years, and the majority of patients have a previous diagnosis of Crohn disease.7 Up to one-third of MCD patients have active gastrointestinal symptoms. Twenty percent of patients with MCD may present without classical manifestations of Crohn disease.8 In these patients, Crohn disease manifests in 2 months to 4 years after the initial presentation of MCD.7 Cutaneous lesions of MCD may present as papules, plaques, nodules, and ulcerations, which may involve the arms, legs, genitalia, and face.9–13 Other anatomic sites reported include the nipple, breast, and ear.14–16 Lesions have also been noted to have predilection for the moist environment of skin folds, including submammary and abdominal creases as well as the perineal and inguinal regions (Figure 1).5 Metastatic Crohn disease may present as a solitary lesion or occur in multiple sites and may be painless or tender upon palpation.7
In the pediatric population, MCD typically presents from the ages of 10 to 14, with about 50% of these patients having concurrent Crohn disease.7 Of these patients, approximately one-half have active gastrointestinal symptoms. In children who present with MCD lesions without evidence of Crohn disease, subsequent onset of gastrointestinal manifestations occurs from 9 months to 14 years after the initial presentation of MCD.7 The genitalia appear to be the most common area of involvement in children with MCD; the most common cutaneous manifestation presents as labial, penile, and/or scrotal swelling with or without accompanying erythema.7,17,18 Genital ulcerations have also been reported.17,19
In comparing the duration of symptoms between adults and children, a recent literature review found that adults may have a longer duration of MCD lesions on average when compared to children.7 The frequency of MCD in males compared to females appears to be approximately equal,7 although some reports show a slight predilection toward females.12,18,20 Although Crohn disease typically affects the terminal ileum more often than the large bowel, cutaneous manifestations of Crohn disease appear to occur more often in patients who have involvement of the colon.12 Despite this, there does not appear to be any relationship between active gastrointestinal disease and the presence of MCD.12,17
Metastatic Crohn disease presents microscopically as sterile, noncaseating granulomatous inflammation located primarily in the superficial papillary and deep reticular dermis with occasional extension into the subcuticular fat (Figures 2 through 5). The granulomas consist of Langerhans giant cells, epithelioid histiocytes, lymphocytes, and occasional plasma cells.4,20 It may be difficult to compare the inflammatory process of MCD to a previous gastrointestinal specimen with Crohn disease because granulomas tend to be uncommon in gastrointestinal biopsies and sparse to absent in surgical resections. Perivascular granulomatous inflammation surrounding the dermal vessels may also be noted in MCD lesions.10,21 Necrobiosis consisting of collagen degeneration accompanied by granulomatous inflammation has also been reported as a rare feature of MCD.22 Eosinophils may also present as a histopathologic feature of MCD lesions.20
There are a number of differences between the microscopic findings of primary gastrointestinal Crohn disease and that of MCD. The lymphoplasmacytic infiltrate in the mucosa of primary Crohn disease can be heterogeneous and may occur in small patches or as well-circumscribed lymphoid aggregates, in contrast to the predominantly diffuse pattern commonly seen in the dermis and subcutis of MCD.20,23 Acute inflammatory cells may be focally present in the crypt lumens (crypt abscess) or in the crypt epithelium (cryptitis) in primary Crohn disease, whereas neutrophils are rarely a feature in MCD lesions.20 Although occurring infrequently, granulomas in primary Crohn disease typically present as closely arranged collections of histiocytes with no foreign body giant cells present.23 The presence of granulomas in MCD is the most prominent histopathologic finding, and Langerhans giant cells are frequently seen along with epithelioid histiocytes and an accompanying lymphoplasmacytic infiltrate.4,20 As mentioned previously, perivascular granulomatous inflammation and eosinophils can be seen in MCD, whereas both of these characteristics are not common features in primary Crohn disease.10,20,23 Although ulceration of MCD lesions can occur, the ulcers in previously reported cases have not been described as fissuring or aphthouslike.20 Skip lesions, neural hypertrophy, Paneth cell metaplasia, and pyloric gland metaplasia have not been observed in MCD.
The histopathologic features of MCD compared to Crohn disease directly involving the skin (ie, perianal, peristomal, perifistular) are similar overall, with anatomic location being the main differentiating feature. Metastatic Crohn disease lesions by definition occur at sites discontiguous from the gastrointestinal tract, whereas lesions of Crohn disease directly involving the skin are located at sites continuous with the gastrointestinal tract.
The underlying etiology of MCD is currently unknown. It has been suggested that antigens or immune complexes stemming from the gastrointestinal tract in primary Crohn disease travel through the circulatory system and deposit in the skin, creating perivascular granulomatous features seen on microscopic examination of MCD lesions.3 Autoimmune cross-reactivity has also been suggested, where antibodies specific to antigens in the gastrointestinal tract that may be responsible for inflammatory Crohn disease react with skin antigens of similar structure.20 There is evidence that the antigens in the gastrointestinal tract may be due to intracellular bacteria, although no evidence of bacterial RNA has been noted in cutaneous lesions of Crohn patients.24 The granulomatous inflammation in MCD has also been attributed to a type IV hypersensitivity reaction wherein T cells cross-react with skin antigens, resulting in an inflammatory response similar to that seen in the gastrointestinal tract of Crohn disease.25
The differential diagnosis of MCD consists of any granulomatous entities that may involve the skin. These include, but are not limited to, cutaneous sarcoidosis, erythema nodosum, pyoderma gangrenosum, hidradenitis suppurativa, mycobacterial disease, and foreign body reaction. Cutaneous sarcoidosis consists of granulomas located in the skin with minimal lymphocytic infiltrate (also termed “naked” granulomas). This granulomatous inflammation is different from that of MCD, which usually consists of a prominent lymphoplasmacytic infiltrate. Furthermore, unlike in MCD, epidermal ulceration is relatively uncommon in cutaneous sarcoidosis.20 Erythema nodosum is one of the most common cutaneous manifestations of Crohn disease and presents microscopically with granulomatous inflammation involving the septae of the subcutis (ie, septal panniculitis) with a mixed inflammatory infiltrate including neutrophils in the acute phase.24 Although MCD may extend deep into the subcutis, neutrophils are rarely seen as part of the inflammatory infiltrate. A form of pyoderma gangrenosum known as superficial granulomatous pyoderma may also be mistaken histopathologically for MCD. However, the presence of focal neutrophilic abscesses and pseudoepitheliomatous hyperplasia distinguishes this entity from MCD.26 Hidradenitis suppurativa involves suppurative granulomatous inflammation with folliculitis and abscess formation. Although it may involve anatomic sites common to MCD such as the anogenital region with granulomatous lesions, its follicular involvement with keratin plugging and ruptured follicles make its microscopic diagnosis distinct from MCD.
For all granulomatous lesions, appropriate ancillary stains for infectious etiology (Gram stain, periodic acid–Schiff/Gomori methenamine silver, acid-fast bacilli) and cultures should be performed in order to rule out mycobacterial disease, fungal infection, and other microbial agents. Granuloma formation with caseating necrosis should also point towards a differential diagnosis of infectious etiology as opposed to MCD. Polarizing microscopy may also be utilized in order to rule out granulomatous lesions of the skin caused by foreign material.
A previous diagnosis of Crohn disease may aid in the diagnosis of MCD, although, as previously mentioned, MCD may present without classical gastrointestinal manifestations of Crohn disease. A gastrointestinal workup for inflammatory bowel disease should be considered when MCD is diagnosed without a previous history of Crohn disease.
To the best of our knowledge, there are no clinical trials to date regarding the treatment of MCD, and proposed treatment regimens have been largely anecdotal. Numerous agents have been used in the literature with varying success, including oral and topical steroids, oral antibiotics, azathioprine, sulfasalazine, 6-mercaptopurine, metronidazole, and infliximab.5,8,12,25,27,28 Infliximab appears to show promising results with respect to severe and refractory cases of MCD.27,29 Hyperbaric oxygen has also been utilized in the treatment of MCD.30 Patients appear to have also responded to surgical debridement, especially in cases refractory to medical therapy.14,31 Although considered rare, cases involving spontaneous regression of MCD lesions have also been reported.10,21
Metastatic Crohn disease is a rare cutaneous manifestation of Crohn disease. It is defined as the presence of noncaseating granulomatous lesions of the skin at sites anatomically separate from the gastrointestinal tract. Adults and children tend to have different clinical presentations. The differential diagnosis of MCD includes infectious and noninfectious entities presenting as granulomatous skin lesions. A variety of therapeutic modalities have been described in the literature, with infliximab and surgery showing the most promise in terms of severe, refractory cases.
From the Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
The authors have no relevant financial interest in the products or companies described in this article.