Correspondence Clinical Letter
Clinical Letter Metastatic Crohn’s disease: a diagnostic and therapeutic challenge
DOI: 10.1111/ddg.12560
Dear Editors, due to its heterogeneous clinical presentation and histology, metastatic Crohn’s disease poses a particular diagnostic and therapeutic challenge. Herein, the topic is systematically presented based on two case descriptions.
Case 1 A 35-year-old patient presented with an asymptomatic nodule on the right elbow (Figure 1). He had a known history of Crohn’s disease (treated for three years with infliximab 5 mg/ kg every 8 weeks). Upon clinical remission, immunosuppressive therapy had been discontinued. The remainder of the integument as well as the mucous membranes were unremarkable. Internist follow-up of Crohn’s disease showed no disease activity. Differential diagnoses included metastatic Crohn’s disease, atypical mycobacteriosis, and (eczematous) psoriasis. Histology revealed a deep granulomatous inflammatory reaction with numerous multinucleated giant cells (foreign-body type), surrounded by a lymphocytic inflammatory infiltrate. There were also focal areas of necrosis in the dermis (Figure 2). Various special stains (PAS, Giemsa, auramine, Ziehl-Neelsen) failed to identify any pathogen, and no foreign-body material was detected under polarized light.
Figure 1 Solitary, crusty erythematous-brown plaque measuring two centimeters in diameter.
Figure 2 Deep granulomatous inflammation with numerous multinucleated giant cells (foreign-body type).
Culture for (atypical) mycobacteria and PCR to find Mycobacterium tuberculosis complex DNA were negative. The Quantiferon test was negative. Chest X-ray was normal and consistent with the patient’s age. Initially, psoriasis was clinically suspected and topically treated with mometasone cream, leading to worsening of the skin lesion with development of a purulent secretion. Topical therapy with calcipotriene was likewise unsuccessful. Wound healing was delayed following biopsy. The patient was offered excision of the solitary lesion. In the meantime, there was another flare-up of his Crohn’s disease, resulting in small bowel resection and systemic corticosteroid therapy (prednisolone 1 mg/kg daily). On this treatment, the skin lesion healed completely.
Case 2 A 55-year-old patient presented with multiple subcutaneous tender nodules on the arms and legs (Figure 3). Crohn’s disease had been diagnosed six months earlier, affecting a long segment of the terminal ileum. Besides metastatic Crohn’s disease, erythema nodosum, nodular vasculitis, and subcutaneous nodular sarcoidosis were considered in the differential diagnosis. Histological examination showed a granulomatous inflammatory reaction involving the entire dermis (Figure 4). Because of the pronounced inflammatory infiltrate around the granulomas, the histological appearance was not typical of sarcoidosis. Instead, metastatic Crohn’s disease and pathogen-induced granulomatous inflammation were considered likely. In this case, too, special stains failed to identify any pathogen. Culture for mycobacteria and PCR were negative, as was the Quantiferon test.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
571
Correspondence Clinical Letter
Previous topical corticosteroid therapy at an outside facility had not resulted in any improvement of the skin lesions. They did, however, briefly improve on immunosuppressive therapy with azathioprine (2 mg/kg daily). Due to pancreatitis, azathioprine had to be discontinued, again leading to the exacerbation of skin lesions. The patient was hospitalized for systemic corticosteroid therapy (prednisone 80 mg IV for 4 days) and concomitant topical therapy with diclofenac gel and wet dressings, which resulted in rapid improvement of the skin lesions. As methotrexate 20 mg SQ weekly (initiated by the treating internists) failed to control the gastrointestinal symptoms, treatment was switched to adalimumab (Humira® 40 mg SQ every 14 days). On this systemic therapy, the gastrointestinal symptoms ceased and the patient also remained asymptomatic with respect to his skin.
Discussion
Figure 3 Multiple subcutaneous, tender and partially inflamed, nodules on the upper and lower extremities.
Figure 4 Granulomatous inflammatory reaction involving the entire dermis.
572
The term “metastatic Crohn’s disease” (MMC) was first used by Parks et al. in 1965 for specific Crohn’s lesions located not directly adjacent to inflammatory bowel lesions [1]. MMC is characterized by initially sterile, granulomatous skin lesions that may occur as solitary or disseminated nodules, plaques, and ulcerations [2]. On the skin, metastatic Crohn’s disease primarily presents with papules, plaques, or ulcerations, and there may be secondary crusting and scarring [3]. On the (genital) mucosa, the predominant findings are ulceration or fissures, more rarely isolated lymphedema or even condyloma-like papules or plaques [3]. Crohn’s disease is a chronic inflammatory bowel disease, the incidence of which has been increasing in Western industrialized countries, and is currently highest in Europe (24.3/100,000 per year) [4]. It is characterized by, sometimes fistulating, chronic inflammation of the entire digestive tract, potentially developing anywhere from the oral mucosa to the anus. Extraintestinal cutaneous manifestations of Crohn’s disease occur in up to 40 % of patients, and include nonspecific lesions such as pyoderma gangrenosum, erythema nodosum, or erythema multiforme [5]. Perianal and peristomal skin lesions (in continuity with bowel lesions) have also been frequently described [5]. Other nonspecific skin manifestations of Crohn’s disease also include oral aphthae or gingivitis. By contrast, specific cutaneous lesions of Crohn’s disease in the form of MMC are very rare. To date, only about 100 cases have been described in the literature, though a higher overall prevalence has to be assumed due to the problems that frequently arise in making the correct diagnosis. Typical predilection sites include the (lower) extremities and, in children, the genital area, but MMC may occur anywhere on the body. In children with Crohn’s disease, involvement of
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
Correspondence Clinical Letter
the skin in the genital region is comparatively frequent, for instance, in the form of painless penis edema [6]. It is safe to assume that metastatic Crohn’s disease is underdiagnosed in children, too. Histopathological findings are characterized by noncaseating epithelioid cell granulomas with a surrounding lymphoid infiltrate [7, 8]. While the papillary and reticular dermis are typically involved, lesions sometimes extend into the subcutaneous tissue. The granulomas consist of Langhans giant cells, histiocytes and lymphocytes, sometimes also plasma cells [1, 2]. Histopathologically, metastatic Crohn’s disease resembles gastrointestinal lesions. However, there are differences. For instance, unlike primary bowel lesions in Crohn’s disease, neutrophils are more rarely detected histologically [2]. While the presence of multinucleated giant cells is characteristic of metastatic Crohn’s disease, they are absent in gastrointestinal Crohn’s disease [7]. Despite intensive research, the pathogenesis of Crohn’s disease has not been fully elucidated. A multifactorial pathomechanism consisting of genetic factors, environmental influences, microbial factors, and immunological mechanisms is suspected [9, 10]. A genetic predisposition for developing chronic inflammatory bowel disease is generally accepted [11]. The treatment of MMC poses a particular challenge, not least because, due to the small number of cases, there are no randomized controlled studies. Although there is no established standard therapy, a graphic treatment algorithm has recently been published [3]. As shown in the present cases, skin lesions may occur both asynchronously and synchronously with gastrointestinal symptoms. Especially in case of an asynchronous pattern, the question arises as to the least burdensome adequate treatment with respect to the organism as a whole. Topical corticosteroid therapy may be attempted, possibly with an occlusive dressing due to the involvement of deeper skin layers. Short-term use of systemic corticosteroids or antibiotics is also possible [7]. In case of isolated genital involvement in childhood, circumcision may lead to complete resolution in 80 % of male patients, and is therefore considered the treatment of first choice [12]. The use of systemic immunosuppressive medication has to be critically weighed against the long-term therapeutic adherence it requires. In severe disease, TNF-α blockers are regarded as the therapy of first choice [13]. Successful treatment has also been described with cyclosporine [14] as well as azathioprine and sulfasalazine [7]. New antibodies such as vedolizumab (antibody against α4β7-integrin on T lymphocytes) to treat Crohn’s disease are the subject of clinical studies [15]. In the future, the use of prebiotics to effect regulator T cells will possibly become
more important [16]. However, the significance of such therapeutic approaches for the treatment of MMC cannot be assessed at present. Despite the usually good overall efficacy and side effect profile of the aforementioned systemic medications, these treatments present both physicians and patients with the challenge of close monitoring due to potential, albeit rare, side effects (including sepsis, CBC abnormalities, hepatotoxicity or nephrotoxicity). In summary, the diagnosis and treatment of metastatic Crohn’s disease require an interdisciplinary approach, involving close collaboration of dermatologists and gastroenterologists in particular. Conflict of interest None.
Nina Lang, Wolfgang Hartschuh, Alexander Enk, Ferdinand Toberer Universitäts-Hautklinik, Ruprecht-Karls-Universität Heidelberg, Heidelberg
Correspondence to Dr. med. Nina Lang, MD Universitäts-Hautklinik Im Neuenheimer Feld 440 69120 Heidelberg Germany E-mail: [email protected]
References 1 2 3
4
5 6
7 8
Parks AG, Morson BC, Pegum JS. Crohn’s disease with cutaneous involvement. Proc R Soc Med 1965; 58: 241–2. Emanuel PO, Phelps RG. Metastatic Crohn’s disease: a histopathologic study of 12 cases. J Cutan Pathol 2008; 35: 457–61. Kurtzman DJB, Jones T, Lian F, Peng LS. Metastatic Crohn’s disease: A review and approach to therapy. J Am Acad Dermatol 2014; 71(4): 804–13. Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54.e42; quiz e30. Burgdorf W. Cutaneous manifestations of Crohn’s disease. J Am Acad Dermatol 1981; 5: 689–95. Keiler S, Tyson P, Tamburro J. Metastatic Cutaneous Crohn’s Disease in Children: Case Report and Review of the Literature. Pediatric Dermatology 2009; 26: 604–9. Siroy A, Wasman J. Metastatic Crohn disease: a rare cutaneous entity. Arch Pathol Lab Med 2012; 136: 329–32. Lebwohl M, Fleischmajer R, Janowitz H et al. Metastatic Crohn’s disease. J Am Acad Dermatol 1984; 10: 33–8.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
573
Correspondence Clinical Letter
9
Eckburg PB, Relman DA. The role of microbes in Crohn’s disease. Clin Infect Dis 2007; 44: 256–62. 10 Molendijk I, Peeters KC, Baeten CI et al. Improving the outcome of fistulising Crohn’s disease. Best Pract Res Clin Gastroenterol 2014; 28: 505–18. 11 Festen E, Weersma R. How will insights from genetics translate to clinical practice in inflammatory bowel disease? Best Pract Res Clin Gastroenterol 2014; 28: 387–97. 12 Mirheydar HS, Friedlander SF, Kaplan GW. Prepubertal male genitourinary metastatic Crohn’s disease: report of a case and review of literature. Urology 2014; 83: 1165–9.
574
13
14
15 16
Antunes O, Filippi J, Hébuterne X et al. Treatment algorithms in Crohn’s – up, down or something else? Best Pract Res Clin Gastroenterol 2014; 28: 473–83. Carranza DC, Young L. Successful treatment of metastatic Crohn’s disease with cyclosporine. J Drugs Dermatol 2008; 7: 789–91. Haddley K. Vedolizumab for the treatment of inflammatory bowel disease. Drugs Today (Barc) 2014; 50: 309–19. Haag L, Siegmund B. Exploring & exploiting our ‘other self’ – does the microbiota hold the key to the future therapy in Crohn’s? Best Pract Res Clin Gastroenterol 2014; 28: 399–409.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
Clinical Letter Metastatic Crohn’s disease: a diagnostic and therapeutic challenge
DOI: 10.1111/ddg.12560
Dear Editors, due to its heterogeneous clinical presentation and histology, metastatic Crohn’s disease poses a particular diagnostic and therapeutic challenge. Herein, the topic is systematically presented based on two case descriptions.
Case 1 A 35-year-old patient presented with an asymptomatic nodule on the right elbow (Figure 1). He had a known history of Crohn’s disease (treated for three years with infliximab 5 mg/ kg every 8 weeks). Upon clinical remission, immunosuppressive therapy had been discontinued. The remainder of the integument as well as the mucous membranes were unremarkable. Internist follow-up of Crohn’s disease showed no disease activity. Differential diagnoses included metastatic Crohn’s disease, atypical mycobacteriosis, and (eczematous) psoriasis. Histology revealed a deep granulomatous inflammatory reaction with numerous multinucleated giant cells (foreign-body type), surrounded by a lymphocytic inflammatory infiltrate. There were also focal areas of necrosis in the dermis (Figure 2). Various special stains (PAS, Giemsa, auramine, Ziehl-Neelsen) failed to identify any pathogen, and no foreign-body material was detected under polarized light.
Figure 1 Solitary, crusty erythematous-brown plaque measuring two centimeters in diameter.
Figure 2 Deep granulomatous inflammation with numerous multinucleated giant cells (foreign-body type).
Culture for (atypical) mycobacteria and PCR to find Mycobacterium tuberculosis complex DNA were negative. The Quantiferon test was negative. Chest X-ray was normal and consistent with the patient’s age. Initially, psoriasis was clinically suspected and topically treated with mometasone cream, leading to worsening of the skin lesion with development of a purulent secretion. Topical therapy with calcipotriene was likewise unsuccessful. Wound healing was delayed following biopsy. The patient was offered excision of the solitary lesion. In the meantime, there was another flare-up of his Crohn’s disease, resulting in small bowel resection and systemic corticosteroid therapy (prednisolone 1 mg/kg daily). On this treatment, the skin lesion healed completely.
Case 2 A 55-year-old patient presented with multiple subcutaneous tender nodules on the arms and legs (Figure 3). Crohn’s disease had been diagnosed six months earlier, affecting a long segment of the terminal ileum. Besides metastatic Crohn’s disease, erythema nodosum, nodular vasculitis, and subcutaneous nodular sarcoidosis were considered in the differential diagnosis. Histological examination showed a granulomatous inflammatory reaction involving the entire dermis (Figure 4). Because of the pronounced inflammatory infiltrate around the granulomas, the histological appearance was not typical of sarcoidosis. Instead, metastatic Crohn’s disease and pathogen-induced granulomatous inflammation were considered likely. In this case, too, special stains failed to identify any pathogen. Culture for mycobacteria and PCR were negative, as was the Quantiferon test.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
571
Correspondence Clinical Letter
Previous topical corticosteroid therapy at an outside facility had not resulted in any improvement of the skin lesions. They did, however, briefly improve on immunosuppressive therapy with azathioprine (2 mg/kg daily). Due to pancreatitis, azathioprine had to be discontinued, again leading to the exacerbation of skin lesions. The patient was hospitalized for systemic corticosteroid therapy (prednisone 80 mg IV for 4 days) and concomitant topical therapy with diclofenac gel and wet dressings, which resulted in rapid improvement of the skin lesions. As methotrexate 20 mg SQ weekly (initiated by the treating internists) failed to control the gastrointestinal symptoms, treatment was switched to adalimumab (Humira® 40 mg SQ every 14 days). On this systemic therapy, the gastrointestinal symptoms ceased and the patient also remained asymptomatic with respect to his skin.
Discussion
Figure 3 Multiple subcutaneous, tender and partially inflamed, nodules on the upper and lower extremities.
Figure 4 Granulomatous inflammatory reaction involving the entire dermis.
572
The term “metastatic Crohn’s disease” (MMC) was first used by Parks et al. in 1965 for specific Crohn’s lesions located not directly adjacent to inflammatory bowel lesions [1]. MMC is characterized by initially sterile, granulomatous skin lesions that may occur as solitary or disseminated nodules, plaques, and ulcerations [2]. On the skin, metastatic Crohn’s disease primarily presents with papules, plaques, or ulcerations, and there may be secondary crusting and scarring [3]. On the (genital) mucosa, the predominant findings are ulceration or fissures, more rarely isolated lymphedema or even condyloma-like papules or plaques [3]. Crohn’s disease is a chronic inflammatory bowel disease, the incidence of which has been increasing in Western industrialized countries, and is currently highest in Europe (24.3/100,000 per year) [4]. It is characterized by, sometimes fistulating, chronic inflammation of the entire digestive tract, potentially developing anywhere from the oral mucosa to the anus. Extraintestinal cutaneous manifestations of Crohn’s disease occur in up to 40 % of patients, and include nonspecific lesions such as pyoderma gangrenosum, erythema nodosum, or erythema multiforme [5]. Perianal and peristomal skin lesions (in continuity with bowel lesions) have also been frequently described [5]. Other nonspecific skin manifestations of Crohn’s disease also include oral aphthae or gingivitis. By contrast, specific cutaneous lesions of Crohn’s disease in the form of MMC are very rare. To date, only about 100 cases have been described in the literature, though a higher overall prevalence has to be assumed due to the problems that frequently arise in making the correct diagnosis. Typical predilection sites include the (lower) extremities and, in children, the genital area, but MMC may occur anywhere on the body. In children with Crohn’s disease, involvement of
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
Correspondence Clinical Letter
the skin in the genital region is comparatively frequent, for instance, in the form of painless penis edema [6]. It is safe to assume that metastatic Crohn’s disease is underdiagnosed in children, too. Histopathological findings are characterized by noncaseating epithelioid cell granulomas with a surrounding lymphoid infiltrate [7, 8]. While the papillary and reticular dermis are typically involved, lesions sometimes extend into the subcutaneous tissue. The granulomas consist of Langhans giant cells, histiocytes and lymphocytes, sometimes also plasma cells [1, 2]. Histopathologically, metastatic Crohn’s disease resembles gastrointestinal lesions. However, there are differences. For instance, unlike primary bowel lesions in Crohn’s disease, neutrophils are more rarely detected histologically [2]. While the presence of multinucleated giant cells is characteristic of metastatic Crohn’s disease, they are absent in gastrointestinal Crohn’s disease [7]. Despite intensive research, the pathogenesis of Crohn’s disease has not been fully elucidated. A multifactorial pathomechanism consisting of genetic factors, environmental influences, microbial factors, and immunological mechanisms is suspected [9, 10]. A genetic predisposition for developing chronic inflammatory bowel disease is generally accepted [11]. The treatment of MMC poses a particular challenge, not least because, due to the small number of cases, there are no randomized controlled studies. Although there is no established standard therapy, a graphic treatment algorithm has recently been published [3]. As shown in the present cases, skin lesions may occur both asynchronously and synchronously with gastrointestinal symptoms. Especially in case of an asynchronous pattern, the question arises as to the least burdensome adequate treatment with respect to the organism as a whole. Topical corticosteroid therapy may be attempted, possibly with an occlusive dressing due to the involvement of deeper skin layers. Short-term use of systemic corticosteroids or antibiotics is also possible [7]. In case of isolated genital involvement in childhood, circumcision may lead to complete resolution in 80 % of male patients, and is therefore considered the treatment of first choice [12]. The use of systemic immunosuppressive medication has to be critically weighed against the long-term therapeutic adherence it requires. In severe disease, TNF-α blockers are regarded as the therapy of first choice [13]. Successful treatment has also been described with cyclosporine [14] as well as azathioprine and sulfasalazine [7]. New antibodies such as vedolizumab (antibody against α4β7-integrin on T lymphocytes) to treat Crohn’s disease are the subject of clinical studies [15]. In the future, the use of prebiotics to effect regulator T cells will possibly become
more important [16]. However, the significance of such therapeutic approaches for the treatment of MMC cannot be assessed at present. Despite the usually good overall efficacy and side effect profile of the aforementioned systemic medications, these treatments present both physicians and patients with the challenge of close monitoring due to potential, albeit rare, side effects (including sepsis, CBC abnormalities, hepatotoxicity or nephrotoxicity). In summary, the diagnosis and treatment of metastatic Crohn’s disease require an interdisciplinary approach, involving close collaboration of dermatologists and gastroenterologists in particular. Conflict of interest None.
Nina Lang, Wolfgang Hartschuh, Alexander Enk, Ferdinand Toberer Universitäts-Hautklinik, Ruprecht-Karls-Universität Heidelberg, Heidelberg
Correspondence to Dr. med. Nina Lang, MD Universitäts-Hautklinik Im Neuenheimer Feld 440 69120 Heidelberg Germany E-mail: [email protected]
References 1 2 3
4
5 6
7 8
Parks AG, Morson BC, Pegum JS. Crohn’s disease with cutaneous involvement. Proc R Soc Med 1965; 58: 241–2. Emanuel PO, Phelps RG. Metastatic Crohn’s disease: a histopathologic study of 12 cases. J Cutan Pathol 2008; 35: 457–61. Kurtzman DJB, Jones T, Lian F, Peng LS. Metastatic Crohn’s disease: A review and approach to therapy. J Am Acad Dermatol 2014; 71(4): 804–13. Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54.e42; quiz e30. Burgdorf W. Cutaneous manifestations of Crohn’s disease. J Am Acad Dermatol 1981; 5: 689–95. Keiler S, Tyson P, Tamburro J. Metastatic Cutaneous Crohn’s Disease in Children: Case Report and Review of the Literature. Pediatric Dermatology 2009; 26: 604–9. Siroy A, Wasman J. Metastatic Crohn disease: a rare cutaneous entity. Arch Pathol Lab Med 2012; 136: 329–32. Lebwohl M, Fleischmajer R, Janowitz H et al. Metastatic Crohn’s disease. J Am Acad Dermatol 1984; 10: 33–8.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
573
Correspondence Clinical Letter
9
Eckburg PB, Relman DA. The role of microbes in Crohn’s disease. Clin Infect Dis 2007; 44: 256–62. 10 Molendijk I, Peeters KC, Baeten CI et al. Improving the outcome of fistulising Crohn’s disease. Best Pract Res Clin Gastroenterol 2014; 28: 505–18. 11 Festen E, Weersma R. How will insights from genetics translate to clinical practice in inflammatory bowel disease? Best Pract Res Clin Gastroenterol 2014; 28: 387–97. 12 Mirheydar HS, Friedlander SF, Kaplan GW. Prepubertal male genitourinary metastatic Crohn’s disease: report of a case and review of literature. Urology 2014; 83: 1165–9.
574
13
14
15 16
Antunes O, Filippi J, Hébuterne X et al. Treatment algorithms in Crohn’s – up, down or something else? Best Pract Res Clin Gastroenterol 2014; 28: 473–83. Carranza DC, Young L. Successful treatment of metastatic Crohn’s disease with cyclosporine. J Drugs Dermatol 2008; 7: 789–91. Haddley K. Vedolizumab for the treatment of inflammatory bowel disease. Drugs Today (Barc) 2014; 50: 309–19. Haag L, Siegmund B. Exploring & exploiting our ‘other self’ – does the microbiota hold the key to the future therapy in Crohn’s? Best Pract Res Clin Gastroenterol 2014; 28: 399–409.
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306
