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Metastatic Crohn Disease
   Crohn disease is a chronic granulomatous
    inflammatory bowel disorder that may involve
    any segment of the gastrointestinal tract.
Extraintestinal manifestations including
  ◦ ocular findings,
  ◦ musculoskeletal pathology, and
  ◦ Mucocutaneous manifestations.

Mucocutaneous findings
 are the most frequent extraintestinal manifestation

 22% to 44% of patients present with changes

 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).
   Perianal,       peristomal,and       perifistular
    inflammatory lesions most common cutaneous
    manifestations lesions
   Parks et al - 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.
   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.

   In adults, age of onset - 29 to 39 years.

   Majority of patients have a previous diagnosis
    of Crohn disease.
   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.

   In these patients, Crohn disease manifests in
    2 months to 4 years after the initial
    presentation of MCD.
   Cutaneous lesions of MCD may present as
    papules, plaques, nodules,and ulcerations, which
    may involve the arms, legs, genitalia, and face.
   Predilection for the moist environment of skin
    folds, including
    ◦ submammary
    ◦ and abdominal creases
    ◦ perineal and inguinal regions
   present as a solitary lesion or occur in multiple
    sites
   painless or tender upon palpation.
Left submammary crease ulcer with well-defined
         border exuding purulent fluid.
   In the pediatric population, ages of 10 to 14
   50% of these patients having concurrent Crohn
    disease.
   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.
   The genitalia appear to be the most common
    area of involvement; most common cutaneous
    manifestation presents as

    ◦ labial, penile, and/or scrotal swelling with or without
      accompanying erythema.
    ◦ Genital ulcerations have also been reported.
   Males = females

   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
   Presents as sterile, noncaseating granulomatous
    inflammation     located   primarily   in   the
    superficial papillary and deep reticular dermis
    with occasional extension into the subcuticular
    fat.

   The granulomas consist of Langerhans giant
    cells, epithelioid histiocytes, lymphocytes, and
    occasional plasma cells.
   Perivascular    granulomatous      inflammation
    surrounding the dermal vessels.
   Necrobiosis consisting of collagen degeneration
    accompanied by granulomatous inflammation.
   Eosinophils may also present.
Low-power image of left submammary crease ulcer with
underlying noncaseating granulomatous inflammation of the
papillary and reticular dermis
Higher magnification of left submammary crease lesion with
deep dermal granulomatous inflammation consisting of
multinucleated giant cells, epithelioid histiocytes, and a
lymphocytic infiltrate
Low-power image of an abdominal skin biopsy illustrating
diffuse granulomatous inflammation involving the
papillary and reticular dermis
Labial biopsy showing diffuse inflammation of the
papillary dermis consisting of multinucleated giant
cells, epithelioid histiocytes, and a lymphocytic
infiltrate
CROHN’S DISEASE                  MCD

   Lymphoplasmacytic               predominantly diffuse
    infiltrate in the mucosa         pattern commonly seen in the
                                     dermis and subcutis.
   Acute inflammatory cells        neutrophils are rarely a
    may be focally present in        feature
    the crypt lumens (crypt
    abscess) or in the crypt        The presence of granulomas
    epithelium (cryptitis)          Langerhans giant cells are
   Closely arranged                 frequently seen along with
                                     epithelioid histiocytes and an
    collections of histiocytes       accompanying
    with no foreign bodygiant        lymphoplasmacytic infiltrate
    cells present.
CROHN’S DISEASE                MCD

   Not seen                      Perivascular
                                   granulomatous
   Skip lesions, neural           inflammation and
    hypertrophy, Paneth cell       eosinophils
    metaplasia, and pyloric
    gland metaplasia.             ulceration of MCD
                                   lesions can occur.
   Lesions of Crohn              Metastatic Crohn
    disease directly               disease lesions by
    involving the skin are         definition occur at sites
    located at sites               discontiguous from the
    continuous with the            gastrointestinal tract
    gastrointestinal tract.
   underlying etiology of MCD - 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.
   Autoimmune cross-reactivity also been suggested
   The granulomatous inflammation 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
   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.
   Epidermal ulceration is relatively uncommon in
    cutaneous sarcoidosis.
Erythema nodosum :

   one   of    the    most    common      cutaneous
    manifestations of Crohn disease
   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.
Superficial granulomatous pyoderma :

   the presence of focal neutrophilic abscesses
    and pseudoepitheliomatous hyperplasia
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.
For all granulomatous lesions,
 appropriate   ancillary stains for infectious
  etiology    (Gram      stain,     periodic  acid–
  Schiff/Gomori methenamine silver, acid-fast
  bacilli) &
 cultures       to    rule     out    mycobacterial
  disease, fungal infection, and other microbial
  agents
 Polarizing microscopy may also be utilized to
  rule out granulomatous lesions of the skin
  caused by foreign material.
   A gastrointestinal workup for inflammatory
    bowel disease should be considered when MCD
    is diagnosed without a previous history of
    Crohn disease
   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
   Infliximab appears to show promising results
    with respect to severe and refractory cases of
    MCD.
   Hyperbaric oxygen has also been utilized in the
    treatment of MCD
   Patients appear to have also responded to
    surgical debridement, especially in cases
    refractory to medical therapy.
   Although considered rare, cases involving
    spontaneous regression of MCD lesions have
    also been reported
   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.

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Metastatic Crohn Disease

  • 2. Crohn disease is a chronic granulomatous inflammatory bowel disorder that may involve any segment of the gastrointestinal tract.
  • 3. Extraintestinal manifestations including ◦ ocular findings, ◦ musculoskeletal pathology, and ◦ Mucocutaneous manifestations. Mucocutaneous findings  are the most frequent extraintestinal manifestation  22% to 44% of patients present with changes  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).
  • 4. Perianal, peristomal,and perifistular inflammatory lesions most common cutaneous manifestations lesions  Parks et al - 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. 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.  In adults, age of onset - 29 to 39 years.  Majority of patients have a previous diagnosis of Crohn disease.
  • 6. 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.  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.  Predilection for the moist environment of skin folds, including ◦ submammary ◦ and abdominal creases ◦ perineal and inguinal regions  present as a solitary lesion or occur in multiple sites  painless or tender upon palpation.
  • 8. Left submammary crease ulcer with well-defined border exuding purulent fluid.
  • 9. In the pediatric population, ages of 10 to 14  50% of these patients having concurrent Crohn disease.  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.
  • 10. The genitalia appear to be the most common area of involvement; most common cutaneous manifestation presents as ◦ labial, penile, and/or scrotal swelling with or without accompanying erythema. ◦ Genital ulcerations have also been reported.
  • 11. Males = females  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. Presents as sterile, noncaseating granulomatous inflammation located primarily in the superficial papillary and deep reticular dermis with occasional extension into the subcuticular fat.  The granulomas consist of Langerhans giant cells, epithelioid histiocytes, lymphocytes, and occasional plasma cells.
  • 13. Perivascular granulomatous inflammation surrounding the dermal vessels.  Necrobiosis consisting of collagen degeneration accompanied by granulomatous inflammation.  Eosinophils may also present.
  • 14. Low-power image of left submammary crease ulcer with underlying noncaseating granulomatous inflammation of the papillary and reticular dermis
  • 15. Higher magnification of left submammary crease lesion with deep dermal granulomatous inflammation consisting of multinucleated giant cells, epithelioid histiocytes, and a lymphocytic infiltrate
  • 16. Low-power image of an abdominal skin biopsy illustrating diffuse granulomatous inflammation involving the papillary and reticular dermis
  • 17. Labial biopsy showing diffuse inflammation of the papillary dermis consisting of multinucleated giant cells, epithelioid histiocytes, and a lymphocytic infiltrate
  • 18. CROHN’S DISEASE MCD  Lymphoplasmacytic  predominantly diffuse infiltrate in the mucosa pattern commonly seen in the dermis and subcutis.  Acute inflammatory cells  neutrophils are rarely a may be focally present in feature the crypt lumens (crypt abscess) or in the crypt  The presence of granulomas epithelium (cryptitis)  Langerhans giant cells are  Closely arranged frequently seen along with epithelioid histiocytes and an collections of histiocytes accompanying with no foreign bodygiant lymphoplasmacytic infiltrate cells present.
  • 19. CROHN’S DISEASE MCD  Not seen  Perivascular granulomatous  Skip lesions, neural inflammation and hypertrophy, Paneth cell eosinophils metaplasia, and pyloric gland metaplasia.  ulceration of MCD lesions can occur.  Lesions of Crohn  Metastatic Crohn disease directly disease lesions by involving the skin are definition occur at sites located at sites discontiguous from the continuous with the gastrointestinal tract gastrointestinal tract.
  • 20. underlying etiology of MCD - 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.  Autoimmune cross-reactivity also been suggested  The granulomatous inflammation 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
  • 21. Cutaneous sarcoidosis,  Erythema nodosum,  Pyoderma gangrenosum,  Hidradenitis suppurativa,  Mycobacterial disease, and  Foreign body reaction
  • 22. 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.  Epidermal ulceration is relatively uncommon in cutaneous sarcoidosis.
  • 23. Erythema nodosum :  one of the most common cutaneous manifestations of Crohn disease  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. Superficial granulomatous pyoderma :  the presence of focal neutrophilic abscesses and pseudoepitheliomatous hyperplasia
  • 25. 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.
  • 26. For all granulomatous lesions,  appropriate ancillary stains for infectious etiology (Gram stain, periodic acid– Schiff/Gomori methenamine silver, acid-fast bacilli) &  cultures to rule out mycobacterial disease, fungal infection, and other microbial agents  Polarizing microscopy may also be utilized to rule out granulomatous lesions of the skin caused by foreign material.
  • 27. A gastrointestinal workup for inflammatory bowel disease should be considered when MCD is diagnosed without a previous history of Crohn disease
  • 28. 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  Infliximab appears to show promising results with respect to severe and refractory cases of MCD.
  • 29. Hyperbaric oxygen has also been utilized in the treatment of MCD  Patients appear to have also responded to surgical debridement, especially in cases refractory to medical therapy.  Although considered rare, cases involving spontaneous regression of MCD lesions have also been reported
  • 30. 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.