Multicentric cutaneous Crohn ' s disease : A case report and review of literature

A patient presented with skin lesions at sites not contiguous with Cro' •• 1's disease of the bowel and with specific histological features of C rohn 's disease occurring two weeks from the onset of bowel symptoms. Currently a number of nonspecific skin conditions such as erythema nodosum, pyoderma gangrenosum and erythema multiforme are accepted as being the most common skin manifestations of C rohn's disease. It is likely, however, that specific lesions ofCrohn's disease in the skin have been underdiagnosed either because of lack of biopsy or misinterpretation of the histology. Twenty-three cases with specific Crohn's disease in the skin have been recorded in the past 25 years, since the condition has been recognized. Sarcoidosis has been a common misdiagnosis. The literature relating to multicentric Crohn's disease is reviewed and attention drawn co its protean and masquerading features. An argument is made for the use of the term 'multicentric' rather than 'metastatic' in relation to cutaneous Crohn'sdisease. Can) Gastroenterol 1990;4(2):59-63

S KIN IS Tl IE MOST COMMON SITE OF extra intestinal ma nifestations of Crohn 's disease.These c uta n eous manifestations can be divided into nongran u loma wus and gra nulornatous lesions (1 ).The common nongranulomatous lesions are erychema nodosum, erythema multiforme and pyoderma gangrenosum.The most usual fo rms of granulomatous inflammation are contiguous perianal, perifistular or peristomal extension of the bowel disease, with a reported incidence of up to 4 7% in C rohn's coli tis (2).
'Metastatic Crohn 's disease', defined as cuta neous granulomatous lesions separated from the bowel, the fist ula or stomal opening by normal intervening skin (3 ), has been onl y occasionally reported.
The authors have had the opportunity co observe initially and follow fo r four years a patient with suc h cutaneous lesions and intermittent arthralgia.
except for the repair of an anal fissure and a hemorrhoidectomy in 1982.She had had two normal pregnancies with normal deliveries.She had been taking oral concracepti ves fo r the past 12 years.
Early in October 1985 she noticed increased bowe l frequency, usually precipitated by meals.This progressed gradually to five loose and watery bowel movements daily.Over the next two weeks mucus and bright red blood appeared.She developed a sensation of rectal fullness and burning followed by fever and chills, requiring admission to a local hospital where a large ischioreccal abscess was drained.Her symptoms persisted despite treatment with sulfasalazine.
Figure 1) Vulva/ lesions In the two weeks prior to admission the patient developed painless, blisterlike, erythematous and slightly papular lesions approximately 1 cm in diameter, invo lving the skin of her arms, face, chest, abdomen and legs.Some of these developed central umbilication with surrounding hemorrhage.Most of them cleared eventually, with mild scarring.She also developed painful aphthous ulceration of the mouth and vagina associated with mild fever and chills.
On admission she was afebrile and in moderate distress due to pain in the perianal region.General physical exam ination was normal apart from skin and mucous membranes.The mucosa[ surface of the left side of the lower lip Figure 2) Lesions on arm Figure 3) Lesion from arm showing typical granuloma with lymphocytes, epithelial his, tiocytes and mufrinucleate giant cells showed a superficial u leer approximate, ly 1.5 cm in greater diameter, with an erythematous, indurated border.The intergluteal cleft, perianal area, perineum and vulva showed extensive dis, crete ulcerations ( Figure 1).There were papular lesions scattered randomly over the arms, legs, t runk and buttocks (Figure 2).Some of t he papules and nodules showed central ulceration producing an umbilicated surface covered with a hemorrhagic crust.
Lesions from the buttock and left leg were biopsied and both showed central necrosis and ulceration of the epidermis and upper dermis.The surrounding dermis showed numerous l ymphocytcs, epith e lial histiocytes and multi, nucleated giant cells which, in areas, formed small granulomas (Figure 3).Stains for acid-fast bacilli and fungi were negative.
The patient was examined by sigmo idoscopy under anesthesia and was found to have a rectovaginal fistula.An upper gastrointestinal series and small bowel follow through showed no abnorma lities.Hemoglo bin was 11 6 g/Lj white blood cell count 12,800/mm with 59% granulocytes, 16% band forms and 17% lymphocytes; albumin was 26 g/L.The standard routine investigations were normal.Sulfasalazine She was readmitted on December J, 1985 with migrato ry swell ing a nd tenderness of the small jo ints, knees and elbows as well as symptoms of dryness and fo reign body sensation of the eyes.She had not been taking the metronidazole prescribed on a recent admission.She had two or three soft bowel movements per day witho ut blood or mu cus.The interglu teal, perianal and perinea!ulcerations had cleared.The rectovaginal fistula was no longer detectable.The majority of the previously present skin lesions were resolving, but a few new lesions had appeared about the arms.Most of these were hyperpigmented macules without signi ficant sca rr in g.A few n ew erythematous nodules were present on the upper arms, one of which was biopsied.The histo logy showed prominent patchy inflammation invo lving all layers of the dermis with the greatest involvement in the reticular dermis.
The deepest part of the biopsy was necrotic.In the reticular dermis there were one or two epithe lio id granulomas.Special stains for acid-fast bacilli and fungi were negative.C ulture for Mycobacterium tuberculosis grew no organisms (Figure J ).
The patient refused aspiration of the swollen knee joints, and the multiple effusions subsequently d isappeared.Eye exa min atio n was no rmal and the symptoms subsided.
A co lo n oscop ic examin at io n d emo nstrated irregularl y infla med mucosa with linear ulcerations involving t he cecum.The sigmo id colon showed nonspecific acute and chronic inflammat ion.Bio psy of the cecum showed mi ld acute inflammation related to crypt struc tures with a n epithelioid granulorna consistent with C rohn's d isease (Figure 4).Laboratory investigations showed an erythrocyte sedimentation rate of l 04 mm/h.The lupus erythematosus cell preparation, serum compl eme nt leve ls, antimi toc h o ndri a l a ntib odi es, ant inuclea r a ntibo dies, rheumato id factor , Manto ux (five tuberculosis units), and chest x-ray examination were all negative or normal.She was treated with prednisone 60 mg daily, and azathioprine 100 mg daily followed by gradual reduction and tapering of the dose until it was discontinued two weeks after discharge.
The patient was d ischarged home but returned t wo mon t hs later because of a perianal abscess that required surgical drainage.She had also developed swelling with effusion in the right knee joint which promptly cleared up on reinstitution of treatment wi th azath ioprine and ora l prednisone.By August 1986 perianal drainage had stopped compl e te ly a nd th e patie nt was asymptomatic.
O ver the next three years she had two more episodes o f symptomat ic clinical relapse ( increased bowel frequency, abdomina l cramps, recurrent swelling of the right knee and drainage fro m perianal fistu la).These episodes responded to t reatment with prednisone.Her cutaneous lesions remained quiescent throughout and the prednisone was tapered off.Colonoscopy had been performed in April 1989.ln May 1989, she was asymptomatic and showed localized areas of redness and friability with a few scattered aphthous ulcerations in the cecum and midsigmoid colon.Histology revealed inflammatory changes with distortion of the crypts and Pan eth cell metaplasia.When last seen on August 16, 1989 she had no symptoms except for an occasional ache in the right knee and was taking no medication.

DISCUSSION
'Metastatic' Crohn 's d isease is a rare-1 y reported cutaneous manifestation of C rohn's disease.
The first two patients were reported by Parks and colleagues in 1965 (4).Their fi rst case was t hat of a 70-year-old female with C rohn's disease and an ulcer under her righ t breast which showed a 'sarcoidal granulo matous reaction'.T he second case was a man with Crohn's disease and a penile ulcer, also showing a granulomatous reaction.The authors comment that t he skin lesions d istantly removed from the d iseased bowel were of 'the nature o f metastasis'.Mountain (3) was the first to define the criteria fo r 'metastatic' skin lesions and to recognize that granulomatous involvement of the skin could be seen in periorificial, peristomal or 'metastatic' skin locations.
Over t he years a further 21 patients (1 1 m a les and 12 fe males) wit h 'metastatic' Crohn's disease have been described.The age range has been from 16 to 70 years, with a mean age of 39 .8.In most cases the race of the patient has not been specified, but there have been at least o ne C hinese (5) and two black patients ( 6,7) .
C uta neous les io n s ha ve bee n repo rted on widespread areas of the body.Initially the lesions were thought to be confined to intertrigino us sites (3,4,(8)(9)(10) , but later lesions were found also in nonintertriginous areas of the skin (6, 11 -14).In slightly mo re than one-quarter of cases, lesions occurred on mo re than one anatomical region, while the remainder were confined to a single anatomical site, the most common being the external genitalia (26% of cases), followed by the trunk (17%), with the upper limbs, lower limbs, and head and neck being less frequently and approximately equally involved.
O n e pa tie n t presen ted wi th a n erysipelas-like lesion of the face ( 14).
Histologically all cases have shown noncaseating, sarcoid-like granulomas.In some cases the granulomas were close ly related to de rma l o r su bcutaneous blood vessels (11 ,12, 18), while in others they were present rando m I y th ro ugh o ut the de rmis (5,7,9,14,17,20) or in both the dermis and the subcutis (13,14,19,2 1).
The prese nt patient, in common with all previously reported cases, had inflammatory d isease invo lving the large bowel.This has been shown to be associated with a high incidence of extra intestinal manifes tations of presumed immuno logical nature (23 ).Patients showing ileitis alone have not been reported to show multicentric skin lesions.
There have been no reports to date of skin lesions preceding the bowel symptoms.In the present patient the skin lesions followed the onset of bowel sympto ms by only two weeks.Reports in the literature give a range of two months to 19 years from rhe d iagnosis 62 of Crohn's disease of the bowel to the first appearance of skin lesions.The present case is thus the shortest interval to be reported to date.The appearance of skin lesions is not clearly related to the activity of the bowel disease (1 2).Skin lesions occurred when the bowel disease was 'asymptomatic' or 'controlled ' in e ight of the 22 pati ents (6,7,11,12,14,16), and have also been reported in patients who had a previous total proctocolectomy (3)(4)(5)(6)16).
Reports on the e ffectiveness of various fo rms of treatment are conflicting because of t he lack of exact documentation and the use of more than one modality of treatment per patie n t.Systemic corticos tero ids, either alone or in combination with o ther agents, have been the most freq uen ti y used treatment (3,7,12,13,17,19-2 1 ).They have been reported as both effective (1 2,13, 17) and ineffective ( 19) .lntralesional corticosteroids were effective in one case (13).O ne patient with an erysipelas-like eruption o n the face responded to top ica l flu o rinated co rt icostero ids (14 ).Sumat hipala (1 6) a lso reported a response to topical fluorinated corticosteroids while Cockburn ( 19) found them ineffective.
Sulfasalazine has been the next most extensively used agent.Four patients reported in the literature were already on this drug when the skin lesions appeared (9, 11 ,18,1 9), and in none could a beneficial response be attributed to the drug.
O ther forms of treatment have been reported in individual cases includ ing dapsone (1 2), azathioprine (8), oral zinc ( 4) and 6-me rcaptopurine ( 4 ).However, as these are ind ividual case reports, the results are difficult to assess.Systemic anti biotics have no t been consistently effective.Surgica l treatments including repeated curettage (3 ) and ex tensive resection of lesions involving the genitalia (5,6,17) appearto have been effective.
Spontaneous remission has occurred without any active treatment (14) and it is possible that this occurred in o ther cases although treatment was given to the patients (7,8,11 ,18 ).The present patient may fall into this category be-cause she was initially very poorly compliant with her medication and yet the skin lesions resolved.
Long tenn follow-up of the patients reported in the literature has not been adequately documented to allow reliable concl usions of the natural history of the lesions.T he course and behavio ur of the les io ns are unpredictable.Some have had long term remission of skin disease (6, 11 , 14) on or off treatment, but others continue to have either persistent lesions or clumps of recurrent lesions (1 2,13 ).In the presen t pati en t t he skin les ions remained healed over a four year period of relapses and remissions of gut and jo int symptoms.
'Metastatic' cutaneous involvement in Crohn's d isease is probably much more common than the literature indicates, being underd iagnosed through a low index of suspicion.Skin lesions may be overlooked as trivial or nonspecific, or may be misdiagnosed as other condit ions.Burgdorf (1 ) has called ' metastati c Crohn's d isease' still another great imitator, and he describes many condi t io ns, such as c utaneous vasculitis, with which it has been confused.Thus any unexplained skin eruption in a patient with inflammatory bowel disease should be examined critically and biopsied for the characteristic granulomatous infiltrate.It is only in this way that the true incidence of cutaneous involvement in Crohn's disease will be fully appreciated.
W hil e Croh n ' s disease occurs predo minantly in the terminal ileum or th e co lo n , it may occur in more prox ima l parts s uch as t he more prox ima l sma ll bowel, stomach, esophagus and even the oral cavity.le is freq uently associated with involvement of extraintestinal structures such as skin, jo ints (22), eyes (23 ), blood vessels (11), muscles (9 ), and liver (24).The tendency to involve the term inal il eum and co lo n pred o mi nantl y remains unexplained.
The term 'metastatic' may be inappropriate, as it implies distant spread fro m a given site.The skin lesions present more as a concurrent manifestation of multisystem involvement with inflammatory bowel disease.The term 'metastatic' would be better replaced by 'multicentric cutaneous' Crohn's disease, which would also differentiate it from contiguous involvement.It may be that further study and longer followup of patients will provide more information as to why these lesions occur in only certain patients with Crohn's disease.It might be speculated that local factors such as trauma, vascular supply, chemical, physical or infective factorsor more general ones such as a change in immune status -may play a role in defining the site of the lesions.

Figure 4 )
Figure 4) Biopsy of cecum showing acute inflammatory change and epithelioid granuloma consistent w1rli Crohn 's disease