ARTICLE
Auteur(s) : Hiroshi Miida1,
Takashi Kazama2, Noriyoshi Inomata2, Hideaki
Takizawa3, Mitsuya Iwafuchi4, Masaaki
Ito1, Ayako Komai5, Takashi
Hashimoto5, Kyouko Togashi2
1Division of Dermatology, Department of Cellular
Function, Course for Molecular and Cellular Medicine, Niigata
University Graduate School of Medical and Dental Sciences. 1-757
Asahimachi-dori, Niigata, 951-8510, Japan
2Division of Dermatology, Kido Hospital, Niigata,
Japan
3Division of Internal Medicine, Kido Hospital, Niigata,
Japan
4Division of Pathology, Department of Medical
Technology, School of Health Sciences, Faculty of Medicine, Niigata
University, Niigata, Japan
5Department of Dermatology, Kurume University School of
Medicine, Kurume Fukuoka, Japan
accepté le 21 Decembre 2005
Paraneoplastic pemphigus (PNP), first described by Anhalt et al
[1], is an autoimmune mucocutaneous disease associated with an
underlying neoplasm. Mucosal lesions are typically present in the
oral cavity, and also frequently found in the eye, anogenital
region, upper digestive and respiratory tracts [1-5]. Respiratory
involvement with clinical features of bronchiolitis obliterans is
often a cause of death [5, 6]. On the other hand, lesions in the
colon epithelium have never been reported. We describe the first
case of PNP with lesions in the colon epithelium.
Case report
A 57-year-old Japanese woman developed fever, cough and aphthae on
her tongue in October 2000. These were followed by many painful
erosions and ulcerations of the tongue, oral mucosa and lips, and
bilateral conjunctivitis. At the beginning of November, the patient
was first admitted to the department of otolaryngology in Kido
Hospital and treated with oral antibiotics and steroids, without
success. Five days after admission, she was referred to the
department of dermatology of the hospital. In the meantime, a few
purple-red macules with flaccid blisters had appeared on her trunk.
A biopsy specimen from the lower lip showed numerous
dyskeratotic keratinocytes, focal acantholysis and an extensive
lichenoid interface dermatitis with vacuolar degeneration of
epidermal basal layer and subepidermal microdetachments ( (figure 1) ). Direct
immunofluorescence (DIF) microscopy studies revealed the presence
of IgG on the surface of some keratinocytes, and deposition of
complement component 3 (C3) on the surface of keratinocytes in the
lower epidermis and along the cutaneous basement membrane zone. By
indirect IF (IIF) microscopy using human skin as substrate, the
patient’s serum was found to contain circulating autoantibodies
binding to the cytoplasmic cell membrane of keratinocytes and the
basement membrane zone with a titer of 1:160. Using 1 M sodium
chloride-induced split skin as a substrate, deposits of IgG were
seen along the epidermal side of the basement membrane at a titer
of 1:40. The patient’s serum immunoblotted two proteins of 210 and
190 kDa from EDTA-separated normal human epidermis extracts ( (figure 2) ).
Enzyme-linked immunosorbent assay using recombinant desmoglein 1
(Dsg1) and desmoglein 3 (Dsg3) detected antibodies to Dsg3 (108.36
Index) but not to Dsg1. Furthermore, IIF on the rat bladder showed
that IgG antibodies bound strongly to the cell surface of the
transitional epithelium. These results led to a diagnosis of PNP
[1, 2, 4].
Levels of tumor markers CEA and CA19-9 were elevated, at 6.0
ng/mL and 91.5 U/L respectively (normal range 0-5.0 ng/mL and
0-37.0 U/L, respectively). Other laboratory data were within normal
limits. A bone marrow biopsy did not show any abnormal finding.
Chest radiography and computed tomography (CT) and brain CT showed
no specific changes.
On November 27, the patient experienced sudden, intense
abdominal pain and diarrhea. A provisional diagnosis of
gastroenteritis was made and a treatment with scopolamine
butylbromide and oral antibiotics was started with symptom
improvement. Abdominal CT and magnetic resonance imaging (MRI)
revealed thick mesenterium and a small amount of ascites in the
pouch of Douglas. While upper gastrointestinal endoscopy revealed
no abnormalities in the esophagus, stomach and duodenum,
colonoscopy showed many aphthae-like erosions in the colon
epithelium ( (figure
3) ) between the cecum and rectum. A biopsy specimen from
the colon lesions demonstrated edema and acute inflammatory cell
infiltration of the upper mucosa, and mucoepithelial cell
degeneration and detachment from the tunica propria ( (figure 4) ). These
findings are reminiscent of the lichenoid lymphocytic infiltrate
with vacuolar degeneration of the basal epidermal layer and
dyskeratotic cells observed in PNP. On the other hand, this
histological picture is different from that of pseudomembranous
colitis which contains a large amount of fibrin. Stool cultures
were negative, although a test for Clostridium difficile toxin was
not carried out. DIF revealed deposition of C3 on the colon
basement membrane, while IgG deposition was not observed. IIF on
the human colon showed IgG antibodies binding neither to the cell
surface nor the basement membrane.
The patient was treated with oral dexamethasone 8 mg/day and eye
drops. Most erosions and blister lesions on both the oral mucosa
and the skin gradually resolved.
At the end of December, the patient suddenly developed
generalized peritonitis and, a few days later, sepsis and acute
renal failure which led to death on 13 February 2001. An autopsy
was not performed.
Discussion
The present case has the characteristic clinical, histological and
immunological features of PNP. In our patient, no neoplasm could be
detected, although CEA and CA19-9 values were raised and a markedly
thickened mesenterium was found by abdominal CT and was not further
investigated due to intervening complications. Indeed, a few cases
of PNP in the absence of a known neoplasm have been reported [4,
7].
Anhalt et al. [1] showed that the autoantibodies of PNP patients
could bind to colon epithelium. Therefore, PNP lesions in the colon
epithelium can be expected, although they have not been reported so
far. We believe that this is the first report of a PNP case with
colon epithelial lesions.
In our patient, the biopsy specimen from the colon had similar
histology to that associated with PNP. However, it is unclear
whether the observed deposition of C3 at the colon basement
membrane is associated with PNP. There are reports that deposits of
complement are found in the colon in inflammatory bowel disease,
colitis and ileitis [8], suggesting that they may be associated
with inflammation of the colon.
Interestingly, colon lesions have been reported in patients
affected with other autoimmune blistering skin diseases, in
particular bullous pemphigoid [9] and atypical IgA/IgG pemphigus
[10]. Similarly to these cases, the mechanisms underlying colon
lesion formation in our patient remain to be determined. It might
be speculated that autoantibodies to common antigens between the
skin and colon may be induced during the course of the disease and
damage the colon epithelium. Among the autoantigens targeted in
autoimmune blistering disorders, only type VII collagen, the
epidermolysis bullosa acquisita antigen, has been shown to be
expressed in the colon basement membrane zone [11]. On the other
hand, desmoglein2 (Dsg2) is present in the colon but not in the
epidermis. Iwatsuki et al. have reported that Dsg2 induction
frequently occurs in pemphigus lesions [12]. We hypothesize that
Dsg2 induction might also occur in PNP lesions and autoantibodies
to the antigen might be then induced and damage the colon.
In the future, more reports of PNP with colon lesions should be
expected and investigated.
References
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