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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3154-3155
CORRESPONDENCE
Is Complicated Celiac Disease or Refractory Sprue an Intestinal
Intra-Epithelial Cryptic T-Cell Lymphoma?
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LETTER |
To the Editor:
We have read with interest the report by Carbonnel et al1
which suggests that complicated celiac disease (CD) is a form of
cryptic T-cell lymphoma in four patients. We have recently published a similar study of six patients with complicated CD, which we
classified as refractory sprue,2 in which we not only suggested a possible T-cell lymphomatous origin, but also showed that
the clonal population was derived from intra-epithelial lymphocytes (IEL), based on the following observations:
(1) Histological analysis showed that the lymphoid infiltrate
predominated in the surface epithelium of the duodenal biopsy specimens, as in classical CD. There was a marked increase in the
number of IEL (105 ± 27 IEL per 100 epithelial cells v
18 ± 3 IEL per 100 epithelial cells in normal), but these were
morphologically normal with no cytological evidence of malignancy.
(2) The immunophenotype was abnormal, insofar as the IEL expressed
cytoplasmic (cCD3) but not surface CD3 (sCD3) and were negative for
TCR  , TCR  , and CD8 expression. As with normal IEL, they
expressed the E7 (CD103) integrin. This abnormal phenotype was
confirmed by immunocytometric analysis of CD103+ sorted
lymphocytes isolated from duodenal biopsy specimens in two patients. In
contrast, lamina propria lymphocytes showed a normal CD3+,
CD4+, TCR+, CD103 phenotype.
(3) The clonal TCR configuration identified in the duodenal biopsy
samples of all patients was shown in two cases to be identical to that
identified in the sorted CD103+, sCD3 IEL population.
Several of these findings have been confirmed by Carbonnel et al, thus
reinforcing a probable intra-epithelial origin for the clonal
T-lymphoid population. In fact, the histological lesions described by Carbonnel et al in the duodenal biopsy specimens are
identical to those observed by us, being similar to those of classical
CD. These include subtotal or total villous atrophy, an increase in
IEL, crypt hyperplasia, and lamina propria inflammation. Both studies
also describe ulcerated lesions in either the duodenum (one case) or
jejunum (three patients). Ulcerative jejunitis is recognized to occur
in complicated CD and has been suggested to represent a prelymphomatous
(T) state.3 The immunophenotype (cyt CD3+,
CD103+, CD8, CD4) described
by Carbonnel in one case is also virtually identical to that described
by us but differs in the expression of TCR , which we did not
detect, using the F1, TCR-specific, monoclonal antibody. Most
normal IEL and lamina propria lymphocytes express TCR. The
immunohistochemical study of Carbonnel did not differentiate these two
lymphoid populations; TCR expression may reflect the nontumoral
lymphoid population associated with lymphomatous cells. Therefore, the
phenotype of the abnormal cells may be identical in both studies. This
abnormal phenotype differs from that observed in active, classical CD,
when the majority of T lymphocytes are cCD3+,
CD8+.2 The persistence and the intestinal
dissemination of the clonal population described by Carbonnel was also
a frequent finding in our patients.2
Given the virtually identical clinical, histological, immunological,
and molecular features in the two series, it is probable that both
describe the same pathogenic entity. However, the clinical evolution of
the patients differed somewhat, insofar as three of the four patients
described by Carbonnel developed evident lymphoma within 4 to 31 months
of diagnosis and none of our six patients had done so, with a median
follow-up of 5 years (range, 1 to 11 years). In a more extensive series
(Cellier et al: manuscript in preparation), we have also
observed evolution to frank lymphoma in 3 of 20 patients with
refractory sprue. Therefore, it is clear that the identification of an
immunologically abnormal, clonal T-lymphoid population may, in some
patients, preceed development of lymphoma by several years. However, it
is important to note that, even in the absence of overt lymphoma, the
prognosis is poor in this category of patient. In the 10 patients of
the two series, 5 are resistant to a gluten-free diet, 3 responded only temporarily and are steroid dependant, and 7 of the 10 have died within
10 years of diagnosis, 3 from lymphoma and 4 from malnutrition. Therefore, it is important to identify this group, independently of the
risk of malignant transformation.
Carbonnel et al suggested that molecular analysis of TCR gene
configuration represents a useful method of identification of cases
with complicated CD/refractory sprue. Although our data are in keeping
with this, we suggest that immunohistological identification of
abnormal CD3+, CD8 IEL on frozen or
paraffin-embedded material4 may represent a simple, rapid
alternative that can be applied prospectively or retrospectively.
Parallel analysis of a large series by both immunological and molecular
techniques, which we are currently undertaking, will determine which
represents the most reliable, predictive, and cost-effective strategy.
In conclusion, the entity described by Carbonnel as complicated CD is
probably identical to our series of refractory sprue and corresponds to
a group of patients with a poor prognosis due either to development of
T-cell lymphoma or to complications of malabsorption. Early
identification of this group by immunological or molecular techniques
will allow more appropriate therapy and improved understanding of the
pathogenic mechanisms underlying this disorder.
Nicole Brousse
Virginie Verkarre
Service d'Anatomie et de Cytologie
Pathologiques
Hôpital Necker-Enfants Malades
Paris,
France
Natacha Patey-Mariaud de Serre
Service d'Anatomie
Pathologique
Centre Hospitalier Le Raincy-Montfermeil
Hôpital
Laennec
Paris, France
Christophe Cellier
Service
d'Hépato-Gastroentérologie
Hôpital
Laennec
Paris, France
Nadine Cerf-Bensussan
CIJ INSERM
97-10
Faculté Necker-Enfants Malades
Paris,
France
Eric Delabesse
Elisabeth Macintyre
Service
d'Hématologie Biologique
Hôpital Necker-Enfants
Malades
Paris, France
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REFERENCES |
1.
Carbonnel F, Grollet-Bioul L, Brouet JC, Teilhac MF, Cosnes J, Angonin R, Deschaseaux M, Châtelet FP, Gendre JP, Sigaux F:
Are complicated forms of celiac disease cryptic T-cell lymphomas?
Blood
92:3879, 1998[Abstract/Free Full Text]
2.
Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni JP, Burtin ML, Guy-Grand D, Bouhnik Y, Modigliani R, Barbier JP, Macintyre E, Brousse N, Cerf-Bensussan N:
Abnormal intestinal intraepithelial lymphocytes in refractory sprue.
Gastroenterology
114:471, 1998[Medline]
[Order article via Infotrieve]
3.
Ashton-Key M, Diss TC, Pan L, Du MQ, Isaacson PG:
Molecular analysis of T cell clonality in ulcerative jejunitis and enteropathy-associated T cell lymphoma.
Am J Pathol
151:493, 1997[Abstract]
4.
Patey N, Cellier C, Cuenod-Jabri B, Mauvieux L, Canioni D, Cervoni JP, Macintyre E, Leborgne M, Barbier JP, Cerf-Bensussan N, Brousse N:
Apports de l'étude immunohistochimique sur coupe en paraffine pour le diagnostic de maladie coeliaque résistante au régime sans gluten.
Gastroenterol Clin Biol
21:A163, 1997 (abstr)
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