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Contents lists available at ScienceDirect

Digestive and Liver Disease

journal homepage: www.elsevier.com/locate/dld

Position Paper

Gastrointestinal lymphomas: French Intergroup clinical practice

recommendations for diagnosis, treatment and follow-up (SNFGE,
FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH)夽
Tamara Matysiak-Budnik a,∗ , Bettina Fabiani b , Christophe Hennequin c ,
Catherine Thieblemont c , Georgia Malamut d , Guillaume Cadiot e , Olivier Bouché e ,
Agnès Ruskoné-Fourmestraux b
a
Institut des Maladies de l’Appareil Digestif, CHU, Hôtel Dieu, GELD (Groupe d’Etude des Lymphomes Digestifs), Nantes, France, France
b
GHU Est Parisien—Hôpital St. Antoine, APHP, GELD, Paris, France
c
GHU Paris Nord—Hôpital St. Louis, APHP, LYSA (Lymphoma Study Association), Paris, France
d
GHU Ouest— Hôpital Européen Georges Pompidou, APHP, CELAC (Centre d’Expert national des Lymphomes Associés à la maladie Coeliaque), Paris, France
e
CHU Robert Debré, Reims, France

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: This document is a summary of the French Intergroup guidelines on the management of
Received 18 September 2017 gastro-intestinal lymphomas, available on the web-site of the French Society of Gastroenterology, SNFGE
Received in revised form (www.tncd.org), updated in September 2017.
26 November 2017
Methods: This collaborative work was realised under the auspices of several French medical societies
Accepted 4 December 2017
and involved clinicians with specific expertise in the field of gastrointestinal lymphomas, including gas-
Available online xxx
troenterologists, haematologists, pathologists, and radiation oncologist, representing the major French
or European clinical trial groups. It summarises their consensus on the management of gastrointestinal
Keywords:
Gastric lymphoma
lymphomas, based on the recent literature data, previous published guidelines and the expert opinions.
Intestinal lymphoma Results: The clinical management, and especially the therapeutic strategies of the gastro-intestinal lym-
MALT phomas are specific to their histological subtypes and to their locations in the digestive tract, with the
National French recommendations particularity of gastric MALT lymphomas which are the most frequent and usually related to gastritis
induced by Helicobacter pylori.
Conclusion: Lymphomas are much less common than epithelial tumours of gastro-intestinal digestive
tract. Their different histological subtypes determine their management and prognosis. Each individual
case should be discussed within the expert multidisciplinary team.
© 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction countries between 0.58 and 1.31/100,000 inhabitants and the usual
age of diagnosis is between 50 and 70 years [2,3]. Stomach is the
Primary gastro-intestinal lymphomas (PGIL) are non-Hodgkin most frequent site of these lymphomas, followed by the small intes-
lymphomas (NHL) derived from MALT (Mucosa Associated Lym- tine and the colon [4]. Both B and T lymphocytes may give rise to
phoid Tissue) [1]. PGIL are rare, corresponding to 1% of all PGIL, but B-cell lymphomas are much more frequent (90%) than
gastro-intestinal tumours. Their incidence varies among different T-cell lymphomas (10%.)
PGIL comprise different clinico-pathological entities which
should be distinguished since their cellular origins and clini-
夽 On behalf of the Thesaurus National de Cancérologie Digestive (TNCD),
cal presentations determine their evolution and treatment. Rare
Société Nationale Française de Gastroentérologie (SNFGE), Fédération Franco-
prospective studies taking into account the recent classifica-
phone de Cancérologie Digestive (FFCD), Groupe Coopérateur multidisciplinaire en tions and proposing standardised treatments [4–6], improved our
Oncologie (GERCOR), Fédération Nationale des Centres de Lutte Contre le Cancer knowledge on these lymphomas. Although gastro-intestinal loca-
(UNICANCER), Société Française de Chirurgie Digestive (SFCD), Société Française tions represent 36% of the extra-nodal forms of NHL, these tumours
d’Endoscopie Digestive (SFED), Société Française de Radiothérapie Oncologique
remain rare, which, together with the great diversity of their
(SFRO), SociétéFrançaise d’Hématologie (SFH).
∗ Corresponding author at: IMAD, Hépato-Gastroentérologie & Oncologie Diges- anatomo-clinical forms and their sometimes slow progression,
tive, Hôtel Dieu, 1 Place Alexis Ricordeau, 44093 Nantes, France. explain the difficulty of developing randomised therapeutic trials
E-mail address: tamara.matysiakbudnik@chu-nantes.fr (T. Matysiak-Budnik).

https://doi.org/10.1016/j.dld.2017.12.006
1590-8658/© 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Matysiak-Budnik T, et al. Gastrointestinal lymphomas: French Intergroup clinical practice recom-
mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
https://doi.org/10.1016/j.dld.2017.12.006
G Model
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specific to the digestive localisations. In consequence, the indica- Table 1

Different histopathological types of gastrointestinal lymphomas (according to WHO
tion of chemotherapy in the chemo-sensitive forms comes mainly
classification 2016, Ref. [11]).
from randomised studies performed in nodal NHL which are much
more frequent. The recent recommendations, like those published B Lymphomas
• Extra-nodal marginal zone of the Mucosa Associated Lymphoid Tissue:
by the European Gastro-Intestinal Lymphoma Study Group (EGILS)
MALT including alpha Chain Disease (IPSID)
[7] or by the European Society for Medical Oncology (ESMO) [8,9], • Diffuse large B-cell
concern essentially gastric lymphomas and derive mainly from the • Mantle cell
results of small series or expert opinions. • Burkitt
The clinical management of the PGIL, and particularly the thera- • Follicular
T Lymphomas
peutic strategies, are specific to their histological types and to their
•Associated or not with an intestinal-type enteropathy (with or without
location in the digestive tract, with the particularity of gastric MALT villous atrophy) of low and especially high grade of malignancy
lymphomas which are the most frequent and usually related to
Helicobacter pylori (H. pylori) — induced gastritis.
this is the only indirect diagnostic test not affected by proton pump
inhibitor (PPI) or antibiotic treatment. The 13 C-labelled urea breath
2. Methodology test is useful for confirming the eradication of bacteria after the
treatment. Moreover, the molecular methods, and in particular a
This collaborative work was realised under the auspices of sev- real-time PCR may be used for H. pylori detection. This method has
eral French medical societies and involved clinicians with specific excellent sensitivity and specificity, it also allows the detection of
expertise in the field of gastrointestinal lymphomas, including mutations associated with macrolides resistance, and it does not
gastroenterologists, haematologists, pathologists, and radiation require specific conditions for the transport of the biopsies. How-
oncologist, representing the major French or European lymphoma ever, there have been no larger studies testing PCR in patients with
study groups. It summarises their consensus on the manage- MALT lymphoma but only some case reports have been reported
ment of gastrointestinal lymphomas, based on the recent literature [11].
data (original publications, prospective non randomised studies, The H. pylori-positive status is defined as a positive histology
reviews), previous published guidelines and the expert opinions and/or a positive serology [12]. It should be noted that histology,
[7,8]. The recommendations outlined below do not generally fulfil 13 C-urea breath and culture should be performed after an interval
the criteria for high level evidence since no prospective randomised of at least 4 weeks from any antibiotic treatment and at least 2
trials are available in the field of this rare disease. The two levels weeks after stopping the PPI [12,13].
of recommendations, designed as “recommendations” or “options”,
are mainly based on expert opinions.
4. Histomorphological classification

3. Diagnosis The different types of primary lymphomas of the digestive tract

were initially described by Isaacson [1], but currently the latest
The diagnosis of lymphoma is based on histology and should be 2016 WHO classification for all NHL is considered the reference
always confirmed by an expert pathologist [7]. In France, a sec- and diagnosis should be given according to this classification [14].
ond histological analysis by an expert pathologist belonging to It takes into account the cellular origin of the proliferation, deter-
the national group of expert pathologists for lymphomas (LYM- mined according to morphological and immuno-histochemical
PHOPATH), is mandatory for all types of lymphomas. criteria (Table 1).
For histological diagnosis, several biopsies must be obtained The most frequent are B-cell lymphomas (90% of cases), and
(10–20) from the tumour area and additionally from the normally very rare T-cell lymphomas. The majority of PGIL originate from
looking antral and corpus mucosa (for the assessment of the pres- MALT. In Western countries, gastric lymphomas are the most fre-
ence of H. pylori and associated lesions, like atrophy and intestinal quent and they are represented by two major types: extra-nodal
metaplasia). The biopsies are fixed in formalin for histological, marginal zone lymphomas (MZL-MALT, also called MALT lym-
immuno-histochemical and molecular analysis. Frozen biopsies are phomas), corresponding to the proliferation of small B-cells, and
not necessary for routine diagnosis but can be recommended for diffuse large B-cell lymphomas (DLBCL), composed of large B-cells,
clinical research. More rarely, the diagnosis is made during emer- usually developed de novo, but sometimes evolving from trans-
gency surgery performed for complications, like haemorrhage or formed MALT lymphomas. In the intestine, all the varieties of NHL,
obstruction (especially for lymphomas located in the small intes- similar to the nodal types, can be found.
tine) [10]. In extra-nodal gastric MALT lymphomas, after eradication of
For gastric forms, testing for H. pylori is mandatory. The method H. pylori and for the follow-up, the histological results are given
of choice is histology, based on the assessment of biopsies taken according to the GELA (Groupe d’Etude des Lymphomes de l’Adulte)
from the antrum and from the body, away from mucosal lesions, histological scoring system [15] (Table 2).
performed using Giemsa or cresyl violet staining, and if necessary, Because of important prognostic and therapeutic implications,
completed by immuno-histochemistry with anti-H. pylori antibod- the histological sub-type of the lymphoma must be accurately
ies. In case of negative histology, serology is recommended, and established. The opinion of expert pathologists, reviewing the slides

Table 2
Histological scoring system of GELA for the post-treatment assessment of gastric MALT lymphomas (According to Copie-Bergman et al. [15]) .

Score Lymphoid infiltrate LEL Stroma

CR Absent or scattered plasma cells and small lymphocytes in LP Absent Normal or empty LP and or fibrosis
pMRD Aggregates of lymphoid cells or lymphoid nodules in the LP/MM and/or SM Absent Empty LP and/or fibrosis
rRD Dense, diffuse or nodular extending around glands in the LP Focal or absent Focal empty LP and/or fibrosis
NC Dense, diffuse or nodular Present — May be absent No changes

CR: complete histological remission; pMRD: probable minimal residual disease; rRD: responding residual disease. NC: no change; LP: lamina propria. MM: muscularis mucosa.
SM: submucosa. LEL: lymphoepithelial lesions.

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mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
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and applying complementary techniques, is recommended for all 5.3.2. Options

types of lymphomas in order to confirm the diagnosis [7]. Looking Optionally, other explorations may be proposed (of debatable
for clonality is not mandatory but can be useful in case of diffi- interest or according to the type of lymphoma):
cult diagnosis. Searching for a (11;18) translocation in MZL-MALT
is optional, and if possible, may be carried out by the FISH technique 1. Osteomedullary biopsy, systematic for certain types of lym-
on formalin-fixed biopsies [9] since it may be predictive of response phoma (follicular B lymphomas or mantle B-cell lymphomas),
to treatment. Indeed, it has been shown that the presence of this optional for other types (for gastric MALT lymphomas: only if
translocation in tumour cells is associated with the non-regression there is no regression after eradication of H. pylori and optional
of lymphoma after eradication of H. pylori [16] and with a lower for large B-cell lymphomas) [21].
response rate to chemotherapy [17]. 2. FDG-PET to determine the chemosensitivity under treatment by
immuno-chemotherapy for diffuse large B-cell lymphomas and
5. Pre-treatment workup and staging follicular lymphomas. This examination is undergoing evalua-
tion in marginal zone MALT lymphomas where it is generally
Pre-treatment work-up recommendations are based on the negative. High FDG uptake has nevertheless been found at a
experts’ agreement [7,9]. Two levels of work-up can be distin- lesser degree in MALT lymphomas not responding to H. pylori
guished: the reference level (recommended examinations), usually eradication leading to the suspicion of transformation [22].
applied for all types of lymphomas, and the optional level, com- 3. Study of the cerebral spinal fluid (with cytocentrifugation) for
prising examinations indicated depending on the type/site of lymphomas with a high risk of invasion or relapse in the cen-
lymphoma and on clinical situation. tral nervous system (high grade of malignancy like DLBCL with
extensive tumour mass, or Burkitt’s histological subtype).
5.1. Clinical examination and blood tests 4. Electrocardiogram and study of myocardial function (ventricu-
lar ejection fraction or cardiac ultrasound if anthracyclines are
5.1.1. Recommendations considered) as pre-therapeutic procedures for lymphomas with
Clinical examination includes the evaluation of WHO general sta- a high grade of malignancy before chemotherapy.
tus, the presence of general signs, and the physical examination
including the examination of peripheral lymph nodes, liver, spleen, 5.4. Clinical stage
and ENT examination.
Blood tests should include complete blood count, beta- Clinical stage is expressed according to the Ann Arbor staging
2-microglobulin level, serum protein immunofixation, lactate system modified by Musshoff. Most of the primary digestive lym-
dehydrogenase (LDH) level, and viral serologies (HIV, hepatitis B phomas (70% of cases) are localised and correspond to stage IE
and C). (involvement of the digestive wall), stage IIE1 (involvement of the
peri-tumoral lymph nodes), or stage IIE2 (involvement of distant
lymph nodes, with a worse prognosis). Another staging system spe-
5.1.2. Options
cific for gastric localisations, explored by endoscopic ultrasound,
Additionally, and depending on the type of lymphoma, other
is the EGILS (European Gastro-Intestinal Lymphoma Study) group
tests may be performed like H. pylori serology (in gastric lym-
staging system, inspired by the TNM classification [23].
phomas, especially if absence of bacteria in histology) [12], liver
Besides the clinical stage, other parameters have been identified
tests, uricemia, anti-endomysium and anti-transglutaminase anti-
in the International Prognostic Index for non-Hodgkin lymphomas.
bodies (for T-cell lymphomas), or a search for a monoclonal
This index determines the prognosis and therapeutic approach for
lymphoid population in the blood.
aggressive lymphomas with a high grade of malignancy. It takes
into account the patient’s age, the WHO general status, the LDH
5.2. Endoscopic workup level and the number of extra-nodal sites involved. It can be adapted
for the large cell digestive lymphomas and it should be emphasised
5.2.1. Recommendations that the majority of gastric large-cell NHL are classified as hav-
Endoscopic workup includes oesophago-gastro-duodenoscopy ing a good prognosis, as they are often localised, developed in the
and ileo-colonoscopy with systematic biopsies, even in the absence patients with a good WHO general status and a normal LDH level
of macroscopic lesions [18]. Endoscopic ultrasound is indicated in [4,5].
gastric lymphoma, since it has a prognostic value at diagnosis and
sometimes during a follow-up in the case of medical treatment [19],
and may also be proposed for rare localisations in the oesophagus 6. Treatment and prognosis
or in the rectum.
6.1. Gastric B-cell lymphomas

5.2.2. Options
6.1.1. Extra nodal marginal zone MALT lymphomas (with small
Magnetic resonance enterography or even enteroscopy (if small
B-cells, low grade of malignancy)
intestine biopsies are necessary for diagnosis), as well as video-
6.1.1.1. Recommendations. Recommendations come from experts’
capsule endoscopy (rarely useful), may be proposed in case of small
agreement from EGILS recommendations [7] and ESMO guidelines
intestinal lymphomas [20].
[8].
Since most of these lymphomas are localised, eradication of H.
5.3. Other explorations pylori is the first-line treatment of choice for all gastric MALT lym-
phomas. This treatment is usually indicated for H. pylori-positive
5.3.1. Recommendations lymphomas (positive histology and/or serology), but it is also rec-
Abdominal, pelvic and thoracic CT-Scan is mandatory in all types ommended if the H. pylori status is negative [24,25]. As for the
of lymphomas, as well as the CT-Scan and/or endoscopy of the therapeutic regimen to be used, we can refer to the latest Maastricht
nasal cavity and biopsies if there remains a doubt after the ENT consensus which recommends, as the first line of empirical treat-
examination or in the presence of ENT symptoms. ment, either a bismuth-based quadruple therapy or concomitant

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mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
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quadruple therapy [13]. The control endoscopy of the lymphoma 6.1.1.2. Treatment in case of non-regression of the lymphoma after
has to be performed 6 weeks after the completion of treatment to eradication of H. pylori. Radiotherapy or chemotherapy can be
check the evolution of endoscopic lesions (to make sure that there proposed in case of non-regression after the eradication of H.
is no macroscopic progression) and eradication of H. pylori. Addi- pylori (large tumour mass, non-regression of endoscopic lesions,
® ®
tionally, a 13 C-labelled urea breath test (Helikit , OrInfai ) should lymphomatous infiltrate persisting after at least 24 months of
be performed to confirm the eradication of the bacteria. follow-up), or in H. pylori-negative lymphomas, or those with
Endoscopic follow-up of gastric lymphoma, with multiple biop- t(11;18) translocation, less susceptible to respond to eradication
sies on scar zones, should be performed every 6 months for the first treatment. Surgery is only proposed in case of perforation or haem-
two years, then once a year for a duration not defined by guidelines. orrhage uncontrolled by endoscopic treatment, which is extremely
The tumour response is assessed both, endoscopically and rare.
histologically: scarring of macroscopic lesions and histological
regression of the lymphomatous infiltration best evaluated by
the GELA histological scoring system [15]. This grading should 6.1.1.3. Radiotherapy. Low-grade small B-cell NHL are sensitive to
always be performed in the context of reviewing and comparing low doses of radiotherapy. For localised gastric lymphomas, exclu-
to the previous biopsies. It shows a good inter-observer agree- sive radiotherapy used in case of failure of antibiotics treatment
ment. According to this system, the following types of histological gives very good results without long-term side-effects [31]. The
response can be distinguished: (1) complete histological response first published results, based mainly on small, retrospective series
(CR), corresponding to the complete disappearance of tumour of patients (n = 6–20 gastric MALT lymphomas), showed a com-
infiltration; (2) probable minimal residual disease (pMRD), corre- plete remission rate of 96–100% fora median follow-up of 1.3–4.1
sponding to the persistence of some lymphocytic aggregates in the years [32–36]. The excellent results and good tolerance of the low-
chorion; (3) responding residual disease (rRD), corresponding to dose (30 Gy) radiotherapy, have been recently confirmed by a larger
the persistence of infiltration of the chorion by lymphocytes, with prospective French GELD/FFCD study including 53 patients with a
no lympho-epithelial lesion, considered as a partial response; (4) no long-term follow-up (median of 4.9 years), showing a response rate
change (NC), corresponding to the absence of change in comparison of 98% and an overall survival linked to the lymphoma of 94% [37].
to the initial biopsies, considered as non-response to treatment. The recommended dose in conformational radiotherapy is 30 Gy
Complete remission is defined as the absence of macroscopic in classic fractionation (1.8–2 Gy/session and 5 sessions per week)
lesions and negative histology (CR or pMRD) in two subsequent delivered on the gastric volume and the epigastric lymph nodes
follow-up examinations, partial remission as normalisation or [37,38].
reduction of macroscopic findings with histological rRD, and sta-
ble disease as unmodified macroscopic lesions and/or histological 6.1.1.4. Chemotherapy and immunotherapy. Chemotherapy has
NC. Finally, progressive disease is defined by worsening of macro- been mainly assessed for extra-nodal disseminated MALT lym-
scopic lesions, or lymphoma dissemination, or transformation into phomas, more rarely for localised gastric lymphomas [17]. In a
DLBCL [7]. phase III trial of 401 patients with localised or disseminated MALT
The published series reported variable rates of remission accord- lymphoma of gastric or other origin, the regimen combining ritux-
ing to the modalities of initial workup and clinical stage. The imab and chlorambucil proved to be better than chlorambucil or
endoscopic ultrasound at diagnosis has a prognostic and predic- rituximab used in monotherapy, with a response rate of 80%, 62%
tive value of the lymphoma’s response to the eradication of H. and 55%, respectively, and the corresponding 5-year progression-
pylori [18,19,26], but is of little help for follow-up. The chances free survival rate of 72%, 59% and 58% [39]. These differences in
of complete remission are 80% in case of stage IE (or TN0M0B0, overall survival were found in all patients but also in subgroups, in
as assessed by endoscopic ultrasound, according to Paris staging particular in the subgroup of gastric MALT lymphomas.
system) and H. pylori-positive status [19,27,28]. The presence of Maintenance therapy with rituximab with an infusion of
t(11;18) translocation in the tumour cells is associated with resis- 375 mg/m2 every 2 months for 2 years has only shown first-line
tance (no regression) of the lymphoma to H. pylori eradication benefit in nodal follicular lymphomas [40]. For other indolent lym-
[16,29]. phomas, both non-follicular and MALT lymphomas, maintenance
The tumour response can be slow, which necessitates a follow- therapy is not recommended and is being currently assessed in
up of up to 24 months after eradication of bacteria (median time all loc alisations of MALT lymphomas in phase II IELSG Trial. Also,
of occurrence of remission is 6 months with the extremes from 3 although proposed by some authors in localised forms, chemother-
to 24 months). The remission must only be pronounced after at apy should be rather reserved for disseminated MALT lymphomas.
least two successive negative examinations (experts’ agreement). Polychemotherapy regimens containing anthracyclines should be
In some cases, a microscopic lymphomatous residual disease (in proposed only for the cases of histological transformation into
the absence of endoscopic lesions), histologically defined as the aggressive lymphoma and are not justified in first-line treatment
presence of some pathologic lymphoid islets, can persist 2 years (expert opinion).
or even more after bacterial eradication, and its significance is not Some long-term complications of chemotherapy in indolent
known [30]. In these cases, the continuation of surveillance should MALT lymphomas have been reported, particularly a significant
be rather privileged over an active treatment. In all these cases, the increase of secondary cancers [41]. The option of surveillance
new GELA histological grading system may help to better standard- (“watch and wait” strategy) after antibiotics treatment can also be
ise a definition of the remission of lymphoma. discussed (in case of so-called microscopic lymphomatous residual
According to the currently available data coming from the long- disease, in the absence of endoscopic lesions, in elderly patients, in
term 25-year follow of the first patients having achieved remission, patients with comorbidities) [30].
the relapses are rare but early (up to 2 years), and the risk of trans-
formation or dissemination is also low, as shown in the study by
Zullo et al. [28], pulling together the results of 32 published series 6.1.2. Diffuse large B-cell lymphomas (DLBC)
(1271 cases of gastric lymphomas treated with antibiotics) [28]. 6.1.2.1. Recommendations. The reference treatment is a R-CHOP
chemotherapy regimen combining rituximab with CHOP (doxoru-
bicin, cyclophosphamide, vincristine, prednisone) for 6 or 8 cycles
every 3 weeks [42].

Please cite this article in press as: Matysiak-Budnik T, et al. Gastrointestinal lymphomas: French Intergroup clinical practice recom-
mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
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Systematic eradication of H. pylori is recommended with the aim ment is the combination of CVP or CHOP chemotherapy combined
to treat the potentially associated proliferation of small MALT-type with rituximab, followed by the maintenance therapy with ritux-
B-cells [43]. imab at 375 mg/m2 every 2 months for 2 years.

6.1.2.2. Options. In young subjects with a large disseminated 6.2.5. Burkitt lymphomas
tumour mass (stage IV, elevated LDH), which is rare in PGIL, the These lymphomas are usually observed in children and young
indication of intensifying chemotherapy with autologous stem cell adults; digestive presentations, particularly ileo-caecal, are not
transplantation, can be discussed with haematologists. There is no rare. Initial chemotherapy in an urgency and should be per-
indication of radiotherapy in DLBC digestive lymphomas. formed in a specialised haematology department [52]. Intensive
chemotherapy regimens, including a prophylactic intrathecal treat-
6.2. Intestinal B-cell lymphomas ment and adapted to the initial prognostic factors, allow achieving a
high cure rate. They comprise an anthracycline, cyclophosphamide,
Different forms of these lymphomas, defined according to their high doses of methotrexate and cytarabine. Surgery is not indicated,
cellular origin, have different prognosis and, accordingly, they except for an emergency surgery in case of complications.
require different therapeutic strategies [10,44].
6.2.6. Immunoproliferative small intestinal disease (IPSID) —
6.2.1. Intestinal DLBCL alpha chain disease
The most frequently they are treated by chemotherapy com- IPSID are mainly represented by the alpha chain disease (ACD),
bined with rituximab, just like DLBCL of other localisations. The described especially in young patients living around the Mediter-
treatment strategy and its duration depend on the initial prognostic ranean basin, decreasing in prevalence and almost disappeared in
analysis (cf supra stomach NHL) Western countries. ACD corresponds to an extranodal marginal
The only indication of surgery are complications, generally inau- zone MALT lymphoma affecting the exocrine IgA mucosal system
gural (obstruction, perforation, etc.). In this case, surgery is usually [53]. A study has highlighted the pathogenic role of Campylobac-
followed by adjuvant chemotherapy (4 cycles of R-CHOP) (expert ter jejuni in tumour proliferation [54]. The lymphoma is primarily
agreement) [4,42]. localised in the small intestine and in the mesenteric lymph nodes
but can affect the stomach, colon, rectum, the more distal and
6.2.2. Mantle cell lymphomas peripheral abdominal lymph nodes, the Waldeyer’s ring, the bone
This is the most frequent histologic type of intestinal lymphoma- marrow and other organs.
tous polyposis. These lymphomas are often disseminated with The disease progresses from a plasmocyte stage of a low degree
multifocal involvement of several segments of the digestive tract. of malignancy (stage A) to an immunoblastic stage of a high degree
Localisations in the lymph nodes, bone marrow and blood are fre- of malignancy (stage C). In the intermediate stage B, the cellular
quent. They are characterised by a relative chemoresistance and infiltrate is made up of dystrophic plasmocytes and a small number
unfavourable evolution after chemotherapy at conventional doses of immunoblasts. Different grades of malignancy can be observed
[9,45,46]. Currently, the young patients (under 65 years of age) at the same time at different sites, and thus an exhaustive work-up
undergo R-DHAX (P or C) type induction therapy, followed by con- is necessary.
solidation with intensification and autologous hematopoietic stem The therapeutic strategy depends on the patient’s age and
cell transplantation, and maintenance therapy with rituximab for general status, which can be altered at all stages, both because
2 years. The treatment is realised in haematology departments. of associated malabsorption/exudative enteropathy and of the
In patients over 65 years of age and under 80, the treatment tumour itself. An appropriate diet, enteral or parenteral nutrition
with R-CHOP with maintenance therapy with rituximab for at least is necessary, and specific deficiencies (iron, folates, calcium, mag-
2 years is the current recommendation [9,47]. nesium, oligo-elements, vitamins, etc.) must be corrected.
The choice of the treatment depends on the grade of malignancy
6.2.3. Extra-nodal marginal zone lymphoma of MALT (definitions specific to the ACD):
Unlike gastric marginal zone lymphomas of MALT, those lym-
phomas localised in the intestine are rare and there is no consensus - the lesions at stage A, limited to the gastro-intestinal tract and
on their management. In localised forms, abstaining from therapy to the satellite lymph nodes, are treated by oral macrolide or
can be justified. In the other cases, the treatment of reference is a tetracycline antibiotics, combined with anti-parasitic treatment.
combination of rituximab and an alkylating agent (chlorambucil). Out of 28 patients treated in this way, 39% achieved a complete
R-CHOP combination must be reserved for cases with suspicion remission [53]. Because of the unpredictable character of the
of transformation. Radiotherapy is not possible due to intestinal progression of stage A towards the stages of higher degree of
mobility and related risk of toxicity. malignancy, chemotherapy must be started early enough (quite
rapidly) in patients who don’t respond to antibiotics;
6.2.4. Follicular lymphomas - the patients with stages B and C (transformation into large B-cells
Probably due to their better identification, primary follicular lymphoma), besides the antibiotic and anti-parasitic treatment
lymphomas (small B-cells) of the digestive tract are more fre- which can improve the malabsorption syndrome, should receive
quently diagnosed and it seems that they are not as rare as it was chemotherapy including an anthracycline (R-CHOP) if only nutri-
previously thought. They are in general found in the small intes- tional and digestive status allows it. Some patients have benefited
tine and are often discovered fortuitously. They may be localised from intensification with autologous stem cell transplantation
(in the duodenum for example) or multifocal in the digestive tract (expert opinion).
with sometimes endoscopic aspect of lymphomatous polyposis
[48–50]. 6.3. Intestinal T-cell lymphomas
Initial abstaining from therapy is justified in the asymptomatic
forms with low tumour mass (GELF criteria), like in nodal forms of Intestinal T-cell lymphomas are rare, representing less than
follicular lymphomas, whatever the patient’s age [51]. 1% of all NHL. The unfavourable prognostic character of the T
The treatment is indicated in the symptomatic tumours and/or phenotype is well established. There are currently no specific rec-
those with high tumour mass (GELF criteria). The reference treat- ommendations for the clinical management of these lymphomas.

Please cite this article in press as: Matysiak-Budnik T, et al. Gastrointestinal lymphomas: French Intergroup clinical practice recom-
mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
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Besides the intestinal localisations of virus-induced T-cell lym- 7. Surveillance

phomas (linked to HTLV-1 or to EBV like nasal T or NK/T-cell
lymphomas), those linked to immune deficiencies, orCD4+ T-cell 7.1. After immuno-chemotherapy or radiotherapy
lymphomas of the chorion [55], we can distinguish T-cell lym-
phomas associated with enteropathies, in particular with celiac Classically, the surveillance of lymphomas after chemotherapy
disease [56,57]. and/or radiotherapy includes a post-treatment work-up and then
The lymphomatous complications of celiac disease are rare an annual check-up for 10 years comprising: clinical examination,
(<3/100,000 inhabitants per year), but very severe. Two types biological tests (LDH, beta 2 microglobulin, hepatic biology) and in
of refractory celiac disease have been identified, known as non- some cases, according to the type of lymphoma, a CT-scan of the
clonal type I refractory sprue (RS I) and clonal type II refractory abdomen and chest, as well as an endoscopic examination of the
sprue (RS II). RS II is considered as a lymphoma of low grade of main site initially affected.
malignancy which is intraepithelial, associated with celiac dis-
ease and characterised by an expansion of small intraepithelial
7.2. Non-standardised attitude adjusted to the histological type
lymphocytes (IEL) of abnormal phenotype (no expression on the
(experts’ agreement)
surface of the CD3 T-cell receptor complex, but intracellular CD3+
by IHC and CD8−, CD103+) [57]. It progresses into T-cell lym-
1. For high grade of malignancy lymphomas, clinical monitoring
phomas with a high grade of malignancy in 30–50% of cases at
every 6 months for the first 2 years, then once a year, with clinical
5 years and its prognosis is poor with less than 45% of patients
and endoscopic examinations and measurement of LDH levels,
still alive 5 years after diagnosis [58]. Diagnosis is difficult and
can be proposed. The proposed length of follow-up varies from
requires specific immunohistochemical, phenotypic and molec-
5 to 10 years (expert opinion), and no imaging examination (CT
ular studies (PCR Multiplex). Coming from the small intestine,
scan or FDG-PET) is recommended. The optimal frequency of
the abnormal IEL of the refractory sprue can spread within the
endoscopic tests is not determined.
entire digestive tract (distal small intestine, stomach, colon), cir-
2. For the low grade of malignancy lymphomas, because of a per-
culate in the blood and invade the bone marrow and various
manent risk of relapse (follicular NHL), a regular long-term
epithelia such as the skin, the lungs, and the sinuses because of
monitoring and further examination according to clinical signs,
their epitheliotropic nature. More recently, granular leukaemias
are indicated.
(LGL, Large granular lymphocytic Leukaemia) have been identified,
which, from the periphery, invade the intestine of celiac patients,
leading to the resistance to a gluten-free diet. LGL should be dis- For marginal zone MALT lymphomas, after H. pylori eradication,
tinguished from RS II which is the first differential diagnosis to annual clinical and endoscopic monitoring for at least 10 years has
consider, since it is also characterised by the persistent malab- been proposed. However, monitoring from 5 years onwards can
sorption syndrome, villous atrophy and an intestinal T-cell clone be spaced out (but there is no standardised scheme) [7]. Surveil-
in celiac patients. Flow cytometry enables the diagnosis by show- lance of the remaining stomach is extremely important, especially
ing the usual expression of CD8 and CD57 markers in these patients in the presence of intestinal metaplasia or dysplasia on gastric
[59]. biopsies, because of an increased risk of adenocarcinoma in these
The poor prognosis of the RS type II is linked to the absence patients. Indeed, the cases of gastric adenocarcinoma have been
of efficient treatments as those currently used (corticosteroids observed during the follow-up of cured lymphomas [28,30,62,63].
and immunosuppressive drugs) bring only a partial and tem- Furthermore, the epidemiological study of Capelle et al. [64] from
porary response [58]. Two new therapeutic strategies for RS II the Netherlands showed that the risk of gastric adenocarcinoma in
are being currently evaluated by National French Expert Cen- patients with a history of gastric lymphoma was multiplied by 6 as
tre for Lymphomas Associated with Celiac Disease (“CELAC”): compared to the general population [64].
(1) a classical treatment with chemotherapy–autograft, and (2)
a targeted therapy with anti-IL-15 agents. The objective is 8. Treatment of recurrence
to cure patients with RS II and to prevent the appearance
of T-cell lymphomas with a high grade of malignancy called In gastric MALT lymphomas, a true relapse is an exception and
“Enteropathy Associated T-cell Lymphoma” (EATL). These T-cell usually corresponds to incompletely regressed lymphoma, some-
lymphomas are rare (estimated incidence of 0.22–1.9/100,000 times related to the persistence of H. pylori infection. In these cases,
inhabitants) [60] but of a poor prognosis with a survival rate and if the absence of bacteria is confirmed, an alternative treatment
not exceeding 20% at 5 years. The EATL can be diagnosed dur- should be proposed.
ing emergency surgery and can reveal celiac disease. Conversely, In other histological subtypes, especially of high grade of malig-
when celiac disease is known, the lymphoma must be screened nancy, and in other localisations, relapses have much poorer
in case of a resistance to a gluten-free diet, and its diagno- prognosis. These patients should be managed in haematology
sis can be difficult. It is done by enteroscopy, CT-Scan of the department. Salvage chemotherapy regimens consist in proto-
chest and abdomen, PET-Scan or even laparotomy or exploratory cols combining platinum, etoposide, high doses of cytarabine or
laparoscopy. ifosfamide and etoposide. In young patients, intensification with
The management and treatment of EATL should be always autologous hematopoietic stem cell transplantation may be con-
discussed in the multidisciplinary meeting. Nutritional status, pos- sidered.
sibility of using chemotherapy and surgical reduction of the tumour
are independent prognosis factors in EATL survival in uni-and
Conflict of interest
multivariate analysis [61]. Given the fact that more than 80% of
None declared.
EATL are CD30+, a phase 2 clinical trial using anti-CD30 anti-
body is currently open in France (Phase 2 Study of Brentuximab
Vedotin and CHP followed by autologous stem cell transplan- Acknowledgements
tation as frontline treatment of enteropathy-associated T-cell
lymphoma). We thank the review committee: L. Bedenne MD PhD and P.
Maingon, MD PhD (CHU Dijon).

Please cite this article in press as: Matysiak-Budnik T, et al. Gastrointestinal lymphomas: French Intergroup clinical practice recom-
mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
https://doi.org/10.1016/j.dld.2017.12.006
G Model
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T. Matysiak-Budnik et al. / Digestive and Liver Disease xxx (2017) xxx–xxx 7

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Please cite this article in press as: Matysiak-Budnik T, et al. Gastrointestinal lymphomas: French Intergroup clinical practice recom-
mendations for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFH). Dig Liver Dis (2017),
https://doi.org/10.1016/j.dld.2017.12.006