Working Group and reviewers
Working Group: A. RUSKONÉ-FOURMESTRAUX (Saint-Antoine APHP, Paris), B. Fabiani (Saint-Antoine APHP, Paris), C. Harkins (Saint-Louis APHP), G. Malamute (HEGP APHP, Paris), T. MATYSIAK-BUDNIK (CHU Nantes), C. Taylor (Saint-Louis APHP, Paris)
Proofreading: L. BEDENNE (CHU Dijon), P. Maingon (APHP)
How to cite this chapter: Matysiak-Budnik T, Fabiani B, Harkins C, Taylor C, Malamute G, Cadiot G, mouthful O, Ruskoné-Fourmestraux A. Gastrointestinal lymphomas: French Intergroup Clinical Practice recommendations for diagnosis, treatment and Follow-up (SNFGE, FFCD, GERCOR, Monocancer, SFCD, SFED, SFRO, SFH). Dig liver say. 2018; 50 (2): 124-31.
10.1 Introduction
Primary gut lymphomas are non-Hodgkin (NHL) lymphomas, derived by definition of MALT (Mucosa Associated Lymphoid tissue) (Isaacs, 2005) and include different anatomocliniques entities that should be well known because their Cell origin and their clinical presentation condition their evolution and treatment.
NHL is rare, corresponding to 1% of gastrointestinal tumours. Their incidence varies by country between 0.58 and 1.31/100 000 inhabitants and the average age of their occurrence is between 50 and 70 years (Lepage, 2006). The stomach is the most common site, followed by the small intestine and the colon. B lymphomas (90%) were more common than T lymphomas (10%).
Few have been the prospective studies, taking into account recent classifications and proposing homogeneous treatments (Fischbach, 2000, Koch, 2001, Ruskoné-Fourmestraux, 1993) which have made it possible to know them better. Although gastro-intestinal locations account for 36% of the extra-ganglion forms of NHL, these tumours remain infrequent, explaining, with the diversity of anatomocliniques forms and their often slow evolution, the difficulty of putting Point of randomized therapeutic trials specific to digestive locations. Thus, the indication of chemotherapy is based on the chemo-sensitive forms of the results of randomized studies obtained for the much more numerous ganglion NHL. The published recommendations mainly concern gastric lymphomas and are derived from the results of small series or expert opinion, such as those recently published by the European Gastrointestinal Lymphoma Study Group (EGILS group = European Gastro-Intestinal Lymphoma Study Group) (Ruskoné-Fourmestraux, 2011) or by the European Society of Oncology (ESMO) (Zucca, 2013).
The management of these gastrointestinal lymphomas, particularly the therapeutic strategies are specific to the histological type and their localization in the gut with the peculiarity for the gastric lymphoma of the MALT, the most common, The origin of Helicobacter pylori (H. pylori) gastritis.
10.2 Diagnostics-Pathology Classification
The diagnosis of lymphoma is done and confirmed by proofreading of experts:
On endoscopic biopsies, more rarely during an emergency surgery for digestive hemorrhage or occlusion (Hail location) (Fischbach, 2008);
Biopsies must be multiple (10 to 20) and performed in tumor but also non-tumoral areas of the den and gastric body (research of H. pylori and associated lesions such as atrophy and intestinal metaplasia);
Biopsies should be fixed in formalin for histological, immuno-histochemical and molecular biology studies;
Freezing is not useful for diagnosis but can be recommended in principle in the context of protocol studies.
For gastric forms the search for H. pylori is systematic:
In histology by staining of GIEMSA or cresyl violet or even by immunohistochemistry with anti-H antibody. Pylori
The culture with sensitivity, is recommended after failure of a first line treatment, by a reference laboratory after dispatch on Portagerm ® transport medium in an isothermal flask at 4 °c;
Serology is systematic especially in the absence of H. pylori in histology;
The carbon 13-labelled urea respiratory test is useful in asserting the disappearance of the bacterium 4 to 6 weeks after the end of treatment;
Molecular methods (in particular real-time PCR) have excellent sensitivity and specificity and can also detect mutations of H. pylori associated with resistance to macrolides. They do not require specific transport precautions. However, there were no broad studies testing PCR in patients with MALT lymphomas with only a few reported cases (Franco, 2005).
The positive H. pylori status is defined as positive histology and/or positive serology (Lehours, 2003). Direct testing is done remotely from any antibiotic treatment (at least 4 weeks) and after the PPI (at least 2 weeks).
Cl
Assifications Anatomo-Pathological (appendix I):
The different types of primary gastrointestinal lymphomas have been identified by Isaacs (Isaacs, 2005), but the last who 2016 classification for the NHL as a whole is the reference and the diagnosis must be given according to it (Swerdlow, 2016). It takes into account the cellular origin of the proliferation determined on morphological and immuno-histochemical criteria.
These are B lymphomas in 90% of cases, rarely T-lymphoma. Most of the primary digestive lymphomas are derived from MALT (Mucosa Associated Lymphoid tissue). In Western countries, gastric lymphomas are the most common. These are either extra-ganglion lymphomas of the marginal zone or MALT lymphoma, small-cell proliferations B, or large B-cell lymphomas, rarely by transformation of precedents, usually de novo. In the gut, all the NHL varieties can meet.
For extra-ganglion gastric lymphomas of the marginal area of malt (so-called gastric lymphomas of Malt), the score of Wotherspoon is no longer used. On the other hand, after eradication of H. pylori and for follow-up, pathology results are given according to the score of GELA (Adult Lymphoma Study Group (copy-Bergman, 2003) (appendix I).
Given the prognostic and therapeutic implications, the histological subtype of lymphoma must be accurately established. A notice to pathologists of reference is recommended for all types of lymphomas in order to confirm the diagnosis (rereading of the blades and complementary techniques by expert groups of current studies or LYMPHOPATH network of the Cnib) ( Ruskoné-Fourmestraux, 2011). The search for clonality, not obligatory, can be useful in cases of difficult diagnosis. The search for a translocation such as t (11; 18) for the lymphomas of the marginal area of the MALT is optional, if accessible it is carried out by technique of FISH on the biopsy fixed in formaldehyde (Dreyling, 2013). It has been shown that this translocation within tumor cells was associated with the persistence of gastric lymphoma of MALT after eradication of H. pylori (Liu, 2002) and a lower rate of response to chemotherapy (Levy, 2010).
10.3 Extension Balance: Pre-thépautiques exploration-clinical stage
10.3.1.10.3.2 Clinic. Biological 10.3.3. Endoscopic 10.3.4. Other 10.3.5 explorations. Clinical stages for reference examinations This assessment is generally the same regardless of the histological type and the seat of lymphoma (expert agreement) (Ruskoné-Fourmestraux, 2011, Zucca, 2013).
10.3.1. Clinic
Who general state
General signs
Review: Ganglion areas, liver, spleen, ent exam
10.3.2. Biological
References
CBC
Electrophoresis and immuno-fixation of blood proteins
Ldh
HIV serology, hepatitis B and C
Options (questionable interest or by type of lymphoma):
H. pylori serology (gastric lymphomas and especially if negative histology for the bacterium) (Lehours, 2003) Uricémie hepatic biology
Anti-endomysium and anti-transglutaminase antibodies (T-lymphomas)
Blood research of a monotypical lymphoid subpopulation
10.3.3. Endoscopic
References
Œso-Gastro-duodenoscopy and ileocecal-colonoscopy with systematic biopsies even in the absence of macroscopic lesions (Fischbach, 2008);
echo-Digestive endoscopy for gastric localization: prognostic interest in diagnosis and rarely for follow-up if medical treatment (Fischbach, 2002, Levy, 1997, Palazzo, 1993, Ruskoné-Fourmestraux, 2001).
Options (questionable interest or by type of lymphoma):
Enteric-MRI or enteroscopy if grêliques biopsies needed for diagnosis (rare contingency);
Vidéocapsule, rarely useful (Flieger, 2005);
echo-Endoscopy (in addition to the stomach) possibly for the rare varices or rectal locations.
10.3.4. Other explorations
References
Thoraco-abdominal-pelvic Scanner
Scanner and/or endoscopy of the cavum and biopsies in case of doubt to the ENT examination or if symptomatology ent
Options (questionable interest or by type of lymphoma):
Systematic ostéomédullaire biopsy for certain types of lymphoma (follicular B, B-cell coat for example) it became optional for others (for gastric MALT: only if not regression after H. pylori eradication and optional For large cell B lymphomas (Cheson, 2014).
TEP-FDG to determine chemotherapy sensitivity under immuno-chemotherapy treatment for large B-cell diffuse lymphomas and follicular lymphomas. This examination is being evaluated in the lymphomas of the marginal area of the MALT where it is generally negative. However, some hyperbindings have been found to a lesser extent in the lymphomas of MALT that do not respond to eradication of Helicobacter pylori, which is suspected of transformation (Song, 2011, Treglia, 2015).
CSF study (with cytocentrifugation) for lymphomas with high risk of attack or relapse at the central nervous system (high degree of malignancy or high tumor mass or histological subtype Burkitt)
ECG and study of myocardial function: fraction of ventricular ejection or cardiac ultrasound if anthracyclines envisaged for lymphomas of high degree of malignancy.
10.3.5. Clinical Stages
Given according to the "classification " of Ann Arbor modified by Musshoff, it reports the results of the extension balance (Musshoff, 1977). Some primary digestive lymphomas are localized (70% of cases): IE stage (digestive parietal impairment) or IIE1 stage (para-tumor ganglionic impairment) or IIE2 (node damage at a distance from the worst prognosis). Other specific classifications of digestive locations are used in particular that of the group EGILS inspired by the classification TNM (Paris staging System) (Ruskoné-Fourmestraux, 2003). It is useful for gastric locations explored by endoscopic to codify parietal damage (appendix II).
In addition to the clinical stage, other parameters have been identified in the international prognostic Index for non-Hodgkin lymphomas. This condition, for the so-called aggressive lymphomas of high degree of malignancy, the prognosis and the therapeutic attitude. It takes into account the age, the WHO general state, the level of LDH and the number of extra-ganglion. This index can be adapted for large-cell digestive lymphomas knowing that the majority of large-cell gastric NHL will be categorized as a good prognosis because they are most often localized, with a good general state and a level of LDH Normal (Fischbach, 2000, Ruskoné-Fourmestraux, 1993).
10.4 Treatments
10.4.1.10.4.2 Gastric B lymphomas. 10.4.3 intestinal B lymphomas. 10.4.4 intestinal T lymphomas. Studies and observatories for intestinal lymphomas B and T 10.4.1. Gastric B lymphomas
10.4.1.1. Lymphomas of the marginal area of MALT (small B-cells called low malignancy)
References: (Agreement of Experts, recommendations EGILS: Ruskoné-Fourmestraux, 2011, ESMO: Dreyling, 2013)
Eradication of H. pylori: In principle reserved for lymphomas of positive H. pylori status (histology and/or positive serology), but recommended even if H. pylori status is negative (Park, 2010, Raderer, 2006). As for the choice of treatment, we can refer to the last recommendations of Maastricht (Malfertheiner et al, 2017), GUT 2017), or the HAS of 2017. The optimal option is to propose a treatment guided by a sensitivity study (sensitivity), i.e. "oriented" treatment. However, if this study cannot be carried out, a "probabilistic" treatment can be proposed. In France, given the rate of resistance to the important clarithromycin, in the first line two treatments can be proposed, namely the Concomitantic Quad therapy (IPP x 2 + amoxicillin 1g x 2 + metronidazole 500mg x 2 + clarithromycin 500 mg x2 during 14 days), which is the quadruple therapy containing bismuth (IPP x 2 + PYLERA ®) for 10 days. In the second line, alternative treatment is proposed which is not used in the first line, whereas the third line must be guided by sensitivity (Malfertheiner, 2017).
⇒ Controls 6 weeks after the end of the treatment to verify the eradication of H. pylori (C13 urea respiratory test: Helikit ® or INFAI ®) and the absence of endoscopic progression of lymphoma.
⇒ Endoscopic Follow-up (multiple scar biopsy) every 4 to 6 months for 1 year then every 6 months in the second year and then once a year.
The tumour response is assessed endoscopy and histologically: scarring of macroscopic lesions and histologic regression of lymphocytic infiltration, which is best assessed according to the GELA classification (copy-Bergman, 2003):
The disappearance of tumor infiltration (complete response: CR) or the persistence of a few clusters of lymphocytes in the chorion (probable minimal residual disease: PMRD) are considered as signing a complete clinical remission.
The persistence of infiltration of chorion by lymphocytes, without lympho lesion (responding residual disease: RRD), is considered to be a partial response.
The absence of change from initial sampling (no change: NC) is considered a non-response to treatment.
The published series report varying remission rates based on the balance sheet and initial clinical stage. The initial echo-Endoscopy has a prognostic and predictive value of the lymphoma response to the eradication of the bacterium (Fischbach, 2002, Levy, 1997, Ruskoné-Fourmestraux, 2001) but is not useful for follow-up. Thus the chances of complete remission are 80% for the stage IE forms (evaluated by ECHO-endoscopy) and H. pylori positive Status: (Fischbach, 2000, Ruskoné-Fourmestraux, 2001, Janssen 2009, Zullo, 2010). A T (11; 18) translocation in tumor cells is accompanied by lymphoma resistance to H. pylori eradication (Liu, 2002).
The tumor response may be slow, requiring a follow up to 24 months (median of the remission occurring 6 months; extremes from 3 to 24 months). Remission can only be affirmed after at least two negative successive checks (expert agreement; See European Group recommendations, EGILS).
At 18 months or 2 years or more, sometimes persists a disease called residual lymphomateuse microscopic (absence of endoscopic lesions) defined histologically by some pathological lymphoid islets, of which one does not know the fate (Fischbach, 2007) . In these cases the continuation of surveillance may be preferred to alternative oncology treatment (Ruskoné-Fourmestraux, 2011). In any case, the new anatomopathologic classification of GELA should allow the future to better codify for the clinician the regression or not of lymphoma.
The current decline for the first patients put in remission is 25 years, relapses are rare but early (2 years), and so are transformations or releases as reported in the Zullo study of the results of 32 published series (1271 Cases of antibiotic-treated gastric lymphomas) (Zullo, 2010).
Treatments for non-regression of lymphoma after H. pylori eradication:
Surgery since the H. pylori era is only proposed in the case of perforation or uncontrolled bleeding in endoscopy which is extremely rare.
Radiotherapy or chemotherapy can be proposed in case of non-regression after eradication of H. pylori (large tumor mass, non regression of endoscopic lesions, infiltrated lymphomateux persistent after 24 months of follow-up) or in forms at H. pylori status Negative or translocation T (11; 18) positive which does not regress after antibiotic therapy.
Radiotherapy (appendix III)
NHL Small-cell low malignancies are susceptible to low doses of radiation therapy. For localized gastric lymphomas, exclusive radiotherapy in case of failure of antibiotic treatment gives very good results without long-term side effects: The first results published on essentially retrospective series Limited numbers (n = 6 to 20 gastric lymphomas of MALT) with a complete remission rate of 96 to 100% for a median of follow-up between 1.3 and 4.1 years (Zullo bis, 2010) Gobbi, 2009, Tomita, 2009, Tsang, 2003, Vrieling, 2008, Wirth, 2013). The excellent results and safety of low-dose radiotherapy, 30 Gy, have just been confirmed by the prospective study of GELD/FFCD for long-term monitoring (median of 4.9 years) in 53 patients with a response rate of 98% and overall survival related to L Ymphome of 94% (Ruskoné-Fourmestraux, 2015).
The recommended dose of conformational radiotherapy is 30 gy in classical fractionation (1.8 to 2 Gy/session and 5 sessions per week) on gastric volume and périgastriques ganglion areas (Grade B; Annex III) (Ruskoné-Fourmestraux, 2015, Nam, 2014).
Chemotherapy and immunotherapy (see Protocols annex IV):
Chemotherapy has been evaluated primarily for disseminated extra-ganglion MALT lymphomas, more rarely for localized gastric lymphomas (Levy, 2010).
The Rituximab and Chlorambucil Association was found to be superior to monotherapy chlorambucil and monotherapy rituximab in a phase III trial of 401 patients with either gastric or non-localized or disseminated MALT lymphoma (ZUCCA, 2013) regarding the response rate (80% vs. 62% vs. 55%, respectively) and the non-progression survival rate at 5 years (72% vs 59% vs 58%). This difference in results was found in the subgroups of patients, particularly in the gastric MALT lymphoma (Grade B; Annex IV).
Rituximab maintenance with an infusion of 375 mg/m² every 2 months for 2 years showed a first-line benefit only in follicular ganglion lymphomas (rooms, 2011). For other indolent lymphomas, non-follicular type such as malt type, maintenance is not recommended and is currently being evaluated in all-location malt lymphomas (IELSG Test 38, Phase II). Also currently, although some propose chemotherapy in localized forms, it is rather envisaged for disseminated MALT Lymphomas (see annex IV protocols). A polychemotherapy containing anthracyclines is to be kept in case of histological transformation in aggressive lymphoma and is not justified in the first line (expert opinion).
Some long-term complications of chemotherapy in indolent lymphomas have been reported, including a significant increase in secondary cancers (Sacchi, 2008). They encourage to consider in RCP the indications of these treatments in relation to the indolent nature of these lymphomas of MALT.
Thus the option monitoring only after antibiotics can be envisaged (so-called residual lymphomateuse microscopic disease, absence of endoscopic lesions, elderly patient, field) (Fischbach, 2007).
Clinical trials or cohorts:
GELD Cohort (Digestive Lymphoma Study Group) gastric lymphomas of MALT located after H. pylori eradication: Prognostic factors and clinical surveillance with satellite studies of molecular biology. Gastroenterology Coordinator: Dr Agnès RUSKONÉ-FOURMESTRAUX, Hôpital St Antoine, 75012 PARIS. Tel 01 49 28 31 70. Agnes. Fourmestraux E-mail @ aphp.fr; Coordinator Proofreading Committee pathological Anatomy: Dr. Bettina Fabiani Pathological Anatomy Department of Prof. Jean-François Jackie, Hôpital St Antoine, 750012 PARIS. Tel 01 49 28 21 76. E-mail bettina.fabiani@aphp.fr; Molecular biology: Dr. Pascale CERVERA; Hematology: Service of Prof. M. MOHTY).
Cohort of gastric lymphomas of the MALT of the Henri Mondor Hospital. Gastroenterologists: Dr. Michaël LEVY, Prof. Jean-Charles DELCHIER (Coordinator); Hematologist: Prof. Corinne Hafeez; Pathologists: PR Christiane copy-BERGMAN, Prof. Philippe GAULARD; Molecular biology: Prof. Karen LEROY, Prof. Marie-Hélène DELFAU-LARUE.
10.4.1.2. Diffuse large cell lymphoma B (DLBC)
Reference (Protocol annex IV):
R-Chop chemotherapy combining rituximab with chop (doxorubicin, cyclophosphamide, vincristine, prednisone) (Grade A) for 6 or 8 cycles every 3 weeks (Raderer, 2002).
Eradication of systematic H. pylori in order to treat possible small-cell proliferation of associated MALT type.
It has been demonstrated in ganglion lymphomas (but never in gastric lymphoma studies alone) that the association of Rituximab with Chemotherapy ("R-CHOP" protocol) is a superior survival compared to CHOP alone (Cherry, 2002).
Options:
In the young subject with large and disseminated tumour mass lymphoma (stage IV, High LDH), a rare contingency in the gastric NHL, discuss with the hematologists the indication of an intensification of chemotherapy under the guise of a Self-grafting of stem cells (Grade A for NHL of this type histological). No indication of radiation therapy in digestive DLBC lymphomas.
10.4.2. Intestinal B lymphomas
Different forms depending on their cell origin can be encountered. They have prognosis and therefore very different treatments (Matysiak-Budnik, 2013, Kim, 2011, Salar, 2006).
10.4.2.1. Large-cell diffuse lymphoma B
The most common are treated by chemotherapy associated with rituximab, such as large cell lymphomas (B) from other locations. The regimen and duration of treatment depend on the initial prognostic analysis (see supra NHL stomach)
The only indication of the surgery is in case of inaugural complication. It is then followed by adjuvant chemotherapy (4 cures of R-CHOP; annex IV) (Agreement of Experts) (Raderer, 2002, Ruskoné-Fourmestraux, 1993).
10.4.2.2. Lymphomas of the mantle
This is the most common histological type of intestinal lymphoma polyposes. These lymphomas are often disseminated with multifocal impairment of several segments of the gastrointestinal tract. ganglion, medullary or even blood locations are common. They are characterized by relative chemoresistance and pejorative evolution after conventional dose chemotherapy (Ruskoné-Fourmestraux 2010, Ruskoné-Fourmestraux, 1997, Dreyling, 2013).
Currently, the youngest subjects (less than 65 years) are in an R-DHAX (P or C) type of induction treatment, followed by a consolidation by therapeutic intensification with autografting of hematopoietic stem cells, and a treatment Maintenance by Rituximab for 2 years. The management is done in the departments of Hematology.
In subjects over 65 years and under 80 years, R-CHOP treatment with maintenance by Rituximab for at least 2 years is the current recommendation (Kluin-Nelemans, 2011, Dreyling, 2013) (Grade B).
10.4.2.3. Extra-ganglion lymphomas of the marginal area of MALT (low degree of malignancy)
Unlike gastric lymphomas in the marginal area of MALT, those located in the intestine are rare and their care is not consensual.
In localized forms, therapeutic forbearance can be justified.
In other cases, the reference treatment is an association rituximab and alkylating (chlorambucil). The R-CHOP association must be reserved in case of suspicion of transformation.
Radiation therapy is unforeseeable because of intestinal mobility.10.4.2.4. Follicular lymphomas
Because they are better identified, follicular lymphomas (small B-cells) of the gut are not as rare as we thought. They are usually intestinal, and fortuitous discovery. These are sometimes localized forms (duodenal for example), sometimes more dispersed in the digestive tract with sometimes endoscopic lymphomateuse Polypose (Damaj, 2003, Kodama, 2005, Misdraji, 2011).
Initial therapeutic forbearance is justified in asymptomatic forms of low tumour mass (GELF criterion), like the ganglion forms of follicular lymphomas, regardless of the age of the patient (Brice, 1997).
When treatment is necessary in the symptomatic and/or high tumor mass: (criterion GELF), the reference treatment is based on the combination of a rituximab-associated treatment with CVP or CHOP with a maintenance Rituximab of 375 mg/m2 every 2 months for 2 years (most used form of this maintenance treatment).
10.4.2.5. Burkitt lymphomas
These lymphomas are observed in children and young adults; Digestive presentations including ileocecal-caecales are not rare.
First chemotherapy in specialized hematology service is a therapeutic emergency (Paw, 2007)
Intensive chemotherapy including prophylactic intrathecal treatment and adapted to the initial prognostic factors have a high healing rate. They include Anthracycline, cyclophosphamide, high-dose methotrexate, and cytarabine.
No indication of surgery except for emergency intervention in case of complication.
10.4.2.6. IPSID-alpha Chain disease (M-Ca)
The M-Ca described in young patients living around the Mediterranean basin, saw its prevalence decrease to the point that it almost disappeared in western countries. It is an extra-ganglionic lymphoma of the marginal zone or MALT lymphoma reaching the IgA-exocrine system of the mucous membranes (Rambaud, 1994, Rambaud, 1989). One study highlighted the pathogenic role of Campylobacter jejuni in tumor proliferation (Lecuit, 2004). Lymphoma is mainly located in the hail and mesenteric ganglia, but can affect the stomach, the recto-colon, the more disproportionate and peripheral abdominal ganglia, the Waldeyer ring, the bone marrow and the other organs.
The disease evolves from a myelomatous stage of low malignancy (stage a) to a immunoblastic stage with a high degree of malignancy (stage C). At stage B, intermediate between the previous ones, the cellular infiltration is made of plasma frankly dystrophic and a small number of immunoblasts. Above all, several grades of malignancy can be observed at the same time from one site to another. Therefore a comprehensive extension balance must be achieved.
The therapeutic indications take into account the age and general condition, which can be altered at all histological grades, both because of the exudate malabsorption/enteropathy and the tumor itself.
Depending on the case, appropriate dietetics, enteral or parenteral nutrition is required. Specific deficiencies (iron, folate, calcium, magnesium, trace elements, vitamins...) will be corrected.
The treatments are based on the grade of malignancy (definitions specific to the M-Ca):
-Stage lesions limited to the gastrointestinal tract and to the satellite glands are treated by oral antibiotic therapy, macrolide or cyclin, associated for 1 month with Metronidazole, which eradicates a possible giardiasis; Any other parasitic is also treated.
Of 28 patients treated, 39% went into complete remission (Rambaud, 1994, Rambaud, 1989). Due to the unpredictability of the evolution of stage a towards a high degree of malignancy, chemotherapy (cf infra) must be established early in patients who have not responded to antibiotics.
-Stages B and C (transformation into large cells B) in addition to antibiotic and antiparasitic treatment as it can improve the malabsorption syndrome, are covered by chemotherapy including a anthracycline (R-CHOP) if the nutritional state and Digestive allows. Some patients have benefited from intensified stem cell autografting (expert opinion).
10.4.3. Intestinal T-lymphomas
T-digestive lymphomas are rare, accounting for less than 1% of NHL. The pejorative prognostic character of the T-phenotype is established (Gfsdgs, 1998) and leads to the evaluation of alternate therapeutic approaches. There are no current specific recommendations for digestive T lymphomas. Besides intestinal localization of Viro-induced T-lymphomas (related to HTLV1 or EBV such as t or NKT nasal lymphomas), those related to immune deficiency, or CD4 + t lymphomas of Chorion (Malamute, 2015), the T-lymphomas associated with Enteric, especially those associated with celiac disease (Camus, 1999, storeroom, 2000). Lymphoma complications of celiac disease are rare, less than 3/100 000 inhabitants per year, but serious. Dr. Pantry's team has identified clonal refractory sprue, known as type II (SR II) as opposed to type I, which is non-clonal. SR II is considered to be a lymphoma of low degree of malignancy, intra-epithelial, associated with celiac disease and is characterized by an expansion of small intraepithelial lymphocytes of abnormal phenotype (no surface expression of the complex CD3-T receptor, but CD3 + in intracellular IHC and CD8-, CD103 +) (Pantry, 2000, Pantry, 1998). It is complicated in T lymphoma of high degree of malignancy in 30 to 50% of cases at 5 years and its prognosis is dark with less than 45% of patients alive 5 years after diagnosis (Malamute, 2009). Its diagnosis is difficult and requires specialized immunohistochemical, phenotypic and Molecular Biology (Multiplex PCR) studies. From the proximal small intestine, the abnormal dregs of the refractory sprue can propagate to the entire digestive tract (distal hail, stomach, colon), circulate in the blood and locate in the bone marrow, and various epitheliums such as skin, Lungs, the sinuses because of their épithéliotropisme. More recently, LGL (Large granular lymphocytic Leukemia)-grain leukemias have been identified which, from the periphery, invade the intestines of patients celiac giving them resistance to gluten-free diet. This is a differential diagnosis of SR II due to the persistence of malabsorption syndrome, villous atrophy, and intestinal T-clone in celiac patients. Flow cytometry allows diagnosis by showing the usual expression of CD8 and CD57 markers in these patients (Malamute, 2012).
The poor prognosis of SR II is related to the lack of effective treatment since those usually used (corticosteroids and immunosuppressants) have only a partial and provisional effect (Malamute, 2009). The "CELAC" Network (national Expert Centre for lymphomas associated with celiac disease) disseminates diagnostic and surveillance techniques and criteria for SR II and invasive lymphomas. Thus 26 regional expert centres are networked to improve the management of patients by organising a centralised anatomopathologic proofreading (hospital Necker Sick Children, Professor N. Bush, Dr J. BRUNEAU) and meetings of Concertations Multidisciplinary. are discussed in particular in RCP, two new therapeutic strategies for SR II: 1-a classical treatment by chemotherapy-autografting subject to an Inca PHRC ("Sprue autograft", PHRC Inca, closed trial) 2-a therapy targeted by The use of IL-15 intra-lymphocyte signaling pathway inhibitors (proposed JAK 3 inhibitors).
The goal is to cure patients with SR II and to prevent the onset of high-degree malignancies called "Enteropathy Associated T cell Lymphoma" (EATL). These T lymphomas of high degree of malignancy (EATL) are rare (incidence estimated between 0.22 and 1.9/100000 inhabitants) (Inkling, 2002) but dark prognosis with survival not exceeding 20% to 5 years. EATL can be diagnosed during a surgical emergency and reveal celiac disease. On the other hand, when celiac disease is known, lymphoma must be sought in the face of resistance to gluten-free diet and its diagnosis can be difficult. It is based on enteroscopy, thoraco-abdominal computed tomography, toe-scan or laparotomy or laparoscopic Explorer.
The management and treatment of EATL of all these intestinal lymphoproliférations are also discussed in the CELAC National RCP (cf. § 10.4.4.).
10.4.4. Studies and observatories for intestinal lymphomas B and T
The diversity of Anatomo-clinical forms and their rarity require consultation between clinicians and pathologists.
-GELD Observatory for intestinal B lymphomas with specific treatment of each histological subtype Dr Agnès Ruskoné-Fourmestraux, Hôpital St Antoine, 75012 PARIS. Tel: 01 49 28 31 72. E-mail: agnes.fourmestraux@aphp.fr (Anatomo-Pathology Coordinator: Dr Bettina Fabiani, Saint Antoine Hospital, bettina.fabiani@aphp.fr).
-Clinical trials of haematological protocols of ganglion forms for mantle cell lymphoma (Lymphomateuse polypose), B large cell lymphomas and MALT lymphomas, and T. Contact lymphomas Pr. C. Taylor, St. Louis Hospital, Hematology-oncology service, Paris. LYSA representative: E-mail catherine.thieblemont@aphp.fr.
-Intestinal T Lymphoma Observatory of the CELAC Group (National Expert Center for lymphomas associated with celiac disease (Coordinator PR Christophe storeroom, PR Georgia malamute European Hospital Georges Pompidou. christophe.cellier@aphp.fr; georgia.malamut@aphp.fr).
-Test for anti-IL-15 antibody in refractory sprue type II (CELIM-RCD-002), International test Celimmune LLC (Principal investigator USA: Dr Francisco Leon; Investigators France: PR Christophe storeroom/PR Georgia Malamute; first Inclusions planned in January 2016.
10.5 Monitoring
10.5.1 after immuno-chemotherapy or 10.5.2 radiation therapy. Uncodified Attitude to modulate according to the Histological type (Expert agreement) 10.5.1. After immuno-chemotherapy or radiotherapy
Classically, surveillance of lymphomas after chemotherapy and/or surgery and/or radiotherapy provides a post-therapeutic and then annual checkup for 10 years including: A clinical examination, a biological control (LDH, Beta 2 microglobulinémie, Hepatic biology) and possibly depending on the type of lymphoma an abdominal-thoracic scanner and an endoscopic control of the main site initially reached.
10.5.2. uncodified Attitude to modulate according to the Histological type (expert agreement)
High degree of malignancy: clinical surveillance every 3 months during the 1st year then every 6 months in the 2nd year, then once a year, with clinical examination, endoscopic and LDH rate; Duration of follow-up: 5 – 10 years (expert opinion). No imaging tests are recommended, either by scanner or by FDG-PET scan. The optimum frequency of endoscopic controls is indeterminate.
Low degree of malignancy: risk of permanent relapse (follicular NHL) Hence regular long-term monitoring and clinical sign-oriented complementary examinations.
For lymphomas in the marginal area of MALT after eradication of H. pylori, clinical and endoscopic surveillance was proposed, annually for at least 10 years. However, monitoring from 5 years can be spaced in the knowledge that nothing is codified (Ruskoné-Fourmestraux, 2011). The monitoring of the stomach left in place is all the more important because there is dysplasia or metaplasia on the biopsies, in fact cases of gastric adenocarcinomas were reported during the monitoring of lymphomas cured (Fischbach, 2007; Zullo, 2010; Copy-Bergman, 2005). The Dutch epidemiological study of Capelle et al has increased by 6 the risk of gastric adenocarcinoma in relation to a general population in patients with a history of gastric lymphoma regardless of treatment ( Capelle, 2008).
10.6 Treatment of recurrences
For lymphomas of the marginal area of the MALT of the stomach, recurrences are exceptional it would be more forms that have been incompletely regressed, they must suggest a bad eradication of H. pylori. Otherwise propose a different alternative treatment of the first.
In other histological locations and subtypes, they are poor prognosis. These patients should be taken care of in haematological settings. Catch-up chemotherapy are based on protocols associating platinum, etoposide, aracytine at high doses or ifosfamide and etoposide. In the young answering subjects, it is permissible to consider an intensification with reinjection of autologous hematopoietic stem cells ("autograft") in the hematologic environment.
10.7 Annex 1-histo-pathological classifications
A-different types of gastrointestinal lymphomas according to the WHO classification (Swerdlow, 2016) B lymphomas
Extra-Ganglionic of the marginal area of lymphoid tissue associated with mucous membranes: MALT = Mucosa associated lymphoid tissue whose disease of the heavy chains (Alpha...)
Diffuse to large cells
of the mantle
De Burkitt
Follicular
T lymphomas
Whether or not associated with intestinal type enteropathy (with or without villous atrophy) of low and especially high degree of malignancy
B-histological Score of GELA for the post-therapeutic evaluation of gastric lymphomas of MALT. According to copy-Bergman et al. 2003 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: Lamia Propray. MM: Muscularis mucosa. SM: Submucosa. LEL: lymphoepithelial Lesions
10.8 Appendix 2-Clinical stages of non-Hodgkin lymphomas
Musshoff modified Ann Arbor Classification for the Gastrointestinal tract (Musshoff 1977).
Stage IE attainment of one or more sites of the gastrointestinal tract without ganglionic damage
Stage II attainment of one or more sites of the gastrointestinal tract and the regional ganglia without extra-abdominal damage.
Modification of Musshoff:
Stage III = Attainment of only contiguous lymph nodes
II2E stage = attainment of noncontiguous regional lymph nodes.
Third Stage
Localized impairment of the digestive tract associated with a ganglionic attack on either side of the diaphragm. *
Stage IV
Reaching one or more extra-ganglion and/or extra-abdominal organs +/-particularly superficial ganglionic damage associated.
* Stage III generally not met in digestive lymphomas
PARIS staging system for gastrointestinal lymphomas: New classification adapted to the digestive tract including stomach and elaborated by the European Group EGILS (European gastro-Intestinal Lymphoma Study Group) (Ruskoné-Fourmestraux, 2003).
TX extension not specified
To no lymphoma
T1m Mucosal Damage
T1SM/mucosal damage
T2 suffering from mucosal muscle and S/serous
T3 reaching the serous
T4 extension serous and beyond to the neighbourhood organs
NX unknown lymph node invasion
No node invasion
N1 Regional lymph node invasion
N2 remote abdominal lymph node invasion
N3 extra abdominal lymph node invasion
MX unknowns extension Balance
MO no other metastatic localization
M1 invasion of tissues not contiguous to the digestive lesion (peritoneum, pleura) or organs (e.g. Cavum, parotid, ocular annexes, lung, liver, breast, other gastrointestinal site)
BX unexplored Marrow
B0 No medullary injury
B1 medullary infiltration
10.9 Annex 3-Technical radiotherapy (Ch. Harkins)
Irradiation Technique
Supine Patient
High energy photons (? 10 MV)
A three-or four-beam configuration, minimum is required. The setting up of these beams will be aided by the conformational technique
All beams should be used at each session
The treatment will be done in a patient with an empty stomach, so away from the meals.
Target Volumes
whole stomach, i.e. from Cardia to the enclosed lair (gastric lymphoma, especially those from the marginal area of MALT being a multi-focal disease)
Peri-gastric ganglion areas.
Conformational Technique
Sick in treatment position
Reference Axes defined
Scan: Make cuts every 1 cm, and if possible every 0.5 mm from the lower third of the esophagus up to 3 to 5 cm below the lower part of the Den
The clouding of the stomach will be done by making the patient swallow a very small amount of contrast liquid (20 to 30cc). A larger quantity leads to an increase of the gastric volume and thus to an overestimation of the volume-target GTV (macroscopic tumor volume): Stomach from the cardia and including the whole den
CTV (Clinical tumor Volume: Target volume Anatomoclinique): Inclusion of peri-gastric ganglia, these are the ganglia of the small curvature (relay 1.3 and 5) and those of the great curvature (relay 2.4 and 6) of the Japanese classification (JPN J Surg, 1981; 11 : 127-139 and Marescaux J, Emanuel S. EMC Surgical Techniques-digestive tract, 1997, 40:32)
PTV (Projected tumor volume): A margin of 1 cm will be achieved around the GTV
Critical organs to bypass: kidneys, liver. Dose-volume histograms for each of these organs will be carried out. Usually, the simplest technique that best protects these organs consists of three beams (one anterior and two lateral). More complex techniques can sometimes be useful, especially to decrease the volume of irradiated hepatic parenchyma.
Doses
Extra-ganglion lymphomas from the marginal area of MALT: 30 Gy
Splitting 1.8 to 2 Gy/session; 5 sessions per week
Prescription of anti-HT3 and proton pump inhibitors.
10.10 Appendix 4-Chemotherapy + rituximab
⇒ Chemotherapy and immunotherapy for non-Hodgkin lymphomas with small cell malignancies:
Protocols including Rituximab-chlorambucil
Induction phase: Rituximab (Mabthera ®) weekly 375mg/m² x 4 injections (S1 to S4) associated with chlorambucil 6mg/m2/day for 6 weeks
Therapeutic Evaluation during Week 7 to week 8.
Consolidation: 4 monthly cures each with an infusion of rituximab to J1 with the taking of chlorambucil 6mg/m2/day for 2 weeks every month
NFS Monitoring for dose adjustment. Abundant beverages.
⇒ Chemotherapy + immunotherapy for diffuse lymphomas with large B-cells known as high malignancies: 6 to 8 repeated cycles at three-week intervals
R-CHOP
CYCLOPHOSPHAMIDE 750mg/m2 IV J1
doxorubicin 50mg/m2 IV J1 (after checking for good myocardial function)
VINCRISTINE 1, 4mg/m2 IV J1 without exceeding the dose of 2mg
Prednisone 60mg/m2 po J1 to J5
+ RITUXIMAB (Mabthera ®) 375mg/m2. : Infusion Rates (according to tables) adapted to the cure number and to the body surface. Administered in J1 with CHOP or JO
R-Mini CHOP (elderly):
CYCLOPHOSPHAMIDE 600 mg/m2 IV J1
doxorubicin 25mg/m2 IV J1 (after checking for good myocardial function)
VINCRISTINE 1, 4mg/m2 IV J1 without exceeding the dose of 2mg
Prednisone 60mg/m2 po J1 to J5
+ RITUXIMAB (Mabthera ®) 375mg/m²: Infusion Rates (according to tables) adapted to the cure number and to the body surface. Administered in J1 with CHOP or JO
Dose Adjustment:
Treatment resumed at full doses if PN > 1.5 x 109/L and Pads > 100 x 109/L, otherwise report.
In primary or secondary prophylaxis if severe neutropenia (< 0.5 x 109/L) let alone so complicated a febrile episode, use of hematopoietic growth factors (G-CSF) and/or dose reduction according to context: Age, nutritional status, Curative or palliative intent.
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