Current support for marginal area lymphoma
Summary
The lymphomas of the marginal Zone (LZM) have three histological subentitys: the "MALT" type LZM (Mucosae Associated Lymphoïd tissue), the ganglionic LZM, and the LZM splenic. Immunophenotyping is essential for diagnosis. Helicobacter pylori is frequently responsible for gastric localization. Its eradication may be enough to cure the sick. The treatment of ganglion forms is similar to that of follicular lymphoma. The eradication of hepatitis C virus, involved in the development of some splenic LZM, may suffice. In the absence of viral infection, splenectomy is the first therapeutic choice. Like other lymphopathies indolent, disseminated forms remain incurable and are treated only in the presence of clinical and/or biological effects of the disease.
Introduction
Classified in non-Hodgkin (NHL) lymphomas of indolent B phenotype, the lymphomas of the marginal Zone (LZM) account for 11% of the total NHL. They discreetly touch more men than women. The median age for diagnosis is 60 years. They include three histologic Subentitys: the LZM developing within the Extraganglionnaire lymphoid tissue present in the mucous membranes ("MALT, Mucosae Associated Lymphoïd tissue" LZM), the Ganglionic LZM, invasive exclusively Lymph nodes and bone marrow and, finally, the LZM splenic, invading the spleen. 1
The immunophenotyping can be used to distinguish this monoclonal lymphoproliferation, consisting of small cells, chronic lymphoid leukemia (LLC), follicular lymphoma (LF), Lympho-myelomatous (LPL), or mantle cells (LCM) ( Table 1). 1 The results of this examination must sometimes be integrated with those of cytology and genetics in order to be able to assert the diagnosis.
Differential diagnosis of small cell lymphoproliférations
The role of infectious agents in the pathogenesis of certain forms of the disease is currently demonstrated and the eradication of the offending infection may be sufficient to obtain a prolonged complete remission or even a cure. 2 Apart from these cases, patients Carriers of a localized disease can be cured, depending on location, by surgery or radiotherapy. 3 Like other lymphopathies indolent, disseminated forms remain incurable. Treatment should therefore only be undertaken in the presence of clinical and/or biological effects of the disease.
Lymphoma of the marginal area of the MALT TYPE
Pathology
These lymphomas can take birth within any organ containing lymphoid tissue. Digestive locations are the most frequent and, among them, 85% are in the stomach. 1 in these locations, the pathogenic role of Helicobacter pylori is well demonstrated. In Ileal, cutaneous and ocular locations, relationships, more or less narrow according to geographical area, are reported, with infection with Campylobacter Jejuni, Borrelia burgdorferi and Chlamydia Psitacci, respectively. 4.5 these Lymphomas also occur more frequently in patients with autoimmune disease. Histologically, tumor infiltration is follicular and consists of small lymphocytes that are difficult to differentiate from those found in other B-cell lymphoproliférations. The realization of a immunophenotyping is therefore indispensable (table 1). Careful examination of the hyperfollicular areas may reveal the presence of larger cells signing an aggressive transformation, a rare occurrence whose frequency varies according to the organ originally reached. 1
Symptomatology
The symptomatology depends on the invaded organ. Gastric impairment is accompanied by a low-specific table of abdominal pain or dyspepsia that motivates the completion of endoscopy and diagnostic biopsy. Intestinal locations are frequently diagnosed as a result of an endoscopic checkup conducted in a context of weight loss with diarrhea or subobstruction. When lymphoma originates in other locations, less clinically speaking, the diagnosis may be later, following the exploration of fatigue, weight loss, night sweating or unexplained fever.
Initial balance Sheet
In the history, it is advisable to look for a history of gastric ulcer in relation to Helicobacter pylori infection, Lyme disease, inflammatory bowel disease or autoimmune disease.
Clinically, a careful dermal examination is carried out in search of infectious signs related to an infection with Borrelia burgdorferi. Biologically, complete blood, ionogram, renal and hepatic functions, levels of β2-microglobulin and lactate dehydrogenase (LDH), sedimentation velocity (VS) are systematic. Depending on the location and the suspected pathogen, other biological tests are performed (table 2). 6
Initial assessment of non-Hodgkin (NHL) lymphomas of type Mucosae Associated Lymphoïd tissue (MALT)
are also carried out, a thoraco-abdominal scanner, a unilateral bone biopsy and a high digestive endoscopy with biopsies in search of Helicobacter pylori. 3, 6, 7 in patients treated with proton pump inhibitors (PPIs), biopsies can be falsely negative. In this case, the positivity of Serology provides an argument for prior contact with the bacterium. FDG-Pet/CT-scan is not recommended in the presence of this histology, but sometimes reveals unsuspected hypermetabolic lesions. 8 Other complementary examinations performed depend on location (table 2).
Staging
In the presence of a gastrointestinal LZM, the Lugano classification is used. 3 more appropriate than the Ann Arbor staging, it takes into account the degree of mucosal infiltration on which the response to antibiotic treatment depends. It clarifies the importance of the Loco-Regional extension (table 3).
Stadifications of Lugano and Paris
Prognostic factors
Few prognostic factors have been defined in this pathology. Skin LZM have the best prognosis. that of mammary, gastric and intestinal LZM is more unfavourable. 9 The search for translocation (11-18) (Q21; q21) is recommended. 10 it indicates a risk of resistance to antibiotic therapy and treatment by alkylating agents. Other translocations are described as T (14-18) (Q32; q21), T (1-14) (P22; q32), and T (3; 14) (P14; q32). 1 Recently, the International Group for the study of Extraganglionnaires Lymphomas reported the predictive survival value without progression and overall A prognostic index incorporating age (greater than or less than 70 years), LDH rate, and stage (localized or advanced) of the disease. 11
Treatment (Figure 1, table 3)
Figure 1.
Treatment of lymphoma of the marginal zone of type Mucosae Associated Lymphoïd tissue (MALT)
NHL: Non-Hodgkin's lymphoma; IPP: proton pump inhibitors; ATB: antibiotics; RC Histo: histological complete remission; Pos: positive; Neg: Negative; HP: Helicobacter pylori.
Treatment depends on the extent of the disease and, for the localized forms, the identification of a responsible pathogen.
Localized MALT type LZM
Gastric LZM, linked to Helicobater pylori infection, are treated by combination of a double or triple antibiotic therapy and an IPP (table 4). 12,13 The choice of the association of antibiotics used depends on the sensitivity of Helicobacter pylori, variable depending on the region concerned. A respiratory test with urea, carried out four to six weeks after the end of antibiotic therapy and at least two weeks after the PPI is stopped, helps to control the eradication of the bacterium. In the event of failure, a second-line antibiotic treatment may be attempted. Two to three months after completion of treatment, an endoscopic control with multiple biopsies evaluates the microscopic response. A catch-up treatment should only be introduced if there is a significant progression. 3
Ocular forms can be treated empirically by doxycycline (table 4). 14 in the case of symptomatic progression, the application of low-dose radiotherapy (< 25 Gy) or monochemotherapy based on a alkylating agent ( Cyclophosphamide, Chlorambucil) is recommended (see the GELF criteria in the box in Figure 1). 15
Cutaneous forms respond to local corticosteroid treatment and radiotherapy. 16
Intestinal forms, occurring in the context of inflammatory intestinal diseases, require multidisciplinary management in collaboration with gastro-gastroenterologists. 16
Antibiotic therapies directed against pathogens of the marginal Zone lymphoma (LZM) type Mucosae Associated Lymphoïd tissue (MALT)
Disseminated MALT type LZM
The treatment of advanced LZM is identical to that of follicular lymphomas. Only patients with therapeutic criteria defined by the GELF (Follicular Lymphoma Study Group, figure 1) should be treated, usually by immuno-(poly)-chemotherapy. 17 administration of rituximab, monoclonal antibody Directed against the CD20 antigen present on the surface of tumor B lymphocytes, associated with chlorambucil, Bendamustine, CVP ("R-CVP", rituximab, cyclophosphamide, vincristine and prednisone), provides excellent survival rates without progression. 18,19 No therapeutic association has been shown to be superior in terms of overall survival (median survival of twenty years). The use of Anthracyclines ("R-CHOP", rituximab, cyclophosphamide, Hydroxydaunorubicine, vincristine and prednisone) is reserved for rare patients with high tumour masses or signs of aggressive transformation.
The decision to treat disseminated skin forms depends on the size of the tumor mass and the rate of progression. Topical treatment is used to delay the use of systemic treatment at the cost of low side effects. 6
Followed
After treatment, and for three years, patients with gastric localization are monitored semi-annually by endoscopy. In other cases, the follow-up is clinical. The use of complementary explorations is limited to patients symptomatic or abnormal in their clinical examination. Compared to the general population, patients present an increased risk of developing gastric adenocarcinoma, justifying a long-term clinical follow-up. 7
Lymphoma of the marginal ganglionic ZONE
Pathology
Representing 1% of all NHL and 10% of LZM, the Ganglionic LZM is histologically identical to the MALT-type LZM. It is distinguished by the absence of extraganglionnaire flooding. Only a bone marrow attack, invaded in 70% of cases, is compatible with this diagnosis. The median age is 50 years. This lymphoma appears to develop on a ground of chronic inflammation, sometimes linked to an infection (hepatitis B or C, HIV and, to a lesser extent, EBV or CMV) or to an autoimmune disease (disseminated lupus erythematosus, syndrome of disease, polyarthritis Rheumatoid). However, there are too few arguments to be able to establish a causal link. Histologically, tumor cell size is variable and proliferation can be nodular or diffuse. Here too, immunophenotyping plays a key role in allowing differential diagnosis with other small cell lymphoproliférations (table 1). In cytogenetics, many anomalies are described, but none are pathognomonic. Evolution is generally indolent, but some patients may have a more aggressive deformation (transformation into diffuse B lymphoma to large cells). 1.20
Symptomatology
The symptomatology is not very specific. The patient can consult his family doctor following the appearance of a ganglionic mass. This can result in the compression of a blood vessel, with secondary edema, or a nerve ending, with a painful symptomatology. Bronchial compression may be responsible for coughing. At a more advanced stage, the patient may present an alteration of his general condition with the presence of general symptoms.
Initial balance Sheet
In this entity, no association with a pathogen has been demonstrated. A biology similar to that carried out in the case of MALT LZM is recommended (table 2). According to the latest recommendations regarding the use of FDG-PET/CT-Scan, published in July 2014, this examination must be part of the initial balance sheet. A unilateral bone biopsy and a thoraco-abdominal CT study are essential. 7.8
Prognostic factors
Among the prognostic factors cited in the literature, an age of over 60 years, an abnormal LDH rate, and a poor general condition darken the prognosis. The Flipi (Follicular Lymphoma International Prognostic Index, prognostic index of follicular lymphomas) can also be used. 21
Treatment (Figure 2, table 5)
Figure 2.
Treatment of ganglionic marginal zone lymphoma
NHL: Non-Hodgkin's lymphoma.
Table 5.
Chemotherapy regimens
IV: intravenous; PO: Per OS; MB: minibag; IVD: Intravenous direct; *: Maximum 2 mg total dose; DT: Total dose.
Localized ganglion LZM
As in the case of follicular lymphomas, the application of 24 Gy radiation therapy can cure patients with a localized form.
LZM ganglion disseminated
Asymptomatic patients with no tumor syndrome criteria, as defined by GELF, are routinely monitored without treatment.
Symptomatic patients without tumor syndrome criteria benefit from chlorambucil-based monochemotherapy, ideally coupled with rituximab. 15
Patients with one of these criteria should benefit from a rituximab-based immunochimiothérapie, such as "R-CVP" (Rituximab, cyclophosphamide, vincristine and prednisone), possibly associated with a anthracycline ("R-CHOP") if There are bad prognosis factors. Bendamustine, in combination with rituximab, is a very interesting drug in this indication. 18,19
Followed
As with MALT-type LZM, after treatment, patients are clinically and biologically monitored quarterly for two years and then semi-annually for three years and then yearly. Imaging tests are prescribed only to patients with symptoms or clinical signs suggestive of progression.
Lymphoma of the splenic marginal ZONE
Pathology
Representing 2% of the NHL ensemble, this lymphoma invades the spleen, the peri-splenic ganglia and frequently the marrow. Although tumour cells carry cytoplasmic extensions, the diagnosis requires immunophenotyping (table 1). 1 constant, splenomegaly may cause abdominal pain or dyspepsia. Biologically, anemia or immunological thrombocytopenia may occur.
Initial balance Sheet
As with MALT-type LZM, the initial assessment involves the completion of an exhaustive biology (table 2). The search for seroconversion for hepatitis C virus is recommended. A unilateral bone biopsy and a thoraco-abdominal scanner complete the balance sheet. FDG-PET/CT-scan is not part of the initial assessment of this lymphoma. 7.8
Prognostic factors
Many prognostic factors have been identified including the 7q31 deletion, the presence of a monoclonal compound, a high β2-microglobulin rate, a white blood cell count greater than 20,103/μl, or lymphocytes greater than 9,103/μl. The Thread (Italian Lymphoma Foundation) has developed a prognostic index to stratify patients into three different prognostic groups, taking into account the levels of LDH (normal or pathological), hemoglobin (less than or greater than 120 g/L) and Albumin (less than or greater than 35 g/L) and demonstrated an impact on non-progression and overall survival as patients do not present or carry one or more adverse factors. 22 – 25
Treatment (Figure 3, table 5)
Figure 3.
Treatment of marginal zone lymphoma (LZM) splenic
NHL: Non-Hodgkin's lymphoma; HCV: Hepatitis C virus; SMZL: Non-Hodgkin's lymphoma of the splenic marginal zone.
Only patients with LZM in relation to seroconversion for hepatitis C virus, those with a painful splenomegaly, or those with cytopenia (absolute neutrophil rate or platelets less than 103/μl and 80,103/μl, should be treated. 26 hemolytic anemia is not a therapeutic indication unless it does not respond to the usual treatments. The choice of treatment for hepatitis C should be done in collaboration with the gastroenterologist. 27 patients with aggressive forms (increase in LDH, presence of abdominal adenopathies, more than 20% of large cells within the Tumors) are treated as those carrying LZM ganglion. The other patients are oriented towards the splenectomy. In case of surgical contraindication, the patient has a monochemotherapy. The addition of rituximab improves therapeutic outcomes, but should be cautious in case of hepatitis B virus infection or C. 28,29
Conclusion
Once a diagnosis of certainty has been obtained, the treatment of these indolent lymphopathies depends on the identification of a causal infectious agent whose eradication can allow healing. In other cases, localized forms are supported by surgery or radiotherapy while the treatment of more extensive diseases currently requires the use of polychimiothérapies, not aplasiantes for the most part. The rituximab, coupled with chemotherapy, improves the results, but its use is not harmless during viral co-infections. On the other hand, the overall survival benefit is not shown. The new targeted therapies (BTK inhibitors, lenalidomide...) are also promising in this area.
Practical Implications
A large proportion of LZM (lymphomas in the marginal zone) of the gastric Mucosae associated Lymphoïd tissue (MALT) are linked to Helicobacter pylori infection
> The initial assessment of the MALT type LZM involves the production of a thoraco-abdominal scanner, a simple bone biopsy and a complete digestive endoscopy with multiple biopsies. PET-Scan is not part of the initial balance sheet of LZM other than ganglion
> LZM linked to Helicobacter pylori infection are treated, for the first purpose, by the combination of a proton pump inhibitor and a triple or quadruple antibiotic therapy
> The treatment of MALT-type LZM, not related to bacterial infection, is identical to that of other lymphomas indolent
> Splenic LZM can develop in a context of hepatitis C. Eradicating this virus may be enough to cure the patient
The diagnosis of Ganglionic LZM is only applied after excluding that of other lymphoproliférations indolent phenotype B
> The prognosis of LZM is very encouraging, but an aggressive transformation can occur
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