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Primary gastric lymphoma

Written2020-06Ana Maria Corazon Monzon, Luis Miguel Juárez Salcedo, Diego Conde Royo, Samir Dalia
Centro de Salud Adelfas, Madrid, Spain, (AMCM), Gregorio Maran University Hospital, Madrid, Spain (LMJS), Principe de Asturias University Hospital, Madrid, Spain (DCR), Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA (SD).

Abstract Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma and represents a wide spectrum of disease, ranging from indolent low-grade marginal zone lymphoma or mucosa associated lymphoid tissue lymphoma (MALT) to aggressive diffuse large B-cell lymphoma. PGL is a relatively rare cancer and easily misdiagnosed due to its unspecific symptoms of the digestive tract. The incidence of this disease is increasing making it necessary for clinicians to understand the clinical symptoms, workup and treatment of these lymphomas.

Keywords Primary gastric lymphoma, Helicobacter pylori, mucosa associated lymphoid tissue lymphoma (MALT), diffuse large B-cell lymphoma.

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ICD-Topo C420,C421,C424
Atlas_Id 1519

Clinics and Pathology

Disease The most common extranodal site of affection in NHL is the stomach. Primary gastric lymphoma (PGL) is a rare tumor, with an incidence of the 4% to 20% of all non-Hodgkin lymphomas (NHL), and approximately 5% of primary gastric neoplasm (Al-Akwaa et al., 2004). The small intestine and ileocecal regions follow in frequency (Herrmann et al., 1980). Histopathologically, almost 90% of the PGL are of B-cell lineage with very few T-cell lymphomas and Hodgkin lymphoma. The marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type (MALT lymphoma) in 40% of the cases, and diffuse large B-cell lymphoma (DLBCL) in 60%, are the most usual B cell types (Juarez-Salcedo LM).
Etiology There is an important association between infection episodes by Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), Epstein-Bar virus (EBV), hepatitis B virus (HBV) and human T-cell lymphotropic virus-1 (HTLV-1) (Engels 2007). Campylobacter jejuni (C. jejuni) had been also described as an important organism implicated in the pathogenesis of MALT-lymphoma, specifically of immunoproliferative small intestinal disease (IPSID) (Lecuit et al., 2004). Other potential pathological conditions as celiac disease, inflammatory bowel disease, and immunosuppression are also related.i
Epidemiology PGL occur mainly in patients older than 50 years of age, but patients in the second decade of life could be also affected (Kyriacou et al., 199; Kitamura et al., 1996). Males are two to three times more likely to develop PGL than females (Shimm et al., 1983; Cogliatti et al., 1991).
Clinics The initial symptomatology is unspecific, remembering gastritis, peptic ulcer disease, pancreatic disorder, or functional disorder of the stomach, rather than that of lymphoma. The physical examination could be normal in more than 50% of cases, delaying the diagnosis (Ferrucci et al., 2007). The most common symptoms reported include weight loss, nausea, vomiting, abdominal fullness, and indigestion. Weakness, night sweats, jaundice, fever, and dysphagia occur less frequently. Other uncommon symptoms are gastric obstruction and perforation, fever, hepatomegaly, splenomegaly, and lymphadenopathy (Medina-Franco et al., 2007). In some cases, physical exam findings include epigastric tenderness, adenopathy, and palpable epigastric masses (Parsonnet et al., 1994).
The examination of biopsy samples taken during an esophagogastroduodenoscopy (EGD) is the gold-standard diagnosis method. EGD by itself cannot identify or discriminate gastric lymphoma from the more common gastric carcinomas. However, there are three main injury patterns that can be recognized during an endoscopic examination: ulceration, diffuse infiltration, and a polypoid mass (Taal et al., 1991). Although these findings are not specific for PGL, EGD is an indispensable tool for the initial diagnosis and follow-up of cases as well as for obtaining multiple stomach biopsies specimens (specially antrum and corpus), duodenum and at the gastro-esophageal junction. The presence of active H. pylori in tissue samples obtained by EGD must also be tested in all cases through immunohistochemistry.
Chest and abdomen Computed tomography (CT) scan, exclude systemic, lymph-nodal extension and-or infiltration of the adjacent structures. Gastric wall thickening or mass lesion can be identifying in the 85% of cases by this method, while lymphadenopathy is reported in only 50% of them (Brown et al., 2000). Endoscopic ultrasonography (EUS) is an accurate technique in the evaluation of the extent and invasion of the lesion. The depth of lymphomatous infiltration and the presence of perigastric lymph nodes became in important additional information for future therapeutic planning strategies (Zelenetz et al., 2014).
Due to the variable physiologic FDG activity in the stomach and its different degree of uptake in various histologic subtypes, 18F-FDG PET/TC is not considering an adequate diagnostic technique for PGL.
Treatment Treatment of early-stage, H. pylori-positive, MALT type gastric Lymphoma:
Until now, the most widely accepted initial treatment option for localized disease is the eradication of H. pylori using the triple therapy based on the combination of proton-pomp inhibitors (PPI), clarithromycin with either amoxicillin or metronidazole for 10 to 14 days (Fuccio et al., 2008). Levofloxacin has also been used in patients whose initial triple therapy had failed; in that case, triple therapy would include levofloxacin, amoxicillin, and a PPI for 14 days (Fallone et al., 2016).
Several studies have confirmed the effectiveness of antibiotic therapy with long-term remissions in 70-100% of patients with localized, HP-positive, MALT lymphomas. However, failure in H. pylori eradication is not uncommon (20-30%); although some tumors exhibit a slow response to therapy. The time necessary to reach a complete remission varied from 3 months to more than a year (Stathis et al., 2009). MALT tumors have an indolent nature, which allows physicians to continue watchful waiting before determining next treatment.
To assess MALT lymphoma remission, a first endoscopy is performed 3-6 months after completion of antibacterial treatment, thus allowing for checking of the H pylori status histologically at the same time.
Treatment of patients with H. pylori-negative MALT-type gastric lymphoma:
Almost 10% of MALT lymphomas are unrelated to H. pylori infection, and the pathogenesis remains unclear (Asano et al., 2015). One hypothesis is the relationship between genetic alterations (t(11;18)) and the NF-kB activation. The second one is related to an infectious cause different than H. pylori, for example, infections associated with C. jejuni.
Although no clear therapeutic guidelines have been established for those patients without the presence of H. pylori at diagnosis, several studies have reported that a percentage patient responded to antibiotic therapy. Predictive factors for non-responsiveness included: multiple lesions, lesions in both proximal and distal parts of the stomach, and the presence of t(11;18).
The use of chemotherapy and immunotherapy has been reported in gastric MALT lymphoma of all stages; however, there is no evidence to indicate the most effective regimen. Patients with localized disease, who neither responded to antibiotic therapy or radiation therapy, should be considered for systemic chemotherapy. The efficacy of various chemotherapy agents has also been reported either as monotherapy or in combinations with anti-CD20 monoclonal antibodies.
Treatment of high-grade gastric lymphomas:
Diffuse large B-cell lymphoma represents the most common histological type of gastric lymphoma, sometimes called high-grade gastric lymphoma. Before current multimodality therapy was established, high-grade lymphoma was recognized as a negative prognostic factor for survival, associated with lower complete remission rate and a shorter survival rate (Taal et al., 1996).
Nowadays, the treatment of PGL has shifted away from surgery, toward chemotherapy regimens. In a time, surgery is now limited to cases of perforation, hemorrhage, or obstruction due to the tumor, it is no longer the cornerstone of treatment with its mortality rate reaching up to 8% (Roukos et al., 1994).
Treatment of a DLBCL-PGL consists on anthracycline based chemo immunotherapy. Clinical studies performed on nodal DLBCL offers scientific support for these regimens. These studies have shown a significant improvement in overall survival rates (Aviles et al., 2004). The most commonly used chemotherapeutic regimen for DLBCL of the stomach is a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone and rituximab (R)-CHOP.
Front-line chemo-immunotherapy with three to four cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed by "involved-field" radiotherapy could be considered as a gold standard option for localized stages (stages I and II in the Lugano Classification)(Bacon et al., 2007). Advanced-stage patients (Ann Arbor stage III/IV) usually undergo 6-8 cycles of R-CHOP in order to obtain a complete remission rate similar to their nodal counterparts (Pfreundschuh et al., 2017). Recent studies have reported the benefits of consolidation radiation therapy after chemotherapy in nodal DLBCL, however, its role on PGL is controversial.
There may be a role of interim PET scan in regards of decision to pursue radiation therapy (Pfreundschuh et al., 2017). PET CT should be done at the end of therapy and if the patient has progressive disease the consideration for second-line treatment (salvage chemotherapy) for DLBCL with a regimen such as R-ICE or GDP-R followed by autologous stem cell transplantation should be considered (Van Den Neste et al., 2017).
Prognosis The overall prognosis of PGL is dependent on tumor characteristics and host-related factors, such as histological subtype, age and performance status (PS).
Several risk factors have been studied that may contribute to survival. In previous studies female gender, low-grade histology, good PS, and surgical resection have been reported to be associated with good overall survival.
The international prognosis index (IPI) developed for DLBCL (Age>60 years, advanced stage, poor PS, and elevated LDH) is a commonly used and is predictive of survival in PGL. While the prognosis of gastric lymphoma has been based largely on clinical factors, these factors could not explain why patients at the same stage of the disease and with similar clinical characteristics, have different prognoses.


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This paper should be referenced as such :
Corazon Monzon AM, Juárez Salcedo LM, Conde Royo D, Dalia S
Primary gastric lymphoma;
Atlas Genet Cytogenet Oncol Haematol. in press
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