Key points

Introduction

Malignant lymphomas are divided into Hodgkin disease and the heterogeneous group of non-Hodgkin lymphomas (NHLs) ( Fig. 1 ). Sixty percent of the latter arise in lymph nodes (nodal lymphoma), while 40% are of an extranodal origin. The gastrointestinal tract is by far the most frequent site of manifestation for extranodal NHL (primary gastrointestinal lymphoma). A secondary involvement of the gastrointestinal tract (secondary gastrointestinal lymphoma) by disseminated nodal NHL can be found in up to 20% of cases when investigated systematically.

Classification of malignant lymphoma.

Introduction

Malignant lymphomas are divided into Hodgkin disease and the heterogeneous group of non-Hodgkin lymphomas (NHLs) ( Fig. 1 ). Sixty percent of the latter arise in lymph nodes (nodal lymphoma), while 40% are of an extranodal origin. The gastrointestinal tract is by far the most frequent site of manifestation for extranodal NHL (primary gastrointestinal lymphoma). A secondary involvement of the gastrointestinal tract (secondary gastrointestinal lymphoma) by disseminated nodal NHL can be found in up to 20% of cases when investigated systematically.

Classification of malignant lymphoma.

Classification of gastrointestinal lymphoma

Box 1 represents the World Health Organization (WHO) classification as established in 2002 and updated in 2008. More than 70% of primary gastrointestinal lymphomas present as gastric lymphoma. In terms of numbers, marginal zone B-cell lymphomas of mucosa-associated-lymphoid tissue (MALT) are predominant. The second most common types of gastric lymphoma are the diffuse large B-cell lymphomas with or without MALT components. T-cell lymphomas are extremely rare in the stomach but comprise a considerable part of intestinal lymphoma (EATCL: enteropathy-associated T-cell lymphoma). The various lymphoma entities are characterized by differences in pathogenesis, biologic behavior, and treatment options. This article exclusively focuses on extranodal gastric marginal zone B-cell lymphoma of MALT, subsequently named MALT lymphoma.

Pathogenesis of gastric MALT lymphoma

Intensive basic research and clinical research during the last 2 decades has substantially enriched the understanding of the development and progression of gastric MALT lymphoma. MALT is acquired in a secondary process against a background of chronic antigen stimulation. As early as in the late 1980s, attention had been drawn to Helicobacter pylori , which was then still referred to as Campylobacter pylori . The bacterium causes chronic gastritis and leads to the formation of intramucosal lymph follicles showing the morphologic characteristics of MALT. These changes proved to be reversible after bacterial eradication treatment. There are convincing data from histomorphological, molecular biologic, epidemiological, and experimental studies that H pylori is the decisive pathogenetic factor for the development of gastric MALT lymphoma. Up to 98% of patients with gastric MALT lymphoma are H pylori positive when tested by serology. However, only a small minority of all H pylori -infected individuals develops gastric MALT lymphoma. Virulence factors of the bacterium do not obviously determine this risk. There is, however, growing evidence that genetic host factors may play an important role in this context.

If any further evidence were needed for the pathogenic significance of H pylori for the development of gastric MALT lymphoma, it has been provided by experience with eradication treatment. In the first series of 6 patients with stage I gastric MALT lymphoma, successful eradication of H pylori led to a complete and lasting regression of the lymphoma. The authors concluded that H pylori eradication should be the first choice of treatment. This was a quite audacious statement at that time considering the small number of patients treated in this way. However, it turned out to be right.

Clinical features of gastric MALT lymphoma

The clinical features of gastric MALT lymphoma are nonspecific, including abdominal symptoms, pain, vomiting, diarrhea, weight loss, and overt or occult gastrointestinal bleeding. However, gastric MALT lymphomas are also often found incidentally at endoscopy. Complications such as obstruction, perforation, or bleeding are rarely observed.

Prognostic factors in gastric MALT lymphoma

In the early 1990s, Cogliatti and colleagues and Radaszkiewicz and colleagues for the first time analyzed 2 large retrospective series of MALT lymphomas. Their main findings were that the grade of malignancy (MALT lymphoma vs diffuse large B-cell-lymphoma [DLBCL] with or without MALT components) and stage of the disease are the 2 major prognostic factors and therapeutic determinants. This conclusion has since been confirmed by several prospective studies. Accurate staging requires a thorough endoscopic biopsy protocol (gastric mapping) and other staging procedures as outlined in this article and demonstrated in Fig. 2 and Box 2 .

Gastric mapping.

Translocation t(11;18) is the most common genetic aberration in gastric MALT lymphoma. It is found in 25% of cases, more frequently in cases at stage II or above than in stage I. T(11;18) has also been proven to be of prognostic value as it strongly predicts the response of gastric MALT lymphoma to H pylori eradication. Nevertheless, routine testing for t(11;18) within the staging process is not mandatory, as H pylori eradication is recommended as the initial treatment irrespective of the bacterial status.

Diagnosis and staging

In view of the nonspecific appearance of gastric MALT lymphoma and potential sources of error in endoscopic and biopsy diagnosis, it is necessary to obtain a sufficient number of biopsies from macroscopic lesions and normal-appearing mucosa. This procedure, named gastric mapping (see Fig. 2 ), is strongly recommended in the German S3 guideline as well as in the European EGILs Consensus Report of 2011. In general, such a biopsy protocol is not performed during a routine diagnostic endoscopy. Therefore, a second esophagogastroduodenoscopy will be necessary in most cases.

Lymphoepithelial lesions represent the histomorphological characteristic of gastric MALT lymphoma. Additional criteria include a diffuse infiltrate of small to medium-sized B-lymphocytes that are similar to centrocytes (‘centrocytoid’). Immunophenotypically, these cells express pan-B-cell markers (CD20), while they show no immunoreactivity for CD5, CD10, and CD11c. Staining for Ki67 may help in identifying large cell components. There is a widely accepted consensus that the diagnosis of gastric MALT lymphoma is based on histomorphological criteria according to the WHO classification.

Once the diagnosis of gastric MALT lymphoma is established and confirmed by a reference pathologist, a staging procedure follows. Box 2 summarizes the various examinations that must be done. Endoscopic ultrasound and bone marrow puncture are strongly recommended, while ileocolonoscopy should be considered. For staging, the Ann Arbor classification is still used, with Musshoff’s modification and taking the Radaszkiewicz differentiation of stage I into I1 and I2 into account ( Table 1 ). The Paris staging system is an alternative based on the well-known TNM classification system. However, this system has not yet been validated by prospective studies.

Table 1

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