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Gastric Lymphoma

  • Hongbo Yu
  • Xiangshan Fan
Chapter

Abstract

Non-Hodgkin lymphoma in the gastric cardia is mostly lowgrade with a predominance of marginalzone B-cell lymphoma, also known as MALToma, which is primarily related to H. pylori infection. In contrast, highgrade lymphoma in this region is uncommon, occurs mainly in the elderly population, and shows high heterogeneity in cell types and prognosis. Therefore, accurate morphologic pathologic diagnosis and molecular characterization is essential for patient management.

Keywords

Stomach Non-Hodgkin lymphoma Marginalzone lymphoma Diffuse large B-cell lymphoma Cancer H. pylori 

Introduction

The gastrointestinal (GI) tract is the predominant site of extranodal lymphoma involvement. Primary lymphomas of the GI tract are rare, while secondary GI involvement is relatively common. Despite their rarity, primary lymphomas of the GI tract are important since their evaluation, diagnosis, management, and prognosis are distinct from that of lymphoma at other sites and other cancers of the GI tract. The GI tract is the predominant site of extranodal non-Hodgkin lymphomas.

Epidemiology

The stomach is the most common extranodal site of lymphoma and accounts for 68–75% of GI lymphomas [1, 2]. Primary gastric lymphoma accounts for 3% of gastric neoplasms and 10% of lymphomas [3]. Gastric lym phoma reaches its peak incidence between the ages of 50 and 60 years. There is a slight male predominance.

Clinical Features

Patients with gastric lymphoma typically present with nonspecific symptoms frequently seen with more common gastric con ditions, such as peptic ulcer disease, gastric adenocarcinoma, and non-ulcer dyspepsia. The most common presenting symptoms include epigastric pain or discomfort (78–93%), loss of appetite (47%), weight loss (25%), nausea and/or vomiting (18%), bleeding (19%), and early satiety [1, 4, 5, 6, 7].

Systemic B symptoms (fever, night sweats) are seen in 12% of patients. Weight loss is frequently due to local compromise of GI structures and is not always considered as a B symptom in this setting. Hematemesis and melena are uncommon. The duration of symptoms preceding the diagnosis is quite variable, ranging from a few days to 6 years.

The physical examination is often normal but may reveal a palpable mass and/or peripheral lymphadenopathy when the d isease is advanced. Laboratory studies also tend to be normal at presentation. Anemia or an elevated erythrocyte sedimentation rate may be present in selected cases [4, 8, 9].

Diagnostic Evaluation

The diagnosis of gastric lymphoma is usu ally established during upper endoscopy with biopsy. Laparotomy and laparoscopy are typically reserved for patients with complications such as perforation or obstruction. Findings on upper endoscopy are diverse and may include mucosal erythema, a mass or polypoid lesion with or without ulceration, benign-appearing gastric ulcer, nodularity, and thickened, cerebroid gastric mucosal folds [10]. Multiple biopsies should be obtained from the stomach, duodenum, gastroesophageal junction, and from abnormal appearing lesions. An endoscopic ultrasound may help determine the depth of invasion and the presence of enlarged perigastric nodes [11, 12, 13, 14, 15]. The pattern seen on endoscopic ultrasound (EUS) may correlate with the type of lymphoma that is present. In one series, f or example, superficial spreading or diffuse infiltrating lesions on EUS were seen with mucosa-associated lymphoid tissue lymphoma (MALT), while mass-forming lesions were typical of diffuse large B-cell lymphoma [14]. Pathologic evaluation is required for the determination of lymph node involvement. EUS alone has suboptimal accuracy in distinguishing benign from malignant lymph nodes [11, 12, 13, 14, 15]. When combined with endoscopic biopsy, however, overall accuracy approaches 90% (versus 66% for EUS alone). Even higher accuracy rates may be achi evable if flow cytometry is performed [16]. Thus, caution is warranted in the interpretation of findings using EUS or CT alone.

Pathology

The diagnosis of gastric lymphoma may be suggested by endoscopic and imaging findings but must be confirmed by biopsy. Both suspicious appearing lesions and normal appearing mucosa should be biopsied since gastric lymphoma can occasionally present as multifocal disease with involvement of tissue that appears to be unaffected on initial visualization [17].

Endoscopists should aim to attain the largest biopsy specimen possible. Conventional pinch biopsies may miss the diagnosis, since gastric lymphoma can infiltrate the submucosa without affecting the mucosa; this problem is most likely to occur when no obvious mass is present. Jumbo biopsies, snare biopsies, biopsies within biopsies (“well technique”), and needle aspiration can all serve to increase the diagnostic yield in such cases. EUS-guided fine-needle aspiration biopsy (FNAB) [18, 19, 20] or endoscopic submucosal dissection [21] may provide even greater diagnostic capability.

The vast majority (greater than 90%) of gastric lymphomas are approximately equally divided into two histologic subtypes:
  1. 1.

    Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) (previously called MALToma , MALT-type lymphoma, or MALT lymphoma) (38–48%)

     
  2. 2.

    Large B-cell lymphoma, primarly diffuse large B-cell lymphoma (45–59%)

     

The remaining cases of gastric lymphoma may represent any histology, but the most commonly seen are mantle cell lymphoma (1%), foll icular lymphoma (0.5–2%), and peripheral T-cell lymphoma (1.5–4%) [17, 22].

Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT)

Morphology

The lymphoma cells exhibit dense l ymphocytic infiltrate in the lamina propria (Fig. 8.1). The lymphoma cells of marginalzone lymphoma are small to intermediate in cell size, with round to slightly irregular nuclei, condensed chromatin, indistinct nucleoli, and abundant, pale cytoplasm. The accumulation of more pale-staining cytoplasm frequently leads to a monocytoid appearance (Fig. 8.2). Plasmacytic differentiation is present in 1/3 of cases (Fig. 8.3). Extremely rarely, Russell body gastritis may resemble a neoplastic process due to the marked expansion of the lamina propria with distension of fundic glands. However, immunohistochemistry may confirm a polyclonal pattern of plasma cells as an unusual reactive lesion of the gastric mucosa [23]. Occasional large cells resembling centroblasts or immunoblasts are usually present. Lymphoepithelial lesions (Fig. 8.2) are aggregates of three or more marginalzon e lymphoid cells with distortion or destruction of the gastric epithelium, often together with eosinophilic degeneration of epithelial cells. This is a common feature in MALT lymphoma. The lymphoma cells sometimes s pecifically colonize the germinal centers of reactive lymphoid follicles, leading to follicular colonization.
Fig. 8.1

Dense lymphocytic infiltrate in lamina propria

Fig. 8.2

Monocytoid appearance of neoplastic lymphocytes and lymphoepithelial lesions (arrows)

Fig. 8.3

Plasmacytic differentiation is a common feature

Immunophenotype

The lymphoma cells are u sually positive for CD20 and CD79a, but negative for cytokeratin, CD5, CD10, and CD23 (Fig. 8.4). CD43 stain can be positive in 50% of the cases. Staining for CD21 and CD35 shows expanded follicular dendritic meshwork. Demonstration of lightchain restriction is important in establishing the diagnosis. Molecular diagnostic studies for IgH gene rearrangements are usually necessa ry to confirm the diagnosis.
Fig. 8.4

Immunophenotypic features of gastric marginalzone lymphoma. In (a), pancytokeratin (AE1/AE3) highlights lymphoepithelial lesions in residual benign gastric crypts. Neoplastic lymphocytes are immunoreactive to CD20 in (b). CD3 stain in (c) exhibits mixed normal T cells. In (d), neoplastic B cells show aberrant expression of CD43. Increased number of plasma cells is demonstrated with CD138 in (e). By immunohistochemistry, H. pylori bacteria (arrow) are highlighted at the surface of gastric mucosa in (f)

Cytogenetic Abnormalities

Chromosomal translo cations include t (11;18)(q21;q21), t (1;14)(p22;q32), t (14;18)(q32;q21), and t (3;14)(p14.1;q32). Trisomy 3, 18, or less commonly of other chromosomes is a nonspecific but also not infrequent fin ding. The t (11;18) is the most common abnormality detected in gastric tumo rs, while others are more common at other locations.

Prognosis

MALT lymphomas have an indolent natural course and are slow to disseminate. The tumors are sensitive to radiation therapy; local treatment may be followed by prolonged disease-free intervals. Protracted remissions may be induced in H. pylori-associated gastric MALT lymphomas by antibiotic therapy. Cases with t (11;18)(q21;q21) appear to be resistant to H. pylori era dication therapy.

Large B-Cell Lymphoma

Gastric large B-cell lymphoma consists of a heterogeneous category of lymphomas and include diffuse large B-cell lymphoma (DLBCL), Epstein-Barr virus (EBV)-positive DLBCL, and plasmablastic lymphoma. Gastric DLBCL may arise de novo or as part of large-cell transformation of MALT lymphoma and other lowgrade B-cell lymphomas. The extent of the highgrade component varies in different cases. Rarely, DLBCL arising from other sites may involve the stomach, such as primary mediastinal large B-cell lymphoma [22]. Large cell transformation (Richter syndrome) of chronic lymphocytic leukemia/small lymphocytic lymphoma may manifest as gastric DLBCL [24]. Gastri c DLBCL may involve any part of the stomach, including gastric cardia (Fig. 8.5).
Fig. 8.5

Diffuse large B-cell lymphoma occurred in the gastric cardia of a 92-year-old man as an ulcerated mass (a). The biopsy of this mass demonstrated infiltrate of large neoplastic lymphocytes (b) with round/oval to irregular nuclei and moderate amount of cytoplasm (c), invading into the muscularis mucosae (d)

Morphology

Gastric DLBCL usually presents as a single large ulcerated or exophytic lesion with transmural inva sion and occasionally as multiple lesions. Histologically, gastric DLBCLs are indistinguishable from those found in nodal diseases. Typically, the architecture of gastric glands is almost completely effaced by tumor cells. Large neoplastic lymphoma cells infiltrate in diffuse sheets and have round, oval, irregular, or lobulated nuclei, distinct nucleoli, and moderate amount of cytoplasm, resembling centroblasts or immunoblasts (Fig. 8.6a). A few small reactive lymphocytes can be seen scattered among large tumor cells. In the cases of Epstein-Barr virus (EBV)-positive gastric DLBCL (Fig. 8.6b, c), the lesions often show large neoplastic lymphocytes, Hodgkin/Reed-Sternberg-like cells, with variable amounts of reactive small lymphocytes, plasma cells, and histiocytes. Plasmablastic lymphoma is rare, often in human immuno deficiency virus-infected patients, and composed of diffuse proliferation of large discohesive neoplastic cells (Fig. 8.6d), which resemble immunoblasts or plasmablasts. Cases with more plasmacytic differentiation are also seen. Very rarely, tumor cells may show large central artefactual vacuolar changes, displacing the nuclei to the periphery of the lymphoma cell, mimicking signet ring cells. In this and almost all gastric DLBCL, poorly differentiated carcinoma should be included in the differential diagnosis. Immunophenotyping with pancytokeratin, S100, and lymphoma markers should be routinely uti lized in daily practice to hel p make an accurate diagnosis.
Fig. 8.6

Large neoplastic lymphoma cells in DLBCL infiltrate in diffuse sheets and may resemble centroblasts or immunoblasts (a). EBV-positive DLBCL shows Hodgkin/Reed-Sternberg-like cells, large lymphocyts, and reactive small lymphocytes (b) positive nuclear staining pattern demonstrated by in situ hybridization for Epstein-Barr virus encoded RNA (EBER) (c). Discohesive large neoplastic cells, which resemble immunoblasts or plasmablasts, are found in gastric plasmablastic lymphoma (d)

Immunophenotype

Immunohistochemically, gastric DLBCL cells are immunoreactive again st pan-B-cell markers, such as CD20, CD19, CD79a, and PAX5, but negative to T-cell markers (Fig. 8.7). About half of cases are MUM1-and CD43-positive. BCL6 immunoreactivity is variable. Typically, the transformed gastric DLBCLs from MALT lymphoma are CD10-negative but often BCL-6 positive. In contrast, gastric de novo DLBCL is often CD10-positive, and some are BCL2-positive.
Fig. 8.7

Immunophenoty pic characteristics o f the lymphoma case shown in Fig. 8.5. Neoplastic large lymphoid cells are strongly immunoreactive to CD20 (a), CD10 (b), variably positive to BCL6 (c), but negative for BCL2 (d) . These cells show aberrant expression of CD43 (e) and strong positivity to Ki67 in over 90% of cells (f)

For plasmablastic lymphoma, neoplastic large plasmacytoid cells are positive for CD38 (Fig. 8.8a), CD138, and MUM1 (Fig. 8.8b), but negative for B-cell markers, such as PAX5, CD20 (Fig. 8.8c), CD79a (Fig. 8.8d), and T-cell markers. Ki67 proliferative index is often very high (not shown). In situ hybridization for EBV-encoded RNA (EBER) may be positive in 70% of ca ses, especially in HIV-positive patients [10]. The rearrangement involving MYC gene can be found with interphase fluorescence in situ hybridization in 67% of cases [10, 25].
Fig. 8.8

Neoplastic large plasmacytoi d cells are positive for CD38 (a) and MUM1 (b) but negative for CD20 (c) and CD79a (d), supporting the diagnosis of plasmablastic lymphoma

Cytogenetic Abnormalities

Gastric DLBCL may have complex cytogenetic abnormalities w ith clonal rearrangements of immunoglobulin (IG) heavy- and light-chain genes. Translocations involving BCL6 and MYCgenes may play a key role not only in the progression of gastric MALT lymphoma to DLBCL but also in the tumorigenesis of de novo DLBCL as well. BCL2 gene rearrangement, however, is rare. Thus, “double-hit” lymphoma is very rare among primary gastric lymphoma, while patients with multiple gene amplifications and/or copy number gains in BCL6, and “MYC, BCL2 double-expresser” gastric DLBCL, have a poor clinical outcome [26]. Mutations with loss of heterozygosity in regions 5q21 (APC gene locus), 9p21 (INK4A/ARF), 13q14 (RB), and 17p13 (P53), and allelic imbalances in 2p16, 6p23, and 12p12-13 have been reported in gastric DLBCL [27]. Cytogenetic abnormalities such as t(11;18) and trisomy 3 (most often involv ing chromosomes 12 and 18) can be detected in some cases of gastric MALT lymphoma but rare in both de novo and transformed DLBCLs. Some gastric DLBCL tumors may be positive for EBV markers [28] and granular cytoplasmic anaplastic lymphoma kinase (ALK) expression [29, 30]. Very rarely, M YC gene rearrangement can be found in plasmablastic lymphoma without EBV infection in an immunocompetent young adult [25].

The case illustrated in Fig. 8.5 showed clonal IGH gene rearrangement. Further fluorescence in situ hybridization analysis for high-grade B-cell lymphoma demonstrated the majority of neoplastic cells with one copy of MYC and two copies of BCL6. Rearrangements o f MYC and BCL6 genes were observed in about 70% of cells analyzed, and unusual IGH-BCL2 single fusion pattern was identified in about 20% of cells. The overall changes were consi stent with high-grade B-cell lymphoma with the features intermediate between DLBCL and Burkitt’s lymphoma, which was renamed as high-grade B-cell lymphoma, NOS (not otherwise specified) in the 2016 revision of World Health Organization (WHO)Classific ation of Hematopoietic and Lymphoid Neoplasms [31].

Prognosis

Primary gastric DLBCL is a highly heterogeneous malignant tumor. The 5-year survival of patients with gastric DLBCL is significantly worse than that of patients with MALT lymphoma. There is no significant d ifference in clinical behaviors between transformed MALT lymphoma and primary DLBCL [32, 33]. DLBCLs are further divided into germinal center B- (GCB) and non-GCB subtypes by Hans, Choi, and Tally immunohitochemical algorithms. Primary gastric DLBCL tends to show a higher prevalence of GCB subtype with a better 5-year overall survival rate than that of other DLBCL types [32]. IGH-involved translocation in DLBCL has been found to be an independent prognostic factor, in addition to younger age and early stage, for better overall survival and event-free survival [9]. H. pylori-positive gastric “pure” DLBCL, as a distinct subtype, may be less aggressive and respond to H. pylori eradication and conventional chemotherapy [34]. Expression of BCL6 by tumor cells is also regarded as a favorable factor [8]. In contrast, poor outcomes in patients with g astric DLBCL are associated with advanced clinical stages, expression of BCL2 [8, 33] and BLIMP-1 [33], elevated serum levels of lactate dehydrogenase [8], and EBV infection, likely due to resistance to standard chemoradiotherapy [35]. Plasmablastic lymphoma is rapidl y progressive and a lmost invariably fatal.

Summary

Non-Hodgkin lymphoma in the gastric cardia shows a predominance of lowgrade marginalzone B-cell lymphoma, also known as MALToma, which is primarily related to H. pylori infection. Highgrade non-Hodgkin lymphoma in the gastric cardia is rare and occurs mainly in the elderly population. It is heterogeneous in cell type, pathogenesis, and prognosis. Accurate morphologic pathologicdiagnosis and molecular characterization is essential for patient management.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineVA Boston Healthcare SystemWest RoxburyUSA
  2. 2.Harvard Medical School, Brigham and Women’s HospitalBostonUSA
  3. 3.Department of PathologyThe Affiliated Drum Tower Hospital, Nanjing University Medical SchoolNanjing, JiangsuPeople’s Republic of China

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