Sandbox:Mazia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overveiw

GI lymphomas typically present with nonspecific signs and symptoms attributable to the site of involvement. This topic review will discuss the salient clinical features and diagnostic evaluation of GI lymphomas. The management of GI lymphoma is presented separately. Stomach is the most commonly involved site (60%-75%) in gastrointestinal tract followed by small bowel, ileocecal region and rectum[25]. Gastric lymphoma accounts for 3%-5% of all malignant tumors of the stomach[26]. Although the incidence of gastric carcinoma has been reduced, the incidence of primary gastric lymphoma is increasing[27]. H. pylori play a role in the development of most MALT lymphomas. However, its exact mechanism has not been fully understood, although a chronic inflammation may enhance the probability of malignant transformation via B cell proliferation in response to H. pylori mediated by tumor-infiltrating T cells[28]. H. pylori may play a similar role in development of DLBCL and few studies have shown complete remission after eradication therapy alone[28]. It has been shown that individuals with positive HBsAg have an increased risk of developing NHL[29]. It was reported that HBV plays a role in the development of B-cell NHL[30]. In contrast, primary gastric lymphoma with a T-cell phenotype is relatively rare, accounting for only 7% of primary gastric lymphomas in HTLV-1 infected endemic areas and a relatively large number of such cases are secondary gastric involvement of adult T-cell leukemia. Primary gastric T-cell lymphoma without HTLV-1 infection is rare, and sporadic cases have been reported[31]. The age of most gastric lymphoma patients is over 50 years with a relative predilection in males. Clinical symptoms of gastric lymphoma are nonspecific and indistinguishable from other benign and malignant conditions. The most common complaints of gastric lymphoma patients are epigastric pain, weight loss, nausea and vomiting. Occasionally, an abdominal mass is palpable. Lymphadenopathy is rare and its patients often have no physical signs. Perforation, bleeding, or obstruction is very uncommon. Unlike nodal lymphoma, B constitutional symptom is not common.

Although all histological kinds of nodal lymphoma can arise from th Gastrointestinal tract is the most common extranodal site involved by lymphoma accounting for 5%-20% of all cases[1]. Primary gastrointestinal lymphoma, however, is very rare, constituting only about 1%-4% of all gastrointestinal malignancies. Gastrointestinal lymphoma is usually secondary to the widespread nodal diseases. Although virtually lymphoma can arise from any region of the gastrointestinal tract, the most commonly involved sites in term of its occurrence are the stomach followed by small intestine and ileocecal region[2]. Histopathologically, almost 90% of the primary gastrointestinal lymphomas are of B cell lineage with very few T-cell lymphomas and Hodgkin lymphoma. Certain histological subtypes have been noted to have a relative predilection site as mucosa-associated lymphoid tissue (MALT) lymphoma in stomach, mantle cell lymphoma (MCL) in terminal ileum, jejunum and colon, as well as enteropathy-associated T-cell lymphoma (EATL) in jejunum, and follicular lymphoma (FL) in duodenum with a geographic variation in its distribution[3]. Multifocality, however, has been noticed particularly in MALT lymphoma and follicular lymphoma. Certain risk factors have been implicated in the pathogenesis of gastrointestinal lymphoma including Helicobacter pylori (H. pylori) infection, human immunodeficiency virus (HIV), celiac disease, Campylobacter jejuni (C. jejuni), Epstein-Barr virus (EBV), hepatitis B virus (HBV), human T-cell lymphotropic virus-1 (HTLV-1), inflammatory bowel disease and immunosuppression[4,5]. Marker expression and translocations of common histological types of gastrointestinal lymphoma are depicted in Table ​Table11

The head and neck region is the second most common site for extra-nodal lymphoma accounting for 10%-15% of all cancers in this region. Approximately 2.5% of all malignant lymphomas originate from the oral and paraoral region, and the majority of them in the Waldeyer’s ring include adenoids, palatine tonsils, base of tongue and oropharyngeal walls. Tonsil is the most frequently involved site (> 50%) of tumors, followed by nasopharynx and base of tongue[10]. Several factors are known to increase the risk of oropharyngeal lymphoma including EBV. The affected patients are usually at the age of over 50 years with a predilection of males. The most common clinical presentations of oropharyngeal lymphoma include airway obstruction, hearing pain, progressive enlarging painless local mass, dysphagia and foreign body sensation in the throat. Cervical lymphadenopathy is present in over 50% patients with tonsillar lymphoma[11].

More than 80%-90% of oropharyngeal lymphomas belong to the B-cell lineage of non-Hodgkin lymphoma (NHL)[12]. Diffuse large B-cell lymphoma (DLBCL) is the most common type of primary oral and paraoral NHL with a small percentage of thymic T-cell type. Histologically, DLBCL, composed of intermediate-large cells which may be noncleaved, cleaved and immunoblastic, shows B-cell lineage with expression of pan-B-cell antigens (CD19, CD20, CD22, CD79A, and PAX5/BSAP), and is less commonly positive for germinal centre cell markers (CD10 and BCL6) and negative for T-cell antigens. A small number of cases show a translocation between the BCL-2 gene on chromosome 18 and the IgH gene on chromosome 14, t (14;18)[13]. Other lymphomas involving the Waldeyer’s ring include 15% B-cell lymphomas in extranodal marginal zone of MALT, 8% peripheral T-cell lymphomas, 6% follicular lymphomas, and 3% MCLs. Hodgkin lymphoma (HL) involving the oropharynx is very rare accounting for about 1%-5% of all Hodgkin diseases. The majority of oropharyngeal HL are of lymphocyte predominant and nodular sclerosis type on histopathology with a common immunophenotype of Reed Sternberg cells positive for CD15, CD30 and negative for CD45, CD20, and EMA, which can rule out the diagnosis of NHL[14].

Radiologically, oropharyngeal lymphoma typically appears in barium studies as a lobular mass near the base of tongue in the palatine fossa with the overlying mucosa usually being nodular. The appearance of oropharyngeal lymphoma can be hard to differentiate from more common pharyngeal carcinomas. Because the signal intensity of lymphoma is similar to that of normal tissue, the MR signal characteristics cannot reliably show the early lymphomatous involvement at these sites. CT or PET with FDG and CT (PET/CT) has proved their usefulness both in diagnosis and staging of the disease and in assessment of its response to therapies[15]. Certain features that may favor the diagnosis of NHL on imaging are the short clinical history and a large homogeneous mass which displaces rather than invades local structures and large homogeneous non-necrotic cervical nodes[16].

Esophageal lymphoma The esophagus is a rarely involved site, accounting for < 1% of all gastrointestinal lymphomas. Esophageal involvement usually results from metastasis from cervical or mediastinal lymph nodes or extension from gastric lymphoma. Primary esophageal lymphoma is extremely rare, with less than 30 cases reported in the literature[17-19]. The majority are the DLBCL type of NHL. Only few cases of MALT lymphoma, MCL, T-cell lymphoma and HL involving the esophagus have been reported[19-22]. The etiology of esophageal lymphoma is unknown and the role of EBV in its pathogenesis is controversial. It has been shown that esophageal lymphoma is most common in immunocompromised patients, with HIV infection as a probable risk factor[17]. The age of presentation is variable. The common symptoms of patients with esophageal lymphoma include dysphagia, odynophagia, weight loss, chest pain or present as a result of complications such as hemorrhage, obstruction or perforation with a tracheoesophageal fistula. Constitutional B symptoms (fever, night sweats) are not typically present.

Almost all cases of primary esophageal lymphoma are DLBCLs with positive surface markers of tumor cells on immunofluorescent staining for immunoglobulin G and κ light chain. MALT lymphoma of the esophagus, however, unlike that of stomach, is not associated with H. pylori. HL of the esophagus is extremely rare. Follicular lymphoma affecting the esophagus is a part of multifocal presentation in the gastrointestinal tract.

Radiological and endoscopic findings in esophageal lymphoma vary greatly and are nonspecific, which poses diagnostic challenges when it is differentiated from other benign and malignant lesions. Radiographic patterns of esophageal lymphoma, described in the literature[18-20], include stricture, ulcerated mass, multiple submucosal nodules, varicoid pattern, achalasia-like pattern, progressive aneurysmal dilatation, and tracheoesophageal fistula formation, and none of them is diagnostic. The morphological features seen at endoscopy are nodular, polypoidal, ulcerated or stenotic[21]. EUS has gained clinical acceptance for the assessment of lymphoma and preoperative staging, because it can accurately depict the structural abnormalities and depth of invasion of the lesions. EUS findings, however, are not pathognomonic, with presentation varied as anechoic, hypoechoic or even hyperechoic masses[22]. CT findings in esophageal lymphoma are nonspecific and not diagnostic, with features such as thickening of the wall mimicking other common tumors, such as esophageal carcinoma. CT, however, they are valuable for the evaluation of the extraluminal component of esophageal mass, its mediastinal extension, fistula formation, and status of lymph nodes, thus playing a role in staging disease, assisting in stratification of available treatment modalities, evaluating treatment responses, monitoring disease progression, and detecting relapses[23]. Recently, incorporation of PET/CT has emerged as an indispensable tool in staging the disease and following up the patients with extranodal involvement of Hodgkin’s and non-Hodgkin’s lymphoma, with an increased sensitivity and specificity. Diffuse large B-cell non-Hodgkin lymphoma of the esophagus is manifested as circumferential thickening of the wall, with diffuse increased FDG uptake. However, the intensity of FDG uptake in lymphoma is influenced by various intrinsic tumor factors such as histological features and grade, as well as various extrinsic factors. FDG PET/CT can also detect the indolent lesions that are undetectable on conventional cross-sectional imaging[24].