Esophageal lymphoma is rare, accounting for less than 1% of all gastrointestinal lymphomas. Involvement of the esophagus is most commonly the result of contiguous spread from the proximal stomach, adjacent mediastinal lymph nodes, or cervical lymph nodes.
Primary esophageal lymphoma is even rarer. Taal et al found only 2 cases of primary involvement in their series of 37 patients with esophageal non-Hodgkin lymphoma.[1] In another series of 1467 cases of gastrointestinal (GI) lymphoma, primary esophageal lymphoma accounted for only 3 cases. Fewer than 25 cases have been reported in the past few decades. A 2014 case report appears to be the first to describe a diagnosis of primary esophageal Burkitt lymphoma in a 17-year-old female.[2]
Persons with esophageal lymphoma have varying presentations and a relatively poor prognosis. Invasion of the esophagus may result in hemorrhage, obstruction, or perforation with the development of a tracheoesophageal fistula. Tracheoesophageal fistula most often results in death secondary to aspiration pneumonia. Even when surgically repaired, such fistulae are likely to recur. (See Prognosis.)
Since the advent of human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), esophageal lymphoma has assumed greater significance and must be considered in the differential diagnosis of immunosuppressed patients presenting with esophageal symptoms.. (See Etiology and DDx.)[3, 4]
The majority of lymphomas involving the esophagus are thought to represent secondary involvement from an adjacent site. In most cases, esophageal lymphomas involving the distal esophagus represent extension from the proximal stomach.
Lymphomas arising in the middle third of the esophagus may be secondary to mediastinal lymph node enlargement with involvement of the esophagus. Another site of involvement, the proximal esophagus, may represent extension from adjacent cervical lymph nodes.
Dawson et al developed the following 5 criteria needed to identify a primary GI lymphoma (see Presentation and Workup)[5] :
Complications of esophageal lymphoma may include the following (see Prognosis and Presentation)[6] :
The etiology of primary GI lymphoma is unknown, but various risk factors have been recognized or proposed.
HIV infection has been recognized as a risk factor for the development of primary GI lymphoma; the relative risk of developing non-Hodgkin lymphoma for persons infected with HIV is 104 times that of people who are not infected with the virus.
Most of the GI tract lymphomas are of the B-cell type; however, the significance of the Epstein-Barr virus (EBV) as an etiologic factor is controversial. Although EBV is strongly related to B-cell proliferation in Burkitt lymphoma, its exact role in GI lymphoma is unknown.
Deoxyribonucleic acid (DNA) probes have found the proto-oncogene C-myc transcription in 75% of AIDS-associated lymphomas, which suggests a role for the C-myc oncogene.
GI tract lymphoma is fairly common, making up approximately 10% of all lymphomas. In non-Hodgkin lymphoma, the most common extranodal site is the GI tract, which is involved in 5-20% of patients during life and up to 50% of patients at autopsy.[7, 8]
The most common GI sites for lymphoma are the stomach (48-50%), small bowel (30-37%), and ileocecal region (12-13%). The esophagus is the least common site of involvement, with less than 1% of patients with GI lymphoma presenting with esophageal lymphoma.
Because of the extreme rarity of esophageal lymphoma and the small number of reported cases, a trend cannot be established regarding which sex is more commonly affected. In one series, 12 of 17 patients were men. In another report, involving patients with HIV-associated esophageal lymphoma, the patients were typically 40-year-old men who were profoundly immunosuppressed. A final series of 6 cases of primary esophageal lymphoma included 5 men and 1 woman.
The age at presentation of esophageal lymphoma is highly variable, with cases reported in patients as young as 17 years and as old as 86 years. In one series, patients with primary esophageal lymphoma not associated with HIV infection/AIDS tended to be older (mean age, 61y) than those in the HIV infection/AIDS associated group (mean age, 40y).
The data regarding the prognosis of GI lymphoma indicate a variable mortality rate. Prognosis depends on the stage of the disease at diagnosis and the feasibility of surgery or chemotherapy. Mortality also depends on the underlying health of the patient, as demonstrated by the overall poor prognoses of patients who are infected with HIV.
It has also been found that patients with T-cell lymphoma have higher rates of esophageal perforation and poorer overall survival rates than do patients demonstrating a B-cell phenotype.
The International Non-Hodgkin's Lymphoma Prognostic Factors Project found the following characteristics in higher-risk patients:
The 5-year survival rate for patients with 0-1 of these risk factors was 73%; with 2 factors, 51%; with 3 factors, 43%; and with 4 factors, 26%.
The small number of cases of esophageal lymphoma makes predicting survival difficult. The longest reported period of disease-free survival in a person with esophageal lymphoma who was not infected with HIV is 13 years 5 months; this patient had been treated with combination chemotherapy and radiotherapy.
Esophageal lymphoma in patients with HIV/AIDS is commonly high grade, large cell or immunoblastic, aggressive, and poorly responsive to chemotherapy. Survival rate averages have been poor (ie, 4-6 mo).
In HIV-infected persons, the presence of AIDS, a CD4 count of less than 100/µL, and a low Karnofsky score are associated with a poor prognosis.
In HIV-positive patients in a low-risk category, including those with a CD4 count of greater than 100/µL, an absence of opportunistic infections, and good performance status, response rates similar to those of HIV-negative patients may be achieved.
Most patients present with dysphagia.[9] Other symptoms include odynophagia, weight loss, chest pain, fever, fatigue, abdominal pain, and hoarseness. Patients may present with a history consistent with secondary achalasia. Patients do not typically present with fever or night sweats (B symptoms).
In patients with HIV, one should consider an underlying esophageal lymphoma in patients with infectious esophagitis or idiopathic esophageal ulceration that is refractory to therapy. Most patients with AIDS who develop esophageal lymphoma have a prior history of opportunistic infections, such as those caused by Pneumocystis carinii (eg, P carinii pneumonia), Candida species, cytomegalovirus, and herpes simplex virus.
Physical examination is generally not helpful in diagnosing esophageal lymphoma. However, in a review of esophageal lymphoma in 10 patients without HIV, the following characteristics were noted:
Physical examination appears to be most useful in excluding generalized peripheral lymphadenopathy, which, by definition, should not be present in primary esophageal lymphoma.
No specific laboratory blood tests are required for the diagnosis of esophageal lymphoma. In primary esophageal lymphoma, the WBC count is, by definition, within the reference range.
Anemia and thrombocytopenia are common in AIDS patients who present with lymphoma. The CD4 count is usually low. In a series of 22 AIDS patients with non-Hodgkin lymphoma, 2 of whom had esophageal involvement, the mean CD4 cell count was 80.8 ± 119.6/µL.
Initial staging studies include a complete blood count (CBC), a bone marrow biopsy, and computed tomography (CT) scans of the chest, abdomen, and pelvis. Classification of esophageal lymphoma as a primary lesion can only be made once the criteria of Dawson et al are fulfilled.[5] (See Overview.)
The radiographic appearance of esophageal lymphoma varies and is somewhat nonspecific; therefore, esophageal lymphoma is a difficult diagnosis to confirm with radiographic studies.
Barium swallow
Esophageal lymphoma has no pathognomonic appearance. Barium swallow studies of the esophagus may reveal thickened folds with nodular, polypoid, ulcerated, or stenotic features. A radiographic picture consistent with pseudoachalasia may also be present. However, these features cannot help to differentiate esophageal lymphoma from other benign or malignant esophageal diseases.
CT scanning is not diagnostic in esophageal lymphoma; instead, it is used in staging of the disease and in evaluating response to therapy.[10]
Esophagogastroduodenoscopy (EGD) is the only way to directly visualize and biopsy esophageal lymphoma.[11] The morphologic appearance of the tumor may be of little help, especially in patients with acquired immunodeficiency syndrome (AIDS), in whom candidal superinfection is common. An exception to this occurs in cases of mantle cell lymphoma with esophageal involvement in which multiple white submucosal nodules or plaques have been described.[12, 13, 14] In these settings, endoscopic findings vary from other types of esophageal lymphoma, wherein the tumor may appear as an ulcerated, polypoid, or submucosal mass.
Routine endoscopic biopsies may not be useful in making a diagnosis because of the submucosal nature of the lesion. In one study, all patients required repeat endoscopy and biopsy to confirm the diagnosis. Endoscopic biopsies may have a false-negative rate of greater than 30%. Endoscopic mucosal resection of the esophageal lesion has a greater diagnostic yield.
In one series, 27 patients with lymphomatous involvement of the esophagus were identified. Of these, 3 had primary esophageal lymphoma. EGD confirmed the diagnosis in 81% of patients, although 19% required surgical exploration to establish the diagnosis.
If suspicion for esophageal lymphoma is high, consider other diagnostic modalities (eg, computed tomography scans, surgical biopsy).
In one case report of primary esophageal lymphoma, the endosonographic features were reported as diffuse, homogenous, hypoechogenic esophageal wall thickening. Esophageal lymphomas may demonstrate anechoic areas.
Endoscopic ultrasonographically guided fine-needle aspiration (EUS-FNA) of suspicious submucosal lesions may help to obtain tissue and to establish a diagnosis, such as mucosa-associated lymphoid tissue lymphoma (MALT).[15] In patients who receive chemotherapy or radiation for primary esophageal lymphoma, EUS may be helpful in evaluating the response to treatment.
Most reported cases of primary esophageal lymphoma are diffuse large cell lymphomas of the B-cell immunotype. In general, surface markers of the tumor cells reveal positive immunofluorescent staining results for immunoglobulin G (IgG) and kappa light chain.
Mucosa-associated lymphoid tissue (MALT) lymphoma has been found in the esophagus and is being increasingly reported, although still very rare. Unlike MALT lymphoma of the stomach, MALT lymphoma of the esophagus does not appear to be associated with Helicobacter pylori.[16, 17]
Other histologic variants include anaplastic large cell lymphoma, with 3 cases reported in the literature, and mantle cell lymphoma.[18, 12]
Gupta et al summarized the histologic findings of 17 patients with primary esophageal lymphoma. All but 1 had non-Hodgkin lymphoma, with large cell lymphoma being the most common histologic subtype.
If the tumor type is difficult to determine on hematoxylin and eosin staining, using monoclonal antibodies to the leukocyte common antigen may help to differentiate hematopoietic from nonhematopoietic malignancies. This may be useful for patients in whom it is difficult to distinguish a poorly differentiated carcinoma or sarcoma from a lymphoma.
Data vary regarding therapy and prognosis in primary esophageal lymphoma. Choice of therapy depends on the histologic grade of the tumor and the extent of esophageal involvement. The initial therapy for primary esophageal lymphoma has included chemotherapy, surgical resection, and radiotherapy. Studies have indicated that nonsurgical approaches have had equivalent outcomes to those of surgical strategies in patients with GI lymphoma.
Some authors prefer combined therapy, with local resection plus chemotherapy and/or radiotherapy as the initial therapy. Others prefer chemotherapy alone as the therapeutic modality of choice.
Surgical resection is reportedly curative in some cases of primary GI lymphoma, though surgery is primarily used for the diagnosis and treatment of complications. The role of surgery greatly depends on the stage of disease at the time of diagnosis and on the underlying medical condition of the patient.
A 2014 case report of a Japanese patient with esophageal mucosa-associated lymphoid tissue (MALT) lymphoma appeared to be successfully treated with endoscopic submucosal dissection (ESD).[19] The authors suggested that this procedure may be superior to endoscopic mucosal resection for early esophageal MALT lymphoma with respect to the lateral and vertical margins of the resected specimen.
Carefully monitor adverse effects of chemotherapy or radiotherapy. In addition, carefully follow the patient's nutritional status. Consider placement of a gastric or jejunal feeding tube if the patient cannot maintain his or her nutritional status because of dysphagia or odynophagia.
Transfer to a specialized cancer center may be required for further treatment (eg, chemotherapy, radiotherapy, surgical intervention).
The chemotherapy regimen most commonly used is a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (a regimen referred to as CHOP). Other chemotherapy regimens have been used, but none have demonstrated greater efficacy than CHOP. Data indicate that the addition of rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody approved by the US Food and Drug Administration (FDA) for use in various B-cell lymphoma subtypes, results in higher response rates and improved survival rates, although the experience is limited in primary GI lymphoma.
The regimen can be modified, depending on the patient's performance status and other comorbid conditions.
Radiotherapy can be used as a single modality, but it is most often used in conjunction with chemotherapy. Risks of radiotherapy include development of esophagotracheal or esophago-aortic fistulae.
The primary medical therapy for esophageal lymphoma is chemotherapy, with the most common regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Cyclophosphamide, doxorubicin, and vincristine are administered on day 1 of a 5-day cycle. Prednisone is administered on days 1-5 of the 5-day cycle. Cycles are repeated every 21-28 days for a total of 6 or more cycles. Rituximab may be added as an adjunct therapy.
Clinical Context: Cyclophosphamide has antineoplastic activity mediated by its 2 active metabolites. These metabolites are alkylating agents that prevent cell division by cross-linking DNA strands. Cyclophosphamide is absorbed almost completely from the GI tract, making it bioavailable in either oral (PO) or intravenous (IV) forms. Excretion is primarily via urine. Because of the rarity of esophageal lymphoma, the dose should be determined on a case-by-case basis.
Clinical Context: Doxorubicin is an anthracycline antibiotic that can intercalate with DNA, affecting many of the functions of DNA, including synthesis. This agent is administered intravenously. Doxorubicin distributes widely into bodily tissues, including the heart, kidneys, lungs, liver, and spleen. It does not cross the blood-brain barrier and is excreted primarily in bile.
Clinical Context: Vincristine is a vinca alkaloid that is cell cycle–specific (M phase). The mitotic apparatus is arrested in metaphase via disruption of the microtubules. Absorption of vincristine through the GI tract is variable; therefore, administer the drug intravenously. It is metabolized extensively in the liver and excreted primarily via bile. Neurotoxicity is the limiting factor during therapy. Peripheral neuropathy is vincristine's most common adverse effect at usual doses.
Clinical Context: Prednisone is a glucocorticoid that acts as an immunosuppressant by stimulating the synthesis of enzymes needed to decrease the inflammatory response. It also acts as an anti-inflammatory agent by inhibiting the recruitment of leukocytes and monocyte-macrophages into affected areas via the inhibition of chemotactic factors and factors that increase capillary permeability. Prednisone is readily absorbed via the GI tract and is metabolized in the liver. Inactive metabolites of prednisone are excreted via the kidneys. Most of the adverse effects of corticosteroids are dose or duration dependent.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.
Clinical Context: The rituximab antibody is a genetically engineered chimeric mouse/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and neoplastic B lymphocytes.
The most common adverse reactions to rituximab were infusion reactions, some of which were fatal. Bowel perforation has been reported with rituximab. Patients reporting abdominal pain during therapy should be evaluated for perforation of the intestinal tract.
Reactivation of hepatitis B has been demonstrated; patients at high risk for hepatitis B should be screened prior to initiation of therapy. No studies have been conducted to determine if dose adjustment is necessary in patients with hepatic or renal dysfunction.
Monoclonal antibodies are antibodies targeted against specific antigenic determinants. They can be specific to growth factors, cytokines, and cell surface molecules found on tumor cells.