Primary pulmonary low-grade B-cell lymphomas of mucosa associated lymphoid tissue (MALT) represent a distinct subset of non-Hodgkin’s lymphomas. These rare tumors generally remain localized in their primary extranodal site, allowing local resection to be curative in most cases; however, making the proper diagnosis can prove challenging due to the tumor’s ability to produce IgM monoclonal proteins, which are seen with a variety of other conditions. The authors report the case of a patient who presented with a persistent cough and a new interstitial infiltrate. The patient was initially thought to have Waldenström’s macroglobulinemia because a monoclonal IgM gammopathy was identified. After medical intervention failed, the patient underwent a right thoracotomy, and pathologic evaluation of the lung tissue revealed MALT lymphoma. The authors conclude that the presence of an IgM monoclonal protein in serum should lead clinicians to direct the workup toward genetic and immunohistochemical techniques so that a definitive diagnosis can be obtained.
Primary pulmonary non-Hodgkin’s lymphomas are rare, estimated to account for only 3.6% of extranodal lymphomas.1,2 Kurtin and colleagues suggest that the true frequency of primary pulmonary mucosa associated lymphoid tissue (MALT) lymphoma may be as low as 0.49%.3
Diagnosis is made by histopathologic examination with immunohistochemical analysis of tissue samples. The histopathologic hallmark of extranodal MALT lymphoma is tumor cell infiltration of parenchymal epithelium with formation of lymphoepithelial lesions. Additionally, centrocyte-like or small-cleaved lymphocytes in a parafollicular distribution are characteristic of this low-grade B-cell lymphoma.
MALT lymphomas have indolent clinical courses and usually maintain sustained localization in their primary extranodal site. These characteristics led Saltzstein to coin the term “pseudolymphomas,” and these do not require aggressive therapy.4 Limited local excision, with or without low-dose chemotherapy, has been shown to be curative. We present a rare case of primary pulmonary low-grade B-cell lymphoma of the MALT variety, associated with an IgM kappa monoclonal gammopathy.
A 75-year-old black man presented to the department of pulmonary medicine reporting weakness and a persistent, sputum-producing cough. He had been hospitalized recently for exacerbation of chronic obstructive pulmonary disease and since then had grown progressively weaker and had a notably decreased appetite.
His chest radiograph showed a new interstitial pulmonary infiltrate at the right lung base, superimposed upon severe underlying interstitial fibrosis (Figure 1). Subsequent computed tomography (CT) scans confirmed the findings and provided evidence of end-stage pulmonary fibrosis with honeycomb changes (Figure 2). There was also consolidation of the right lower lung, consistent with lobar pneumonia, a small right pleural effusion, and cystic changes in the right upper lung, secondary to bronchiectasis. A bronchoscopy revealed no endobronchial lesions, and transbronchial biopsies showed no evidence of tumor. Cultures of the bronchoscopic specimens returned no evidence of mycobacterial, fungal, or other bacterial etiology for the pulmonary infiltrate. A presumptive diagnosis of community-acquired pneumonia was made and the patient was treated with antibiotics.
The patient’s pulmonary infiltrate did not improve, and further diagnostic testing was undertaken. His serum IgM level was elevated to 2,769 mg/dL (average level for males older than 13 years is 22–240 mg/dL and 33–293 mg/dL for females older than 13 years). Serum protein electrophoresis demonstrated a monoclonal protein. Serum protein immunofixation electrophoresis revealed a monoclonal gammopathy of the IgM kappa type. Urine protein immunofixation electrophoresis found monoclonal-free kappa light chains. Bone marrow biopsy showed an abnormal, increased small lymphocyte population. Cytogenetic analysis demonstrated a translocation between the long arm of chromosome 11 at region 2, band 1, and the long arm of chromosome 18 at region 2, band 1 [t(11;18)(q21;q21)].
Based on these findings, a diagnosis of Waldenström’s macroglobulinemia (WM) was made, and the patient was treated with fludarabine (an antimetabolite). The pulmonary infiltrate persisted, and the patient underwent a right thoracotomy, with a right lower lobe wedge lung biopsy. The lung tissue showed a diffuse, interstitial small lymphocyte infiltration of the interalveolar septae and bronchioles (Figure 3), which corresponded to the new infiltrate seen on his chest radiograph. No lymphocytoplasmic features were present. Immunohistochemical stains showed the lymphocyte infiltration was composed of uniform small B-cell lymphocytes that were positive for CD20 (Figure 4) and bcl-2. These cells were negative for CD3, CD5, CD10, and bcl-1 (cyclin D1). Based on the histopathologic, immunohistochemical, and cytogenetic findings, the diagnosis of a primary extranodal low-grade B-cell marginal zone lymphoma (MZL) of the MALT variety was made.
The patient had a normal recovery and was discharged to home in stable condition on postoperative day 7; however, 1 month later, the patient was readmitted with exacerbation of chronic obstructive pulmonary disease and intubated. At the request of his family, all ventilatory support was withdrawn, and the patient died on hospital day 7.
In the early 1990s, 19 European and American hematopathologists met to establish an updated classification of lymphoid neoplasia. The group was known as the International Lymphoma Study Group, and their new classification came to be known as the Revised European and American Classification of Lymphoid Neoplasms (REAL).5 REAL differed from the Kiel classification because it was based not only on morphology but also on genetic and immunologic criteria. REAL defines seven major categories of non-Hodgkin’s B-cell lymphoma: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), B-prolymphocytic leukemia, mantle cell lymphoma (MCL), MZL, lymphoplasmacytoid lymphoma (LPL), follicle center lymphoma (FCL), and hairy cell leukemia (HCL).6 Today, REAL is widely accepted by hematologists and pathologists. Morphologic, immunophenotypic, cytologic, and genetic data are obtained and integrated for a precise diagnosis and classification.
MZL is further divided into extranodal (MALT), nodal, and splenic types. MALT lymphoma is characterized by a monoclonal B-cell proliferation in and around various mucosal tissues. The lymphoma cells have been described as “centrocyte-like,” due to their small size and slight nuclear clefting. The diagnosis of extranodal MZL, MALT type, includes the histopathologic observation of a diffuse sheet-like infiltrate of marginal zone B-cells with the characteristic lymphoepithelial lesions. The lymphomatous infiltrate may be found within the epithelium of the gastrointestinal tract, bronchioles, or salivary glands. Paradoxically, MALT lymphomas rarely arise where MALT is normally present. The reason for this seems to be that MALT lymphomas generally arise in lymphoid tissue that has been altered as a result of some preexisting inflammatory disorder, such as Helicobacter pylori colonization in the stomach or follicular bronchiectasis in the lungs.7
Immunohistochemical testing of tissue samples will be positive for CD20; negative for CD5, CD10, bcl-1, and bcl-6; and positive or negative for bcl-2 (Figure 5). CD20 is positive in all small B-cell lymphomas. The protein bcl-1, characteristic of MCL, is universally negative for MZL. CD5 is useful at this level to differentiate MZL from SLL. There have been reports of CD5-positive MZL, but these are uncommon.8 CD10 and bcl-6 are useful for differentiating FCL from MZL. Expression of the bcl-2 protein is not helpful, because both FCL and MZL may express bcl-2 in a large percentage of cases.6
One of the most recent keys in diagnosing extranodal MZL of the MALT type is finding a structural karyotype abnormality in the presence of the clinical and pathologic features previously outlined. One focus of current genetic research is the resistance of H pylori to antibiotic therapy. It previously has been shown that eradicating H pylori with antibiotics leads to regression and cure of gastric MALT lymphoma in 75% of cases.9 Subsequent studies have shown that a large proportion of antibiotic-resistant MALT lymphomas have genetic anomalies that may confer this resistance. Many genetic abnormalities have been reported, including t(9;14)(p13;q32), t(11;18)(q21;q21), t(1;14)(p22;q32), or 6q21 deletions.
Cytogenetic studies have shown that t(9;14)(p13;q32) is associated with LPL in approximately half of patients who lack a monoclonal paraprotein.10 REAL classifies WM, which is characterized by the presence of an IgM paraprotein, as an LPL. This specific translocation up-regulates the PAX-5 gene, known to be involved in multiple neoplasias.10 The PAX-5 gene encodes for a transcription factor, B-cell-specific activation protein (BSAP), which is needed for B-cell development. Up-regulation of BSAP appears to increase B-cell proliferation.10 Studies of gastric MALT lymphoma have shown t(11;18)(q21;q21) in approximately 30% of cases.9 This translocation leads to the expression of a chimeric transcript fusing the 5’ end of the apoptosis inhibitor-2 gene to the 3’ end of the novel MALT lymphoma-associated translocation gene. Liu and associates report that, although infrequently, t(1;14)(p22;q32) has been found in association with MALT-type lymphoma.9 This translocation deregulates another novel gene, bcl-10, which is proapoptotic. A 2002 study showed that between 42% and 63% of MALT lymphomas studied had deletions of 6q21.10 Fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) are the current technologies used to detect these karyotype abnormalities.
In 1948, Waldenström described a malignancy of lymphoplasmacytoid cells that produce IgM monoclonal proteins.11 The sex and age distribution of WM among patients is similar to MZL in that the disease is slightly more common in men and the incidence increases with age.12 The clinical manifestations and laboratory abnormalities are related to direct tumor infiltration and to the amount and specific properties of IgM.13 WM is often associated with lymphadenopathy and hepatosplenomegaly. The most serious clinical manifestation is hyperviscosity syndrome, due to the large size of the IgM protein molecule. Patients who progress to this syndrome may present with the classical triad of visual changes, mental status changes, and bleeding.14 Monoclonal IgM immunoglobulins may also cause cold agglutinin disease and cryoglobinemia. WM may involve bone marrow, as originally described by Waldenström, but unlike multiple myeloma, it does not cause lytic bone lesions or hypercalcemia.11 A serum IgM monoclonal protein is present in the serum in excess of 30 g/L (average for males older than 13 years is 0.22—2.40 g/L and 0.33”-”2.93 g/L for females older than 13 years). Renal excretion of the corresponding light chains is uncommon but is found in up to 20% of patients, of whom 80% excrete free monoclonal light chains of the kappa isotype.
LPL and CLL/SLL may cause WM. Some authors have suggested that it can also be caused by extranodal MZL (MALT type) and that this entity should be considered when making the differential diagnosis for patients who exhibit the clinicopathologic features of WM.14
The treatment of WM differs greatly from the treatment of MALT lymphoma. An effective treatment for WM is chemotherapy with 25 mg/m2 of fludarabine daily for 5 days, every 4 weeks. Because 80% of the IgM paraprotein is intravascular, plasmapheresis may be used in cases of serious hyperviscosity.12 Extranodal MALT lymphomas often take an indolent course and remain localized at their primary site for a long time, making local surgical excision highly effective. MZL also responds to low-dose (30–36 Gy) radiation therapy, and a 2002 study showed an overall 5-year survival rate of 83% to 90%, regardless of clinical stage.15 Newer treatments have shown promise, including cladribine (2-chlorodeoxyadenosine), a purine analog that has revolutionized treatment of HCL, inducing complete remission in 84% of patients studied.16,17 Hyper-CVAD protocol consists of administering 300 mg/m2 fractionated cyclophosphamide twice daily for 3 days, 50 g/m2 doxorubicin on day 4, 2 mg vincristine on days 4 and 11, and 40 mg dexamethasone on days 1 through 4 and 11 through 14. This regimen, combined with stem cell transplantation, has also been shown to improve prognosis.17
Although primary pulmonary low-grade B-cell lymphomas of the MALT variety are rare, they represent a distinct subset of non-Hodgkin’s lymphomas. Their propensity to remain indolent in their primary extranodal site makes local resection curative in most cases. The clinical presentation of these lymphomas and their ability to produce IgM monoclonal proteins can make definitive diagnosis challenging. In our case, a monoclonal IgM gammopathy was initially interpreted as indicative of WM. Of patients with MALT lymphoma, 43% may have a monoclonal gammopathy, with half of these patients having an IgM isotype.3 The presence of an IgM monoclonal protein in serum may be seen in a variety of conditions and should direct the workup toward genetic and immunohistochemical techniques to obtain a definitive diagnosis.
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