Pathology International 2004; 54: 712–718

Blackwell Science, LtdOxford, UKPINPathology International1320-54632004 Japanese Society of PathologySeptember 2004549712718Case ReportIntestinal MALT lymphomaT. Saito

et al

.

Correspondence: Tadashi Saito, CT, Department of Pathology,Narita Red Cross Hospital, 90-1 Iida-cho, Narita, Chiba 286-8523,Japan. Email: saito.chu923@j-wave.net

Received 23 March 2004. Accepted for publication 20 May 2004.

Case Report

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) arising in the small intestine with monoclonal cryoglobulinemia

Tadashi Saito,1,2 Jun-ichi Tamaru,2 Hirohisa Kishi,1 Junko Kayao,1 Yoshihiko Kuzuu,1 Hisashi Wakita,3 Akiko Adachi,2 Shinji Itoyama2 and Ittaku Mikata4

Departments of 1Pathology and 3Internal Medicine, Narita Red Cross Hospital, 4Chiba University School of Medicine, Chiba and Department of 2Pathology, Saitama Medical Center, Saitama Medical School, Saitama, Japan

A case of small intestinal extranodal marginal zone B-celllymphoma of mucosa-associated lymphoid tissue (MALTlymphoma) with monoclonal cryoglobulinemia is described.The patient was a woman in her mid-sixties with purpura ofthe bilateral lower legs and abdominal pain. An immuno-serological investigation showed expression of IgM-kappatype monoclonal cryoglobulin. A renal biopsy specimenrevealed proliferative glomerulonephritis with cryoglobulindeposition. Physical examination disclosed a stenosis,edematous changes and ascariasis in the small intestine.In aspiration cytology of the ascites, proliferation of theatypical lymphoid cells with plasmacytoid differentiationwas observed. These cells were positive for B-lineage anti-gens in immunocytochemistry, and showed an immunoglo-bulin heavy-chain gene rearrangement in Southern blottingand chromosomal alteration in G-banded karyotype analy-sis. Although medicinal treatment was used, the patientdied of general prostration. The diagnosis of intestinalMALT lymphoma was made at autopsy. Expression of API2-MALT1 fusion transcripts was detected by reversetranscription–polymerase chain reaction analysis usingformalin-fixed, paraffin-embedded tissue. Intestinal MALTlymphomas with API2-MALT1 expression have distinctiveforms of infiltration compared with those without transloca-tion. Therefore, detection of API2-MALT1 fusion transcriptsis useful for evaluating the prognosis and clinical behaviorof the disease.

Key words: API2-MALT1, ascariasis, cryoglobulinemia, cyto-genetics, gastrointestinal tract, malignant lymphoma, MALTlymphoma

Although extranodal non-Hodgkin’s lymphoma of the gastro-intestinal tract arises in about one-third of all extranodal non-

Hodgkin’s lymphomas, extranodal marginal zone B-cell lym-phoma of the mucosa-associated lymphoid tissue (MALTlymphoma) arising in the small intestine is relatively rare.1–3

Furthermore, extranodal MALT lymphoma is frequently com-plicated by the expression of monoclonal cryoglobulins.4,5

However, cases of small intestinal MALT lymphoma withmonoclonal cryoglobulinemia have not been reported previ-ously. In the present report, we describe a case of smallintestinal MALT lymphoma with monoclonal cryoglobuline-mia. Recently, t(11;18)(q21;q21) translocation has frequentlybeen detected in low-grade MALT lymphomas, and this trans-location is considered to be an important primary event inthe development of MALT lymphoma.6,7 Current studies havesuggested that this translocation was caused by the fusionof the API2 gene on chromosome 11 and the novel genetermed MALT1 on chromosome 18.8 It has been suggestedthat this translocation activates nuclear factor (NF) kappa B,and API2-MALT1 fusion exhibits increased resistance to apo-ptosis. In our present case, API2-MALT1 fusion transcriptscharacteristic of MALT lymphoma were detected by reversetranscription–polymerase chain reaction (RT–PCR).

CLINICAL SUMMARY

A Japanese woman in her mid-sixties complained of abdom-inal discomfort, nausea and vomiting. She was admitted tothe Department of Internal Medicine, Narita Red Cross Hos-pital (Chiba, Japan) in 1997 for the evaluation of peripheraledema, abdominal pain and purpura of the bilateral lowerlegs. She underwent a colonic polypectomy in 1995, but itwas not a neoplastic lesion. In terms of the patient’s familyhistory, her father and mother had colon cancer and gastriccancer, respectively.

The patient weighed 52 kg, had blood pressure of 148/67 mmHg and a regular pulse of 60 beats per minute. Uri-

Intestinal MALT lymphoma 713

nalysis on admission showed a weakly positive (+) test forprotein and a strongly positive (+++) test for occult blood.Initial laboratory tests revealed the following concentrations:serum total protein, 4.5 g/dL; lactate dehydrogenase, 611 IU/l; urinary acid, 8.2 mg/dL; serum C reactive protein concen-tration was elevated, 23.5 mg/dL; and the rheumatoid factorwas positive. Other serum isozymes relating to liver andkidney function were within normal limits. Peripheral bloodand bone marrow aspirates were non-specific, without evi-dence of lymphoproliferative disorders. Immunoserologicalanalyses revealed serum concentrations as follows: IgG,664 mg/dL; IgA, 159 mg/dL; IgM, 47.9 mg/dL; C3, 69.3 mg/dL; and C4, <10 mg/dL. Serum immunoelectrophoresis onspecific antisera revealed the expression of cryoglobulinidentified as a monoclonal kappa type IgM. A percutaneousrenal biopsy was performed, which showed diffuse prolifera-tive glomerulonephritis. X-ray films of the abdomen showedileus-like findings, stenosis and edematous changes of thesmall intestine. A barium enema examination showed ascar-iasis of the small intestine (Fig. 1). An ascaricide was pre-scribed, and one organism of ascarisis lumbricoides wasexcreted. Because the patient’s general status was improvingwith medicinal treatment, she was discharged about 1 monthlater. Subsequent treatment and periodic medical examina-tions were followed-up as an outpatient.

Nineteen months later, the patient complained of hemato-chezia, abdominal distention, pain, orthopnea and bloody,loose stool. She was hospitalized again, and abdominalphysical examinations were performed. A barium enemaexamination revealed a stenosis and edematous changes ofthe small intestine as before. Massive abdominal asciteswere also observed; the cytomorphological findings of whichshowed proliferation of the plasmacytoid, atypical lymphoid

cells. A chromosomal analysis was performed using theabdominal ascites. A Southern blot analysis using adigoxygenin-labeled IgH gene joining region (JH) probe wasperformed using high molecular DNA prepared frommononuclear cells isolated from abdominal ascites, whichexhibited clonal IgH gene rearrangements. Because immu-noglobulin gene rearrangement and chromosomal alterationwas observed, the existence of a lymphoproliferative disorderwas strongly suspected. No peripheral lymphadenopathy,extranodal tumor masses or skeletal lytic lesions wereobserved. Although the patient continuously underwentmedicinal treatment, her general status did not improve.

Ten months later, the patient’s abdominal distention andupper abdominal pain progressed. Despite the possibility ofintestinal perforation, palliative treatment was continuedbecause of the patient’s poor general status. The patient diedof general prostration, considered to have arisen from theintestinal ailment. An autopsy was performed and the diag-nosis of small intestinal malignant lymphoma was confirmed.

PATHOLOGICAL FINDINGS

While the patient was in hospital, yellowish-opaque abdomi-nal ascites were often presented. These sediments werecomposed of small to medium-sized atypical lymphoid cellswith plasmacytoid differentiation. Atypical plasmacytoid cellsvaried from atypical cells resembling mature plasma cellsto multinucleated, pleomorphic plasmacytoid cells (Fig. 2).In the immunocytochemical staining by an indirect methodusing CD20 (L26, DakoCytomation, Glostrup, Denmark),CD79a (JCB117, DakoCytomation) and anti-epithelial mem-brane antigen (E29, DakoCytomation), small to medium-sized atypical lymphoid cells showed the expression of CD20and CD79a. Plasmacytoid atypical cells also expressedCD20 and CD79a, in which the minorities of the atypical cellsshowed expression of epithelial membrane antigen.

In the percutaneous renal biopsy specimen, diffuse prolif-erative glomerulonephritis was observed (Fig. 3). The glom-erulus became swollen with cells, and the glomerularcapillary loops partly adhered to the parietal epithelium. Inendocapillary proliferation, there was a marked increase inglomerular cells and infiltration of the inflammatory cells.These infiltrating cells were composed of histiocytes includ-ing foamy cells and polymorphonuclear leukocytes. Thick-ness of the glomerular basement membrane and doublecontour of the loops was also observed by periodic acid-methenamine-silver (PAM) staining. Occasionally periodicacid–Schiff-positive hyaline material was deposited on thepreglomerular arterioles and tubular epithelium. Immuno-fluorescent staining showed diffuse deposition of IgM (Dako-Cytomation) and C3 (DakoCytomation) along the glomerularbasement membrane (Fig. 3).

Figure 1 Barium enema examination of the upper gastrointestinalregion. Stenosis and an ileus-like lesion was seen (arrow). An organ-ism of ascarisis lumbricoides was also observed (arrowhead).

714 T. Saito et al.

An autopsy was performed approximately 1 h after thepatient’s death. Significant macroscopic findings were pre-dominantly observed in the upper gastrointestinal tract.Widespread stenosis, edematous changes and ulcer forma-tions with focal hemorrhages were observed in the ileum.Autopsy findings suggested the possibility that abnormalfindings such as stenosis and edematous changes of thesmall intestine seen in the physical examinations at ante-mortem might have originated from infiltration of the tumorcells. Intestinal perforation by the infiltrating tumor was alsoobserved in the ileum proximal to the ileocecal valve. Histo-

logical examinations of the resected small intestine indicatedMALT lymphoma (Figs 4,5). Microscopically, malignant lym-phoma cells widely infiltrated the mucosal layer of the ileum,occasionally forming large tumor masses in the submucosallayer. In the region nearby the intestinal perforation, the tumorcells invaded profoundly under the subserosal tissue beyondthe muscularis. Findings of a lymphoepithelial lesion charac-teristic of MALT lymphoma were occasionally observed butnot distinct. Reactive follicular formations were seen in thesubmucosal structures, which were destroyed by the infiltrat-ing tumor. In addition to infiltrating the lungs, liver and spleen,

Figure 2 Cytological findings of theabdominal ascites. Proliferation of theatypical lymphoid cells with plasma-cytoid differentiation was observed. Inthe immunocytochemistry, the tumorcells stained positive for CD79a(inset).

Figure 3 Histological findings of therenal biopsy specimen. (a) The findingsof proliferative glomerulonephritis wasseen (HE stain; original magnification,¥400). (b) Immunofluorescent stainingshowed a diffuse deposition of IgMalong the glomerular basement mem-brane (original magnification, ¥400).

a b

Intestinal MALT lymphoma 715

the tumor cells invaded the bone marrow and lymph nodesaround the abdominal aorta and mesenteric nodes.

The tumor cells consisted of small to medium-sized atypi-cal cells with frequently cleaved nuclei. Atypical cells withplasmacytoid differentiation were also observed. In immuno-histochemical staining with the LSAB method using CD20and CD79a, the tumor cells expressed CD20 and CD79a.Tumor cells with plasmacytoid differentiation cytoplasmicallyshowed expression of IgM and the kappa-light chain byimmunohistochemical staining with the LSAB method usingthe antibodies for IgM (DakoCytomation) and kappa-lightchain (DakoCytomation). G-banded karyotype analysis iden-tified 46, XX, add11 (q13), add18 (q21) (Fig. 6a). To investi-gate the expression of API2-MALT1 fusion transcripts oftenseen in extranodal MALT lymphomas, RT–PCR was per-formed using the primer sets with a common sense primer

covering the known break points on the API2 gene andantisense primers targeting the break points on the MALT1gene (Sigma Genosys Japan Corp, Ishikari, Japan). Primersets, detailed protocol and cycle conditions in each PCRwere fixed by making modifications on procedures contrib-uted by authors.9–11 As shown in Fig. 6b, an API2-MALT1fusion transcript was confirmed in this RT–PCR analysis.

DISCUSSION

In the present article, we reported a case of small intestinalMALT lymphoma with monoclonal cryoglobulinemia. Smallintestinal extranodal MALT lymphomas, but not immuno-proliferative small intestinal diseases (IPSID), are relativelyuncommon.,1–3 To our knowledge, a study mentioning the

Figure 4 Histological findings of the resected small intestine at autopsy. (a) Atypical lymphoid cells infiltrate the superficial mucosa (originalmagnification, ¥200). (b) Tumor cells are composed of medium to large atypical cells with pale cytoplasm and atypical cells with plasmacytoiddifferentiation (original magnification, ¥400).

a b

Figure 5 Histological findings of the resected small intestine at autopsy. (a) A lymphoepithelial lesion is observed (original magnification,¥300). (b) Colonized reactive follicle center is also seen (original magnification, ¥200).

a b

716 T. Saito et al.

relationship between small intestinal MALT lymphoma andmonoclonal cryoglobulinemia has not been reported.

Monoclonal cryoglobulins have been shown in associationwith multiple myeloma, Waldenstroem’s macroglobulinemiaand other lymphoproliferative disorders. Between 5 and 10%of patients with multiple myeloma have cryoprecipitable mon-oclonal proteins.12,13 In this condition, cold perceptibility isusually associated with monoclonal IgG, IgA and Bense–Jones proteins. In contrast, Waldemstroem’s macroglobuline-mia or other lymphoproliferative disorders such as low-gradeB-cell lymphoma or chronic lymphocytic leukemia have IgMwith kappa- or lambda light chain.14,15 The clonal nature ofthe B-cell expansion associated with monoclonal cryoglobu-linemia has been proven in some patients by studies dem-onstrating the rearrangement of responsible immunoglobulin

genes, in which some patients with monoclonal cryoglobu-linemia eventually develop malignant lymphoproliferativedisorders.14 In the present case, an immunoserologicalinvestigation revealed the expression of monoclonal cryoglo-bulins of kappa type IgM. Southern blot analysis disclosed aclonal IgH gene rearrangement. Results of the immunosero-logical and cytogenetic analysis were consistent with theabove clinical features of lymphoproliferative disorders corre-lated to monoclonal cryoglobulinemia.

The cytomorphological features of MALT lymphoma havebeen described in previous reports.16,17 The lymphoma cellsseen in MALT lymphoma have relatively abundant, pale cyto-plasm and small to medium-sized slightly irregular nuclei withmoderately dispersed chromatin and inconspicuous nucleoli.In immunophenotyping, the tumor cells are CD20+, CD79a+,

Figure 6 Results of the chromosomalanalysis and multiplex reverse tran-scription–polymerase chain reaction(RT–PCR). (a) G-banded karyotypewas identified to be a 46, XX, add11(q13), 18(q21) (arrows). (b) Detectionof API2-MALT1 fusion transcript byRT–PCR analysis. The API2-MALT1fusion transcript was found in the sec-ond PCR-B (arrow). N, no template;PA, positive control for second roundPCR-A (primers: PA2, PM1, PM3 andPM5); PB, positive control for secondround PCR-B (PA4, PM1, PM3 andPM5); PC, positive control for PCR-C(PA6, PM1, PM3 and PM5); A–C, RNAsamples extracted from the presentcase (A, using primers for the secondPCR-A; B, second PCR-B; C, secondPCR-C). Beta-actin mRNA is amplifiedin all cases.

a

(b)

404 bp309 bp

147 bp123 bp110 bp

90 bp

190 bpb _actin

N PA PB PB PC A B C

Intestinal MALT lymphoma 717

typically express IgM, but express IgA or IgG less frequently.Light chain restriction is also seen.18

Histological examination of the resected small intestine atautopsy revealed findings of MALT lymphoma with plasma-cytoid differentiation. In the immunocytochemistry, most ofthe tumor cells were CD20+ and CD79a+. Atypical plasma-cytoid cells stained positive for IgM and the kappa chaincytoplasmically. Immunoglobulin light chain restriction wasobserved. The results of the immunocytochemical studiessupported the immunophenotypical characteristics of MALTlymphoma.

In the present case, cytomorphological features of theatypical cells obtained from the abdominal ascites needed todifferentiate from plasma cell myelomas or other malignantlymphomas showing a plasmacytoid differentiation. BecauseMALT lymphoma cells often exhibit differentiation to plasma-cytoid cells, it is necessary to morphologically discriminatebetween the other B-cell lymphomas such as plasma cellmyelomas, follicular lymphomas or lymphoplasmacytic lym-phomas (LPL).19,20 In particular, LPL is one of the most diffi-cult diseases to distinguish from MALT lymphoma. Thetumor cells in LPL consist of small lymphocytes, plasmacy-toid lymphocytes and plasma cells, and the cytomorpholog-ical features often overlap with those of MALT lymphoma.The WHO classification of haematopoietic and lymphoid tis-sue has proposed that the term LPL should be used only insignificant representative cases, and has given the opinionthat malignant lymphomas showing typical morphology inmarginal zone cells or lymphoproliferative disorders withbulky extranodal tumor masses except for the liver, bonemarrow and spleen showing a growth pattern of destructiveinfiltrates of extrafollicular B-cell should be classified asMALT lymphomas.21 In the present case, findings of lym-phoepithelial lesion characteristic of MALT lymphoma wereoccasionally observed. Histological findings were compatiblewith characteristics of MALT lymphoma defined by WHOclassification.

G-banded karyotyping in the present case revealed addi-tional materials in the 11q13 and 18q21 locations. In partic-ular, 18q21 is a region of the MALT1 gene where a correlationwith the development of MALT lymphoma has beenmapped.22 Recent studies disclosed that t(11;18)(q21;q21)translocation has frequently been detected in low-gradeMALT lymphomas, and this translocation has been thoughtto be an important primary event in the development of MALTlymphoma.6,7 T(11;18) leading to API2-MALT1 fusion tran-script was frequently seen in gastrointestinal and pulmonaryMALT lymphomas.23,24 Intestinal MALT lymphomas with API2-MALT1 expression tended to invade the profound layerbeyond the submucosal structure, and the tumor cells showthe disseminations to the local node or distal site.7,25 In thepresent case, the tumor cells widely invaded the submucosallayer of the ileum. Infiltrations to the lungs, liver, spleen, bone

marrow and lymph nodes around the abdominal aorta andmesenteric nodes were also observed. These infiltrationforms are in agreement with those of gastrointestinal MALTlymphomas with API2-MALT1 fusion transcripts. Becauseintestinal MALT lymphomas with API2-MALT1 expressionhave distinctive forms of infiltration compared with those with-out translocation, detection of API2-MALT1 fusion transcriptsis useful for evaluating the prognosis and clinical behavior ofthe disease.

In the present case, G-banded karyotyping revealed addi-tional materials in chromosome 11q13 and 18q21. Thesechromosomal findings differed from typical translocationseen in MALT lymphoma with API2-MALT1 expression. API2-MALT1 fusion might be concerned cryptically with chromo-somal abnormalities in the genetic phase. Most likely,because various translocations would conspire to occur afterAPI2-MALT1 fusion, representative chromosomal transloca-tion might not be observed morphologically.

As has been mentioned, expression of monoclonal cryo-globulin was identified by immunoserological investigationsin the present case. The relationships between primary mono-clonal macroglobulinemia and MALT lymphoma has beendiscussed in previous reports, in which the monoclonal com-ponent of serum IgM was observed frequently in MALT lym-phomas with t(11:18).26–28 In patients with mature B-cellneoplasms, findings of glonerulonephritis by cryoglobulindeposition frequently occur as in the present case.29 If abnor-mal serum proteins with monoclonal structures are identified,it might be necessary to perform detailed investigations inorder to distinguish the lymphoproliferative disorders. In thepresent case, findings suggesting the existence of malignantlymphoma were mainly observed in cytological examinationsof the abdominal ascites at ante-mortem. Detailed cytomor-phological and cytogenetic analysis of atypical lymphoid cellsobtained from abdominal serous effusions was useful forestablishing the diagnosis of malignant lymphoma.

Incidentally, the patient in the current case presented withan infection of ascarisis lumbricoides. Because the patient’sintestinal ailments continued and her general status did notseem to improve, although medicinal treatment was used totreat the infection of ascarisis lumbricoides, we concludedthat the intestinal ailments seen in the present case wererelated to the development of malignant lymphoma ratherthan the association with infectious diseases. However, someauthors have suggested that several bacterial inflammatorydiseases or autoimmune diseases might form the substratefor MALT lymphoma development.30,31 Recently, a case ofMALT lymphoma combined with tuberculous enteritis at thesame site in the jejunum was described.32 We could not findany previous reports suggesting a relationship betweenMALT lymphoma development and parasitization as a pre-cursor lesion. Further research regarding the correlationbetween the incidence of MALT lymphoma and chronic

718 T. Saito et al.

inflammation originating from various infectious conditions isrequired.

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