INTRODUCTION

Mucosa-associated lymphoid tissue (MALT) lymphomas arise in numerous extranodal sites such as the stomach, salivary gland and thyroid, most of which lack native lymphoid tissue but acquire MALT in close association with chronic inflammation or autoimmune processes. MALT lymphomas appear to have similar clinical, pathological and molecular features regardless of organs of origin (1).

The ocular adnexal region is also a site predisposed to MALT lymphoma. Malignant lymphomas in this site have been subject to diagnostic dilemma because they are composed predominantly of small lymphoma cells often lacking distinct cellular atypia, some of which have an appearance very close to that of small lymphocytes (2). Therefore, it is often difficult to make a differential diagnosis between lymphoma and reactive lymphoid hyperplasia (RLH). In some previous studies, malignant lymphomas and RLH were not clearly distinguished, and they were categorized together as a lymphoproliferative disorder (3). Some investigators have recently reported clinicopathological features of orbital lymphoproliferative disorders along with the identification of MALT lymphoma (4, 5, 6, 7), but few of them referred to the details of RLH.

In the present study, we attempted to characterize clinicopathologic features of ocular adnexal lymphoproliferative disorders, focusing in particular on MALT lymphomas and RLH. We also conducted molecular genetic studies to determine whether MALT lymphomas of this site have characteristics similar to those of other extranodal sites.

MATERIALS AND METHODS

Cases, Diagnostic Criteria, and Clinical Information

Cases involving orbital adnexal region were retrieved from the files between 1989 and 1999 in the Department of Pathology, Okayama University Medical School. All of these cases had hematoxylin and eosin-stained (H & E) sections available for reevaluation, by which 76 consecutive cases of lymphoproliferative disorders were chosen for this study. All patients were Japanese adults. Immunohistochemical staining was performed using an avidin-biotin-peroxidase technique with the following antibodies: monoclonal antibodies (MAbs) to Ig and Ig obtained from Novocastra Lab Co. Ltd (Newcastle, U.K.), MAbs to Bcl-2, CD20, CD79a and CD45RO and polyclonal antibodies to CD3 from DAKO Japan (Tokyo, Japan), and MAb to cyclin D1 from Zymed Co. Ltd. (So-SF, CA). Snap-frozen sections were also made in 25 of the cases, and rearrangement of Ig genes was examined by Southern blot analysis using a probe for the joining region of Ig heavy chain (IgH) and for the T-cell receptor (TCR) beta chain. The cases were subdivided into RLH, atypical lymphoid proliferation (borderline lesions) and lymphomas based on histomorphological and immunohistological features (Fig. 1). Definite lymphomas were classified according to the Revised European-American Lymphoma (REAL) classification (8). MALT lymphomas were diagnosed not only histologically but also by confirming the clonality by immunohistochemical Ig light-chain restriction. Immunogenotypic analysis by Southern blotting was also performed in 5 cases. Histological criteria for diagnosis of MALT lymphomas corresponded to the description by Isaacson and Norton (2). The clinical information of each patient, including therapeutic and follow-up data, was obtained from the medical records and, if needed, from physician. Primary ocular adnexal lymphoma was confined to the cases in which symptoms of the orbital lesion preceded those of the extraorbital involvement by more than 5 months and it was regarded as important that the primary orbital tumor was more larger than any other lesions at diagnosis. The anatomic localization of the lesions was defined as proposed by Knowles et al. (9) but was slightly modified. Briefly, ocular adnexal area was subdivided into eyelid, conjunctiva and orbit, but those involving the lacrimal glands (superolateral anterior orbit) and the lacrimal sac were documented separately.

FIGURE 1.

Primary MALT lymphoma of the conjuctiva (A, B) and reactive lymphoid hyperplasia in the lacrimal gland (C, D). A (case 17) and B (case 25): note monotonous infiltration of centrocyte-like cells with Dutcher bodies. C and D (case 57): note hyperplastic reactive follicles occupying the lacrimal gland. Lymphocytes in the interfollicular areas show no atypia.

Full figure and legend (38K)

DNA Amplification and Detection of Clonality

DNA was extracted from unstained, formalin-fixed, paraffin-embedded samples prepared according to a previously published method (10). Amplification of IgH genes was performed by seminested PCR, using primers directed to the framework 2 region and to the joining region (JH) as described previously (11). At least two DNA samples were extracted from each paraffin block and separately subjected to PCR reaction. The DNA amplification of each material was carried out more than once. The amplified products from each patient were electrophoresed in parallel. The determination as 'clonal' was made only when a single or dominant discrete band was consistently reproduced from different specimens.

Analysis of Nucleotide Sequences

DNA was recovered from the clonal bands and directly sequenced using an ABI sequencer with dye terminators (Perkin Elmer, Warington, UK). Sequence primers were identical to the primers used in the second PCR. All sequencing was performed in both directions. The sequence data was adopted only when the results from at least two independent PCR reactions were completely consistent. The identification of the VH gene, Ig diversity (D) genes, and JH genes for germline sequences was performed by comparing those genes with the V Base, a comprehensive database of human Ig germline gene sequences compiled from published sequences (V BASE sequence directory, I.m. Tomlinson, MRC Center for Protein Engineering, Cambridge, UK). The sequence analysis software Genetyx (Software Development, Tokyo, Japan) was used. For the germline D gene attribution, the longest homology was adopted with a minimum of six successive matches or seven successive matches, interrupted by one mismatch (12).

Statistical Analysis

To compare the average ages, we used the Student's t test. Other comparisons were made by Fisher's exact test.

RESULTS

Clinicopathological Features

Out of 76 patients, 52 patients were diagnosed with malignant lymphomas, 22 with RLH, and 2 with atypical lymphoid proliferation since they lacked the morphological features of definite lymphoma or B-cell clonality in spite of the proliferating behavior which suggested lymphoma. All of the malignant lymphomas showed B-cell phenotype by immunohistochemistry (CD20 or CD79a) but not T-cell phenotype (CD3 or CD45RO). All of follicular lymphoma and mantle cell lymphoma displayed positivity to MAbs to Bcl-2 and Cyclin D1, respectively. The age of the patients (43 males and 33 females) ranged from 23 to 86 years (mean, 59.3 years). The follow-up period was from 0 to 120 months except for 9 patients who were lost to follow-up. The chief complaints were periorbital swelling (41%), palpable mass (28%) and irritation or pain (28%), followed by proptosis, conjunctival hyperemia, conjunctival mass and diplopia. There was no difference in terms of these complaints between those with lymphoma and those with RLH.

The frequency and clinical features of each diagnostic category are summarized in Tables 1, 2, 3, 4 and 5. The most common primary lymphoma of the ocular adnexa was MALT lymphoma. The periods from the onset of symptoms to the diagnosis varied from 1 to 160 months (mean, 18.8 months) except in the case of one patient who had an extraordinarily long clinical course and had been under the observation for over 25 years as a case of 'pseudolymphoma' without disease manifestation outside the orbit (case 14). MALT lymphoma was confined to the primary site in all patients except one who presented with a clinical stage IIEA disease and who relapsed 82 months after the diagnosis (case 6). Local treatment was chosen for most patients with MALT lymphoma, but no patients died of the lymphoma during the follow-up period ranging from 1 to 120 months (mean, 32 months) except for 2 patients who were lost to follow-up. Compared to the primary non-MALT type ocular adnexal lymphoma, MALT lymphoma tended to be more localized (P < 0.05) and less frequently resulted in disease-related death (P < 0.05), but there was no statistical difference in terms of the age of the patients, the site of intraorbital involvement, bilaterality of the tumor or future relapse (Table 6).

TABLE 1 - Histologic and Immunophenotypic Classification of 76 Ocular Adnexal Lymphoproliferative Disorders.

Full table

TABLE 2 - Primary Ocular Adnexal Lymphomas.

Full table

TABLE 3 - Secondary or Concurrent Ocular Adnexal Lymphomas.

Full table

TABLE 4 - Reactive Lymphoid Hyperplasia.

Full table

TABLE 5 - Summary of Clinical Features of Ocular Adnexal Lymphoproliferative Disorders at Presentation.

Full table

TABLE 6 - Incidence of Clinical Parameters According to the Histological Classification of the Primary Ocular Adnexal Lymphoma.

Full table

Patients with RLH had a duration of chief complaints ranging from 2 to 132 months (mean, 18.6 months). The lacrimal gland was involved more frequently in RLH than in MALT lymphoma and other primary ocular adnexal lymphomas (P < 0.001). One of the patients with RLH developed systemic diffuse large B-cell lymphoma 83 months after the initial presentation but without orbital involvement (case 53). The average age of the patients with RLH, MALT lymphoma and diffuse large B-cell lymphoma was 54.8, 60.3 and 65.2 years, respectively (statistically not significant).

Detection of Ig Gene Rearrangement Using PCR

PCR analysis was performed on DNA extracted from the specimens of 37 cases of primary ocular malignant lymphoma and 19 of RLH. Rearranged IgH genes were detected in 57% of malignant lymphomas (55% of MALT lymphomas and 60% of diffuse large B-cell lymphomas) and 0% of RLH. In a patient with diffuse large B-cell lymphoma, the right lacrimal gland morphologically exhibited an RLH pattern and immunohistologically demonstrated no Ig light chain restriction, and the left lacrimal gland displayed diffuse large B-cell lymphoma (case 38). Interestingly, however, the same monoclonal PCR band of the amplified IgH gene DNA was detected in both lesions, which implied that the RLH-like lesion of the right lacrimal gland harbored lymphoma cells (data not shown).

Analysis of VH Family Usage of MALT Lymphoma

PCR products from 10 patients with primary ocular adnexal MALT lymphoma were unselectively subjected to direct sequencing. The assignment of the sequences to VH families and germlines indicated biased usages of some germlines (Table 7). The DP-63 gene was found to be utilized in all 3 cases of MALT lymphoma using VH4 family genes. DP-54 and DP-47 genes were used in 2 of the 7 cases which expressed the VH3 families, respectively. Homology to the germline nucleotide sequences varied from 81.9% to 98.6% with an average of 92.6%. The usage of D and JH germlines seemed to be randomly distributed. The length of the CDR3 was diverse, with a mean of 23.1 nucleotides.

TABLE 7 - Sequence Analysis of the Immunoglobulin Heavy-Chain Genes (IgH) Expressed in the Primary Ocular Adnexal MALT Lymphoma.

Full table

DISCUSSION

MALT lymphoma has been reported to occur in the ocular adnexa (13, 14). In the present study, MALT lymphoma constituted 86% of the classifiable primary ocular adnexal lymphomas. This rate is higher than the 50–64% rate in previous reports (4, 6) but is consistent with the rate reported by a study from Japan (7). This discrepancy possibly reflects the low incidence of follicular lymphoma and chronic lymphocytic lymphoma/leukemia in countries of the far east (15, 16). MALT lymphoma is a very indolent lymphoma and remains a localized disease for a long period of time. In our study, only one case (3%) showed extraorbital involvement; this incidence was lower than that of the previous reports (4, 6, 7).

Some authors have used PCR analysis to detect IgH clonality of ocular adnexal lymphoid lesions (5, 6, 14, 17, 18, 19, 20), but it is not clear how often PCR reveals the clonality of ocular adnexal MALT lymphomas. We detected a monoclonal B-cell growth in 55% of the cases of MALT lymphoma by using PCR; in general, the PCR technique demonstrates the presence of a monoclonal B-cell population in 25 to 70% of the cases of MALT lymphoma (21).

The sequencing study of the VH gene revealed that the VH3 family was predominantly utilized in the ocular adnexal MALT lymphomas, a finding which is compatible with that of the other recent reports (22, 23). In addition, DP-63, DP-54 and DP-47, which are reported to be frequently involved in autoantibody production (24, 25, 26, 27), were the closest germline VH genes in 7 of 10 cases examined. Frequent utilization of the germline VH genes associated with autoantibody production is also a distinctive feature of MALT lymphoma arising in other anatomical sites (28, 29, 30, 31, 32, 33). These findings strongly suggest that ocular adnexal MALT lymphoma also belongs to the same category as that of marginal zone B-cell lymphoma. It is interesting to note, however, that the germline usage in the salivary gland MALT lymphoma differs quite a bit from that of our analysis (Table 8; 34, 35, 36, 37, 38). In the salivary gland the VH1 family genes were preferentially used and almost all of them were V1–69 (DP-10) genes (32, 33, 37) and not DP-63. In our study, all VH4 cases utilized DP-63. This distinct difference in VH gene usage does not seem to occur accidentally. Antigens which are involved in inducing chronic inflammation or autoimmune processes preceding MALT lymphoma may differ according to the anatomical sites.

TABLE 8 - Frequency of VH Family Usage in Primary Ocular Adnexal MALT Lymphoma: Comparison with Low-Grade MALT Lymphoma of Other Organs and Adult Peripheral B Cells.

Full table

In our study, one (5%) of the patients with RLH developed lymphomas afterward. Previous studies reported that 21 to 29% of patients with RLH of the ocular adnexa develop lymphomas (3, 9, 39), which is a relatively higher rate than ours. This might be due to differences in the diagnostic criteria.

The average age of patients with MALT lymphoma was 5.5 years older than that of patients with RLH. This may reflect the malignant progression of the reactive phase, although the difference in age distribution was not statistically significant (P = 0.16). Polito et al. (5) reported that some cases of orbital non-Hodgkin's lymphoma were preceded by polyclonal lymphoid hyperplasia. We found that RLH involved lacrimal glands at a significantly high rate. The lacrimal gland is often affected with chronic inflammation as is also the case in the salivary glands. The presence of autoantibodies or Sjögren's syndrome is an interesting issue to investigate, but it was not satisfactorily addressed in the present study.

Immunogenotypic studies revealed that none of the cases of RLH showed clonal B-cell proliferation. Previously, some RLH cases were reported to be clonal according to PCR (5, 17, 18). It is possible that such cases contained lymphomatous elements since some of those cases of RLH showed Dutcher's bodies or immunohistological Ig light chain restriction. Nonetheless, it should be noted that PCR may detect a small monoclonal population of lymphoid cells in the absence of clinical or histological evidence of lymphoma. Hsi et al. (40) reported that a monoclonal PCR pattern was present in 15% of patients with chronic active gastritis associated with Helicobacter pylori, although none of them developed lymphoma during a median follow-up period of 58 months, ranging from 1 to 66 months. Whether similar findings would be observed in ocular adnexal lymphoid lesions is a subject for investigation.

Low-grade MALT lymphomas sometimes show high-grade transformations. In our study, low- and high- grade components coexisted in the specimens of two cases. These cases strongly indicate that some large-cell lymphomas can originate from a high-grade transformation of MALT lymphomas, even if not all of them do. The average age of patients with diffuse large B-cell lymphoma was 4.5 years older than that of patients with MALT lymphomas, but the difference was not statistically significant.

In conclusion, the ocular adnexal lymphoproliferative disorders were diagnosed according to the REAL Classification of lymphoid neoplasms and related to the clinical data. The detection of B-cell clonality by means of PCR analysis improved the accuracy of the diagnosis. A major proportion of the primary lymphoid proliferation were divided into RLH, MALT lymphoma and diffuse large B-cell lymphoma. As reported for the gastric lymphoma, MALT lymphoma may arise from RLH and in part transform into diffuse large B-cell lymphoma, with cell proliferation presumably driven by stimulation of antigens involved in autoimmune mechanisms. The pathogen which triggers the neoplastic process in the ocular adnexa was considered to be different from that which triggers the MALT lymphoma of other organs based on molecular genetic analysis.

References

1. Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. Semin Hematol 1999; 36: 139–147. | PubMed | ISI | ChemPort |
2. Isaacson PG, Norton AJ. Extranodal lymphomas. Edinburgh, UK: Churchill Livingstone; 1994.
3. Knowles DM, Jakobiec FA. Orbital lymphoid neoplasms: a clinicopathologic study of 60 patients. Cancer 1980; 46: 576–589. | PubMed | ISI |
4. White WL, Ferry JA, Harris NL, Grove AS Jr. Ocular adnexal lymphoma. A clinicopathologic study with identification of lymphomas of mucosa-associated lymphoid tissue type. Ophthalmology 1995; 102: 1994–2006. | PubMed | ISI | ChemPort |
5. Polito E, Galieni P, Leccisotti A. Clinical and radiological presentation of 95 orbital lymphoid tumors. Graefes Arch Clin Exp Ophthalmol 1996; 234: 504–509. | PubMed | ISI | ChemPort |
6. Coupland SE, Krause L, Delecluse HJ, Anagnostopoulos I, Foss HD, Hummel M, et al. Lymphoproliferative lesions of the ocular adnexa. Analysis of 112 cases. Ophthalmology 1998; 105: 1430–1441. | Article | PubMed | ISI | ChemPort |
7. Nakata M, Matsuno Y, Katsumata N, Takenaka T, Kobayashi Y, Narabayashi M, et al. Histology according to the Revised European-American Lymphoma Classification significantly predicts the prognosis of ocular adnexal lymphoma. Leuk Lymphoma 1999; 32: 533–543. | PubMed | ISI | ChemPort |
8. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–1392. | PubMed | ISI | ChemPort |
9. Knowles DM, Jakobiec FA, McNally L, Burke JS. Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and eyelids): a prospective multiparametric analysis of 108 cases during 1977 to 1987. Hum Pathol 1990; 21: 959–973. | Article | PubMed | ISI | ChemPort |
10. Wright DK, Manos MM. Sample preparation from paraffin-embedded tissues. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ, editors. PCR protocols: a guide to methods and applications. San Diego: Academic Press; 1990. p. 153–158.
11. Ramasamy I, Brisco M, Morley A. Improved PCR method for detecting monoclonal immunoglobulin heavy chain rearrangement in B cell neoplasms. J Clin Pathol 1992; 45: 770–775. | PubMed | ISI | ChemPort |
12. Corbett SJ, Tomlinson IM, Sonnhammer ELL, Buck D, Winter G. Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, "minor" D segments or D-D recombination. J Mol Biol 1997; 270: 587–597. | Article | PubMed | ISI | ChemPort |
13. Medeiros LJ, Harris NL. Lymphoid infiltrates of the orbit and conjunctiva. A morphologic and immunophenotypic study of 99 cases. Am J Surg Pathol 1989; 13: 459–471. | PubMed | ISI | ChemPort |
14. Wotherspoon AC, Diss TC, Pan LX, Schmid C, Kerr-Muir MG, Lea SH, et al. Primary low-grade B-cell lymphoma of the conjunctiva: a mucosa-associated lymphoid tissue type lymphoma. Histopathology 1993; 23: 417–424. | PubMed | ISI | ChemPort |
15. Shih LY, Liang DC. Non-Hodgkin's lymphomas in Asia. Hematol Oncol Clin North Am 1991; 5: 983–1001. | PubMed | ISI | ChemPort |
16. The T- and B-Cell Malignancy Study Group. Statistical analyses of clinico-pathological, virological and epidemiological data on lymphoid malignancies with special reference to adult T-cell leukemia/lymphoma: a report of the second nationwide study of Japan. The T- and B-Cell Malignancy Study Group. Jpn J Clin Oncol 1985; 15: 517–535.
17. Takano Y, Okudaira M. Molecular-genetic analysis of ocular adnexal benign lymphoid hyperplasias by a two-step polymerase-chain-reaction. J Cancer Res Clin Oncol 1992; 118: 581–586. | PubMed | ISI | ChemPort |
18. Ohshima K, Kikuchi M, Sumiyoshi Y, Kobari S, Yoneda S, Takeshita M, et al. Clonality of benign lymphoid hyperplasia in orbit and conjunctiva. Pathol Res Pract 1994; 190: 436–443. | PubMed | ISI | ChemPort |
19. Hardman-Lea S, Kerr-Muir M, Wotherspoon AC, Green WT, Morell A, Isaacson PG. Mucosal-associated lymphoid tissue lymphoma of the conjunctiva. Arch Ophthalmol 1994; 112: 1207–1212. | PubMed | ChemPort |
20. White VA, Gascoyne RD, McNeil BK, Chang WY, Brewer LV, Rootman J. Histopathologic findings and frequency of clonality detected by the polymerase chain reaction in ocular adnexal lymphoproliferative lesions. Mod Pathol 1996; 9: 1052–1061. | PubMed | ISI | ChemPort |
21. Bertoni F, Cotter FE, Zucca E. Molecular genetics of extranodal marginal zone (MALT-type) B-cell lymphoma. Leuk Lymphoma 1999; 35: 57–68. | PubMed | ISI | ChemPort |
22. Kon H, Sato T, Suzuki J, Kon S. Molecular analysis of ocular adnexal lymphoid proliferations. Characteristics of immunoglobulin VH, D and J segment usage. Pathol Res Pract 1996; 192: 523–531. | PubMed | ISI | ChemPort |
23. Coupland SE, Foss HD, Anagnostopoulos I, Hummel M, Stein H. Immunoglobulin VH gene expression among extranodal marginal zone B-cell lymphomas of the ocular adnexa. Invest Ophthalmol Vis Sci 1999; 40: 555–562. | PubMed | ISI | ChemPort |
24. Pascual V, Victor K, Lelsz D, Spellerberg MB, Hamblin TJ, Thompson KM, et al. Nucleotide sequence analysis of the V regions of two IgM cold agglutinins. Evidence that the VH4–21 gene segment is responsible for the major cross-reactive idiotype. J Immunol 1991; 146: 4385–4391. | PubMed | ISI | ChemPort |
25. Williams DG, Taylor PC. Clonal analysis of immunoglobulin mRNA in rheumatoid arthritis synovium: characterization of expanded IgG3 populations. Eur J Immunol 1997; 27: 476–485. | PubMed | ISI | ChemPort |
26. Mitamura K, Suenaga R, Wilson KB, Abdou NI. V gene sequences of human anti-ssDNA antibodies secreted by lupus-derived CD5-negative B cell hybridomas. Clin Immunol Immunopathol 1996; 78: 152–160. | Article | PubMed | ISI | ChemPort |
27. Dersimonian H, Long A, Rubinstein D, Stollar BD, Schwartz RS. VH genes of human autoantibodies. Int Rev Immunol 1990; 5: 253–264. | PubMed | ChemPort |
28. Qin Y, Greiner A, Trunk MJ, Schmausser B, Ott MM, Müller-Hermelink HK. Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma. Blood 1995; 86: 3528–3534. | PubMed | ISI | ChemPort |
29. Kurosu K, Yumoto N, Mikata A, Taniguchi M, Kuriyama T. Monoclonality of B-cell lineage in primary pulmonary lymphoma demonstrated by immunoglobulin heavy chain gene sequence analysis of histologically non-definitive transbronchial biopsy specimens. J Pathol 1996; 178: 316–322. | Article | PubMed | ISI | ChemPort |
30. Du M, Diss TC, Xu C, Peng H, Isaacson PG, Pan L. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 1996; 10: 1190–1197. | PubMed | ISI | ChemPort |
31. Chapman CJ, Dunn-Walters DK, Stevenson FK, Hussell T, Isaacson PG, Spencer J. Sequence analysis of immunoglobulin variable region genes that encode autoantibodies expressed by lymphomas of mucosa associated lymphoid tissue. J Clin Pathol: Mol Pathol 1996; 49: M29–M32. | ISI | ChemPort |
32. Bahler DW, Miklos JA, Swerdlow SH. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood 1997; 89: 3335–3344. | PubMed | ISI | ChemPort |
33. Miklos JA, Swerdlow SH, Bahler DW. Salivary gland mucosa-associated lymphoid tissue lymphoma immunoglobulin V(H) genes show frequent use of V1–69 with distinctive CDR3 features. Blood 2000; 95: 3878–3884. | PubMed | ISI | ChemPort |
34. Du MQ, Xu CF, Diss TC, Peng HZ, Wotherspoon AC, Isaacson PG, et al. Intestinal dissemination of gastric mucosa-associated lymphoid tissue lymphoma. Blood 1996; 88: 4445–4451. | PubMed | ISI | ChemPort |
35. Qin Y, Greiner A, Hallas C, Haedicke W, Müller-Hermelink HK. Intraclonal offspring expansion of gastric low-grade MALT-type lymphoma: evidence for the role of antigen-driven high-affinity mutation in lymphomagenesis. Lab Invest 1997; 76: 477–485. | PubMed | ISI | ChemPort |
36. Tierens A, Delabie J, Pittaluga S, Driessen A, DeWolf-Peeters C. Mutation analysis of the rearranged immunoglobulin heavy chain genes of marginal zone cell lymphomas indicates an origin from different marginal zone B lymphocyte subsets. Blood 1998; 91: 2381–2386. | PubMed | ISI | ChemPort |
37. Bahler DW, Swerdlow SH. Clonal salivary gland infiltrates associated with myoepithelial sialadenitis (Sjögren's syndrome) begin as nonmalignant antigen-selected expansions. Blood 1998; 91: 1864–1872. | PubMed | ISI | ChemPort |
38. Zouali M, Theze J. Probing VH gene-family utilization in human peripheral B cells by in situ hybridization. J Immunol 1991; 146: 2855–2864. | PubMed | ISI | ChemPort |
39. Polito E, Leccisotti A. Prognosis of orbital lymphoid hyperplasia. Graefes Arch Clin Exp Ophthalmol 1996; 234: 150–154. | PubMed | ISI | ChemPort |
40. Hsi ED, Greenson JK, Singleton TP, Siddiqui J, Schnitzer B, Ross CW. Detection of immunoglobulin heavy chain gene rearrangement by polymerase chain reaction in chronic active gastritis associated with Helicobacter pylori. Hum Pathol 1996; 27: 290–296. | PubMed | ISI | ChemPort |