ABSTRASTS on MALT lymphoma and Salivary Glands

0) Br J Cancer 2000 Aug;83(4):454-7

Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma.

Raderer M, Vorbeck F, Formanek M, Osterreicher C, Valencak J, Penz M, Kornek G, Hamilton G, Dragosics B, Chott A

Department of Internal Medicine I, University of Vienna, Austria.

Lymphoma of the mucosa-associated lymphoid tissue (MALT) type usually arises in MALT acquired through chronic antigenic stimulation triggered by persistent infection and/or autoimmune processes. Due to specific ligand-receptor interactions between lymphoid cells and high-endothelial venules of MALT, both normal and neoplastic lymphoid cells display a pronounced homing tendency to MALT throughout the body. In the case of neoplastic disease these homing properties may be responsible for lymphoma dissemination among various  MALT-sites. According to this concept, we have standardized staging procedures in all patients diagnosed with MALT-type lymphoma. All patients with MALT-type lymphoma underwent standardized staging procedures before treatment. Staging included ophthalmologic examination, otolaryngologic investigation, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen and bone marrow biopsy. Biopsy was performed in all lesions suggestive for lymphomatous involvement, and evaluation of all biopsy specimens was performed by a reference pathologist. 35 consecutive patients with histologically verified MALT-type lymphoma were admitted to our department. Twenty-four patients (68%) had primary involvement of the stomach, five (15%) had lymphoma of the ocular adnexa, three(8.5%) had lymphoma of the parotid, and three (8,5%) of the lung. Lymph-node involvement corresponding to stage EII disease was found in 13 patients (37%), only one patient with primary gastric lymphoma had local and supradiaphragmatic lymph-node involvement (stage EIII). Bone marrow biopsies were negative in all patients. Overall, eight of 35 patients (23%) had simultaneous biopsy-proven involvement of two MALT-sites: one patient each had lymphoma of parotid and lacrimal gland, conjunctiva and hypopharynx, conjunctiva and skin, lacrimal gland and lung, stomach and colon, and stomach and lung. The remaining two patients had bilateral parotideal lymphoma. Staging work-up was negative for lymph-node involvement in all of these eight patients. The importance of extensive staging in MALT-type lymphoma is emphasized by the demonstration of multiorgan involvement in almost a quarter of patients. In addition, our data suggest that extra-gastrointestinal MALT-type lymphoma more frequently occurs simultaneously at different anatomic sites than MALT-type lymphoma involving the GI-tract.

1) J Dermatol 2000 Jul;27(7):450-2

Salivary gland MALT lymphoma associated with Helicobacter pylori infection in a patient with Sjogren's Syndrome.

Nishimura M, Miyajima S, Okada N

Department of Dermatology, Osaka Kosei-nenkin Hospital, Japan.

We report a case of salivary gland MALT lymphoma in Sjogren's syndromeassociated with localized H. pylori infection. A 76-year-old woman had a history of bilateral cheek masses for two years. Histologically, the parotid glands were invaded by numerous centrocyte-like cells to form lymphoepithelial lesions. The tumor cells showed immunohistological differentiation into B cells. Southern blotting demonstrated immunoglobulin gene rearrangement. These results indicated that the tumors were MALT lymphoma. H. pylori, as assessed by the urease test(CLO test; BML Ltd., Tokyo, Japan), was positive in the tumor specimen. After wide local excision of the tumors followed by radio therapy and oral administration of antibiotics and proton pump inhibitor, no evidence of recurrence was found during the 24-months of follow up. H. pylori infection in the salivary gland is rare, although the source of infection and transmission of H. pylori organisms has been thought to be the oral cavity. We discussed the association between H. pylori infection and salivary gland MALT lymphoma. The microorganism may play a role as an additional antigenic stimulus for the development of salivary gland MALT lymphoma as well as for the development of gastric MALT lymphoma. This means that H. pylori can play a role in lymphoma progression as booster of B cell lymphoproliferation.

2) Am J Dermatopathol 2000 Jun;22(3):205-11

Extranodal marginal zone B-cell lymphoma of the skin: a morphologic and immunophenotypic study of 11 cases.

Tomaszewski MM, Abbondanzo SL, Lupton GP

Department of Dermatopathology, Armed Forces Institute of Pathology, Washington,

District of Columbia 20306-6000, USA

Extranodal marginal zone B-cell lymphoma (MZBL) is a recently recognized low-grade lymphoma that has been well described in other organs such as the stomach and salivary gland. It has only recently been described in skin, where it may be difficult to distinguish from reactive processes and other types of B-cell lymphoma such as follicle center lymphoma. These cases may have been classified as pseudolymphomas in the past. Extranodal MZBL was referred to as mucosa-associated lymphoid tissue (MALT) lymphoma before the Revised European-American Classification of Lymphoid Neoplasms was published in 1994. Important histologic features that aid in the diagnosis of MALT lymphoma are atypical lymphocytes (centrocyte-like and monocytoid B cells) often admixed with plasmacytoid lymphocytes, a prominent plasma cell component, lymphoepithelial lesions, intranuclear inclusions (Dutcher bodies), and reactive germinal centers that may be colonized by neoplastic cells. Immunophenotypic studies demonstrating a B-cell phenotype, light chain restriction, coexpression of CD43, and staining of atypical lymphocytes with bcl-2 support a diagnosis of MALT lymphoma. We studied 11 cases of extranodal MZBL of the skin from the Armed Forces Institute of Pathology files. There were six women and five men ranging in age from 30 to 69 years (median, 54 years). The anatomical sites included the trunk, head and neck areas, and upper extremities. There were no other sites of disease besides the skin in any of the cases. The follow-up period ranged from 5 months to 8 years (median, 24 months). Histologic results included an atypical lymphoid infiltrate with B-cell phenotype, reactive germinal centers, and a variable plasma cell component in all cases. No Dutcher bodies or lymphoepithelial lesions were noted. Extranodal MZBL of skin is a diagnostic challenge because of a heterogeneous cellular infiltrate that may be interpreted as a reactive process. The most significant neoplasm with which it is confused is follicular lymphoma. It is important to recognize the characteristic histologic and immunophenotypic features of extranodal MZBL so that the appropriate therapeutic approach may be applied.

3) Ann Med Interne (Paris) 2000 Mar;151(2):93-6

Gougerot-Sjogren syndrome disclosed by MALT lymphoma of the salivary glands.Report of 3 cases

Chehata S, Laatiri MA, Bouaouina N, Bouzouita K, Slimane K, Mokni M, Korbi S, Bouzouita H, Ennabli S

Service d'Hematologie Clinique, CHU Farhat-Hached, Sousse, Tunisie.

Sjogren's syndrome is characterized by an increased risk of developing non-Hodgkin's lymphoma. The lymphoma is most frequently extra-nodal, preferentially affecting the salivary gland: low-grade MALT lymphoma. Conversely, underlying Sjogren's syndrome has been recently identified by some authors in patients with non-Hodgkin's lymphoma. In the present report, we present three cases of Sjogren's syndrome disclosed by low-grade salivary gland MALT lymphoma. The patients were all women aged 33, 38 and 52 years. Extension work-up revealed nodal and bone marrow involvement in one case and no evidence of disseminated disease in the two others. Using the European criteria, all of our patients had certain Sjogren's syndrome. Labial salivary gland biopsy and immunopathological studies in newly diagnosed low-grade MALT lymphoma would be helpful in identifying the real frequency of this association.

4) Blood 2000 Jun 15;95(12):3878-84

Salivary gland mucosa-associated lymphoid tissue lymphoma immunoglobulin V(H) genes show frequent use of V1-69 with distinctive CDR3 features.

Miklos JA, Swerdlow SH, Bahler DW

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.

Salivary gland mucosa associated lymphoid tissue (MALT) type lymphomas are B-cell neoplasms that develop out of a reactive infiltrate, often associated with Sjogren's syndrome. Previous reports from our laboratory involving 10 patients suggested these lymphomas expressed a restricted immunoglobulin (Ig) V(H) gene repertoire with over use of V1-69 gene segments. To better determine the frequency of V1-69 use and whether there may also be selection for CDR3 structures, we sequenced the V(H) genes from 15 additional cases. Over half of the potentially functional V(H) genes (8 of 14) used a V(H)1 family V1-69 gene segment, whereas the other cases used different gene segments from the V(H)1 (V1-46), V(H)3 (V3-7, V3-11, V3-30.3, V3-30.5), and V(H)4 (V4-39) families. The 8 V1-69 V(H) genes used 5 different D segments in various reading frames, but all used a J4 joining segment. The V1-69 CDR3s showed remarkable similarities in lengths (12-14 amino acids) and stretches of 2 to 3 amino acids between the V-D and D-J junctions. They did not resemble CDR3s typical of V1-69 chronic lymphocytic leukemias. This study extends our earlier work in establishing that salivary gland MALT lymphomas represent a highly selected B-cell population. Frequent use of V1-69 appears to differ from MALT lymphomas that develop at other sites. The high degree of CDR3 similarity among the V1-69 cases suggests that different salivary gland lymphomas may bind similar, if not identical epitopes. Although the antigen specificities are presently unknown, similar characteristic CDR3 sequences are often seen with V1-69 encoded antibodies that have anti-IgG or rheumatoid factor activity.

5) Nihon Rinsho Meneki Gakkai Kaishi 2000 Feb;23(1):49-56

Sjogren's syndrome with MALT (mucosa-associated lymphoid tissue) lymphoma in a 13-year-old girl: a case report

Fukumoto Y, Hosoi H, Kawakita A, Yamamoto S, Akioka S, Hibi S, Matsumura T,Tokiwa K, Sawada T

Department of Pediatrics, Kyoto Chidren's Research Hospital, Kyoto Prefectural University of Medicine.

We report A case of Sjogren's syndrome complicated with MALT (mucosa-associated lymphoid tissue lymphoma) in childhood. Additionally, Helicobacter pylori infection into the gastric mucosa was highly suspected in this case. A 13-year-old girl suffering from multiple joint pain had received treatment as Juvenile Rheumatic Arthritis with no clinical improvement until introduction to our hospital. On admission to our hospital, high levels of serum anti-SSA and anti-SSB (80.2 and 16.1 holds, respectively) were detected. Minor salivary gland biopsy showed a typical histological finding for Sjogren's syndrome as infiltrating lymphocytes around the excretory ducts. Computed tomography and 67Gallium scintigraphy showed a gastric tumor, and it was diagnosed as primary gastric B-cell MALT lymphoma by the histopathological findings. Additionally, Helicobacter pylori infection into the gastric mucosa was highly suspected.Recently it is emphasized that infection of Helicobacter pylori is related with gastric MALT lymphoma. There has been no reports of children who have Sjogren's syndrome associated with malignant lymphoma. Taken together, Helicobacter pylori infection superimposed with Sjogren's syndrome might accelerate clinical course in our particular case.

6) Mod Pathol 2000 Jan;13(1):4-12

Sjogren's syndrome and MALT lymphomas of salivary glands: a DNA-cytometric and interphase-cytogenetic study.

Ihrler S, Baretton GB, Menauer F, Blasenbreu-Vogt S, Lohrs U

Institute of Pathology, Ludwig Maximilians University, Munchen, Germany.

Stephan.Ihrler@lrz.uni-muenchen.de

Few and conflicting cytogenetic data are available concerning the chromosomal constitution of (mainly gastric) extranodal marginal zone B-cell non-Hodgkin's lymphoma arising from mucosa-associated lymphoid tissue (MALT)-type lymphoma.The majority of salivary gland MALT lymphomas are thought to develop from longstanding Sjogren's syndrome/benign lymphoepithelial lesion (BLEL). We tried to achieve a better comprehension of related cytogenetic alterations by comparing DNA-ploidy and numerical chromosomal (#) aberrations, assessed by different techniques of DNA cytometry (image cytometry) and interphase cytogenetics using nonradiographic in situ hybridization (centromere specific probes for #3, 7, 12, 18) on 12 cases of BLEL, 13 low-grade MALT lymphomas (LG-MALT-L) and 4 high-grade MALT lymphomas (HG-MALT-L) of salivary gland. Both techniques were applied on tissue sections preferentially, enabling a reliablemeasurement of histomorphologically identified areas. No case of BLEL showed cytogenetic abnormalities. Three of 4 HG- and 2 of 13 LG-MALT-L exhibited complex chromosomal gains in nonisotopic in situ hybridization, which were reflected by DNA nondiploidy in image cytometry. In 6 of 13 LG- and lof 4 HG-MALT-L, one or two numerical chromosomal aberrations were demonstrated by nonisotopic in situ hybridization, which could not be resolved by image cytometry. In the 11 DNA-diploid LG-MALT-L, trisomies 18, 3, and 12 were found in 36, 12, and 9%, respectively. In conclusion, comparing BLEL, which showed no chromosomal aberrations, with LG- and HG-MALT-L, an increase in frequency and number of numerical aberrations and DNA nondiploidy was seen. Peritetraploid DNA nondiploidy might be characteristic for HG-MALT-L of salivary gland as it is a rare finding in MALT lymphomas of other sites. It is unclear whether the documented chromosomal aberrations in LG-MALT-L, especially increased rate of trisomy 18, indicate a pathogenic impact or merely reflect genetic instability.

7) Am J Surg Pathol 2000 Jan;24(1):100-6

Mucosa-associated lymphoid tissue-type lymphomas occurring in post-transplantation patients.

Hsi ED, Singleton TP, Swinnen L, Dunphy CH, Alkan S

Department of Clinical Pathology, Cleveland Clinic Foundation, OH 44195, USA.

Post-transplantation lymphoproliferative disorders (PTLDs) are usually Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders that vary in their morphologic spectrum. Extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue-type (MALT-type) have not been considered to be part of this spectrum. The authors encountered five such cases recently. The clinical, histopathologic, and immunophenotypic features are reported. There were three men and two women with a mean age of 51.2 years (range, 48-63 years). Two patients were cardiac transplant recipients, two patients were liver transplant recipients, and the remaining patient was a renal transplant patient. Sites of lymphoma were the stomach in three patients and the parotid gland in two patients. Mean time to the lymphoma was 84 months after transplantation. All patients had morphologic features of low-grade extranodal marginal zone lymphomas of the MALT-type, and Helicobacter pylori was present in all three gastric cases. All patients exhibited the B-cell immunophenotype and were negative for EBV by in situ hybridization. These lymphomas were treated with a variety of modalities, including reduction of immunosuppression, antibiotics, surgical resection, radiation therapy, and chemotherapy. At last follow-up, one patient had developed signet ring adenocarcinoma at 27 months but had no evidence of PTLD, one patient relapsed at 17 months but is alive with stable disease at 24 months, and the remaining patients were alive without disease at 11, 12, and 14 months. Extranodal low-grade MALT-type lymphomas can occur in the post-transplantation setting and generally develop years after transplant. As seen in immunocompetent patients, EBV appears to play no role in the pathogenesis of these lymphomas. These lymphomas appear to have more in common with MALT-type lymphomas in nonimmunocompromised patients than conventional PTLDs, although they occur in "at-risk" patients due to their immunosuppressive therapy. These lymphomas do not appear to be clinically aggressive. Recognition of MALT-type lymphomas in the post-transplantation setting as an indolent disease avoids unnecessary treatment.

8) Recenti Prog Med 1999 Nov;90(11):585-91

MALT lymphomas of the salivary glands. Review of the literature apropos of a case in a patient with hepatitis C virus infection

Caramaschi P, Biasi D, Carletto A, Ambrosetti A, Mocella S, Randon M, Bambara LM

Dipartimento di Medicina Clinica e Sperimentale, Universita, Verona.

We describe a 68-year old woman affected by chronic hepatitis C virus infection; hypertransaminasemia was first observed at the age of 46 years, when the patient was diagnosed uterus carcinoma. Since 1994 she had complained of xerostomia, xerophtalmia, pain at the left parotid and laterocervical adenomegaly. Neck ultrasound examination revealed enlarged intraglandular, submandibular and laterocervical lymph nodes. Fine-needle aspiration of both left parotid and laterocervical lymph nodes was not diagnostic. The histologic examination of the surgical biopsy of the left parotid and the right submandibular salivary gland allowed to diagnose mucosa-associated lymphoid tissue lymphoma (MALT lymphoma).The patient was given alpha-interferon obtaining a clinical remission of the lymphoma and transitory normalization of transaminase level. The authors review the literature about some aspects of MALT lymphomas: a) the etiopathogenesis of MALT lymphomas and the mechanisms suspected to be involved in the evolution from a "benign" lymphoepithelial infiltrate to a neoplastic disorder; b) the relationship between chronic inflammatory diseases as Sjogren's syndrome and chronic C virus infection and MALT lymphomas, particularly MALT lymphomas of the salivary glands; c) the significance of the evidence of a B-cell clonality in the context of a lymphoepithelial lesion; d) diagnostic and therapeutic aspects of MALT lymphomas of the salivary glands.

9) J Clin Oncol 1999 Apr;17(4):1254

Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients.

Zinzani PL, Magagnoli M, Galieni P, Martelli M, Poletti V, Zaja F, Molica S, Zaccaria A, Cantonetti AM, Gentilini P, Guardigni L, Gherlinzoni F, Ribersani M, Bendandi M, Albertini P, Tura S

Institute of Hematology and Medical Oncology "Seragnoli," University of Bologna,

Bologna, Italy. seragnol@kaiser.alma.unibo.it

PURPOSE: Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma. PATIENTS AND METHODS: From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient). RESULTS: Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported. CONCLUSION: Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.

10) Blood 1999 Oct 1;94(7):2247-51

Simultaneous phenotypically distinct but clonally identical mucosa-associated lymphoid tissue and follicular lymphoma in a patient with Sjogren's syndrome.

Aiello A, Du MQ, Diss TC, Peng HZ, Pezzella F, Papini D, Giardini R, Pilotti S, Pan LX, Isaacson PG

Department of Histopathology, University College London Medical School, London,UK.

A 44-year-old woman with a 12-year history of Sjogren's syndrome (SS) developed a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the parotid gland. Two years later, she presented with generalized lymphadenopathy and hepatosplenomegaly and a follicular lymphoma was diagnosed. To investigate the relationship of the two histologically distinct lymphomas, we re-examined their histology and immunophenotype and studied the lymphomatous tissue from the parotid, cervical lymph node, and spleen using molecular genetic methods. Histologic and immunophenotypic studies confirmed the previous diagnoses and also identified a previously unnoticed focus of follicular lymphoma in the second parotid gland biopsy. Polymerase chain reaction (PCR) amplification of the rearranged Ig heavy-chain gene showed the same sized dominant product in the MALT lymphoma and the follicular lymphoma. Similarly, PCR analysis of the t(14:18) translocation yielded an identical sized band from both MALT and follicular lymphoma. Cloning and sequencing of the Ig PCR products showed an identical CDR3 sequence from each lesion, indicating a common clonal lineage. The follicular lymphoma of the parotid gland lymph node and the follicular lymphoma of the spleen showed an identical mutation signature to that of the salivary gland MALT lymphoma. We propose that follicular lymphoma in the parotid gland lymph node may have resulted from colonization of lymphoid follicles by MALT lymphoma cells, following which the tumor cells were induced to express a follicular lymphoma phenotype, due to Bcl-2 overexpression caused by t(14;18), leading to a change in clinical behavior resulting in rapid widespread dissemination of disease. These observations suggest that the distinct phenotypes of low-grade B-cell lymphomas may be the consequence of interplay between genetic and local microenvironmental factors.

11) HNO 1999 Jul;47(7):637-41

Sjogren syndrome and bilateral MALT lymphoma of the parotid gland

Klussmann JP, Guntinas-Lichius O, Heilig B, Wagner M, Jungehulsing M, Michel O

Klinik und Poliklinik fur Hals-Nasen-Ohrenheilkunde, Universitat zu Koln.

Sjogren's syndrome is an important autoimmune disease in the head and neck. Patients have an increased arrival risk of up to 6% per year for developing B-cell lymphomas, including mucosa-associated lymphoid tissue (MALT) lymphomas. The following case report shows this relation and the difficulty of differentiating clinically recurrent swelling of the parotid gland in Sjogren's syndrome from malignant lymphoma. A 64-year-old woman had a 2-year history of indolent, recurrent swelling of both parotid glands. Blood examination showed elevated ESR and a hypergammaglobulinemia. Immunosuppressive therapy produced no improvement. Two years after the diagnosis of Sjogren's syndrome, swelling of the left parotid gland persisted. Superficial parotidectomy of the left side was performed and histopathological examination revealed a MALT-related lymphoma. Subsequent parotidectomy of the right side also showed infiltration of the gland by a MALT lymphoma. Postoperative radiation therapy was given. During the follow-up period no recurrence or systemic disease was detected. Patients with Sjogren's syndrome should be examined regularly by the otolaryngologist. If a lymphoma cannot be ruled out, open biopsy must be considered for histological diagnosis. Prognostic factors for developing a lymphoma are possibly a high ESR and hypergammaglobulinemia. Further prognostic factors have to be evaluated.

12) Laryngorhinootologie 1998 Dec;77(12):723-7

Histopathogenesis of chronic sialectatic parotitis as precursor of myoepithelial sialadenitis lesion

Ussmuller J, Donath K

Univ. Hals-Nasen-Ohren-Klinik Hamburg-Eppendorf.

BACKGROUND: Chronic sialectatic parotitis (CSP) is classified as a characteristic form of chronic recurrent parotitis the etiology and pathogenesis of which still remains unclear. The multiplicity of different therapeutic advices, especially the permanent failure of antibiotic treatment, underlines the lack of an appropriate causal therapy. CASE REPORT: Detailed histopathological investigations of an 41-year old woman were possible over a seven-year period. These follow-up observations enabled clarification of the histopathogenesis of CSP by means of immunohistochemistry. RESULTS: During the course and development of CSP different stages can be observed: The initial phase is characterised by mild infiltration of B-lymphocytes (CD20, CD45 R) and plasma cells in the environment of ectatic ducts. Progredient stages show neogenetic lymph follicles periductular as well as metaplasia of the ductal epithelium. Terminal phases of CSP are characterised by near-total lymphatic transformation of parenchyma, follicular lymphatic hyperplasia (KiM4) and myoepithelial proliferation. In this phase myoepithelial sialadenitis (MESA,i.e. benign lymphoepithelial lesion, possibly part of Sjogren's syndrome) develops. Beyond it low grade non-Hodgkin's lymphoma of the MALT-Type of the submandibular gland occurred finally. CONCLUSIONS: CSP presents as a precursor of MESA. Immunohistological detection of follicular dentritic network (KiM4) within extensive lymphatic hyperplasia periductular demonstrates overshooting humoral immune reaction of B-lymphocytes. Hence, CSP should be classified with regard to pathogenesis as an immunopathological disorder of the MALT system.

13: Am J Clin Pathol 1999 Jan;111(1 Suppl 1):S94-103

Lymphoid proliferations of the salivary glands.

Harris NL

Department of Pathology, Massachusetts General Hospital, Harvard Medical School,Boston, USA.

Lymphoid proliferations of the salivary glands can be either reactive or neoplastic. Reactive lesions include cystic lymphoid hyperplasia--a multicystic ductal proliferation with reactive germinal centers, seen most often in intravenous drug users infected with HIV--and the lymphoepithelial sialadenitis of Sjogren's syndrome (so-called benign lymphoepithelial lesion [BLEL] or myoepithelial sialadenitis [MESA]). This lymphoid proliferation involves infiltration of ductal epithelium by lymphocytes of marginal zone or monocytoid B-cell type, forming lymphoepithelial lesions (epimyoepithelial islands). Patients with lymphoepithelial sialadenitis have a 44-fold increased risk of developing salivary gland or extrasalivary lymphoma, of which 80% are marginal zone/MALT type. Broad strands of marginal zone or monocytoid B cells around lymphoepithelial lesions and monotypic immunoglobulin detection by immunohistochemistry are considered diagnostic of MALT lymphoma. B-cell clones are detected in over 50% of cases of MESA by molecular genetic methods, but this does not correlate with overlymphoma. "Nodal" type B-cell lymphomas of the salivary glands are either follicular lymphoma (35%), which may arise in intrasalivary gland lymph nodes and behave similarly to follicular lymphoma in other sites, or diffuse large B-cell lymphoma (30%), which may arise de novo or secondary to either MALT or follicular lymphomas.

14: Rev Med Interne 1998 May;19(5):319-24

Gougerot-Sjogren syndrome and malignant lymphoproliferative syndromes.

Grosbois B, Jego P, Leblay R

Service de medecine interne G, Hopital Sud, Rennes, France.

INTRODUCTION: This review is aimed at defining the frequency, anatomical and clinical presentation, pathogenesis, predictive factors and treatment ofmalignant lymphoproliferative diseases occurring in the course of Sjogren's syndrome. CURRENT KNOWLEDGE AND KEY POINTS: The frequency of non-Hodgkin's lymphoma (NHL) is estimated to be about 7%. Other malignant lymphoproliferative diseases (Waldenstrom's macroglobulinemia, multiple myeloma, Hodgkin's disease) are rarely observed. NHL is most frequently extranodal (affecting the salivary glands, stomach, lung, etc) in low grade malignancy (MALT lymphoma [mucosa associated lymphoid tissue]). The pathogenesis of NHL in Sjogren's syndrome is a multi-step process, including B cell monoclonal proliferation, oncogenic and/or infectious agents, and/or cytokines. Various predictive factors such as persistent enlargment of parotid glands, adenopathy, splenomegaly, mixed cryoglobulinemia, monoclonal gammopathy, suggest potential lymphoma evolution. The treatment of Sjogren's syndrome-associated NHL depends on the type of lymphoma. Moreover, in patients with low-grade lymphoma therapeutical strategies varies according to the stage and evolution of the disease. FUTURE PROSPECTS AND PROJECTS: Future prospective longitudinal studies should permit to define the best criteria for malignant transformation and to improve therapeutical strategies.

15: J Pediatr 1998 Aug;133(2):290-2

MALT lymphoma of labial minor salivary gland in an immunocompetent child with a gastric Helicobacter pylori infection.

Berrebi D, Lescoeur B, Faye A, Faure C, Vilmer E, Peuchmaur M

Service d'Anatomie et de Cytologie Pathologiques, d'Hemato-Immunologie, and de Gastro-Enterologie Pediatrique, Hopital Robert Debre, Paris, France.

We report a pediatric case of a mucosa-associated lymphoid tissue lymphoma of the labial minor salivary gland in an immunocompetent patient. Chronic gastritis with Helicobacter pylori was disclosed and managed with antibiotic therapy. With eradication of Helicobacter pylori there was complete remission of the lymphoma.

16: Scand J Urol Nephrol 1998 May;32(3):234-6

Indolent behaviour of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue involved in salivary glands, renal sinus and prostate.

Araki K, Kubota Y, Iijima Y, Suzuki H, Sasagawa I, Nakada T, Maeda K, Arai S

Department of Urology, Yamagata University School of Medicine, Japan.

We report a case of MALT lymphoma (malignant lymphoma of mucosa-associated lymphoid tissues) involved in the salivary glands, the renal sinus and the prostate. The masses have been progressing very slowly and the patient has remained alive without any treatment for 5 years from the first symptom of this disease.

17: J Oral Pathol Med 1998 May;27(5):229-32

Minor salivary gland hyalinisation and amyloidosis in low-grade lymphoma of MALT.

Odell EW, Lombardi T, Shirlaw PJ, White CA

Department of Oral Medicine and Pathology, United Medical and Dental Schools, Guy's Hospital, London, UK.

Two patients with low-grade lymphoma of mucosa-associated lymphoid tissue (MALT) arising in primary Sjogren's syndrome developed solitary nodules in their lips. Histologically both lesions showed enlargement and hyalinisation of single minor salivary glands with acinar atrophy, loss of most ducts and conversion into almost acellular sclerotic eosinophilic masses. In one case the lesion was shown to contain an amyloid component. No amyloid was detected in the second case but deposition of collagen and basement membrane and sclerotic neoplasm were excluded.

18: Blood 1998 Mar 15;91(6):1864-72

Clonal salivary gland infiltrates associated with myoepithelial sialadenitis (Sjogren's syndrome) begin as nonmalignant antigen-selected expansions.

Bahler DW, Swerdlow SH

Division of Hematopathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Myoepithelial sialadenitis (MESA) is the reactive salivary gland lymphoid infiltrate that occurs in patients with Sjogren's syndrome. Although it is well established that mucosa-associated lymphoid tissue (MALT)-type lymphomas may develop from MESA, the issue of whether monoclonal B-cell populations in early MESA-associated lesions represent MALT lymphomas or more benign types of expansions has been very controversial. In addition, it is unknown whether antigen stimulation plays a role in the development or growth of MESA-associated clones. To investigate these issues, we have analyzed the Ig VH genes used by MESA-associated clones in sequential biopsies obtained from contralateral sites of seven different patients. In three cases, single clones were identified in the follow-up biopsies that were distinct from the single clones identified in the initial specimens, whereas in three other cases, the same clone was identified in both the initial and subsequent specimens. In the remaining case, two clones were identified in the second biopsy specimen, one of which was distinct from the initial clone. Of the 11 distinct clones identified in the 14 specimens that were analyzed, 8 were derived from a V1-69 VH gene segment, whereas the other 3 were derived from a V3-7 VH gene segment. In addition, the MESA clones also showed conserved amino acids sequence motifs in their third complementarity-determining regions (CDR3), some of which were encoded by N nucleotides. The marked VH gene restriction along with the similar CDR3 sequences suggests that MESA-associated clones even from different patients may bind the same or similar antigens and are selected for clonal expansion on that basis. The high rates of ongoing VH gene mutation observed in some of the cases futher suggest that the growth of early MESA clones is still dependent on antigen stimulation. In addition, our finding that different biopsies from the same patient may contain distinct clones indicates that some MESA-associated clones have not yet evolved to malignant lymphomas.

19: J Oral Pathol Med 1997 Nov;26(10):454-7

Absence of Helicobacter pylori DNA in salivary lymphoepithelial lesions.

Jordan RC, Diss TC, Millson C, Wilson M, Speight PM

Department of Laboratory Medicine, Sunnybrook Health Sciences Centre, Toronto,Canada.

Helicobacter pylori is a common cause of chronic gastritis and has been implicated as the main agent responsible for the development of lymphomas of mucosa associated lymphoid tissue (MALT) in the stomach. An uncommon cause of salivary gland swelling is salivary lymphoepithelial lesion (SLEL), which shows histological features of acquired MALT and is associated with the development of MALT-type lymphomas. Since H. pylori has been identified in the oral cavity, we hypothesised that this organism might act as a potential antigen for thedevelopment of MALT in salivary glands. Routinely processed biopsies of 20 SLELwere screened for H. pylori DNA using a sensitive two-stage PCR technique to amplify the 16S ribosomal RNA gene. Immunoglobulin heavy chain gene monoclonality was determined by amplifying the VDJ gene using a nested PCR technique. All SLEL had histological features of organised MALT and 14 cases showed Ig heavy chain gene monoclonality consistent with MALT lymphoma. None of the SLEL contained H. pylori DNA. In contrast to the putative role of H. pylori as an antigenic stimulus in gastric MALT lymphomas, it appears not to play a role locally in the development of MALT or MALT lymphomas of the salivary gland.

20: Ann Oncol 1997 Sep;8(9):883-6

Nongastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas: clinical and therapeutic features of 24 localized patients.

Zinzani PL, Magagnoli M, Ascani S, Ricci P, Poletti V, Gherlinzoni F, Frezza G, Bendandi M, Stefanetti C, Merla E, Pileri S, Tura S

Institute of Hematology and Oncology Seragnoli, Bologna, Italy.

BACKGROUND: Peripheral B-cell lymphoma of the marginal zone (MALT, low-grade), presenting as localized, extranodal disease, usually affects the elderly. The gastrointestinal tract is the most frequently involved extranodal location, representing 70% of all MALT lymphomas. Recently, numerous other extranodal sites involved by MALT lymphomas have also been described. PATIENTS AND METHODS: From January 1990 to October 1995, 24 patients with untreated nongastrointestinal low-grade MALT lymphoma were submitted to treatments ranging from the local approach of radiotherapy and local alpha-interferon (alpha-IFN) administration to chemotherapy. The tumours were located in the lung (seven cases), conjunctiva (four cases), lachrymal gland and orbital soft tissue (four cases), salivary glands (three cases), skin (three cases), breast (two cases), and thyroid (one case). All patients had low-grade stage IE tumours. RESULTS: Chemotherapy was administered in 11 patients (six with lung, three with salivary gland, one with breast, and one with thyroid locations); radiation therapy was employed in seven patients (three with lachrymal gland, three with skin, and one with breast locations); local alpha-IFN administration was administered in five patients (four with conjunctival, and one with lachrymal gland sites); and surgery was employed in one patient with a lung tumour. All patients achieved complete remissions; three local recurrences and two relapses in other sites were observed. The global five-year survival rate was 100% with a relapse-free survival rate of 79%. CONCLUSIONS: These data confirm the significant efficacy of different therapeutic approaches to specific sites inbes obtaining a good remission rate for nongastrointestinal localized low-grade MALT lymphomas.

21: Mod Pathol 1997 Sep;10(9):872-8

Coexistence of different B-cell clones in consecutive lesions of low-grade MALT lymphoma of the salivary gland in Sjogren's disease.

Lasota J, Miettinen MM

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, D.C., USA.

Low-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the salivary gland are usually indolent diseases with a protracted clinical course. Recurrent multifocal disease has been shown to represent identical clones in some cases, and intraclonal variation resulting from continuing somatic hypermutation has been described, but emergence of novel, major clones upon recurrent disease has not been documented. We analyzed three consecutive biopsy specimens of parotid lymphoid infiltrates of a young woman with Sjogren's disease. The immunoglobulin heavy chain (IgH) gene rearrangements were first amplified using FR2/LJH-VLJH consensus primers. Then, the PCR products were cloned, sequenced, and compared. On the basis of the sequences of the complementarity determining region 3 (CDR3), clone-specific primers were designed and used to evaluate the presence of similar sequences in different biopsy specimens. Recurrent parotid lymphoid infiltrates during a span of 9 years showed histologically similar features consistent with low-grade MALT lymphoma. Polymerase chain reaction amplification showed a clonal pattern of IgH gene rearrangement in all of the lesions with similar product sizes, suggesting the identity of the clones, but two major clones with different CDR3 sequences were found. Intraclonal variation was seen among the sequences seen in the three lesions consistent with the occurrence of somatic hypermutations. Primers specific to the clone seen in the first two lesions failed to amplify products from the third lesion, but primers specific to the third clone showed similar products in the second clone in a small quantity, indicating that this clone persisted and expanded. Our results suggest that different B-cell clones might dominate during the course of low-grade MALT lymphoma of the salivary gland. This implies that in some cases, these processes can represent oligoclonal B-cell proliferations.

22: Hum Pathol 1997 Jul;28(7):850-61

Salivary gland lymphoid infiltrates associated with lymphoepithelial lesions: a clinicopathologic, immunophenotypic, and genotypic study.

Quintana PG, Kapadia SB, Bahler DW, Johnson JT, Swerdlow SH

Department of Pathology, University of Pittsburgh School of Medicine, PA, USA.

The criteria for distinguishing benign lymphoepithelial lesions (BLEL) from low grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type in salivary glands and the significance of genotypically documented clonality in this setting are controversial. In addition, the clinical implications of a neoplastic diagnosis are unclear. The histopathologic features of 68 specimens from 49 patients with at least one salivary gland biopsy with LEL together with available clinical data were, therefore, reviewed. Paraffin section immunohistochemical (IHC) stains for kappa, lambda, CD3, CD20, and CD43; in situ hybridization (ISH) for kappa and lambda; and polymerase chain reaction (PCR) for immunoglobulin (Ig) HC rearrangement were performed. The 61 salivary gland specimens were classified as BLEL-13, BLEL with monocytoid B-cell (MBC) halos (BLEL-halo-8), low grade B-cell lymphoma of MALT type with confluent zones of MBC or other atypical lymphocytes (ML-MALT-24), low grade B-cell lymphoma of MALT type with monoclonal plasma cells (ML-MALT-PC-12), and high grade B-cell lymphoma of MALT type (MALT-high grade-4). Soft tissue and perineural invasion was not observed in BLEL and was most common in the MALT lymphomas. Lymph node involvement was identified in six patients at the time of their salivary gland MALT lymphomas but in none with BLEL. CD43+ B cells were seen most commonly in ML-MALT but were present in all other categories except MALT-high grade. Clonal B cells were identified by PCR in 5 of 12 BLEL, 5 of 8 BLEL-halo, 17 of 22 ML-MALT, 6 of 10 ML-MALT-PC, and 3 of 3 MALT-high grade biopsies. All ML-MALT-PC were clonal by ISH or IHC. Repeat biopsies in 14 patients most commonly showed a BLEL/ML-MALT lesion in an ipsilateral or contralateral salivary gland with one transformation to a MALT-high grade. Although only a few patients are known to have received chemoradiation or radiation therapy, most patients with low-grade lesions have pursued an indolent course. These data show the presence of two types of borderline lesions within the spectrum of lymphoid proliferations associated with salivary gland LEL. One has clonal B cells without histological features of neoplasia and the other nonconfluent MBC extending beyond the confines of LEL ("halos"). They share some features with the infrequent nonneoplastic BLEL and others with the more common low-grade B-cell lymphomas of MALT. A few high-grade B-cell lymphomas of MALT were also identified including a rare example of transformation from a low- to high-grade lesion. The optimal therapeutic approach for the borderline and low-grade lesions and the reason why so many of the lymphoproliferative lesions associated with LEL remain localized to the neck remain to be defined.

23: Blood 1997 May 1;89(9):3335-44

Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas.

Bahler DW, Miklos JA, Swerdlow SH

Department of Pathology, University of Pittsburgh School of Medicine, PA, USA.

Salivary gland mucosa-associated lymphoid tissue (MALT) type lymphomas are typically indolent B-cell neoplasms that are often associated with Sjogren's syndrome. To better define the cell of origin and evaluate whether antigen receptor stimulation may be playing a role in tumor growth, the Ig heavy and light chain variable genes (VH and VL) expressed by five salivary gland MALT lymphomas were cloned and sequenced. Comparison to known germline sequences indicated that three of the lymphoma VH genes were derived from 51p1, a member of the VH1 family, while the other two used different VH gene segments from the VH3 family, 22-2B and HG19. All five of the VL genes belonged to the VkIII family, with three derived from Humkv325 and the other two from the Vg and Humkv328 genes. Numerous point mutations relative to the proposed germline genes were present in all of the lymphoma VH and VL genes. In addition, the VH and VL genes from each lymphoma showed intraclonal sequence heterogeneity indicative of ongoing somatic hypermutation. Because the process of Ig gene hypermutation is thought to occur at the germinal center stage of B-cell development, these findings suggest the MALT lymphoma cell of origin may be a germinal center B cell. Selection against mutations that result in replacement of amino acids suggested that Ig stimulation may be important for lymphoma growth. The possibility that antigen receptor stimulation may be involved in the growth of salivary gland MALT lymphomas is further suggested by the noted restricted use of VH and VL gene segments.

24: Hum Pathol 1997 Feb;28(2):166-73

B-cell gene rearrangement in benign and malignant lymphoid proliferations of mucosa-associated lymphoid tissue and lymph nodes.

Torlakovic E, Cherwitz DL, Jessurun J, Scholes J, McGlennen R

Department of Laboratory Medicine and Pathology, University of Minnesota Hospital and Clinics, Minneapolis, USA.

The polymerase chain reaction (PCR) with polyacrylamide gel electrophoresis was used to study patterns of immunoglobulin heavy chain (IgH) gene rearrangement (GR) in formalin-fixed, paraffin-embedded specimens of lymphomas and reactive conditions of mucosa-associated lymphoid tissue (MALT) and lymph node. DNA amplification was performed directly on sections obtained from paraffin blocks. Five patterns of PCR products were observed: a single band, two or more discrete bands, smearing, a single band overlying a smear, and two or more bands over a smear. A pure polyclonal pattern (smear) was observed in all of the reactive lymph nodes but in only 15% of cases of Helicobacter pylori (HP) gastritis with lymphoid hyperplasia, 25% of cases of HP gastritis without lymphoid hyperplasia, and 37% of colonic specimens of various types. Patterns consisting of multiple bands with or without background smearing were common in gastritis, colitis, and gastric lymphomas. Single bands or dominant bands were present in all lymph node and salivary gland lymphomas, 12 of 14 cases of gastric lymphoma, and 17 of 20 cases of HP gastritis with lymphoid hyperplasia. These bands were reproducible in deeper sections from the same paraffin block or similar areas sampled in different blocks in all of the lymph node and salivary gland lymphomas, 11 of 12 gastric lymphomas, but only 1 of 17 cases of HP gastritis with lymphoid hyperplasia. Bands were also found in 3 of 20 cases of HP gastritis without lymphoid hyperplasia and 17 of 38 colonic specimens, but these were not reproducible. The complexity of patterns of IgH GR in acquired MALT compared with lymph nodes may be the result of a relative paucity of B-cell clones or preferential proliferation of B-cell clones with a limited area of distribution.

25: Am J Surg Pathol 1996 Aug;20(8):1011-23

Marginal zone lymphoma (low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type) of skin and subcutaneous tissue: a study of 15 patients.

Bailey EM, Ferry JA, Harris NL, Mihm MC Jr, Jacobson JO, Duncan LM

Department of Pathology, Massachusetts General Hospital, Boston 02114-2698, USA.

Extranodal low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT )type occurs in the gastrointestinal tract, salivary gland, thyroid, orbit, lung, and breast. We report 15 patients with MALT-type lymphomas involving skin and subcutaneous tissue. All patients had tumors with histologic features of low-grade B-cell lymphoma of MALT type, including marginal zone cells (15 of 15 cases), plasmacytic differentiation (10 of 15 cases), Dutcher bodies (three of 15 cases), and reactive germinal centers (10 of 15 cases). All expressed pan B-cell antigens and monotypic immunoglobulin. Seven patients (five women, two men) aged 29 to 86 years (median, 53 years) had primary MALT-type lymphoma of skin (6) or subcutaneous tissue (1). One patient had persistent disease, and four patients had relapses involving skin, subcutaneous tissue, breast, orbit, and lymph node. At last follow-up (11-121 months; median, 36 months), one patient was alive with disease, and six patients had no evidence of disease. Three patients (two women, one man) aged 36 to 67 years (median, 57 years) had concurrent MALT-type lymphoma involving both subcutaneous tissue and extracutaneous sites at primary diagnosis, including lung, breast, orbit, lymph node, and bone marrow. One patient responded to treatment but relapsed with lymphoma of the skin and breast. The other two patients had persistent disease despite treatment. One patient died of disease at 25 months, and, at last follow-up (7 and 46 months), two patients were alive with disease. Five patients (four women and one man) aged 29 to 72 years (median, 63 years) had secondary skin or subcutaneous involvement by MALT-type lymphoma with primary tumors of ocular adnexa (3) or parotid gland (2). All five patients had relapses, which involved skin or subcutaneous tissue, parotid gland, lacrimal gland, breast, and lymph node. At last follow-up (61-137 months), two patients were alive with disease and three were alive with no evidence of disease. Low-grade B-cell lymphomas of MALT type may arise in or secondarily involve the skin and subcutaneous tissue and have a tendency to affect middle-aged to older women. These tumors are characterized by multiple extranodal relapses and are associated with long patient survival. Patients with primary MALT-type lymphomaof skin or subcutaneous tissue without extracutaneous involvement at diagnosis were more likely to experience prolonged disease-free survival than patients with extracutaneous spread at presentation (p < 0.03).

26: J Clin Pathol 1996 Jul;49(7):595-7

B cell lymphoma of the thymus and salivary gland.

Di Loreto C, Mariuzzi L, De Grassi A, Beltrami CA

Department of Medical and Morphological Research, University of Udine, Italy.

A case of primary low grade B cell lymphoma of the salivary gland associated with a low grade B cell lymphoma of the thymus and involvement of the skin is reported. The lesions in the salivary gland and in the thymus showed the typical features of a lymphoma arising from the mucosa associated lymphoid tissue (MALT) and comprised lymphatic follicles, centrocyte-like (CCL) cells and lymphoepithelial lesions. Immunohistochemistry and Southern blot analysis supported the hypothesis that these lesions can originate from the same cellular clone. These findings confirm the occurrence of low grade B cell MALT lymphoma in the thymus and the possibility of spread of MALT lymphoma to other mucosal sites.