Dr. Egon R. Casanova M.D.
Internal Medicine – Hematology
Assistant Professor of Hematology
Faculty of Biologic Science
University of Concepcion
Concepcion – Chile
Non-Hodgkin lymphoma (NHL) is a heterogeneous disease including a large variety of different diseases. The broad category of NHL includes indolent as well as aggressive lymphomas. MALT lymphomas (Mucosa Associated Lymphoid Tissue) lymphoma arise in the extranodal, mucosal lymphoid tissue and represent as many as 7.6% of all lymphomas. This type of NHL has only been recognized as a distinct entity in recent years (1). It may affect extranodal structures such as the eye, gastrointestinal tract (GIT) specially the stomach, thymus, larynx, pharynx, lungs and salivary glands. The NHL-MALT type is generally of low grade and has indolent course. However, about 10% of cases have regional lymph nodes and bone marrow involvement.
NHL-MALT type arises in areas where chronic inflammation is often present such as GIT, respiratory tract (BALT: Bronchus-Associated Lymphoid Tissue lymphoma), salivary and lachrymal glands. Most of those organs lack native lymphoid tissue but acquire MALT in close association with chronic inflammation or autoimmune processes being the typical examples NHL-MALT type in the stomach associated with H. Pylori and parotid MALToma with Sjögren syndrome. The frequency of NHL-MALT type is in GIT 50%, respiratory tract 10%, head and neck 10% (orbit, sinuses, thyroid gland, salivary glands and Waldeyer’s ring) and others 30% (kidney, urogenital tract as prostate, uterus and Fallopian tubes, liver, breast, pancreas, gallbladder).
Salivary glands involvement by NHL-MALT is associated in 10% of cases with Sjögren syndrome. Parotid is the most frequently involved salivary gland (70%), followed by submaxilar glands (30%). Primary parotid NHL represents 1% of all NHL and 8.6% of all parotid neoplasm (2). The presence of intraglandular lymph nodes are common in parotid glands. NHL arising from these lymph nodes are not MALT type but low-grade follicular lymphoma that typically does not involve the salivary tissue.
The goal of this paper is to present a clinical case of parotid gland NHL-MALT type reviewing our present state-of-the-art of our knowledge on the molecular biology of maltomas.
A 40-year-old married woman, who had been well until three months earlier when a painless slow growing lump in the right parotid gland appeared. There was no history of fever, sweats or weight loss but she had a history of rheumatoid arthritis and Sjögren syndrome five years earlier. She is moderate smoker (10-12 cigarettes/day for 20 years) and have no allergy and no alcohol intake. Normal menstruation. On physical examination a 4 cm in diameter, non tender, rubbery consistency and solitary parotid tumor was found. No lymphadenopathy and Waldeyer’s ring compromise was present. The lungs, heart, and breasts were normal. The liver and spleen were not felt, and no abdominal tenderness or mass was detected. The extremities were normal. Parotid glands echotomography showed a solid substitution within the right parotid confirmed with computed tomography (CAT) scan of the neck. A tumorectomy was performed. Biopsy: diffuse infiltration of small monocytoid and centrocytic lymphocytes that distorted the normal arquitecture of the parotid gland. Pan B markers; CD19, CD20 (+) in 80% of cells, Pan T markers CD3, CD5 (+) in 20% of cells, cyclin D1 (-), and Bcl-2 (+), concluding in Malignant Diffuse non-Hodgkin Lymphoma MALT-type. The values for Beta-2-microglobulin, plasma uric acid, LDH, VDRL, blood sugar, creatinine, C-reactive protein, HIV, TNF-alpha, IL-6, TSH, ANA and complete blood count were all normal. Rheumatoid factor: 228 IU/ml (<20), VHS: 41 mm/h, IgA, IgM, IgE, C’3, C’4 all normal, IgG: 2815 mg/dl (700-1800), plasma protein electrophoresis policlonal increase of gamma globulin, immunoelectrophoresis of heavy and light chains normal (increase normal IgG). ECG, plain chest-X-ray, bone marrow biopsy, chest and abdominal CAT scans all normal. Reticulocytes count: 0.5%, Ferritin 13 ng/ml, blood iron 48 ug/dl, transferrin 220 mg/dl, transferrin saturation 21%. Diagnosis: 1) Primary Non-Hodgkin lymphoma-MALT-Type Stage I-E of right parotid. 2) Collagen-vascular disease: Rheumatoid Arthritis, Sjögren syndrome. 3) Chronic tabaquism. The patient was treated with local-regional radiotherapy (4500 cGy) with total recovery. Two years later she consults for the appearance of spots and ecchymoses in the skin of the trunk and in both upper and low extremities. On examination blood pressure was 120/70, pulse 68x’ and no fever. The parotid glands were normal. She presented right epistaxis and petechiae on the body, no enlarged lymph nodes and no liver or spleen felt. Complete blood count Hto: 38.3%, Hb: 12.8 g/dl, MCV and MCHC normal, white blood cell count (WBC) 2700/ul, differential 1-1-0-0-4-52-39-3 and platelets count 4000/ul. A diagnosis of autoimmune thrombocytopenic purpura was made receiving the patient a course of prednisone (60 mg/day) recovering the WBC and platelet count to normal 16 days later. At present, five years later, she is in well condition with abscense of parotid tumor.
Primary NHL of the salivary gland is an uncommon tumor and within its rarity most often occurs in the parotid gland (70%) and belongs to MALT type (3). NHL-MALT-type of the parotid gland generally is localized or occasionally may be one component of a disseminated lymphoma (4,5). MALT are the extra-nodal equivalent of monocytoid (marginal zone) B-cell lymphomas that occur in lymphoid organs such as the lymph node. MALT lymphomas regardless of organs of origin, have similar clinicopathological and molecular features; they are generally indolent, tends to remain localized for long period of time even without treatment and eventually the tumor may disseminate or transform to a higher grade. In the parotid gland this low-grade MALT lymphoma is rare usually arising in a background of benign lymphoepithelial lesion or myoepithelial sialadenitis that is associated with collagen-vascular disease specially with the autoimmune disease Sjögren's syndrome, however, occasionally may develops in patients who do not have a history of autoimmune disease (5,6,7,8). It has been reported that 80-85% of primary parotid gland tumors are benign and 15-20% are malignant and within this, 1-5% are malignant lymphomas. The histological distinction of myoepithelial sialadenitis from low-grade B-cell MALT lymphoma can be a difficult diagnostic challenge. Immunophenotyping by flow cytometry analysis may be useful in showing an aberrant phenotype or immunoglobulin light-chain restriction, may help to support a diagnosis of malignant lymphoma in most cases. Molecular genetic analysis for immunoglobulin gene rearrangements also may be useful in showing monoclonality (5,8,9). Chronic inflammatory process other than Sjögren's syndrome may provide in addition, a substrate for the development of parotid MALT lymphoma (4). Sjögren's syndrome is usually seen in middle-aged women (9 out of 10 patients are women) but may also occurs in all age groups and in children. It is a chronic autoimmune disease that ends in the destruction of the gland, characterized by concurrent keratoconjunctivitis sicca, xerostomia, and rheumatoid arthritis. The benign lymphoepithelial lesions that occur in this syndrome appear as unilateral or bilateral parotid swellings. Enlargement of the parotid gland is seen in approximately 50 percent of patients with Sjögren's syndrome and as pointed out before, patients with Sjögren syndrome have increased risk of developing lymphoma. In summary, we can say that lymphoid proliferations of the salivary glands can be either reactive (lymphoepithelial sialadenitis of Sjögren syndrome) or no-reactive or malignant (NHL-MALT type in 80% of cases derived from lymphoepithelial sialadenitis) (10).
In the thymus, the relationship between lymphofollicular hyperplasia and NHL-MALT-type is uncertain. Parrens et al (11) analyzed 14 cases with a diagnosis of thymic follicular hyperplasia in patients with connective tissue disease (n = 2), myasthenia gravis (n = 11), or both (n = 1). In 11 cases, well-defined reactive lymphoid follicles were surrounded by a continuous layer of medullary epithelial cells, with polyclonal rearrangement of the immunoglobulin heavy chain gene (IgH). In 3 cases, ill-defined lymphoid follicles with sheets of centrocytic-like B cells disrupting the medullary cytokeratin epithelial network were observed on certain sections. These cells expressed the phenotypic features of memory B cells with CD20, CD79a, and Bcl-2 positivity and CD5, CD10, CD23, and Bcl-6 negativity, and a monoclonal rearrangement of the IgH gene.
In the ocular adnexa malignant lymphomas and reactive lymphoid hyperplasia are sometimes difficult to differentiate morphologically and have often been categorized together as a lymphoproliferative disorder. Immunogenotypic characters of these diseases have not yet been well clarified. In one study MALT lymphoma constituted 86% of the primary lymphomas and an autoimmune mechanism may be involved in the lymphomagenesis of ocular adnexal MALT lymphoma (12).
a) Translocations: Translocations play a central role in the pathogenesis of MALT lymphomas, being the most important t(11;18)(q21;q21) present in about 50% of cytogenetically abnormal low grade MALT lymphomas. Other translocations are t(11;14)(q13;q32), t(1;14)(p22;q32) and t(1;2)(p22;p12) being the last two rare but recurrent translocations.
a.1) t(11;18)(q21;q21): This translocation, appearing to be the key genetic lesion in MALT lymphomas (present in about 50% of cases), yields overexpression of a chimeric transcripts encoding structurally distinct API2/MALT1 fusion protein (API2 = APoptosis Inhibitor-2 / MALT-1 = Mucosa Associated Lymphoid Tissue lymphoma Translocation gene-1). API2 gene sequence located in chromosome 11q21 encode Inhibitors of APoptosis (IAPs) known as c-IAP2, HIAP1, and MIHC, while MALT1 alias MLT (MALT Lymphoma-associated Translocation) is in chromosome 18q21 encoding several Ig-like C2-type domains. Pathophysiologically, the increase of API2 encoding IAPs leads to the inhibition of apoptosis yielding long-lived or immortal cells with genetic instability that survive long enough to acquire other DNA damage (e.g.: p53 gene alteration or deletion, overexpression of Bcl-10) ending in a malignant process (13,14,15). In fact, MALT lymphomas with the t(11;18) translocation manifest increased nuclear staining of Bcl-10 in addition to overexpression of MALT1 (16,17).
a.2) t(1;14)(p22;q32) and t(1;2)(p22;p12): The presence of these genetic anomalies mean the translocation of Bcl-10 gene (1p22) to the immunoglobulin heavy chain locus (14q32) or to the immunoglobulin kappa light chain locus (2p12) resulting in deletion of regions of the Bcl-10 gene and/or dysregulation (overexpression) of Bcl-10 protein leading to increase cell proliferation and gene instability (17,18).
Interest has focused on the cytoplasmic regulatory protein Bcl-10, thought to play an important role together with API2/MALT1 chimeric gene in the genesis of extranodal, marginal zone (MALT) lymphomas. Normally, Bcl-10 is expressed only in lymphoid tissues and the breasts. It is expressed in addition, in the malignant counterpart B-cell lymphomas. The presence of Bcl-10 may be demonstrated by immunohistochemistry of formalin-fixed and paraffin-embedded tissues using mouse anti Bcl-10 monoclonal antibodies. In normal B-cell follicles, Bcl-10 protein shows different expression among various B-cell populations of the B-cell follicle, being expressed abundantly in the germinal center, weakly in the mantle zone and moderately in the marginal zone. This fact indicates that Bcl-10 function is essential for normal T and B-cell development (proliferation, maturation and regulation of apoptosis). Irrespective of their stage of B-cell maturation, Bcl-10 is predominantly expressed in the cytoplasm. In T and B lymphocytes Bcl-10 acts as a regulator of lymphocyte proliferation that specifically connects antigen receptor signaling to NF-kB activation and promote apoptosis and suppress malignant transformation in vitro. The NF-kB proteins are normally activated by Bcl-10 after lymphocytes encounter their antigens (e.g.: invading organisms such as bacteria) causing lymphocytes to fully multiply and mature and release antibodies and effector lymphocytes targeted against those specific antigens. Experimentally in mice lacking the Bcl-10 gene, lipopolysaccharide (LPS) or endotoxin failed to stimulate B cell proliferation. Bcl-10 belongs to a family of gene/proteins containing caspase recruitment domains (CARD) involved in regulation of apoptotic pathway accomplishing antioncogene function promoting apoptosis and suppressing malignant transformation in vitro. It has been reported that Bcl-10 and MALT1 cooperate in a final common cascade of events leading to increased activity of the NF-kB signaling pathway (16,17). It is not surprising that the critical NF-kB pathway should be involved in MALT lymphomas, given that this family of transcription factors is activated by both antigenic stimulation and inflammatory cytokines. The contributory factors that currently support the model of MALT lymphoma pathogenesis is given by a milieu of chronic infection, chronic inflammation and lasting oxidative stress providing all a common background for the development of MALT lymphomas leading to chromosomal translocations and mutations (4,10). Interestingly, Chlamydia species share many features with H. pylori, because they too are associated with chronic persistent infection; induce a polyclonal lymphoid infiltrate in extranodal mucosa-associated sites; and have been implicated as cofactors in the development of both carcinoma and lymphoma (18). These common threads may prove to be part of the fabric of MALT lymphoma pathogenesis. MALT lymphomas with t(1;14)(p22;q32) showed strong Bcl-10 expression in both the nucleus and cytoplasm and MALT lymphomas lacking the translocation may exhibit Bcl-10 expression in both the nucleus and cytoplasm although at a much lower level. Follicular and mantle cell lymphomas generally displayed Bcl-10 expression compatible to their normal cell counterparts. In MALT lymphomas the subcellular localization of Bcl-10 is frequently altered in comparison with their normal cell counterparts, suggesting that ectopic Bcl-10 expression may be important in the development of this type of tumor (19). Finally, Bcl-10 has been described associated to colon cancer, germ cell tumor, lymphomas (MALT, follicular), mesothelioma and sezary syndrome.
a.3) t(11;14)(q13;q32): Generates the chimeric gene Bcl-1/IgH in B-cell malignancies. This translocation will be analyzed in the next paragraph cyclin dependent kinases.
b) Cyclin dependent kinases: Physiologically, DNA damage activate checkpoint pathways producing G1 or G2 cell cycle arrest. At G1 the DNA may be repaired or if such repair is not feasible apoptosis is induced, while G2 checkpoint prevents inappropriate mitosis of unrepaired DNA. Cell cycle progression is driven by cyclin-dependent kinases (CDK) in association with specific cyclin proteins. The tumor suppressor p53 re-enforces G2 arrest through the CDK inhibitor p21. Genotoxic stresses stabilize p53 protein allowing it to function as a nuclear transcription factor that induces expression of several target genes including p21, Bax (pro-apoptotic protein) and the inhibitor of p53 Mdm2 (20,21). Mdm2 (Murine double minute 2) protein binds to p53 inactivating and targeting it for destruction by ubiquitinaton. p21 functions as a universal cyclin-dependent kinase inhibitory (CDKI) protein, with affinity for G1 and G2 cyclin-CDK complexes. Most human cancers contain mutations in the cell cycle proteins (oncogenes) that lead to inappropriate stimulation of the cell cycle, and hence uncontrolled cell division. Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression whose function is frequently deregulated in most human tumors either by increased expression (overexpression) of activating cyclins (e.g.: frequently cyclin D and E); decreases expression of inhibitory peptides (e.g. p16 and p21); or substrate loss (e.g. p53, retinoblastoma gene deletion). Cyclin D1 alias Bcl-1 (B-cell leukemia/lymphoma-1), CCND1 (CyCliN D1) or PRAD1 (parathyroid adenomatosis 1) may be overexpressed in malignancies being detected by monoclonal antibodies in paraffin sections. Bcl-1 controls cell cycle at G1/S transition (restriction point) by the binding to CDK4 and 6 (cyclin D1-CDK4-6 complex inhibited by p15, p16, and p21). The complex cyclin D1-CDK4-6 phosphorilates Rb releasing E2F that induce the synthesis of proteins required by the cell to move from G1 to S going on to the cell division. The Bcl-1 sequence is located in chromosome 11q13. The translocation t(11;14)(q13;q32) generates the chimeric gene Bcl-1/IgH in B-cell malignancies placing Bcl-1 on chromosome 14 near JH (junction genes of IgH). This translocation implies no fusion protein but promoter exchange resulting in that the Ig gene enhancer stimulates the expression of Bcl-1 being this the oncogenic mechanism that results in overexpression of Bcl-1 which accelerates the cell transit through the G1 phase. The expression of cyclin D1 protein (nuclear localization) is cell cycle dependant with maximal expression at the end of G1 keeping high levels until M. t(11;14) is more frequently found in mantle cell lymphoma, B-prolymphocytic leukemia, splenic lymphoma with villous lymphocytes and rarely in chronic lymphocytic leukemia and multiple myeloma. The prognosis vary according to the disease.
c) Adhesion molecules: In general, the expression of adhesion molecules on neoplastic cells imply the attachment of malignant cells to their tissue of origin with low probability of metastasis, the contrary occurs in the absence of such molecules. Expression of adhesion molecules in low-grade B-cell NHL-MALT-type of the gastrointestinal tract has been reported in recent years. Yi-Xuan Liu et al (22) examined the lymphocytic homing receptors 4ß7 integrin, L-selectin, VLA-4 and Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) in low-grade lymphoma of the gastrointestinal tract and other organs such as the ocular adnexa and thyroid, observing changes in the expression pattern associated with high-grade transformation. Neoplastic cells in gastrointestinal low grade NHL-MALT-type were found to be 4ß7 integrin (+) and L-selectin (+) (keep the aherence to tissue of origin) while in gastrointestinal high-grade lymphoma and diffuse large B-cell lymphoma 4ß7 integrin and L-selectin were negative (-) (high risk of metastasis). Endothelial cells in gastric MALT lymphomas expressed MAdCAM-1. Most cases in the ocular adnexa with low-grade MALT lymphoma were 4ß7 integrin (-), L-selectin (+); and in the thyroid, most cases of both low- and high-grade MALT lymphoma were 4ß7 integrin (-), L-selectin (-). These findings show that 4ß7 integrin and L-selectin may play an important role in the lymphocyte homing of gastrointestinal low-grade MALT lymphoma and in the loss of 4ß7 integrin expression throughout the course of high-grade progression.
Treatment: Currently, stage I malignant lymphoma including intermediate or high grade MALTomas originating in the parotid gland may be successfully treated by surgical procedure directed to remove the tumor (tumorectomy), total parotidectomy and/or local-regional radiotherapy. In stage II radiotherapy plus chemotherapy (CHOP) is the treatment of choice (18). However, at present new ways of treatment are under study, one of these is the use of cyclin dependent kinase inhibitors, that produce cell cycle phase arrest by inhibition of CDK phosphorilation acting as tumor suppressor (23). Other currently assay is the use of Mdm2 inhibitors that may exert an anti-tumor effect restoring normal p53 activity in malignant cells with Mdm2 overexpression (24). On the other hand, Bcl-10 overexpression is associated to colon cancer, germ cell tumor, lymphoma (follicular, MALT), mesothelioma and Sezary syndrome so the development of drugs that block the activity of Bcl-10 (inhibitor of apoptosis and regulator of lymphocyte proliferation) could be in addition an effective treatment.
The parotid gland maltoma developed in our patient was associated with Sjögren syndrome that gave an autoimmune substrate for the development of such malignancy. In addition, she was cyclin D1 negative meaning that there was not overexpression of cyclin D1, being this an important fact in the indolent behavior of NHL-MALT type, making a difference with mantle cell lymphoma and B-prolymphocytic leukemia that have an aggressive behavior. On the contrary, Bcl-2 was positive in our patient signaling that the apoptotic machinery was normally functioning making the malignant cells sensitive to chemotherapy and radiotherapy as it was confirmed by the response to radiotherapy administered. Currently five years later, the patient is in well health condition enough time to be considered cured from NHL-MALT type of the right parotid gland.
As a corollary, we may say that indolent or aggressive characteristic of malignant cells depend on their biological behavior that ultimately rests on the DNA. As greater is the DNA damage affecting different cell functions, the major is the aggressiveness of the malignant cells. This emphasizes the importance of the laboratory work in establishing the different DNA damage characterizing the several kinds of cancers being for this purpose quite useful the DNA microarray technique. This knowledge allow us to establish from the clinical viewpoint, the prognosis and the likelihood of the response to treatment and in addition the development of new more specific and effective drugs to control the malignant diseases.
Citation: Casanova ER. Parotid gland non-Hodgkin lymphoma – MALT type. Clinical Case. Molecular analysis. www.egoncasanova.cl 2005
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