Dr. Egon R.
Casanova M.D.
Internal Medicine – Hematology
Assistant
Professor of Hematology
Pathophysiology
Department
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.
DISCUSSION
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).
MOLECULAR ANALYSIS
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.
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Citation: Casanova
ER. Parotid gland non-Hodgkin lymphoma – MALT type. Clinical Case. Molecular analysis.
www.egoncasanova.cl 2005
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