2. Overview
Lymphatic system and histology
What is MALT?
Introduction to MALT Lymphomas
Diagnosis and other workup studies
Differential diagnosis
IPSID
Assessment of post eradication biopsies
Conclusion
3. Lymphatic System
I. Primary lymphoid organs:
1. Bone marrow
2. Thymus
II. Secondary lymphoid organs:
1.Spleen
2. Lymph node
3. MALT
4. Lymphoid cells array:
Germinal center – Ag exposed B cells
Mantle – Naïve(unexposed) B cells zone
Marginal zone – memory cells residence(external part)
5. Marginal zone??
It is the external part of the secondary lymphoid follicles.
This anatomic compartment is more prominent in lymphoid organs that are
continuously exposed to a high flow of external antigens, particularly the
spleen, mucosa-associated lymphoid tissue (MALT) and the mesenteric lymph
nodes.
Contain B cells with more pale abundant cytoplasm
6. Mucosa-associated lymphoid tissue
(MALT):
It is scattered along mucosal linings in the human body
and constitutes the most extensive component of human
lymphoid tissue. These surfaces protect the body from an
enormous quantity and variety of antigens.
The tonsils, the Peyer patches within the small intestine,
and the vermiform appendix are examples of MALT.
7. MALT
The epithelium appears columnar and contains cells with
deeply invaginated basal surfaces - microfold cells or M-cells
MALT lacks afferent lymphatics because all such lymphoid
structures actively sample exogenous antigens directly
from the mucosal surfaces through a characteristic follicle-
associated epithelium containing "microfold" or "membrane"
(M) cells.
These specialized thin epithelial cells effectively transfer
soluble and especially particulate antigens such as
microorganisms from the gut lumen.
8.
9.
10. PEYER'S PATCH
Unencapsulated organized lymphoid nodules in small intestine, the appendix and
colorectum
Marginal zone B cells enter the overlying dome shaped epithelium, where
they form the lymphoepithelium.
The epithelium in this area contains a population of specially adapted cells, M
cells, which facilitate the transport of large molecules across the epithelial
barrier.
The area around follicle contains T-cells, plasma cells and accessory cells.
11.
12.
13. World Health Organization (WHO) classification, there are
3 different MZL entities with specific diagnostic criteria,
different behavior, and therapeutic implications
1)The extranodal MZL of MALT type (MALT lymphoma)
2)The splenic MZL, with or without villous lymphocytes
3)Nodal MZL
14. replacement of the lymphoid follicles of the white pulp by neoplastic cells. The marginal zone is expanded. The
15.
16. •Partial / total effacement of architecture, interfollicular infiltrate of monocytoid, centrocyte-like B cells that are 2 - 3×
larger than small lymphocytes
•Tumor cells surround and infiltrate follicles, have moderately abundant pale cytoplasm, round / irregular nuclei with
clumped chromatin
17. MALToma definition:
It is an extranodal lymphoma comprising morphologically heterogenous B cells
including marginal zone(centrocyte like cells),cells resembling monocytoid
cells, small lymphocytes and scattered immunoblast ,centroblast like cells
and plasmacytoid cells.
18.
19. History
1st reported by Isaacson and Wright in 1983 as a a group
of indolent B cell lymphoma that occurred specifically
at extranodal sites
20. Epidemiology:
Extranodal marginal zone lymphoma of MALT lymphoma is the 4th commonest
B cell nonHodgkin’s lymphoma(NHL) worldwide.
Accounting for about 9% of all B cell lymphoma and 50% of primary gastric
lymphoma
Most commonly encountered in GI tract with stomach the most frequently
involved.
Most cases are middle aged and elderly, usually over 50 years.Median age is
61years
Slight female preponderance. (M:F ratio-1:1.2)
21. Sites of MALToma
Gastric and other gastrointestinal (GI) sites (50%)
Salivary glands(14%)
Skin(11%)
Orbits ,Conjunctiva(12%)
Lung(14%)
Breast(4%)
Thyroid(4%)
Liver
22.
23. Few interesting facts about etiology:
Density and detectability of H.pylori decreases as lymphoma evolves from
chronic gastritis
In seropositive patients the organism is undetectable
Patients with Sjogrens syndrome or LESA(lymphoepithelial sialadenitis) have a
44 fold increased risk of developing overt lymphoma.85% of lymphoma in
patients with SS/LESA are MALT lymphoma
Patients with Hashimoto’s have 3 fold increase risk of developing lymphoma
and 70 fold increase risk of developing thyroid lymphoma
25. Persistence of H.pylori causes chronic inflammation
Inflammation leads to infiltration of immune cells in order to
remove the microorganisms
B and T lymphocytes-produce antibodies
macrophages-produce APRIL
Neutrophils-produce ROS-
that damage DNA of B lymphocytes-leads to overexpression
of oncogenes or alteration of signalling pathway
26. Clinical features:
Most patients with MALTomas have no physical findings; lymphadenopathy is
rare. When symptoms of MALTomas are present, they are nonspecific and are
related to the organs involved.
Chronic fatigue ,Low-grade fevers ,Weight loss ,Shortness of breath
20% have bone marrow involvement
Recurrent respiratory infections may be observed in some patients, especially
in patients with pulmonary MALTomas.
Patients with conjunctival MALTomas may present with blurry vision or visual-
field defects.
27. Clinical features of GI MALtoma
Vague upper abdominal symptoms
Dyspepsia
Nausea and vomiting
Lower intestinal symptoms
Disordered bowel habit
Vague discomfort
Rectal bleeding
28. Diagnostic criteria Dawson’s criteria
Used for labelling primary gastrointestinal lymphoma:
(1) absence of peripheral lymphadenopathy at the time of presentation
(2) lack of enlarged mediastinal lymph nodes
(3) normal total and differential white blood cell count
(4) predominance of bowel lesion at the time of laparotomy with only lymph
nodes obviously affected in the immediate vicinity
(5) no lymphomatous involvement of liver and spleen
29.
30. Workup:
All the patients with GI lymphoma should have an endoscopy
It may form a single dominant mass with erythema, thickened folds and
erosions
Polyps may be seen
Occasionally a more solid lesion with or without ulceration is seen
31.
32.
33. Biopsies
Standard staging workup and multiple deep gastric biopsies must be taken
and processed for lymphoma and stain for H. Pylori.
Bx from both suspicious appearing and normal lesion – since lymphoma can
be multifocal with intervening normal appearing mucosa
Aim for largest biopsy specimen as possible
Conventional pinch biopsy may miss diagnosis, since lymphoma may
infiltrate s/mucosa without involving mucosa – more so when no obvious
mass
Jumbo biopsy can increase yield in suspected cases
EUS guided Bx increase outcome
34. Approximately 70% of gastric MALT lymphomas respond to Hp eradication
therapy alone with enduring remission.
Determination of Hp status
Stains: Giemsa, Warthin starry, Toluidine blue.
Urea breath test
Rapid urease test
Culture: Brain heart infusion broth
Stool polymerase chain reaction based studies
Serological based studies- most accurate as circulating antibodies may be present
up to 2 years following eradication.
35.
36. Histopathology
Early stage
Closely resembles the normal MALT.
Expansion of the marginal zone around reactive follicles, that may have intact
mantles.
Cells in the marginal zone are composed of, centrocyte type cells - closely
resemble small lymphocytes with abundant pale cytoplasm and well-defined cell
borders, cells resembling monocytoid cells, small lymphocytes, and scattered
immunoblast and centroblast like cell.
Dutcher bodies may be seen.
Variable plasma cell infiltrate in one-third of MALT lymphomas
In the earliest stages these can be recognised by clusters of 3 or more
cytologically atypical neoplastic cells in the epithelium.
37. Followed by
Infiltration of neoplastic cells into the gland/crypt epithelium with
destruction of architecture resulting in lymphoepithelial lesions.
With the disease progression the intact lymphoid follicle are overrun by
lymphoma cells.The lethal effect on the epithelial cells become progressively
enlarged with eosinophilia of the epithelium and eventually are destroyed
38.
39.
40.
41.
42.
43. MALT lymphoma can have multifocal microlymphoma
Microlymphoma- Neoplastic lymphocytic cells around a single follicle.
Smallest infiltrate
Molecular techniques are helpful
44.
45. Immuno-histochemistry
Pan B cell markers such as CD19, CD20, CD22, CD79a, and PAX5 are
positive.
Aberrant expression of CD 43 in about 50% of cases.
Express bcl2
Surface Ig- IgM or IgA, and rarely IgG.
Negative for CD5, CD23, cyclinD1, CD10 and bcl-6
Staining for cytokeratin-highlight the lymphoepithelial lesions
Antibodies to bcl-6 and CD10- residual germinal centres.
Light chain restriction(kappa more than lambda)
46. Compared to chronic gastritis, the lymphoid infiltrate in MALT lymphoma extends deeper into the
lamina propria .
Immunohistochemistry for CD20 shows many B-cells and contains lymphoepithelial lesions in
which neoplastic B-cells infiltrate and eventually overrun epithelial structures
IHC negative for CD3
47.
48. Molecular tests
Molecular test
PCR assay of immunoglobulin heavy chain assist in documentation
of monoclonality
But monoclonality may also be seen in gastritis
Characterised by several recurrent chromosomal translocations
which involve NF-kB signalling pathway
49.
50. Antibiotic resistant cases should raise the suspicion of presence of t(11;18)
(q21;q21) but are less agressive
Diagnosis is done by
Interphase fluorescence in situ hybridisation with MALT1 dual-color break-
apart
API2-MALT1 dual color fusion probes
Reverse transcription polymerase chain reaction (RTPCR) of the API2-MALT1
fusion transcript
51. Molecular testing
t(11;18)(q21;q21)- API2-MALT1- present in about 25%.This creates a novel
functioning fusion product by translocating the terminus region of apoptosis
inhibitor 1 (API1) gene to the carboxy terminus of MALT1.—this activate the
NF-kB pathways.
t(1;14)(p22;q32) -BCL10-IGH.It is present in about 5% of gastric MALT
lymphomas, translocation of the BCL-10 gene into to come under influence of
immunoglobulin heavy chain(IGH) gene-resulting pathway leads to activation
of NF-kB pathways.Trisomies 3, 12, and 18 are associated with this
translocation
52. How to substantiate NFkB pathway
involvement??
This observation is substantiated by the fact that treatment with
bortezomib a proteasome inhibitor with inhibitory effects on the
NF𝜅B signal pathway —induces complete remissions in a substantial
proportion of MALT lymphoma patients.
53.
54. Differential diagnosis:
1)Reactive process(H.pylori gastritis,lymphoepithelial sialadenitis,Hashimoto’s
thyroiditis)
Early phases of MALToma resemble reactive process
How to differentiate??
Destructive infiltrates of extrafollicular B cells typically with morphology of
marginal zonal cells.Later stages easy to differentiate
Immunophenotypic demonstration of light chain restriction-Neoplastic infiltrate
CD43-marker of neoplastic population
Molecular studies can be done
55. Differential diagnosis:
Follicular lymphoma: Presence of a significant extrafollicular component-
MALToma. CD10+, bcl-6+, aberrant expression of bcl-2 protein –Follicular
lymphoma
Mantle cell lymphoma : Morphologically similar .CD5+, cyclinD1 staining
CLL/SLL: CD5+/CD23+
Burkitt lymphoma: CD19,CD20,CD22,surface IgM positive; 60-80% of cases
CD10 positive
56. Therapy:
Surgery is no longer indicated- due to presence of microlymphoma foci.
Radiotherapy
Standard chemotherapy with or without immunotherapy- chlorambucil or
cyclophosphamide or thalidomide.
57.
58. Response to therapy
Cases with deep infiltration of the gastric wall ,lymphnode involvement are
less likely to respond to eradication therapy
t(11;18)(q21;q21)is a predictor that response to Hp eradication alone is
unlikely
Success of Hp eradication should be confirmed and urea breath test is the
most accurate determinant of presence of small residual Hp colonies
59. ASSESSMENT OF POST ERADICATION
BIOPSIES
The GELA group(Group d’Etude des Lymphomes de l’Adulte) has developed
a scheme for assessment of post eradication biopsies.
The scoring system assess the lymphoid infiltrate in the mucosa, the
degree of regression associated fibrosis and the presence of
lymphoepithelial lesions and divides the finding into four groups
60.
61. Pulmonary MALT Lymphoma:
Single or multiple nodules
Presents with cough and dyspnoea
Lymphangitic pattern of infiltration, spreading along
bronchovascular bundles, interlobular septa and visceral
pleura with replacement of pulmonary parenchyma
lymphoepithelial lesion
62. Salivary Gland MALT Lymphoma:
Atrophic acinar tissue infiltrated by small lymphocytes and plasma cells
Haloes or collars of pale monocytoid B cells around these islands
63. IMMUNOPROLIFERATIVE SMALL
INTESTINAL DISEASE(IPSID)
Subtype of MALT lymphoma
Frequently encountered in the Middle East, Mediterranean countries and
Cape region of South Africa and in some parts of Indian sub-continent.
At any age but mainly in young adults (range, 10-35 years; mean, 25-30 years)
Associated with infection with campylobacter jejuni
Type of MALT lymphoma is associated with synthesis of abnormal IgA chain
May transform into large cell lymphoma
64.
65. Pathogenesis
Chronic C jejuni infection develops due to defective gut mucosal immunity.
The cytolethal distending toxin of C jejuni may cause double-stranded DNA
breaks in proliferating germinal center B cells that are even normally liable
for mutations, deletions, and insertions.
Truncated heavy chain–producing plasma cells are selected due to the
absence of variable determinants on the surface; they proliferate and
progress resulting in IPSID
EBV infection in previously unexposed children may result in Burkitt
lymphoma of the intestine.
66.
67. HISTOPATHOLOGY
Generally characterised by sheets of plasma cells with scanty small lymphocytes.Widening of
villi seen
Stage A
Lymphoplasmacytic infiltrate is confined to the mucosa and mesenteric lymph nodes
No cytological atypia
Endoscopic examination appears normal- responsive to antibiotic therapy
Stage B
Nodular mucosal infiltrates develop and there is extension below the muscularis mucosae
Minimal degree of cytological atypia
Occasional immunoblast like cells
Endoscopically as thickening of mucosal folds
68. Stage C
Presence of large masses and transformation to frank large cell lymphoma.
Numerous centroblasts and immunoblasts are present.
Plasmacytic differentiation is still evident
Marked cytological atypia including Reed-Sternberg-like cells.
Mitotic activity is increased
69.
70. IPSID
Immunophenotypically similar to classic MALT lymphoma.
The immunologic hallmark of IPSID is the presence of anomalous α heavy chain
protein in the serum detected in 20% to 90% of patients
Plasma cells show synthesis of IgA (usually IgA1) and light chain production is
absent.
Serum and duodenal juice shows raised levels of IgA.
Genetically the translocations seen in classical MALtoma has not been
demonstated here
71. Conclude
MALToma represents specific lymphoma with characteristic clinical ,morphological
and molecular features
Earliest distinguishing feature to differentiate from reactive infiltrate is extension
of atypical small B cells away from follicles into superficial mucosa
IHC to distinguish MALToma-CD5-/CD23-/CD 10-/bcl6-/cyclinD1-
Majority of gastric MALT lymphoma are associated with infection by Hp
Posteradication biopsy specimen are assessed by GELA scoring but time for
determing lack of response to therapy is variable and unpredictable
72. References:
Massimo Pignatelli, Patrick Gallagher. Recent Advances in Histopathology-23.
2014 J P Medical Ltd.
Gastric MALT lymphoma: old and new insights.Angelo Zullo, Cesare Hassan,
Lorenzo Ridola, Alessandro Repici, Raffaele Manta, Alessandro Andriani.Ann
Gastroenterol. 2014; 27(1): 27–33.
Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up.E Zucca and others.Annals
of Oncology 2013, October 24th Supplement 6, pages 144-8.
Chris M Bacon, Ming-Qing Du, Ahmet Dogan. Mucosa-associated lymphoid
tissue (MALT) lymphoma: a practical guide for pathologists. J Clin Pathol
2007;60:361– 372.
