Department of Oral Pathology & Microbiology

Kothiwal Dental College & Research Centre

Moradabad

LYMPHOMAS OF
HEAD
Under guidance of:
& NECK
Dr (Mrs) V.R.Brave
Dr N.N.Singh
Dr G.Sreedhar Presented by:
Dr Diksha Singh Dr. Kanika Sethi
PG III rd YEAR
Contents :
• Click to Lymphoid tissue
• Lymphomas
Diagnosis
• Hodgkin’s Lymphoma
• Non Hodgkins Lymphoma
• Primary lymphoid
• tissue
Secondary peripheral
lymphoid organs
Lymph nodes
Spleen
MALT
 Progenitor lymphoid stem cells

Virgin lymphocytes

cortex paracortex
Placements
• Superficial
- cervical
- axillary
- inguinal
• Deep
- mediastinum
- intra abdominal
- mesentric
Lymph Node
Cortex

Trabeculae
Follicles

Hilum

capsule
Primary & Secondary follicles

GERMINAL CENTRE
PRIMARY FOLLICLES
SECONDARY FOLLICLES
Cells of outer cortex (sec. lymphoid follicle)
Germinal centre

• B cells
• Follicular dendritic cells

Present antigen to B cell

Antibody producing plasma cells

B cells proliferate
(persist after an
Memory B cells immune response

 macrophages
 Small lymphocytic
Small cleaved

Large cell cleaved &

noncleaved
Large cell
noncleaved
Lymphomas
• Lymphomas are primary malignancies of
lymph nodes and the peripheral
lymphatics.
• Lymphomas are malignant neoplasms of
the lymphocyte cell lines.
• Lymphomas are classified into two main
types:
Hodgkin lymphoma
Non‐Hodgkin lymphoma.
How to approach for lymphoma
diagnosis??
• Technical factors:
touch preparations
snap freezing
culture
cytogenetic analysis, flow cytometry
• Morphological Evaluations:
general morphologic assessment
ascertaining the pathologic process to be Lymphoma
determining the cell size and classification
- reactive histiocytes/ endothelial cell nuclei
- cell size, nuclear configuration, cytoplasmic
characteristics, cellular organization(F/ D)
• Immunohistochemical Studies
Immunohistochemical studies
• Ques 1: How imp are these immunohistochemical
studies in the evaluation of lymphoid proliferations?

• Ques 2: How useful are frozen section or paraffin section

immunohistochemistry , or flow cytometry?

• Ques 3: Which antibody to select?

Initial panel for lymphoma typing
• Step 1: LCA: to confirm neoplasm is composed of
lymphocytes.
• Step 2: confirm the lineage of neoplastic cells
B cell origin: Pan B cell markers (CD20,CD79a)
T cell origin: Pan T cell markers(CD3, CD45RO)
NK cell lineage: CD56
Step 3: confirm specific WHO histologic subtypes: CD 5,
CD10,Bcl-2, CD23.
If doubt of RS cells: CD15 +, CD 30+, CD 45 -,EMA -
Paraffin section immunohistochemistry in evaluation of
lymphoid neoplasm
Purpose Antibodies
Identify B cells CD20, CD79a
Identify clonal B cells Kappa , lambda
Identify follicular lymphomas Bcl-2+ follicles
Identify non follicular B cell neoplasms CD43 & CD20/79a co-expression
Identify B cell subsets typical of B CLL CD23
Identify T cells CD3, CD5
Identify T cell subsets CD8, CD4
Identify NK/T cell subsets CD56, CD57
Identify RS cells CD 15+, CD30+, CD45-, EMA-
Identify “L&H” RS cells in lymphocyte CD20, EMA±,ring of CD57+ cells
predominant HD
Identify lymphoblasts TdT
Identify myeloid / monocytic cells Lysosyme, myeloperoxidase
Identify mast cells tryptase
Identify Langerhans cells CD1a, S100
 Cytogenetic findings
Lymphoma type specific Oncogene/tumor mechanism
chromosomal suppressor gene
translocation
Follicular lymphoma T(14;18)(q32;q21) Bcl2 Overexpr of Bcl 2as a
result of juxtaposition
of gene with Ig H
Lymphoplasmacytic T(9;14)(p13;q32) Pax5 Overexpr of pax5 as a
lymphoma result of juxtaposition
of gene with Ig H

Mantle cell lymphoma T(11;14)(q13;q32) bcl1 Overexp of bcl 1(cyclin

D1) as a result of
juxtaposition of gene
with Ig H
Burkitt’s lymphoma T(8;14)((q24;q32) C-myc Deregulated
T(8;22)(q24;q11) expression of c-myc
T(2;8)(p12;q24) due to juxtaposition of
gene with Ig H,Ig k,Igλ
Diffuse large B cell Ranslocation involving Bcl 6 Overexp of bcl6 due to
lymphoma 3q27 with many chr juxtaposition of gene
partners with TCR gene
Extranodal marginal T(11;18)(q21;q21) API 2, MLT Production of chimeric
zone B cell lymphoma protein, inhibiting
of MALT type apoptosis
Terminology confusion
• Primary: lymphoma that first manifests in the particular gland,
regardless of the subsequent stage of the disease, whether it arises
in the parenchyma or intraglandular lymph nodes,or whether it is
associated with an autoimmune disorder.
• When a lymphoma develops in a patient with a known history
of malignant lymphoma, we arbitrarily designate it as secondary.

• Others use the term primary only when the lymphoma

originates in the parenchyma (MALT) as opposed to
intraglandular lymph nodes.

• Still others apply the term primary only when the lymphoma
appears de novo and secondary when it is associated with an
underlying autoimmune disorder, such as Sjogren syndrome.
Hodgkin’s
Disease
Hodgkins disease
• Thomas Hodgkin
1832
• Bimodal age
incidence. Peaks in
young adulthood
with secondary
peak in elderly.
• In old m/c in males,
in young equal sex
predilection.
Lymph node involvement

Painless, contiguous, enlargement first cervical, then axillary, inguinal,

mediastinal. Non tender, mobile from side to side & rubbery.
Nodes are ovoid smooth & discreet
Classification:
• subclassified according to the growth pattern. cytological
features of the RS cell, mixture of inflammatory cells
(particularly the number of small lymphocytes), and
connective tissue deposition.
• Rosenthal (1936) (Lymphocyte
predominance/subordinance/absence)
Jackson Parker 1947 Lukes Butler 1966 Rye classification
1966
Paragranuloma L& H nodular Lymphocte
L & H diffuse predominant
Granuloma Mixed cellularity Mixed cellularity
Nodular sclerosis Nodular sclerosis
sarcoma Diffuse fibrosis Lymphocyte depleted
Reticular
WHO 2001/REAL Classification
• Lymphocyte predominance, nodular
• Classical
- lymphocyte rich
- mixed cellularity
- nodular sclerosis
- lymphocyte depletion
Constitutional symptoms
• Young adult with asymptomatic nodal
enlargement
• Pel ebstein fever
• Malaise , night sweats, unexplained wt loss >
10% in prior 6 mnths
• Pruritis
• Dysphagia – enlarged mediastinal nodes
• Pain on alcohol consumption.
Histology common to all HL
• The diagnosis of HL depends on the
identification of characteristic neoplastic
cells (Reed‐Sternberg cells and its
variants) against the proper cellular
background.
Reed Sternberg cells
Described 1898 Sternberg, 1902 Reed

60-80 µm
Variants of RS cells
Nodular Lymphocyte
predominance HL
• solitary peripheral lymph nodes of neck, groin,axilla.
• 80% stage I or II.
• Nodal architecture obliterated.
• Nodules composed predominantly of small lymphocytes.Scanty
eosinophills and plasma cells.
• L& H cells are main feature.
• Few areas in between the nodules may show aggregates of larger
and paler lymphocytes---T lymphocytes as rosettes around L&H
cells.
• CD20 +, bcl6 +, EMA +, CD30-.
• Clonal Ig gene rearrangement not detected in NLPHL
• D/D-
• progressive transformation of germinal centres (PTGC)
• Follicular Lymphomas(bcl2 expression)
nLPHL showing multiple, large, dark staining
discrete nodules punctated by pink foci
occupied by histiocytes
 nLPHL showing large L& H cells
scattered in background of small
lymphocytes

nLPHL showing large L& H cells

with folded or lobated nuclei
Progressive transformation of germinal centres- PTGC
All nodules in NLPHL are large.In Follicular lymphoma nodules are
often closely packed and spill over into perinodal tissue
Lymphocyte predominant

Best prognosis
Small lymphocytes predominate
L& H popcorn cells
Nodular sclerosis
• Most common type
• Lacunar RS cells and
nodular masses
divided by birefringent
bands of sclerosis
D/D
• Nectrotizing lymphadenitis and cat scratch
disease: extensive necrosis may mar the
neoplastic nature.CD30+
• Malignant fibrous histiocytoma:
• Large cell lymphomas
Mixed cellularity
• No nodular grouping
• Numerous mononuclear
RS cells and few diagnostic
RS cells
• Background of small
lymphocytes, plasma cells,
eosinophills,
neutrophills,and histiocytes
Lymphocyte Rich Classic HL
• Mononuclear cells
• Rare RS cells
• L&H cells absent
Lymphocyte depletion HL
• Relative lack of
lymphocytes
• Non birefirengent
fibrous tissue
• Nodal architecture
effaced
• Abundance of bizzare
RS cells
• Worst prognosis
Pathology Nodular Lymphocy Nodular Mixed Lymphocy
lymphocyt te rich scelrosis cellularity te
e depletion
predomina
nce
Diagnostic Rare or rare present Easy to find Easy to find
RS cells absent
Major RS L& H cells Mononuclear Lacunar Mononuclear Mononuclear
cell variant RS cells cells RScells RS cells
Appropriate
Lymphocytes and/ or Lymphocytes, plasma cells, histiocytes,
inflammatory
histiocytes only eosinophils and/or neutrophils
background
Other Nodular Usually RS cells and RS cells and May show
diagnostic pattern diffuse variants tend variants diffuse
features to form show fibrosis
aggregates, dispersed
producing distribution
vague without
nodules. nodular
Dense grouping
fibrous
bands
traverse the
lesion
Cotsworld staging classification
Nature of RS cells
• All types of myeloid and lymphoid cells
• Heterogenous entity
• In LPHLn , L&H variant express B cell
markers(CD20,CD74).Nodules have
morphologic and immunoarchitectural
similarity to germinal centre. Hence B cell
lineage.
• Clonal Ig H and / or L chain
• CD3 positivity.T cell lineage
NON HODGKINS
LYMPHOMA
• All malignant lymphomas other than Hodgkin’s
disease.
• Mainly B and less commonly T cell lineage
• Relatively common than HL
• Mainly adults(males)
• Nodal or extranodal(40%), GIT most common.
• B cell lymphomas as common phenotypes in
extranodal sites.
• Diffuse B cell lymphomas
• Burkitt’s Lymphoma
• T cell & NK cell lymphomas
• Extranodal marginal zone lymphomas
Clinical difference between Hodgkin’s &
Nonhodgkin’s Lymphoma

Hodgkin’s disease Non Hodgkin’s Lymphoma

More often localized to a single More frequent involvement of

axial group of nodes( cervical, multiple peripheral nodes
mediastinal, para aortic)

Orderly spread by contiguity Noncontiguous spread

Mesentric nodes and Waldeyer’s Waldeyer’s ring and mesentric
ring rarely involved nodes commonly involved

Extranodal involvement Extranodal involvement common

uncommon
Classificatio
ns
Rappaport classification of NHL(1966)

GROWT Mixed
H Undiff cell
PATTER Lympho
N erntia cytic
Nodular Diffuse ted histiocyti
c
Lymphoc
Lymphoc
ytic ,poor
ytic , well
differenti
ly
differntiat
Histiocytic
ated
ed
 Lukes-Collins Revised Classification of Undefined Cell
and Lymphoid Neoplasms

• Undefined cell neoplasms

Acute undefined Leukemias
B- cell neoplasms
• Lymphoid neoplasms B-cell acute lymphocytic leukemias. including B-cell
T-cell neoplasms Prolymphocytic leukemia
• Acute undefined leukemia Small B-cell lymphoid neoplasms, including chronic
• T-cell acute lymphocytic leukemia lymphocytic leukemia
• Adult T-cell leukemia Myeloma
• Small T-cell neoplasms. including chronlc Hairy cell leukemia (leukemic reticuloendotheliosis)
lymphocytic leukemia T
Mantle zone lymphomas
• Convoluted T-lymphotna/lymphoblastic (thymic
lymphoma)
Marginal zone lymphomas
• Immunoblastic T-cell lymphoma, including
Parafollicular (monocytoid) B-cell lymphomas
peripheral T-cell lymphonm Follicular center cell lymphomas, including Burkitt’s
• Other T-cell ncoplasms. Including lymphoma and non-Burkitt’s types Immunoblastic
• Lymphoepithelioid T-lymphocytic Lymphoma of B cells
lymphoma (Lennert’s lymphoma), Large-B-cell lymphomas
• T-zone lymphoma
• Cerebriform T-cell lymphoma (mycosis fungoides
and Sezary syndrome)
• Extranodal T lymphomas
•
Updated Kiel Classification of Non-
Hodgkin's Lymphomas
B Cell Lineage T CELL Lineage
• LOW GRADE • Lymphocytic: chronic lymphocytic and
prolymphocytic leukemia
Lymphocytic: chronic lymphocytic and
• Small. cerebriform cell-mycosis
prolymphocytic leukemia; hairy cell
leukemia
fungoides. Sezary's syndrome
• Lymphoepithelioid (Lennert's
Lymphoplasmacytic/cytoid (LP
immunocytoma) lymphoma)
Plasmacytic
• Angioimmunoblastic (AILD. LgX)
Centroblastic/centrocytic
• T-zone
• Pleomorphic. small cell (HTLV-I +)
Follicular ± diffuse
• Pleomorphic, medium and large cell
Diffuse
• Immunoblastic (HTLV-1 L )
Centrocytic
• Large-cell anaplastic (Ki- I + )
• High-Grade • Lymphoblastic
Centroblastic
* lmmunohlastic
* Large-cell anaplastic (Ki- I )
Burkitt lymphoma
Lymphoblastic
 National Cancer Institute Working Formulation ( 1982)
• Low-grade
• A. Malignant lymphoma, snlall lymphocytic (SL)
Chronic lymphocytic leukemia
Plasmacytoid
High-grade
• B. Malignant lymphoma, follicular, predomlnantly small cleaved cell (FSC) H. Malignant lymphoma. large cell, immunoblastic (IBL)
Plasmacytoid
Diffuse
Clear cell
Sclerosis
Polymorphous
• C. Malignant lymphoma. follicular. mixed small cleaved and large cell (FM)
Epitheloid cell component
Diffuse areas I. Malignant lymphoma, lymphoblastic (LBL)
Sclerosis Convoluted
Nonconvoluted
• Intermediate-grade J. Malignant lymphoma, small, noncleaved cell (SNC)
• Burkitt’s tumor
D. Malignant lymphoma, follicular, predominantly large cell (FL)
Follicles
Diffuse areas
Miscellaneous
Sclerosis
Composite, mycosis fungoides. extramedullary
• E. Malignant lymphoma, diffuse, small cleaved cell (DSc) plasmacytoma. ?histiocytic
Sclerosis
• F. Malignant lymphoma. diffuse. mixed small and large
• G. Malignant lymphoma, diffuse. large cell (DL) cell (DM)
Cleaved
Noncleaved
Sclerosis
WHO/ REAL Classification of Lymphoid
Neoplasms
B-Cell Neoplasms
Precursor B-cell neoplasm Mature (peripheral) T neoplasms
Precursor B-lymphoblastic T-cell chronic lymphocytic leukemia / small
leukemia/lymphoma lymphocytic lymphoma
(precursor B-acute T-cell prolymphocytic leukemia
lymphoblastic leukemia) T-cell granular lymphocytic leukemiaII
Mature (peripheral) B-neoplasms Aggressive NK leukemia
B-cell chronic lymphocytic leukemia / small Adult T-cell lymphoma/leukemia (HTLV-1+)
lymphocytic Extranodal NK/T-cell lymphoma, nasal type#
lymphoma Enteropathy-like T-cell lymphoma**
B-cell prolymphocytic leukemia Hepatosplenic γδ T-cell lymphoma*
Lymphoplasmacytic lymphoma‡
Subcutaneous panniculitis-like T-cell
Splenic marginal zone B-cell lymphoma lymphoma*
(+ villous
Mycosis fungoides/Sézary syndrome
lymphocytes)*
Hairy cell leukemia Anaplastic large cell lymphoma, T/null cell,
primary cutaneous type
Plasma cell myeloma/plasmacytoma Peripheral T-cell lymphoma, not otherwise
Extranodal marginal zone B-cell lymphoma of characterized
MALT type Angioimmunoblastic T-cell lymphoma
Nodal marginal zone B-cell lymphoma Anaplastic large cell lymphoma, T/null cell,
(+ monocytoid B
primary systemic type
cells)*
Follicular lymphoma Hodgkin’s Lymphoma (Hodgkin’s Disease)
Mantle cell lymphoma Nodular lymphocyte predominance Hodgkin’s lymphoma
Diffuse large B-cell lymphoma Classic Hodgkin’s lymphoma
Mediastinal large B-cell lymphoma Nodular sclerosis Hodgkin’s lymphoma
Primary effusion lymphoma† (grades 1 and 2)
Burkitt’s lymphoma/Burkitt cell leukemia§ Lymphocyte-rich classic Hodgkin’s
T and NK-Cell Neoplasms lymphoma
Precursor T-cell neoplasm Mixed cellularity Hodgkin’s lymphoma
Precursor T-lymphoblastic Lymphocyte depletion Hodgkin’s
leukemia/lymphoma
(precursor T-acute lymphoma
lymphoblastic leukemia

†
Not described in REAL classification
§
Includes the so-called Burkitt-like
Etiology
• Variations in ethnic group suggest genetic
predisposition
• Immunodeficiency—acquired/ congenital
• Defective immune response to EBV
• Chromosomal translocations
t(8:14), t(8:22) t(2:8) in Burkitt’s
lymphoma
t(11:14) in mantle cell lymphoma
 Indolent (good) Aggressive(bad) Highly
aggressive(ugly)

Protypic entities Follicular lymphoma Diffuse large Bcell Burkitt’s

B CLL/ SLL lymphoma
Mantle cell lymphoma Peripheral T cell
Lymphoma
lymphoma

Age group Older adults Any age Children , young

adults

Tumor growth rate Slow; low Fast Very fast,

proliferative fraction proliferative fraction
≥ 95%

Bone marrow Very common uncommon common

involvement

Natural history if Indolent course; Killing patients in 1- Early dissemination,

untreated taking many years to 2 yrs killing patient in
kill patient weeks to months

Response to poor responsive Very responsive

treatment

Survival curve
years
Clinical presentation
• Lymphomas of oral region vary with their site of origin and tumor
type
• Plasmacytoma & Burkitt s lymphoma show striking predilection for
1° involvement of bone.
• Microscopic characterization is imp for staging & therapy
• Biopsy coupled with tissue based immunologic studies
• In H& N lymphomas may be seen within regional lymph nodes and
extranodal lymphoid sites known as MALT
• within oral cavity: nodal ---Waldeyer;s ring
• extranodal --- lymphoid tissue in base of tongue and soft palate,
major and minor salivary glands
• If bone involvement ---- alveolar bone loss and tooth mobility
• Swelling , pain, numbness and pathologic #
Follicular B cell lymphoma
• Follicular centre B cells showing follicular
organization
• 22-40% of NHL
• rare in oral cavity
• complete effacement of nodal architecture
by neoplastic follicles.
• Follicles composed of range of follicular
centre like cells, including small and large
cleaved cells and occasionally large
noncleaved cells.
Extranodal marginal Zone Lymphoma

• A.k.a Lymphoma of MALT

• Mucosal sites in extranodal tissues
including GIT, SG, lung, thyroid skin.
• Indolent lymphoma
• Tumor composed of centrocyte like cells
 A diffuse small lymphoid cell or mixed small and medium sized lymphoid cell proliferation
BENIGN OR MALIGNANT?
PAN B & T markers
Mixture of T& B cells
predominance of B cells
Assess cytology of B & T cell predominance of T cells

B cells in
dense sheets
B cells in dense
With few T Atypical cells are Atypical cells are
sheets With
cells selectively B cells selectively Tcells
many T cells

Look for abberrant

Look for abberrant immunophenotype
immunophenotype of T cell,EBER +
of B cell cells
B &T cells are
small in size

present absent absent Aberrant EBER

cells present

Possibly
B Cell lymphoma REACTIVE. Ig & Peripheral T/NK
gene rearrangement to
Cell lymphoma
be followed up
 Criteria For Distinction Of Benign From Malignant
Proliferations

REACTIVE PROLIFERATION NEOPLASTIC DISORDER

Retention of normal architecture Architectural effacement
absent follicles but retention of
subcapsular , cortical & medullary
sinuses
Heterogenous proliferations of cell More homogenous proliferations
subsets--- mottled appearence
Presence of a specific cell
population outside of its normal
envoirnment or without its usual
growth pattern
Presence of lymphoid dysplaia

Immunophenotypic studies used to differentiate benign

from neoplastic proliferations
references
• Diagnostic Histopathology of tumors.Christofer Fletcher.Second
edition.Vol 2
• Anderson’s Pathology.10th edition.Vol 1
• Surgical Pathology of head and neck.Leon Barnes.Vol 2.
• Oral pathology.Clinical pathologic corealations.Regezi, scuibba,
Jordan
• Oral non-Hodgkin’s lymphoma: review of the literature and World
Health Organization classification with reference to 40 cases.
Spencer Kemp. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2008;105:194-201)
• Nodal aggressive B-cell lymphomas: a diagnostic approach. Sonam
Prakash, Steven H Swerdlow. J Clin Pathol 2007;60:1076–1085.
• Primary non-Hodgkin's lymphoma of the oral tongue. Gopal
Krishna Maheshwari, Harshad Acharatlal Baboo, Nilesh Manubhai
Shah, Mahesh Hirjibhai Patel, Rakesh Shah. Turk J Cancer
• 2001;31(3):121-124
 "At first I was
confused on this
subject. Now I am
still confused but
at a much higher
level."