Dr Tashi Agarwal
Moderator : Dr Abha Mathur
• Historically- a mess
– 1940s Gail and Mallory
– 1950s Rappaport
– 1970s Lukes-Collins
– 1970s Kiel
– 1982 Working
– 1994 REAL
– 2001, 2008 WHO
Rappaport Classification (1966)
• First popularly used system
• Divided growth patterns into nodular and diffuse;
• cells types into well differentiated, poorly differentiated (cleaved follicular
center cells), histiocytic (large cells) undifferentiated (round; between
lymphocytes and histiocytic), and Burkitt’s.
Lukes-Collins Classification (1973)
• Based on proposed cell of origin; follicular center cells, cleaved or
uncleaved; immunoblasts; B or T Cells
Kiel Classification (1973)
• Based on low and high grade, Centroblastic, Lymphoblastic, Immunoblastic
• Low grade: Lymphocytic, Lymphoplasmacytoid, Centrocytic, Centroblastic
Working Formulation for Clinical Use
• Intended to establish a common language of communication between
pathologists and clinicians rather than to represent specific disease
• An individual patient can progress from one histologic type to another
Low Grade: Small lymphocytic, follicular small cleaved,
follicular mixed(small cleaved and large cell)
Intermediate Grade: follicular large cell, diffuse large cell, diffuse small
cleaved cell, diffuse mixed (small and large cell)
High Grade: Immunoblastic, lymphoblastic, small non-cleaved.
Misc : Composite, Mycosis fungoides, Histiocytic, Extramedullary
plasmacytoma, Unclassifiable, Other
REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF B
– CELL LYMPHOMAS
REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF
THE T/NK CELL LYMPHOMAS .
Small lymphocytic lymphoma
• Also called as Chronic lymphocytic leukaemia
• Low grade lymphoma in the Working Formulation
• Typically middle-aged to elderly
• Prolonged evolution, scanty symptoms, good survival
• Most have blood and bone marrow involvement, as well as other organs,
at presentation (Stage IV)
• SLL are always of B cell type.
• B-lymphocytes (surface IgM, IgD, CD19+, CD20+) but 70% express T-cell
marker CD5; most are also CD23+, CD10–
• Chromosomal abnormalities likely: most common trisomy 12, or 13q–
• Differential diagnosis: follicular lymphoma, NLPHL, mantle cell lymphoma
• Rare follicular centers or sinuses may remain, but nodal architecture is
usually completely and diffusely effaced
• The predominant cells are monomorphic small lymphocytes with relatively
round nuclei, clumped chromatin, inconspicuous nucleoli, barely visible
cytoplasm and scant mitotic activity.
• Some of the larger cells have distinct nucleoli (“paraimmunoblasts”).
• They form ill-defined aggregates, pale-staining proliferation centers or
• Proliferation centers are a very useful histologic finding because they are
found only in CLL/SLL. Occasional CLL/SLLs may appear somewhat nodular,
raising the differential diagnosis of a follicular lymphoma or NLPHL.
• Cases of SLL can be divided into three categories
1. Those with absolute lymphocytosis
2. Those associated with monoclonal gammopathy
3. Those with neither.
• In the cases associated with monoclonal gammopathy neoplastic
lymphocytes may exhibit morphological signs of plasmacytoid
differentiation. These cases are referred to as small lymphocytic
lymphoma with plasmacytic differentiation.
• Transformation of a small lymphocytic leukaemia into a blastic,
histiocytic, large cell neoplasm is known as Richter syndrome.
• Sometimes, cases of SLL are seen with typical RS cell, possible
transformation to HL; may be mediated by EBV.
• Few cases show dysproteinemia by secreting immunoglobulins of one
sort or another.
• Small lymphocytic lymphoma/chronic lymphocytic leukemia (lymph node).
A, Low-power view shows diffuse effacement of nodal architecture. B, At
high power the majority of the tumor cells are small round lymphocytes. A
larger cell with a centrally placed nucleolus, is also present in this field
• Chronic lymphocytic leukemia. This peripheral blood smear is flooded with
small lymphocytes with condensed chromatin and scant cytoplasm. A
characteristic finding is the presence of disrupted tumor cells (smudge
• In the Working Formulation, the predominantly small cleaved and mixed cell
types are low grade, and the predominantly large cell type is intermediate
• Nodular pattern of growth.
• Arise from follicular center cells: B-Cells (CD19+, CD20+, CD22+. CD79a+)
• Germinal centre marker, CD10+(CALLA), BCL6+, BCL2+
• CD5-, CD43-.
• Comprise 50% of adult non-Hodgkin’s lymphomas
• Usually elderly (median age 60-65); unusual under 40 (especially small cleaved
type), uncommon in blacks
• The hallmark genetic alteration of follicular lymphoma is t(14;18)(q32;q21),
found in 85% of cases. Which leads to the overexpression of the anti-apoptotic
• Differential diagnosis : Atypical follicular hyperplasia, marginal zone
lymphoma with follicular growth pattern and mantle cell lymphoma.
• Fuzzy edge of neoplastic nodule of follicular lymphoma(B), as opposed to
sharp edge bound by the mantle zone in follicular hyperplasia(A).
• Homogenous population of small cleaved cells in follicular lymphoma(B)
as opposed to polymorphic composition seen in follicular hyperplasia(A).
• Marked contrast between the cleaved cells of follicular lymphoma(B) and
the regular mature lymphocytes of small lymphocytic lymphoma.
• Grossly and at low-power examination, the most distinctive feature of these
tumors is the nodular pattern of growth.
• With progression of the disease it acquires a diffuse pattern.
• The cytologic composition of the neoplastic nodules is characterized by a mixture
of small and large lymphoid cells.
• The small cells have scanty cytoplasm and an irregular, elongated cleaved nucleus
with prominent indentations and infoldings; the size is similar to normal
lymphocytes, the chromatin is coarse, and the nucleolus is inconspicuous. These
cells have been variously referred to as germinocytes, centrocytes, poorly
differentiated lymphocytes, and small cleaved follicular center cells.
• The large cells are two or three times the size of normal lymphocytes; they have a
distinct rim of cytoplasm and a vesicular nucleus with one or three nucleoli often
adjacent to the nuclear membrane. These cells, have been designated over the
years as germinoblasts, centroblasts, histiocytes, large (cleaved or noncleaved)
follicular center cells, large lymphoid cells, and lymphoblasts.
• Some may be binucleated and simulate Reed–Sternberg cells.
Even distribution of neoplastic follicles in follicular lymphoma(B), as opposed to the
predominantly cortical distribution typical of follicular hyperplasia(A). Gross appearance
of a lymphnode in follicular lymphoma with neoplastic nodules bulging onto the
Follicular lymphomas are subdivided into three categories, respectively
designated in the WHO classification as follows:
Grade 1, with 0–15 centroblasts (large nucleolated cells) per high-power field.
Grade 2, with 6–15 centroblasts per high-power field.
Grade 3, with more than 15 centroblasts per high-power field.
• Cases with admixed centrocytes are referred to as grade 3a, while cases with
solid sheets of centroblasts are referred to as grade 3b.
Grade 1 follicular lymphoma are often asymptomatic, generalized and have a
good prognosis. Grade 3 tumors are more commonly localized at the time of
presentation but run a more aggressive clinical course and become diffuse.
Grade 2 tumors are intermediate between these two but closer to grade 1.
• In some cases of follicular lymphoma (particularly grade 1), malignant cells
are found in the peripheral blood; hematologists refer to them by the
inelegant term ‘buttock’ cells because of their prominent nuclear cleft. No
prognostic significance has been assigned to this finding.
1. Presence of fine or coarse bands of fibrosis that accentuate even more
the nodular character of the lesion. This feature is more commonly seen
in grade 3 tumors
2. Presence of monocytoid B cell/marginal zone differentiation. In about
10% of follicular lymphomas, discrete foci of monocytoid B cells are seen,
typically appearing on low-power examination as a pale rim around the
3. Deposition of proteinaceous material in the center of the nodules, similar
to that seen in some reactive conditions, particularly the plasma cell
variant of Castleman disease
4. Presence of large cytoplasmic eosinophilic globules – presumably
immunoglobulins – or a single vacuole that push the nucleus laterally and
result in a signet ring effect.
5. Clearcut plasmacytic differentiation in some or many of the neoplastic
follicular center cells.
6. Presence of cells with cerebriform nuclei (similar to those of T-cell
lymphoma) or multilobated nuclei.
7. Permeation of the tumor follicles by small round lymphocytes of
presumably mantle zone origin, the appearance simulating that of
progressively transformed germinal centers (‘floral’ variant)
8. Presence of rosettes made up of cytoplasm and cytoplasmic processes of
the lymphoid tumor cells and simulating the appearance of a
9. Presence of hyaline vascular follicles similar to those seen in the
vascular-hyaline type of Castleman disease.
10. Inversion of the usual staining pattern as seen on low-power
examination so that the neoplastic follicles appear darker than the
surrounding lymphoid tissue. This pattern, which is referred to as the
‘reverse’ or ‘inverse’ variant of follicular lymphoma, carries no prognostic
11. Prominent epithelioid granulomatous response.
12. Preserved reactive germinal centers in some foci of the involved lymph
node. This feature is said to be a strong indicator of limited disease stage
Mantle cell lymphoma
• Low-grade neoplasm
• AKA: mantle zone lymphoma, intermediate lymphocytic, centrocytic
lymphoma, diffuse small cleaved cell lymphoma
• Not part of working formulation.
• 3% to 10% of all cases of non-Hodgkin lymphoma
• Middle age to elderly (median = 58); M:F=3:1
• Most have sIgM, sIgD; B cell: CD19+, CD20+, CD23–; T-Cell: CD5 and CD43,
overexpression of cyclin D1
• Immunophenotype most closely matches the B-cell of primary lymphoid
follicles and the mantle-zone B-cells of secondary lymphoid follicles
• Usually see t(11;14)(q13;q32)
• Differential diagnosis: mantle zone hyperplasia, Castleman disease, grade
1 follicualr lymphoma, B and T cell lymphoblastic lymphoma (from blastoid
Immunoreactivity for cyclin D1 in mantle zone lymphoma.
• Lymph nodes show complete or partial architectural effacement by a very
monotonous-appearing infiltrate of small lymphocytes.
• Four growth patterns are observed. The most common is a diffuse growth,
followed by either vaguely nodular, mantle zone, or (rarely) follicular-
appearing growth patterns.
• The classic cytology of the infiltrate is small to medium-sized cells with
condensed chromatin and indented nuclei.
• Other much less common cytologic variants include small-cell (CLL-like),
pleomorphic (often resembling DLBCL), and blastoid, with dispersed
nuclear chromatin and a high mitotic rate (resembling lymphoblastic
lymphomas). The latter two types often are lumped together as “blastoid”
• Two common morphologic features of mantle cell lymphoma are
hyalinized blood vessels and a scattering of epithelioid histiocytes, the
former representing an important diagnostic clue and the latter
sometimes resulting in a starry sky appearance.
Lymph node, mantle cell lymphoma. At low power, note the dense,
homogeneous diffuse growth pattern.
High power view of mantle cell lymphoma. There are subtle abnormalities of
Marginal zone B-cell lymphoma
• Not part of Working Formulation
• B-cell malignancy: CD19+, CD20+; CD5–, CD23–, CD10–; 30-35% are EMA
positive. Cyclin D1 -
• No rearrangements of the bcl-1 or bcl-2 genes
• Cell of origin is unclear
• Strong association with autoimmune disorders, such as Sjögren disease.
• Tend to be indolent lymphomas, but can transform to a large cell
lymphoma which behaves much more aggressively;
• Include low or high grade in diagnosis
• They represent a related family of neoplasms showing morphologic
evidence of differentiation into cells of marginal zone type.
• These cells are thought to have the capacity to mature into both
monocytoid B cells and plasma cells, and to display tissue-specific homing
• A corollary of this proposal is that the various clinical syndromes may be
the result of the homing pattern
• Divided into three subgroups.
1. Nodal marginal zone lymphoma
• Also c/a monocytoid B-cell lymphoma as the tumor cells have been
regarded as the neoplastic counterpart of the monocytoid B lymphocytes.
• Tumor consists of small to medium-sized lymphocytes with round or
slightly indented nuclei and relatively abundant clear cytoplasm, usually
located in lymph nodes.
• Plasmacytoid features are prominent in some cases.
• The pattern of involvement is predominantly sinusal and interfollicular.
• Similar to extranodal marginal zone lymphoma, some cases exhibit loss of
function of A20.
2. Extranodal marginal zone lymphoma of
mucosa-associated lymphoid tissue
• This is a neoplasm in which the cell population – all of small size – has
been described as including small round lymphocytes, monocytoid B cells,
cells with slightly irregular nuclei (centrocyte-like), plasmacytoid cells, and
plasma cells. Occasional large lymphoid cells may also be seen.
• This tumor was originally described at extranodal sites in relation to
mucosae or glandular epithelia, such as gastrointestinal tract, salivary and
lacrimal glands, lung, thyroid, conjunctiva, bladder, and skin.
• This lymphoma type exhibits distinctive chromosomal translocations
including t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and
• Trisomy 3 and trisomy 18 are found in some cases.
3. Splenic marginal zone lymphoma.
• Cases of lymphoma involving the marginal zone of the spleen have been
reported, sometimes in association with bone marrow and peripheral
• The disease is probably related if not identical to that reported under the
term ‘splenic lymphoma with villous lymphocytes’.
Lymphnode involvement by marginal zone B cell lymphoma. There are
numerous residual germinal centres.
Lymphnode involvement by marginal zone B cell lymphoma.
( small and large cell) lymphoma
• Diffuse mixed lymphoma is not a specific lymphoma type but a
heterogeneous category composed of lymphomas of various types that
share a mixed composition of large and small lymphoid cells.
• It includes: (1) the diffuse mixed cell form of follicular lymphoma; (2)
peripheral T-cell lymphoma; (3) lymphoplasmacytic lymphoma with an
increased number of immunoblasts (also known as polymorphic
immunocytoma); (4) T-cell-rich large B-cell lymphoma; and (5) some
examples of marginal zone B-cell lymphoma with an admixture of large
cells; and probably others.
• The differential diagnosis among these various entities is based on a
combination of clinical, morphologic, and immunohistochemical criteria
Diffuse large B cell lymphoma
• AKA: Diffuse histiocytic lymphoma, Reticulum cell sarcoma
• Occurs in both children and adults, mostly the latter (median age 57 yrs)
• Grow as large bulky fleshy mass - may resemble carcinoma
• Greater tendency for extranodal presentation (40%) including digestive tract, skin,
• ~50% limited to one side of diaphragm (vs 90% for follicular)
• Bone marrow/liver involvement less common
• 50-60% B-Cell, 5-15% T-Cell, 5% histiocytic, 30-40% no markers (most B-Cell by
• Associated with translocations involving the bcl-6 gene
• Rapid progression, poor prognosis if untreated, but aggressive chemotherapy can
yield good result, in particular rituximab (anti-CD20 therapy).
• Median survival: 1-2 yrs
Gross appearance of lymphnodes involved by non-Hodgkin lymphoma of the diffuse
large cell type. The nodes are large and show a homogenous tan cut surface. 43
• Microscopically, the pattern of nodal involvement is by definition diffuse.
However, it may be complete or partial, and on occasion it may be
interfollicular or sinusal.
• There is commonly extranodal extension, sometimes with accompanying
sclerosis. Mitoses are numerous and a starry sky pattern may be present.
• It is characterized morphologically by large size of the cells, vesicular
nuclei with prominent nucleoli, and relatively abundant cytoplasm, and
immunophenotypically by expression of B-lineage markers.
• Accordingly, some pathologists simply use the term DLBCL without
qualifiers. Others prefer to keep subclassifying them whenever possible
into the types listed below:
Lymph node, diffuse large-B-cell lymphoma. Note the numerous large cells with
their dispersed chromatin and moderately prominent nucleoli. Some of the cells
have nucleoli that lie close to the nuclear membrane, as is typical of
• This one being by far the most common.
• This is regarded as the diffuse counterpart of follicular lymphoma of large
cell type (grade 3) and is thought to be more aggressive.
• It is composed of an admixture in varying proportions of cleaved and
noncleaved large cells.
Medium and high power views of diffuse large B cell lymphoma of large cleaved type.47
• In this form, the predominant tumor cell has the appearance of an
immunoblast: large vesicular nucleus with prominent central nucleolus
and thick nuclear membrane, and a deeply staining amphophilic and
pyroninophilic cytoplasm with a distinct nuclear hof.
• Some of the cells are binucleated or multinucleated and simulate Reed–
Sternberg cells, and others acquire plasmacytoid features (cartwheel
chromatin, larger perinuclear hof).
• Immunoperoxidase staining often shows intracytoplasmic
Medium and high power view of diffuse large B-cell lymphoma of immunoblastic type.49
• This rare variant is characterized by the presence of large bizarre tumor
cells, some resembling Reed–Sternberg cells, often growing in a cohesive
pattern and/or sinusal pattern mimicking carcinoma.
• Despite the obvious morphologic similarities, this tumor is biologically
unrelated to the anaplastic large cell lymphoma.
1. Sclerosis: Diffuse large cell lymphomas can undergo marked sclerosing
changes, similar to those seen in follicular lymphomas.
2. Spindling of tumor cells: This phenomenon, which is probably related to
the aforementioned fibrosis, seems to be more common in large cell
lymphomas of mediastinum and bone, but it can be seen in any location,
including lymph nodes.
3. Presence of a myxoid stroma: that can simulate the appearance of
myxoid malignant fibrous histiocytoma or myxoid chondrosarcoma.
4. Rosette formation: This peculiar change, originally described in follicular
lymphoma, has also been seen in large cell lymphoma.
5. Filiform cell prolongations: Large cell lymphomas exhibiting this
spectacular feature have been designated anemone cell, microvillous,
filiform cell, villiform cell, and porcupine lymphomas.
6. Signet ring features: rarely seen in large cell lymphoma and may simulate
7. Sinusal pattern of spread, in which the tumor cells are predominantly or
entirely confined to the lymph node sinuses (and therefore should be
referred to as sinusal rather than sinusoidal) resulting in an appearance
closely simulating that of metastatic carcinoma, malignant melanoma, or
anaplastic large cell lymphoma.
8. Interfollicular pattern of growth: This is more common in T-cell tumors
but has also been described in B-cell neoplasms.
9. Nuclear multilobation: Although originally thought to be a feature of T-
cell tumors, this alteration is now known to be more common in B-cell
Immunophenotype and Molecular
These mature B-cell tumors express CD19 and CD20 and show variable
expression of germinal center B-cell markers such as CD10 and BCL6. Most
have surface Ig.
1. One frequent pathogenic event is dysregulation of BCL6, a DNA-binding
zinc-finger transcriptional repressor that is required for the formation of
normal germinal centers.
2. BCL6 can also silence the expression of p53, the “guardian of the
genome” This “anti-p53” activity may serve to prevent the activation of
DNA repair mechanisms.
3. MYC (8q24) translocation is found in up to 10% of DLBCLs.
4. Another 10% to 20% of tumors are associated with the t(14;18), which (as
discussed under follicular lymphoma) leads to the overexpression of the
anti-apoptotic protein BCL2
Gene expression profiling studies can identify two major groups of DLBCLs:
(1) Germinal center B-cell-like (GCB) DLBCL that expresses genes
characteristic of germinal center B cells, and is correlated with presence of
t(14;18) translocation and C-REL amplification.
(2) Activated B-cell-like (ABC) DLBCL that expresses genes normally induced
during in vitro activation of peripheral blood B cells, and is correlated with
presence of BCL6 translocation.
• The GCB group is associated with a better prognosis than the ABC group,
with 5-year overall survival of 60% versus 35% with CHOP or CHOP-like
• However, currently it is not a requirement to distinguish between these
two groups of DLBCLs, because techniques are not yet available.
1. Primary mediastinal (thymic) large B-cell lymphoma.
2. Intravascular large B-cell lymphoma (angiotropic lymphoma).
3. T-cell/histiocyte-rich large B-cell lymphoma.
4. Primary DLBCL of the central nervous system.
5. DLBCL associated with chronic inflammation.
6. EBV-positive DLBCL of the elderly.
7. Plasmablastic lymphoma.
8. ALK+ large B-cell lymphoma.
9. Primary effusion lymphoma.
Peripheral T-cell and NK-cell
• Peripheral (post-thymic) T-cell and NK-cell lymphoma is the generic group
given to a family of tumors composed of neoplastic lymphocytes with
phenotypic and genotypic features of mature T cells or NK cells.
• This is an extremely heterogeneous group of lesions, many of them
occurring primarily at extranodal sites, and which have received a myriad
• Most of them were identified as entities long before their peripheral T-cell
or NK-cell nature was ascertained.
• Peripheral T-cell and NK-cell lymphomas in general are highly aggressive.
• Immunohistochemical studies are always required to confirm their T-cell
or NK-cell nature.
• They are commonly immunoreactive for CD3, CD45RO, CD2, CD5, and
• NK-cell lymphomas are commonly CD2+, CD3+, CD5–, and CD56+
• Most cases of peripheral T-cell lymphoma express a CD4+/CD8– mature
• T-cell lymphomas exhibit clonal rearrangements of the γ and β T-cell
receptor genes, although about 10% of cases may show simultaneous
clonal rearrangements of the immunoglobulin heavy chain gene.
• Recurrent chromosomal translocations have been identified in only a
minority of cases. t(5;9)(q33;q22), which results in ITK–SYK fusion.
Mycosis fungoides and Sézary syndrome
• Lymphadenopathy, particularly in the axillary and inguinal areas, is present
in approximately 70% of patients with MF/SS, and nodal involvement has
been documented in more than 60% of autopsied cases.
• Nodal changes in patients with MF/SS have three basic patterns:
1. Nonspecific reactive type,
2. Dermatopathic lymphadenopathy, and
3. Frank lymphomatous involvement.
• Nonspecific patterns are generally follicular or paracortical lymphoid
• Nodes affected by MF/SS show either partial or complete architectural
effacement by atypical lymphocytes, which often have cerebriform
nuclei but may have immunoblastic features.
Morphologic Pattern NCI
Nonspecific reactive LN-0 — —
LN-1 and LN-2
Frank lymphoma, partial
or complete effacement
LN-4 Category III or IV 94%
Lymph node involved by transformed-cell variant of mycosis fungoides/Sézary
syndrome. The neoplastic cells have features of immunoblasts: large cells with
abundant cytoplasm, dispersed chromatin, and prominent central nucleoli.62
• Enteropathy-type T-cell lymphomas commonly involve intra-abdominal
lymph nodes, particularly within the mesentery. The neoplastic infiltrates
consist of small intrasinus aggregates or sheets of tumor cells that may
expand the paracortex.
• Hepatosplenic T-cell lymphomas may affect splenic hilar nodes and other
intra-abdominal nodes. It is usually exemplified by partial interfollicular
and sinus infiltrates of tumor cells.
• Subcutaneous panniculitis-like T-cell lymphomas rarely involve lymph
nodes, and no good descriptions of nodal infiltrates exist.
• Extranodal NK/T-cell lymphomas, nasal type are T-cell or true NK-cell
lymphomas that usually arise in the sinonasal area or skin and may rarely
involve nodes. The nodes are often effaced by lymphocytes of variable size
and nuclear atypia. Perivascular and intravascular infiltrates that are
angiodestructive are usually present and associated with areas of
• Angioimmunoblastic T-cell lymphoma shows clonal rearrangements of
the T-cell receptor genes in most cases and of the immunoglobulin genes.
• In some patients, the B-cell proliferation can evolve into an overt large B-
cell lymphoma.Chromosomal alterations in angioimmunoblastic T-cell
lymphoma are common but nondistinctive.
• The gene expression profile shows a strong contribution by the admixed
follicular dendritic cells, B cells and stromal components, as well as
overexpression of genes characteristic of normal follicular helper T cells.
Peripheral T-cell lymphoma with a high content of non-neoplastic histiocytes.
• The tumor type originally described by Lennert as malignant lymphoma
with a constantly high number of epithelioid cells and variously known
as Lennert lymphoma and lymphoepithelioid lymphoma.
• Microscopically, there is effacement of the architecture by a
lymphohistiocytic infiltrate, often accompanied by plasma cells and
eosinophils and by proliferation of small vessels with plump endothelial
• The polymorphic nature of the infiltrate and the occasional presence of
Reed–Sternberg-like cells often elicit a mistaken diagnosis of Hodgkin
lymphoma. The key to the diagnosis resides in the atypical appearance of
the small lymphocytes located between the reactive histiocytes.
• In addition to Hodgkin lymphoma, the differential diagnosis includes
• Adult T-cell leukemia/lymphoma, an HTLV-1-related pleomorphic T-cell
lymphoma occurring in an endemic form in Japan.
• Peripheral T-cell lymphoma not otherwise specified shows a gene
expression profile distinct from that of angioimmunoblastic T-cell
lymphoma and anaplastic large cell lymphoma. It shows diverse profiles,
indicating that it represents a heterogeneous category.A proportion of
cases (5–11%) show association with EBV, and seem to have a worse
• NK-cell lymphomas rarely occur outside East Asia, and most have
extranodal location (sinonasal, skin, gastrointestinal tract, and testes).
They are usually associated with EBV and often display angiocentric
characteristics. The tumor cells are frequently pleomorphic large
lymphocytes that contain azurophilic cytoplasmic granules on
Romanovsky-type-stained touch imprints or smears. The neoplastic cells
lack surface CD3 (but may express cytoplasmic CD3)
Peripheral large T-cell lymphoma in a patient from Japan.
Anaplastic large cell lymphoma
• AKA: Ki-1 lymphoma
• Almost all are CD30+ ( Ki 1). Usually EMA+, positive for interleukin-2
receptor, clusterin (in a Golgi pattern), cadherins, and galectin-3. PAX 5-
• Only cases of T- or null-cell lineage are included in the category of ALCL;
cases of B-lineage are simply diagnosed as ‘diffuse large B-cell lymphoma,
• The hallmark of this lymphoma type is translocation of ALK (anaplastic
lymphoma kinase gene on 2p23)
• ALCLs with ALK translocation have a much more favorable prognosis than
• Clinically, two types of presentation are recognized: a systemic form and a
primary cutaneous form.
Strong membranous and Golgi-type immunoreactivity for CD30 in anaplastic large
• Two types are segregated based on ALK expression, owing to differences in
clinical features and prognosis.
1. ALK+ ALCL tends to occur in children and young adults, and the outcome
is good if appropriate treatment is given.
2. ALK– ALCL tends to occur over a wider age range, especially older adults,
and is associated with a poor outcome similar to peripheral T-cell
lymphoma not otherwise specified.
• Several morphologic variants of ALCL (usually ALK+) have been described;
Small cell, lymphohistiocytic, and others.
1. Systemic ALCL
• Microscopically, the infiltrate has a polymorphic appearance, often with a
variable admixture of neutrophils, lymphocytes, and histiocytes, with the
highly atypical large lymphoma cells showing marked pleomorphism. The
nuclei of these cells are often horseshoe shaped or multilobed, and
nucleoli are prominent. The cytoplasm is abundant and eosinophilic.
Cohesive growth and preferential sinusal involvement are common.
• The undue prominence of the latter feature in some cases was one of the
reasons for this lesion to be mistakenly placed in the category of
• ALCL can also simulate malignant melanoma, undifferentiated carcinoma,
and various types of soft tissue sarcoma.
A and B, Anaplastic large cell
A, Packing of the peripheral sinus.
2. Primary cutaneous ALCL
• The cutaneous form occurs predominantly in adults and has an indolent
course, with some of the individual lesions regressing spontaneously.
• In retrospect, it should be acknowledged that the cases originally reported
as regressive atypical histiocytosis and most of the cases diagnosed as
malignant histiocytosis belong to this category.
• In contrast to systemic ALK+ ALCL, primary cutaneous ALCL does not
exhibit ALK translocation. Instead, 26–57% of cases
show IRF4/MUM1 translocation, although the partner gene is currently
not yet known.
• Usually children and adolescents (accounts for 1/3 of childhood non-
Hodgkin’s lymphomas)- also adults
• Anterior mediastinal mass in 50-80% (thymic region)
• CSF and skin involvement not uncommon
• Untreated: rapid dissemination, leukemia, death in months
• Gross: soft, white, foci of hemorrhage and necrosis
• M/E: Diffuse, monomorphic pattern of lymphocytes (round nuclei with
“delicate” convolutions, fine chromatin, small nucleoli, and high mitotic
rate) - focal “starry sky” areas. It preferentially involves the paracortical
• Differential diagnosis: Thymoma, Ewing sarcoma/PNET, Burkitt
lymphoma, and the blastoid variant of mantle cell lymphoma.
Lymphoblastic lymphoma. In this example the presence of delicate
Approximately 80–85% of lymphoblastic lymphomas show T-cell markers.
That is T lymphoblastic lymphoma.
• The immunohistochemical hallmark of lymphoblastic lymphoma is TdT, a
marker for precursor lymphoid cells. In approximately 90% of the cases,
these tumors express all of the pan–T-antigens, such as CD1, CD2, CD7,
cytoplasmic CD3, and CD43. Practically all cases express CD71.
In approximately 15–20% of the cases of lymphoblastic lymphoma, the tumor
cells express B-cell rather than T-cell markers. These tumors are referred
to as B lymphoblastic lymphoma.
• These tumours express CD19, CD20, CD21, and CD24.
• Bulky, fleshy tumors, ± necrotic areas
• Peripheral lymphadenopathy is rare; Bone marrow involvement late,
• Responsive to chemotherapy (especially African), 50% relapse
• Strong association with EBV.
• The hallmark genetic change is t(8;14), t(2;8), or t(8;22), which fuses
the MYC gene with an immunoglobulin heavy chain, kappa light chain, or
lambda light chain gene. As a result, the MYC gene is overexpressed,
promoting cell cycle progression and inhibiting differentiation.
• CD10+, Bcl-6+, CD43+ but CD5-, CD23-, Bcl-2-, CD138- and Tdt-. Another
important feature of BL is that nearly 100% of nuclei of the neoplastic cells
are Ki-67-positive. Cytoplasmic immunoglobulin may be present.
• Differential diagnosis: Diffuse large B cell lymphoma, B cell lymphoma
• Burkitt lymphoma is a high-grade malignant lymphoma composed of germinal
center B cells which can present in three clinical settings:
1. Endemic. This occurs in the equatorial strip of Africa and is the most
common form of childhood malignancy in this area. The patients
characteristically present with jaw and orbital lesions. Involvement of the
gastrointestinal tract, ovaries, kidney, and breast are also common.
2. Sporadic. This is seen throughout the world. It affects mainly children and
adolescents, and has a greater tendency for involvement of the abdominal
cavity than the endemic form.
3. Immunodeficiency-associated. This is seen primarily in association with HIV
infection and often occurs as the initial manifestation of the disease.
• The tumor cells are monotonous small (10-25μm) round cells. The nuclei
are round or oval and have several prominent basophilic nucleoli. The
chromatin is coarse and the nuclear membrane is rather thick. The
cytoplasm is easily identifiable; Mitoses are numerous, and a prominent
starry sky pattern is the rule, although by no means pathognomonic.
• In well-fixed material, the cytoplasm of individual cells ‘squares off’,
forming acute angles in which the membranes of adjacent cells abut on
• Occasionally, the tumor is accompanied by a florid granulomatous
• Numerous fat vacuoles in cytoplasm (Oil Red O positive)
E/M: abundant ribosomes, lipid inclusions, no glycogen, nuclear
Burkitt lymphoma with characterstic starry sky appearance.
Other Non hodgkin lymphoma
• Leukemias and myeloma
• Lymphomatoid granulomatosis
• Hairy cell leukemia: The lymph nodes can be involved by the disease and
this involvement is characterized by diffuse infiltration of the subcapsular
sinuses, cortex, and medullary cords by typical small mononuclear cells
having nuclei slightly larger than those of lymphocytes, fine chromatin
pattern, relatively abundant cytoplasm, and essentially no mitotic activity.
Despite the extensiveness of the infiltrate, the nodal architecture is
• Lymphoma of plasmacytoid dendritic cells. These were formerly known
as plasmacytoid T-cell or plasmacytoid monocytic lymphomas.
• The various types of primarily extranodal T-cell lymphomas.
Lymph node involvement by hairy cell leukemia.
Composite and discordant
• On occasion one encounters two distinct types of lymphoma in the same
patient, either sequentially or simultaneously, even in the same lymph
• The occurrence of two different and well-delineated varieties of
lymphoma occurring in a single anatomic site or mass is known as
composite lymphoma, and the occurrence of two different types of
lymphoma at separate anatomic sites has been referred to as discordant
The most important manifestations of this phenomenon:
1. Low-grade B-cell lymphoma (small lymphocytic, follicular, or T-cell-rich B-
cell lymphoma) that transforms into a diffuse large B-cell lymphoma.
2. Transformation of mantle cell lymphoma into a higher-grade tumor
3. Low-grade T-cell lymphoma (such as mycosis fungoides) that transforms
into a large T-cell lymphoma.
4. Combination of NLPHL and other lymphomas, particularly diffuse large
5. Combination of ‘classic’ Hodgkin lymphoma and large B-cell lymphoma.
6. Combination of classic Hodgkin lymphoma and follicular lymphoma,
representing one of the commonest forms of composite lymphoma.
7. Combination of classic Hodgkin lymphoma and peripheral (post-thymic)
T-cell lymphoma.Some of these tumors express CD20.
8. Combination of classic Hodgkin lymphoma and chronic lymphocytic
9. Combination of classic Hodgkin lymphoma and marginal zone B-cell
10. Transformation of classic Hodgkin lymphoma into anaplastic large cell
11. Malignant lymphomas with B- and T-cell neoplastic components.
12. Combination of small lymphocytic lymphoma and dendritic cell
Composite lymphoma of mediastinum. A) large B cell lymphoma with sclerosis, B) nodular
sclerosis Hodgkin lymphoma.
• Malignant histiocytosis is no longer regarded as a bona fide entity.
• The term malignant histiocytosis was first proposed by Rappaport for a
disease characterized by a systemic, neoplastic proliferation histologically
resembling histiocytes and their precursors.
• However, cell marker and molecular analysis studies have shown that
most cases are actually examples of lymphoma, usually anaplastic large
cell (CD30+) lymphoma or peripheral T-cell lymphoma (with or without a
hemophagocytic syndrome component).
• Therefore, ‘Malignant histiocytosis’ is not a single disease entity and
effort should be made to classify each case based on a thorough
immunohistochemical and molecular evaluation.
• Typical peripheral sinus involvement in the disease formerly known as malignant
histiocytosis. However, this case proved to be anaplastic cell lymphoma. 90
in immunodeficiency states
• An increase in the incidence of malignant lymphoma has been
documented in most types of congenital and acquired immunodeficiency.
• Chronic antigenic stimulation – possibly by oncogenic viruses – and
perhaps loss of antibody feedback inhibition of the lymphoid proliferation
may account for the high rate of lymphoid malignancies.
• The EBV in particular has been repeatedly implicated.
• Patients with genetically determined immune deficiencies have an
increased incidence of malignant tumors, especially lymphomas.This
includes Ataxia–telangiectasia, Wiskott–Aldrich syndrome, X-linked
lymphoproliferative syndrome, common variable immunodeficiency, and
severe combined immunodeficiency syndrome.
Organ transplant recipients
• The incidence of lymphoma is increased in recipients of all types of organ
transplant as a direct or indirect result of the induced immunosuppression.
• In renal transplant recipients, this incidence is in the order of 4–6%.
• Skin tumors, malignant lymphomas, Kaposi sarcoma, and cervical
carcinoma are the most common neoplasms.
• Patients with HIV infection are at a high risk for developing malignant
tumors, principally Kaposi sarcoma and malignant lymphoma.
• It has been estimated that approximately 3% of AIDS patients develop
NHL, and that the risk is 60-fold greater than in the normal population.
• The majority of cases present with multiple sites of extranodal
involvement, with a high incidence of involvement of the GIT, CNS, Bone
marrow, liver, oral cavity, body cavities, and heart. Practically all cases are
B-cell lineage of Burkitt or large B-cell type.
• Acquired diseases of the immune system in which an increased incidence
of lymphoma has been recorded include rheumatoid arthritis,
Large B-cell lymphoma in a recipient of a renal transplant.
LYMPHOMA TYPE SPECIFIC
MECHANISM OF LYMPHOMAGENESIS
Reactivity in Hematopoietic-Lymphoid
Pan-leukocyte CD45 B cells, most T cells,
Most non-Hodgkin lymphomas and leukemias
B-cell-related CD10 Precursor B cells,
cells, and some
Many precursor B lymphoblastic
leukemias/lymphomas; some precursor T
lymphoblastic leukemias/lymphomas; many
follicular lymphomas; Burkitt lymphoma;
some DLBCL; angioimmunoblastic T-cell
CD20 B cells Most B NHL, L&H RS cell in LPHL; RS cells in
some cases of classic HL
CD21 Mantle and
marginal zone B
Some mantle and marginal lymphomas;
follicular dendritic cell tumors
CD23 Mantle zone B cells;
Chronic lymphocytic leukemia/small
CD45RA B cells and subset of
B-cell NHL; L&H cells in LPHL; some T-cell
lymphoid and myeloid leukemias
B-cell related CD138 Plasma cells; some epithelial
cells and fibroblasts
Plasma cell neoplasms; some variants
Bcl-6 Mainly germinal center B
cells; some T cells
Follicular lymphoma; Burkitt
lymphoma, some DLBCL; some T-cell
lymphomas, L&H cells of LPHL
MUM1 Plasma cells; rare germinal-
center B cells; some T cells
Plasma cell neoplasms; many DLBCL;
Hodgkin lymphoma; ALCL; primary
PAX5 Many B cells Most B-NHL; L&H cells in LPHL; RS cells
in classic Hodgkin lymphoma; some
acute myeloid leukemias
B cells, plasma cells B-cell NHL and plasma cell neoplasms
T-cell related CD1a Cortical thymocytes
Precursor T-cell lymphoblastic
leukemia/lymphoma; Langerhans cell histiocytosis
CD2 T and NK cells Many T-cell lymphomas and leukemias
CD3 T cells Most T-cell neoplasms
CD5 T cells and subset
of small B cells
Many T-cell lymphomas and leukemias and small
lymphocytic lymphoma/chronic lymphocytic
leukemia and mantle cell lymphoma
CD7 Most T cells and NK
Many T-cell lymphomas and leukemias
CD43 T cells, some
Most T-cell lymphomas; some B-cell
lymphomas;AML, and plasma cell neoplasms
CD45RO Most T cells, some
some myeloid cells
Most T-cell lymphomas; some B-cell lymphomas
CD57 Some NK cells,
subset of T cells
Some NK- and T-cell lymphomas/leukemias and
some lymphoblastic lymphomas
βF1 (β chain
T cells Many T-cell lymphomas
Hodgkin-related CD15 Granulocytes and some
RS cells in most cases of NS, MC, and
LDHL; some T and B large-cell
lymphomas; some carcinomas
CD30 Activated B and T cells,
RS cells in most cases of NS, MC, and
LDHL; most cases of ALCL; other T-
and B-cell NHL
L&H RS cells in LPHL; plasma
cell neoplasms; anaplastic
large-cell lymphoma; some
other B and T large-cell NHL
and many epithelial tumors
Cyclin D1 Minimal to no expression in
normal lymphoid cells
Mantle cell lymphoma, hairy cell
leukemia, and some cases of myeloma
ALK1 No expression in normal
Most cases of T or null ALCL; rare
cases of DLBCL
CXCL13 Some T cells, dendritic cells
and histiocytes in germinal
centers; some T cells,
histiocytes in paracortex
Langerhans cells Langerhans cell neoplasms
Miscellaneous CD34 Progenitor cells Some acute myeloid leukemias and some
CD56 NK cells, few T cells Many NK-cell neoplasms
CD68 Macrophages and
True malignant histocytosis; many myeloid
S-100 Langerhans cells,
Langerhans cell histiocytes, sinus
histiocytosis with massive
lymphadenopathy; rare T-cell lymphomas,
Tdt Precursor marrow
Most precursor B- or T-lymphoblastic
leukemias/lymphomas; some acute
Ki-67 Proliferating cells
(not in GO phase of
MyeloperoxidaseMyeloid cells Myeloid leukemias
B cells, T cells
Most follicular lymphomas; many other
diffuse NHL and leukemias