non hodgkin lymphoma
TRANSCRIPT
NON HODGKIN LYMPHOMA
by Dr Tashi Agarwal
Moderator : Dr Abha Mathur
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NHL: Classification
• Historically- a mess
– 1940s Gail and Mallory
– 1950s Rappaport
– 1970s Lukes-Collins
– 1970s Kiel
– 1982 Working
– 1994 REAL
– 2001, 2008 WHO
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Classifications 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, Centroblastic3
Working Formulation for Clinical Use (1982)
• Intended to establish a common language of communication between pathologists and clinicians rather than to represent specific disease entities.
• 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, Extramedullaryplasmacytoma, Unclassifiable, Other
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REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF B – CELL LYMPHOMAS
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REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF THE T/NK CELL LYMPHOMAS .
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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
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M/E
• 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 pseudofollicles.
• 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.
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• 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 neoplasticlymphocytes may exhibit morphological signs of plasmacytoiddifferentiation. 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.
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• 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 (arrow).
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• 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 cells). 14
Follicular lymphoma
• In the Working Formulation, the predominantly small cleaved and mixed cell types are low grade, and the predominantly large cell type is intermediate grade
• 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 protein BCL2
• Differential diagnosis : Atypical follicular hyperplasia, marginal zone lymphoma with follicular growth pattern and mantle cell lymphoma.
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Follicular lymphoma stained for BCL2
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• Fuzzy edge of neoplastic nodule of follicular lymphoma(B), as opposed to sharp edge bound by the mantle zone in follicular hyperplasia(A).
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• Homogenous population of small cleaved cells in follicular lymphoma(B) as opposed to polymorphic composition seen in follicular hyperplasia(A).
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• Marked contrast between the cleaved cells of follicular lymphoma(B) and the regular mature lymphocytes of small lymphocytic lymphoma.
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• Grossly and at low-power examination, the most distinctive feature of these tumors is the nodular pattern of growth.
M/E
• 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.
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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 surface(C ).
c
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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.
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• 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.
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Morphological variations
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 neoplastic follicles.
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 neoplasticfollicular center cells.
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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 neuroendocrine neoplasm
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 significance.
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
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Mantle cell lymphoma
• Low-grade neoplasm
• AKA: mantle zone lymphoma, intermediate lymphocytic, centrocyticlymphoma, 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 blastoidvariant)
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Immunoreactivity for cyclin D1 in mantle zone lymphoma.
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M/E
• 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” variants.
• 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.
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Lymph node, mantle cell lymphoma. At low power, note the dense, homogeneous diffuse growth pattern.
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High power view of mantle cell lymphoma. There are subtle abnormalities of nuclear contour.
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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
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• 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 patterns.
• A corollary of this proposal is that the various clinical syndromes may be the result of the homing pattern
• Divided into three subgroups.
1. Extranodal
2. Nodal
3. Splenic
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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.
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2. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
MALT lymphoma
• 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 t(3;14)(q14;q32).
• Trisomy 3 and trisomy 18 are found in some cases.
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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 blood involvement.
• The disease is probably related if not identical to that reported under the term ‘splenic lymphoma with villous lymphocytes’.
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Lymphnode involvement by marginal zone B cell lymphoma. There are numerous residual germinal centres.
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Lymphnode involvement by marginal zone B cell lymphoma.
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Diffuse mixed ( 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
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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, skeletal system.
• ~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 gene rearrangement)
• 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
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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:
1. Centroblastic
2. Immunoblastic
3. Anaplastic
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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 centroblasts. 45
1. Centeroblastic
• 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.
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Medium and high power views of diffuse large B cell lymphoma of large cleaved type. 47
2. Immunoblastic
• 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 intracytoplasmicimmunoglobulin.
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Medium and high power view of diffuse large B-cell lymphoma of immunoblastic type. 49
3. Anaplastic
• 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.
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Morphological variants
1. Sclerosis: Diffuse large cell lymphomas can undergo marked sclerosingchanges, 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.
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Cont..
6. Signet ring features: rarely seen in large cell lymphoma and may simulate metastatic adenocarcinoma.
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 tumorsbut 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 neoplasms.
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Immunophenotype and Molecular pathogenesis
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
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Cont..
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 therapy.
• However, currently it is not a requirement to distinguish between these two groups of DLBCLs, because techniques are not yet available.
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Clinicopathological variants.
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.
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Peripheral T-cell and NK-cell lymphomas
• 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 of designations.
• Most of them were identified as entities long before their peripheral T-cell or NK-cell nature was ascertained.
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• 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, andCD7.
• NK-cell lymphomas are commonly CD2+, CD3+, CD5–, and CD56+
• Most cases of peripheral T-cell lymphoma express a CD4+/CD8– mature helper phenotype.
• 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.
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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 hyperplasia.
• Nodes affected by MF/SS show either partial or complete architectural effacement by atypical lymphocytes, which often have cerebriformnuclei but may have immunoblastic features.
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Classification
Morphologic Pattern NCI Classification
Dutch Classification
T-Cell Clonality
Nonspecific reactive LN-0 — —
Dermatopathiclymphadenopathy
LN-1 and LN-2
LN3
Category I
Category II
46%
Frank lymphoma, partial or complete effacement
LN-4 Category III or IV 94%
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Lymph node involved by transformed-cell variant of mycosis fungoides/Sézarysyndrome. 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 interfollicularand 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 parenchymal necrosis.
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• 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.
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Peripheral T-cell lymphoma with a high content of non-neoplastic histiocytes.
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• 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 cells.
• 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 angioimmunoblastic lymphadenopathy.
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• 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 prognosis.
• 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 angiocentriccharacteristics. 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)
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Peripheral large T-cell lymphoma in a patient from Japan.
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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, anaplastic variant’.
• The hallmark of this lymphoma type is translocation of ALK (anaplasticlymphoma kinase gene on 2p23)
• ALCLs with ALK translocation have a much more favorable prognosis than ALK– ALCLs.
• Clinically, two types of presentation are recognized: a systemic form and a primary cutaneous form.
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Strong membranous and Golgi-type immunoreactivity for CD30 in anaplastic large cell lymphoma.
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• 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
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• 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 malignant histiocytosis.
• ALCL can also simulate malignant melanoma, undifferentiated carcinoma, and various types of soft tissue sarcoma.
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A and B, Anaplastic large cell lymphoma.
A, Packing of the peripheral sinus.
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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.
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Lymphoblastic lymphoma
• 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
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• 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(thymic-dependent) zone.
• Differential diagnosis: Thymoma, Ewing sarcoma/PNET, Burkittlymphoma, and the blastoid variant of mantle cell lymphoma.
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Lymphoblastic lymphoma. In this example the presence of delicate convolutions seen.
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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.
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Burkitt lymphoma
• Bulky, fleshy tumors, ± necrotic areas• Peripheral lymphadenopathy is rare; Bone marrow involvement late,
leukemia rare• 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 unclassified.
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• 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.
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M/E
• 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 each other.
• Occasionally, the tumor is accompanied by a florid granulomatousreaction.
• Numerous fat vacuoles in cytoplasm (Oil Red O positive)
E/M: abundant ribosomes, lipid inclusions, no glycogen, nuclear pockets/projections
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Burkitt lymphoma with characterstic starry sky appearance. 82
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 subcapsularsinuses, 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 partially preserved.
• 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.
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Lymph node involvement by hairy cell leukemia.
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Composite and discordant lymphomas
• On occasion one encounters two distinct types of lymphoma in the same patient, either sequentially or simultaneously, even in the same lymph node.
• 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 lymphoma.
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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 (‘blastic transformation’).
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 cell lymphoma.
5. Combination of ‘classic’ Hodgkin lymphoma and large B-cell lymphoma.
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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 leukemia.
9. Combination of classic Hodgkin lymphoma and marginal zone B-cell lymphoma.
10. Transformation of classic Hodgkin lymphoma into anaplastic large cell lymphoma.
11. Malignant lymphomas with B- and T-cell neoplastic components.
12. Combination of small lymphocytic lymphoma and dendritic cell neoplasm
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Composite lymphoma of mediastinum. A) large B cell lymphoma with sclerosis, B) nodular sclerosis Hodgkin lymphoma.
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Malignant histiocytosis
• 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 histologicallyresembling 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.
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• Typical peripheral sinus involvement in the disease formerly known as malignant histiocytosis. However, this case proved to be anaplastic cell lymphoma.
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Lymphoma 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.
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Primary immunodeficiencies.
• 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.
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HIV
• 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 extranodalinvolvement, 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.
Others:
• Acquired diseases of the immune system in which an increased incidence of lymphoma has been recorded include rheumatoid arthritis, Sjögren syndrome.
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Large B-cell lymphoma in a recipient of a renal transplant.
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LYMPHOMA TYPE SPECIFIC CHROMOSOMAL TRANSLOCATION
ONCOGENE OR TUMOR SUPRESSOR GENE IMPLICATED
MECHANISM OF LYMPHOMAGENESIS
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Category
CD Antigen or Antibody
Reactivity in Normal Cells
Reactivity in Hematopoietic-Lymphoid Neoplasms
Pan-leukocyte CD45 B cells, most T cells, macrophages, and granulocytes
Most non-Hodgkin lymphomas and leukemias
B-cell-related CD10 Precursor B cells, follicular-center B cells, and some follicular-center T cells
Many precursor B lymphoblastic leukemias/lymphomas; some precursor T lymphoblastic leukemias/lymphomas; many follicular lymphomas; Burkitt lymphoma; some DLBCL; angioimmunoblastic T-cell lymphoma
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 cells, FDC
Some mantle and marginal lymphomas; follicular dendritic cell tumors
CD23 Mantle zone B cells; some FDC
Chronic lymphocytic leukemia/small lymphocytic lymphoma
CD45RA B cells and subset of T cells
B-cell NHL; L&H cells in LPHL; some T-cell lymphoid and myeloid leukemias
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B-cell related CD138 Plasma cells; some epithelial cells and fibroblasts
Plasma cell neoplasms; some variants of DLBCL
Bcl-6 Mainly germinal center B cells; some T cells
Follicular lymphoma; Burkittlymphoma, 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 effusion lymphoma.
PAX5 Many B cells Most B-NHL; L&H cells in LPHL; RS cells in classic Hodgkin lymphoma; some acute myeloid leukemias
Anti-immunoglobulin heavy and light chains
B cells, plasma cells B-cell NHL and plasma cell neoplasms
T-cell related CD1a Cortical thymocytesand Langerhanscells
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 cells
Many T-cell lymphomas and leukemias
CD43 T cells, some macrophages, granulocytes, and plasma cells
Most T-cell lymphomas; some B-cell lymphomas;AML, and plasma cell neoplasms
CD45RO Most T cells, some macrophages, 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 of T-cell receptor)
T cells Many T-cell lymphomas
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Hodgkin-related CD15 Granulocytes and some macrophages
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, plasma cells
RS cells in most cases of NS, MC, and LDHL; most cases of ALCL; other T-and B-cell NHL
Epithelial membrane antigen
Various epithelia, plasma cells
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 tissue
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
Langerin(CD207)
Langerhans cells Langerhans cell neoplasms
Miscellaneous CD34 Progenitor cells Some acute myeloid leukemias and some precursor lymphoblastic leukemias/lymphomas
CD56 NK cells, few T cells Many NK-cell neoplasms
CD68 Macrophages and granulocytes
True malignant histocytosis; many myeloid leukemias
S-100 Langerhans cells, IDRC, sometimes FDC
Langerhans cell histiocytes, sinus histiocytosis with massive lymphadenopathy; rare T-cell lymphomas, myeloid leukemias
Tdt Precursor marrow cells, cortical thymocytes
Most precursor B- or T-lymphoblastic leukemias/lymphomas; some acute myeloid leukemias
Ki-67 Proliferating cells (not in GO phase of cell cycle)
Proliferating cells
MyeloperoxidaseMyeloid cells Myeloid leukemias
bcl-2 Nonfollicular-center B cells, T cells
Most follicular lymphomas; many other diffuse NHL and leukemias
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LYMPHOMA
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