Lymphoma

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Lymphoma at cut-up. (WC/Emmanuelm)

Lymphoma is almost a specialty for itself. It can be subclassified a number of ways.

This article is an introduction to lymphoma. An introduction to lymph nodes and lymph node pathology that is not lymphoma are in the articles lymph node and lymph node pathology.

A general introduction to haematopathology is in the haematopathology article.

General

The presentations are variable and similar to that of other malignancies. They may include:

  • Mass effect.
  • Weight loss.
  • Fever.
  • Night sweats.
  • Infection.
  • Incidental:
    • Routine blood work for something unrelated.
    • Life insurance work-up.

B symptoms

  • May be seen in Hodgkin lymphoma and non-Hodgkin lymphoma.
  • Presence correlates with higher stage.
  • Predictor of poor prognosis independent of stage.

All of 'em are required to call "B symptoms"[1] - mnemonic These Bothersome features cause Wednesday Night Fever:[2]

  • Weight loss - >10% in 6 months.
  • Night sweats.
  • Fever - 38 degree C that is unexplained.

Note:

  • A symptoms do not exist. The term comes from the staging system. In the "A" of the staging system the above symptoms are absent.

Lymphoma classification

Lymphomas can be divided into:

Other categorizations:

  • T cell lymphomas (rare).
  • B cell lymphomas (more common).

Two most common NHLs:

Leukemia as a med student

Histologic classification

  1. "Size".
  2. Nodularity.

"Size"

  • The single most important factor for classifying lymphomas.
  • Not really based on size.
"Large" "Small" Utility
Nucleoli present absent most discriminative
Size >2x RBC dia. <2x RBC dia. moderate
Chromatin pattern "open" (pale) "closed" moderate/minimal
Cytoplasm mold-minimal
basophilic cytoplasm
scant cytoplasm minimal

Histologic terms

  • Lymphomas = cells look discohesive, may be difficult to differentiate from poor differentiated carcinoma.
  • Auer rods = acute myeloid leukemia.
    • Granular cytoplasmic rod (0.5-1 x4-6 micrometres).
    • Not pathognomonic.
  • Reed-Sternberg cells = Hodgkin's lymphoma.
    • Large cell - very large nucleus.
      • Classically binucleated.
  • Russell bodies = plasmacytoma (+others).
    • Eosinophilic, large, homogenous immunoglobulin-containing inclusions.[3]
      • Mott cell is a cell that contains Russell bodies.[3]
  • Effacement of nodal architecture.
  • Loss of proliferation centers.

IHC

General

  • CD45.
    • AKA common lymphocyte antigen.
    • Useful to differentiate from carcinomas (e.g. small cell carcinoma).

Others:

T cell markers

  • CD2 -- T cell marker (all T cells).
  • CD3 -- T cell marker (all T cells).
    • CD4 -- subset of T cells.
    • CD8 -- subset of T cells.
  • CD7 -- often lost first in T cell lymphomas.
  • CD5 -- +ve in CLL & mantle cell lymphoma.
  • CD43 -- +ve in mantle cell lymphoma
  • ALK1[4] - prognostic in anaplastic large cell lymphoma (ALCL).[5]
  • TIA1 - cytotoxic T-cell.[6]
  • Granzyme B.

B cell markers

  • CD10 -- follicle center.
  • BCL6 -- follicle center.
  • BCL2 -- normally negative in germinal centers (GCs), marks T cell; +ve in small B cell lymphomas.
  • MUM1 -- -ve in follicular lymphoma, +ve in DLBCL that did not arise from follicular lymphoma.

Plasma cell

Follicular dendritic cells

  • CD23 -- follicular dendritic cells.
  • CD21 -- follicular dendritic cells, considered more sensitive than CD23.[10]

Hodgkin's lymphoma

Classic
  • CD30 +ve -- Hodgkin's lymphoma (most sensitive).
  • CD15 +ve.
  • PAX5 +ve.
  • EMA -ve.
  • EBER +ve/-ve.

Others:

  • CD20, CD45: weak +ve or -ve.
NLPHL
  • CD20 +ve.
  • CD30 -ve, CD15 -ve.
  • EMA +ve/-ve.
  • EBER -ve.

Others

  • Myeloperoxidase - in PMNs.
  • Glycophorin C.
  • CD61 -- megakaryocytes.
  • TdT.
  • CD34.

Molecular pathology

  • T cell clonality study.
  • B cell clonality study.

Chromosomal translocations

Hodgkin's lymphoma

General

  • Abbreviated HL.

Microscopic

By definition, HL has Reed-Sternberg cells (RSCs).

Classical HL

Features (classic HL):

  • Reed-Sternberg cell.
    • Large binucleated cell.
      • May be multinucleated.
      • May have a horseshoe-like shape.
    • Macronucleolus - approximately the size of a RBC (~8 micrometers).
    • Well-defined cell border.

Notes:

  • Large mononuclear cells are common (so called "mononuclear RSCs") but not diagnostic.

Images (classic HL):

Subtypes

There are four CHL subtypes:[11]

  1. Nodular sclerosis CHL - ~70% of CHL.
    • Mixed cellular background - T cell, plasma cells, eosinophils, neutrophils and histiocytes.
    • Nodular sclerosing fibrosis - thick strands fibrosis.
  2. Mixed cellularity CHL - ~20-25% of CHL.
    • Like nodular sclerosis - but no fibrosis.
    • May be associated with HIV infection.[12]
  3. Lymphocyte-rich CHL - rare.
    • T lymphocytes only (no mix of cells).
  4. Lymphocyte-depleted CHL - rare.
    • May be associated with HIV infection.[12]

Memory device:

  • The subtypes prevalence is in reverse alphabetical order.

Nodular lymphocyte-predominant HL

Features (nodular lymphocyte-predominant Hodgkin's lymphoma):

  • Popcorn cell (previously known as Lymphocytic & histiocytic cell (L&H cell)[13]) - variant of RSC:
    • Cells (relatively) small (compared to classic RSCs).
    • Lobulated nucleus - key feature.
    • Small nucleoli.
  • Subtle nodularity at low power (2.5x or 5x objective).

Images (NLPHL):

Small cell lymphomas

This grouping includes:

  • Follicular lymphoma.
  • Marginal zone lymphoma.
    • Nodal marginal zone lymphoma.
    • Extranodal marginal zone lymphoma (MALT lymphoma).
    • Splenic marginal zone lymphoma.
  • Mantle zone lymphoma.
  • Small lymphocytic lymphoma (SLL) / chronic lymphocytic leukemia (CLL).
  • Hairy cell leukemia.

Diffuse large B-cell lymphoma

General

  • Abbreviated DLBCL.

Microscopic

Features:[14]

  • Large cells -- 4-5 times the diameter of a small lymphocytes.
  • Typically have marked cell-to-cell variation in size and shape.
  • Cytoplasm usu. basophilic and moderate in abundance.
  • +/-Prominent nucleoli, may be peripheral and/or multiple.

Notes:

  • Large bizarre cells can occasionally mimic Reed-Sternberg cells, seen in Hodgkin lymphoma.

Intravascular lymphoma

Burkitt's lymphoma

General

  • Abbreviated BL.
  • Subtyped by etiology.

Microscopic

Features:

  • "Starry-sky pattern":
    • The stars in the pattern are: tingible-body macrophages.
      • Tingible-body macrophages = macrophages containing apoptotic tumour cells.
    • The tumour cells are the sky.
  • Tumour cells:[16]
    • Medium-sized (~1.5-2x the size of a RBC) with uniform size ("monotonous") -- key feature.
    • Round nucleus.
    • Small nucleoli.
    • Relatively abundant cytoplasm.
    • Brisk mitotic rate.

Image: Starry-sky pattern - Ed Uthman (WC).

Plasma cell neoplasms

  • These arise from plasma cells.
  • AKA plasma cell myeloma, plasmacytoma.
  • Multiple myeloma (a clinical diagnosis) fits into this category.

Acute myeloid leukemia

General

  • May afflicits young adult.
  • Males>females.

Complications

  • Chloroma - soft tissue mass.
  • Leukostasis.
    • Occurs - lungs and brain.[17]
  • Hyperviscosity syndrome.
  • Spontaneous bleeding with low platelet counts.

Classification

There are two classifications:

  1. FAB (French-American-British) - based on histologic appearance/maturation.
  2. WHO classification.

Histology

Enteropathy-associated T-cell lymphoma

  • Abbreviated EATL.
  • AKA enteropathy-type T-cell lymphoma (ETTL).

Angioimmunoblastic T-cell lymphoma

  • Abbreviated AITL.

General

  • Rare.
    • Common among T-cell lymphomas.
  • Middle age or elderly.

Microscopic

Features:

  • Intermediate size cells with:
  • "Empty" sinus; subcapsular sinuses "open".

Images:

IHC

Features - positives:[19]

  • CD3 +ve.
  • CD5 +ve.
  • CD43 +ve.

Others:

  • CD4 +ve and CD8 +ve with CD4>CD8.
  • CD20 +ve/-ve!
  • CD10 +ve/-ve!
  • CD21 +ve -- prominent FDC meshworks;[20] tumour cell not +ve.

Negatives:

  • CD30 -ve.[19]
  • CD15 -ve.[19]
  • CD7 -ve.
  • TIA-1 -ve.

Primary mediastinal B-cell lymphoma

  • Abbreviated PMBL.
  • AKA primary mediastinal large B-cell lymphoma.

Anaplastic large cell lymphoma

  • Abbreviated ALCL.

Cutaneous T cell lymphoma

See Dermatologic neoplasms.

General

  • Abbreviated as CTCL.
    • Sézary syndrome is a subset of CTCL.

Microscopic

Features:[21]

  • Cerebriform nucleus (Sézary cell):[22]
    • Hyperchromatic.
    • "Convoluted" = twisted, coiled.[23]

Images:

T-cell large granular lymphocytic leukemia

General

Microscopic

Features:

  • Large cell lymphoma.

Images:

IHC

  • CD57 +ve -- important.
  • CD3 +ve.
  • CD5 +ve.
  • CD45 +ve.

Lymphoplasmacytic lymphoma

Waldenström macroglobulinemia redirects here.

General

Features:[24]

  • B cell neoplasm.
  • Secretes monoclonal IgM.

Note:

  • Waldenström macroglobulinemia is a type of lymphoplasmacytic lymphoma[25] - it is characterized by:

Clinical

Features:[24]

  • Symptoms of blood hyperviscosity - these include:
    • Visual impairment.
    • Neurologic impairment.
    • Bleeding.
    • Cryoglobulinemia - may have Raynaud phenomenon.
  • Hemolysis.
  • Bence-Jones proteinuria - seen in over half of patients.[26]

Treatment:

  • Watchful waiting or chemotherapy.
  • Hyperviscosity syndrome: plasmapheresis.

Microscopic

Features:[24]

DDx:

IHC

Features:[27]

  • PAX5 +ve.
  • CD20 +ve.
  • CD38 +ve.
  • CD138 +ve.

Others:[27]

  • CD5 -ve.
  • CD10 -ve.
  • CD23 -ve.
  • CyclinD1 -ve.
  • CD3 -ve.
  • CD7 -ve.

Adult T-cell leukemia/lymphoma

General

  • Etiology: Human T-cell Lymphoma Virus 1 (HTLV-1).[28]
  • Poor prognosis ~ 1 year survival with treatment.

Microscopic

Features:[29]

  • Cloverleaf nuclei.
    • Nuclei with multiple lobulations.

Image:

IHC

Features:[31]

  • CD3 +ve.
  • CD5 +ve.
  • CD25 +ve.
  • CD45 +ve.
  • HTLV-1 +ve.

Others:[31]

  • CD7 -ve.
  • CD20 -ve.
  • CD79a -ve.

Hepatosplenic T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type

  • Abbreviated as ENKL or ENKTCL.
  • AKA extranodal natural kill lymphoma
  • AKA angiocentric lymphoma.

Table of lymphoma

B cell lymphomas

Name Size of cells Site Histomorphology IHC Translocations Clinical Prevalence DDx
Follicular lymphoma small (centrocytes) lymph node, germinal center abundant atypical follicles (lack GC polarity, lack polar mantle zone), effaced sinuses, scattered large cells (centroblasts) CD10+, bcl-6+[32] t(14,18) usually indolent, may transform to DLBCL very common DLBCL, other small cell lymphomas
Mantle cell lymphoma small, monomorphic lymph node, mantle zone monomorphic lymphoid, abundant mitoses. +/-scattered epithelioid histiocytes, sclerosed blood vessels CD5+, CD23-, CD43+, cyclin D1+[32] t(11;14)(q13;q32)[33] indolent ??? uncommon other small cell lymphomas, PTGC, Castleman disease, Burkitt's lymphoma
Extranodal marginal zone lymphoma (MALT lymphoma) small mucosa-associated lymphoid tissue, GI tract + elsewhere +/- lymphepithelial lesion (cluster of 3+ cells in epithelium) CD21+, CD11c+, CD5-, CD23-[32]  ??? indolent ??? common other small cell lymphomas, neuroendocrine tumours
Precursor B-cell lymphoblastic lymphoma/ leukemia small lymph node ???, bone marrow nuclei slightly large than resting lymphocytes, scant basophilic cytoplasm, irregular nuclear membrane, no nucleoli, stippled chromatin[34] CD10+, CD5-, TdT+, CD99+[32] +/-t(12;21)[35] aggressive ??? uncommon small cell lymphomas
Hairy cell leukemia small bone marrow, peripheral blood perinuclear clearing, clear cytoplasm, central nucleus CD25+, CD103+, CD5-[36] translocations ? splenomegaly, no lymphadenopathy, pancytopenia, good prognosis with Tx uncommon small cell leukemias/lymphomas (e.g. SMZL)
Burkitt's lymphoma medium, monomorphic lymph node, germinal center (???) tingible-body macrophages ("starry sky" appearance), round nucleus, small nucleoli, mitoses +++ CD10+, BCL6+, BCL2- t(8;14) (q24;q32) rapid growth, may be associated with EBV, HIV/AIDS uncommon DLBCL, mantle cell lymphoma
Diffuse large B cell lymphoma large cells (>2x RBC, often larger), variable size lymph node usually, germinal center sheets of large discohesive cells; if only nodular = follicular lymphoma MIB1 >40% none / like follicular lymphoma t(14,18) / c-MYC (like Burkitt lymphoma) poor prognosis very common Burkitt lymphoma, ALCL, Hodgkin lymphoma
Primary mediastinal B-cell lymphoma large (>2x RBC, often larger), variable size mediastinum histomorphology ? IHC ? translocations ? predominantly young adults, better prognosis than DLBCL uncommon DLBCL
B cell small lymphocytic lymphoma /
chronic lymphocytic leukemia
small lymph node (???) proliferation centres CD5+, CD23+, CD43+, cyclin D1- trisomy 12; deletions of 11q, 13q, 17p[37] good prognosis / indolent course common other small cell lymphomas

T cell lymphomas

Name Size of cells Site Histomorphology IHC Translocations Clinical Prevalence DDx
Angioimmunoblastic lymphoma size of cells ? site ? histomorphology ? IHC ? translocations ? clinical ? prevalence ? DDx ?
Enteropathy-type T cell lymphoma size of cells ? site ? histomorphology ? IHC ? translocations ? clinical ? prevalence ? DDx ?
Precursor lymphoblastic lymphoma / leukemia size of cells ? site ? histomorphology ? IHC ? translocations ? clinical ? prevalence ? DDx ?
Adult T-cell lymphoma / leukemia size of cells ? site ? cloverleaf nuclei (multilobular nuclei) IHC ? translocations ? poor prognosis ~ 1 year survival w/ Tx; d/t HTLV-1 prevalence ? DDx ?
Peripheral T cell lymphoma (NOS) size of cells ? site ? histomorphology ? TIA-1+ translocations ? clinical ? prevalence ? DDx ?
Anaplastic large cell lymphoma large deep & subcapsular sinuses of LN eosinophilic cytoplasm, nucleoli, often cohesive, wreath cell (C-shaped nucleus) CD30+/-, Alk+/-, CD4+, CD3- t(2,5)(p23;q35)[38] clinical ? uncommon carcinoma
Extranodal NK/T cell lymphoma nasal type large ??? nasal ??? histomorphology ? EBER+, CD16+, CD56+, CD57-, TIA-1+, Granzyme B+ translocations ? common in East Asia uncommon DDx ?
Blastic NK cell lymphoma size of cells ? site ? histomorphology ? IHC ? translocations ? clinical ? prevalence ? DDx ?

See also

References

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