[ Home Page ] [ Site Map ]

Lymphoproliferative Disorders

• B-cell Precursors (c-ALL, pre B-ALL, pre-pre B-ALL)
• T-cell Precursors
• Biphenotypic Lineage Acute Leukaemia

• Chronic Lymphocytic Leukaemia
• Atypical CLL
• Mantle Cell Lymphoma
• B-Prolymphocytic Leukaemia
• Marginal Zone Lymphoma
• Large Cell Transformation of CLL
• Follicular Lymphoma
• Non-endemic Burkitt's Lymphoma
• Diffuse Large B-cell Lymphoma
• Myeloma, Plasmacytoma and MGUS
• Hairy Cell Leukaemia

• T-Prolymphocytic Leukaemia
• Large Granular Lymphocytosis
• Mycosis Fungoides / Sezary Syndrome
• Lymphomatoid papulosis and CD30⁺ cutaneous anaplastic lymphoma
• Adult T-cell Leukaemia/Lymphoma
• Nodal T-cell Lymphomas

Precursor T and B Cell Acute Lymphoblastic Leukaemia

• The term lymphoblastic leukaemia is reserved for tumours of precursor lymphocytes and should not be used for any type of acute leukaemia with a peripheral T- or B-cell phenotype.
• The precursor nature of the cells is established by the demonstration of Tdt, the lack of surface antigen receptor expression and in most cases by the expression of CD34.
• Sub-classification is by cell lineage and stage of differentiation as described below.
• The FAB morphological classification is considered obsolete and is not to be used in the final comments and conclusions.
• Precursor Lymphoblastic Leukaemia is the preferred term for all cases including those presenting with nodal or soft tissue disease.

In describing lymphoblastic leukaemia the following sub-classification will be used:

B-cell Precursors

Common ALL

Pre B-ALL

Pre-pre B-ALL

With subsequent availability of cytogenetics data, lymphoblastic leukaemia cases will be further classified where possible into the following sub-groups:

• t(9;22)
• t(v;11q23)
• t(1;19)
• t(12;21)

T-cell Precursors

A single category should be used without further subclassification.

Biphenotypic Lineage Acute Leukaemia

Peripheral (mature) B-cell Tumours

Chronic Lymphocytic Leukaemia

In all peripheral blood reports the B-lymphocyte count should be stated. All cases with greater than 5x10⁹/L B-cells with the appropriate phenotype should be diagnosed as CLL (recommendations of the working group on CLL of the National Cancer Institute). When the B-cell count is less than 5x10⁹/L, it should be reported as

'a population of cells with CLL phenotype is present, but this is of uncertain clinical significance in the absence of nodal and bone marrow disease'

CLL treatment response criteria

Atypical CLL

• Cases that are CD5⁺CD23^- should be reported as Atypical CLL/Mantle Cell Lymphoma, awaiting FISH results for t(11;14).
• Class-switched CLL (ie those expressing surface IgG rather than sIgD) - these cases should be reported as 'of undetermined significance'.
• Trisomy 12 or any 2 of the following:
  
  • CD11a
  • FMC7
  • strong CD20
  • CD38
  • strong Ig/CD79b

Cases with mantle cell phenotype but no evidence of t(11;14) should be regarded as atypical B-CLL.

Mantle Cell Lymphoma

Large Cell Transformation of CLL

B-Prolymphocytic Leukaemia

Marginal Zone Lymphoma

Systemic Marginal Zone Lymphoma

These disorders are characterised by BM infiltration with small-medium sized lymphocytes with some evidence of plasma cell differentiation. BM infiltration is nodular or diffuse; a paratrabecular pattern is rare and should raise the possibility of follicular lymphoma. The B-cells should possess the phenotype: CD5^- CD10^- CD19⁺ CD20⁺ CD23^-.

These cases are all characterised by BM infiltration associated with variable degrees of peripheral blood, nodal and splenic involvement. Lymph nodes show expansion of interfollicular areas with small lymphocytes, monocytoid B-cells and plasma cells. Reactive germinal centres are present but may be invaded by neoplastic cells.

Isolated nodal disease is rare and the absence of BM infiltration should alert to the possibility of an occult extranodal marginal zone lymphoma particularly when a cervical node is involved. Splenic samples show a marginal zone pattern of infiltration with preservation of germinal centres. Again the CD5^- CD10^- CD20⁺ CD23^- Bcl-1^- Bcl-2⁺ phenotype is seen.

Extranodal marginal zone lymphoma

Follicular Lymphoma

• Follicular growth pattern. Very rare cases may be diffuse.
• Mixed population of centrocytes and centroblasts
• Immunophenotype: typically CD10⁺ CD19⁺ CD20⁺ CD23^- CD45RA⁺ CD75⁺ (variants show CD10^- CD23⁺, and may have sIgD).
• Expression of bcl-2 or t(14:18) - about 5% of otherwise typical cases are negative for bcl-2. This must be stated on the report.
• para-trabecular pattern of marrow infiltration.

The term transformed follicular lymphoma is used when part of the node is diffusely replaced by large lymphoid cells with centroblastic morphology or in patients with diffuse large B-cell lymphoma who have a documented history of follicular lymphoma or when there is evidence of follicular lymphoma in the bone marrow.

Non-endemic Burkitt's Lymphoma

Essential diagnostic features include a Ki67 positive fraction of approx 100% and a t(8;14) or equivalent shown by cytogenetics or FISH. In typical cases the cells are medium sized blasts with round nuclei, central nucleoli and basophilic cytoplasm although it is recognised that variants exist. Almost all cases will have the phenotype: sIgM⁺⁺ CD10⁺ CD19⁺ CD20⁺ CD38⁺. Where only blood and marrow involvement are present the term leukaemic phase of Burkitt's lymphoma will be used.

Where no cytogenetic data are available the diagnosis can be made on the basis of morphology, immunophenotype and proliferation rate. However, this must be made clear in the report.

The terms Burkitt-like lymphoma (a morphological variant of Burkitt's lymphoma), ALL-L3 and B-ALL are all obsolete and should not be used.

Diffuse Large B-cell Lymphoma

The term leukaemic phase of DLBCL is used when peripheral blood and marrow disease is present. Cells must express sIg and should be CD34^- and Tdt^-, with no evidence of a t(8;14) or variant.

T-cell rich B-cell lymphoma is a descriptive term only and if used it must be made clear that this is part of the spectrum of DLBCL.

Extranodal Diffuse Large B-cell Lymphoma: the morphological features are similar to those seen in nodes. These can diagnosed as primary extranodal lymphomas if there is morphological evidence of an underlying marginal zone lymphoma or if the tumour is stage 1E or 2E.

Myeloma, Plasmacytoma and MGUS

Myeloma

The following table gives the frequency of myeloma phenotypes:

CD19-CD56+	70%
CD19-CD56-	25%
CD19+CD56+	5%
CD19+CD56-	<1%

A diagnosis of myeloma will be made when >10% of plasma cells with an abnormal phenotype are present, and the trephine if available shows an interstitial or diffuse pattern of infiltration.

If there are <10% of plasma cells in the aspirate, consisting of a population of both normal and myeloma plasma cells, a diagnosis of MGUS is made.

If there are <10% plasma cells, all with a myeloma phenotype, this is suggestive of myeloma but needs supporting clinical features.

If there are 5-10% of plasma cells all with a myeloma phenotype, this is suggestive of myeloma but needs supporting clinical features. A population of both normal and myeloma plasma cells suggests a diagnosis of MGUS.

The term Plasma Cell Leukaemia will not be used. A comment of PB involvement by myeloma will be made, giving the absolute number detected by flow cytometry at diagnosis. Detection of >1x10⁶/L circulating plasma cells identifies patients with a significantly worse prognosis.

Response criteria in myeloma.
In patients with a previous known diagnosis of myeloma:

1. <5% plasma cells with "myeloma phenotype" and/or identifiable infiltrate on trephine sections is reported as 'continuing marrow infiltration by myeloma'.
2. <5% plasma cells with abnormal phenotype but no identifiable infiltrate on trephine is reported as 'morphological remission but low level residual disease detected by flow cytometry'.
3. <5% plasma cells / no phenotypically abnormal plasma cells / no evidence of trephine infiltration is reported as 'no evidence of myeloma'.

Plasmacytoma

1. Solitary or multiple plasmacytoma of bone. This diagnosis requires less than 5% plasma cells on a routine bone marrow, otherwise the diagnostic criteria for myeloma/MGUS will apply.
2. Soft tissue infiltration by myeloma. This occurs in patients known to have myeloma. It is very rarely a presenting feature.
3. Plasmacytoma of soft tissue (respiratory tract, skin etc). This requires a normal bone marrow examination to exclude 2. However, this is not considered as part of the spectrum of myeloma. It may be more appropriately considered as a variant of marginal zone lymphoma.

Examination of the bone marrow is essential in all cases.

Hairy Cell Leukaemia

Mature T-cell Tumours

T-Prolymphocytic Leukaemia

T-Chronic Lymphocytic Leukaemia

Large Granular Lymphocytosis

A heterogeneous group of disorders that have a common feature of lymphocytes containing cytoplasmic granulation. The majority of patients show an indolent clinical course, though very rare cases present with leukaemic features (high WBC, extensive marrow and organ infiltration), these cases have a very poor prognosis. The lymphocytosis can be due to:

1. increase in T cells with LGL morphology and co-expression of NK associated antigens CD16, CD56 and/or CD57
2. NK cells (CD3^-)
3. a mixture of 1 and 2.

Reporting the T cell proliferations: these should be further divided into CD4⁺, CD8⁺ or gamma/delta-positive subtypes. A CD8⁺ CD16⁺ CD56^- phenotype is invariably predictive for monoclonality and there is a high incidence of rheumatoid arthritis, neutropenia, and Felty's syndrome amongst this sub-group. All cases with this phenotype should be referred for TCR studies at presentation.

For presentation cases a further specimen should be requested in 3-6 months to establish the persistent or transient nature of the lymphocytosis. Further samples should be requested only in the presence of new clinical features. Persistent cases should be referred for TCR studies.

Reporting NK cell expansions: in the case of an increased NK cell count (>1x10⁹/l) or an abnormal phenotype (HLA-DR⁺, CD45RO⁺, CD56⁺CD16^-) a follow up sample should be requested and the presence of tissue involvement ascertained. TCR studies are uninformative. Normal phenotype for NK cells is:
CD2⁺CD3^-CD4^-CD5^-CD7⁺CD8^-/dim CD16⁺CD56⁺CD57^+/-HLA-DR^-CD45RO^-.

Mycosis Fungoides / Sezary Syndrome

When the patient is known to have cutaneous T-cell lymphoma of mycosis fungoides type and peripheral blood involvement develops in the course of the disease this should be reported as 'Peripheral blood / marrow involvement by cutaneous T-cell lymphoma'. The T-cell count should be stated on the report, there should be >1x10⁹/l lymphoma cells by morphology or immunophenotyping.

In cases of CD4⁺ T-cell leukaemia with Sezary cell like morphology but without skin disease the term Peripheral CD4⁺ T-cell leukaemia should be used.

A definitive diagnosis of mycosis fungoides requires the following features:

1. an intra-epidermal infiltrate of small to intermediate sized T-cells showing nuclear atypia. Pautrier abscesses should be present without significant epidermal oedema. Except in very rare cases the intra-epidermal infiltrate should be CD4⁺.
2. a perivascular or diffuse upper dermal infiltrate containing a mixture of small lymphocytes and atypical T-cells.

Where possible the diagnosis should be supported by the demonstration of an atypical peripheral T-cell phenotype, eg loss of CD5 or CD7 and/or T-cell monoclonality by PCR.

The diagnosis of typical Mycosis Fungoides requires the appropriate clinical features to be present.

Lymphomatoid papulosis and CD30⁺ cutaneous anaplastic lymphoma

Lymphomatoid papulosis

1. a wedge shaped lesion with a peripheral zone which contains a mixed inflammatory infiltrate and a central zone containing atypical large lymphoid cells. In the central zone there may be necrosis or ulceration.
2. the characteristic cells are large with highly anaplastic or multilobated nuclei. They have a T-cell phenotype with strong CD30 expression. EMA and ALK1 are negative.

The definitive diagnosis requires a history of self-healing lesions.

Type B: consists of self-healing papules morphologically identical to Mycosis Fungoides (CD30^-).

CD30⁺ cutaneous anaplastic lymphoma

The cells are the same as in lymphomatoid papulosis but occur in the context of a progressive non-healing lesion. The presence of ALK1 and EMA almost certainly implies that the tumour is a systemic anaplastic lymphoma. These markers must be shown to be negative for a diagnosis of primary CD30⁺ cutaneous anaplastic lymphoma to be made.

Other T-cell lymphomas in the skin: All other T-cell lymphomas presenting in the skin must be assumed to part of a systemic lymphoma.

Adult T-cell Leukaemia/Lymphoma

T-cell Lymphomas that are predominately nodal

Angio-immunoblastic type

• Lymph node. The key features are:
  • replacement of nodal architecture
  • proliferation of thick walled vessels, follicular dendritic cells and plasma cells
  • neoplastic population of CD3⁺ CD4⁺ CD45RO⁺ T-cells. This population is polymorphic with a mixture of intermediate and large lymphoid cells showing nuclear irregularity.
• Clinical Feature:
  • B-symptoms
  • hypergammaglobulinaemia +/- paraprotein
  • immune haemolysis.

Anaplastic Large Cell Lymphoma

The diagnosis of the common type of this tumour requires the presence of large cells with anaplastic morphology including multinucleated forms. These cells should have a T-cell or null phenotype, that is usually abnormal and strong expression of CD30. In early nodal disease the cells have a sinusoidal or perivascular pattern of infiltration.

ALK-1 expression is indicative of the t(2;5) and identifies a favourable prognostic group within this category. This may become a defining feature.

Mature T-cell lymphoma - common type

Rare types of T-cell lymphomas: Intestinal T-cell lymphoma, panniculitis associated T-cell lymphoma and hepato-splenic T-cell lymphoma.

Hodgkin's Lymphoma

Classical Hodgkin's Lymphoma

The essential features are:

• classical type Reed-Sternberg (RS) cells and/or lacunar cells and mononuclear Hodgkin's cells. In almost every case these will have the phenotype CD3^- CD15⁺ CD30⁺ CD45^-. CD20 expression is variable.
• effacement of nodal architecture by an infiltrate which includes T- and B-lymphocytes, eosinophils, plasma cells and macrophages.

Classical Hodgkin's Lymphoma is sub-divided into:

Lymphocyte-rich:

- classical RS cells in a mainly lymphocytic background showing either a nodular or diffuse pattern.

Nodular sclerosing types 1 and 2:

- all NS cases require septal fibrosis with birefringent collagen and nodule formation. In NS2 25% of nodules have a lymphocyte depleted pattern.

Mixed Cellularity:

- cases of classical Hodgkin's Lymphoma not meeting the criteria for NS or LR.

Lymphocyte Predominant Nodular Hodgkin's Lymphoma

The essential features are:

• partial or complete replacement of the node by expanded abnormal follicles which include a mixture of mantle zone B-cells, T-cells including CD57⁺ cells and follicular dendritic cells. Epithelioid macrophages are also present.
• Large mononuclear B-cells and polylobated cells (L&H cells) with the phenotype CD10^- CD15^- CD20⁺ CD30^- CD45⁺ CD75⁺ Bcl-2^-.

[ Home Page ] [ Site Map ]