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淋巴瘤 - Small lymphoid cell infiltrate


更新时间:2008-08-05 15:48:46 作者: 陈国璋




DIFFUSE SMALL LYMPHOID CELL INFILTRATE: Approach to diagnosis John K.C. Chan

DIFFUSE SMALL LYMPHOID CELL INFILTRATE
REACTIVE LYMPHOID HYPERPLASIA
LYMPHOMA Most commonly B-cell lymphoma;rarely, T or NK cell lymphoma

REACTIVE LYMPHOID INFILTRATE versus SMALL CELL LYMPHOMA
Reactive lymphoid infiltrates are often dominated by reactive lymphoid follicles (B-cell-rich), although some may be diffuse (T-cell-rich)
Morphologic features suggestive of lymphoma:
Destructive infiltrate (such as invasion of epithelium/ glands, and prominent permeation of fibrous stroma)
May show cytologic atypia (many small to medium-sized cells with irregular nuclei; many cells with clear cytoplasm)
Cellular monotony, if present

Special tests for lymphoma vs reactive lymphoid infiltrate
Abnormal immunoarchitecture
Reactive lymphoid infiltrate:
Commonest pattern -- B cells forming follicles (1o or 2o), separated by many interfollicular T cells
Sometimes -- Predominantly diffuse sheets of T cells, with few B cells [Distinction from a T-cell lymphoma will be difficult: diagnosable only if there is definite cytologic atypia and/or aberrant immunophenotype]
Sheets of B cells (diffuse or interfollicular), accompanied by limited numbers of T cells, strongly suggest a diagnosis of small B-cell lymphoma

Special tests for lymphoma vs reactive lymphoid infiltrate
Aberrant immunophenotype
Expression of antigens not normally expressed in B cells: interpretation by comparing with corresponding CD20 and CD3 stains
CD43
Cyclin D1
CD5

Special tests for lymphoma vs reactive lymphoid infiltrate
Immunoglobulin light chain (kappa/lambda) restriction
Diagnostic if monotypic Ig demonstrated
Sometimes results are brilliant
But sometimes results are disappointing, with strong background (can occasionally be solved by in-situ hybridization for Ig mRNA) or unsatisfactory staining of the lesional cells

If findings are inconclusive .....
Resort to an interim designation of “atypical lymphoid hyperplasia”, and advise follow-up or taking a larger biopsy
Usually no significant consequence even if this is already lymphoma because small B-cell lymphomas are generally indolent

DIFFUSE SMALL B-CELL LYMPHOMAS
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)
Lymphoplasmacytic lymphoma
Mantle cell lymphoma
Marginal zone B-cell lymphoma
Extranodal MALT type
Nodal
Follicular center lymphoma, diffuse variant

In poorly fixed or suboptimally processed tissue,Burkitt lymphoma or lymphoblastic lymphoma may
look deceptively like small cell lymphoma.Making such a mistake would be disastrous.Always consider these lymphoma types whenever the presumptive diagnosis is "small cell lymphoma" in a young person.

Small B-cell lymphomas: Difficulties in classification
Classification can be difficult
Morphologic overlap (e.g. small round lymphocytes can be seen in marginal zone B-cell lymphoma, B-CLL and mantle cell lymphoma; but tumor cells of these lymphoma types can also show irregular nuclei)
Technical factors
Small biopsies

Small B cell lymphomas: Difficulties in classification
Classification is important because of different prognosis:
Extranodal marginal zone B-cell lymphoma of MALT often a localized disease, with excellent prognosis
Worst for mantle cell lymphoma

Mantle cell lymphoma: Constant or common features
Diffuse, vaguely nodular, or mantle zone growth pattern
No proliferation centers
No or few large transformed cells
Scattered solitary epithelioid histiocytes are common
Hyaline thickening around capillaries

Mantle cell lymphoma: Constant or common features
Cytology
Usually monotonous population
Small cells with irregularly folded nuclear membrane
Fairly dense chromatin; indistinct nucleolus
Scanty cytoplasm
Interspersed “naked” nuclei of FDC

Mantle cell lymphoma: Uncommon features or variants
Can have round nuclei resembling B-CLL
Can resemble monocytoid B-cells
Scattered polykaryocytes
Blastoid variant
Fine chromatin, resembling lymphoblasts (but TdT negative)
Mitotically active
More aggressive

Mantle cell lymphoma: Uncommon features or variants
Pleomorphic variant (“centrocytoid centroblastic lymphoma”)
Variation in tumor cell size
Large tumor cells with irregular nuclei (cytoplasm still scanty)
Occasional bizarre cells
Nucleoli seen in some cells
Chromatin variable: dense to more open
Often misdiagnosed as large B-cell lymphoma

B-CLL/small lymphocytic lymphoma
Proliferation centers are the pathognomonic feature of B-CLL/SLL (found in 70-80% of cases)
In some cases, proliferation centers are not formed: but prolymphocytes and paraimmunoblasts are more dispersed among the small lymphocytes

Lymphoplasmacytic lymphoma
A diagnosis by exclusion
This probably should not be diagnosed in a mucosal site (more likely to represent extranodal marginal zone MALT lymphoma)
Using such restricted definition, clinical evidence of Waldenstrom’s macroglobulinemia is common

Extranodal marginal zone B-cell MALT lymphoma
Morphologic spectrum very broad: small lymphocytes, centrocyte-like cells or monocytoid B cells
Cell population often heterogeneous (variegated color on low magnification), although some cases can appear monomorphous
Reactive lymphoid follicles often present in background (and can show colonization)

Extranodal marginal zone B-cell MALT lymphoma
Lymphoepithelial lesions commonly found
Remember that NOT all small B-cell lymphomas of mucosal sites represent this entity. Other B-cell lymphomas can occur in mucosal sites.

Diffuse variant of follicular center lymphoma
Diffuse counterpart of grade 1 or 2 follicular lymphoma
Appears to be rare. Bcl-2 rearrangement may serve as a marker for this entity
Some cases may have a prior history of follicular lymphoma, or careful search may reveal a focal follicular component  Diagnosis should have been simply “follicular lymphoma” instead
Clinical features and behavior not well defined yet

SMALL B CELL LYMPHOMAS: MORPHOLOGIC CLUES
Pathognomonic of B-CLL/SLL: Proliferation centers or interspersed prolymphocytes & paraimmunoblasts
Favoring mantle cell lymphoma:
Monotonous population, esp. with interspersed “naked” nuclei (FDC)
Mantle zone growth pattern
Solitary epithelioid histiocytes
Hyalinized venules

Small cell lymphomas: morphologic clues
Favoring extranodal marginal zone B-cell lymphoma of MALT:
Clear cells/monocytoid cells
Prominent lymphoepithelial lesions
Admixed larger lymphoid cells:
B-CLL/SLL
MALT lymphoma
Many Dutcher bodies or cytoplasmic Ig inclusions:
Lymphoplasmacytic lymphoma
MALT lymphoma

How to solve problem?
Immunohistochemistry most helpful
CD5
CD23
Cyclin D1
IgD
Follicular center cell markers, e.g. bcl-6, CD10
Follicular dendritic cell marker, e.g. CD21

CD23
CD23 normally stains subpopulations of IgD+ B cells and follicular dendritic cells
Value:
Positive in B-CLL/SLL
Highlighting FDC network in mantle cell lymphoma
Follicle center lymphoma can also be positive

Cyclin D1
Cyclin D1 expression is the hallmark of mantle cell lymphoma, and is negative in other lymphoma types (except very rare cases of B-CLL, and some cases of hairy cell leukemia and myeloma)
Nonetheless, up to 7% of mantle cell lymphomas are cyclin D1 negative

Cyclin D1
Only nuclear staining is acceptable as positive staining
To declare a lymphoma negative for cyclin D1, one must ascertain that the immunostain is working properly
Look for internal positive controls (interspersed histiocytes, endothelial cells or epithelial cells)
If none, the immunostain should be considered invalid

IgD
Polyclonal antiserum against IgD works well in paraffin sections
IgD typically positive in naive B-cell neoplasms:
B-CLL/SLL
Mantle cell lymphoma (most cases)
Also positive in splenic marginal zone B-cell lymphoma

Immunophenotype of small B cell lymphomas

  CD5 CD23 IgD Cyclin D1 CD10 or Bcl-6
B-CLL/SLL + + + - -
Lymphoplasmacytic - - - - -
Mantle cell + - + + -
Marginal zone - - - - -
Follicular lymphoma, diffuse - +/- - - +

Bcl-2 immunostain is useless in this setting

Small B-cell lymphomas: Immunohistochemistry
Immunohistochemistry helps greatly with classification
But exceptions can always occur (i.e. immunophenotype can deviate from classical profile)
Marginal zone B-cell lymphoma: most difficult, because essentially there are no positive identification markers

Small B-cell lymphomas: Immunohistochemistry
FDC markers (such as CD21) also helpful:
Irregular loose meshworks in mantle cell lymphoma
Highlighting unnoticed neoplastic follicles present focally in follicular lymphoma (diffuse type)
Some FDC networks can also be seen in extranodal marginal zone B-cell lymphoma

Unsolvable problems
Morphologic / immunohistochemical distinction between extranodal marginal zone B cell lymphoma and lymphoplasmacytic lymphoma can be very difficult
Lymphoplasmacytic lymphoma is a diagnosis by exclusion
May need to report as "small cell lymphoma, either extranodal marginal zone B cell or lymphoplasmacytic lymphoma". Clinical correlation is helpful (e.g. presence of paraprotein or marrow involvement favors the latter diagnosis)

Unsolvable problems
Proper classification may remain impossible despite thorough work-up (e.g. inconclusive immunophenotype): can label as "small B cell lymphoma, not further classifiable"
If difficulties in classification are due to small size of sample or artefacts, advise follow-up and repeat biopsy
 

 

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