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淋巴瘤 - Small lymphoid cell infiltrate


更新时间:2008-06-11 11:53:36 作者: 陈国璋



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

DIFFUSE SMALL LYMPHOID CELL INFILTRATE

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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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