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淋巴瘤 - Benign or malignant lymphoid proliferation


更新时间:2008-07-04 15:17:38 作者: 陈国璋



BENIGN OR MALIGNANT LYMPHOID PROLIFERATION:
How to solve the problem and application of ancillary tools
John K.C. Chan
Hong Kong
 

IS THE LYMPHOID PROLIFERATION BENIGN OR MALIGNANT?
Very easy to very difficult
Problems:
  Some benign lymphoid proliferations can mimic lymphoma, e.g. infectious mononucleosis
  Some lymphomas may be mistaken for lymphoid hyperplasia, e.g. MALT lymphoma
Good quality histologic section is a must
High quality immunohistochemistry is often required to aid in diagnosis
 

Pre-requisite in assessing whether a lymphoid proliferation is benign or malignant
Familiar with the “normalcy range”:
 Architecture of lymph node or extranodal lymphoid tissues
 Normal cell types
 Special cell types that may occur in reactive conditions
 Normal immunoarchitecture of lymph node and extranodal lymphoid tissues

GENERAL CRITERIA FAVORING A REACTIVE LYMPHOID PROLIFERATION OVER LYMPHOMA
 Preserved (albeit distorted) architecture (with intact sinuses in lymph node)
 Not forming expansile mass within the lymphoid tissue
 Mixture of lymphoid cell types
 Lacks cellular atypia
** Always some exceptions to these criteria

Abnormal architecture
Morphologic:
Effacement of architecture:
  Lymph node - Loss of cortical follicles and loss of sinuses
  Tonsil - Diffuse infiltrate with loss of reactive follicles
Formation of an expansile mass lesion within the lymphoid proliferation

Abnormal architecture
Morphologic:
 Back-to-back arrangement of lymphoid follicles
 Abnormal appearance of follicles, e.g. lacking mantles, lacking tingible body macrophages
 Coalescence of the broad marginal zones

Abnormal architecture
Immunohistochemical:
  Diffuse sheets of B cells: presence of CD20/CD79a+ B cells outside follicles in excessive numbers (at least one low power field)
  Presence of sheets of CD3+ T cells is of no help, since either reactive lymphoid proliferation or T-cell lymphoma can give rise to this pattern

Evidence of invasion
Morphologic:
Invasion of epithelium/ gland, forming prominent lymphoepithelial lesions (Beware: normal lymphoepithelium of Waldeyer’s ring)
Permeation of interstitial tissues:
Mucosal sites – Extensive permeation between glands, accompanied by loss of glands
Extensive permeative infiltration of adipose tissue

Evidence of invasion
Morphologic:
Invasion of blood vessel walls
Prominent permeation of fibrous stroma, producing single-file pattern
Tonsil: Irregular, infiltrative base [NOTE: This can sometimes be seen in infectious mononucleosis]

Evidence of invasion
Morphologic:
Follicular proliferation: Atypical lymphoid cells found in interfollicular zone
Destruction of the mantles of lymphoid follicles
Colonization of lymphoid follicles
Extensive lymphoid follicles in perinodal tissue

Evidence of invasion
Immunohistochemical:
Interfollicular zone rich in CD20+ B cells
Follicular proliferation: Interfollicular zone rich in CD10+ lymphoid cells
Follicular proliferation: Infiltration of vessel wall by CD10+ cells

Cytologic atypia
Morphologic:
Presence of significant numbers of cells not normally found in reactive lymphoid tissues

Presence of very rare Reed-Sternberg-like cells is okay,
and does not constitute cytologic atypia.
Presence of rare atypical lymphoid cells is also okay.

Cytologic atypia
Morphologic:
Very large cells (>3 times diameter of small lymphocyte nuclei)
Most cells show irregular nuclei (NOTE: small lymphoid cells with irregular nuclei may be present in extranodal lymphoid tissue)
Many cells exhibit granular chromatin pattern

Cytologic atypia
Morphologic:
Clear cells (excluding monocytoid B cells). Don’t mistake retraction artefact for cytoplasmic clearing -- clear cells must be seen among non-clear cells in the same field [Caution: some clear cells may be seen in autoimmune lymphoproliferative syndrome]
Many unexplained medium-sized cells [Caution: must exclude monocytoid B cells, marginal zone cells and plasmacytoid monocytes. Medium-sized are not uncommon in autoimmune lymphoproliferative syndrome]

Cytologic atypia
Immunohistochemical atypia
Expression of precursor/ immature cell marker TdT
Abnormal immunophenotype

Abnormal immunophenotype: B cells
Immunoglobulin light chain restriction
Aberrant expression of markers not normally expressed or expressed in minority of B cells
CD5  ---------------------- To interpret aberrant staining, need
CD43  ----------------------to compare with a corresponding CD3 stain
Cyclin D1
Bcl-2 expression in follicular center cells

Abnormal immunophenotype: T cells
Abnormal subset marker expression (with exceptions, e.g. precursor cells, ALPS):
CD4+ CD8+ (double positive)
CD4- CD8- (double negative)
Loss of pan-T markers
CD2, CD3, CD5, CD7 (CD7 sometimes also lost in reactive lesions)
Expression of markers not normally expressed or expressed only in minority of T cells
ALK, CD56, gd T cell receptor

Autoimmune lymphoproliferative syndrome
ALPS is an inherited disorder of lymphocyte apoptosis
Lymph node often mimics T-zone lymphoma, with many clear cells and medium-sized cells
Increase in CD4- CD8- T cells (which are CD45RO-, CD57+)
The possibility of ALPS should always be considered in infants or children presenting with lymphadenopathy

What are the minimal criteria to ascertain a diagnosis of malignancy?
No single feature is pathognomonic of malignancy-- there is exception to every rule
Atypical cells may be seen in some benign conditions, e.g. autoimmune lymphoproliferative syndrome
Vascular invasion may be seen in infectious mononucleosis
Monotypic plasma cells can be seen in plasma cell type Castleman disease
Consider a combination of features (preferably fulfilling at least several criteria of malignancy)

To surrender: ATYPICAL LYMPHOID HYPERPLASIA
“Worrisome” lymphoid proliferations that are not sufficiently diagnostic of lymphoma
Not a clinical or pathologic entity
Merely an interim designation
This term should NOT be used if a more specific diagnosis can be made

Atypical lymphoid hyperplasia
Factors influencing frequency
Expertise of pathologist
Quality of histologic section
Availability of special studies
What to do?
Apply all available ancillary techniques
Advise follow-up
Repeat biopsy (immediate or later)
Careful handling of repeat biopsy specimens for special studies

WHAT ABOUT VALUE OF MOLECULAR STUDIES?

Ig or TCR gene rearrangement
Most B-cell lymphomas show clonal rearrangements of Ig heavy and light chain genes
Most T-cell lymphomas show clonal TCR gene rearrangements
Reactive lymphoid proliferations usually do not show Ig or TCR gene rearrangements

Common misconceptions in hematopathology

"Since PCR is such a sensitive technique,
one can exclude lymphoma
if no clonal bands are found."

The truth: No, lack of clonal Ig or TCR
gene rearrangement by PCR analysis
does not totally rule out lymphoma.
While PCR is very sensitive (able to
pick up clonal population ~1%), there is
an inherent false negative rate of ~30%
due to failure to amplify the abnormal clone.

Abuse of molecular investigations
Indiscriminate use of PCR for Ig/TCR gene rearrangement on lymphoid lesions that have not been thoroughly worked up by immunohistochemistry
----------Results are more often misleading than helpful, especially since false positive and false negative results are not uncommon

Abuse of molecular investigations
Taking PCR results seriously while disregarding significant morphologic or immunohistochemical findings
-----------For example, calling a lymph node that is highly suspicious for follicular lymphoma benign simply because PCR for Ig is negative
-----------Diagnosing a benign lymphoid lesion as follicular lymphoma because of demonstration of BCL2 rearrangement

My approach to use of molecular investigations in diagnostic hematopathology
Use sparingly, i.e. only when absolutely necessary
Negative results are always less than significant than positive results [Can be false negative!]
Positive PCR is used to support a diagnosis of lymphoma only if the morphology/immunophenotype is very suspicious. Never order PCR if the findings are not suspicious.
Disregard molecular results (especially done by laboratories you don’t know) if they conflict with the morphologic/ immunophenotypic findings


 

 

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