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淋巴瘤 - Follicular and nodular pattern


更新时间:2008-07-10 15:55:01 作者: 陈国璋



FOLLICULAR AND NODULAR PATTERN:Approach to diagnosis
John K.C. Chan
Hong Kong
 

PREDOMINANTLY MEDIUM-SIZED TO SMALL FOLLICLES

MEDIUM-SIZED TO SMALL FOLLICLES:Main differential diagnoses
Follicular lymphoma
Reactive follicular hyperplasia
Mantle cell lymphoma, nodular
Marginal zone B-cell lymphoma with follicular colonization
Hyaline-vascular Castleman disease
Follicular T cell lymphoma (very rare)

Reactive follicular hyperplasia: Typical histologic features
Preserved sinuses
Follicles predominantly in cortex; they are frequently irregular (sometimes serpentine) in shape
Follicles separated by an appreciable amount of interfollicular tissue
Follicles show:
well defined mantles
tingible body macrophages
polarity (but not seen in every follicle due to plane of sectioning)
predominance of large cells, or a mixture of small and large cells

Follicular lymphoma vs reactive follicular hyperplasia
1 major criterion or 3 minor criteria.
But confirm by ancillary tests if uncertain
Major criterion
Closely packed follicles throughout, with scanty interfollicular tissues

Diagnosis of follicular lymphoma
In the remaining 20% of cases (non-crowded follicles), a combination of minor criteria (3) have to be considered, and supplemented by ancillary studies as required

Follicular lymphoma vs reactive follicular hyperplasia
Minor criteria
No tingible-body macrophages
Cellular monotony: centrocyte predominance
No cellular polarisation
Absent or incomplete mantles
Follicles in perinodal tissues
Dysplastic follicular center cells, e.g. signet ring cells, frequent cytoplasmic globules
Atypical cells in interfollicular tissues
Invasion of walls of blood vessels

Caveats: Unusual follicular hyperplasia
Explosive follicular hyperplasia of HIV infection: often deficient in mantles [Clues: follicle lysis; polarity often prominent]
Reactive follicular hyperplasia in childhood: mantles often thin or even absent
Rheumatoid lymphadenopathy: may be rich in centrocytes; macrophages may be sparse

Caveats: Unusual follicular hyperplasia
Many reactive small T-lymphocytes within follicles, producing a picture of small cell predominance
Poorly fixed tissues: reactive follicles can appear worrisome

Follicular lymphoma: Potential misdiagnosis as reactive follicular hyperplasia due to ……
Discrete or thick mantles in some cases
Presence of tingible-body macrophages
Presence of a mixed cell population
Polarity observed in some follicles

Follicular lymphoma vs RFH: ancillary techniques
Immunostaining for bcl-2
Most useful immunostain
Normal: Both T and B cells positive except follicle center cells
Look for positive staining of cells in follicle centers: positive staining supports diagnosis of lymphoma
Potential pitfall: Some cases of RFH have many reactive small T cells (bcl-2 +) within follicles; always compare with a CD3 immunostain in interpretation

Common misconceptions in hematopathology
"Negative bcl-2 stain rules out follicular lymphoma"
The truth: It does not. 20-25% of follicular lymphoma cases are negative.
Pursue with other tests to confirm or refute a diagnosis of follicular lymphoma

Bcl-2 staining in follicular lymphoma

Grade(Cytologic composition) Bcl-2 immunoreactivity
I (predominantly small cells) 100%
II (mixed small and large cells) 85%
III (predominantly large cells) 75%

Follicular lymphoma vs RFH: ancillary techniques
Look for evidence interfollicular invasion
Densely packed CD20+ or CD79+ B-cells between follicles is indicative of interfollicular invasion
Presence of a significant number of CD10+ lymphoid cells (not neutrophils, which are also CD10+) between follicles also indicates interfollicular invasion
Look for vascular invasion
Many CD10+ cells in the walls of perinodal blood vessels

Follicular lymphoma vs RFH: ancillary techniques
Look for monoclonality or low proliferation index
Immunostain for Ig to look for light chain restriction
Lack of polarity, as demonstrated by Ki67. A low Ki67 index favors diagnosis of follicular lymphoma over RFH (mean index 15.6% vs 64.9%); a high Ki67 index is inconclusive
Molecular analysis
Ig gene rearrangement by Southern blot or PCR (Note that PCR may have false negative results)
Detection of BCL2 gene rearrangement by Southern blot, PCR or FISH
Caveat:
Reactive follicles heavily infiltrated
by T cells may show an apparently
low Ki67 index

Summary: Follicular lymphoma vs RFH
Abnormal architecture
- Close packing of follicles
- Abnormal follicles (lack mantle, polarity, tingible body macrophages)
Evidence of invasion
- Atypical cells in interfollicular zone
- Excess CD20+ or CD10+ cells in interfollicular zone
CD10+ cells invading vessel walls
Follicles in perinodal tissues
Cytologic atypia
- Follicle center cell dysplastic or small cell predominance
- Abnormal immunophenotype: Bcl2+, light chain restriction

Summary: Most helpful immunostains for distinguishing follicular lymphoma from RFH
CD20 and CD3 (to look for excessive number of B cells in interfollicular zone)
Bcl-2
CD10 (to look for interfollicular invasion)

Age is an important consideration in
diagnosis of follicular lymphoma.
This diagnosis should be made with utmost caution
and only with support by ancillary techniques
in children and young adults.

MANTLE CELL LYMPHOMA, NODULAR
Mantle cell lymphoma can show a striking follicular growth pattern – closely packed follicles with or without mantles (and rich in FDC)
Thus always consider the possibility of mantle cell lymphoma for any "grade 1 follicular lymphoma" because of different prognosis: prognosis of mantle cell lymphoma much worse than follicular lymphoma

Common misconceptions in hematopathology
“Since the problem is follicular lymphoma
versus mantle cell lymphoma, let's
perform bcl-2 immunostain (positive
result will support the former diagnosis).”

The truth: Wrong. Positive bcl-2 stain is
seen in many different lymphoma types
(including mantle cell lymphoma).
CD10 and bcl-6 should be used instead
to support a diagnosis of follicular lymphoma

  Mantle cell lymphoma Follicular lymphoma, grade 1
Cell composition Usually monotonous; nuclei with overall roundish contour despite foldings Scattered centroblasts identified; markedly elongated, triangular and angulated nuclei, if present, suggest follicular lymphoma
Immunostain CD5+, cyclin D1+, CD10- CD5-, cyclin D1-, CD10+
Genetics t(11;14) implicating CCND1 t(14;18) implicating BCL2

MARGINAL ZONE B-CELL LYMPHOMA WITH FOLLICULAR COLONIZATION
Marginal zone B-cell lymphoma can show striking follicular colonization, mimicking follicular lymphoma
Differences from follicular lymphoma:
A recognizable neoplastic component growing in the marginal zone
Uncommon to have back-to-back follicles
Presence of lymphoepithelial lesions
CD10-, bcl-6-

HYALINE-VASCULAR CASTLEMAN DISEASE
Hyaline-vascular follicles
Follicle centers often atrophic (rich in FDC, with few B cells)
Penetrated by hyalinized venules
Broad mantle zones of small lymphocytes with concentric or onion-skin arrangement

LARGE LYMPHOID NODULES
LARGE LYMPHOID NODULES: Main differential diagnoses
Nodular lymphocyte predominant Hodgkin lymphoma (N-LPHL)
Nodular lymphocyte-rich classical Hodgkin lymphoma (N-LRCHL)
Progressive transformation of germinal centers (PTGC)
Follicular lymphoma, floral or N-LPHL-like variant
Nodular B-cell-rich follicular dendritic cell tumor (very rare)

Mimicker of large nodular pattern
Lymphoblastic lymphoma
Rapid growth of tumor cells, stretching the connective tissue framework, can produce a large nodular pattern
These expansile nodules differ from follicles in being surrounded by pink-staining blood vessels or fibrous stroma

NODULAR LPHL (N-LPHL)
Often young age, M > F
Solitary enlarged lymph node rather than matted nodes
Mostly involving superficial nodes (cervical, inguinal, axillary); almost never mediastinal
Often stage I/II disease at presentation (80%)
Tends to develop late relapses at the same or another site, despite treatment (median time to relapse = 53 months)

N-LPHL: Pathology
Lymph node architecture:
Usually totally effaced
But a rim of residual nodal tissue (with reactive follicles) can occur in periphery; only rarely are reactive follicles intimately mixed with the neoplastic nodules
The characteristic nodules:
Large, round, dark-staining
Usually closely packed, sometimes separated
May appear mottled due to presence of histiocytes
May be surrounded by a wreath of histiocytes

N-LPHL: Pathology
The neoplastic cells:
L&H cells (lymphocytic and histiocytic cells), also known as “popcorn” cells
L&H cells characterized by
Multilobated nuclei
Thin nuclear membrane
Fine chromatin
Multiple small basophilic or eosinophilic nucleoli
Moderate amount of amphophilic cytoplasm

N-LPHL: Pathology
Appropriate cellular background:
Nodules are rich in small lymphocytes (B cells), which can be mixed with histiocytes
Internodular zone rich in small lymphocytes (T cells), which can be mixed with histiocytes
There must be very few or no plasma cells, eosinophils and neutrophils
Occasional fibrous bands are acceptable
May have a diffuse component

N-LPHL: Are diagnostic RS cells required for diagnosis?
No, they are not required for diagnosis
In fact, they are usually absent or sparse in most cases
Nonetheless, in some cases, diagnostic Reed-Sternberg cells and mononuclear Hodgkin cells can be present (such cases are difficult to distinguish from N-LRCHL)

N-LPHL: Unusual morphologic findings
Some lymphocytes within the nodules can be medium-sized, with light-staining cytoplasm:
They form pale clusters, and often surround L&H cells; sometimes they can even be found between nodules
They are shown immunohistochemically to be reactive T cells (often with high Ki67 index, and with weak to moderate expression of CD30)

 N-LPHL: Immunophenotype
L&H cells (within and between nodules):
B-lineage markers, e.g. CD20, CD79a, J-chain, PAX5, Oct-2, Bob.1
EMA+; BCL6+; CD30-; CD15-
Nodules:
Rich in small B cells and follicular dendritic cells
CD20+ L&H cells stand out prominently because they are rosetted by CD20- CD3+ T cells
Rich in Leu7+ cells, with some surrounding CD20+ L&H cells
Can be infiltrated by small to large numbers of T cells

N-LPHL: Is immunohistochemistry required for diagnosis?
Although previously thought to be accurately “diagnosable” by morphology alone, recent studies suggest that immunohistochemistry is essential for confirmation of diagnosis, in particular distinction from N-LRCHL

N-LPHL: Is morphologic analysis reliable?
German study:
Even experts are wrong in about 20% of cases (as shown by immunohistochemistry)
Survival data show that immunohistochemical criteria are superior to morphologic assessment alone in assigning a diagnosis of N-LPHL

Evolution of N-LPHL
With time, reactive T cells increase within nodules, accompanied by a reduction in B cells. Eventually a nodule may be composed of CD20+ L&H cells residing among small T cells, with practically no small B cells
The diffuse component may also increase with time (CD57+ cells may become less abundant in such areas)
------------------Associated with high-stage disease and more frequent relapse

N-LPHL: Relationship with T-cell-rich large B-cell lymphoma
Marked morphologic and immunophenotypic overlap of diffuse component in N-LPHL with TCRBL
Current recommendation: A diagnosis of TCRBL should not be made if there is a definite component of N-LPHL is identified
Nonetheless, at least some cases of TCRBL are histogenetically related to N-LPHL

 N-LPHL: relationship with progressive transformation of germinal centers (PTGC)
PTGC shows histologic similarities with N-LPHL
There is a postulated relationship between N-LPHL and PTGC

PROGRESSIVE TRANSFORMATION OF GERMINAL CENTERS (PTGC)
A reactive condition characterized by scattered large “transformed” follicles among usual-looking reactive follicles
Totally benign per se
Chance of developing N-LPHL:
Focal changes of PTGC: risk minimal
Florid PTGC: 1-5%

Progressive transformation of germinal centers
Large expansile follicles are scattered among usual reactive follicles, and are several times their diameter
Large follicles comprise mostly small lymphocytes
Admixed isolated or small groups of germinal center cells
Some may have single or multiple remnant germinal centers (which can be quite large)
No L&H cells

Common misconceptions in hematopathology
"There is invasion of germinal centers
by strands of small lymphocytes,
so this represents PTGC."

The truth: Wrong. PTGC is defined
by presence of occasional large
expansile dark-staining follicles
disposed among usual-looking
reactive follicles.

Common misconceptions in hematopathology
"There are many large dark-staining
lymphoid nodules, and L&H cells
are not easily found. Thus this
represents PTGC."

The truth: Incorrect. If there are
closely packed large lymphoid nodules,
it is more likely to represent
nodular lymphocyte predominant
Hodgkin lymphoma.

  N-LPHL PTGC
CD20 Nodules have a moth-eaten pattern; no demarcation between mantle and follicle center Discrete nodules of packed CD20+ cells; thick mantles are usually obvious
T-cell rosettes around CD20+ large cells Many Rare or absent
CD57+ rosettes Common None

NODULAR LYMPHOCYTE-RICH CLASSICAL HODGKIN LYMPHOMA (N-LRCHL)
LRCHL is an uncommon form of classical Hodgkin lymphoma
Subtypes:
Nodular (more common)
Diffuse
The nodular subtype can be very difficult to distinguish from N-LPHL

N-LRCHL: Clinical features
Similarities with N-LPHL:
M > F
Mediastinal involvement very rare
B symptoms rare
Usually early stage disease (stage I/II in 70% vs 80%)
Differences from N-LPHL:
Slightly older (median age 43 vs 35 years)

  N-LRCHL Other types of classical HL
Stage I 46% 10-21%
B symptoms Uncommon (11%) 35-42%
Bulky disease Uncommon (11%) 40-54%
Mediastinal involvement Uncommon (15%) 40-80%

N-LRCHL: Behavior
Survival slightly worse than N-LPHL (5 yr survival 80% vs 98%)
Relapse rate similar to N-LPHL (17% vs 21%), but multiple relapses are infrequent (5% vs 27%)
Relapses are less responsive to treatment than in N-LPHL, and thus survival after relapse is worse
Some cases may evolve to mixed cellularity, nodular sclerosis or lymphocyte depletion Hodgkin lymphoma

N-LRCHL: Pathology
Large nodular pattern similar to N-LPHL; residual reactive germinal centers can be seen in some neoplastic nodules
Nodules and interfollicular zone composed of small lymphocytes, with few plasma cells or eosinophils
Reed-Sternberg cells are sprinkled in and between the nodules. In some cases, they are found in expanded mantle zones (so-called follicular Hodgkin lymphoma). RS cells are never found in germinal centers.

 N-LRCHL: Immunophenotype
Large cells (within and between nodules):
CD20 negative or positive in heterogeneous pattern
PAX5+ (weak or moderate), Oct2/Bob1 -/+
CD30+, CD15 commonly +, BCL6 – (or focal weak)
Nodules:
Rich in small B cells and follicular dendritic cells
T cells rosette around the large cells
Some Leu7+ cells present, but not rosetting around the large cells

  N-LRCHL N-LPHL
Residual germinal centers in nodules Common Rare
Large cells Mostly R-S cell variants with prominent nucleoli Mostly L&H cells, but some cases can have R-S-like cells
CD20 staining in large cells - / + (heterogeneous) +
CD30, CD15 CD30+, CD15+/- -
EBV Positive in 30-50% Negative

FOLLICULAR LYMPHOMA MIMICKING PTGC (FLORAL VARIANT)
Neoplastic follicles are very large, and often not crowded
Usually thick (sometimes thin) mantles, with irregular inward extensions, resulting in serrated, amoeboid or floral configuration of neoplastic germinal centers
More likely than conventional follicular lymphoma to be grade 3 or grade 2
Unexpectedly, some cases express CD5

FOLLICULAR LYMPHOMA MIMICKING N-LPHL
Some cases of follicular lymphoma (grade 1) exhibit very large and dark-staining follicles, resembling NLPHL (scattered centroblasts and FDC simulating L&H cells)
Overlaps with floral variant of follicular lymphoma
Features supporting diagnosis of follicular lymphoma:
The large cells are not as large as L&H cells
Large cells are CD10+, and are not rosetted by T cells
Significant component of centrocytes (CD10+) inside follicles

LARGE LYMPHOID NODULES: SUMMARY APPROACH
Low magnification: Are all nodules abnormal?
If all abnormal, favor lymphoma over PTGC
Assess cytologic composition of abnormal nodules
L&H or RS cells: Hodgkin lymphoma
Many centrocytes: follicular lymphoma
Cells with indistinct borders and prominent nucleoli: FDC tumor
Immunohistochemistry to analyse phenotype of large cells and background cells

 

 

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