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淋巴瘤 -Large cells in small cell background-approach


更新时间:2008-05-27 17:38:17 作者: 陈国璋



LARGE CELLS SCATTERED IN A BACKGROUND OF SMALL LYMPHOCYTES:Approach to diagnosis
John K.C. Chan
Hong Kong


ATYPICAL LARGE CELLS IN BACKGROUND OF SMALL CELLS:Major differential diagnoses
-> Classical Hodgkin lymphoma
-> Nodular lymphocyte predominant Hodgkin lymphoma (predominantly diffuse)
-> T-cell/histocyte-rich large B-cell lymphoma (TCRBL)
-> Reactive lymphoid hyperplasia
. Lymphomatoid granulomatosis
. Peripheral T cell lymphoma with R-S-like cells
. B-CLL/SLL with Reed-Sternberg-like cells

LYMPHOMATOID GRANULOMATOSIS
-> First described by Liebow et al as a pulmonary angiocentric polymorphous atypical lymphoreticular infiltrate with prominent necrosis; nature of the disease process was uncertain
-> Prototype: Pulmonary involvement (bilateral peripheral lung nodules, solitary mass, or diffuse infiltrate).
-> Other common sites of involvement: skin, CNS, kidney

Lymphomatoid granulomatosis

-> Previously included under the umbrella concept of “angiocentric immunoproliferative lesions” and erroneously thought to be a T-cell lymphoma. Now known to be an EBV+ clonal B cell proliferation with a rich background of reactive T cells.
  .Atypical large cells are CD20+, Ki67+, EBV+, CD30-
  .Clonal rearrangement of Ig gene on PCR
-> Patients often show subtle or overt immunodeficiency (including AIDS)

“Angiocentric immunoproliferative Lesion” (LYG/PR complex)

Large B-cell
lymphoma,
LYG type
(EBV+)
More common
in Caucasians
NK/T cell
lymphoma
(EBV+)
More common
in Orientals


Lymphomatoid granulomatosis: Behavior
  Natural history is highly variable
  Spontaneous regression in ~20%
  Most show progression
  Usual treatment scheme: steroid +/- chemotherapy (such as cyclophosphamide) --> ~50% CR
  Alternative treatment approach: interferon a2b --> promising preliminary results

Lymphomatoid granulomatosis
Histologic triad:
   Atypical polymorphous lymphoid infiltrate often with a granuloma-like appearance
   Angioinvasion
   Prominent geographic necrosis
Confirmation of diagnosis:
   CD20 (large cells) and CD3 (reactive small cells)
   CD56 to exclude NK lymphoma
   ISH for EBER, or immunostain for EBV LMP-1


Lymphomatoid granulomatosis: Grading

Grade 1
Sparse EBV+ cells
<5/HPF
Grade 2
Scattered EBV+ cells,
5-20/HPF
Grade 3
Many EBV+ cells,
>20/HPF


Atypical lymphoid proliferation?............Frank lymphoma
Worse prognosis


Lymphomatoid granulomatosis

  Lymphomatoid granulomatosis TCRBL
Location Always extranodal Often nodal
Geographic necrosis Always Only occasional
Angiocentric growth Always Usually absent
EBV association Consistent Rare

PERIPHERAL T-CELL LYMPHOMA WITH REED-STERNBERG-LIKE B CELLS
Rare -- more likely to be seen in angioimmunoblastic T-cell lymphoma
Scattered very large RS-like cells (reactive)  B-lineage, EBV+, CD30+
Can be mistaken for classical Hodgkin lymphoma or TCRBL
How to reach a diagnosis: recognizing the atypia of the background T lymphoid cells

B-CLL/SLL WITH REED-STERNBERG-LIKE CELLS
-> In rare cases of B-CLL/SLL, there are scattered Reed-Sternberg-like cells, which can show activated B cell, RS cell or intermediate immunophenotype
-> These large cells are EBV+ (EBER+, LMP1+)
-> How to reach a diagnosis:
     Monotonous background small lymphocytes +/- proliferation centers
     Small lymphocytes are B cells with coexpression of CD5 +/- CD23

B-CLL/SLL with Reed-Sternberg-like cells
This phenomenon has increased in recent years due to popularity of fludarabine therapy (highly immunosuppressive) for B-CLL, allowing emergence of EBV+ B-cell clones
When can a superimposed classical Hodgkin lymphoma (Hodgkin lymphoma-type Richter syndrome) be diagnosed?
The appropriate cellular background must be present, e.g. T lymphocytes, plasma cells, polymorphs

HODGKIN LYMPHOMA:Definition
A lymphoma characterized by:
 presence of Reed-Sternberg cells and their variants
 in an appropriate reactive cellular environment
 

Reed-Sternberg cells and variants
Diagnostic Reed-Sternberg cells
Mononuclear Hodgkin cell
Lacunar cell
L&H cell
Pleomorphic Reed-Sternberg cell
No need to find diagnostic Reed-Sternberg cells in rendering a diagnosis of Hodgkin lymphoma.
It’s okay if cells are large enough, with prominentnucleoli and compatible immunophenotype.
 

Appropriate cellular environment
Depending on the specific subtype of Hodgkin lymphoma, presence or absence of the following:
 Small lymphocytes, with few or no immunoblasts
 Histiocytes
 Plasma cells
 Eosinophils and neutrophils
 Fibroblasts

Classical Hodgkin lymphoma
Large neoplastic cells (RS cells and variants, e.g. mononuclear, lacunar cells): most, or at least some have large eosinophilic inclusion-like nucleoli
Background often rich in a mixture of lymphocytes, plasma cells, histiocytes and eosinophils, except lymphocyte-rich classical Hodgkin lymphoma

Classical Hodgkin lymphoma: Immunophenotype
Large cells (“crippled” B cells):
CD30 +
CD15 commonly +
CD20 – or heterogeneous +
CD79 – or focally +
PAX5 +
Oct.2, Bob.1: both negative or positive for one marker
EMA -
Background lymphocytes:
Mostly CD3+ T cells, CD4+ >> CD8+

N-LPHL, predominantly diffuse
Some cases of N-LPHL may have an extensive diffuse component, rendering it difficult to recognize as LPHL
Immunophenotype of large cells (L&H cells):
B lineage (e.g. CD20+, CD79a+, Oct2+, Bob.1+)
CD30-
EMA+, Bcl-6+
Background lymphocytes: Mostly T cells in the diffuse component, but many are CD57+

N-LPHL, predominantly diffuse
Basis of diagnosis is recognition of a focal nodular component:
Morphologically (i.e. focal nodules), or
By immunohistochemical staining (nodular aggregates of large CD20+ cells +/- CD20+ small B cells)
 

T-CELL/HISTIOCYTE-RICH LARGE B-CELL LYMPHOMA
Mimics Hodgkin lymphoma or T-cell lymphoma
Different studies have used different criteria for inclusion. Using strict criteria (dispersed large B cells, >90% T lymphocytes), some studies report the following characteristics:
Usually high-stage disease (>90% stage III/IV)
Poor prognosis (5-yr survival 20%)

T-cell/histiocyte-rich large B-cell lymphoma

Conventional
diffuse large B
cell lymphoma
(mostly follicular
center cell type)
with a rich
infiltrate of reactive
T cells
Closely related
to diffuse
form of
lymphocyte
predominant
Hodgkin
lymphoma
(paragranuloma)

T-cell/histiocyte-rich large B-cell lymphoma: Pathology

Large lymphoid cells:
Isolated or at most in small groups
Can resemble centroblasts (large noncleaved cells), immunoblasts, L&H cells, or Reed-Sternberg cells
CD20+; often CD30-, EMA+/-, Bcl6+, EBV-
Background cells:
Numerous small T lymphocytes (which may appear slightly activated): >90% of cell population
Can have variable numbers of histiocytes, eosinophils, plasma cells

By definition, no identifiable component of
nodular lymphocyte predominant Hodgkin lymphoma
morphologically or on immunostaining


TCRBL vs classic Hodgkin lymphoma

  TCRBL Classical HL
Large cells Variable morphology and size: indistinguishable from reactive large cells to frankly atypical Reed-Sternberg cells and variants
Small lymphocytes Often slightly activated Usually non-activated
Eosinophils Absent or numerous Often numerous
B cell markers Uniformly CD20+ and CD79+; Oct-2/Bob.1+ CD20- or heterogeneous +; CD79-/+;
CD30 : CD15 -/+ : - Oct-2/Bob.1 - or + for one marker
+ : +/-
EBV Usually negative Positive in 30-60%

TCRBL vs diffuse LPHL

  TCRBL LPHL, diffuse
Large cells Variable morphology Popcorn cells
Background T cells Often slightly activated; mostly CD8+ TIA1+ cytotoxic Usually non-activated; mostly CD4+ CD57+
Tumor cells within nodules of small B cells Absent Present at least focally

The distinction is quite difficult,
because large cells are basically B cells

Large cells in background of small cells: Summary approach to diagnosis
Morphology
Focal presence of large cells within nodules of small lymphocytes: Diagnostic of N-LPHL
Many eosinophils: Favor classical Hodgkin lymphoma, but can sometimes be seen in TCRBL
Cells with huge inclusion-like nucleoli: More common in classical Hodgkin lymphoma, but can also be seen in some TCRBL and N-LPHL

Assess morphology of large cells

  Large cells still acceptable for immunoblast/ centroblast Large cells atypical, but most are smaller than x3 small lymphocyte nucleus Most large cells have nuclei larger than x3 small lymphocyte nucleus
Reactive Х Х
TCRBCL
Hodgkin Х Х

Large cells in background of small cells: Summary approach to diagnosis
Immunohistochemistry (A must!!)
Must correlate marker expression with cell type
N-LPHL, TCRBL, lymphomatoid granulomatosis: the large cells are basically B cells -- uniformly positive for various B markers
Classical Hodgkin lymphoma: “crippled” and activated B cells, i.e. CD30+, and negative or incomplete expression of B markers (e.g. CD20-/+, Oct.2/Bob.1-)
Reactive hyperplasia: Large cells often B cells (heterogeneous CD20 staining) or mixed B and T cells

TCRBL
Lymphomatoid granulomatosis
LPHL, diffuse
Classical
Hodgkin lymphoma
Neoplastic cells are basically genuine B cells, expressing the full complement of B cell-associated markers Neoplastic cells are “crippled” B cells, whereby B cell markers are not expressed at all, or expressed incompletely

Large cells in background of small cells: Summary approach to diagnosis
Immunohistochemistry (A must!!)
Large B cells within nodules of small B cells: diagnostic of N-LPHL
Ig light chain restriction, if demonstrable: TCRBL
Ig light chain polytypic in large cells: Reactive lymphoid hyperplasia

TCRBL versus reactive hyperplasia: For cases with no or minimal atypia of the large cells, light chain restriction has to be demonstrated to support a diagnosis of lymphoma

Large cells in background of small cells: Summary approach to diagnosis
Special studies
EBV is positive in:
Some cases of classical Hodgkin lymphoma
Lymphomatoid granulomatosis
B-CLL/SLL or peripheral T cell lymphoma with RS cells
EBV is negative in N-LPHL, and often negative in TCRBL
 

Large cells in background of small cells: Summary approach to diagnosis

Background small cells

B cells Mostly T cells
B-CLL with
RS-like cells
All other entities in D.Dx. (e.g. HL, TCRBL,
LPHL, LyG, T lymphoma with RS cells,
reactive hyperplasia)
  Nodules of small B cells are seen in LPHL focally

 

 

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