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更新时间:2008-07-18 16:21:14 作者: 陈国璋



Case history

M/29
Biopsy of left supraclavicular lymph node

CD20, CD3
Negative
CD30
Negative
LCA (CD45)
Negative
Kappa, Lambda, Oct-2, Bob.1
Negative
Cytokeratin
Negative
S100 protein
Negative

Diagnosis
Lymph node – Metastatic seminoma,
masked by epithelioid granulomas

Take-home message
Germ cell tumor (especially seminoma) can potentially be mistaken for a large cell lymphoma or granulomatous inflammation
Lymphadenopathy may represent the first presentation of the tumor
This has to be considered in young or middle-aged men, when the various hematolymphoid stains are negative
Useful markers: CD117, Oct-3/4

Case history
M/35
Cervical lymph node enlargement
Biopsy is performed

CD20, CD3
Normal immunoarchitecture
(no excessive B cells between follicles)

Diagnosis
Lymph node –
In-situ follicular lymphoma

In-situ follicular lymphoma
Morphology is that of usual reactive follicular hyperplasia or atypical follicular hyperplasia
But some germinal centers surprisingly are shown to harbor aggregates of strongly bcl-2+ follicular center cells

In-situ follicular lymphoma: clinical significance
A proportion of patients have synchronous conventional follicular lymphoma at other sites
~23% of patients develop definite evidence of follicular lymphoma subsequently
Some remain asymptomatic without progression:
  Early colonization by follicular lymphoma?
  Earliest stage of development of follicular lymphoma?
  Merely preneoplastic?

In-situ follicular lymphoma: Nature
Molecular studies demonstrate clonal B-cells with BCL2 gene rearrangement in the bcl-2+ follicles
The asymptomatic non-progressive group: Similar to monoclonal gammopathy of unknown significance?

Take-home message
In-situ follicular lymphoma can be difficult to recognize or diagnose
Liberally perform bcl-2 immunostain for any lymph node with features of “reactive follicular lymphoma” but with some follicles looking “unusual”

Case history
F/40
Left inferior orbital mass

EBER in-situ hybridization
Negative

Diagnosis
Orbit – Subcutaneous panniculitis-like T-cell lymphoma
[Patient also had panniculitis]

Subcutaneous panniculitis-like T-cell lymphoma
Definition: A cytotoxic T-cell lymphoma which preferentially infiltrates subcutaneous tissue
WHO 2001: “Most cases are derived from aβ cells, although 25% may be gd positive”
Change in definition in WHO 2008: Cases expressing gd T-cell receptor are excluded, and classified as “cutaneous gamma-delta T-cell lymphoma”

Subcutaneous panniculitis-like T-cell lymphoma: Clinical features
Presentation: solitary or multiple subcutaneous nodules (limbs > trunk)
Dissemination to LN and other organs uncommon and often late
17% have hemophagocytic syndrome
59% have B symptoms

Subcutaneous panniculitis-like T-cell lymphoma: Behavior
When originally described, considered an aggressive lymphoma (due to inclusion of cutaneous gd  T-cell lymphoma)
Prognosis in fact highly favorable, with 5-yr overall survival 82%
  91% for cases without hemophagocytic syndrome
  46% for cases with hemophagocytic syndrome

Subcutaneous panniculitis-like T-cell lymphoma: Pathology
Usually confined to subcutis (at most minimal extension to lower dermis)
Lace-like pattern of interstitial infiltrate
Rimming of fat spaces
Necrosis and apoptosis common
Lymphoma cells: minimally atypical small cells to medium-sized or large cells
Interspersed phagocytic histiocytes common

Subcutaneous panniculitis-like T-cell lymphoma: Biologic features
Pan T+
Most cases CD4-, CD8+
TCR-aβ
Cytotoxic makers+ (e.g. TIA-1)
CD56-
TCR genes: rearranged
EBV: negative

  Subcutaneous panniculitis-like T cell lymphoma Extranodal NK/T cell lymphoma involving skin
Age Younger (median 30) Older (median 53)
Extracutaneous disease Uncommon Common
Dermal involvement Absent Common
Nature of tumor T cell neoplasm, with TCR rearrangement Mostly NK neoplasms, with germline TCR
EBV Negative Positive


 

  Subcutaneous panniculitis-like T cell lymphoma Panniculitis, e.g. erythema nodosum, lupus profundus
Lobular septa Often obliterated Usually preserved septa
Lymphoid follicles Very rare Common
Rimming of fat spaces Common Uncommon
Cell types Cytologic atypia minimal to definite;
CD8+ T cells
No cytologic atypia; mixture of T cells (CD4 and CD8), B cells, plasma cells


 

  Subcutaneous panniculitis-like T-cell lymphoma Cutaneous gd T-cell lymphoma
T-cell receptor β gd
Hemophagocytic syndrome 17% 50%
Morphology No or minimal dermal involvement Dermal and epidermal involvement common
Usual immunophenotype CD4-, CD8+, CD56- CD4-, CD8-, CD56+/-
5-yr overall survival 82% 11%

Take-home message
Subcutaneous panniculitis-like T-cell lymphoma is diagnosed based on:
  Cytologic atypia
  Interstitial infiltration of fat
  Compatible immunophenotype (predominantly CD8+)
Must exclude:
  Extranodal NK/T cell lymphoma (CD56+, EBV+)
  Cutaneous gd T-cell lymphoma (dermal involvement; often CD56+)

Case history
F/78
Generalized lymphadenopathy and fever
Recent development of skin rash
Lymph node biopsy performed

Diagnosis
Lymph node –
Angioimmunoblastic T-cell lymphoma, with a partial follicular growth pattern

Angioimmunoblastic T-cell lymphoma: Clinical features
Age: elderly
Presentation:
  Generalized lymphadenopathy (LN usually <3 cm)
  Hepatosplenomegaly (2/3)
  Fever, constitutional symptoms (>1/2)
  Skin rash, effusion (>1/3)
25% have antecedent drug reaction or viral infection
Polyclonal gammopathy (>1/2), autoimmune hemolytic anemia (1/3), circulating immune complexes
Stage: >90% stage III or IV

Angioimmunoblastic T cell lymphoma
Subtle dysfunction of immune system
   Autoimmune disease-like features
   Reactivation of EBV infection (B cells)---------Emergence of EBV+ large B cell lymphoma
   Prone to various types of infections (Up to 50% deaths are from infections).....Mycobacterium, CMV, Aspergillus, Pneumocystis carinii

Angioimmunoblastic T cell lymphoma: Morphologic features favoring diagnosis
Prominent arborizing venules
Lymphoid cells usually have round instead of irregular nuclei as characteristic of peripheral T-cell lymphoma
Clear cells frequently seen
Background rich in plasma cells and eosinophils
Interspersed irregular-shaped pale pink foci harboring plump spindly cells (FDC)

Angioimmunoblastic T cell lymphoma: Traditional immunohistochemical features
T markers positive; usually CD4+ (T helper)
Extrafollicular meshworks of FDC (CD21+), often around blood vessels
Often many isolated or groups of CD20+ reactive B cells in background (some of them are large)

Early phase of angioimmunoblastic T cell lymphoma
Presence of hyperplastic follicles – these follicles may lack mantles due to erosion (Ree 1998; Attygalle 2002)
Lymphoma localized to expanded interfollicular zone
Very difficult to distinguish from reactive lymphoid hyperplasia

Angioimmunoblastic T-cell lymphoma
Now this is believed to be a lymphoma of germinal center T-helper cells
Evidence:
Association with meshworks of follicular dendritic cells
CD4+ (89%)
CD10+ (30-90%)
Bcl6+ (76%)
CXCL13+ (89-100%), a chemokine critically involved in B cell migration into germinal centers
PD1+ (100%)

Angioimmunoblastic T-cell lymphoma: Various growth patterns
Diffuse (classical) [can have regressed B-cell follicles]
With hyperplastic B-cell follicles
Follicular growth pattern
Perifollicular growth pattern
Understandable because this lymphoma is a neoplasm of follicular T-helper cell

Take-home message
The morphologic spectrum of angioimmunoblastic T-cell lymphoma is broader than previously recognized
Presence of hyperplastic follicles
Formation of neoplastic nodules/follicles (? Relationship with “follicular T-cell lymphoma”)
Perifollicular growth (? Relationship with “peripheral T-cell lymphoma with perifollicular growth”)
More markers are now available to aid in diagnosis of this lymphoma type (versus peripheral T cell lymphoma unspecified): CD10, bcl-6, CXCL13

Case history
M/53
Fever, lymphadenopathy (cervical, axillary and groin) and shortness of breath
Skin rash over body
Impaired liver function
Lymph node biopsy

CD30, Immunoglobulin
Negative
Is it a large cell lymphoma (T cell)?

Diagnosis
Lymph node –
Acute lymphadenitis, consistent with
HHV6-associated lymphadenitis
[Reference: Maric I, et al. Mod Pathol 2004;17:1427-1433]

Lymph node containing viral inclusions
Viral inclusions are seen only for certain viruses, e.g. none for EBV infection
Cytomegalovirus (CMV)
Very large cells, with large nuclear inclusions and small basophilic cytoplasmic inclusions
Immunocompromised host: numerous CMV infected cells throughout lymph node
Immunocompetent host: Single CMV infected cells scattered among monocytoid B cells
 

Lymph node containing viral inclusions
Herpes simplex lymphadenitis
In a background of lymphoid hyperplasia, there are circumscribed foci of necrosis
HSV inclusions seen in some cells (ground glass nuclei; fractured chromatin; nuclear inclusion surrounded by halo; multinucleated giant cells)

Lymph node containing viral inclusions
Human herpes virus-6 lymphadenitis
Usually with fever, fatigue, generalized lymphadenopathy and deranged liver function
Lymph node shows paracortical hyperplasia with a mixture of cells, many with nuclear inclusions (mostly CD4+ T lymphocytes)
May show prominent apoptosis

Take-home message
Do not mistake viral lymphadenitis for a large cell lymphoma (cells with nuclear inclusions mimicking immunoblasts with prominent nucleoli)
Few diseases give rise to recognizable viral inclusions in lymph node – their presence will permit a specific diagnosis to be made

Case history
M/70
Previous history of non-Hodgkin lymphoma
Presented this time with a skin nodule
 

CD20-, CD3-
So what would you consider?
Non-hematolymphoid tumor?
Unusual hematolymphoid neoplasms? 
  Myeloid leukemia
 “Null” cell lymphoma
  Plasmablastic neoplasm

Diagnosis
Skin – Large B-cell lymphoma,
with loss of CD20 expression due to prior Rituximab (anti-CD20) therapy

Take-home message (I)
Assessment of the lineage of a recurrent lymphoma using CD20 may not be successful due to loss of CD20 after anti-CD20 (Rituximab) therapy
However, other B-cell markers will still be expressed, e.g. CD79a, PAX5

Take-home message (II)
Alternatively, if a large B-cell lymphoma is suspected but CD20 is negative (and CD3 is also negative), consider:
Prior Rituximab (anti-CD20) therapy, and obtain the relevant clinical history from the clinician
CD20 negative B-cell neoplasms, e.g. plasmablastic neoplasm, ALK+ large B-cell lymphoma

Case history
M/47
Axillary lymph node core needle biopsy

Small B-cell lymphoma?

Diagnosis
Lymph node – Large B-cell lymphoma

Needle biopsy for lymphoid lesions
Some cases are easy:
Good cytologic details
Diffuse and dense monotonous infiltrate of abnormal lymphoid cells
In such straight-forward cases, a simple immunohistochemical panel may be adequate for rendering a diagnosis and classification

Problems in interpretation of needle biopsies
Artefacts resulting from biopsy procedure
Crush/ distortion artefact
Compression artefact
Limitations inherent to biopsy
Limited material for assessment
Sampling error
General diagnostic problem, unrelated to needle biopsy (but problem magnified by limited material and artefacts)

Artefacts resulting from biopsy procedure
Crush/ distortion artefacts

Disrupted cells, the nature of which cannot be determined morphologically

Crush/distortion artefacts: possible solutions
Immunostains often still work, and may thus help to ascertain the nature of the distorted cells
Interpret in the context of all available materials, including prior specimens

Artefacts resulting from biopsy procedure
Compression artefact

Nuclei become smaller than they actually are. Nuclei appear dark-staining, and nucleoli are often obscured
The danger: Mistaking a high grade lymphoma
for a low grade lymphoma!

Compression artefact: possible solutions
Recognize this artefact: make “mental” adjustment of nuclear size; look for mitotic figures and apoptotic bodies
Cut a thinner section: nucleoli become more obvious
Examine immunostained slide: nuclear details easier to appreciate in the light hematoxylin counterstain
Perform Ki67 immunostain liberally, to avoid pitfall of mistaking high-grade lymphoma for small cell lymphoma

Take-home message
In needle biopsy of lymph nodes (or extranodal tissues), the cells often appear smaller than they actually are
The greatest risk is mistaking a high-grade lymphoma for a low-grade small cell lymphoma
Always perform Ki67 to assess proliferative fraction – a high index indicates a high-grade rather than low-grade lymphoma

Case history
F/28
Solitary skin nodule over forehead

Diagnosis
Skin – Primary cutaneous small-medium CD4+ T-cell lymphoma

Analysis of case
Main morphologic feature suggesting diagnosis of malignancy: cytologic atypia

Analysis of case
Immunohistochemistry: Although there are many B cells, the atypical cells are selectively CD3+, supporting that this is a neoplasm of T cells

Analysis of case
Immunohistochemistry: The large cells are selectively CD8+, i.e. homogeneous population supporting a neoplastic process

Primary cutaneous small-medium CD4+ T-cell lymphoma
Usually presenting with solitary plaque or tumor (in contrast to mycosis fungoides)
Most commonly face, neck and upper trunk
Histology:
Dense diffuse or nodular dermal infiltrate
Predominance of small/medium-sized lymphoid cells (up to 30% of large cells may be present)
CD3+, CD4+, CD8-, CD30-

Primary cutaneous small-medium CD4+ T-cell lymphoma
Favorable prognosis
5-year survival 60-80%
Cases presenting with solitary or localized skin disease seem to have an especially favorable prognosis

Take-home message
In determining the nature of extranodal lymphoid infiltrates, a diagnosis can be arrived in most cases through morphologic and immunohistochemical assessment
Primary cutaneous small/medium CD4+ T-cell lymphoma has a highly favorable prognosis in contrast to the usual peripheral T-cell lymphomas


 

 

 

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