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淋巴瘤 - Diffuse infiltrate of large cells


更新时间:2008-06-18 15:16:13 作者: 陈国璋


DIFFUSE INFILTRATE OF LARGE CELLS:
Approach to diagnosis
John K.C. Chan
Hong Kong
 


Problems in diagnosis
-> Lymphoma or non-hematolymphoid neoplasms?
-> Malignant lymphoma or reactive immunoblastic proliferation? [This issue need not be raised if large cells show frank atypia lymphoma]
-> Classification and lineage assignment for the lymphoma

LYMPHOMA OR NON-HEMATOLYMPHOID?
-> While the distinction is easy in most cases (e.g. gland formation or keratinization in carcinoma), it can be difficult at times
-> Some carcinomas are permeative and dyscohesive, mimicking lymphoma
-> Melanoma is of course a great histologic mimicker!
-> On the other hand, lymphomas can take up myriads of unusual growth patterns mimicking carcinoma or sarcoma

Lymphomas: rare morphologic variants
-> Myxoid
-> Sarcomatoid (spindly cells)
-> Signet ring cells
-> Fibrillary matrix and rosettes
-> Microvillous
-> Sinusoidal
-> Anaplastic


Morphologic assessment
-> Assess growth pattern and cytology
-> Morphologic features suggestive of lymphoma:
 Highly permeative growth
 Basophilic or amphophilic cytoplasm
 Multilobated nuclei


Morphologic assessment
-> Features suggestive of carcinoma:
 Nuclear streaming and nuclear molding
 Cohesive growth
 Sharp interface with stroma
-> Features suggestive of melanoma:
 Cohesively non-cohesive
 Fine brown pigment


Lymphoma or non-hematolymphoid?

  LCA Cytokeratin S100 protein
Lymphoma + - -
Carcinoma - + -/+
Melanoma - - +
Sarcoma - - -/+


Lymphoma or non-hematolymphoid?
-> Some lymphomas may be LCA negative, especially anaplastic large cell lymphoma and lymphoblastic lymphoma
-> Rare cases of lymphoma and plasmacytoma can be cytokeratin positive (often in a dot pattern)
-> If lymphoma is highly likely, can replace “LCA, CK, S100” panel with “CD20, CD3” as first panel to save time and expenses



LARGE CELL HEMATOLYMPHOID NEOPLASMS: Main considerations
-> Diffuse large B-cell lymphoma
-> Anaplastic large cell lymphoma
-> T or NK cell lymphoma predominated by large cells
-> Anaplastic plasmacytoma / plasmablastic lymphoma
-> Classical Hodgkin lymphoma predominated by large cells
 Histiocytic / dendritic cell neoplasm
 Pleomorphic variant of mantle cell lymphoma


DIFFUSE LARGE B-CELL LYMPHOMA:Clinical features
-> Age: broad range, median 64 years
-> Presentation: rapidly enlarging mass in nodal or extranodal site (extranodal up to 40%)
-> 5-yr survival: overall 46%; failure-free 41% (improved with use of Rituximab)

Diffuse large B-cell lymphoma: Pathology
-> Diagnosis easy in most cases:
 Large cell lymphoid neoplasm
 B-lineage marker positive
-> Growth pattern:
 Diffuse +/- sclerosis
 Can be deceptively cohesive, mimicking carcinoma
-> Mitotic figures usually easy to find
-> Variable numbers of reactive small lymphocytes in background


Diffuse large B-cell lymphoma: Cytology
-> Nuclear size: Large or medium
-> Nuclear shape: Round, irregular or multilobated
-> Chromatin pattern: Variable
-> Nucleoli: Often distinct; solitary or multiple; central or membrane-bound
-> Cytoplasm: Variable staining qualities, e.g. basophilic, amphophilic, clear


Diffuse large B-cell lymphoma: Is subclassification worthwhile?
-> Some studies report immunoblastic lymphoma to have a worse prognosis than centroblastic lymphoma, but some studies report no difference
-> Greatest problem: Lack of reproducible morphologic criteria to distinguish between the two
-> WHO classification: Morphologic subclassification is optional for diffuse large B-cell lymphoma

Diffuse large B cell lymphoma
-> A heterogeneous category awaiting reproducible criteria (morphologic, immunohistologic or molecular) to delineate meaningful subtypes
-> Currently it appears that LBCLs with a germinal center cell molecular signature have a better prognosis than those without, but studies based on immunostaining for germinal center markers show conflicting results

Diffuse large B-cell lymphoma: Immunophenotype
-> Pan-B markers +, e.g. CD20, CD79a, PAX-5
-> CD3 negative
-> Surface or cytoplasmic Ig usually + (IgM>IgG>IgA)
-> Other markers:
 Germinal center cell markers: CD10 ~40%; bcl-6 ~60%
 Bcl-2 ~50% (worse prognosis, but may be overcome by adding Rituximab to chemotherapy regime)
 CD5 ~10% (de novo CD5+ cases not related to CLL or mantle cell lymphoma; apparently worse prognosis)
 CD30 ~10%


PLASMACYTOMA: Problems in diagnosis
-> Anaplastic plasmacytoma can cause difficulties in diagnosis, because tumor cells may not look plasmacytic but appear pleomorphic and bizarre
-> Plasmacytoma can show confusing immunophenotype:
 CD43+ (D.Dx. T cell lymphoma)
 Cytokeratin+ (D.Dx. carcinoma)
 EMA+ (D.Dx. carcinoma)
 CD31+ (D.Dx. angiosarcoma)


Plasmacytoma: Clues to diagnosis
-> Past history of myeloma, if present
-> Some large cells have coarsely clumped (clockface) chromatin
-> An appreciable amount of amphophilic or basophilic cytoplasm
-> Tumor looks like large cell lymphoma, but negative for conventional B and T markers


Plasmacytoma: How to confirm diagnosis?
-> CD20-: almost always negative
-> Ig+ (or ISH for Ig mRNA)
-> CD79a+/- (<50% positive)
-> CD138+ (note that carcinoma can be positive)
-> MUM1+ (note that melanoma can be positive)
-> CD45+/-: not uncommonly positive (focal) despite claims otherwise in older literature
-> Oct-2+, Bob.1+: most helpful for confirming B lineage when other markers are negative


A high index of suspicion is required in making
a diagnosis of anaplastic plasmacytoma.
This diagnosis in particular should be
considered in biopsies from:
Head and neck mucosal sites;
Vertebral bone or paravertebral tissues.

PLASMABLASTIC LYMPHOMA
-> Aggressive lymphoma
-> Variable clinical scenarios:
 Oral cavity/GI tract of HIV+ subjects [50% EBV+; HHV8-]
 Complicating multicentric Castleman disease, often HIV+ [EBV-; HHV8+]
 Now also recognized in various sites of non-immunocompromised subjects
 Primary effusion lymphoma?
 ALK+ large B cell lymphoma?
 HHV8+ germinotropic large B cell lymphoma?

Plasmablastic lymphoma: Pathology
-> Morphologic features of plasmablast:
 Nuclei often round and vesicular
 Prominent nucleoli
 Basophilic cytoplasm, often with pale Golgi zone
-> Cells “frozen” at the stage of plasmablasts, with little or no maturation into plasma cells
-> Mitotically active


Plasmablastic lymphoma: Immunophenotype
-> CD20- (rarely, CD20 can be positive); CD79-/+
-> CD138+/-; CD38+; VS38+ (Although not lymphoid cell specific, these are good plasma cell markers)
-> MUM1+ (Although MUM1 shows restricted expression in normal cells, its expression is found in many lymphoma types)
-> Cytoplasmic Ig++ (usually IgG type)
-> Oct-2+; Bob.1+
-> LCA/CD45 variable
-> CD30-
-> Ki67 index >95%

Same as
Plasmacytoma, except less likely to be CD56 or cyclin D1+?


ALK+ large B-cell lymphoma
-> Obliteration of nodal architecture, often with sinusoidal involvement
-> Neoplastic cells immunoblast-like, with basophilic cytoplasm, +/- paranuclear hof
-> Can be deceptively cohesive, mimicking carcinoma
-> Immunophenotype:
  Similar to plasmablast (CD20-, CD79-)
  ALK+, CD30-, IgA+, EMA+
  Interestingly, CD4 and perforin expression common


CLASSICAL HODGKIN LYMPHOMA RICH IN LARGE CELLS
-> Some cases of classical HL, especially nodular sclerosis (BNLI grade 2 or syncytial variant) and lymphocyte depletion types, show morphologic overlap with ALCL or diffuse large B cell lymphoma
-> Geographic necrosis (sometimes suppurative) is common in HL
-> Immunohistochemical studies very helpful, although not always conclusive


“Grey zone lymphoma” for cases with intermediate features

  Classical HL Large B cell lymphoma ALCL
CD3 - - +/-
CD20 -/+ + (uniform staining) -
PAX-5* + + -
EMA - - +/-
ALK1 - - +/-
Clusterin - - +
EBV +/- Usually - -


SUMMARY APPROACH TO DIAGNOSIS: large cell hematolymphoid neoplasms

LARGE CELL HEMATOLYMPHOID NEOPLASM: Morphology
-> Abundant pink cytoplasm: Histiocytic/ dendritic cell tumor
-> Abundant amphophilic cytoplasm with Golgi zone: ALCL, plasmacytoma, plasmablastic lymphoma
-> Indistinct cell borders: Dendritic cell tumor
-> Coarsely clumped chromatin: Plasmacytoma
-> Inclusion-like nucleolus: Hodgkin lymphoma, plasmablastic lymphoma


Large cell hematolymphoid neoplasm: growth pattern and background
-> Angiocentric growth, necrosis: NK cell lymphoma
-> Sinusoidal growth: ALCL, sinusoidal large B cell lymphoma
-> Geographic necrosis rimmed by large cells: Hodgkin lymphoma, some large B-cell lymphomas
-> Inflammatory cells in background: Hodgkin lymphoma, ALCL, FDC tumor
-> Amyloid: Plasmacytoma


With a presumptive diagnosis of “diffuse large B cell lymphoma” in a child, consider:

Follicular lymphoma, grade 3, follicular/diffuse Reactive immunoblastic proliferation Underlying immunodeficiency (esp. if EBV+)


CD20+ CD3+ large cell hematolymphoid neoplasm

↓→ Exclude artefactual staining

B-cell lymphoma aberrantly expressing CD3?
T-cell lymphoma aberrantly expressing CD20?
Biphenotypic lymphoma?



Pursue with B-lineage specific markers: PAX-5, Oct-2, Bob.1;
T-lineage specific markers: CD2, CD7, CD4, CD8, LAT;
perform molecular studies as necessary to determine lineage


CD20- CD3- large cell hematolymphoid neoplasm
-> Anaplastic large cell lymphoma-------------        Work-up with CD30, other B markers
-> Plasmacytoma; plasmablastic lymphoma-------       (CD79a, Oct-2, Bob.1), other T markers,       
-> Peripheral T cell lymphoma (CD3- cases)----        and clusterin
-> Classical Hodgkin lymphoma-----------------
-> Histiocytic and dendritic cell neoplasms................Reassess morphology, and
-> Extramedullary myeloid tumor............................apply appropriate immunostains
 

Further stain for CD30, B markers, T markers

B-markers positive CD30+, CD79a-, pan T- Pan T+, CD30+/-
Plasmacytoma;Plasmablastic lymphoma Null cell ALCL;Classical Hodgkin lymphoma ALCL;Peripheral T cell lymphoma
  Add ALK, EMA, clusterin (ALCL); PAX-5, CD15, EBV-LMP1 (HL) Add ALK
 




 

 

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