Journal ReadingJournal Reading

2006-05-05

Presented by Dr.陳志榮

ALK-Positive Anaplastic Large Cell Lymphoma MimiALK-Positive Anaplastic Large Cell Lymphoma Mimickingcking

Nodular Sclerosis Hodgkin’s LymphomaNodular Sclerosis Hodgkin’s LymphomaReport of 10 CasesReport of 10 Cases

Jose´ Vassallo, MD, PhD,*† Laurence Lamant, MD, PhD,* Laurence Brugieres, MD, PhD,‡

Fanny Gaillard, MD, PhD,§ Elias Campo, MD, PhD,k Pierre Brousset, MD, PhD,*

and Georges Delsol, MD*

~~Am J Surg Pathol 2006;30:223–229

INTRODUCTIONINTRODUCTION

Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL):

(1) biologically distinct entities.

(2) share some morphologic features. In 10 years, 380 cases of ALK-positive ALCL

(1) 10 cases: originally diagnosed as nodular sclerosis classic HL (NSHL) on conventional histopathological examination.

INTRODUCTIONINTRODUCTION Anaplastic large cell lymphoma (ALCL) (1) first described as a distinct type of non -Hodgkin lymphoma in 1985. (2) characterized by the expression of the CD30 antigen. (3) large cell non-Hodgkin lymphomas, malignant histiocytosis, and Hodgkin lymphoma (HL). (4) approximately 3% to 5% of non-Hodgkin lymphomas in adults and 10% to 30% in children.

INTRODUCTIONINTRODUCTION

REAL and the WHO classification, recognized only ALCL of T/null cell phenotype as a distinct entity.

(1) large cells with anaplastic morphologic features, expressing the CD30 antigen.

(2) a clear B-cell phenotype were included in the broad group of diffuse large B-cell lymphomas.

REAL classification: ‘‘ALCL Hodgkin-like’’ or ‘‘Hodgkin related’’ to take into c

onsideration the existence of cases with intermediate morphologic and phenotypical features between ALCL and HL.

INTRODUCTIONINTRODUCTION ALK1 antibody: confirmed that ALCL and HL are clinically and biological

ly different entities. ALCL is a T/null cell neoplasm, positive for cytotoxic mar

kers, such as TIA1, granzyme B, and perforin, but negative for EBV.

About 60% to 80% of ALCLs express the NPM-ALK protein resulting in the t (2;5), which is absent in HL.

WHO classification: three histologic variants of ALCL (common, lymphohistiocytic, and small cell variants) and does not include a ‘‘Hodgkin-like variant’’ ALCL.

INTRODUCTIONINTRODUCTION

grey-zone lymphomas

(1) HL with some features reminiscent of ALCL.

(2) the syncytial variant of nodular sclerosis => fibrosis is evident and neoplastic cells are present in large sheets.

MATERIALS AND METHODSMATERIALS AND METHODS 10 ALCL with Hodgkin-like features in the Laboratory of

Pathology of the Hoˆ pital Purpan, University of Toulouse, Toulouse, France

CD20, Pax5/BSAP (BD Biosiences), CD3, CD15, CD30, CD43, EMA, ALK protein, perforin,BNH-9 (GD), and the latent membrane protein 1 of the Epstein-Barr virus (LMP1/EBV, clone CS1-4, Dako).

In 7 cases with available paraffin blocks, additional T-cell markers, namely, CD2, CD4, CD5, CD7, and CD8, were tested.

In 6 cases, in situ hybridization for EBV using the EBER probe (Dako) was also available.

RESULTSRESULTS

Among 380 cases diagnosed as ALK-positive ALCL, 10 were considered to be good examples of Hodgkin-like ALCL (2.6%).

RESULTSRESULTS

HistopathologyHistopathology

Intense capsular fibrosis forming cellular nodules delimited by thick fibrous bands: all cases (except one)

Morphology is variable: most of them were mononucleated, with moderate to abundant eosinophilic cytoplasm.

Nucleus : round, oval- or kidney-shaped, with more or less coarse chromatin and small- to medium-sized nucleoli.

Binucleated neoplastic cells with prominent nucleoli reminiscent of Reed-Sternberg cells were observed in variable numbers: all cases

HistopathologyHistopathology 5 cases: mummified cells were seen and in two rar

e lacunar-like cells. Sinus involvement: all cases but mostly focal. 6 cases: neoplastic atypical cells were scattered in

a cellular background consisting of lymphocytes and plasma cells, or formed small nests.

4 cases: sheets of cohesive neoplastic cells were present.

HistopathologyHistopathology Hallmark cells. 4 cases: moderate to prominent perivascular pattern of neo

plastic cells. Residual germinal centers were prominent in 5 cases, scarc

e in 1, and absent in 4 cases. Small lymphocytes predominated in the background in all

case. Eosinophils and neutrophils were present in moderate num

bers in only 1 case. Histiocytes were also present in variable numbers, no epith

elioid granulomas.

Immunohistochemical Immunohistochemical FindingsFindings

Immunohistochemical Immunohistochemical FindingsFindings

7 cases: overall T-cell phenotype of neoplastic cells 3 cases: null/undetermined phenotype. 6 cases: CD43 was expressed by neoplastic cells. 6 cases: BNH-9 antibody strongly positive in 3 and focally

in 1. 8 cases: LMP1/EBV was not detected in neoplastic cell

=> confirmed by in situ hybridization technique using the EBER probe in 6 cases.

DISCUSSIONDISCUSSION There was no definite criteria for differentiating ALCL fro

m HL before the availability of ALK1 antibody =>‘‘Hodgkin-related’’ or ‘‘Hodgkin’s-like’’ALCL Orscheschek et al : suggested that HL and ALCL were clos

ely related because they were able to demonstrate t(2;5) in about 70% to 80% of HL.

These results have not been confirmed by multiple studies using a variety of techniques.

It is now largely recognized that ALCL and HL are distinct entities and, despite that there may be morphologic overlap between ALCL and HL, there is no true biologic borderline.

DISCUSSIONDISCUSSION

The present study further demonstrates the existence of rare cases of ALK-positive ALCL resembling HL, and some of these cases were diagnosed as HL by expert hematopathologists on morphologic ground alone.

In effect, all these cases showed lymph node features suggesting NSHL, namely, nodular fibrosis associated with capsular thickening and tumor cells resembling Reed-Sternberg cells.

In addition, these cases contained sheets of atypical cells as seen in NSHL associated with scattered atypical cells further accentuating the resemblance to HL, including the presence of some lacunar-like cells and mummified cells (5 of our cases).

DISCUSSIONDISCUSSION

The detection of atypical cells within residual lymphatic sinuses seen in all cases is characteristically observed in ALCL but may occasionally be observed in HL (about 5% of our cases)

Some ‘‘hallmark cells’’ were observed but were rather scarce, and the predominant cell population consisted of large mononuclear cells without specific morphologic features.

DISCUSSIONDISCUSSIONThese cases were categorized correctly only

after immunostaining:

(1)Atypical cells were positive for ALK protein=>cytoplasmic, nuclear, and nucleolar staining pattern.

(2) 1 case suggests an association with the t(2;5) and the expression of NPM-ALK protein.

DISCUSSIONDISCUSSION 3 cases: large cells were scattered among a predo

minant population of ALK-positive small cells associated with non-neoplastic small lymphocytes.

The detection of a perivascular pattern, which was obvious in 4 cases, supports such a hypothesis because this finding has been reported as a frequent feature in the ‘‘small cell variant’’ ALCL but has not been noted in HL.

DISCUSSIONDISCUSSION

Tumor cells were strongly positive for CD30 and EMA but negative for CD15 antigen.

CD15:

(1) about 75% of HL,

(2) may be occasionally found in rare cases of

ALK-positive ALCL.

=>these cases did not resemble HL, and the staining was restricted to the paranuclear area.

DISCUSSIONDISCUSSION

EMA: (1) observed in the majority of ALCL =>3 cases only a proportion of malignant cell were

positive. (2) weak staining: about 5% of HL. (3) such a positive staining in a given case should qu

estion the diagnosis of HL and require additional stainings, namely, ALK and T-cell markers.

DISCUSSIONDISCUSSION

Overall, T-cell phenotype of neoplastic cells was confirmed in 7 cases, but only 4 cases were positive for CD3, which is in agreement with previous studies on ALCL, because only one fourth of ALCL expressed this antigen.

CD3: may be positive in rare cases of HL, but the staining is usually cytoplasmic (dotlike staining).

DISCUSSIONDISCUSSIONAs previously reported in ALCL, 4 cases of

the present series were positive for other T-cell markers (CD2, CD4, CD5, and/or CD7) and perforin.

CD4: has been reported in RS, but convincing staining is very rare and all other T-cell markers, particularly perforin, are not expressed by RS cell.

DISCUSSIONDISCUSSION

Most of our cases (6 of 9 cases) were positive for CD43. (1) this antigen is expressed by the majority of ALCL and,

before the availability of ALK1 antibody. (2) CD43 was a useful marker in the differential diagnosis

between ALCL and HL, because it is reported positive in only 5% of HL.

The cases of the present study were negative for EBV. => ALCL is not an EBV-associated disease (1) immunohistochemistry (LMP1) (2) in situ hybridization (EBER probe)

DISCUSSIONDISCUSSION

Consequently, we think that lesions showing morphologic features of NSHL, with or without sinusoidal growth pattern, but negative for CD15, should not be diagnosed as Hodgkin-like ALCL unless they are positive for ALK

If they are negative for ALK protein, these lesions deserve additional immunostaining, including Pax5 and several T-cell markers and PCR to look for a clonal T-cell population to rule out an atypical T-cell non-Hodgkin lymphoma (eg, nodal cytotoxic T-cell lymphoma).

If they are negative for T-cell markers and for PCR, these lesions should be considered as HL and treated as such.

DISCUSSIONDISCUSSION

Our results support the need of recognition of a Hodgkin-like morphologic variant of ALCL, not to suggest a relationship between the two entities but to alert the surgical pathologist to systematically include in the first line panel of antibody anti-EMA and, if positive, to ask for ALK staining.

Thank You!