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Journal Reading. 2006-05-05 Presented by Dr. 陳志榮. ALK-Positive Anaplastic Large Cell Lymphoma Mimicking Nodular Sclerosis Hodgkin ’ s Lymphoma Report of 10 Cases. Jose´ Vassallo, MD, PhD,*† Laurence Lamant, MD, PhD,* Laurence Brugieres, MD, PhD,‡

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journal reading

Journal Reading


Presented by Dr.陳志榮


ALK-Positive Anaplastic Large Cell Lymphoma MimickingNodular Sclerosis Hodgkin’s LymphomaReport 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

  • 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.

  • 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


(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


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

  • ALK1 antibody:

confirmed that ALCL and HL are clinically and biologically different entities.

  • ALCL is a T/null cell neoplasm, positive for cytotoxic markers, 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.
  • 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 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.
  • Among 380 cases diagnosed as ALK-positive ALCL, 10 were considered to be good examples of Hodgkin-like ALCL (2.6%).
  • 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
  • 5 cases: mummified cells were seen and in two rare 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.
  • Hallmark cells.
  • 4 cases: moderate to prominent perivascular pattern of neoplastic cells.
  • Residual germinal centers were prominent in 5 cases, scarce in 1, and absent in 4 cases.
  • Small lymphocytes predominated in the background in all case.
  • Eosinophils and neutrophils were present in moderate numbers in only 1 case.
  • Histiocytes were also present in variable numbers, no epithelioid granulomas.
immunohistochemical findings1
Immunohistochemical Findings
  • 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.

  • There was no definite criteria for differentiating ALCL from HL before the availability of ALK1 antibody

=>‘‘Hodgkin-related’’ or ‘‘Hodgkin’s-like’’ALCL

  • Orscheschek et al : suggested that HL and ALCL were closely 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.
  • 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).
  • 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.
  • These 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.

  • 3 cases: large cells were scattered among a predominant 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.
  • 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.

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

  • 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).
  • As 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.
  • 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)

  • 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.
  • 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.