Table 1.

Meta-analysis of studies demonstrating the presence of EBV in ALCL

Date of Study	Total Number of Cases	Country of origin of the patients	Method of EBV Assessment	Number of EBV+ Cases*	ALCL Classification Scheme	Immunocompetency Status	Comments	Reference
1991	47	Germany	PCR	5/19	Updated Kiel	Competent	Positive cases: T-cell phenotype (18 T-cell, 1 Null-cell) All LMP1+ cases were PCR and EBER positive as well.	[33]
			LMP1-IHC	2/19
			EBNA2-IHC	0/19
			EBER1/2- ISH	2/2
1992	13	Netherlands	PCR	6/13	Updated Kiel	Nl	All “ALCL” cases characterized as >75% CD30+ cells (4/11 T-cell phenotype EBV+ by PCR, 2/2 Null-cell phenotype EBV+ by PCR)	[34]
			EBER1/2- ISH	2/5
			LMP1-IHC	1/13
			EBNA2-IHC	0/13
1992	8	Germany	Southern Blot	1/3	Updated Kiel	NI	4 cases with immunophenotyping available are T-cell in origin	[35]
			Dot Blot	1/4
			BamH1W-ISH	2/4
1992	8	USA	PCR (2 rounds)	8/8	NI	NI	PCR positivity may be from tumor infiltrating non-neoplastic lymphocytes	[36]
			Southern Blot	0/4
			BamH1W-ISH	0/4
1992	26	Denmark	LMP1-IHC	1/26	Updated Kiel	Competent	Positive case: “Null-cell” phenotype (19 T-cell, 7 Null-cell)	[37]
			EBNA2-IHC	0/26
1994	4	Netherlands, Hungary, France	EBER1/2-ISH	1/2	Updated Kiel	NI	Cutaneous cases excluded	[38]
			PCR	2/4
			LMP1-IHC	1/4
1995	16	Germany and Austria	PCR	5/16	Updated Kiel	Competent	11 T-cell, 3 Null-cell (the 2 B-cell phenotype cases cannot be subtracted from available data)	[39]
			EBER-ISH	1/5
1995	13	USA and Hong Kong	EBER1-ISH	3/13	NI	Competent	T-cell lineage determined by CD43 and CD45RO (15 T-cell, 3 Null-cell)	[40]
			LMP1-IHC	1/13
1996	40	Italy	LMP1-IHC	10/40	Updated Kiel, REAL	3 pts HIV+	Phenotype of LMP+ cases not specified (18 T-cell, 22 Null-cell)	[41]
1996	14	Denmark	EBER1/2- ISH	1/14	NI	NI		[42]
1997	67	Japan	EBERV2-ISH	4/54	Stein et al. and	NI	All EBER+ cases: ALK-; All	[44]
			LMP1-IHC	7/31	Suchi et al. [3,43]		LMP+ cases: ALK+ (cases of cutaneous ALCL and HD-like ALCL were excluded in this analysis)
1997	6	Japan	EBER (Dia-latron)	1/55	NI	Competent	(4 T-cell, 2 Null-Cell)	[45]
			EBER(DAKO)	2/5
			BamH1W-ISH	6/6
			LMP1-IHC	1/1
			PCR	5/5
1999	66	Japan	EBER1/2- ISH	4/42	Updated Kiel, REAL	NI	All positive cases: ALK-(0/32 EBV+ ALK+ cases)	[46]
1999	13	S. Korea	EBER-ISH	3/13	REAL	NI	EBER type not specified	[47]
2000	48	Netherlands and Austria	EBER1/2-ISH	2/48	REAL	Competent		[48]
			LMP1-IHC	1/2
2000	143	Japan	EBER1/2- ISH	12/58	Stein et al. and Suchi et al. [3,43]	Competent	All positive cases: ALK1-(0/80 EBV+ ALK+ cases)	[28]
2002	46	India	EBER1-ISH	9/46	NI	Competent	All LMP1+ cases also EBER+, all PCR+ cases also EBER+	[49]
			LMP1-IHC	5/46
			PCR	6/6
2002	74	Netherlands	EBER1/2-ISH	6/74	WHO 2001	Competent	All positive cases: ALK-	[8]
2004	37	Pakistan	EBER1-ISH	2/12	REAL, WHO 2001	NI		[50]
			PCR	7/28
2006	42	S. Korea	EBER1-ISH	2/3	EORTC	Competent	Only 3 systemic cases cited	[51]
			LMP1-IHC	2/3
2007	16	NI	EBER-ISH	1/16	WHO 2001 and 2005 SHP/EAHP consensus panel	NI	Positive case: ALK- T-cell phenotype (0/12 EBV+ ALK+ cases)+	[5]
2008	63	USA	EBER-ISH	3/45	WHO 2001	NI	Positive Cases: 1 ALK+, 2 ALK-	[17]

NI: Not indicated; IHC: immunohistochemical stain; ISH : In situ hybridization; LMP1: Latent membrane protein-1; EBER: EBV-encoded RNA-1; EBNA2: EBV nuclear protein-2; BamHIW: BamH1-W internal repetitive fragment of the EBV genome.

^*EBV positivity is restricted to cases of T-cell or Null-cell phenotype (with EBV evident on the neoplastic cells in IHC and ISH studies), excluding whenever possible the B-cell phenotypes included in ALCL in the earlier papers and cases of primary cutaneous ALCL.

#Cases which could not be determined to NOT be of B-cell origin were excluded from the analysis. Probable ALCL cases determined by uniform CD30 expression and some indication of either T- or null-cell phenotype (CD2, CD3, CD5, CD43, EMA) with no expression of CD15.

⁺Only cases which the panel firmly decided were ALK- ALCL are included.