Strong BCL10 nuclear expression identifies gastric MALT lymphomas that do not respond to H pylori eradication

Approximately 75% of gastric mucosa associated lymphoid tissue (MALT) lymphomas can be cured by Helicobacter pylori eradication.¹ It would be very useful to identify, at the time of diagnosis, the 25% of cases of gastric MALT lymphoma that will not respond to H pylori eradication. In general, lymphomas at stage II_E or above do not respond to H pylori eradication.²,³,⁴ However, the prognostic value of staging in stage I_E cases is very limited, although tumours that involve the muscularis propria or serosa (stage I_E2) show a higher failure rate than those restricted to the mucosa and submucosa (stage I_E1).²,³,⁴ Paradoxically, the majority of gastric MALT lymphomas at diagnosis are at stage I_E but 20% of these cases will not respond to H pylori eradication.

In a previous study, we have examined the value of t(11;18)(q21;q21) in prediction of the response of gastric MALT lymphoma to H pylori eradication. Among the 111 cases of gastric MALT lymphoma studied, t(11;18)(q21;q21) was present in 42/63 (67%) non‐responsive cases, including 26/43 (60%) at stage I_E.⁵ In contrast, translocation was detected in only 2/48 responsive cases and the two translocation positive cases showed a temporary response to H pylori eradication.⁵ Based on the same series of cases, we examined the value of t(1;14)(p22;q32)/IGH‐BCL10 in prediction of the response of gastric MALT lymphomas to H pylori eradication.

Of the 111 cases examined, 75 including 35 from the complete regression group and 40 from the non‐responsive group, had adequate tissue specimens for evaluation of BCL10 staining. Two cases showed strong BCL10 nuclear staining in virtually all tumour cells (fig 1), similar to that seen in t(1;14)(p22;q32) positive cells,⁶ while the remaining cases displayed either weak cytoplasmic or weak nuclear staining. Both cases with strong BCL10 nuclear staining were from the H pylori eradication non‐responsive group; one case (case No 1) had stage II_E disease and showed no response 12 months after H pylori eradication while the other (case No 2) had stage I_E disease and showed no response eight months after H pylori eradication. As shown in our previous study, both cases were t(11;18)(q21;q21) negative.⁵

Figure 1 BCL10 immunohistochemistry. Both cases 1 and 2 show strong BCL10 nuclear staining in virtually all tumour cells, similar to that seen in tumour cells with t(1;14)(p22;q32).

To ascertain whether the two cases that showed strong BCL10 nuclear staining were positive for t(1;14)(p22;q32) or variant, interphase fluorescence in situ hybridisation (FISH) with BCL10 break‐apart dual colour probes, IGH break‐apart probes, IGκ break‐apart probes, and BCL10/IGH dual colour dual fusion translocation probes were performed.⁶,⁷ Both cases failed to show evidence of BCL10 gene break or amplification. Case No 2 showed an IGH break, but FISH with BCL10/IGH dual colour dual fusion translocation probes failed to show evidence of BCL10/IGH translocation. To further investigate these cases, we performed real time quantitative reverse transcription‐polymerase chain reaction of BCL10 mRNA. Unfortunately, adequate tissue materials were available only in case No 2. The level (ΔCt = 3.4) of BCL10 mRNA expression in this case was compatible with that in MALT lymphoma with t(1;14)(p22;q32) (mean 1.60 (SD 2.37)), well above that in those without the translocation (6.94 (1.72)).⁶

To further assess the impact of t(1;14)(p22;q32) on the clinical behaviour of MALT lymphoma, we retrospectively reviewed the clinical presentation of 11 cases, including six from the stomach with known BCL10 involved translocation (table 1). Of these cases, nine including all those from the stomach, were at stage II_E or above. Although clinical presentation and follow up data were not available in each case, three cases (Nos 1, 2 and 7) presented unusual wide dissemination, including pleural effusion, and blood and bone marrow involvement (table 1).

Table 1 Clinical feature of mucosa associated lymphoid tissue (MALT) lymphoma with t(1;14)(p22;q32) or variants.

Case No	Age	Sex	Primary site	Genetic investigations	BCL10 involved chromosomal translocation	BCL10 IHC	Staging*	Dissemination	Clinical follow up
18	71	M	Stomach	Karotyping, interphase FISH, molecular cloning	t(1;14)(p22;q32)	Strong nuclear staining	IVE	Perigastric lymph nodes, omentum, spleen, pleural effusion, blood	n/a
2	48	F	Stomach	Karotyping, interphase FISH	t(1;14)(p22;q32)	n/a	IVE	Perigastric and splenic hilus lymph nodes, pleural involvement, bone marrow involvement?	4 cycles of MCP chemotherapy, partial remission, alive at two year follow up
3	67	M	Stomach	Karotyping, interphase FISH	t(1;2)(p22;q12)	Strong nuclear staining	IIIE	Perigastric lymph nodes and spleen	Chemotherapy with chlorambucil, complete remission in three year follow up
4	73	F	Stomach	Interphase FISH	Yes	Strong nuclear staining	IIIE	Perigastric and mesenteric lymph nodes,	Low dose chlorambucil chemotherapy, complete remission at 1.5 year follow up
5	49	M	Stomach	Interphase FISH	Yes	Strong nuclear staining	IVE	Lung	n/a
6	n/a	n/a	Stomach	Karotyping, interphase FISH	t(1;14)(p22;q32)	Strong nuclear staining	IIE	n/a	n/a
79	63	F	Lung	Karotyping, interphase FISH	t(1;14)(p22;q32)	n/a	IVE	Blood, bilateral pulmonary involvement, pleural and ascitic effusions, retroperitoneal lymph node	8 year low grade B cell lymphoma, then presented an aggressive clinical course presenting with lymphocytosis, pleural and ascitic effusions, partially response to chemotherapy, died of disease
89	49	F	Lung	Karotyping, interphase FISH	t(1;14)(p22;q32)	n/a	IIE	n/a	n/a
9	57	F	Lung	Interphase FISH	IGH‐BCL10 fusion	Strong BCL10 nuclear staining	IE	No clinical evidence	Data on treatment not available, but patients alive without evidence of disease for 16 years
10	32	F	Breast	Karotyping, interphase FISH	t(1;14)(p22;q32)	n/a	IIE	Axillary lymph nodes	6 cycles of CHOP therapy followed by surgery, complete remission in two year follow up
11	75	F	Breast	Interphase FISH	IGH‐BCL10 fusion	Strong BCL10 nuclear staining	IE	No clinical evidence	n/a

*Ann Arbor‐Musshoff staging system for extranodal lymphoma; the clinical stage was likely to have been underestimated as appropriate staging was unlikely to be carried out in each of these archival cases.

IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; n/a, not available.

Taken together, our results suggest that gastric MALT lymphomas with strong BCL10 nuclear expression or t(1;14)(p22;q32) are mostly likely resistant to H pylori eradication.

Acknowledgements

This study was supported by research grants from Leukaemia Research Fund, UK and Deutsche Krebshilfe. The authors thank J Audouin, L Bedenne, O Bouche, Marie‐Christine Copin, Y Bouhnik, J Fournet, A De Mascarel, Ph Moreau, J Lafon, A Pariente, and F Piard of the Groupe d' Etude des Lymphomes Digestifs (GELD), France; T. Thomas and PL Zinzani of Università degli Studi di Bologna, Italy; and M Stolte of Institut fur Pathologie, Klinikum Bayreuth, Germany, for contribution of part of the specimens used for this study.