Primary gastrointestinal anaplastic large cell lymphoma

Primary gastrointestinal anaplastic large cell lymphoma

Pathology (- 2017) -(-), pp. 1–7 A N ATO M I C A L PAT H O L O G Y Primary gastrointestinal anaplastic large cell lymphoma YI-YING LEE1,*, KATSUYOSH...

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Pathology (- 2017) -(-), pp. 1–7

A N ATO M I C A L PAT H O L O G Y

Primary gastrointestinal anaplastic large cell lymphoma YI-YING LEE1,*, KATSUYOSHI TAKATA2,*, REN-CHING WANG3, SHEAU-FANG YANG4 AND SHIH-SUNG CHUANG5,6,7 1

Department of Pathology, Chi-Mei Medical Center, Liouying, Taiwan; 2Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 3Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 4Department of Pathology, Kaohsiung Medical University Hospital and School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 5Department of Pathology, Chi-Mei Medical Center, Tainan, 6 Department of Pathology, Taipei Medical University, Taipei, and 7Department of Pathology, National Taiwan University, Taipei, Taiwan; *these authors contributed equally to this work and should both be considered first authors

Summary Primary gastrointestinal anaplastic large cell lymphoma (GIALCL) is rare. We report eight new cases. The median age was 61.5 years (range 10–88), most frequently involving the stomach (n = 3) and small intestine (n = 4). The neoplastic hallmark cells in all cases expressed CD30. Anaplastic lymphoma kinase (ALK) protein was expressed in two cases (25%). By in situ hybridisation, all cases were negative for Epstein–Barr virus and for DUSP22/IRF4 gene translocation. At a median follow-up time of 37.5 months, four patients died of disease, one was alive with disease, and three were disease-free. Our literature review showed that GI-ALCL occurred mainly in older patients and was characterised by a low rate of ALK expression, a high rate of T-cell lineage, and a frequent occurrence in the small intestine. Incorporating our two ALK+ GI-ALCL cases together with the four cases in the literature, the median age was 34 years (range 10–56), with four (67%) cases in the small intestine. The six patients were all alive with a median follow-up of 21 months. The 5-year overall survival of our six patients with ALK− GI-ALCL was 40%, in contrast to 100% with ALK+ GIALCL. The prognosis for ALK− GI-ALCL was poor, while that for the ALK+ counterparts was good. Key words: ALK; anaplastic large cell lymphoma; CD30; gastrointestinal tract; peripheral T-cell lymphoma. Received 20 February, revised 18 May, accepted 18 May 2017 Available online: xxx

rearrangement and protein expression: primary cutaneous ALCL, systemic ALK+ ALCL, and systemic ALK− ALCL.1,3 The most frequent genetic alteration of ALK+ ALCL is translocation between the ALK and nucleophosmin (NPM) genes.4,5 NPM-ALK fusion protein is responsible for the activation of ALK catalytic domain and for lymphomagenesis in ALK+ ALCL.6 Molecular pathogenesis of ALK− ALCL is less well understood, but is thought to involve misregulation of several signalling pathways and translocations at the DUSP22/IRF4 and TP63 genes in a proportion of cases.7–9 Tumorigenesis of both ALK+ and ALK− ALCL also depends on signalling through IRF4 and MYC.10,11 The overall 5-year survival rate of ALK+ ALCL approaches 80%, in contrast to only 48% in ALK− ALCL.1 Both ALK+ and ALK− ALCL frequently involve both lymph nodes and extranodal sites (including skin, bone, soft tissues, lung and liver); however, extranodal sites are less commonly involved in ALK− ALCL.1 ALCL arising from extranodal sites other than the skin is uncommon. Primary ALCL of the gastrointestinal tract (GI-ALCL) is rare and most reported cases are isolated case reports or small case series except for the report by ten Berge et al., in which there were 14 patients of ALK− GI-ALCL but with incomplete clinicopathological data.12 Here we report the detailed clinicopathological findings of eight additional cases of GI-ALCL and the results of our literature review.

MATERIALS AND METHODS Case selection

INTRODUCTION Anaplastic large cell lymphoma (ALCL) is characterised by cohesive sheets of large atypical lymphoid cells with pleomorphic and often eccentric, horseshoe- or kidney-shaped nuclei and abundant eosinophilic cytoplasm.1 These ‘hallmark’ cells express CD30 on the cell membrane and in the Golgi region.2 The current World Health Organization (WHO) classification distinguishes three types of ALCL based on the location of primary disease and presence or absence of anaplastic lymphoma kinase (ALK) gene

We retrospectively searched cases of GI-ALCL in our institutions from January 2001 to December 2015 diagnosed and classified based on the WHO classification.1 We reviewed the histopathology and medical charts. This study was approved by the Internal Review Board of Chi-Mei Medical Center, Tainan, Taiwan. The study was conducted in accordance with the Helsinki Declaration. Immunohistochemistry Immunohistochemistry was performed for each case using the labelled streptavidin-biotin peroxidase method (LSAB kit; Dako, USA); an antigenretrieval technique was applied as needed for each specific antibody. Information on the antibodies used is listed as Table 1. Appropriate positive controls were used for all primary antibodies.

Print ISSN 0031-3025/Online ISSN 1465-3931 © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved. DOI: http://dx.doi.org/10.1016/j.pathol.2017.05.007 Please cite this article in press as: Lee Y-Y, et al., Primary gastrointestinal anaplastic large cell lymphoma, Pathology (2017), http://dx.doi.org/10.1016/ j.pathol.2017.05.007

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Table 1

Antibodies used in this study

Antigen

Antibody clone

Concentration

Source

AB75 Polyclonal 4B12 4C7 CD7-272 Nr.M7103 L26 Ber-H2 UCHL-1 123C3 2G9 GrB-7 P1-8 E29 MUM1P Monoclonal 8A31 5A6.E9

1:100 1:300 1:150 1:70 1:100 1:100 1:350 1:50 1:250 1:100 1:200 1:50 1:25 1:500 1:100 1:50 1:700 1:350

Leica Dako Leica Leica Leica Dako Dako Dako Biogenex Dako Immunotech Dako Dako Dako Dako Abcam Endogen Endogen

CD2 CD3 CD4 CD5 CD7 CD8 CD20 CD30 CD45RO CD56 TIA-1 Granzyme B Perforin EMA MUM-1 ALK bF1 TCRg

In situ hybridisation (ISH) We performed ISH for Epstein–Barr virus (EBV)-encoded small mRNA (EBER) by using an autostainer (Bond MAX; Vision BioSystems, Australia) and a polymer-based detection system (BondTM Polymer Refine Detection; Vision BioSystems) with an EBV specific probe (BondTM ISH EBER Probe) and 3,30 -diaminobenzidine (DAB) as a chromogen. Interphase fluorescence in situ hybridisation (FISH) for DUSP22/IRF4 rearrangement was performed using a commercially available FISH probe set (Kreatech, The Netherlands) as previously described.13

RESULTS Patients and clinical features We initially identified nine cases diagnosed as GI-ALCL. One of the patients was an 83-year-old male and presented with bloody diarrhoea for one week accompanied by nausea and vomiting. Computed tomography (CT) scans revealed a soft tissue mass (9.1 × 7.7 × 7.5 cm) in the caecum with extension to ascending colon and ileocaecal valve with

Table 2

multiple abdominal lymphadenopathy. ALK− ALCL, with large neoplastic cells expressing CD7 and CD30, was diagnosed via colonoscopic biopsy. Malignant pleural effusion was simultaneously confirmed by cytological examination. However, plasma cell leukaemia occurred 2 months later, and the leukaemic plasma cells were monotypic for lambda light chain. In retrospect, additional immunohistochemical stains on the colonic biopsy showed that the large tumour cells were MUM1 positive and also monotypic for kappa light chain, although negative for CD138 and CD79a. The diagnosis of this case was revised to extramedullary plasmablastic myeloma in the colon with subsequent leukaemic transformation. Accordingly this case was excluded, with the remaining eight cases for this current study. Table 2 lists the clinical data of the eight patients, including four Taiwanese and four Japanese. The patients were six males and two females with a median age of 61.5 years (range 10–88). The primary tumour sites were the oesophagus (n = 1), stomach (n = 2), small intestine (n = 4; two in the terminal ileum, one in the small intestine with unspecified location and mesenteric lymph node; one in the jejunum), and right colon (n = 1). One tumour was perforated (Case 4), while involvement of regional lymph node occurred in five patients. Case 4 had focal marrow involvement in addition to nodal metastasis. Three patients each were at stage IE and IIE, with two patients at IVE. The two cases with stage IVE disease were Cases 3 and 4. Case 3 has been previously reported.14 This 70-year-old female patient presented with epigastric pain with poor appetite for a few months. Computed tomography (CT) scans revealed an ulcerative gastric tumour with peri-gastric lymphadenopathy, and a few small metastatic hepatic nodules. She underwent total gastrectomy and liver biopsy. Histologically, the gastric tumour showed neoplastic lymphocytic infiltration through the whole layer to the serosa with involvement of the regional lymph nodes and the hepatic biopsy specimen. There was no lesion in other organs and this case was staged as stage IVE primary gastric ALK− ALCL. Case 4, a 65-year-old male, presented with fever for more than a week. CT scans revealed hollow organ perforation. Emergency surgery with segmental

Clinicopathological features of the eight cases of gastrointestinal ALCL in the current study

Clinicopathological features

Primary site Biopsy or surgery

Perforation Regional nodal involvement Marrow involvement Stage ALK Chemotherapy Follow-up (months)

Case no./sex/age, years 1/F/64

7/M/53

8/M/10

Terminal Terminal ileum Stomach ileum Partial Total gastrectomy Segmental Segmental Right Biopsy Segmental resection gastrectomy and liver biopsy resection resection hemicolectomy of distal oesophagus and proximal partial gastrectomy − − − + − − − − − + + + − +

Small intestine Segmental resection

− IE − Various regimens and transplantation after relapse DOD (63)

− IIE + Yes: unknown regimen

Oesophagus

2/M/59 Stomach

3/F/70 Stomach

4/M/65

5/M/88

6/M/57

Jejunum

− +

− IE − CHOP

− IVE − CHOP and ESHAP

+ (focal) IVE − Nil

− IIE − CHOP

ND IE − Nil

− IIE + CHOP

NED (81)

DOD (21)

DOD (0.7)

AWD (4)

DOD (0.7)

NED (72) NED (54)

ALCL, anaplastic large cell lymphoma; AWD, alive with disease; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; DOD, died of disease; ESHAP, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin; ND, not done; NED, no evidence of disease.

Please cite this article in press as: Lee Y-Y, et al., Primary gastrointestinal anaplastic large cell lymphoma, Pathology (2017), http://dx.doi.org/10.1016/ j.pathol.2017.05.007

PRIMARY GASTROINTESTINAL ALCL

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resection revealed an annular jejunal tumour, 4 cm in size, with perforation and mesenteric lymphadenopathy. Bone marrow biopsy showed focal marrow involvement. This case was staged as stage IVE primary jejunal ALK− ALCL. Most patients underwent surgical resection and received adjuvant chemotherapy. Clinical follow-up ranged from 0.7 to 81 months with a median of 37.5 months. At the time of the last follow-up, four patients had died of disease, one was alive with disease, and three were free of disease. The 5-year overall survival (OS) of our six patients with ALK− ALCL was 40%. Both patients with ALK+ ALCL were free of disease, at 72 and 54 months after diagnosis.

sometimes horseshoe- or kidney-shaped nuclei with modest amounts of amphophilic cytoplasm (Fig. 1A,B). The neoplastic cells were occasionally clustered and arranged in cohesive aggregates, showing a carcinoma-like growth pattern. Tumour necrosis was discernible but angiodestruction and geographic necrosis were absent in all cases. In the non-tumoural mucosa remote from the tumour, none of the samples displayed features of enteropathy such as increased intraepithelial lymphocytosis, villous blunting, or crypt hyperplasia.

Histopathological findings

Table 3 summarises the results of immunohistochemistry. The hallmark cells in all eight diffusely and strongly expressed CD30 in a perinuclear Golgi- and membraneassociated pattern (Fig. 1C); only 25% (2/8) cases expressed ALK protein, with a cytoplasmic staining pattern in one (Case 7), and both nuclear and cytoplasmic staining in the other (Case 8; Fig. 1F). The tumour cells of five cases

All cases underwent surgical resection and were characterised by focal mucosal ulceration and a transmural infiltrate by sheets of large pleomorphic cells admixed with some reactive histiocytes, small lymphocytes and plasma cells. The large neoplastic cells displayed round or oval, irregular, and

Immunohistochemistry and in situ hybridisdation

(A–E) A representative case of ALK− ALCL (Case 4). (A) An ulcerative ileal tumour with a transmural infiltration showing large cells in the lamina propria and submucosa. (B) High magnification reveals large pleomorphic cells displaying round or oval, irregular-shaped, and sometimes horseshoe- or kidney-shaped nuclei with a modest amount of amphophilic cytoplasm. (C) Strong CD30 immunostaining intensity in a perinuclear Golgi- and membrane-associated pattern. The tumour cells express EMA (D) but not ALK protein (E). (F) Case 8, a small intestinal ALK+ ALCL showing ALK protein expression in both cytoplasmic and nuclear patterns.

Fig. 1

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expressed at least one cytotoxic marker [TIA-1 (5/8 cases), granzyme B (7/8), or perforin (4/4)]. All cases were negative for T-cell receptor (TCR) expression (Case 1 negative for bF1 and the remaining seven cases negative for both bF1 and TCRg). Immunostaining for CD56 and cytokeratin (AE1/ AE3) was all negative. Six of eight cases (75%) expressed MUM-1 and EMA. All the eight tumours tested were negative for EBER and for DUSP22/IRF4 translocation.

Table 3 Immunophenotypic, EBER and FISH results of gastrointestinal ALCL in the current study Case no.

CD2 CD3 CD4 CD5 CD7 CD8 CD20 CD30 CD45RO Lineagea TIA-1 Granzyme B Perforin bF1 TCRg MUM-1 EMA ALK-1 EBER IRF4/MUM-1 FISH

1

2

3

4

5

6

7

8

+(p) + + +(p) − − − + + T + − ND − ND − − − − −

− + − − − − − + − T − + + − − +(p) + − − −

+ + − − + − − + + T + + + − − +(p) − − − −

+ − − − − − − + − T + + ND − − + + − − −

− − − − − − − + − Null + + ND − − − +(p) − − −

− − − − − − − + − Null − + ND − − + + − − −

− − − − − − − + − Null + + + − − +(p) + + − −

− − − +(p) − − − + − T − + + − − + + + − −

Literature review Our literature review showed that there were up to 30 reported cases of GI-ALCL, mostly as single case reports or small case series. Some cases had not been fully characterised phenotypically in terms of T versus null cell origin, and there were even cases without immunostaining for CD30. Furthermore, one of the cases was positive for EBV by EBER.15 In our opinion, this EBV positive case should be reclassified as extranodal natural killer (NK)/T-cell lymphoma. We considered it not worthwhile to list all of these reported GI-ALCL cases as there were too many inconclusive data. As most GI-ALCL cases were negative for ALK,12 we chose to list the fully characterised ALK+ GI-ALCL cases in Table 4.15–18 There are a total of six cases, including our Cases 7 and 8; all were male with a median age of 34 years (range 10–56). The primary sites included oesophagus (n = 1), stomach (n = 1), and small intestine (n = 4). Most cases (5/6, 83%) were of T-cell lineage. The ALK staining pattern in the case of Joshi et al. (Case 2, Table 4) was unspecified, but it was probably of weak cytoplasmic staining as judged by the accompanying figure.16 Of the remaining five cases, three were both cytoplasmic and nuclear and the remaining two were cytoplasmic. As in systemic ALK+ ALCL, the prognosis of the patients with primary ALK+ GIALCL was excellent. All patients were alive with a median follow-up of 21 months; one patient was alive with disease at

ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma receptor tyrosine kinase; bF1, T cell receptor-b; EBER, EBV-encoded small nonpolyadenylated RNA transcript; EMA, epithelial membrane antigen; FISH, fluorescence in situ hybridisation; IRF4, interferon regulatory factor 4; MUM-1, multiple myeloma-1; ND, not done; p, partial expression; TCR-g, T-cell receptor-g; TIA-1, T-cell- intracellular antigen-1. a

T versus null-cell linage is determined by the expression of CD2, CD3, CD4, CD5, CD7, CD8, or CD45RO.

expressed at least one pan T-cell marker (including CD2, CD3, CD4, CD5, CD7, CD8, and CD45RO), indicating a Tcell phenotype, while the remaining three cases showed a null-cell linage. EMA expression was detected in seven (88%) cases, including both ALK+ cases (Fig. 1D). All cases

Table 4

Primary ALK positive ALCL of the gastrointestinal tract in our current study and in the literature Case no. 1

2

3

4

6

M/17 Abdominal pain

M/32 Abdominal pain

Perforation Primary site

Carey et al., 199915 Joshi et al., 200816 Case 4 M/36 M/56 Periumbilical pain Tracheoesophageal fistula; sore throat, odynophagia, dysphagia, dysphonia, weight loss No Yes (as a fistula) Duodenum Cervical oesophagus

No Jejunum

No Stomach

No Small intestine

Marrow involvement Stage Lineage a ALK-1 (pattern) Treatment

N/A N/A T + (c&n) Op + C/T

N/A IE T + (c) C/T

No Junction of jejunum and ileum – IE T + (c&n) C/T

– IIE Null + (c) Op + C/T

– IIE T + (c&n) Op + C/T

Follow-up (months)

NED (24)

NED (18b)

NED (5)

NED (84)

NED (75)

Author, year, ref Sex/Age Presenting symptoms/signs

N/A IIIE T + (?c) C/T and autologous stem cell transplant AWD (6 at least)

Sadiya et al., 201417 Cao et al., 201618

5

Current study Current study Case 8 Case 714 M/53 M/10 N/A Constipation, abdominal distension

ALK-1 staining pattern: c, cytoplasmic; n, nuclear. The ALK staining pattern in the case of Joshi et al. (Case 2, Table 4) was unspecified, but it is of weak cytoplasmic staining as judged by the figure and is not very convincing. ALCL, anaplastic large cell lymphoma; AWD, alive with disease; C/T, chemotherapy; M, male; N/A, not available; NED, no evidence of disease; Op, operation. a b

T versus null-cell linage is determined by the expression of CD2, CD3, CD4, CD5, CD7, CD8, or CD45RO. Provided by Dr Niamathullah Sadiya at SRM Institute for Medical Sciences, Chennai, Tamil Nadu, India.

Please cite this article in press as: Lee Y-Y, et al., Primary gastrointestinal anaplastic large cell lymphoma, Pathology (2017), http://dx.doi.org/10.1016/ j.pathol.2017.05.007

PRIMARY GASTROINTESTINAL ALCL

6 months and the remaining five were free of disease for 5–84 months. We compared the clinicopathological features of our ALK− GI-ALCL with the 73 cases of systemic ALK− ALCL reported by Parrilla Castellar et al.7 As shown in Table 5, the median age of GI and systemic ALK− ALCL was 64.5 and 58.0 years, respectively. GI ALK− ALCLs more frequently expressed granzyme B (p = 0.02) and EMA (p = 0.006) but less frequently expressed BF1 (p = 0.04) as compared to the systemic ALK− ALCL cases (Fisher’s exact test). There was no significant difference in other clinicopathological factors. The 5-year OS of our six patients with ALK− GI-ALCL was 40%, in contrast to 50% in systemic ALK− ALCL and 80% in systemic ALK+ ALCL as reported by Parrilla Castellar et al.7 We then compared our six ALK− (Cases 1–6 in Table 3) versus six ALK+ (Cases 1–6 in Table 4) GI-ALCL. There was no statistically significant difference in any clinicopathological factors (Fisher’s exact test; data not shown); however, the OS of ALK+ GI-ALCL was significantly better than ALK− GI-ALCL (Fig. 2; p = 0.041).

DISCUSSION In the current WHO classification, ALCLs are separated into either ALK+ or ALK− entities.1,3 ALCL commonly involves

Table 5 Comparison between gastrointestinal versus systemic ALK negative ALCL Parameter Median age Gender Female Male TIA-1 Pos Neg Granzyme B Pos Neg EMA Pos Neg TCRbF1 Pos Neg TCRg Pos Neg CD2 Pos Neg CD3 Pos Neg CD4 Pos Neg CD5 Pos Neg CD8 Pos Neg

GI

Systemic

64.5

58

2 4

24 49

4 2

29 43

5 1

23 47

4 2

8 56

0 6

22 28

0 4

1 36

3 3

47 13

3 3

42 29

1 5

30 26

1 5

14 44

0 6

4 50

p value

a

0.69

0.2

0.02

0.006

0.04

0.9 0.15 0.49 0.09 0.57

0.65

ALCL, anaplastic large cell lymphoma; GI, gastrointestinal; Neg, negative; Pos, positive. a

Fisher’s exact test.

5

nodal as well as a wide variety of extranodal sites but rarely arises from the GI tract.1,19,20 In this current study we presented the clinicopathological features of eight additional cases of primary GI-ALCL including six ALK− and two ALK+ cases. Primary GI-ALCL is rare and most reported cases are single cases with hitherto no more than four cases have been part of any single study, except for the report by ten Berge et al.12 In that study of 85 cases of extranodal ALCL from different sites of origin, 14 (16%) cases were considered primary GI-ALCL based on clinical presentation primarily in the GI tract with no or only regional lymph node involvement. All 14 GI-ALCL tumours in that study were negative for ALK. Literature review shows that some of the cases in single case reports were not well characterised phenotypically and it might not be worthwhile to list and review all these reported cases. However, all the cases (n = 14) in the literature investigated for EBER were negative except for Case 2 in the series by Carey et al.15 Using the current diagnostic criteria, this EBER positive case might well be considered extranodal NK/T-cell lymphoma.1,21–23 ALK+ ALCL is more prevalent in children and young adults, while ALK− ALCL tends to occur in older patients, and both types show a male predominance.1,19,20,24 Interestingly, the difference in the median ages in ALK+ and ALK− GI-ALCL was not so prominent: 53 in the former and 65 in the latter patients. Of the five ALK+ GI-ALCL patients, there was only one paediatric patient who was 10 years old. Systemic ALK− ALCL patients carry a worse prognosis than ALK+ ALCL patients when treated with standard chemotherapy.1,19,25 In this current study of GI-ALCL with literature review, we found that most cases (76%) were negative for ALK, and the median age of patients was older than systemic ALCL, either in the ALK+ or ALK− entities. ALK protein expression has been detected in up to 84% of ALCL cases and is commonly found in young patients.4,26,27 Savage et al. showed that 55% of their ALCL cases were ALK+.19 In one of our institutions (Chi-Mei Medical Center in Tainan, Taiwan), the ALK expression rate among all ALCL cases from year 1990 to year 2015 was 48%.28 Similar results were obtained from China and France.29–31 In other studies of adult patients in Germany, Korea, Sweden, and the United States, the proportion of ALK+ ALCL cases ranged from 34% to 43%.25,32–34 Interestingly, ALCL occurring in the bone and soft tissue showed much higher rates (>85%) of ALK expression,35,36 while ALK+ and ALK− cases in the central nervous system were of equal proportion.37 From this current study and literature review, the rate of ALK expression among GI-ALCL was relatively low at 24%. Systemic ALK− ALCL must be distinguished from primary cutaneous ALCL, which shares a similar immunophenotype and histomorphology but is associated with a better prognosis than systemic ALK− ALCL with secondary skin involvement.1 In additional to clinical history, analysis of DUSP22/IRF4 translocation may be useful for differential diagnosis. Recently, Feldman et al. identified this translocation in peripheral T-cell lymphomas.11 Further studies demonstrated that the detection of this translocation is a valuable diagnostic adjunct for primary cutaneous ALCL with a high specificity.13,38,39 In keeping with the previous studies, none of our eight cases exhibited IRF4 rearrangement, supporting the notion that this translocation is not associated with systemic ALCL.

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translocation. Our literature review indicates that GI-ALCL occur mainly in older patients and are characterised by a low rate of ALK expression, a high rate of T-cell lineage, and a frequent occurrence in the small intestine. The prognosis of GI-ALCL is dichotomous: an excellent prognosis in the ALK+ cases but a dismal prognosis in the ALK− patients. Acknowledgements: We thank Dr Niamathullah Sadiya at SRM Institute for Medical Sciences, Chennai, Tamil Nadu, India, for providing the latest follow-up information of their previously reported patient with ALK-positive jejunal ALCL (Case 4, Table 3). We are grateful to Prof MingQing Du and Dr Hongxiang Liu at Cambridge University, Cambridge, UK, for their helpful comments and suggestion on the expression of CD3 and TCR in ALCL. Conflicts of interest and sources of funding: This work was supported by a research grant (CMFHR10568) from ChiMei Medical Center, Tainan, Taiwan (to SSC). The authors state that there are no conflicts of interest to disclose. Comparison of outcomes in patients with ALK− versus ALK+ GIALCL, showing a significantly better overall survival in the latter group of patients.

Fig. 2

In normal T-cells, T-cell receptor (TCR) forms a complex with CD3 for signal transduction. In this current study, CD3 was expressed only in three (38%) of eight cases; and all cases investigated were negative for the expression of TCR bF1 (n = 8) or TCRg (n = 7). Bonzheim et al. have shown that despite the frequent clonal rearrangement of TRB gene, only 4% (1/24) ALK+ systemic ALCL and 7% (1/15) ALK− systemic ALCL cases expressed bF1, and the expression of bF1 was restricted to a subpopulation of the tumour cells. In contrast, 93% (27/29) non-anaplastic peripheral T-cell lymphomas (PTCL), including not otherwise specified subtype (20/22) and angioimmunoblastic T-cell lymphoma (7/7), expressed bF1.40 In that study, all cases stained for TCRgd were negative.40 The authors concluded that defective expression of TCRs is a common characteristic of all types of ALCL, which may contribute to the dysregulation of intracellular signalling pathways controlling T-cell activation and survival.40 Furthermore, as the distinction of ALCL from CD30-expressing PTCL might sometimes be challenging, the absence of TCR expression together with expression of cytotoxic markers may allow systemic ALCL to be delineated from CD30 positive PTCL.40 Our findings of low TCR expression rates among GI-ALCL are in line with the report by Bonzheim et al.40 Furthermore, the vast majority of ALCL harbour inframe functional TCRa and TCRb gene rearrangements,41 further suggesting that the absence of TCR expression in ALCL is likely due to deficient synthesis or assembly of TCRa and TCRb chains rather than a genetic defect. Similarly, in type II refractory coeliac disease, a precursor of enteropathyassociated T-cell lymphoma, the intraepithelial lymphocytes are clonal T-cells with aberrant immunophenotype frequently negative for surface CD3 and TCR expression. Tjon et al. have shown that deficient assembly or synthesis of TCRa and TCRb chains is the cause for lack of surface expression of the TCR-CD3 complex in these IELs.42 The limitation of this study is the inherent retrospective nature and small case number. Nonetheless, we characterised the clinicopathological findings of eight additional cases of GI-ALCL. None of these cases were associated with IRF4

Address for correspondence: Shih-Sung Chuang, MD, Department of Pathology, Chi-Mei Medical Center, 901 Chung-Hwa Road, Yong-Kang District, Tainan 710, Taiwan. E-mail: [email protected]

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PRIMARY GASTROINTESTINAL ALCL

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