Background
The specification of non-Hodgkin lymphoma (NHL) in the “WHO Classification 2008” is based on recent progress in immunohistochemical and genetic analysis and clinical findings, including prognostic data [
1]. Among extranodal NHLs, the alimentary tract is the most frequently affected site [
1,
2]. In the small intestine, diffuse large B-cell NHL (DLBCL) is the most common subtype of lymphoma, followed by mucosa-associated lymphoid tissue (MALT) lymphoma in the elderly, while Burkitt’s lymphoma is the predominant childhood NHL. Appendiceal involvement is extremely rare, constituting less than 1% of all small- and large-intestinal NHLs [
2,
3]. About 50 cases of appendiceal NHL have been previously reported, but immunohistochemical and genetic examinations have been performed in only a limited number of recent cases, including two T/natural killer (NK)-cell NHL cases [
2‐
5]. Among intestinal T/NK-cell NHLs, enteropathy-associated T-cell lymphoma (EATL) has been frequently reported in the elderly [
1,
6‐
8]. Type I EATL is a CD4- and CD8-negative and CD30-positive large-cell lymphoma associated with coeliac disease, and is seen in northern Europe and the United States. Type II EATL is a CD56-positive and CD8-positive or -negative medium-sized lymphoma that is less strongly associated with coeliac disease. There are several reports of nasal-type NK-cell lymphomas with Epstein-Barr virus (EBV) infection in intestine and colon, which are usually encountered in the elderly and rarely in children [
7,
9]. The present case is a CD3-, CD4- and TIA1-positive and CD30-negative (Th1) large-cell lymphoma without EBV infection. CD4-positive T/NK-cell lymphoma has occasionally been reported in the stomach, but is rarely seen in the intestine [
10,
11]. The intestinal bacterial florae,
Helicobacter pylori and
Campylobacter jejuni, may be initiators of abnormal lymphocytic proliferation in the stomach and intestine [
12,
13]. Here, we present what is, to the best of our knowledge, the first report of a childhood case of appendiceal CD4-positive T-cell NHL and discuss the influence of
H. pylori infection.
Discussion
A study by Gustafsson et al. of 2,757 appendiceal tumours included 47 NHLs; immunological studies were performed in 11 cases and all were DLBCL. Several cases of appendiceal MALT-type lymphoma, mantle cell lymphoma and Burkitt’s lymphoma have been reported [
17‐
19]. The present case was diagnosed as CD3-, CD4-, CD5-, CD7-, CD25- and TIA1-positive cytotoxic T-cell NHL. In childhood, ALK-positive anaplastic large cell lymphoma is a major type of CD4- and TIA1-positive cytotoxic T/NK-cell lymphoma. In the present case, this diagnosis was unlikely, because there was no expression of CD30, ALK and EMA [
1]. Most intestinal T/NK-cell NHL are EATL, especially in the jejunum. Patients with EATL usually complain of diarrhoea, malnutrition and abdominal pain [
1,
6]. Type I EATL is a CD4- and CD8-negative and CD30-positive large-cell NHL. Type II EATL is a CD4-negative, CD8-positive or -negative and CD56-positive medium-sized NHL [
1,
8,
11]. In addition, EATL expresses CD7 and TIA1, and is negative for CD4, CD5 and CD25. The current patient had no history of recurrent diarrhoea and malnutrition, which are both frequently found in cases of coeliac and Crohn’s diseases. Intraepithelial lymphocytes (IELs), which are typical for EATLs, were not found in the present case. Weiss et al. [
20] reported on a 6-year-old patient with NK cell-like T-cell lymphoma restricted to the jejunum; the tumour cells were positive for CD3 and CD56 and negative for CD4, CD8 and CD30, and there was no EBV infection, similar to type II EATL. Considered together, these findings suggest that our patient’s lesion had clinicopathological and phenotypic characteristics different from those of EATL.
Primary T-cell NHL involving the appendix has previously been reported in two elderly patients. Kitamura et al. [
4] reported on a case of T/NK-cell NHL in an 84-year-old male. In their study, tumour cells expressed CD3, CD8 and granzyme-B, but were negative for EBV infection. Another case was a 45-year-old male who had received a renal transplant 17 years earlier and had subsequently developed CD56-positive nasal-type EBV-positive large T/NK-cell lymphoma [
5]. The two previously reported cases of appendiceal T-cell NHL occurred in adults. Therefore, the authors believe that this is the first reported case of childhood CD4- and TIA-1-positive cytotoxic T-cell lymphoma in the appendix, or, indeed, in the entire gastrointestinal tract.
This patient received cytotoxic treatment and has been in remission for 2 years. Chuang et al. [
7] evaluated 24 cases of primary T-cell NHL and 6 cases of NK-cell NHL in the gastrointestinal tract [
1]. According to their report, using univariate and multivariate COX proportional hazard regression analysis, NK-cell lineage was associated with poor prognosis. EBV infection plays an important role in the progression of various NHLs [
21]. We speculate that the early clinical stage and EBV-free status of the current patient predicted better prognosis. However, this is a single case and the follow-up period was limited. Identification of additional cases of intestinal T/NK-cell NHL and long-term follow-up is necessary in order to fully understand the clinical features of appendiceal T/NK-cell NHL.
In Japan, gastric carcinoma and MALT-type lymphoma have higher incidences compared with those occurring in other regions of the world [
22]. It was strongly suggested that the East Asian CagA gene and protein have a great influence on the tumourigenesis of these two disorders [
14,
15]. Kiriya et al. [
23] demonstrated that the T-cell reaction against the captured, round-shaped
H. pylori seen in dendritic cells of Peyer’s patches in the small intestine plays a critical role in
H. pylori gastritis. CD4-positive T cells, including Th1 and regulatory T cells, are distributed in the gastric mucosa in
H. pylori infection [
24], and cases of primary CD4-, CD5-, CD25- and TIA1-positive cytotoxic T-cell lymphoma have been reported in the stomach [
10]. Among CD4-positive T cells, neoplastic cells of the present case had phenotypic findings regarding TIA1 expression similar to those of Th1 effector cells [
25].
Helicobacter pylori infection might play a role in abnormal proliferation of CD4-positive cytotoxic T (Th1) cells. However, although Küpeli et al. [
26] in Turkey reported that 3 of 15 cases (20%) of childhood systemic NHL had serological
H. pylori infection and that 2 cases were T-cell type ALCL, they suggested that
H. pylori infection was not an agent responsible for lymphomagenesis.
Acknowledgements
The authors thank Dr. Hiroaki Kumazawa, Department of Surgery, and Dr. Hiroshi Kobayashi, Department of Paediatrics, Chidoribashi Hospital, for patient care. Written informed consent was obtained from his family for publication and any accompanying images.
Competing interests
The authors declare that they have no conflicts of interest.
Authors’ contributions
YM carried out initial pathological diagnosis of this case. YM and MT participated in the sequence alignment and drafted the manuscript. Both authors read and approved the final manuscript.