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Concurrent low grade B-cell non-Hodgkin’s lymphoma of malt type arising in the large intestine, small intestine and stomach
J. Venizelos, D. Tamiolakis, S. Nikolaidou, M. Lambropoulou, G. Alexiadis, N. Papadopoulos (Chirurgia, 102 (1): 99-101)

Introduction
Mucosa associated lymphoid tissue derived lymphoma (MALT lymphoma), first described in 1983 by Isaacson and Wright (1, 2), was recognized only in 1994 as a distinct entity of lymphoma in the revised European-American lymphoma (REAL) classification among the marginal zone B-lymphomas (2), as well as in the most recent classification proposed by the World Health Organization (WHO) (2). Histologically MALT lymphomas are characterized by a proliferation of neoplastic marginal-zone related cells that invade epithelial structures and form characteristic lymphoepithelial lesions. MALT lymphomas are the most common subset of the extranodal lymphomas. They arise not only from the stomach but also from various nongastrointestinal sites, such as salivary gland, conjuctiva, thyroid, orbit, lung, breast, kidney, skin, liver and prostate (2). The origin of MALT lymphoma is an accumulation of autoreactive lymphoid tissue generated by either chronic inflammatory disorders or auto-immune disease such as Helicobacter-Pylori infection of the stomach, Hashimoto thyroiditis, or myoepithelial sialoadenitis of the salivary gland (Sjogren syndrome) (2). This lymphoid tissue becomes genetically unstable with the acquisition of abnormalities such as translocations t11;18 and t1;14, trisomy 3, c-myc (8q24), and p53 (17p13) mutations leading to transformation into MALT lymphoma. MALT lymphomas are low grade lymphomas and histologic progression from a low grade MALT to a high grade lesion is rare, occurring in <10% of the cases and is associated with other genetic events such as p16 or p53 inactivation (2). Clinically MALT lymphomas behave as an indolent disease with a prolonged clinical course. Patients have a good outcome with a long disease-free survival and long overall survival. Several explanations for this indolence have been given, and the most frequently cited reasons are that these lymphomas are believed not to dissemi-nate as often as their nodal equivalents, and then they often remain localized for long periods.
We describe a patient presenting with a disseminated disease at diagnosis. This observation of early dissemination of the disease led us to believe that at diagnosis, MALT lymphoma should be considered a multifocal disease. This has been reported in patients with apparently localized gastric MALT lymphomas who presented with colonic dissemination diagnosed with colonic biopsies (2).
Case report
A 70 year-old woman was admitted to our Hospital because recently her stools were mixed with blood. On clinical examination, her liver, spleen and peripheral lymph nodes were not palpable. All blood tests and CT scans were normal. A colonoscopy was performed up to 100 cm and a thickened wall of the transverse colon was found. The biopsy material received from this area showed histological features of diffuse, low grade NHL of the colon. Bone morrow biopsy showed infiltration by the lymphoma cells. Two months later, while the patient was under chemotherapy, a second colonoscopy was performed up to the small intestine and revealed few nodular areas in the mucosa of the terminal ileum. Histolo-gical examination of the biopsy material received from these areas showed infiltration of the mucosa and submucosa by a NHL with similar morphological and immunological features. Two months later a gastroscopy was performed because of epigastric discomfort. The gastric mucosa was found edematous and focally nodular. Biopsies were taken from the body and the antrum. Histology disclosed a NHL, again with similar morphological and immunological features. After 6 cycles of chemotherapy with COP the patient remains in a good general condition, 14 months after the initial diagnosis.
Histological findings
The biopsy material received from the large intestine, small intestine and stomach included tissue samples from the mucosa and the submucosa. There was a diffuse infiltrate of the lamina propria and the submucosa mainly by small lymphocytes and centrocyte-like cells (Fig. 3). Plasma cell differentiation was noted focally in the superficial aspect of the lamina propria. Occasional lymphoepithelial lesions were indentified (Fig. 2). Immunohistologically tumor cells were positive for LCA, L-26 and negative for UCHL-1, cyclin D1 and mix keratin. l-light chain restriction was found in all biopsy material. Cresyl-Violet stain confirmed the presence of Helicobacter Pylori in the gastric mucosa seen within the gland by Hematoxylin-Eosin stain (Fig. 1).

Figure 1
Figure 2
Figure 3

Discussion
Our case as others described in the literature illustrate the propensity of MALT lymphomas to "home" to different mucosal sites of the gastrointestinal tract at the same time (2-9). It has been described that the intestinal lesions are secondary to the gastric lesions whereas molecular studies in other references show the development of sequential MALT lymphomas from a single clone by the demonstration of an identical immunoglobulin heavy chain gene rearrangement by the polymerase chain reaction (7, 8). Several important properties of B-cell lymphomas can now be studied by analysis of the rearranged Ig gene. Firstly, disseminated lesions and residual disease can be identified by examination of the unique complementarity determining region (CDR) 3 sequence (7, 8). Secondly, the developmental stage (relation to the germinal center reaction) of lymphoma precursor cells can be deduced by analysis of somatic mutations of the variable (VH) region. Thirdly, because somatic mutations may accumulate in the Ig gene during lymphoma development, examination of mutation patterns among different lesions of a lymphoma can be used to delineate its sequential development (7, 8). Finally the role of antigen stimulation in lymphoma growth can be assessed by analysis of ongoing Ig mutations which are the characteristic feature of B cells in persistent response to direct antigen stimulation normally in a germinal center environment.
Du et al (7) have studied six cases of concurrent gastric and intestinal MALT lymphomas by polymerase chain reaction (PCR) amplification, cloning, and sequencing of the rearranged I g gene, a strategy that has been widely used for analysisof clonality and antigen-driven properties of B - cell malignancies. In each case, an identical or nearly identical complementarity determining region 3 sequence was observed between the dominant clones of concurrent gastric and intestinal MALT lymphomas. In four of six cases examined sufficient Ig variable region sequence information was obtained to permit analysis of somatic mutations. The mutation patterns in one case suggested that the intestinal lesion is secondary to the gastric tumor, and the mutation patterns in two cases indicated that the gastric and intestinal lesions are derived from different tumor subclones, which emerge after expansion of a common early tumor clone. Furthermore 3 of 4 cases showed ongoing Ig mutations among different PCR clones at each site. Their results showed that concurrent gastric and intestinal lesions result from dissenination of gastric tumor. Antigen stimulation may play a role in tumor evolution at an early stage, showing both positive and negative selection features. This is consistent with the frequent observation of follicular colonization of lymphoid follicles by MALT lymphoma cells, which indicates access to germinal center environment. This speculation is also supported by the observation that the growth of low grade MALT lymphoma cells in vitro responds to the stimulation by antibodies against the tumor idiotype. However unlike low grade tumors, high grade lesions do not show ongoing mutations.
In conclusion, in a case of MALT lymphoma in any site of the gastrointestinal tract a thorough examination in the rest of the tract might reveal the presence of another MALT lymphoma.

References
1. Isaacson, P.G., Spencer, J., Finn, T. - Primary B-cell gastric lymphoma. Hum. Pathol., 1986, 17:72.
2. Thieblemont, C., Berger, F., Dumontet, C., Moulet, I., Bonafia, F., Felman, P., Saller, G., Coiffier, B. - Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood, 2000, 95:802.
3. Hall, P.A., Levisan, D.A. - Malignant lymphoma in the gastrointestinal tract. Semin. Diagn. Pathol., 1991, 8:163.
4. Hwang, W.S., Vao, J.C., Cheng, S.S., Tseng, H.H.- Primary colorectal lymphoma in Taiwan. Cancer, 1992, 70:575.
5. Donizio, P., Owen, R.A., Shepherg, N.A., Talbot, I.C., Norton, A.J. - Primary lymphoma of the small intestine. A clinicopathological study of 119 cases. Am. J. Surg. Pathol., 1993, 17:429.
6. Isaacson, P.G. - Gastrointestinal lymhoma. Hum. Pathol., 1994, 25:1020.
7. Du, M.Q., Diss, T.C., Peng, H.Z., Wotherspoon, A.C., Isaacson, P.G. - Intestinal dissemination of gastric mucosa-associated lymphoid tissue lymphoma. Blood, 1996, 88:4445.
8. Sterhen, M.R., Farquharson, M.A., Sharp, R.A., Jackson, R. - Sequential malt lymphomas of the stomach, small intestine and gall bladder. J. Clin. Pathol., 1998, 51:77.
9. Fung, C.Y., Grossbard, M.L., Linggood, R.M., Younger, J., Flieder, A., harris, N.L., Graeme-Cook, F. - Mucosa-associated lymphoid tissue lymphoma of the stomach. Cancer, 1999, 85:9.


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