Appendiceal MALT Lymphoma in Childhood – Presentation and Evolution

Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was first described by Isaacson et al. in 1983 (Isaacson & Wright, 1984). According to the WHO lymphoma classification, the indolent B cell lymphoma of MALT type is classified as a marginal zone lymphoma, thus called because it originates from the B lymphocytes normally present in a distinct anatomical location (marginal zone) of the secondary lymphoid follicles (Harris et al., 2001). MALT lymphomas comprise up to 40% of adult non-Hodgkin lymphomas (NHL); the median age at occurrence is 60 years, with a female predominance (Anonymous, 1997). In paediatric age MALT lymphomas are very rare. We report on a case of MALT lymphoma involving the appendix in a 6-year-old immunocompetent girl and its evolution toward an inflammatory bowel disease (IBD) at a middle-term follow-up.


Introduction
Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was first described by Isaacson et al. in 1983(Isaacson & Wright, 1984).According to the WHO lymphoma classification, the indolent B cell lymphoma of MALT type is classified as a marginal zone lymphoma, thus called because it originates from the B lymphocytes normally present in a distinct anatomical location (marginal zone) of the secondary lymphoid follicles (Harris et al., 2001).MALT lymphomas comprise up to 40% of adult non-Hodgkin lymphomas (NHL); the median age at occurrence is 60 years, with a female predominance (Anonymous, 1997).In paediatric age MALT lymphomas are very rare.We report on a case of MALT lymphoma involving the appendix in a 6-year-old immunocompetent girl and its evolution toward an inflammatory bowel disease (IBD) at a middle-term follow-up.

Case report
P.A., a 6-year-old girl, was referred to our institution in May 2005 with a diagnosis of appendicitis.The girl had been complaining of right lower abdominal pain for 6 months.More recently, the pain was exacerbated by walking and coughing.Abdominal ultrasound showed a slight effusion of the pelvic fossa.Her postnatal history showed some period of constipation spaced by regular daily evacuations.Blood examinations showed neutrophil leucocytosis.The patient underwent laparoscopic appendectomy using the three-trocar technique, three endo-loops and the Liga-Sure for the hemostasis.During the laparoscopic exploration no hyperplastic mesenteric lymphnode was found.The appendix appeared moderately hyperemic with a slight enlargement of two-thirds of its distal portion (Fig. 1).
The postoperative course was uneventful and the girl was discharged on day 1, without any complications.The appendix underwent a routine histological examination.The morphological appearance showed thickened lamina propria and submucosa, which were occupied by pseudonodules of immunocompetent cells (Fig. 2), characterized by lymphocytes with small nuclei with a narrow cytoplasmic rim and plasma cell (Fig. 3).Immunohistochemical studies revealed positivity for CD20 (CD20, pan B cell), and   negativity for CD5 (CD5, Pan T cell, and B cell subsets) and CD10 using monoclonal antibodies, and positivity for anti-k (immunoglobulin light chain) using polyclonal antibodies, in addition to a low positivity to Ki-67 (proliferation-associated marker).Extensive further examination revealed that the lymphoma was restricted to the distal portion of the appendix (stage IA) and was not associated with any specific infection.
Abdominal MRI, OGDS, and capsule endoscopy of the ileum were all negative; the search for H. pylori was also negative.No chemotherapy was performed.After a 15-months followup, the patient was doing well (Marte et al., 2008).Calprotectin and clinical evaluation were repeated yearly showing no problem and the patient was asymptomatic.3 year after, the yearly follow-up showed a slight increase of fecal calprotectin values (40µg/g) with recurrent abdominal pain and occasional episodes of diarrhea.The girl underwent a new clinical evaluation, small bowel radiological contrast study, videocapsule, OGDS, and colonoscopic examination.No fever or weight loss was present; erythrocyte sedimentation rate, C-reactive protein level were slightly higher.Perinuclear antineutrophil cytoplasmatic antibodies (pANCA) and Anti-Saccharomyces c e r e v i s i a e ( A S C A ) a n t i b o d i e s a r e n o t increased too.
The small bowel x-ray contrast, OGDS and videocapsule study demonstrated no abnormalities.Colon biopsies revealed a mild nonspecific IBD extending till 90 cm from the anal verge.(Fig. 4,5,6,7)     A 6 weeks cycle of Mesalazine (5ASA), 2gr/day was administered to the patient obtaining the induction of remission and then repeated every 2 months for the prevention of recurrences.At present the patient is doing well and a strict clinical serologic follow-up with calprotectin, P-Anca and ASCA is scheduled every 6 months and, yearly, colonoscopy.

Discussion
Current knowledge of MALT lymphoma is largely based upon studies in adults.MALT lymphoma is rare in children; the available evidence consists mostly of isolated case reports, except for one series of ten cases (Corr et al., 1997), and another including a total of 48 cases (children and young adults) (Taddesse-Heath et al., 1997) and a pediatric NHL trial recruiting children and adolescents from Germany, Austria and Switzerland (Kaatsch et al., 2004).MALT often develops within the context of a pre-existing inflammatory response due to infection or to autoimmune disorder.Many studies show the relationship between H. pylori infection and gastric MALT lymphoma (Isaacson & Whright, 1984;Kurugoglu et al., 2002); some authors have reported a regression of MALT lymphoma in parotid gland (Alkan et al., 1996), lip gland (Berrebi et al., 1998), small intestine (Fischbach et al., 1997) andrectum (Matsudo et al., 1997) following H. pylori eradication.Other risk factors for MALT lymphoma include autoimmune diseases like Hashimoto thyroiditis or Sjogren syndrome, and Borrelia burgdorferi for skin lymphoma.A further prerequisite for the development of MALT lymphoma in children may be the presence of HIV infection (Teruya-Feldestein et al., 1995;Mo et al., 2004).In some patients no risk factors can be identified.The most common sites are the stomach and salivary glands.Others sites are: ocular adnexa, the lungs, thyroid and the skin (Zucca et al., 2000).Some retrospective analyses of histopathological results of appendectomy specimens performed for acute appendicitis in a large sample of patients, including children, report a prevalence of appendiceal malignant tumors ranging from 0.4 (Tchana et al., 2006) to 1.5% (Ravi et al., 2006).Among the malignant tumors, carcinoids have the highest incidence (Tchana et al., 2006;Ravi et al., 2006) and 70-90% of these tumors are discovered incidentally because they are usually restricted to the distal appendix (Akerstrom, 1989;Aranha & Greenle, 1980).From a review of the literature we found only one case of appendix lymphoma in paediatric age presenting with intussusception symptoms (Karabulut et al., 2005).Our report probably represents the first case of MALT lymphoma of the appendix found accidentally in a child during an appendectomy.MALT lymphomas manifest with aspecific symptoms.In our case, the clinical presentation was characterized by recurrent abdominal pain, and the only element of suspicion was the enlargement of the distal portion of the appendix.The subsequent evolution to a mild form of IBD could be considered as an evolution of the appendiceal malt-limphoma for which the phenomenon should be considered a prodromal presentation of a more extensive bowel disease which require a close follow-up and specific therapy (Aomatsu et al., 2011).Otherwise we can't exclude that the subsequent IBD could be an autonomous, subsequent disease considered that, also in this case, there are no data in the Literature.Furthermore, given the previous appendiceal malt-lymphoma, the efficacy of mesalazine alone, without the use of immunosuppressive drugs, can be considered a very favorable factor in our case.In conclusion, even if the occurrence of malignant appendiceal pathology in children is rare (Setty & Termuhlen, 2010), the probability that it is asymptomatic is very high.According to our experience, our case suggests that histological examination should always be performed following appendectomy in children and that if a MALT lymphoma were discovered, a close follow-up is strongly recommended, not only for the MALT lymphoma recurrence but also for its possible evolution towards an inflammatory bowel disease.

Fig. 2 .
Fig. 2. Hematoxylin-eosin staining.The wall of appendix is thickened, and occupied by a compact nodular formation.The serous and muscular tunic appear thin.

Fig. 3 .
Fig. 3. Hematoxylin-eosin staining.Hyperdense lymphocytic population with small nuclei and narrow cytoplasmic rim and some plasmacytoid and monocytoid elements with great and hyperchromatic nuclei.