Non–Hodgkin’s Lymphoma of the Appendix

Infiltration of the appendix as a manifestation of non-hodgkins lymphoma (NHL) at diagnosis or at relapse is a rare finding. We report the history of a patient with gastrointestinal non-hodgkin's lymphoma treated 8 years earlier who presented with symptoms suggestive of acute appendicitis secondary to relapsed NHL.


Introduction
Non-hodgkin's lymphomas (NHL) typically arise in the lymph nodes, spleen, Waldeyer's ring and thymus.However approximately one third are extra-nodal (Zucca et al., 1997(Zucca et al., , 1999)).The gastrointestinal tract is the predominant site of extranodal NHLs, and incidence at this site is increasing (Crump, Gospodarowicz, & Shepherd, 1999).However, infiltration of the appendix as a manifestation of NHL is a rare finding and reports of a relapsed lymphoma of the appendix are even more uncommon.

Case Report
A 61 year old woman was initially diagnosed with gastrointestinal NHL in 2006 after presenting with epigastric pain, dyspepsia and weight loss.She denied any history of coeliac disease.A gastroscopy demonstrated a 4.25cm large ulcer at the angulus of the stomach.Biopsy confirmed a diagnosis of diffuse large B-cell NHL of the stomach.Staging scans and bone marrow aspirate did not reveal any evidence of metastatic disease.She completed six months of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) to complete remission (CR).
Eight years on from her original diagnosis she attended our surveillance outpatient clinic and reported a six month history of dull right iliac fossa pain and flu-like symptoms.She denied any weight loss or night sweats.Physical examination revealed a soft abdomen with tenderness on deep palpation of the right iliac fossa.No mass was palpable and there was no rebound tenderness.There was no evidence of lymphadenopathy.A routine blood panel was unremarkable except for raised LDH (lactate dehydrogenase) levels at 236 units/l (120-220 IU/l) and beta2 microglobulins were elevated at 5.7mg/l (1.2-2.4 mg/l).Anti-TTG (anti-transglutaminase) antibodies were negative at 2.7 u/ml.
A staging CT PET demonstrated increased fluorodeoxyglucose (FDG) uptake at the appendix (SUV max 31) (Figure 1) and mild uptake at the fundus of the stomach.Gastroscopy and biopsies were normal.Colonoscopy showed abnormal swelling of the ileocecal valve however biopsies from this area were also indeterminate.After discussion at a multi-disciplinary meeting (MDM) a decision was made to proceed to an appendectomy.
At surgery it was demonstrated that the appendix had perforated and there was an appendiceal mass adhering to the anterior abdominal wall.Laparoscopy was converted to an open resection with appendectomy and ileocolic resection with side-to-side ileocolic anastomosis.Histology from the surgical specimen demonstrated an atypical lymphoid infiltrate of intermediate to large cells involving the full thickness of the appendiceal wall (Figure 2).Immunohistochemistry was positive for CD45, CD20 and BCL6 and negative for MUM-1, CD10, BCL2 and Cyclin D1.MIB1 proliferation index was 85%.These findings were felt to be consistent with relapsed diffuse large B cell, germinal centre subtype, NHL.Subsequent bone marrow biopsy showed one intratrabecular lymphoid aggregate with increased reticulin suspicious for involvement.After review at a multidisciplinary meeting she was treated with salvage RICE (Rituximab, Ifosfamide, Carboplatin, Etoposide) chemotherapy followed by autologous bone marrow transplant.Her end of treatment day 100 CT PET showed a complete remission (CR) (Figure 3).At her most recent follow up 9 months after CR, there was no evidence of recurrence.

Discussion
The gastrointestinal tract is well established as the most common site of extranodal lymphoma by NHLs.Involvement of the appendix is an exceedingly rare finding and has been described only in isolated case reports (Table 1).To our knowledge, only four cases of recurrent lymphoma in the appendix have been reported in the literature (Tsujimura et al., 2000;Katz, Stein, & Mazzie, 2002;Pickhardt et al., 2002;Chae, Kumar, & Cheema, 2015).The gastrointestinal tract is the most common site of extranodal lymphoma, these account for 4-20% of all primary NHLs and 30-45% of extranodal cases (d'Amore et al., 1994).Table 2 shows the most common sites of GI extra nodal involvement as reported by the two largest studies of GI lymphoma in Greek (128 patients) and German populations (371 patients) (Koch et al., 2001) (Papaxoinos et al., 2006).The appendix, as a site of lymphoma, is so uncommon that it is often omitted in review articles on NHL of the GI tract (Pickhardt et al., 2002;Levine et al., 1997).To our knowledge there has been only one case series on the topic to date and included only five cases (Pickhardt et al., 2002).Rao and Aydinalp (1991) estimated the incidence of primary appendiceal lymphoma at 0.015% of all appendectomy specimens and in one series of 8699 appendectomy specimens by Carpenter (1991), there were 101 neoplasms of which only three were lymphomas.More recently Fu, Wang and Tseng (1994) described in a review of 4458 appendectomy specimens over a 13 year period, only one case was an appendiceal lymphoma.
Table 2. Common sites of involvement (Koch et al., 2001;Papaxoinos et al., 2006) Stomach 68-75% Small bowel (including duodenum) 9% Ileo-cecal region 7% More than one GI site 6-13% Rectum 2% Diffuse colonic involvement 1% Primary appendiceal lymphomas are extremely rare, and relapses in the appendix are even more uncommon.The majority of both primary and relapsed appendiceal lymphomas are non-hodgkin's B-cell lymphomas (Carpenter, 1991).Median age at diagnosis for GI tract NHLs is 55 years (Pickhardt et al., 2002), however appendiceal NHLs do manifest earlier in the second or third decade of life (Carpenter, 1991).The most common presenting symptom is abdominal pain, often localized to the right iliac fossa, and associated nausea and vomiting, mimicking acute appendicitis (Table 1).Rarely they may present with lower GI haemorrhage.Pasquale et al. (1994) identified 46 cases of reported appendiceal lymphoma since 1898, and 31 of these patients presented with acute or subacute right lower quadrant pain, while five were incidentally discovered at appendectomy.Patients with appendiceal lymphoma may also complain of anorexia, weight loss, and a right lower quadrant mass may be present at physical examination (Rao & Aydinalp, 1991).Massive enlargement of the appendix may be present and rarely, may lead to intussusception (Rao & Aydinalp, 1991;Carpenter, 1991).the majority of cases however, clinical findings are often non-specific, thus delaying diagnoses.
As such, the majority of diagnoses are made after surgery, where post-operative histology of the specimen reveals the true diagnosis.Preoperative diagnoses are rare (Pickhardt et al., 2002).On pathological review, diffuse enlargement of the appendix secondary to lymphomatous infiltration is frequently noted, with the average appendiceal diameter measured at 3cm (Pickhardt et al., 2002).That said, the pathogenesis of appendiceal lymphoma remains uncertain, with both intravascular tumour invasion leading to ischaemia of the appendix and subsequent appendicitis or obstruction of the appendiceal lumen leading to appendicitis postulated as mechanisms of promoting dysplasia (Chae, Kumar, & Cheema, 2015).
Reaching the diagnosis radiologically prior to surgery is challenging, and only scant descriptions exist of appendiceal lymphoma revealed on CT (Katz, Stein, & Mazzie, 2002).The five case reports presented by Pickhardt et al. were all retrospectively discovered on CT, three having periappendiceal inflammatory changes (Pickhardt et al., 2002).
Imaging typically shows diffuse enlargement of the appendix in both appendicitis and appendiceal neoplasm, however this may also be misinterpreted as a thickened small bowel loop or an extraintestinal process.A diameter of 6-7mm is well established as the diagnostic threshold for appendicitis on CT and ultrasound, however there is limited data describing the upper limit diameter where infiltrative neoplasms could be considered in the differential (Pickhardt et al., 2002).Inflamed appendices in excess of 15mm are rare (Birnbaum & Wilson, 2000), and imaging from the study by Pickhardt et al., showed diameters greater than 2.5cm (Pickhardt et al., 2002).In that study three of the five patients had associated retroperitoneal or mesenteric adenopathy and of the four patients in whom preoperative CT reports were available, none considered an appendiceal neoplasm prospectively (Pickhardt et al., 2002).
Management of relapsed appendiceal lymphomas is challenging, and there are no clear guidelines due to its rarity.It has previously been postulated that these lymphomas can be successfully treated with an appendectomy, with or without a limited right hemicolectomy (Rao & Aydinalp, 1991).Adjunctive therapy depends on the stage of the disease and the histopathology.Our patient was treated with salvage RICE chemotherapy followed by autologous bone marrow transplant due to her suspicious bone marrow biopsy.
In summary, clinical awareness and suspicion is crucial in achieving the correct diagnosis and initiating treatment.Even without radiological support, physicians should have relapsed lymphoma in their differential when confronted with a patient presenting with GI symptoms, particularly with signs suggestive of appendicitis in those with a background history of lymphoma.

Figure 1 .
Figure 1.Coronal images from PET CT.Markedly abnormal FDG activity (SUV max 31) within the appendix and caecum

Figure 2 .
Figure 2. Diffuse Large B Cell of the Appendix.The appendix wall showed a transmural infiltrate (A) of intermediate to large atypical cells (B).The neoplastic cells were positive for CD45 and CD20, while CD3 and CD5 highlighted a background population of T cells, confirming a Diffuse Large B Cell lymphoma (C).The neoplastic cells stained with BCL6, consistent with germinal centre B-cell like cells (D).MIB1 demonstrated a proliferation index of 85% (C)

Figure 3 .
Figure 3. PET CT coronal image.No evidence of abnormal FDG activity