Two secondary localisation of non-Hodgkin’s lymphomas in the upper gastrointestinal tract

Abstract

Extranodal non-Hodgkin’s lymphomas of the gastrointestinal tract represent 30%–40% of all extranodal lymphomas. Gastric lymphomas are increasingly described in the literature due to the development of diagnostic techniques and the increased incidence, together with the reduced incidence of gastric solid neoplasms. Significant diagnostic difficulties are determined by the non-specificity of the symptoms, which are mostly chronic, characterised by a slow progression. Localisation in the small intestine often appears as surgical urgency, due to the development of an intestinal obstruction or enterorrhagia. We present two cases of extranodal diffuse large B-cell lymphoma localisation, presented as a secondary lesion localised in the first one in the stomach, and in the second one in the first duodenal portion.

Background

Extranodal non-Hodgkin’s lymphomas (NHLs) occur in 20%–30% of total cases,^1–3 primarily in the skin, lung, Waldeyer ring and in the gastrointestinal (GI) tract, where they represent 30%–40% of all extranodal lymphomas.^{4 5} The most commonly involved site is the stomach (50%–60%), followed by the small intestine (30%) and colon (10%).⁴ These NHLs of the intestinal tract originate from the mucosa-associated lymphoid tissue (MALT),^{6 7} which may be a normal component of the mucosa in the Peyer’s patches of the terminal ileum or diffusely distributed as lymphoid aggregates in the lamina propria throughout the entire GI tract. Repetitive inflammation in response to chronic antigenic stimulation by Helicobacter pylori and Campylobacter jejuni or autoimmune disorders can lead to monoclonal proliferation and development of extranodal GI lymphomas.^7–9 MALT lymphocytes undergo chronic modifications, similar to those widely described in the lymph nodes. They come into contact with the antigen, with or without the intervention of specialised cells, they continue the maturation process and finally become plasma cells. This process is regulated by receptors present on the surface of lymphoid cells (homing receptors) which interact with organ-specific adhesion molecules located in the venular endothelium. Lymphomas originating from the GI tract reflect the characteristics of the lymphoid tissue at this site; they justify the different morphological and clinical behaviours compared with nodal NHL. In fact, MALT cells are considered stationary elements, similar to those located in the marginal zone of the spleen. The origin of GI lymphomas’ cells could explain the tendency of this disease to remain localised even for a long time. Gastric lymphomas, despite their rarity, are increasingly described in literature due to the development of diagnostic techniques, the absolute and relatively increased incidence, and the reduced incidence of gastric solid neoplasms reported in recent years. Significant diagnostic difficulties are determined by the non-specificity of the symptoms, which are mostly chronic, characterised by a slow progression and an overlap with the symptomatology from peptic ulcer or gastric carcinoma. Conversely, localisation in the small intestine often appears as surgical urgency, due to the development of an intestinal obstruction or an enterorrhagia.

The radiological and endoscopic appearance of the lesions is not typical, even if it is often described as an increase in the thickness of the gastric wall (more or less localised to a plicar hypertrophy), with peristalsis and transit longer preserved compared with an adenocarcinoma. An endoscopic biopsy can safely diagnose gastric NHL in a limited number of cases, due to the difficulty of reaching the right depth; moreover, the samples must be multiple because the disease is often multifocal.

We present two cases of extranodal diffuse large B-cell lymphoma (DLBCL) localisation, presented as a secondary lesion localised in one case in the stomach, and in the second one in the first duodenal portion. We found only one study in the literature of T-cell leukaemia/lymphoma with gastric involvement.¹⁰ According to Yang et al,¹¹ the most common extranodal NHL localisation is represented by the GI tract, but in the literature we have not found any article. Follicular lymphoma is mostly found in the duodenum, so it represents a separate disease entity.¹² Herein, we describe two peculiar cases with secondary NHL localisation in the upper GI tract.

Case presentation

The patients did not present with clinical symptoms such as gastric pain or heartburn, and only one case showed modest signs of dyspepsia. They had no weight loss, there was no anaemia due to GI bleeding and there was no evidence of concomitant gastric epithelial neoplasms.

First case presentation

The first patient, a man in his 60s, presented with bilateral adrenal enlargement and retroperitoneal enlarged lymph nodes; he underwent an adrenal biopsy and was diagnosed with DLBCL germinal-centre type. He received rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine) and prednisone (R-CHOP) as a front-line regimen and achieved a partial Rrsponse(PR) after the fourth cycle. At final restaging after six cycles, a CT scan and F-fluoro-2-deoxyglucose (18FDG) positron emission tomography (PET) were performed and showed bilateral adrenal disease persistence. The patient started rituximab, oxaliplatin and cytarabine as a second-line regimen.

Investigations

A computed tomography (CT) scan performed after two cycles (figure 1) showed disease progression, with an increase of pathological lymphoid tissue starting from the left adrenal gland and infiltrating both the ipsilateral diaphragmatic pillar and gastric wall with sealed gastric perforation.

Figure 1.

Computed tomography (CT) view of lymphoid tissue starting from the left adrenal gland and infiltrating both the ipsilateral diaphragmatic pillar and gastric wall, with sealed gastric perforation.

Treatment

Due to the risk of perforation, after a multidisciplinary discussion involving surgeons and haematologists, a third-line therapy was considered. The rationale behind continuing with a further line of chemotherapy despite a suspected gastric perforation was that the perforation radiologically appeared sealed. In this case, the pathological process had progressed in a non-acute way, and allowed the formation of inflammatory adhesions between the segment involved by NHL and the neighbouring organs, in a way that ensures the covering of the perforation, without the enteric content leaking into the peritoneal cavity. In the absence of an overt gastric perforation as shown in the CT scan image in figure 1, gastrectomy was not considered a priority and no surgical procedures were performed before hospitalisation, due to the elevated surgical risk in this patient, who did not present with clinical symptoms. Moreover, gastrectomy is not therapeutic for lymphoma and major surgery would have delayed by at least 1 month from the start of chemotherapy in a patient in need of urgent treatment. Indeed, the patient was hospitalised and received the first day of an IVAC regimen (ifosfamide, etoposide and high-dose cytarabine); all the specialists involved in the therapeutic process were alerted. During the first day of the IVAC regimen, about 3 hours after the infusion, the patient showed clinical signs of an acute abdomen due to an overt gastric perforation, so he underwent an emergency total gastrectomy.

Outcome and follow-up

Macroscopic description showed an ulcerated neoplasm of the stomach, 80×50 mm in size, located in the proximal third, bottom of the body, posterior wall, small curve, anterior wall and 10 mm distant from the oesophageal surgical margin and 140 mm from the duodenum.

Histological features showed a diffuse proliferation of large cells with centroblasts/immunoblasts morphology extended to the entire gastric wall, adipose tissue and in two local regional lymph nodes; moreover, subserosal vascular neoplastic infiltration was evident. The neoplastic cells were positive for CD20, CD10, BCL6, BCL2, MYC with high proliferation index Ki67 >90% and negative for T-cell markers and Epstein-Barr virus-encoded small RNA (EBER). Fluorescence in situ hybridization (FISH) analysis did not show rearrangements of BCL2, BCL6 and MYC genes. The final diagnosis was DLBCL, not otherwise specified (NOS), germinal-centre type with double expression of MYC and BCL2 proteins.

The patient died on postoperative day 4, due to septic complications.

Second case presentation

The second case was a man in his 50s, who presented with left testicular painful enlargement and was diagnosed with anaplastic large cell lymphoma (ALCL) (figure 2), ALK-negative after left orchiectomy. On baseline CT scan, multiple supradiaphragmatic and subdiaphragmatic enlarged lymph nodes, hepatic, pulmonary and bone localisation were observed, with a lytic lesion on the right sixth rib. The patient received treatment with cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), prednisone and etoposide regimen. After two cycles, a reduction of the disease burden by more than 60% was reported, thus he received two more cycles. After the fourth cycle, repeated CT and 18F-FDG PET were performed, which showed further reduction of nodal and hepatic localisation, as well as the persistence of skeletal disease and diffuse gastroduodenal hyperaccumulation not present at baseline, with a Deauville score of 5. The patient received brentuximab vedotin every 3 weeks as second-line treatment.

Figure 2.

Anaplastic large cell lymphoma microscopic view: the neoplastic lymphoid cells are characterised by predominant population of small-to-medium-sized neoplastic cells with irregular nuclei. Hallmark cells are present, which are identified for their kidney or horseshoe-shaped nuclei (black arrow) (H&E-OM-32×).

Investigations

After the third cycle, the CT scan (figure 3) and 18F-FDG PET demonstrated a further nodal disease reduction and the appearance of a new bulbar duodenal lesion. An endoscopic evaluation was performed and showed a wide, infiltrating and ulcerating duodenal lesion. The biopsy examination confirmed the diagnosis of T-cell lymphoma.

Figure 3.

Computed tomography (CT) view of bulbar duodenal anaplastic large cell lymphoma.

Treatment

The patient underwent partial gastrectomy with a large resection of the duodenum, extended to 1 cm above the papilla (figure 4). Macroscopic description stated: duodenal tumour with a large base vegetated and ulcerated in the centre, size 45×40 mm; the surrounding mucosa had a slightly raised trabecular appearance with loss of the normal plicar pattern.

Figure 4.

Macroscopic view of duodenal lymphoma.

Outcome and follow-up

Microscopically, almost all layers of the intestinal wall were infiltrated by pleomorphic tumour cells with diffuse and cohesive growth pattern. The neoplastic cells were mainly medium to large size with moderate basophilic cytoplasm. Most of them had hyperchromatic nuclei and prominent nucleoli. ‘Hallmark’ cells were easily detected. Immunohistochemically, tumour cells were characterised by CD30, CD3, CD4, CD2, CD5, TIA-1, granzyme B-positive staining, and CD7, CD8, CD20, CD79a, ALK-negative staining with Ki67 of 80% (figure 5). The EBER genome was also negative. A diagnosis of ALCL ALK-negative was finally made. After the surgery, the patient was referred to haematology for medical therapy.

Figure 5.

Anaplastic large cell lymphoma microscopic view: all malignant cells are positive for CD30 on the cell membrane and the Golgi region (immunostain-OM-32×).

Discussion

We have described two cases of relapsed/refractory NHLs with unusual upper GI localisation. According to several studies, the incidence of gastric lymphomas is continuously increasing. It is difficult to demonstrate whether the increase in incidence is real or simply due to an improvement in diagnostic techniques.¹³ Outdated studies have shown that in the past, malignancies such as gastric lymphomas were actually labelled as adenocarcinomas. However, in recent years, a continuous increase in the number of lymphomas of all types has been registered, while in the last 15 years, there has been a continuous decrease in epithelial tumours of the stomach. The symptomatology of lymphomas is certainly not effective for diagnosis, since it is, even in our case series, completely non-specific, simulating other types of pathology affecting the digestive system. Food transit was also absolutely preserved in both cases. A CT scan of the abdomen was suggestive, demonstrating in the first case a sealed gastric perforation and subsequently after some days the perforation of the posterior wall. In the second case, the CT scan showed that the ALCL had been localised in the first duodenal portion and that the lower part of the neoplasm was facing the papilla of Vater.

DLBCL GI relapse, although uncommon, could represent a feared complication in the disease course. Conversely, to our knowledge, no cases of duodenal localisation of ALCL at relapse have been reported to date and this issue represents the novelty of our report. We have only found few reports of upper GI ALCL localisation at diagnosis, including two cases of primary small intestinal ALCL successfully treated with cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine) and prednisone (standard CHOP regimen), a case misdiagnosed as an intramural haematoma in a teenage girl.^14–16 In a published series more than 20 years ago, four cases presented with baseline involvement of jejunum (one case), contiguous involvement of distal duodenum and jejunum (two cases) and distal duodenum (one case).¹⁷

Endoscopic samples can be negative in a considerable percentage of cases. This may be due to the difficulty in performing samples on a lesion that emerges on the mucosa in a late stage and/or in relatively small areas. In our report, the endoscopic diagnosis was confirmed in both cases. We remark that intraoperative macroscopic findings can mimic an epithelial form.¹⁸ However, even the diagnosis of certainty offers considerable doubts to the surgeon regarding the surgical indication. In fact, even if in the first case we were confident because perforation was demonstrated, in the second case we had the doubt, seeing the CT images that the adjuvant therapy for ALCL could cause a perforation of the first duodenal portion and then an emergency intervention could have been fatal. We also took into consideration that despite the high degree of malignancy, these lesions have a relatively benign clinical course. Medical therapy strongly reduces the lesion and sometimes permits to achieve complete remission. Undoubtedly, follow-up conducted on these patients will indicate strategies to be followed in the future.^{13 19} Surgery is not the first therapeutic approach^19–21 but certainly remains the treatment of choice when complications arise before or during adjuvant therapy for lymphomas localised in the digestive system.

Learning points.

• The first patient had the first localisation at retroperitoneal level and therefore reached the gastric wall by contiguity.

• In the second case, the primitive diagnosis was made on the testicle with the reduction of nodal disease after chemotherapy but subsequent localisation on the first duodenal portion, not involved at diagnosis.

• Surgery is not the first therapeutic approach but certainly remains the treatment of choice when complications arise before or during adjuvant therapy for lymphomas localised in the digestive system.

Ethics statements

Patient consent for publication

Next of kin consent obtained.