Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma associated with coeliac disease

Abstract

Pulmonary mucosa-associated lymphoid tissue (pMALT) lymphomas are rare, representing <1% of lung malignancies. An association between pMALT and autoimmune conditions has been described, but there is a paucity of documented cases linked to coeliac disease. We present the case of a patient with a history of coeliac disease who presented with weight loss but no respiratory symptoms. CT revealed diffuse endobronchial opacities with associated bronchial dilation and pulmonary nodules. Bronchoscopy confirmed widespread polypoid endobronchial lesions. Histology demonstrated diffuse lymphoid infiltrate which stained positive for CD20. Clonality studies confirmed low grade B cell MALT lymphoma. She was treated with anti CD20 monoclonal antibody, rituximab. Prognosis of pMALT is good with 5-year survival >80%. Thus, an index of suspicion and early detection are vital. This case highlights that pMALT should be considered in patients with non-specific symptoms and coeliac disease. Bronchoscopy is a valuable diagnostic tool to be used in these cases.

Case presentation

Our case is a woman in her 70s, never smoker, with a 35-year history of stable coeliac disease and strict adherence to a gluten-free diet. Her past medical history is remarkable only for a localised squamous cell carcinoma of the forehead, successfully treated with surgical resection and adjuvant radiotherapy. She is not on any regular medications and has no known allergies. Of note, her sister has been treated for non-Hodgkin’s lymphoma and her brother underwent surgical resection of a benign intracardial tumour.

While attending a routine gastroenterology outpatient review, she reported unintentional weight loss of 6 kg over a 6-month period. There was no associated change in bowel habit, no respiratory symptoms and no B symptoms such as night sweats. On clinical examination there were no palpable lymph nodes, no hepatosplenomegaly, no masses or clubbing.

Investigations

Laboratory investigations were unremarkable; haemoglobin 13.9 g/L, platelet count 373×10^9/L, white cell count 4.6×10^9/L with normal differentiation, creatinine 69 umol/L, total protein 78 g/L, albumin 45 g/L, total bilirubin 5 umol/L, alanine transaminase 13 IU/L, alkaline phosphatase 107 IU/L, gamma-glutamyl transferase 19 IU/L, vitamin B₁₂ 544 pg/mL, folate 4.9 ng/mL, iron 13 μmol/L, ferritin 90 ug/L, IgG 11.33 g/L, IgA 2.07 g/L, IgM 1.02 g/L, thyroid function tests were within normal range, quantiferon negative, serum protein electrophoresis no paraprotein detected, tissue transglutaminase <7 U/mL. She had mildly elevated rheumatoid factor, however was assessed by a rheumatologist who felt she had no clinical features of a primary connective tissue disease.

A CT scan of her thorax, abdomen and pelvis was arranged which demonstrated ground glass changes adjacent to the right horizontal fissure favoured to be infectious or inflammatory in nature and multifocal pulmonary nodules, the largest 1.4 cm, in the right middle lobe. Repeat imaging to ensure stability of the nodules was advised.

A repeat CT thorax 3 months later showed stability of the previously noted pulmonary nodules. However, CT also demonstrated new foci of extensive endobronchial opacification with associated bronchial dilation, most prominent in the lateral segment of the right middle lobe (figure 1). She was referred for a respiratory opinion and flexible bronchoscopy was arranged.

Figure 1.

Endobronchial opacification within the right middle lobe.

Direct visualisation of the airways at bronchoscopy showed diffuse flesh-coloured polypoid endobronchial lesions throughout the segments of the right upper and middle lobes (figure 2), and samples were taken via bronchoalveolar lavage and endobronchial biopsy. Culture of the bronchial lavage was of normal respiratory flora, negative for mycobacterium and cytology of the fluid did not identify malignant cells. Histology of the biopsy samples confirmed a mixed population of CD3+ T lymphocytes and CD20+ B lymphocytes, but no malignant cells were identified. Congo red stain on the biopsy samples was negative, ruling out pulmonary amyloid.

Figure 2.

Endobronchial polypoid mucosa within the right middle lobe.

The case was discussed at a multidisciplinary meeting (MDM) and the recommendation was to refer for positron emission tomography-CT (PET-CT) and for large bore surgical bronchoscopy, with a view to obtaining larger tissue samples.

PET-CT reported multiple bilateral 18F-2-fluoro-D-glucose avid lung nodules, including a spiculated nodule in the right middle lobe now measuring 2.2 cm. It also commented on further areas of increased tracer uptake associated with segmental bronchi and known endobronchial filling defects (figure 3).

Figure 3.

PET CT demonstrating 18F-2-fluoro-D-glucose (FDG) avidity associated with segmental bronchi and endoluminal filling defects (right upper lobe and left lower lobe).

Biopsies obtained from bronchoscopy demonstrated bronchial mucosa with a dense lymphoid infiltrate which stained positive for CD20.Mixed CD3 and CD5 T cells were present (figure 4). The samples stained negative for CD23, cyclin D1 and CD10 and K167 expression was 20%, consistent with a low grade B cell MALT lymphoma. Clonality studies were subsequently done on the tissue samples. They detected a clonal immunoglobulin gene rearrangement within the sample; however, the presence of t(14;18) BCL2-JH translocation was not identified which rules out follicular lymphoma. The material was insufficient to test for t(11;18) translocation or for fluorescence in situ hybridisation (FISH) analysis. The final report by the pathologist was of a low-grade B cell MALT lymphoma.

Figure 4.

(A) Bronchial biopsy (H&E, ×12.5 magnification). (B) Higher power view of bronchial epithelium (arrows) partly denuded (H&E, ×100 magnification). (C) High power view of atypical lymphoid infiltrate, with large nuclei (H&E, ×400 magnification). (D) Immunostaining for CD20, B cell marker (×400 magnification). (E) Immunostaining for CD3, T cell marker (×400 magnification). (F) Immunostaining for CD5, T cell marker (×400 magnification). (G) Immunostaining for KI67, marker of cell cycle, estimated at 20%.

Pulmonary function tests including spirometry, flow volume loop, lung volumes and gas transfer were normal. The case was rediscussed at the respiratory MDM and the recommendation was to refer to haematology. She was seen by haematology and underwent a bone marrow aspirate and biopsy which was normal indicating no bone marrow involvement.

Treatment

On completion of all necessary investigations, haematology elected to commence single agent rituximab.

Outcome and follow-up

She is tolerating treatment well with no reported side effects. She remains active and at work. She is due to undergo a surveillance CT thorax abdomen and pelvis in 3 months to assess for interval response to treatment. She remains under close follow-up by respiratory and haematology.

Discussion

Primary pulmonary lymphomas (PPLs) are rare clinical entities, representing <1% of lung malignancies. However, MALT lymphomas account for 80% of PPL cases.¹ The age of onset is typically in the fifth or sixth decade, with no gender predominance. Smoking does not appear to be an independent risk factor for development of PPL compared with the general population.² The aetiology of pMALT lymphoma remains elusive but is thought to include cytogenetic abnormalities which promote MALT lymphomas, particularly translocations.³ Chronic infection is also hypothesised to play a role in the development of MALT lymphomas, with causal relationships between pathogen and disease described in extrapulmonary MALT lymphomas such as the relationship between Helicobacter pylori and gastric MALT lymphoma.⁴ However, a causative agent has not yet been identified in the lungs. Chronic antigen stimulation of autoimmune origin is further hypothesised as a predisposing risk factor for developing MALT lymphoma, with 16% of patients with pMALT lymphoma having a concurrent diagnosis of an autoimmune disease at the time of diagnosis. The most commonly described immune disorders include Sjogren’s syndrome, Hashimoto’s thyroiditis and systemic lupus erythematous.² There is a paucity of literature describing coeliac disease associated with pMALT lymphoma.

pMALT lymphoma is usually indolent with approximately half of patients remaining asymptomatic, as in our patient. Symptoms when present are usually non-specific and can include cough, exertional dyspnoea, chest pain and haemoptysis.¹ The radiological features vary widely, with the disease often multifocal (70%–77% of cases) as in our case, and bilateral (60%–70% of cases). The most commonly reported findings are consolidation (55%), a lung nodule (55%), lung masses (50%) or air bronchograms (85%).⁵ Histological analysis is the gold standard for diagnosis, with pulmonary samples obtained via bronchoscopy or CT-guided biopsy where possible. Surgical interventions are reserved for cases where minimally invasive strategies fail to obtain adequate sampling. Macroscopic findings on bronchoscopy are normal in the majority of cases, but the polypoid endobronchial lesions, as described in our case, are very rare.⁶ Flexible endobronchial tissue sampling and diagnosis can be challenging with the sensitivity of bronchial and transbronchial biopsies in detecting MALT lymphoma between 30% and 90%.² Large bore surgical bronchoscopy (sometimes referred to as rigid bronchoscopy) allows for larger volume tissue sampling and definitive management of potential airway complications such as haemorrage. It is typically performed by a thoracic surgeon with the patient under general anaesthesia. The diagnostic yield from transbronchial biopsies taken via large bore surgical bronchoscopy is reported as 78%.⁷ Immunohistological features of MALT lymphoma include the presence of lymphoid infiltrate expanding the marginal zone and tumour cells expressing CD20 and CD79 a antigens, which are CD5-negative.⁸ Molecular biological techniques involve PCR methods to confirm B cell clonality. This is particularly useful where morphological and immunohistochemistry studies have been insufficient to confirm the diagnosis of MALT lymphoma. While confirmatory bone marrow aspirate for morphology and flow cytometry and biopsy are not mandatory in extranodal marginal zone lymphomas such as our case, it is recommended, particularly if only local treatment is planned.⁹ For radiological staging, PET-CT scanning is very useful in the assessment of pulmonary disease with sensitivity of 80%–100%.⁹ The overall prognosis of pMALT lymphoma is good, with 5-year survival >80% and median survival >10 years.¹ However, clear guidance for an optimal approach to treatment of pMALT lymphoma is currently lacking. Treatment options include local therapies such as surgery or radiotherapy for localised disease, with chemotherapy with single or combined agents including an alkylating agent or a purine analogue, reserved for disseminated or advanced disease. Moreover, immunotherapy with anti-CD20 monoclonal antibody, rituximab, has also been used to good effect and is included in the European Society for Medical Oncology 2020 guidelines for treatment for marginal zone lymphomas.⁹

Learning points.

• Pulmonary mucosa-associated lymphoid tissue (pMALT) lymphoma is a rare clinical entity which occurs in association with coeliac disease. Physicians overseeing the care of this cohort of patients should include pMALT within their differential diagnosis when patients report respiratory or non-specific constitutinal symptoms.

• Our case demonstrates the utility of both flexible and rigid (wide-bore surgical) bronchoscopy in the histological diagnosis of pulmonary lymphoma. In particular, it emphasises the role of rigid bronchoscopy in obtaining larger tissue samples to better demonstrate the tissue architecture, thus potentially avoiding the need for a video-assisted thorascopic surgical lung biopsy.

• Positron emission tomography CT is a useful adjunct in the diagnostic pathway in patients with non-specific CT changes and possible pulmonary lymphoma.

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