INTRODUCTION

Primary pulmonary lymphoma (PPL) without extra-pulmonary disease remains a rare entity and a diagnostic challenge. Surprisingly little can be found in the literature on the laboratory features characteristic of PPL, and studies in the early phase of disease evolvement are practically non-existent. We report such a study in a single case, yielding data that may suggest the diagnosis and allow possible insight into disease pathogenesis.

CASE DESCRIPTION

A 75-year-old man presented with dyspnoea on exertion and a dry cough, worse at night, associated with fatigue, anorexia and marked weight loss (87 to 77 kg) over six months. He had no symptoms of heart failure, no pain, fever or sweating. Abnormal routine blood tests preceded the symptomatology.

Past history included diabetes (HbA1c 6.6% on metformin) and mild hypertension (on ramipril) without target organ damage. He never smoked and, as a software engineer, he had no occupational exposures, had no pets, and an unremarkable travel and family history. One year before presentation, normocytic anaemia (Hb 10.6 g/dl) was discovered on routine laboratory tests and gradually worsened, with neither nutrient deficiencies nor apparent cause. Rather, marked positive and negative acute-phase activation developed, of which ferritin levels of 1,514 mg/dl were especially notable (Table 1). Important negatives included absent autoantibodies, normal free light chains and no monoclonal peak (serum/urine). Physical examination was unremarkable. He was comfortable, 96% oxygen saturation on ambient air, had no clubbing, and lung percussion/auscultation were normal. Chest X-ray showed scattered parenchymal densities at the lung bases, with normal heart and mediastinum (Fig. 1A). Chest and abdominal CT demonstrated multiple patchy opacities mostly in the lower lobes (Fig. 1B) without mediastinal lymph nodes or effusions. There were no abnormal imaging findings outside the lungs, but pulmonary changes became more pronounced. After two transbronchial CT-guided biopsies were inconclusive, a video-assisted thoracoscopic lung biopsy was performed, establishing the unequivocal diagnosis of PPL (Fig. 2). Bone marrow biopsy was reactive, and PET CT showed no extra-thoracic activity (not shown). Treatment with cycles of rituximab, cyclophosphamide, vincristine and prednisone (R-CHOP) was started in April 2023. This was well tolerated, and the patient gradually became asymptomatic and gained weight. Within one year, all blood tests normalised (Table 1, March 2024) and a repeat PET CT demonstrated a complete disappearance of hypermetabolic foci in both lungs.

DISCUSSION

While secondary involvement of the lung may occur in up to one-quarter of all patients with non-Hodgkin’s lymphoma, B-cell pulmonary lymphoma without extra-pulmonary disease (PPL) remains a rare entity comprising less than 1% of all non-Hodgkin’s lymphoma, just 3-4% of all extranodal forms, and less than 1% of primary lung neoplasms^[1]. The most frequent type of PPLs (70-90%) is the indolent marginal zone lymphoma arising from the mucosa-associated lymphoid tissue (MALT) as in our patient. The median age of appearance is in the late 60s, supporting the theory of chronic inflammatory stimulation in carcinogenesis by prolonged exposure to local antigens or, less often, an underlying autoimmune disease^[2]. In contrast with the more common Helicobacter pylori-associated gastric MALT lymphoma, no causative agent had been robustly identified in PPL, and smoking is not present in many patients. Clinical presentation is variable, from asymptomatic (in a third or more) to cough, dyspnoea or malaise. In contrast, systemic symptoms, chest pain or haemoptysis are less often encountered, and when present, are non-specific and frequently misdiagnosed as ‘unresolving pneumonia’. CT is the imaging modality of choice, but just like the non-specific clinical presentation, the appearance of nodule(s) <5 cm or area(s) of consolidation, not uncommonly in both lungs (~25%), mimics several reactive diagnoses (e.g. lymphoid interstitial pneumonia) and neoplastic diagnoses (e.g. adenocarcinoma), making pathology indispensable^[2,3]. Thus, MALT PPL must be considered in the context of several other malignant and benign primary lymphoid pathologies of the lungs (Table 2)^[4-6]. Histology and immunostaining are diagnostic and characterised by the presence of lymphoid infiltrate expanding the marginal zone of reactive follicles and showing a low proliferative index (Ki-67 <10%) and monoclonality (positive B-cell immunoglobulin gene rearrangement) as in our patient. The infiltrate is composed of small, atypical cells expressing B-cell antigens CD20 and CD79a and Bcl-2 positivity (Fig. 2), whereas CD10, Bcl-6 and cyclin D1 are negative.

Surprisingly little can be found in the literature on the laboratory features characteristic of PPL. The only mention is that lactate dehydrogenase activity is mostly normal, beta 2 microglobulin may be elevated and in some patients, ‘mild to moderate anaemia, slight leukocytosis’ and monoclonal gammopathy may be associated. Early-phase changes characteristic of sub-clinical PPL have never been reported to the best of our knowledge. Our patient’s detailed laboratory data, however, afforded a month-by-month insight not only into the presentations that clinicians are likely to encounter, but indirectly into disease evolvement and pathogenesis (Table 1). Anaemia of inflammatory disease and monocytosis were the first to appear, preceding any symptom by five months. Its relevance was demonstrated by the changes noted with clinical progression and ultimately, remission. When symptoms developed, these changes deepened and became associated with reactive thrombocytosis; increased ferritin, C-reactive protein and erythrocyte sedimentation rate (positive acute-phase reactants), and reduced albumin and transferrin (negative acute-phase reactants). Globulins increased, due to an increase in the α1, α2 and γ fractions, and mild hyponatraemia due to SIADH secondary to the intrathoracic disease appeared. All changes were related to the PPL, as their complete resolution with treatment demonstrates. These changes have in common a postulated (but unmeasured here) surge of inflammatory cytokines, and their inferred presence months before any symptom is intriguing - and useful to clinicians - and has not been previously reported, to our knowledge. Anaemia of inflammation was the initial manifestation, preceding all symptoms and other accruing laboratory markers. Its mechanism involves the release of multiple inflammatory cytokines by cells of the immune system in response to tumour antigens: IL-6, IL-1 and TNF-α appear to be the most important, stimulating hepcidin production by hepatocytes, which inhibits duodenal iron absorption and blocks release of senescent erythrocytes iron from macrophages^[7]. Inflammatory cytokines (mostly produced by CD4⁺ T cells but also by activated lymphoma cells and macrophages), also directly reduce iron absorption, reduce production/activity of erythropoietin, and mediate hypoferremia, hyperferritinaemia and additional changes such as megakaryocyte growth with reactive thrombocytosis, and neutrophilia (both also related to the expression of colony-stimulating factor cytokines). Recent in vivo studies have established a pathogenic role of increased ferritin levels, for example in mediating macrophage commitment towards an inflammatory phenotype^[8]. Thus, cytokine network changes in B-cell neoplasms, and in MALT lymphomas in particular, are complex. The tumour microenvironment in primary pulmonary MALT lymphoma including tumour cells, epithelial cells, infiltrating immune cells and cytokines^[9] has a key role in the progression and prognosis of the lymphoma. Our report indirectly highlights the early and primary role of inflammatory cytokines in the pathogenesis of PPL. Early recognition of their effects on basic laboratory tests can lead to a more timely suspicion, histology verification of PPL and treatment.