Light Chain Deposition Disease – presenting with Cystic Pulmonary Disorder as primary manifestation - A case report

Abstract

Light Chain Deposition Disease (LCDD) is a rare disease characterized by deposition of abnormal, non-amyloid, monoclonal light chains in tissues, potentially leading to organ dysfunction or failure. In most cases, LCDD occurs secondary to lymphoproliferative conditions, such as underlying B-cell disease. LCDD mainly affects the kidneys, liver and heart.

Pulmonary LCDD (pLCDD) is less common, usually asymptomatic and acknowledged post-mortem. Furthermore, pLCDD exists in three forms i.e. an airway dominant, a nodular and a cystic form, which can all arise from a dominant B-cell clone restricted to the lung without multisystemic involvement.

Herein we present a young man with isolated pLCDD manifested by cystic pulmonary involvement. Surgical lung wedge resection provided histological diagnostic confirmation showing extracellular deposits, which were negative by Congo red staining but positive for κ-light chain by immunohistochemistry and mass spectrometry. There was no sign of underlying hematological disease.

Highlights

• •Light Chain Deposition Disease (LCDD) mainly a systemic disease can only originate and manifest in the lung.
• •Surgical lung biopsy is essential to confirm the diagnosis.
• •Limited treatment options should be in every differential diagnosis of pulmonary nodules & unexplained respiratory symptoms.

1. Introduction

Light Chain Deposition Disease (LCDD) is a systemic monoclonal immunoglobulin deposition disease, first reported by Randall in 1976 [1,2]. Contrary to light chain amyloidosis (AL amyloidosis), the deposits in LCDD are Congo red stain negative and mostly composed of kappa light chain [3], which when deposited in various organs interferes with their structure and function. In most cases, LCDD is a systemic disease, mainly affecting the kidneys, liver and heart [4].

Pulmonary involvement is often asymptomatic and usually diagnosed post-mortem. An isolated pulmonary variant of light chain deposition disease (pLCDD) was first described in 1987 as nodular pLCDD [5]. In addition, a cystic form of pLCDD was reported in 2006 [6].

Isolated cystic pLCDD seems to differ from the systemic form of LCDD primarily in patient characteristics, with respect to age and gender, does not involve extrapulmonary organs and free light chain ratio may be normal [6,7]. The prognosis of pLCDD is reported to be poor and there are no established therapies targeting lung function decline or radiologic progression [8]. In severe cases, stem cell transplantation or lung transplantation is considered [7]. We herein report a case of isolated cystic pLCDD.

2. Case presentation

A 41-year-old man was referred to our outpatient clinic due to progressive dyspnea on exertion and an unintended weight loss of 10 kg over the last two years. In addition, he suffered from heartburn, which resolved with intermittent proton pump inhibitor treatment. He had otherwise no significant prior medical history, used no regular medication and had neither allergies nor a history of smoking or illicit drug use. The patient's family and psychosocial history was not suggestive of genetic disorders or potential lung toxic exposures. In particular, no exposure to common antigens associated with hypersensitivity pneumonitis (HP) was identified.

He had reported mild muscle stiffness in arms and legs, but no other extrapulmonary or constitutional symptomatology suggestive of an underlying systemic autoimmune rheumatic disease. On physical examination, the temperature was 37 °C, oxygen saturation 95 % on ambient air and blood pressure 134/87 mmHg. Clinical examinations of the pulmonary, cardiovascular, abdominal, and neurological systems were unremarkable.

Routine investigations showed hemoglobin (Hb) 15.4 g/dL [Ref: 12–16 g/dL], white blood cells (WBC) 3.9 10⁹/L [Ref: 4.1–9.8 10⁹/L], C-reactive protein (CRP) 7 mg/L [Ref: <5mg/L], Alanine Aminotransferase (ALAT) 50 U/L [Ref: 10–70 U/L], Aspartate Aminotransferase (ASAT) 48 U/L [Ref: 5–45 U/L], Creatine Kinase (CK) 30 U/L [Ref: 50–400 U/L] and Lactate Dehydrogenase (LDH) 224 U/L [Ref: 105–205 U/L].

Supplemental autoantibodies including rheumatoid factor (RF) test and anti-cyclic citrullinated peptide (CCP) were negative as well as antinuclear (ANA) and antineutrophilic cytoplasmic antibodies (ANCA). There were no signs of hypogammaglobulinemia. He had no history suggestive of a primary immunodeficiency disorder and was negative for antibodies to human immunodeficiency virus (HIV) and Hepatitis B/C. Both levels of κ and λ serum free light chains (sFLC) were increased; 36.8 mg/L [Ref: 6.7–22.4 mg/L] and 48.9 mg/L [Ref: 8.3–27.0 mg/L], respectively, but κ/λ sFLC ratio was within normal limits at 0.75, respectively [normal range: 0.31–1.56 mg/L].

Pulmonary function tests (PFTs) results were consistent with a restrictive ventilatory impairment with reduced forced vital capacity (FVC) (47 % of the predicted value) and preserved forced expiratory flow in the first second (FEV1)/FVC ratio. There was no significant improvement in FVC or FEV1 on bronchodilator response test. Additionally, a severe reduction in the single breath diffusing capacity for carbon monoxide (TLCO SB) was evident (34 % of the predicted value). Computed Tomography (CT) of the chest revealed extensive and diffuse ground glass opacities in both lungs, multiple thin-walled cysts with random distribution, mosaic attenuation, and mixed lobular and geographic air trapping on expiratory scans (Fig. 1). Findings were suggestive of typical non-fibrotic hypersensitivity pneumonitis (nfHP), with lymphoid interstitial pneumonia (LIP) as a differential diagnosis. A multi-cystic lesion in the right upper lobe with irregularly thickened walls had different radiological features compared to the other cysts, prompting a recommendation of follow-up chest CT. Bronchoscopy revealed mild lymphocytosis in bronchoalveolar lavage (BAL) fluid (17 %). Bacterial and fungal cultures on BAL fluid were negative and bronchial biopsies were non-diagnostic.

Fig. 1.

CT at time of diagnosis: A. Axial inspiration with thin-walled cysts (black arrow) and diffuse ground-glass opacities (white arrowhead). B. Axial expiration with air trapping (white arrow). C. Coronal inspiration with irregular cyst right upper lobe (black arrowhead).

Considering the combination of image findings typical for nfHP and apparent BAL lymphocytosis, a provisional diagnosis of nfHP was made. This diagnosis was made with moderate confidence, acknowledging the diagnostic uncertainty in the absence of an identified antigen exposure [9]. Given the degree of impairments on PFTs, further invasive diagnostic procedures for histological confirmation were considered contraindicated.

The patient was initially treated with systemic glucocorticoids (40 mg Prednisolone daily). Response evaluation during follow up showed an initial improvement in PFTs values temporally compatible with a significant treatment effect supporting a continued disease-modifying strategy with immunosuppressive medication. Due to considerable glucocorticoid intolerance the treatment was tapered and second-line treatment with mycophenolate mofetil (1 g twice daily) was added. Follow-up chest CTs over the next 8 months revealed marked improvement of ground glass opacities and no new cysts, but increasing solid components in relation to the multi-cystic lesion in the right upper lobe (Fig. 2). Subsequent PET/CT showed increased 18F-deoxyglucose uptake in this lesion suggestive of pulmonary malignancy, but no signs of metastases. There were no enlarged mediastinal or hilar lymph nodes. Due to the young age, possible pulmonary malignancy, and only a provisional diagnosis of nfHP, a surgical wedge resection of the right upper lobe was performed.

Fig. 2.

Axial CT of irregular right upper lobe cyst at (A) time of diagnosis and (B) follow-up after 8 months shows increasing size of solid components at 8 months (black arrows) and reduction of diffuse ground-glass opacities in both lungs.

Histopathological evaluation of the wedge specimen revealed an irregular circumscribed, solitary nodule of eosinphilic, amorphous deposits with foreign body giant cell reaction and focal lympho-plasmacytic infiltrates. The eosinophilic deposits were negative for Congo red stain, non-birefringent, and immunohistochemically negative for amyloid-P, consistent with non-amyloid deposits (Fig. 3). A slight predominance of kappa light chain deposits was revealed by light chain immunofluorescns analysis. The finding was confirmed by mass spectrometry which showed a dominance of kappa light chain deposits. Due to moderate to pronounced lymphoplasmacytic infiltrates in the periphery of the nodule and adjacent lung tissue, possible hematological malignancy was considered. Immunohistochemistry showed predominant polyclonal plasma cell infiltrates, but also areas with a preponderance of cells positive for kappa light chains. Polymerase chain reaction (PCR) revealed clonal rearrangement of the IgH gene.

Fig. 3.

Hematoxylin and eosin stain 20X view with deposits of eosinophilic, non-amyloid amorphous material (asterix) and numerous foreign body giant cells (arrow).

Based on the morphological, immunhistochemical and mass spectrometric findings the diagnosis of LCDD was established.

Urinary analysis revealed no proteinuria, including no monoclonal protein (negative urine electrophoresis and immunofixation). Additionally, the bone marrow smear and biopsy revealed no signs of a systemic plasma cell disorder or other B-cell malignancy.

Finally, in the absence of clinical signs suggesting extapulmonary manifestations, normal transthoracic echocardiographic findings and no biochemical abnormalities consistent with hepatic or renal affection we concluded with isolated pLCDD.

In the follow-up period, CT revealed a stable improvement of the ground glass opacities. MMF was discontinued after 2 years and the treatment was adjusted to monotherapy with low dose Prednisolone (5 mg daily) for another 4 months before discontinuation. To date pulmonary function tests neither progressed nor substantially improved after the initial treatment response on systemic glucocorticoid (Fig. 4). Repeated measurements showed sustained normalization of κ and λ sFLC levels.

Fig. 4.

Trend in PFTs as estimated values in % of predicted. Treatment with Prednisolone was initiated april 2022. Mycophenolate mofetil (MMF) was added may 2022. MMF and Prednisolon were discontinued from May 2024 and October 2024, respectively. First (24.03.2022) and last (02.07.25) PFT evaluations represent pre- and post-treatment, respectively.

3. Discussion

Although the most common variant of monoclonal immunoglobulin deposition disease, LCDD is a rare condition characterized by deposition of light chain immunoglobulins in various body tissues [10].

Hallmarks of LCDD include immunoglobulin deposition in the kidneys, which are almost always affected, with a minority of cases developing extrarenal involvement, primarily in the liver and heart [4,11]. In contrast to the more common systemic presentation of LCDD, isolated pLCDD is rarely diagnosed, although a cystic and a nodular form have been described [6,12,5].

As in our case, the cystic form of pLCDD seems to mainly affect young patients with no other organ involvement [5]. Moreover, in pLCDD monoclonal light chain synthesis seems to be a localized process where monoclonal light chain synthesis occurs isolated in the lung [[5], [13], [14], [15], [16], [17]]. In the present case, bone marrow aspiration and biopsy were normal, no monoclonal component or free light chains were detected in serum or urine, and PCR clonality analysis of the wedge resection specimen suggested a predominant B-cell clone in the lung as the source of pLCDD. Thus no systemic plasma cell disorder or other B-cell malignancy was found.

Owing to the rarity of the disease, the natural history of cystic pLCDD is not well defined. However, cases published to date clearly demonstrate the potential for progressive decline in lung function, ultimately leading to respiratory failure [[6], [7], [18],13].

Because of the uncertain natural history, patients should be followed with serial pulmonary function testing and lung transplantation may be considered in select cases.

Treatment of the underlying lymphoproliferative disorder, if present, should be initiated. However, the extent to which pharmacological therapy alters the natural course of the lung disease remains unclear.

In the present case, initial immunosuppressive treatment was started based on a provisional diagnosis of nfHP. As a result of diagnostic reevaluation by means of histology, the diagnosis of pLCDD was confirmed.

Whether the sustained improvement with initial therapy reflects disease modifying effects in pLCDD, or unclassified, treatable traits specific to our patient remains uncertain. Our patient was treated with Prednislone and mycophenolate mofetil. Glucocorticoids are known to suppress immunoglobulin production [19] and is a well-known drug against malignant plasma cells and utilized in treatment of plasma cell dyscrasias. [20]. Mycophenolic acid, the active substance of mycophenolate mofetil, is known to prevent activation and differentiation of B-cells and suppresses immunoglobulin secretion from activated B-cells [21]. It is therefore not unlikely that the initial treatment effect and lack of progression could be related to the initial treatment with Prednisolone and/or mycophenolic acid.

In the case of progression, pharmacotherapy aiming to reduce the production of FLCs in the lung is reasonable as a measure to avoid lung transplantation. However, there is no high-level evidence in the literature on how to treat pLCDD or known if treatment targeting the light chain production may slow disease production or alter the course of lung function decline. Treatment should be tailored to the rapidity of disease progression and if possible, targeting the underlying cause if identified. Based on case files published, treatment aimed to reduce the underlying production of FLCs has been disappointing. In the case series of pLCDD, published by Lestelle et al. [22], 16 patients were treated with an attempt to target the underlying production of light chains. Of these, 10 patients had evaluable measurements of serum FLC to be used for response assessment. A normalization or reduction >90 % of serum FLCs was only obtained in 30 %. Among patients evalued by FEV1 before and after treatment, none had significant improvement. Most of the patients received alkylating agents, immunomodulators, proteasome inhibitors and/or a anti-CD20 monoclonal antibodies, either alone or in combinations. To our knowledge, no case reports mention the use of more novel anti-plasma cell therapies including anti-CD38 antibodies or the bispecifics antibodies teclistamab, elranatamab and talquetamab. Teclistamab and elranatamab, targeting B-cell maturation antigen (BCMA) could be of special interest as it causes B-cell and plasma cell aplasia. Lung transplantation is, for now, the main treatment option for patients developing respiratory failure. No cases of recurrence after transplantation have been reported [7].

CRediT authorship contribution statement

M. Krauss-Schilling: Data curation, Validation, Visualization, Writing – original draft, Writing – review & editing. E.H. Fyllingen: Conceptualization, Data curation, Visualization, Writing – review & editing. A. Jørgensen: Conceptualization, Validation, Visualization, Writing – review & editing. M. Raki: Data curation, Visualization. S. Spetalen: Formal analysis, Visualization. S.G.F. Wahl: Conceptualization, Data curation, Validation, Visualization, Writing – original draft, Writing – review & editing. T.S. Slørdahl: Conceptualization, Formal analysis, Validation, Visualization, Writing – original draft, Writing – review & editing. H. Moaddab Hønnås: Validation, Writing – review & editing. Ø. Rasch-Halvorsen: Conceptualization, Formal analysis, Investigation, Validation, Visualization, Writing – original draft, Writing – review & editing.

Patient consent

Obtained.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tobias S. Slordahl reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees. Tobias S. Slordahl reports a relationship with Johnson & Johnson that includes: consulting or advisory and speaking and lecture fees. Tobias S. Slordahl reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Tobias S. Slordahl reports a relationship with Takeda that includes: funding grants and speaking and lecture fees. Tobias S. Slordahl reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and speaking and lecture fees. Tobias S. Slordahl reports a relationship with Amgen Inc that includes: consulting or advisory and speaking and lecture fees. Tobias S. Slordahl reports a relationship with GSK that includes: consulting or advisory. Tobias S. Slordahl reports a relationship with AbbVie Inc that includes: speaking and lecture fees. Tobias S. Slordahl reports a relationship with Menarini Group that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.