Dyspnea and cough in a 68-year-old female with light chain deposition disease

Abstract

Light chain deposition disease (LCDD) is a rare hematologic disorder characterized by non-amyloid monoclonal immunoglobulin light chain deposition in multiple organs. Pulmonary LCDD (PLCDD) is an uncommon manifestation of LCDD usually seen in middle-aged patients presenting with radiologic cystic and nodular findings. We report the case of a 68-year-old female who presented with shortness of breath and atypical chest pain. Chest computerized tomography (CT) scan revealed numerous diffuse but basilar predominant pulmonary cysts and mild bronchiectasis without nodular disease. Given concomitant abnormal renal function and hepatic laboratory indices, she underwent biopsy of both organs confirming the presence of LCDD. Directed chemotherapy was initiated and stabilized renal and hepatic progression, but on follow-up imaging, pulmonary disease appeared worse. While therapeutic options targeting other organ involvement are available, their directed efficacy for progressive lung disease is not well known.

Highlights

• •Light chain deposition disease may involve multiple organs including the lungs as cystic and nodular findings.
• •Patients may present with nonspecific shortness of breath, cough, or atypical chest pain.
• •Pulmonary involvement often has a more indolent radiologic course, with most indications for directed treatment targeting renal impairment.
• •Established treatment protocols are unknown in terms of their impact on progressive lung disease.

Abbreviations

ASCT

autologous stem cell transplantation

CR

complete response

CT

computed tomography

DLCO

diffusion capacity for carbon monoxide

ESRD

endstage renal disease

GFR

glomerular filtration rate

LCDD

light chain deposition disease

NFκB

nuclear factor kappa B

PLCDD

pulmonary light chain deposition disease

VGPR

very good partial response

1. Introduction

Light chain deposition disease (LCDD) is a rare hematologic disorder characterized by non-amyloid monoclonal immunoglobulin light chain deposition in multiple organs including the kidneys, spleen, pancreas, thyroid, gastrointestinal tract, adrenals, skin, liver, heart, nervous system, and lungs. However, renal impairment is the most common abnormality with approximately 20% of patients progressing to end-stage renal disease requiring hemodialysis [1,2]. Prior studies suggest a high percentage of LCDD patients also have an underlying lymphoplasmacytic disorder [1] often presenting with elevated serum monoclonal immunoglobulin kappa light chains [3]. LCDD infrequently involves the lungs, but does so more commonly in middle-aged patients [[3], [4], [5]].

We report the case of a 68-year-old female presenting with cystic lung disease leading to a diagnosis of LCDD involving the kidney and liver. We describe presenting signs and symptoms, lung function, radiologic features, as well as prognosis and general approaches to treatment with and without pulmonary involvement.

2. Case description

A 68-year-old Caucasian woman presented with dry cough, intermittent shortness of breath with exertion, and brief episodes of sharp chest pain over several months. She denied fevers, fatigue, and weight loss without history of occupational or environmental exposures. She was a never smoker, with past medical history significant for chronic cholestatic liver disease (suspected primary biliary cirrhosis), hyperlipidemia, hypertension, and fractures after a fall. Vitals and physical examination were unremarkable on presentation, including clear lung fields and normal sinus rhythm without audible murmur or gallop on auscultation. Pulmonary function testing demonstrated a forced vital capacity (FVC) of 2.82 L (99% of predicted), forced expiratory volume in the first second (FEV1) of 2.35 L (107%) of predicted, FEV1/FVC ratio of 85, total lung capacity of 4.77 L (98% of predicted), and isolated reduction in diffusion capacity for carbon monoxide (DLCO) of 10.2 mL/minute/millimeters of mercury (Hg) (50% of predicted). Oxygen saturation at the time of testing was 98% at rest and 96% with three-minute step exercise. Visit chest x-ray suggested normal heart size and pulmonary vascularity, with possible faint reticulation in the lung bases. Given this and the extent of clinical findings, a chest computed tomography (CT) scan was obtained and revealed diffuse but basilar predominant cysts and mild cylindrical bronchiectasis without other parenchymal abnormalities including nodules, consolidation, or ground glass (Fig. 1).

Fig. 1.

Computed tomography images of PLCDD cystic disease at presentation (Panel row 1, A-D; with arrows pointing towards parenchymal cysts) and at 3-years of follow-up (Panel row 2, A-D), demonstrating mild progression in terms of increased cyst size and number.

In a middle-aged non-smoking female presenting with cough and mild dyspnea diffuse lower lobe cystic lung disease, the entertained differential included lymphangioleiomyomatosis, Birt-Hogg-Dube syndrome, amyloidosis, and lymphoid interstitial pneumonia. On further discussion, patient denied history or pneumothoraces or recurrent pleural effusions. There were no skin changes on exam or by history to suggest fibrofolliculoma, prior history of abdominal or renal masses or malignancy, and no family history of cystic lung disease. She also denied signs or symptoms of connective tissue disease, including sicca symptoms, Raynaud's, painless or nonpruritic rash, joint pain or swelling, and myalgias.

Laboratory studies revealed normal complete blood count with hemoglobin of 13.2, white blood cell count of 7.4, and platelet count of 302. A chemistry panel revealed normal electrolytes with elevated serum creatinine of 2.63 (glomerular filtration rate (GFR) of 21). Abnormal liver tests were noted with elevation of alkaline phosphatase at 247 U/L (normal, 35 to 104), alanine aminotransferase at 71 U/L (normal, 7 to 45) and total bilirubin at 1.3 mg/dL (normal, ≤1.2). Fractionated alkaline phosphatase indicated a liver source. Autoantibody panel for both antinuclear and extractable nuclear antigens was obtained and normal. Given the possibility of amyloidosis, serum and urine protein electrophoresis suggested there was no monoclonal spike on serum protein electrophoresis though urine immunofixation confirmed a monoclonal kappa gammopathy. Twenty-four-hour urine protein was elevated at 321 mg (normal <229 mg) with a monoclonal kappa light chain (M-spike) of 82 mg. Serum kappa free light chains were elevated at 68.2 mg/dL (normal 0.33 to 1.94), lambda free light chains were normal at 1.51 mg/dL (normal 0.57 to 2.63), with an increased kappa to lambda light chain ratio of 45.16 (normal, 0.26 to 1.65). CT scan of the abdomen without contrast obtained to assess for renal or hepatic abnormalities revealed irregular contour of the liver with no other findings.

Given abnormal serum and urine protein electrophoresis and renal impairment, a referral was made to Hematology where bone marrow biopsy revealed 5–10% kappa light chain-restricted plasma cells consistent with a likely plasma cell proliferative disorder. Congo red stain for amyloid was negative on bone marrow assessment as well as subsequent fat aspirate. An ultrasound-guided liver biopsy was obtained given concern for a possible infiltrative or obstructive process which demonstrated portal infiltration of plasma cells admixed with rare lymphocytes, with plasma cells testing kappa positive and lambda negative. There were also mild biliary obstructive changes, highlighted by portal edema and ductular reaction. Congo red stain was negative for amyloid. Overall histopathologic findings from the liver suggested low-level portal involvement of kappa light chain-restricted plasma cells as seen on bone marrow biopsy. Nephrology consultation was obtained followed by renal biopsy which revealed marked deposition of kappa-positive material in the interstitium and vessels. Linear glomerular and tubular basement membrane staining was positive for kappa light chain by immunofluorescence. Fine granular and powdery deposits along the glomerular and tubular basement membranes were also seen on electron microscopy, typical of LCDD. Congo red stain was also negative. In conjunction with cystic findings in the lungs, bone marrow biopsy results, and suggestive histopathologic features from two organs with supportive electron microscopy and negative Congo red staining from all sites, a multidisciplinary diagnosis was made of LCDD with multiorgan involvement. Additional lung biopsy was deferred given the known association of cystic findings with LCDD and the preponderance of other confirmed organ involvement.

Given renal involvement and impairment, treatment was initiated with a regimen of cyclophosphamide, bortezomib, and dexamethasone. While this was initially well tolerated with declining serum kappa light chains on short-term follow-up, kidney function continued to worsen. Stem cell harvest and storage was pursued with Bone Marrow Transplant consultation. At one year, as she was not able to tolerate the initial treatment regimen due to side-effects (nausea, fatigue, depressive mood, and complications of diverticulitis), Hematology colleagues curtailed treatment to daratumumab monotherapy. From a pulmonary perspective, as-needed albuterol was provided for occasional dyspnea and chest tightness with symptomatic relief, noting stable arterial blood gas and exercise oximetry. She also noted improved exercise tolerance with increased activity. At three years of follow-up, repeat chest CT suggested cystic lung disease had slightly worsened with increased size in some cysts as well increased number (Fig. 1), now accompanied by new exertional hypoxemia (nadir saturation of 84%) on six-minute walk testing. The remaining lung parenchyma on CT was unremarkable for superimposed infiltrate, fibrosis, or nodules. Repeat pulmonary function testing suggested normal and unchanged lung volumes and spirometry, with further decline in DLCO to 43% of predicted (from 50% 3 years earlier). Transthoracic echocardiogram suggested normal left ventricular size and function with an ejection fraction of 64%. Normal right ventricular size and function was noted with an estimated right ventricular systolic pressure of 28 mmHg (normal <35), and no evidence of right-to-left shunting or pericardial disease. While unexplained exertional hypoxemia still warranted additional evaluation for pulmonary hypertension, including right heart catheterization, the patient chose to defer additional invasive testing and oxygen support with plans for close monitoring and expectant management based on progression of symptoms or radiologic findings on follow-up.

3. Discussion

LCDD rarely involves the lungs and is often asymptomatic though may present with nonspecific symptoms such as cough or dyspnea [[6], [7], [8], [9], [10]]. A recent retrospective study found dyspnea (n = 3, 30%) and chest pain (n = 3, 30%) were the most common respiratory symptoms. However, half of PLCDD patients may have no respiratory symptoms at diagnosis [7], as seen in a series of four biopsy-confirmed PLCDD patients aged 36–64 [11]. PLCDD often affects the lung parenchyma while bronchial or airway involvement may be sporadic. However, large airway involvement has been reported as cylindrical or saccular bronchiectasis [12]. PLCDD is mostly characterized by thin-walled cysts that may be associated with other systemic diseases including Sjögren's, sarcoidosis, limited scleroderma, and hematologic malignancies such as mucosa-associated lymphoid tissue lymphoma [7,13]. A recent study of PLCDD patients revealed that one had Sjögren's for five years, with two diagnosed after biopsy. None had liver, kidney, heart, or nervous system involvement [11]. Another study of seven LCDD patients with cystic lung disease described no other organ involvement [14]. Up to 67% of LCDD cases involve middle-aged patients (median age of 58 years) and appear more common in men [1,3,4,15]. However, recent literature suggests younger women may also be more affected [7]. The median age was 55 years (range, 39–77 years) [7], with another report suggesting cystic lung disease occurred more in women [14].

Lung function in PLCDD varies according to airway or parenchymal involvement. One retrospective study demonstrated normal arterial blood gas measurements despite small airway dysfunction with decreased mean expiratory flows [7]. Small airway involvement with obstruction appears to be related to matrix metalloproteinase break down of elastic fibers from light chain deposition [6]. One study reported 63% of PLCCD patients had normal pulmonary function, with obstructive pattern and isolated reduction in DLCO found in 13% each of the remaining cases [7]. Patients with advanced cystic PLCDD often present with an obstructive ventilatory pattern, low DLCO% (range, 11–28% of predicted), and resting hypoxemia on room air. Approximately 75% demonstrated pulmonary arterial hypertension on right heart catheterization [14].

The radiologic course of PLCDD is often indolent with typical findings of diffuse cysts or nodules progressing more slowly over time [7]. One retrospective study suggested blood vessels found in the cyst wall and or passing through cystic lesions on imaging may be characteristic of PLCDD [11]. The differential for cystic lung disease includes amyloidosis, lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, lymphoid interstitial pneumonia, Birt-Hogg-Dubé syndrome, and metastatic malignancy [[16], [17], [18]]. Our patient had diffuse pulmonary cysts with a lower lobe predominance, narrowing the differential to amyloidosis and lymphoid interstitial pneumonia [5]. A recent study of suspected PLCDD patients presenting with multiple cysts and nodules found one had lymphangiomyomatosis while another had adenocarcinoma in situ on biopsy [11]. One series found 89% of cysts were multiple and located in the lower lungs with half being lobulated or irregular. Seventy-five percent were thin-walled; 62% had only 1–5 cysts while 37.5% had more than twenty cysts. The median diameter of the large cysts was 18 mm (range, 5–68 mm) while median diameter of the large nodules was 13 mm (range, 6–26 mm) [7].

In addition to radiologic abnormalities, LCDD often presents with elevated serum monoclonal immunoglobulin kappa light chains [3]. In one series, 68% of PLCDD had elevated serum kappa light chains with 57% also having elevated serum lambda light chains, 86% and 14% had normal and elevated serum free light chain ratios (kappa to lambda), respectively [7]. PLCDD with cystic findings may be associated with normal serum free light chain ratios [14]. Of note, our patient had normal serum lambda but elevated serum kappa light chains with an increased serum kappa to lambda light chain ratio.

Although radiologic and histologic findings of PLCDD and AL (light chain) amyloidosis may be similar, PLCDD does not demonstrate apple-green birefringence when exposed to Congo red stain and under electron microscopy does not have a fibrillary pattern as seen with amyloidosis. Immunohistochemistry staining often demonstrates elevated lambda light chain-restricted plasma cells in amyloidosis while LCDD more commonly presents with elevated kappa light chain-restricted cells [4,19,20].

The goal of LCDD therapy is to minimize abnormal plasma cell proliferation and light chain synthesis with excretion and deposition into affected organs. As LCDD is rare and commonly involves multiple organs, a universal approach to treatment does not currently exist [21]. The scope of treatment and management options include bortezomib, immunomodulatory drugs such as thalidomide and its analogs lenalidomide and pomalidomide, daratumumab, autologous stem cell transplant (ASCT), and kidney transplantation [22,23]. In renal LCDD, monoclonal light chains interacting with mesangial cell receptors are believed to activate nuclear factor kappa B (NFκB) pathways that stimulate cytokine production leading to glomerulosclerosis [24]. Bortezomib-based induction chemotherapy inhibits NFκB pathways stabilizing glomerular function and reducing proteinuria [25]. Bortezomib has been prescribed as induction therapy in multiple LCDD series [[26], [27], [28]]. One study of three LCDD patients treated with bortezomib induction achieved rapid hematologic response after a mean of two cycles, based on decreased serum-free light chain levels [27]. Another study of four LCDD patients using bortezomib and dexamethasone followed by ASCT found 50% achieved complete hematologic response [28]. One retrospective study of 48 LCDD patients reported bortezomib and dexamethasone (BD) provided better organ and hematological response than prior anti-myeloma regimens such as thalidomide and dexamethasone or vincristine, Adriamycin, and dexamethasone in combination. ASCT alone or as adjunct to induction therapy may produce a durable response in LCDD patients [23,26], with one study demonstrating six LCDD patients with renal impairment having improved renal function. High-dose chemotherapy plus ASCT has also been shown to improve outcomes [23,28,29]. However, Cohen et al. reported no difference among patients who received ASCT [30], with one case report describing dyspnea and rapidly worsening radiographic findings despite high-dose corticosteroids after transplantation [31]. Another study also reported successful treatment of LCDD with bortezomib/dexamethasone without ASCT [27]. Evidence for the use of immunomodulatory agents is limited and needs further evaluation in prospective studies. Mima et al. reported lenalidomide plus prednisolone successfully reduced proteinuria and hematuria after treatment with bortezomib, cyclophosphamide, and dexamethasone [32]. Daratumumab is a monoclonal antibody targeting CD-38, often used in both lenalidomide and bortezomib-based regimens. Seven patients achieved a partial response, defined as more than 50% decrease in serum free light chain, two achieved renal response and four had improved or stable renal function in one series [33]. No data exists on pulmonary response to any of the above therapies in cases where cystic or nodular disease may be worsening or symptomatic at presentation. Lung transplantation has been described in progressive or end-stage PLCDD patients. Hirschi et al. reported a retrospective multicenter study of seven end-stage PLCDD patients who underwent lung transplantation with a median follow-up of 56 months. One patient died from multiorgan failure at 23 days, another from chronic rejection at 56 months, and one from de novo breast cancer at 96 months, with none demonstrating disease recurrence on imaging or histopathology [14]. Colombat et al. reported three cases of severe cystic PLCDD undergoing LT, however long-term outcomes were not assessed [31]. In our case, an approach for multiorgan involvement included cyclophosphamide, bortezomib, and dexamethasone for the first two years with switch to daratumumab monotherapy afterwards due to side-effect intolerance and stabilized renal function. In the three-year follow-up period, chest CT revealed slight progression of cystic findings with worsened exertional hypoxemia.

LCDD prognosis is associated with the type and number of affected organs [1,11]. Prognostic factors include age, presence of plasma cell myeloma, and extrarenal light chain deposition [24]. In one study of 53 patients with biopsy-proven LCDD, median survival was 14 years with death from infection (11.3%), ischemic heart disease (7.5%), endstage renal disease (ESRD) (5.7%), congestive heart failure (3.8%), cerebrovascular accident (1.9%), gastrointestinal bleeding (1.9%), and multiple myeloma (3.8%) [34]. Another retrospective study revealed 10% of deaths were attributable to acute respiratory distress syndrome unrelated to pulmonary manifestations of LCDD [13]. Patients who achieved hematologic complete remission (CR) or very good partial response (VGPR) with chemotherapy had improvements in mean glomerular filtration rate (GFR) of 6.1 mL/min per year. Only three of 21 (14.3%) required hemodialysis despite GFR of 26 mL/min at the start of chemotherapy. These findings suggest patients with LCDD who achieve CR or VGPR have better renal survival (median, 9 years) with improved cardiac and hepatic function [34]. Sayed et al. also noted stronger hematologic responses to therapy contributed to better overall outcomes even in those with already advanced kidney disease [34]. Li et al. reported seven patients (15.9%) who did not receive chemotherapy progressed to ESRD. Patients who received chemotherapy and ASCT appeared to have the best outcomes, followed by chemotherapy alone or no chemotherapy (p = 0.048). Again, renal function was better in patients with hematological CR/VGPR [15]. In addition, patients with LCDD may also pursue ASCT at lower GFR (median, 24/mL/min/year; range, 11–51 mL/min per year) with little risk of precipitating renal dysfunction. While bortezomib-based regimens and melphalan-conditioned ASCT appear to have higher rates of CR/VGPR, further study is needed to delineate the best chemotherapy protocol [34]. For LCCD with pulmonary involvement, Sheard et al. reported only one patient with progressive cystic lung lesions over five years [7]. Some studies suggest PLCDD patients with multiple cystic lesions were more likely to have rapid progression and respiratory failure [6,14,35]. However, another retrospective study revealed most PLCDD patients receiving specific treatment had little pulmonary progression. Twenty percent of such patients still died after a median follow-up of 2.3 years (range, 0.5–9.9 years) [13]. Exertional hypoxemia in our case was not further pursued as preferred by the patient, which may have included right heart catherization to rule out pulmonary hypertension. This unfortunately is a limitation in terms of understanding additional complications or case resolution.

In summary, PLCDD is a rare condition with a broad radiologic but limited serologic and histologic differential. It is often asymptomatic but considered when imaging shows diffuse or patchy cysts and nodules. PLCCD is suspected when blood vessels are visible in the cystic wall or traverse cystic or nodular lesions without zonal predominance on biopsy. LCDD may be associated with lymphoproliferative or autoimmune disorders. Disease management is often pursued with bortezomib induction and/or ASCT, however, further studies are needed to assess specific pulmonary response. Hematologic and renal response to chemotherapy is often associated with better survival, with again no established therapies targeting lung function decline or radiologic progression in those with pulmonary involvement. Although PLCDD often has an indolent clinical and radiologic course, progressive respiratory insufficiency may lead to chronic respiratory failure.

Disclosures/competing interests

None.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors report no disclosures or conflicts of interest with the submission of this case report.