Pulmonary calcified nodules and cysts as the initial presentation of Sjögren’s syndrome secondary nodular pulmonary amyloidosis: a rare case report

Abstract

Background

Secondary pulmonary amyloidosis due to Sjögren’s syndrome (SS) is an uncommon disease. However, pulmonary amyloidosis detected before the diagnosis of SS is exceedingly rare. Herein, we report a unique case of a 40-year-old female who presented with pulmonary calcified nodules and cysts as an initial manifestation of pulmonary amyloidosis. Further diagnostic evaluation revealed SS.

Case presentation

A 40-year-old non-smoking female presented with a cough, whose chest computed tomography (CT) scan revealed many lung cysts along with calcified nodules. Pathology revealed nodular pulmonary amyloidosis. Subsequent investigations excluded common related lymphoproliferative disorders and plasma cell dyscrasias. Combined with elevated levels of antinuclear antibody (1:640), positivity for the anti-Sjögren’s syndrome A (SS-A)/Ro antibody, abnormal tear break-up time (BUT) and Schirmer test, the diagnosis of SS was established.

Conclusions

Pulmonary amyloidosis is a rare pulmonary manifestation of SS, especially with atypical early clinical symptoms, which can render diagnosis challenging. This case highlights that amyloidosis diagnosis precedes SS diagnosis. Moreover, it aims to alert clinicians that when multiple calcified nodules and cystic lesions are observed on chest CT, secondary pulmonary amyloidosis should be considered, and further investigations into related diseases such as SS should be conducted to avoid missed diagnoses.

Introduction

Amyloidosis is a rare disorder characterized by misfolded proteins deposited in extracellular tissues and organs, which can involve a single organ or multiple organs [1]. A total of 10 ~ 20% of patients may have lung involvement [2]. For an accurate diagnosis, radiological findings such as calcified nodules, ground-glass opacities or lung cysts are helpful [3].

SS is an autoimmune disease that usually affects middle-aged women and is characterized by reduced tear and salivary gland secretion. It can involve various organs, including the heart, lungs and kidneys, resulting in complex clinical manifestations. Approximately 9% to 20% of patients have concomitant lung damage. The most common manifestations are chronic interstitial lung disease and tracheobronchial disease. However, other conditions, such as pulmonary amyloidosis and cystic lung disorder, may also occur [4, 5].

This paper describes a rare case of pulmonary amyloidosis secondary to SS with multiple calcified nodules and pulmonary cysts as the initial presentation.

Case presentation

A 40-year-old non-smoking female was admitted to our hospital on August 1, 2024 due to cough with sputum. Three weeks prior to admission, the patient developed this symptom without any obvious cause. She had neither fever nor dyspnea, and no fatigue or weight loss was observed. A high-resolution computed tomography (HRCT) scan of the chest revealed multiple pulmonary nodules with calcification and pulmonary bullae in both lungs (Fig. 1). After 3 weeks of anti-infective treatment, a follow-up HRCT was performed, with findings similar to the initial scan. Lung function tests revealed normal spirometry. To exclude possible lung malignancies, thoracoscopic left upper and lower lobe partial wedge resection was performed on August 2, 2024. Postoperative histopathological examination revealed excessive eosinophilic amorphous proteinaceous material with calcification, confirmed by Congo red staining (Fig. 2).

Fig. 1.

Numerous cysts (blue arrows) and calcified nodules (red arrows) are visible on HRCT

Fig. 2.

Pathological examination of pulmonary nodular amyloidosis (100 × magnification). A Positivity of Congo Red staining. B double refraction with apple green birefringence under polarized microscopy

The immunohistochemistry results were as follows: CD3 (+), CD5 (+), CD20 (+ focal), CD21 (+ focal), CD79a (+), CD38 (+ focal), CD138 (+), Kappa/Lambda (+/+), and Ki-67 (+) < 5%. Thus, nodular pulmonary amyloidosis was identified. Owing to amyloidosis, she was transferred to the hematology and oncology department. The laboratory test results revealed elevated levels of immunoglobulin G (20.32 g/L), rheumatoid factor (347.10 IU/mL) and antinuclear antibody (1:640; granular pattern), and positivity for the anti-SS-A/Ro antibody (Table 1). Normal renal and liver functions were observed. The monoclonal protein, myeloid differentiation factor 88 leucine 265 to proline (MYD88 L265P) mutation, and antineutrophil cytoplasmic antibodies were all negative. Additional test findings were displayed in Table 1.

Table 1.

Laboratory findings

Test items	Laboratory results	Reference range
White blood cell (*10^9/L)	4.2	3.5–9.5
Hemoglobin (g/L)	129	115–150
Platelet (*10^9/L)	329	125–350
Immunoglobulin G (g/L)	20.23	8.6-17.4
Immunoglobulin A (g/L)	4.77	1.00-4.20
Immunoglobulin M (g/L)	1.76	0.50-2.80
β2-microglobulin (mg/L)	2.6	1.0-2.30
Serum κ Free light chain (mg/L)	33.18	3.30-19.40
Serum λ Free light chain (mg/L)	27.70	5.71-26.30
Fκ/Fλ value	1.198	0.26-1.65
Rheumatoid factor (IU/mL)	347.10	<20
Anti-nuclear antibody	1:640	negative
Anti-SS-A/Ro antibody	positive	negative
Brain natriuretic peptide (pg/mL)	27	<100
Cardiac troponin I (ng/mL)	<0.0028	<0.0175
Erythrocyte sedimentation rate (mm/h)	38	0-20.0
24-hour urine protein (mg)	62.7	28.0-141.0
Anti-cyclic citrullinated peptide antibody (U/mL)	<0.5	<5.00
Carbohydrate antigen 19-9 (U/mL)	44.62	<34.00

The electrocardiogram, echocardiography, electromyography, and bone marrow results were normal; serum and urine immunofixation electrophoresis results were negative. Immunoglobulin kappa-deleting element (IGK-Kde) and intron-Kde gene rearrangements were detected, whereas T cell antigen receptor (TCR) gene rearrangements were not. Positron emission tomography-computed tomography (PET-CT) revealed several pulmonary nodules and cysts in both lungs without elevated metabolism (Fig. 3). Subsequently, ocular tests were performed though the patient’s symptoms of dry eye were not apparent. Positive corneal staining was found in the left eye. The BUT was 7 s in the left eye and 5 s in the right eye. The Schirmer test results were as follows: 2 mm per 5 min in the left eye and 2 mm per 5 min in the right eye. However, the patient refused labial gland biopsy. On the basis of the above results, a diagnosis of primary SS with secondary pulmonary amyloidosis was made. Therefore, 0.05% cyclosporine A eye drops, 0.3% sodium hyaluronate eye drops and total glucosides of paeony were administered. The patient is currently under outpatient follow-up.

Fig. 3.

PET-CT shows no increased metabolism in the pulmonary nodule

Discussion

Amyloidosis is a disease characterized by the misfolding and deposition of endogenous proteins in extracellular tissues and organs. Lung involvement may occur in 10 ~ 20% of patients. Pulmonary amyloidosis represents an uncommon clinical condition, that is categorized into three distinct clinicopathological types: diffuse alveolar-septal amyloidosis, nodular pulmonary amyloidosis, and tracheobronchial amyloidosis [6]. According to the above classification, the present patient was diagnosed with nodular pulmonary amyloidosis. Notably, a significant number of pulmonary amyloidosis cases are linked to underlying lymphoproliferative disorders, including SS and mucosa-associated lymphoid tissue (MALT) lymphoma [7]. Jeong et al. discovered that SS, a form of lymphoproliferative disorder, might cause the infiltration of lymphocytes and plasma cells into particular organs, potentially resulting in deposits of immunoglobulin light chains and amyloid fibers [8].

SS-associated pulmonary amyloidosis may present with chronic cough, dyspnea, and hemoptysis. Nonetheless, due to nonspecific clinical symptoms and radiological findings, pulmonary amyloidosis can mimic other lung diseases, such as infectious diseases, interstitial lung disorders and malignancies. Therefore, diagnostic delays or pitfalls often occur, particularly when pulmonary imaging findings are nonspecific and before sicca symptoms become apparent. Notably, many cases of nodular pulmonary amyloidosis are asymptomatic and are frequently found by chance via chest radiography [7]. This is identified radiologically by large, irregular, smooth-bordered, and calcified nodules that are randomly dispersed, either by themselves or in conjunction with lymphocytic interstitial pneumonia (LIP). Nodules with or without calcification were the most common abnormality (78.8%) [7]. Furthermore, during PET scan, glucose analogue (18)F-fluorodeoxyglucose (FDG) has been shown to accumulate in amyloidosis lesions. However, Baqir et al. described 6 related pulmonary amyloidosis patients who underwent PET scanning, 5 of whom had no FDG uptake in the lung [9]. Similarly, Nodules on PET imaging showed no involvement in our patient. These characteristics make it very challenging to differentiate pulmonary nodular amyloidosis from lymphoma and other lung malignancies by radiology alone. Additionally, it is thought that pulmonary amyloidosis is linked to underlying lymphoproliferative conditions, including MALT lymphoma [10]. Thus, invasive techniques such as transbronchial or surgical lung biopsies are needed to distinguish between these conditions. Importantly, numerous calcified nodules with multiple cysts are common presentations of SS-associated amyloidosis [11–13], while the mechanism of cyst development remains unknown. One hypothesis is that the deposition of amyloid protein may lead to brittle and destructive increases in alveolar walls. Another proposition is that the infiltration of amyloid material and inflammatory cells likely causes narrowing of the small airways, subsequently leading to a valve effect and the formation of cystic changes or bullae in the lung [9, 14].

Currently, there is no evidence to support a definitive therapeutic intervention for pulmonary amyloidosis associated with SS. Treatment for pulmonary amyloidosis is primarily selected on the basis of experience or a retrospective analysis of a limited number of cases. In some studies, corticosteroids and immunosuppressants, such as cyclophosphamide or azathioprine, have been administered to patients with SS combined with pulmonary amyloidosis, and good results have been obtained [15]. More recently, Tastekin et al. reported that a patient with SS and nodular pulmonary amyloidosis achieved stable disease after rituximab therapy [16]. Moreover, rituximab has shown improvement in autoimmune inflammatory diseases, particularly in difficult-to-treat settings [17]. Notably, total glucosides of paeony, a Traditional Chinese Medicine, has been widely used to alleviate SS with few adverse reactions in China [18, 19]. However, because localized nodular amyloidosis grows slowly, observation and follow-up may be sufficient, and conservative surgical excision is taken into consideration in patients with large or symptomatic disorders, which have a generally favorable long-term prognosis [20, 21]. Consequently, after balancing the available therapeutic options against the potential danger of immunosuppression, the patient of our case report chose total glucosides of paeony and was subsequently monitored in our clinic. She had been asymptomatic under follow-up for 10 months. Her last outpatient visit was 2 weeks before we completed the revision of our manuscript, and her clinical condition had been stable with no new symptoms.

Pulmonary amyloidosis is a rare pulmonary manifestation of SS, especially with atypical early clinical symptoms, making diagnosis challenging. Clinicians and radiologists should be aware of these lung CT findings of multiple calcified pulmonary nodules and cystic lesions. Thus, a comprehensive evaluation of potential systemic diseases is needed.

Authors’ contributions

Yingming Jin performed the literature search and wrote the raw manuscript. Chaoying Zhang collected case information and original images. Xiyan Zhu revised and edited the manuscript. Zhi Fang designed the study and reviewed the manuscript. All authors read and approved the final manuscript.

Funding

This research was funded by the Clinical Medicine Special Fund Project of Zhejiang Medical Association (Grant No. 2022ZYC-A162).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study protocol was approved by Ethics Committee of Ningbo No.2 Hospital, approval number (2024–162-01).

Consent for publication

Written informed consent was obtained from the patient for the publication of any identifiable data included in this article.

Competing interests

The authors declare no competing interests.