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Department of Internal Medicine, Louisiana State University Health Sciences Center, Shreveport, LA, USADepartment of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
Evaluation of bilateral lung nodules noted on imaging poses a diagnostic challenge to clinicians as it can have many differentials from benign to malignant causes. It becomes especially critical to identify them right when there are underlying autoimmune conditions and risk factors for infection. However, a thorough investigation can lead to the recognition of rare associations as described below. We present here a 57-year-old woman who was admitted to the hospital with shortness of breath. Imaging with a computed tomography (CT) scan showed that she had 8 bilateral cystic pulmonary nodules with focal areas of ground-glass opacity and mediastinal lymphadenopathy. Fibrobronchoscopy and histopathological studies were done on the right middle lobe lung nodule demonstrated that the lung nodule was fibrotic with reactive inflammation but showed no malignant cells. Upon further detailed history and chart review, it was noted that the patient had a history of dry eyes leading to an autoimmune workup showing positive antinuclear antibodies (ANA), anti-Ro, and anti-La antibodies with no follow-up since then. This lead to the suspicion that these nodules could be related to underlying Sjögren's syndrome. Initial inpatient management with intravenous steroids showed significant improvement in her symptomatology. Hence, we present this rare association of lung nodules with Sjögren's syndrome and its management for awareness of this condition.
Insuffisance progressive et atrophie des glandes salivaires et muqueuses de la bouche, des conjonctives (et parfois des muqueuses nasale, laryngée, vulvaire) sécheresse de la bouche, des conjonctives, etc).
Clinical pulmonary involvement in primary Sjögren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data.
although lung nodules are a rare pulmonary manifestation of Sjögren's syndrome, malignancy and infectious causes need to be ruled out as well. We present here a rare case of pulmonary nodules which were thought to be related to a malignancy; however, a biopsy of the lung nodule which was most suspicious of malignancy showed that it was of fibrotic nature and a remote history of dry eyes prompted an autoimmune workup revealing the cause to be related to Sjögren's syndrome.
Case presentation
A 57-year-old female with a past medical history of cirrhosis of the liver, hepatitis C infection (completed treatment), and pancytopenia presented to the hospital due to shortness of breath, productive cough, and chest pain which had progressively worsened over the past few days. Shortness of breath was present during the past few months and had progressively worsened. A review of old records indicated that the patient had a total of 8 bilateral lung nodules for the past 2 years. They were of different characteristics- a subpleural 5mm left upper lobe nodule, a spiculated right middle lobe 7 mm nodule, left lower lobe 8 mm subpleural nodule, an 11 mm ground glass left lower lobe nodule, an 8 mm left lower lobe subpleural nodule, a 12 mm right middle lobe nodule with central cavitation, a tiny subpleural lingular nodularity, and a 13 mm right lower lobe solid calcified nodule. (Fig. 1a). The lesions were characterized as infectious/inflammatory/malignant.. The patient was being followed by pulmonology and was awaiting a lung biopsy before she was admitted to the hospital. She had two admissions over the past year for obstructive pneumonia and was treated with appropriate antibiotics. Upon admission, the patient's respiratory status was stabilized, and workup was started for an acute infectious process. Repeat computed tomography (CT) chest showed similar lung nodules with some consolidation, tree-in-bud and ground-glass opacities in both lungs with a predominance in right upper lobe (Fig. 1b). Tuberculosis was ruled out by 3 negative acid-fast bacilli (AFB) smears. The patient was started on broad-spectrum antibiotics. Her sputum cultures grew methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, so antibiotics were de-escalated. After antibiotics her consolidation improved on chest X-ray (not shown) but nodular lesions persisted. Bronchoscopy was done and the right middle lobe spiculated nodule was biopsied, which ruled out malignancy and showed reactive bronchial cells with macrophages, congo red staining was negative. Detailed medical chart review and further comprehensive history noted treatment for dry eyes in the past, suggesting possible autoimmune etiologies. In the meantime, labs were positive for ANA, SSA, and SSB antibodies. Rheumatology was of the opinion that findings could be related to Sjögren's syndrome; hence, the patient was started on steroids. She showed dramatic improvement after steroids, and was discharged home with a follow-up to rheumatology. We do believe that the repeated pulmonary infections seen in our patient were a result of the underlying Sjögren's and the resultant inability to clear thick secretions.
Fig. 1Chest computed tomography (CT) scan showing multiple pulmonary nodules, in the right lung anterior upper lobe (arrows) (A) and the left lung upper lobe (arrows) (B).
Sjögren's syndrome can occur either as a primary disorder or in association with other connective tissue diseases (secondary SS). It is the second most common systemic autoimmune disorder after rheumatoid arthritis, with an estimated prevalence of 0.5% with a female preponderance (10 to 1 female/male ratio approx.). About 0.4 million to 3.1 million adults in the United States had primary SS in 2005.
The etiopathogenesis of Sjögren's syndrome is not well understood, but it is believed to be multifactorial, combining environmental factors like viral infections (cytomegalovirus, HIV, Human T-cell leukemia virus, and hepatitis C virus),
and hormonal imbalance, leading to an autoimmune epithelitis characterized by chronic glandular inflammation secondary to a deregulated innate and acquired immune response.
Several studies have found an abnormal activation and proliferation of B-cells, promoting plasma cells that secrete pathogenic anti-Ro (SSA) and anti-La (SSB) autoantibodies directed to the small cytoplasmic RNP-bound peptides SSA-60kD, SSA-52kD, and SSB-48kD.
The role of T-cells in Sjögren's syndrome is more controversial, but it is thought that there is an abnormal T-cell activation with secondary cytotoxicity and altered function of regulatory T-cells and T-helper 17 cells.
In addition, the innate immunity in SS is also altered: several studies have shown that epithelial cells are capable of constitutively or inducibly expressing various molecules implicated in promoting chronic innate responses
Toll-like receptor 3 stimulation promotes Ro52/trim21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type i interferon pathway.
Type I and II interferon signatures in Sjögren's syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjögren's related lymphomagenesis.
However, there is extra-glandular involvement in up to 33% of patients with Sjögren's syndrome, affecting most of the systems of the body and making it a true multisystemic disease.
A major system commonly affected in Sjögren's syndrome is the respiratory system, which typically appears late in the course of the disease: the prevalence varies from 10-20%, with an estimated incidence of 10% (±3%) 1 year after diagnosis of Sjögren's syndrome and increases to 20% (±4%) by 5 years.
Clinical pulmonary involvement in primary Sjögren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data.
Airway abnormalities are the most frequent finding in Sjögren's syndrome and are believed to be the result of exocrine glandular destruction and T cell infiltration occurring in the whole airway; however, a morphometric study of the respiratory airway in SS patients did not show bronchial gland atrophy, raising the possibility of a functional, instead of a structural, glandular defect. Airway manifestations include bronchial hyperresponsiveness (observed in 42–60% of patients)
; interestingly, the bronchial hyperresponsiveness observed in Sjögren's syndrome does not respond very well to inhaled corticosteroids in a high proportion of patients (40–60%).
Bronchiolitis is the most common airway disease observed in SS patients, with the frequency ranging between 12 to 24% depending on whether the diagnosis was done based on biopsies or radiological criteria.
Patients with interstitial lung disease (ILD) present mainly with dyspnea and cough and have a higher frequency of rheumatoid factor and antinuclear antibodies with higher levels of gammaglobulins.
In bronchoalveolar lavage (BAL) studies, these patients are found to have lymphocytic alveolitis, mainly with T cell infiltrates, and biopsies show infiltrates in all components of the lung interstitium (alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues).
Several types of ILD have been described by lung biopsy in patients with SS, including nonspecific interstitial pneumonitis (NSIP) (45%), usual interstitial pneumonitis (UIP) (16%), organizing pneumonia (7%), lymphocytic interstitial pneumonitis (LIP) (15%).
Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements.
The lungs have mucosa-associated lymphoid tissue in the bronchi that is analogous to gut-associated lymphoid tissue, and chronic inflammation of the lungs might lead to lymphoproliferative disorders. Patients with Sjögren's syndrome have a 16 to 44-fold increased risk of non-Hodgkin lymphoma; the most common subtypes are Marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue.
But even rarer is the occurrence of pulmonary nodules: most described cases of pulmonary nodules correspond to pulmonary amyloidosis, with fewer than 200 cases described in the literature, most of them in women (98%) and involving multiple nodules in both lungs,
Primary pulmonary amyloidosis is classified based on the patterns of distribution and in three subtypes nodular: tracheobronchial, and diffuse interstitial. In the nodular type, nodules may present with a ground-glass appearance, suggesting an involvement of the adjacent peribronchiolar spaces or can be surrounded by bullae. Pulmonary amyloidosis can be associated with LIP and cystic lesions.
and may pose a challenge for the clinician because of the wide range of possible differential diagnoses (Table 1); however, the predominant location of the nodules sometimes can help to distinguish between these conditions. For example, the nodules seen in sarcoidosis are predominantly in the pleural surfaces or bronchocentric, nodules in silicosis and pneumoconiosis are predominantly in the upper lobes, the nodules observed in asbestosis and metastases are usually located in the lower lobes and the nodules in Kaposi sarcoma are bronchocentric. Other clues in the diagnosis of pulmonary nodules include miliary distribution as seen in tuberculosis and cavitations or calcification as seen in infectious causes and septic emboli.
However, a surgical lung biopsy is generally required to establish the diagnosis and rule out lymphoma, given the association between Sjögren's and low-grade B-cell lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma of the lung.
Surprisingly in our case, histological analysis of the nodules did not show deposits of fibrinoid necrosis surrounded by histiocytes, which are compatible with rheumatoid nodules and have been reported in one case of Sjögren's.
The histology reported the presence of fibrinoid nodules with an inflammatory reaction (Fig. 2A), congo red staining did not show amyloid fibrils ruling out amyloidosis (Fig. 2B). To our knowledge, this is the first case in which pulmonary fibrinoid nodules have been reported in a patient with primary Sjögren's syndrome (SS). Their occurrence can be secondary to the chronic inflammation and immune response observed in patients with Sjögren's. Since nodules are not very commonly observed in Sjögren's and they can mimic metastatic malignant lesions,
their occurrence should lead to a thorough exploration of the patient's history, imaging, and histological studies to rule out malignancy.
Fig. 2Histology of the nodules. A. Shows interstitial fibrosis and chronic inflammation (hematoxylin and eosin staining, magnification × 2.5), B. Does not show amyloid fibrils (congo red staining, magnification x10).
The characteristics of lung nodules can help distinguish autoimmune-related causes from malignancy in some cases. As in rheumatoid arthritis where certain features like nodule multiplicity, smooth border, cavitation, satellite nodules, pleural contact, and subpleural rind of tissue have been associated with benign nodules, Sjögren's does not have a similar scoring system. But subpleural and pleural location,
number >4, and cavitation were all seen in our patient too, demonstrating a similar pattern of benign nodules associated with autoimmune conditions. Further research in this area is needed to come up with specific monitoring guidelines for autoimmunity-associated lung nodules to avoid aggressive interventions and formulate management ideas.
Conclusions
The case that we present here is aimed to bring forward a rare association of fibrotic and inflammatory lung nodules with Sjögren's syndrome and the clinical dilemma that it presents in terms of suspicion of malignancy. We propose to highlight the importance of recognizing autoimmunity as an important cause of lung nodules and that managing these lung nodules requires consistent follow-up imaging, treatment of underlying infections and autoimmunity, biopsying lesions which have a high suspicion of malignancy in terms of characteristics or are increasing in size disproportionate to the underlying disease activity. In these cases, early immunosuppressive therapy and rheumatology involvement will show a fast and good response to treatment.
Author Contributions
The case was conceived by Alexander Carvajal-González with Suma Sri Chennapragada, histopathology was done by Ekin Ozluk. The first draft of the manuscript was written by Alexander Carvajal-Gonzalez, revised by Phani Morisseti and all authors had the opportunity to comment on the manuscript and approve the final version.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Source of funding
None.
References
Gougerot H.
Insuffisance progressive et atrophie des glandes salivaires et muqueuses de la bouche, des conjonctives (et parfois des muqueuses nasale, laryngée, vulvaire) sécheresse de la bouche, des conjonctives, etc).
Clinical pulmonary involvement in primary Sjögren’s syndrome: prevalence, quality of life and mortality – a retrospective study based on registry data.
Toll-like receptor 3 stimulation promotes Ro52/trim21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type i interferon pathway.
Type I and II interferon signatures in Sjögren's syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjögren's related lymphomagenesis.
Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements.
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