Disappearing nodules: spontaneously regressing pulmonary amyloidosis

Abstract

A case report of spontaneous regression of pulmonary amyloidosis, diffuse interstitial pattern, in an elderly patient.

Background

Amyloidosis consists of the deposition of insoluble fibrillar proteins called amyloid, with a spectrum of disease including localised asymptomatic to symptomatic systemic disease. Diagnosis requires biopsy with typing of amyloid. The most common form of systemic amyloidosis is the light chain-related amyloidosis (AL), or primary amyloidosis, where the amyloid deposit contains immunoglobulin light chains, frequently related to plasma cell dyscrasias.¹ Immunoglobulins will also be detectable in serum and urine. Symptoms secondary to amyloid deposition are associated with compression of normal tissue and may involve any organ system. Typical sites of AL amyloid deposition include soft tissue, kidney, liver, spleen, nervous system, heart and lymphatic system.² AL amyloidosis is also the most common type of protein to produce localised amyloid deposits leading to localised disease commonly in skin, eyelids, larynx and urinary tract with rare progression to systemic disease.³ Pulmonary amyloidosis may be either part of systemic (primary amyloidosis or associated with myeloma) or organ-limited amyloidosis.

Case presentation

An 82-year-old woman with previous medical history notable for hypothyroidism, left breast cancer with mastectomy, hypertension, hyperlipidemia, diet-controlled diabetes and gastro-oesophageal reflux disease presented for evaluation of chest pain. Prior to presentation, she tripped over a loose brick and suffered a mechanical fall with injury to her left knee. She noticed left-sided chest pain 1 day later without radiation, which was worsened with eating. Initial evaluation included an ECG showing sinus tachycardia without ischaemic changes and a set of negative cardiac enzymes. Chest X-ray was notable for flattened diaphragms and hyperinflation. Rib X-ray showed no evidence of displaced left rib fracture. D-dimer was elevated to 7.98 mcg/mL. She received a chest CT angiogram to exclude pulmonary embolism. The CT scan demonstrated septal thickening, mediastinal lymphadenopathy, hilar lymphadenopathy calcified hilar lymph nodes, right hilar hypodensity and innumerable 2–3 mm pulmonary nodules (figure 1). Chest pain aetiology was not conclusively determined, and was attributed to gastro-oesophageal reflux and trauma. Chest pain improved without any specific intervention.

Figure 1.

Representative images of initial CT scan showing diffuse pulmonary nodules and lymphadenopathy.

Investigations

Bronchoscopy with endobronchial ultrasound-guided biopsy was performed to exclude malignancy. There were no tracheobronchial abnormalities noted. Biopsies of station 7 and R11 lymph nodes were performed, with limited lymphoid cells present. Transbronchial biopsy of the right upper lobe showed thickened vascular walls and deposit of amorphous material around the bronchiole, which showed apple-green birefringence on Congo red stain. For further evaluation of lymphatic involvement, the patient underwent mediastinoscopy and lymph node biopsies of L2, R2 and R4 performed (figure 2). Tissue showed amorphous material and was stained with Congo red stain, resulting in positive apple-green birefringence consistent with amyloidosis (figure 3). Serum immunofixation identified IgA light chain monoclonal gammopathy. A diagnosis of AL amyloidosis was made. Bone marrow biopsy revealed hypercellular marrow and trilineage haematopoiesis with 5%–10% plasma cells and no evidence of frank myeloma. Further studies to evaluate cardiac function included a normal voltage electrocardiogram (EKG), normal pro-brain naturietic peptide (pro-BNP) of 48 and an echocardiogram demonstrating normal left ventricular systolic function with grade 2 diastolic dysfunction. Liver enzymes were within normal limits and there were no other signs of amyloid deposition.

Figure 2.

Lymph node biopsy showing replacement of 90% lymph node with amyloid.

Figure 3.

Amyloid deposits showing apple-green birefringence on Congo red stain.

Outcome and follow-up

As our patient had asymptomatic pulmonary and nodal disease without evidence of cardiac involvement or systemic disease such as multiple myeloma, oncology consultant recommended expectant management. On repeat CT imaging 6 months later, a decrease in parenchymal disease was noted, thus indicating spontaneous improvement (figure 4). At 1 year post diagnosis, she has not progressed to multiple myeloma and does not demonstrate any additional signs of organ involvement.

Figure 4.

Follow-up CT scan 6 months later showing resolution of pulmonary nodules.

Discussion

AL amyloidosis may involve amyloid infiltration of various organs. Amyloid fibrils are made from various immunoglobulin light chain proteins which are misfolded. Fibrils combine with serum amyloid P and glycosaminoglycans to form beta-pleated sheets.² Amyloidosis symptoms are caused by compression and disruption of normal tissue structures. It is unknown why amyloid fibrils develop. The incidence of amyloidosis at standard autopsy is 0.2%–0.5% of all patients and 10%–15% patients with multiple myeloma.² It is estimated 50% of patients with amyloidosis have pulmonary involvement. However, the lack of symptoms related to pulmonary involvement typically makes it difficult to determine the incidence of pulmonary involvement prior to autopsy.^{4 5} Systemic AL amyloidosis is more common in men and in patients over age 50 years.² The prognosis of AL amyloidosis depends on the involvement of vital organs. The most common causes of death are heart and kidney failure.⁶

In localised AL amyloidosis, multiple forms of parenchymal lung disease have been recognised. These include nodular, diffuse interstitial and tracheobronchial disease.⁷ Our patient has diffuse interstitial parenchymal disease, without symptoms. This type can involve all or any of the interstitial structures (alveoli, septa, capillaries, bronchioles and/or arterioles) and occasionally may occur without overt cardiac involvement.⁸ Symptoms, in the absence of cardiac involvement, are rare. The severity of respiratory impairment depends largely on the degree to which the gas exchange zones (alveolar septa and capillaries) are affected.⁹ Amyloidosis involving gas exchange zones presents with interstitial lung disease. Amyloid deposits may first form in the basal membranes separating alveolar and epithelial cells. Dyspnea may be associated with arterial amyloid deposition.⁵

The management of localised pulmonary amyloidosis is based on symptoms; our patient was monitored without treatment as she was asymptomatic. The spontaneous regression of pulmonary parenchymal disease and pattern of amyloid involvement are noteworthy in this case. There are two reported cases of pulmonary amyloidosis with spontaneous regression. The first was a case report of diffuse alveolar involvement; however, this patient lacked mediastinal and hilar lymphadenopathy.¹⁰ The second case involved type AA amyloidosis presenting with three right upper lobe lung nodules.¹¹

The particular pattern of involvement in our patient is unusual due to the presence of mediastinal and hilar lymphadenopathy with diffuse interstitial pulmonary disease and lack of systemic involvement.^{1 2} Mediastinal and hilar lymphadenopathy, including lymph node calcification, was first reported in 1976.¹² A similar presentation of hilar lymphadenopathy, without any identified pulmonary nodules, has been reported.¹³ A previous review of localised pulmonary AL amyloid indicated 6/126 cases had hilar and/or mediastinal lymphadenopathy.¹⁴ A review from Mayo Clinic identified 55 patients with pulmonary amyloid between 1980 and 1993, noting 17 patients with localised pulmonary disease, none with mediastinal or hilar lymphadenopathy.⁴

Pulmonary amyloidosis may present in a variety of manifestations, and it should remain on the list of differential diagnoses in patients with otherwise unexplained pulmonary nodules.

Learning points.

• Pulmonary amyloidosis may occur as systemic or organ-limited disease and have multiple patterns of involvement.

• Management of organ-limited pulmonary amyloidosis is based on patient symptoms.

• Pulmonary amyloidosis should be considered in the differential diagnosis of diffuse pulmonary nodules.