A 71 year old man presented with progressive dyspnoea and was found to have a large soft tissue mass in the left lung. The lesion was excised and histology demonstrated pulmonary amyloidosis of the nodular type. No underlying systemic illness could be identified. Pulmonary nodular amyloidosis has to be considered in the differential diagnosis of solitary lung lesions. 
Keywords: Pulmonary nodular amyloidosis; Amyloid.

Introduction: 

Rokitansky is generally credited with the first description of Amyloid in 1842 as a firm greyish ‘lardaceous-gelatinous’ substance infiltrating the liver of patients with syphilis and tuberculosis[1]. In 1854 Rudolph Virchow who believed that it was a cellulose-like substance, gave Amyloid its name after noticing that it stained pale blue with Iodine and Sulphuric acid similar to Corpora Amylacea in brain [2]. Amyloidosis of the respiratory tract was recognized by Lesser in 1877[3]. 

Case report: 

A 71 year old man was admitted to hospital with a four month history of progressive dyspnoea and intermittent low-grade pyrexia. Past medical history included Hypertension and Hypercholesterolemia, which were controlled with medication. He had smoked 5-10 cigarettes a day for 15 years before quitting thirty years ago. There was no significant occupational exposure or relevant family history. 

Physical examination of the chest and major systems was non-contributory. Chest radiography demonstrated a large soft-tissue mass in the left upper lobe. Full blood counts, ESR, CRP, Urea, electrolytes and rheumatoid factor were within normal range. Myeloma screen, autoantibody assay and Mantoux test were negative. Flexible bronchoscopy did not demonstrate any abnormal lesions. CT scan of the chest (Fig 1) confirmed the mass lesion in the anterior bronchopulmonary segment (S3) of the Left upper lobe with a few adjacent smaller nodules. CT-guided biopsy was attempted but proved unsuccessful. 

During Video-assisted Thoracoscopy (VATS) under general anaesthesia, a solitary hard nodular mass in the anterior segment of the left upper lobe of lung was identified and excised completely. Histopathology of the excised mass (8cm x 4cm x 3cm) showed Eosinophilic amorphous material interspersed with lymphoplasmocytic infiltrate and prominent multi-nuclear foreign body type of giant cells. (Fig 2) The material stained positive with Congo red and demonstrated apple-green birefringerence to high intensity cross-polarised light confirming the presence of Amyloid protein. Amyloid was not found surrounding the blood vessels, bronchi or within the alveolar septa. Emphysymatous changes were noted in surrounding lung parenchymal tissue. In the absence of clinical evidence suggestive of systemic amyloidosis or underlying blood dyscrasias, the diagnosis of Pulmonary Amyloidosis of the nodular type (PNA) was made. The patient improved following surgery and remains free of symptoms on follow-up at five months.

Fig 1 CT scan of the chest

Fig 2 Histopathology of the excised mass shows Eosinophilic amorphous material interspersed with lymphoplasmocytic infiltrate and prominent multi-nuclear foreign body type of giant cells

Discussion: 

Amyloid is an eosinophilic fibrillar deposit characterised ultra-structurally as a -pleated sheet protein with 7-10 nm non-branching fibrils of indeterminate length in association with Glycosaminoglycans like heparan and dermatan sulphate. Congo Red stained specimens with the characteristic appearance in polarised light is invaluable in the identification of amyloid and Thioflavine may also be used for histological staining [4]. 



Based on the structure of the fibrils, one classification of Amyloidosis comprises of the following: (1) AA - the reactive form associated with inflammatory diseases, (2) AL - seen with myeloma and gammopathies or in localised forms and (3) ATTR - with Trans-thyretin fibril precursors occurring in senile and hereditary varieties [5]. Other principal forms are (4) b2 microglobulin (Ab2M) and (5) b- amyloid precursor protein (Ab). Amyloid deposition in the extra-cellular space results in disrupted tissue architecture and impaired organ function.


The clinical syndromes resulting from amyloidosis involving the respiratory tract are (1) Tracheobronchial amyloidosis - this is usually localised and tend to recur. Parenchymal amyloidosis [6] is the commoner variety with two forms (2) Diffuse alveolar septal pattern (also known as diffuse parenchymal) - occurring in systemic amyloidosis [7] or with underlying monoclonal lymphoplasmacytoid dyscrasia. (3) Nodular Parenchymal - Solitary or multiple nodules with a predilection for the lower lung zones, often attaining a size of upto 15 cm. Pulmonary Amyloidosis of the nodular type (PNA) may be detected on incidental radiology, during bronchoscopy or may present with evident clinical symptoms. These lesions are well localised, almost invariably of the AL type and are often called ‘Amyloidoma’s. They are not associated with systemic involvement of cardiac, renal or neural tissues. 

Multiple amyloid deposits with AA fibril structure constitute a separate and rarer entity, occurring as a reactive manifestation in systemic diseases. This does not seem to be clinically significant and is often only evident on histology at autopsy [8]. Amyloid can be identified in the small vessel walls and along alveolar septa as opposed to the findings in the case described above.

Immunohistochemical demonstration of AL (as opposed to AA or ATTR) protein may not be conclusive in many cases owing to unique structural variations in each individual [9]. A normal radiolabelled serum Amyloid P component scintigraphy (SAP) scan [10] in the absence of monoclonal plasma cell dyscrasia helps to make the diagnosis of localised nodular pulmonary AL amyloidosis. Respiratory function tests may show restrictive defect or reduced gas transfer in the diffuse alveolar type but may not be helpful in the nodular type. Urinalysis for Bence-Jones proteinuria and serum and urine electrophoresis for monoclonal protein should be checked for in these patients.

Pulmonary marginal zone lymphoma (a type of low-grade non-Hodgkin's lymphoma) is associated with localised secondary amyloid deposition [11] and needs to be differentiated from amyloid nodules with surrounding lymphoplasmocytic infiltrate [12]. Primary Sjogrens syndrome, which in turn is linked with lymphoma, has been reported in association with solitary and multiple pulmonary amyloid nodules. 

Surgical resection of amyloid nodules may be necessary to relieve luminal compression of the airway. A review of medical literature suggests good long-term survival with nodular amyloid as opposed to systemic or interstitial pulmonary amyloidosis.

Pulmonary Amyloidosis of the nodular variety (PNA) should be considered and excluded in the differential diagnosis of solitary lung lesions suggestive of primary and secondary lung neoplasms and the case described here underscores the importance of histological confirmation in such cases. 

References:

[1] Rokitansky C. Handbuch der Speciellen Pathologischen Anatomica. Braumuller und Seidel, Vienna: 1842
[2] Virchow R. Die Cellularpathologie inihrer Begründung auf 
physiologische and pathologische Gewebelehre, Berlin:1858, A. Hirschwald
[3] Lesser A. Ein Fall von Endochondroma osteidum mixtum der Lunge mit partieller amyloid Endartung. Virchows Arch (Pathol Anat). 1877;69:404.
[4] Glenner GG. Amyloid deposits and amyloidosis. The -fibrilloses. N Engl J Med 1980;302:1283-1292;1333-1343.
[5] Husby G. Nomenclature and classification of amyloid and amyloidoses. J Intern Med 1992;232:511-512.
[6] Gillmore JD, Hawkins PN. Amyloidosis and the respiratory tract. Thorax 1999;54:444-451.
[7] Cordier JF, Loire R, Brune J. Clinical and pathologic features in a series of 21 patients. Amyloidosis of the lower respiratory tract. Chest 1986;90:827-831.
[8] Looi LM. The pattern of amyloid deposition in the lung. Malays J Pathol 1999 Jun;21(1):29-35.
[9]Tan SY, Pepys MB. Amyloidosis. Histopathology 1994;25:403-414.
[10] Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med 1990;323:508-513.
[11] Lim JK, Lacy MQ, Kurtin PJ et al. Pulmonary marginal zone lymphoma of MALT type as a cause of localised pulmonary amyloidosis. J Clin Pathol 2001 Aug;54(8):642-6. 
[12] Dacic S, Colby TV, Yousem SA. Nodular amyloidoma and primary pulmonary lymphoma with amyloid production: a differential diagnostic problem. Mod Pathol 2000 Sep;13(9):934-40.


Learning points:

• Pulmonary Nodular Amyloidosis is a relatively rare condition. 
• PNA should be considered in the differential diagnosis of solitary lung lesions and may mimic lung neoplasms. 
• Nodular amyloidosis is not commonly associated with underlying systemic disease. 
  
  

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