Q1. C
Q2. B
Q3. D

Metastatic calcification

This case demonstrates the classic findings of so called « metastatic » calcification, histologically characterized by deposition of calcium within the alveolar walls accompanied by filling of alveolar spaces by fibroblastic tissue. The diagnosis can be challenging in small biopsy specimens as the calcium deposits become fragmented during tissue processing and there can be extensive cutting artefact. Areas with preserved parenchyma show deposition and replacement of alveolar walls by hematoxyphilic material which essentially creates a « skeleton » of the alveolar lung parenchyma. The calcification is characteristically restricted to the interstitium, and when there is doubt on routine stains, a Von Kossa stain (Figure 6) can be used to confirm that the deposits are indeed calcium.

Given the « fence like » architecture of lung parenchyma (as it appears in 2 dimensions), this histologic image in a young patient could raise the suspicion of the « chicken wire » calcification seen in chondroblastoma, which can rarely metastasize. However, the calcification in chondroblastoma is pericellular and this case lacks the typical ovoid to epithelioid neoplastic cells. Fibrosing alveolitis, while a good descriptor for the fibrous obliteration of alveolar spaces seen in this case, is an obsolete term for what is now called organizing pneumonia (OP). Indeed, OP is an important differential diagnosis it can be seen associated with metastatic calcification and some cases of cicatricial OP can undergo calcification. The OP associated with metastatic calcification, when present, is usually at the periphery of the lesions and consists of the typical serpiginous and polypoid fibroblastic plugs. Unlike in OP, the alveolar fibroblastic proliferation in metastatic calcification is uniform, generally fills the alveoli completely (« wall to wall »), and is not associated with significant pneumocyte hyperplasia. In addition, when OP calcifies, the calcification occurs within the fibroblastic plugs not the alveolar walls. Other manifestations of extracellular calcium deposition in the lung are the various forms of metaplastic ossification. These are deposits of woven bone (often with marrow elements) which generally form discrete lesions (dendriform/racemose, or nodular), but can occasionally be diffuse. Calcifying fibrous pseudotumor is a well circuscribed tumor which generally occurs in the pleura, ans is characterized by dense hypocellular collagenous stroma with interspersed dystrophic or psammomatous calcification.

Interestingly, while the CT imaging characteristics can be quite dramatic, metastatic calcification is most often asymptomatic. While « metastatic » raises alarm for a neoplastic condition, the term as applied here refers to the ability of the calcium to circulate through the body and deposit at a distant site. As one would surmise, the deposits occur in the setting of altered systemic calcium metabolism, and is seen most commonly in the setting of chronic renal insufficiency with secondary hyperparathyroidism. Other disorders that increase circulating calcium include primary hyperparathyroidism and increased bone turnover in the setting of hematologic malignancies. While metastatic calcification is known to occur in the setting of orthotopic liver transplantation, the precise pathophysiology remains somewhat unclear. It is believed that frequent blood transfusions due to coagulopathy related-blood loss and anemia are involved. The theory is that sodium citrate (in blood products) can chelate ionized calcium and cause hypocalcemia which in turn causes secondary hyperparathyroidism and/or increased calcium supplementation due to apparent hypocalcemia.

It is not uncommon for patients with metastatic pulmonary calcification to have calcifications of other organs such as kidney, stomach and myocardium. As the deposits are often asymptomatic, metastatic calcification can go undiagnosed and is sometimes only identified at autopsy. In this setting, or if surgical specimens are received, the involved areas of the lung have a firm and gritty texture due to both the alveolar filling and extensive calcium deposits. In addition to the histologic features described above, the calcium deposits can elicit a foreign body type giant cell reaction. While chronic pulmonary hemorrhage can result in interstitial deposits and a foreign body type giant cell reaction, the deposits are not calcium but rather iron which encrusts the elastic fibers within alveolar septa.

The management of metastatic pulmonary calcification is centered on treatment of the underlying cause, and in so doing slow or halt the development of further calcification. There is no known treatment that specifically targets and/or causes regression of the lung lesions.

Take home message for trainees:

Location, location, location! When you see calcification try to pinpoint where it is, what structures it involves, and what tissue it is associated with - this will help determine what type of calcification it is and lead to the correct diagnosis.

Chan ED, Morales DV, Welsh CH, et al. Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med 2002;165:1654-69.

Kundel V, Harkin TJ. Metastatic pulmonary calcification following orthotopic liver transplantation. Am J Respir Crit Care Med 2016;193:A1670 (abstract).

Charles Leduc, MD, MSc
Thoracic Pathologist
University of Montreal Health Center
Montreal, Quebec, Canada