March 2021 — Cardiovascular Pathology

The diagnosis in this case is: Mutation in fibrillin-1 (FBN1).

This patient is most likely to have an aortic aneurysm as a result of Marfan syndrome — a condition caused by a mutation in fibrillin-1, an extracellular matrix protein. Marfan has an incidence of approximately 2-3 per 10,000 individuals and occurs in both familial and sporadic forms. Clinically, patients may exhibit a wide constellation of findings including long limbs, scoliosis, pectus excavatum or carinatum, joint laxity, lens subluxation, and prolapse of the atrioventricular valves. As in this case, patients have a higher incidence of glaucoma and are at an increased risk of developing aortic aneurysms.¹ Histologically, aortic resections show medial degeneration and laminar medial necrosis. Historically, this was referred to as a “cystic medial degeneration” — a term that is now out of favor. Normal aortic specimens show three layers of the aortic wall (intima, media, adventia), with the medial layer organized into stacked lamellar units running in parallel. The laminae are composed of elastic tissue, extracellular matrix, smooth muscle cells, and mucopolysaccharides. Medial degeneration is characterized by mucoid extracellular matrix accumulation (MEMA) with elastic fiber thinning and fragmentation.  Laminar medial necrosis is characterized by loss of smooth muscle nuclei, and collapse of elastic fibers.  In Marfan syndrome, the pattern of medial degeneration and laminar medial necrosis can be incredibly severe, with almost complete loss of elastic fibers as is seen in this case (Areas 1 and 2). However, not all of the aortic wall is affected and some non-anuerysmal areas are spared of elastic fiber fragmentation and have normal appearing histomorphology (Area 3). 

MEMA can be subclassified as either translamellar (MEMA-T) or intrlamellar (MEMA-I). In MEMA-T, the extracellular matrix appears as pools or lakes that have expanded and distorted the layers between lamellar units (Area 2). In MEMA-I there is an increase in extracellular matrix without significantly distorting the layered arrangement of lamellar units. While not specific, MEMA-T is observed in several syndromic conditions associated with aortic aneurysms, including Marfan, Ehlers-Danlos, and Turner syndrome. Loeys-Dietz syndrome is a similar connective tissue disorder that is associated with aortic aneurysms and is characterized by mutations of transforming growth factor related proteins (TGFB2, TGFBR1, TGFBR2). While MEMA-T can be seen in Loeys-Dietz patients, the MEMA-I pattern is more closely associated with the syndrome.²

Inflammatory lesions of the aorta can result in aneurysmal changes with a wide variety of inflammatory histologic patterns depending on the underlying etiology (infectious, autoimmune, etc.). Syphillitc aortitis classically shows “tree bark” gross pathology with a characteristic endarteritis obliterans seen histologically. The vessels of the adventia and vasa vasorum are particularly targeted by the inflammatory reaction, leading to ischemic injury to the aorta. Clinically the patients typically present with congestive heart failure and severe cardiomegaly (cor bovinum).³

While systemic hypertension is probably the most common cause of aortic root dilatation and ascending aorta aneurysms, the extent of medial degeneration and laminar medial necrosis is much more attenuated compared to the severe degenerative histopathologic findings in this case.

References

1. Judge, D. P., & Dietz, H. C. (2005). Marfan’s syndrome. Lancet (London, England), 366(9501), 1965–1976. https://doi.org/10.1016/S0140-6736(05)67789-6
2. Halushka, M. K., Angelini, A., et al. (2016). Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria. Cardiovascular Pathology, 25(3), 247–257. https://doi.org/10.1016/j.carpath.2016.03.002
3. Stone, J. R., Bruneval, P., et al. (2015). Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. Cardiovascular Pathology, 24(5), 267-278. https://doi.org/10.1016/j.carpath.2015.05.001