Myxoma pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]Cafer Zorkun, M.D., Ph.D. [3]Ahmad Al Maradni, M.D. [4]
Overview
Cardiac myxoma is a benign intracavitary endocardial mass that represents the most common primary tumor of the heart.[1] Myxoma cells are characterized by undifferentiated mesenchymal cells, which potentially differentiate into many tissues such as blood vessels, glandular structures, and bones.[2] The primary distribution of cardiac myxoma is the left atrium (75%) of the heart, regularly they tend to be located in the fossa ovalis and endocardium of the atrial septum.[3]
Pathogenesis
Pathogenesis
- Cardiac myxoma arises from remnants of subendocardial vasoformative reserve cells, which are primitive mesenchymal cells that are normally involved in the supportive structure of the endocardium.[4][5]
- The exact pathogenesis of cardiac myxoma is not fully understood.[1]
- It is thought that cardiac myxoma is produced by the neoplastic theory, dysembryoplastic theory, histopathogenesis of glandular cells in myxoma or the thrombotic theory.[6][7]
- The site of tumor attachment, normally the foramen ovale, is considered to be consistent with an origin from multipotent mesenchymal cells or from embryonic rests.[8]
Genetics
- Sporadic cardiac myxomas and familial forms are related with several chromosome and gene alterations which involve cardiac development.[9]
- Inherited myxomas are usually present in Carney complex.[9]
- The development of Carney complex is a result of PRKAR1A gene inactivation mutation that is associated with chromosome 17q24.2-q24.3.[9]
- The gene 17q24.2-q24.3 plays an important role in cardiac development and myxomagenesis. The expression of PRKAR1A causes myxomatous changes in the endocardium.[9]
- The encoded protein of PRKAR1A is a type 1A regulatory subunit of protein kinase A.[10]
- Inactivating germline mutations of this gene are found in 70% of people with Carney complex.[10]
- Less commonly, the molecular pathogenesis of Carney complex is a variety of genetic changes at chromosome 2p16.[10]
- Both types of Carney complex are autosomal dominant.[10]
- Despite dissimilar genetics, there appears to be no phenotypic difference between PRKAR1A and chromosome 2p16 mutations.[10]
Associated Conditions
- The Carney complex is characterized by myxomatous neoplasms (cardiac, endocrine, cutaneous, and neural), and a host of pigmented lesions of the skin and mucosae, including the rarely occurring epitheloid blue nevus.[11][12][13]
- Approximately 7% of all cardiac myxomas are associated with Carney complex.[14]
Gross Pathology
- On gross pathology, external appearance, consistency size, and weight are extremely variable findings of cardiac myxoma.[15]
- Tumor consistency depends on the quantity and distribution of fibrous tissue and calcification (it can be smooth, lobulated, friable or gelatinous).[15]
- Myxomas are usually described as gelatinous, irregular surface that fills the left atrium.
- Myxomas that have irregular consistency are more likely to form surface thrombi and embolize.[16]
- Morphologically, these lesions tend to be attached to the endocardium by a broad-based pedunculated stalk.[17]
- In some cases, the attachment to the endocardium can also be without a clear stalk, or sessile.[17]
- Cardiac myxomas are non-invasive tumors, thus there is no infiltration to underlying tissues.[17]
- Cardiac myxomas are intracavitary tumors.[17]
- The distribution is normally within the interatrial septum or adjacent to foramen ovale (75%).[17]
- However, they can also be found in other cardiac chambers, such as right atrium (15%), ventricles (2%) or cardiac valves (rare).[17]
- Large cardiac myxomas are usually located in fossa ovalis.[1]
- The size of the tumor varies from 0.6 to 12 cm, with a mean weight of 40 g.[1]
- Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
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A gelatinous tumor is attached by a narrow pedicle to the atrial septum. The myxoma has an irregular surface and nearly fills the left atrium -
Left atrial myxoma -
Gross pathology atrial myxoma: myxomas are brownish or white and are frequently covered with thrombus
Microscopic Pathology
- On microscopic histopathological analysis, myxoma cells have an ovoid nucleus with large nucleoli, abundant eosinophilic cytoplasm, and indistinct cell borders.[18]
- They are usually arranged in perivascular ring structures (typically, infiltrated by lymphocytes and macrophages).[15]
- The Gamna-Bodies which consist of fibrosis and deposition of iron pigments are a characteristic finding of myxoma tumors.[15]
- Other frequent histological findings, are hemosiderin within the histiocytes, thrombosis, fibrosis and calcifications.[15]
- In some cases, extramedular hematopoises is present and mucin-producing glands can be also seen in the base of the tumor.[15]
- The extracellular matrix forms an alcian blue-positive myxoid stroma, composed of variable amounts of proteoglycans, elastin and collagen.[15]
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![Black arrow (top): Endothelium Black arrow (bottom): Hemosiderin macrophage [19]](/images/3/3e/800px-Atrial_myxoma_edge_high_mag.jpg)
Black arrow (top): Endothelium Black arrow (bottom): Hemosiderin macrophage [19]
![Black arrow (top): Endothelium Black arrow (bottom): Hemosiderin macrophage [19]](/index.php/File:800px-Atrial_myxoma_edge_high_mag.jpg)
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Cardiac myxoma: Gamna Bodies: A peculiar form of fibrosis with deposition of iron pigment, identical to that seen in the spleens of patients with sickle cell anemia, is not uncommon in myxoma. -
Cardiac myxoma: Common features at the interface with the atrial septum include lymphoid aggregates, smooth muscle bundles, and thick walled vessels which angiographically may look like neovascularization. -
Cardiac myxoma: The extramedullary hematopoiesis seen here is present in about 7 percent of cardiac myxomas. -
Cardiac myxoma: Glandular structures are seen in less than 5 percent of cases. In this example, they were limited to the base of the myxoma.
Immunohistochemistry
- Cardiac myxoma cells exhibit immuno-reactivity mainly for calretinin (75–100%) followed by vimentin (>50%), NOTCH1, alpha-1 antichymotrypsin and plakophilin- 2.[20]
- Calretinin plays an important role in the discrimination of mural thrombi and papillary fibroelastoma.[20]
- Another immunohistochemical marker, survivin (an apoptosis inhibitor) has been detected to play an important role in the development and growth of cardiac myxomas.[21]
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| Inmunohistochemistry |
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References
- ↑ 1.0 1.1 1.2 1.3 Grebenc ML, Rosado de Christenson ML, Burke AP, Green CE, Galvin JR (2000). "Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation". Radiographics. 20 (4): 1073–103, quiz 1110–1, 1112. doi:10.1148/radiographics.20.4.g00jl081073. PMID 10903697.
- ↑ Bulkley BH, Hutchins GM (1979). "Atrial myxomas: a fifty year review". Am. Heart J. 97 (5): 639–43. PMID 433739.
- ↑ Grebenc ML, Rosado de Christenson ML, Burke AP, Green CE, Galvin JR (2000). "Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation". Radiographics. 20 (4): 1073–103, quiz 1110–1, 1112. doi:10.1148/radiographics.20.4.g00jl081073. PMID 10903697.
- ↑ Roscher AA, Kato NS, Quan H, Padmanabhan M (1996). "Intra-atrial myxomas, clinical-pathologic correlation based on two case studies including historical review". J Cardiovasc Surg (Torino). 37 (6 Suppl 1): 131–7. PMID 10064365.
- ↑ Acebo E, Val-Bernal JF, Gómez-Román JJ (2001). "Prichard's structures of the fossa ovalis are not histogenetically related to cardiac myxoma". Histopathology. 39 (5): 529–35. PMID 11737312.
- ↑ Orlandi A, Ciucci A, Ferlosio A, Genta R, Spagnoli LG, Gabbiani G (2006). "Cardiac myxoma cells exhibit embryonic endocardial stem cell features". J. Pathol. 209 (2): 231–9. doi:10.1002/path.1959. PMID 16508920.
- ↑ Amano J, Kono T, Wada Y, Zhang T, Koide N, Fujimori M, Ito K (2003). "Cardiac myxoma: its origin and tumor characteristics". Ann Thorac Cardiovasc Surg. 9 (4): 215–21. PMID 13129418.
- ↑ Reynen K (1995). "Cardiac myxomas". N. Engl. J. Med. 333 (24): 1610–7. doi:10.1056/NEJM199512143332407. PMID 7477198.
- ↑ 9.0 9.1 9.2 9.3 Sun Y, Chen X, Sun J, Wen X, Liu X, Zhang Y, Hoffman AR, Hu JF, Gao Y (2015). "A Novel Inherited Mutation in PRKAR1A Abrogates PreRNA Splicing in a Carney Complex Family". Can J Cardiol. 31 (11): 1393–401. doi:10.1016/j.cjca.2015.05.018. PMID 26416542.
- ↑ 10.0 10.1 10.2 10.3 10.4 Carney Complex. Wikipedia. https://en.wikipedia.org/wiki/Carney_complex Accessed on November 24, 2015
- ↑ Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). 1985;64(4):270-83.
- ↑ Iglesias C, Torrelo A, Colmenero I, Mediero IG, Zambrano A, Requenca L. Isolated multiple congential epithelioid blue naevus. British Journal of Dermatology 2005;152:391-393.
- ↑ Gaissmaier et al. (letter and response) Carney Complex. Circulation 1999;100 (25); e150 http://circ.ahajournals.org/cgi/reprint/100/25/e150
- ↑ Reynen, K. (1995). "Cardiac Myxomas". New England Journal of Medicine. 333 (24): 1610–1617. doi:10.1056/NEJM199512143332407. PMID 7477198.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 Di Vito A, Mignogna C, Donato G (2015). "The mysterious pathways of cardiac myxomas: a review of histogenesis, pathogenesis and pathology". Histopathology. 66 (3): 321–32. doi:10.1111/his.12531. PMID 25297937.
- ↑ He DK, Zhang YF, Liang Y, Ye SX, Wang C, Kang B; et al. (2015). "Risk factors for embolism in cardiac myxoma: a retrospective analysis". Med Sci Monit. 21: 1146–54. doi:10.12659/MSM.893855. PMC 4418206. PMID 25900256.
- ↑ 17.0 17.1 17.2 17.3 17.4 17.5 Yoon DH, Roberts W (2002). "Sex distribution in cardiac myxomas". Am. J. Cardiol. 90 (5): 563–5. PMID 12208428.
- ↑ Vaideeswar P, Butany JW (2008). "Benign cardiac tumors of the pluripotent mesenchyme". Semin Diagn Pathol. 25 (1): 20–8. PMID 18350919.
- ↑ Cardiac Myxoma. Libre Pathology URL http://librepathology.org/wiki/index.php/Cardiac_myxoma Accessed on November 19,2015
- ↑ 20.0 20.1 Acebo E, Val-Bernal JF, Gómez-Roman JJ (2001). "Thrombomodulin, calretinin and c-kit (CD117) expression in cardiac myxoma". Histol. Histopathol. 16 (4): 1031–6. PMID 11642722.
- ↑ Lin YS, Jung SM, Wu HH, Shiu TF, Tzai FC, Chu JJ, Lin PJ, Chu PH (2011). "Survivin expression in cardiac myxoma". Chang Gung Med J. 34 (4): 360–6. PMID 21880190.