The Different Types of Necrosis and Their Histological Identifications.
Introduction
Necrosis comes from the Greek origin nekrōsis meaning “death” and later moved to modern Latin to necrosis. Necrosis can be described as a pathological process of cell death which could have been resulted from infections, hypoxia, trauma or toxins. Unlike apoptosis, necrosis is uncontrolled and release lots of chemicals from the dying cell to which causes damage to surrounding cells. Inflammation is often initiated due to necrosis. There are many types of morphological patterns that necrosis can present itself. These are coagulative, liquefactive, caseous, gangrenous which can be dry or wet, fat and fibrinoid.
Necrosis can start from a process called “oncosis”. Oncosis comes from the Greek origin ónkos, meaning swelling. Oncosis occurs when the mitochondria within a cell are damaged beyond recovery by toxins or hypoxia. ATP is thus not being made, which dysregulate the ionic concentration within the cell as the ionic pumps are no longer functioning. Sodium moves into the cell and water follow, making the cell explode. The content that has been released will attract immune cells which will initiate inflammation and release reactive oxygen species (ROS) and enzymes such as proteases. The surrounding tissues may be damaged, and therefore organs may fail to work. In a way, necrosis alerts the immune system to clean through phagocytosis and start local inflammation. However, if the collateral damage is more significant than the process of healing, necrosis will thus increase in size, killing more healthy cells and decrease surrounding body function, which may cause organ failure. Decomposing tissue will increase in number, and micro-organisms may start to replicate and dominate as the immune system struggle to contain the necrosis. Surgery is thus utilised to remove the necrotic tissue by a procedure called debridement and let the healthy tissue take over and heal. Depending on the severity, time, type and extent of the necrosis, the tissues may never heal back to its original function and integrity.
These amazing histology slides and figures are from the Robbins and Cotran pathologic basis of disease, 9th ed, textbook. Consider buying the book as the information is very relevant to the topic.
Figure 1: Demonstrate necrosis of a cell. Notice how the contents leaks everywhere which will induce inflammation and possible organ failure.
Figure from: Robbins and Cotran pathologic basis of disease, 9th ed.
NECROSIS (compared to apoptosis)
Occurs less frequently, involves many cells, may not be localised.
Abnormal and uncontrolled cell death that is associated with a pathological condition.
Caused by external and internal injuries.
Caspase independent pathway.
Inflammation is present.
Cell swells and burst, releasing its content at once.
Swelling of the mitochondria and endoplasmic reticulum occurs.
Leakage and enzymatic digestion of neighbouring cellular contents.
Disrupted plasma membrane structure.
Eosinophilia cell-like present (cells presenting pink on a histology slide).
Nuclear changes: pyknosis, karyorrhexis and karyolysis.
Types of necrosis
Depending on where (such as which organ) and what type of damage occurred in the body, necrosis will have a specific morphological pattern. There are six distinct patterns that are identifiable, and by identifying the pattern, an underlying cause could be identified. Let’s have a look at: coagulative, liquefactive, caseous, gangrenous, fat and fibrinoid necrosis.
Coagulative
Coagulative necrosis generally occurs due to an infarct (lack of blood flow from an obstruction causing ischaemia) and can occur in all the cells of the body except the brain. The heart, kidney, adrenal glands or spleen are good examples of coagulative necrosis. Cells that undergo coagulative necrosis can become dry, hard, and white. What is interesting is that gel-like appearance occurs in dead tissues, but the architecture of the cells is maintained for at least some days. Coagulation occurs as the proteins are degraded and denatured, and an opaque film starts to form.
Gross appearance: a pale segment may be seen in contrast to surrounding healthy tissues. The segment may be hard to the touch.
Microscopic appearance: in an H&E staining tissue, eosinophilia like-cell (cells presenting pink on a histology slide) will be noticeable. Anucleated cells (cells without a nucleus) should be observable with preserved cell outlines.
Figure 2: Demonstrate the gross appearance of a kidney. Notice the yellow necrotic portion.
Figure from: Robbins and Cotran pathologic basis of disease, 9th ed.
Figure 3: Demonstrate the histology slide of the kidney in figure 2. The green star shows healthy cells that are less pink and have nuclei present. The blue star is a Bowman's capsule. The yellow star indicates the necrotic portion. Notice that the architectural structure of the cell is still present, but no nuclei can be seen. You could almost draw a line between damaged and non-damaged cells.
Figure from: Robbins and Cotran pathologic basis of disease, 9th ed.
Liquefactive
Liquefactive necrosis can be associated from bacterial, viruses, parasites or fungal infections. Unlike coagulative necrosis, liquefactive necrosis forms a viscous liquid mass as the dead cells are being digested. The micro-organisms can release enzymes to degrade cells and initiate an immune and inflammatory response. Cellular dissolution and digestion of dying cells may also release further enzymes, which speeds up the liquefying process. The micro-organisms stimulate the leukocyte to home-in on the necrotic area and release powerful hydrolytic enzymes (such as lysozymes) which causes local damage and cells to be lysed, causing a fluid phase. The enzymes responsible for liquefaction are derived from either bacterial hydrolytic enzymes or lysosomal hydrolytic enzymes. These are proteases (collagenases, elastases), DNases and lysosomal enzymes.
A creamy yellow liquid should be present as lots of leukocytes are found to be dead, this is generally called pus. Interestingly, an infarct that involves the nervous system (such as the brain) should present as coagulative necrosis but does not occur, instead liquefactive necrosis is present. It is not fully explained why the nervous system displays liquefactive necrosis without the cause of an infection, but it is suggested that the nervous system does hold a higher amount of lysosomal content, which leads to autolysis and an increased opportunity for these enzymes to digest the cells in the brain.
Gross appearance: liquid-like layer can be seen; pus should be present. Yellowing, softening or swelling of the tissue should be seen. Malacia (softening, or loss of consistency) should be present. A cystic space should be present for tissue resolution.
Microscopic appearance: macrophages and neutrophils, both dead and alive, should be present. Debris and lysed cells should be seen with inflammation. Partial space should be filled with lipids and debris. There is a loss of neurons and glial cells, with the formation of clear space.
Figure 4: Demonstrates liquefactive necrosis. In this particular case, there has been an infarct in the brain. Coagulative necrosis does not occur at the nervous system.
Figure from: Robbins and Cotran pathologic basis of disease, 9th ed.
Figure 5: Demonstrates the histology slide of liquefactive necrosis. Notice the middle where it is pinker with more space and fewer neurons. On high power, macrophages should be present with lipids and debris.
Figure from: The University of Utah Eccles Health Sciences Library.
Caseous
Caseous necrosis occurs when the immune system and body cannot successfully remove the foreign noxious stimuli. For example, tuberculosis is a prime example where there is an aberrant immune response (such as the alveolar macrophages are not responding correctly) to the bacteria as the bacteria has infected the macrophages. The immune system seals off the foreign matter by using fibroblasts and white blood cells such as lymphocytes, neutrophils, NK cells, dendritic cells and macrophages. A granuloma may form with fibroblast cells (which creates an encasing layer), leukocytes and the formation of Langhans giant cells (fusion of epithelioid cells). The organism is not killed but rather contained.
Gross appearance: a yellow-white soft cheesy sphere that is enclosed by a distinct border.
Microscopic appearance: a granuloma should be present. The core is necrotic and uniformly eosinophilic, which is surrounded by a border of activated macrophages and lymphocytes. The core is structureless and should have debris and lysed cells. Langhans giant cells may be seen, and inflammation should also be noticed and present. There is a fibrous case surrounding and enclosing the core; hence fibroblasts should also be seen.
Figure 6: Demonstrates the lung containing caseous necrosis due to tuberculosis. Notice the yellow-white and cheesy debris.
Figure from: Robbins and Cotran pathologic basis of disease, 9th ed.
Figure 7: Demonstrates a granuloma with central necrosis in a lung of a person with tuberculosis. Note the Langhans-type giant cells (with many nuclei arranged in a horseshoe-like pattern at the edge of the cell) around the periphery of the granuloma. Langhans-type giant cells are seen in many types of granulomas and are not specific for tuberculosis.
From: Mutleysmith, on wikipedia.
Gangrenous
Gangrenous necrosis does not demonstrate a specific pattern of cell death but is preferably used in clinical practice to describe the condition. Gangrenous necrosis generally describes the damage that has occurred to the extremities (especially lower) where there is severe ischaemia. These extremities lack in blood supply and oxygen and typically cause coagulative necrosis at different tissue planes (this is also called dry gangrene). Severe frostbite injuries can lead to dry gangrene. If bacterial infection occurred, liquefactive necrosis could also be occurring due to the degrading enzymes and the involvement of the leukocytes. When liquefactive necrosis is present, the term ‘wet’ gangrene is used.
Gross appearance: black skin is generally seen with a degree of putrefaction (the process of decay or rotting in a body or other organic matter). The tissues may look ‘mummified’, be sure to ascertain if this is dry or wet gangrene. Smelling may give a clue if there is an infection.
Microscopic appearance: due to the ischaemia which would suggest dry gangrene, coagulative necrosis histological traits should be seen. If there is a bacterial infection which would suggest wet gangrene, liquefactive necrosis histological traits should be seen.
Figure 8: Demonstrates gangrene, or necrosis of many tissues in a body part. In this case, the toes were involved in a frostbite injury. This is an example of "dry" gangrene in which there is mainly coagulative necrosis.
Figure from: The University of Utah Eccles Health Sciences Library.
Figure 9: Demonstrates gangrene of the lower extremity. In this case, the term "wet" gangrene is more applicable because of the liquefactive component from superimposed infection in addition to the coagulative necrosis from loss of blood supply.
Figure from: The University of Utah Eccles Health Sciences Library.
Figure 10: Gangrenous necrosis involves the tissues of a body part. The inflammation seen here is extending beneath the skin of a toe to include soft tissue (fat and connective tissue at the right) and bone (at the left). Because multiple tissues are non-viable, amputation of such areas is necessary.
Figure from: The University of Utah Eccles Health Sciences Library.
Fat
Fat necrosis does not denote a type of necrosis pattern. Instead, it is used to describe the destruction of fat, for example, due to pancreatic lipases that have been released into the surrounding tissues where the pancreas itself is at risk along with the peritoneal cavity. Acute pancreatitis causes the pancreatic enzymes to leak out from the acinar cells. Once the enzymes come into contact with fat cells, their plasma membrane is liquefied, releasing the fats/triglycerides. The fatty acids combine with calcium through a process called saponification. An insoluble salt is created and gives the appearance of a chalky-white area. Infections, viruses, trauma, ischaemia and toxins could be responsible for the pancreas being damaged and releasing its enzymes. Breast tissues can also have fat necrosis triggered by trauma, for example. To clinically diagnoses and manage pancreatitis see I GET SMASHED Mnemonic: Pancreatitis Causes and Management.
Gross appearance: soft chalky-white area should be seen on the pancreas.
Microscopic appearance: basophilic (bluish) calcium deposits are present. Anucleated adipocytes with a cytoplasm that is more pink and contains amorphous mass of necrotic material. Inflammation would be present.
Figure 11: Demonstrates fat necrosis of the pancreas. Saponification has occurred and these appear grossly as the soft, chalky white areas.
Figure from: The University of Utah Eccles Health Sciences Library.
Figure 12. Microscopically, fat necrosis adjacent to the pancreas is seen here. There are some remaining steatocytes at the left which are not necrotic, as seen as a green star. The necrotic fat cells at the right have vague cellular outlines, have lost their peripheral nuclei, and their cytoplasm has become a pink amorphous mass of necrotic material, as seen as a yellow star.
Figure from: The University of Utah Eccles Health Sciences Library.
Fibrinoid
Fibrinoid necrosis is associated with vascular damage (caused mainly by autoimmunity, immune-complex deposition, infections) and the exudation of plasma proteins (such as fibrin). This pattern typically occurs due to a type 3 hypersensitivity, where an immune complex is formed between an antigen (Ag) with an antibody (Ab). The Ag-Ab complex may be deposited in the vascular walls causing inflammation, complement being activated, and phagocytic cells are recruited, which could be releasing oxidants and other enzymes causing further damage and inflammation. Fibrin, a non-globular protein involved in the clotting of blood, is leaked out of the vessels. The results create an amorphous appearance that is bright pink in an H&E stain. The pathologists call this appearance ‘fribinoid’ which means fibrin-like.
Gross appearance: usually not grossly discernible.
Microscopic appearance: an amorphous appearance that is bright pink in an H&E stain. The deposition of fibrinoid are surrounding the blood vessels. Inflammation should be present.
Figure 13: Demonstrates an artery that is surrounded by a bright ring of necrosis. Inflammation should be present.
Figure from: Robbins and Cotran pathologic basis of disease, 9th ed.
Figure 14: Demonstrates a micrograph showing (intensely pink) fibrinoid necrosis (large blood vessel - right of image) in a case of vasculitis. H&E stain was used.
Figure from: Nephron
Published 30th June 2020. Last reviewed 30th April 2022.
Reference
Adigun R, Basit H, Murray J. Necrosis. Cell (Liquefactive, Coagulative, Caseous, Fat, Fibrinoid, and Gangrenous). [Updated 2019 Jun 30]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430935/.
Kumar, V., Abbas, A. K., Aster, J. (2014). Robbins and Cotran pathologic basis of disease. 9th ed. Philadelphia: Elsevier Saunders. Hardcover ISBN: 9780808924500.
Laskin DL, Sunil VR, Gardner CR, Laskin JD. Macrophages and tissue injury: agents of defense or destruction?. Annu Rev Pharmacol Toxicol. 2011;51:267-288. doi: 10.1146/annurev.pharmtox.010909.105812.
Martin JC, Peters KN, Behar SM. Macrophages clean up: efferocytosis and microbial control. Curr Opin Microbiol. 2014;17:17-23. https://doi.org/10.1016/j.mib.2013.10.007.
ScienceDirect authors. Liquefactive Necrosis. ScienceDirect website. https://www.sciencedirect.com/topics/medicine-and-dentistry/liquefactive-necrosis. Accessed June 25, 2020.
Shetty SK, Naik R, Shetty AS, Rai S, Menezes RG, Kanchan T. Acute Pancreatitis – The Current Concept in Ethiopathogenesis, Morphology and Complications. Pancreatitis - Treatment and Complications, Prof. Luis Rodrigo (Ed.) https://api.intechopen.com/chapter/pdf-preview/31131. ISBN: 978-953-51-0109-3.
The Internet Pathology Laboratory for Medical Education. Histology slides. The University of Utah Eccles Health Sciences Library. https://webpath.med.utah.edu/webpath.html#MENU. Accessed June 25, 2020.