How Pathologists Were Selected
Consumers' Research Council of America has compiled a list of Top Pathologists throughout the United States by utilizing a point value system. This method uses a point value for criteria that we deemed valuable in determining Top Pathologists.
The criteria that was used and assessed a point value is as follows:
Simply put, Pathologists that have accumulated a certain amount of points qualified for the list. This does not mean that Pathologists that did not accumulate enough points are not good health care professionals; they merely did not qualify for this list because of the points needed for qualification.
Similar studies have been done with other professions using a survey system. This type of study would ask fellow professionals whom they would recommend. We found this method to be more of a popularity contest, for instance: professionals who work in a large office have much more of a chance of being mentioned as opposed to a professional who has a small private practice. In addition, many professionals have a financial arrangement for back-and-forth referrals. For these reasons, we developed the point value system.
Since this is a subjective call, there is no study that is 100% accurate. As with any profession, there will be some degree of variance in opinion. If you survey 100 patients from a particular physician on their satisfaction, you will undoubtedly hear that some are very satisfied, some moderately satisfied and some dissatisfied. This is really quite normal.
We feel that a point value system takes out the personal and emotional factor and deals with factual criteria. We have made certain assumptions. For example, we feel that the more years in practice is better than less years in practice; more education is better than less education, etc.
The Top Pathologists list that we have compiled is current as of a certain date and other Pathologists may have qualified since that date. Nonetheless, we feel that the list of Top Pathologists is a good reference of qualified specialists.
No fees, donations, sponsorships or advertising are accepted from any individuals, professionals, corporations or associations. This policy is strictly adhered to, insuring an unbiased selection.
What is Pathology?
Pathology (from Greek pathos, feeling, pain or suffering; and '-ology' signifies 'study of) is the study and diagnosis of disease through examination of organs, tissues, cells and bodily fluids. The term encompasses both the medical specialty which uses tissues and body fluids to obtain clinically useful information, as well as the related scientific study of disease processes.
The histories of both experimental and medical pathology can be traced to the earliest application of the scientific method to the field of medicine, a development which occurred in Western Europe during the Italian Renaissance. Most early pathologists were also practicing physicians or surgeons. Like other medical fields, pathology has become more specialized with time, and most pathologists today do not practice in other areas of medicine.
Origins of gross pathology
The concept of studying disease through the methodical dissection and examination of diseased bodies, organs, and tissues may seem obvious today, but there are few if any recorded examples of true autopsies performed prior to the Renaissance. The first physician known to have repeatedly used anatomic dissection to determine cause of death was an Italian, Antonio Benivieni (1443-1502). Perhaps the most famous early gross pathologist was Giovanni Morgagni (1682-1771). His magnum opus, De Sedibus et Causis Morborum per Anatomem Indagatis, published in 1761, describes the findings of over 600 partial and complete autopsies, organized anatomically and methodically correlated with the symptoms exhibited by the patients prior to their demise. Although the study of normal anatomy was already well advanced at this date, De Sedibus was one of the first treatises specifically devoted to the corrolation of diseased anatomy with clinical illness. By the late 1800's, an exhaustive body of literature had been produced on the gross anatomical findings characteristic of known diseases. The extent of gross pathology research in this period can be epitomized by the work of the Viennese pathologist Carl Rokitansky (1804-1878), who is said to have performed 20,000 autopsies, and supervised an additional 60,000, in his lifetime.
Origins of microscopic pathology
The German physician Rudolf Virchow (1821-1902) is generally recognized to be the father of microscopic pathology. While the compound microscope had been invented approximately 150 years prior, Virchow was one of the first prominent physicians to emphasize the study of manifestations of disease which were visible only at the cellular level. A student of Virchow's, Julius Cohnheim (1839-1884) combined histology techniques with experimental manipulations to study inflammation, making him one of the earliest experimental pathologists. Cohnheim also pioneered the use of the frozen section; a version of this technique is widely employed by modern pathologists to render diagnoses and provide other clinical information intraoperatively.
Modern experimental pathology
As new research techniques, such as electron microscopy, immunohistochemistry, and molecular biology have expanded the means by which biomedical scientists can study disease, the definition and boundaries of investigative pathology have become less distinct. In the broadest sense, nearly all research which links manifestations of disease to identifiable processes in cells, tissues, or organs can be considered experimental pathology.
Pathology as a science
Pathology is a broad and complex scientific field which seeks to understand the mechanisms of injury to cells and tissues, as well as the body's means of responding to and repairing injury. Disease processes may be incited or exacerbated by a variety of external and internal influences, including trauma, infection, poisoning, loss of blood flow, autoimmunity, inherited or acquired genetic damage, or errors of development. One common theme in pathology is the way in which the body's responses to injury, while evolved to protect health, can also contribute in some ways to disease processes. Elucidation of general principles underlying pathologic processes, such as cellular adaptation to injury, cell death, inflammation, tissue repair, and neoplasia, creates a conceptual framework with which to analyze and understand specific human diseases.
Adaptation to injury
Cells and tissues may respond to injury and stress by specific mechanisms, which may vary according to the cell types and nature of the injury. In the short term, cells may activate specific genetic programs to protect their vital proteins and organelles from heat shock or hypoxia, and may activate DNA repair pathways to fix damage to chromosomes from radiation or chemicals. Hyperplasia is a long-term adaptive response of cell division and multiplication, which can increase the ability of a tissue to compensate for an injury. For example, repeated irritation to the skin can cause a protective thickening due to hyperplasia of the epidermis. Hypertrophy is an increase in the size of cells in a tissue in response to stress, an example being hypertrophy of muscle cells in the heart in response to increased resistance to blood flow as a result of narrowing of the heart's outflow valve. Metaplasia occurs when repeated damage to the cellular lining of an organ triggers its replacement by a different cell type.
Necrosis is the irreversible destruction of cells as a result of severe injury in a setting where the cell is unable to activate the needed metabolic pathways for survival or orderly degeneration. This is often due to external pathologic factors, such as toxins or loss of oxygen supply. Milder stresses may lead to a process called reversible cell injury, which mimics the cell swelling and vacuolization seen early in the necrotic process, but in which the cell is able to adapt and survive. In necrosis, the components of degenerating cells leak out, potentially contributing to inflammation and further damage. Apoptosis, in contrast, is a regulated, orderly degeneration of the cell which occurs in the settings of both injury and normal physiological processes.
Inflammation is a particularly important and complex reaction to tissue injury, and is particularly important in fighting infection. Acute inflammation is generally a non-specific response triggered by the injured tissue cells themselves, as well as specialized cells of the innate immune system and previously developed adaptive immune mechanisms. A localized acute inflammatory response triggers vascular changes in the injured area, recruits pathogen-fighting neutrophils, and begins the process of developing a new adaptive immune response. Chronic inflammation occurs when the acute response fails to entirely clear the inciting factor. While chronic inflammation can lay a positive role in containing a continuing infectious hazard, it can also lead to progressive tissue damage, as well as predisposing (in some cases) to the development of cancer.
Tissue repair, as seen in wound healing, is triggered by inflammation. The process may proceed even before the resolution of a precipitating insult, through the formation of granulation tissue. Healing involves the proliferation of connective tissue cells and blood vessel-forming cells as a result of hormonal growth signals. While healing is a critical adaptive response, an aberrant healing response can lead to progressive fibrosis, contractures, or other changes which can compromise function.
Neoplasia, or "new growth," is a proliferation of cells which is independent of any physiological process. The most familiar examples of neoplasia are benign tumors and cancers. Neoplasia results from genetic changes which cause cells to activate genetic programs inappropriately. Dysplasia is an early sign of a neoplastic process in a tissue, and is marked by persistence of immature, poorly differentiated cell forms. Interestingly, there are many similarities in the gene pathways activated in cancer cells, and those activated in cells involved in wound healing and inflammation.
Pathology as a medical specialty
Physicians who practice pathology diagnose and characterize disease in living patients by examining biopsies and other specimens. For example, the vast majority of cancer diagnoses are made or confirmed by a pathologist. Pathologists may also conduct autopsies to investigate causes of death. The medical practice of pathology grew out the tradition of investigative pathology, and many of the academic leaders in pathology today are accomplished in both basic science research and diagnostic practice. However, as with other specialties in medicine, most modern physician-pathologists are employed in full-time practice, and do not perform original research.
Pathology is a unique medical specialty in that pathologists typically do not see patients directly, but rather serve as consultants to other physicians (often referred to as "clinicians" within the pathology community). However, in the United States and in many other countries, pathologists receive the same doctorate training, and undergo the same medical licensure process as other physicians. Pathology is a diverse field, and the organization of subspecialties within pathology vary between nations.
This mastectomy specimen contains an infiltrating ductal carcinoma of the breast. A pathologist will use immunohistochemistry and fluorescent in-situ hybridization to detect markers which determine the optimal chemotherapy regimen for this patient. This mastectomy specimen contains an infiltrating ductal carcinoma of the breast. A pathologist will use immunohistochemistry and fluorescent in-situ hybridization to detect markers which determine the optimal chemotherapy regimen for this patient. Anatomical pathologists diagnose disease and gain other clinically significant information through the examination of tissues and cells.
This generally involves gross and microscopic visual examination of tissues, with special stains and immunohistochemistry employed to visualize specific proteins and other substances in and around cells. More recently, anatomical pathologists have begun to employ molecular biology techniques to gain additional clinical information from these same specimens. Anatomic pathologists serve as the definitive diagnosticians for most cancers, as well as numerous other diseases.
Clinical pathology, also known as laboratory medicine, is the medical specialty concerned with diagnosing diseases based on the analysis of body fluids, such as plasma, urine, stool, respiratory or mucosal secretions, inflammatory exudates, and pleural, pericardial, peritoneal, synovial, or cerebrospinal fluid. The practice of clinical pathology is centered around the clinical laboratory. In modern clinical laboratories, many routine studies are largely automated. The clinical pathologist is responsible for overseeing the work of laboratory technicians, performing quality assurance to assure the validity of test results, performing interpretations of more complex studies, and serving as a consultant to clinicians so that the most appropriate studies can be performed for the diagnosis or assessment of an individual patient's condition. In some areas, non-pathologists, such as other physicians or Ph.D.'s may run clinical labs and perform functions within those specific labs which are similar to the role of a board-certified clinical pathologist.
Sub-specialties within clinical pathology include the following:
In the United States, subspecialty-trained doctors of dental surgery (D.D.S), rather than medical doctors, can be certified by a professional board to practice dental pathology.
Pathology in the United States
In the United States, pathologists are medical doctors (M.D.) or doctors of osteopathic medicine (D.O.), that have completed a four-year undergraduate
program, four years of medical school training, and three to four years of postgraduate training in the form of a pathology residency. Training may be within two primary
specialties, as recognized by the American Board of Pathology: Anatomic Pathology, and Clinical Pathology, each of which requires separate board certification. Many
pathologists seek a broad-based training and become certified in both fields. These skills are complementary in many hospital-based private practice settings, since the
day-to-day work of many clinical laboratories only requires the intermittent attention of a physician. Thus, pathologists are able to spend much of their time
What does a Pathologist Do?
Histopathology is the diagnosis of disease by studying tissue samples (histology). These range from tiny biopsies (for instance, from someone's stomach taken by endoscopy) to organs removed at an operation (e.g. a colon containing a cancer). From these specimens, areas are selected to take sections from, which are stained and examined under a microscope.
This is the major part of the pathologist's job. They are the people who tell other doctors what disease their patient has, whether it is benign (nice) or malignant (nasty), and whether or not it is out. Very few diagnoses of cancer are made without their help, and they play an essential role in deciding the correct treatment for an individual patient.
Cytology is the diagnosis of disease from individual cells, such as cervical smears or fluid from cysts. This is much faster to perform than histology, but has more limited diagnostic abilities: generally, cytology is used as a rapid screening test to determine whether something is malignant or not, with further biopsy being used to get a definitive, histological diagnosis.
Cytopathology is a branch of pathology that studies and diagnoses diseases on the cellular level. The most common use of cytopathology is the Pap smear, used to detect cervical cancer at an early treatable stage.
Two methods of collecting cells for analysis are:
Fine needles are 23 to 27 gauge. Needle diameters and color codes for 23G, 25G and 27G are as follows, respectively: 0,6 mm/Blue-dark, 0,5 mm/Orange, and 0,4 mm/Grey. If a cell-block preparation is indicated, after obtaining diagnostic cytology smears, a wider gauge needle, up to 18 gauge, may be used.
Autopsies are performed in two situations: at the request of clinicians (with relatives' consent) to determine the cause of death, and to see whether the correct diagnosis was made in life and the appropriate treatment given, and at the request of the Coroner, if a death is suspicious or the cause cannot be ascertained (for instance, the deceased had not recently been seen by a doctor). The second case is by far the more common these days.
In gynecology, the Papanikolaou test or Papanicolaou test (also called Pap smear, Pap test, cervical smear, or smear test) is a medical screening method, invented by Georgios Papanikolaou, primarily designed to detect premalignant and malignant processes in the ectocervix. It may also detect infections and abnormalities in the endocervix and endometrium.
The endocervix may be partially sampled with the device used to obtain the ectocervical sample, but due to the anatomy of this area, consistent and reliable sampling cannot be guaranteed. As abnormal endocervical cells may be sampled, those examining them are taught to recognize them. The endometrium is not directly sampled with the device used to sample the ectocervix. Cells may exfoliate onto the cervix and be collected from there, so as with endocervical cells, abnormal cells can be recognized if present but the Pap Test should not be used as a screening tool for endometrial malignancy.
The pre-cancerous changes (called dysplasias or cervical or endocervical intraepithelial neoplasia) are usually caused by sexually transmitted human papillomaviruses (HPVs). The test aims to detect and prevent the progression of HPV-induced cervical cancer and other abnormalities in the female genital tract by sampling cells from the outer opening of the cervix (Latin for "neck") of the uterus and the endocervix.
The sampling technique changed very little since its invention by Georgios Papanikolaou (1883–1962) to detect cyclic hormonal changes in vaginal cells in the early 20th century until the development of liquid based cell thin layer technology. The test remains an effective, widely used method for early detection of cervical cancer and pre-cancer. The UK's call and recall system is among the best; estimates of its effectiveness vary widely but it may prevent about 700 deaths per year in the UK. It is not a perfect test. "A nurse performing 200 tests each year would prevent a death once in 38 years. During this time she or he would care for over 152 women with abnormal results, over 79 women would be referred for investigation, over 53 would have abnormal biopsy results, and over 17 would have persisting abnormalities for more than two years. At least one woman during the 38 years would die from cervical cancer despite being screened." HPV vaccine may offer better prospects in the long term.
It is generally recommended that sexually active females seek Pap smear testing annually, although guidelines may vary from country to country. If results are abnormal, and depending on the nature of the abnormality, the test may need to be repeated in three to twelve months. If the abnormality requires closer scrutiny, the patient may be referred for detailed inspection of the cervix by colposcopy. The patient may also be referred for HPV DNA testing, which can serve as an adjunct (or even as an alternative) to Pap testing.
About 5% to 7% of pap smears produce abnormal results, such as dysplasia, possibly indicating a pre-cancerous condition. Although many low grade cervical dysplasias spontaneously regress without ever leading to cervical cancer, dysplasia can serve as an indication that increased vigilance is needed. Endocervical and endometrial abnormalities can also be detected, as can a number of infectious processes, including yeast and Trichomonas vaginalis. A small proportion of abnormalities are reported as of "uncertain significance".
Samples are collected from the outer opening or os of the cervix using an Aylesbury spatula or (more frequently with the advent of liquid-based cytology) a plastic-fronded broom. The cells are placed on a glass slide and checked for abnormalities in the laboratory. The sample is stained using the Papanicolaou technique, in which tinctorial dyes and acids are selectively retained by cells. Unstained cells can not be visualized with light microscopy. The stains chosen by Papanicolau were selected to highlight cytoplasmic keratinization, which actually has almost nothing to do with the nuclear features used to make diagnoses now.
The sample is then screened by a specially trained and qualified cytotechnologist using a light microscope. The terminology for who screens the sample varies according the country; in the UK, the personnel are known as Cytoscreeners, Biomedical scientists (BMS), Advanced Practitioners and Pathologists. The latter two take responsibility for reporting the abnormal sample which may require further investigation.
In the United States, physicians who fail to diagnose cervical cancer from a pap smear have been convicted of negligent homicide. In 1988 and 1989, Karen Smith had received pap smears which were argued to have "unequivocally" shown that she had cancer; yet the lab had not made the diagnosis. She died on March 8, 1995. Later, a physician and a laboratory technician were convicted of negligent homicide. These events have led to even more rigorous quality assurance programs, and to emphasizing that this is a screening, not a diagnostic, test, associated with a small irreducible error rate.
Liquid based monolayer cytology
Since the mid-1990s, techniques based around placing the sample into a vial containing a liquid medium which preserves the cells have been increasingly used. The media are primarily ethanol based. Two of the types are Sure-Path (TriPath Imaging) and Thin-Prep (Cytyc Corp). Once placed into the vial, the sample is processed at the laboratory into a cell thin-layer, stained, and examined by light microscopy. The liquid sample has the advantage of being suitable for low and high risk HPV testing and reduced unsatisfactory specimens from 4.1% to 2.6%. Proper sample acquisition is crucial to the accuracy of the test; clearly, a cell that is not in the sample cannot be evaluated. Human papillomavirus testing
The presence of HPV indicates that the person has been infected, the majority of women who get infected will successfully clear the infection within 18 months. It is those who have an infection of prolonged duration with high risk types (e.g. types 16,18,33,35) that are more likely to develop Cervical Intraepithelial Neoplasia due to the effects that HPV has on DNA.
By adding the more sensitive HPV test, the specificity may decline. However, the drop in specificity is not definite. If the specificity does decline, this results in increased numbers of false positive tests and many women who did not have disease having colposcopy and treatment. A worthwhile screening test requires a balance between the sensitivity and specificity to ensure that those having a disease are correctly identified as having it and equally importantly those not identifying those without the disease as having it. Due to the liquid based pap smears having a false negative rate of 15-35%, the American College of Obstetricians and Gynecologists citation needed] and American Society for Colposcopy and Cervical Pathology have recommended the use of HPV testing in addition to the pap smear in all women over the age of 30.
Regarding the role of HPV testing, randomized controlled trials have compared HPV to colposcopy. HPV testing appears as sensitive as immediate colposcopy while reducing the number of colposcopies needed. Randomized controlled trial have suggested that HPV testing could follow abnormal cytology or could precede cervical cytology examination.
A study published in April 2007 suggested the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."
In the last decade there have been successful attempts to develop automated, computer image analysis systems for screening.
Automation may improve sensitivity and reduce unsatisfactory specimens. One of these has been FDA approved and functions in high volume reference laboratories, with human oversight.
The physician or operator collecting a sample for the test inserts a speculum into the patient's vagina, to obtain a cell sample from the cervix. A pap smear appointment is normally not scheduled during menstruation, and patients should avoid contamination of the vagina and uterus (for example by a douche) before the exam, to avoid false results. The procedure is usually just slightly painful, because of the neuroanatomy of the cervix. However, this can depend on the patient's anatomy, the skill of the practitioner, psychological factors, and other conditions. Results usually take about 3 weeks. Slight bleeding, cramps, and other discomfort can occur afterwards.
Anatomical pathology (Commonwealth) or Anatomic pathology (U.S.) is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, and molecular examination of organs, tissues, and cells. In many countries, physicians who practice pathology are trained in both anatomical pathology and clinical pathology, the diagnosis of disease through the laboratory analysis of bodily fluids.
Anatomical pathologists diagnose disease and gain other clinically significant information through the examination of tissues and cells. This generally involves gross and microscopic visual examination of tissues, with special stains and immunohistochemistry employed to visualize specific proteins and other substances in and around cells. More recently, anatomical pathologists have begun to employ molecular biology techniques to gain additional clinical information from these same specimens.
Skills and procedures
The procedures used in anatomic pathology include:
This surgically removed segment of colon contains a suspicious polyp. An anatomical pathologist will look for invasive cancer and determine the extend of its spread. This surgically removed segment of colon contains a suspicious polyp. An anatomical pathologist will look for invasive cancer and determine the extend of its spread.
Surgical pathology is the most significant and time-consuming area of practice for most anatomical pathologists. Surgical pathology involves the gross and microscopic examination of surgical specimens, as well as biopsies submitted by non-surgeons such as general internists, medical subspecialists, dermatologists, and interventional radiologists.
Cytopathology is a sub-discipline of anatomical pathology concerned with the microscopic examination of whole, individual cells obtained from smears or fine needle aspirates. Cytopathologists are trained to perform fine-needle aspirates of superficially located organs, masses, or cysts, and are often able to render an immediate diagnosis in the presence of the patient and consulting physician. In the case of screening tests such as the Papanicolaou smear, non-physician cytotechnologists are often employed to perform initial reviews, with only positive or uncertain cases examined by the pathologist. Cytopathology is a board-certifiable subspecialty in the U.S.
Molecular pathology is an emerging discipline within anatomical pathology which is focused on the use of nucleic acid-based techniques such as in-situ hybridization, reverse-transcriptase polymerase chain reaction, and nucleic acid microarrays for specialized studies of disease in tissues and cells. Molecular pathology shares some aspects of practice with both anatomic and clinical pathology, and is sometimes considered a "crossover" discipline.
General anatomical pathologists are trained in performing autopsies, which are used to determine the disease factors contributing to a person's death. Autopsies are important in the ongoing medical education of clinicians, and in efforts to improve and verify the quality of medical care. Deniers are non-physicians who assist pathologists in the gross dissection portion of the autopsy. Autopsies represent less than 10% of the workload of typical pathologists in the United States. However, the autopsy is central to public perceptions of the field, in part due to portrayals of pathologists on television programs such as Quincy, M.E. and Silent Witness.
Forensic pathologists receive specialized training in determining the cause of death and other legally relevant information from the bodies of persons who died in a non-medical or potentially criminal circumstances. Autopsies make up much, but not all of the work of the practicing forensic pathologist, and forensic pathologists are occasionally consulted to examine a survivor of a criminal attack. Forensic pathology is a board-certifiable sub-specialty in the U.S.
Training and certification of Anatomical Pathologists
Anatomic Pathology (AP) is one of the two primary certifications offered by the American Board of Pathology. The other is Clinical Pathology (CP). To be certified in anatomic pathology, the trainee must complete four years of medical school followed by three years of residency training. Many US pathologists are certified in both AP and CP, which requires a total of four years of residency. After completing residency, many pathologists enroll in further years of fellowship training to gain expertise in a subspecialty of AP.
Anatomical Pathology (AP) is one of the specialist certificates granted by the Royal College of Physicians and Surgeons of Canada. Other certificates related to pathology include general pathology (GP), forensic pathology, hematopathology, and neuropathology. Candidates for any of these must have completed four years of medical school and five years of residency training. After becoming certified in either AP or GP, it is common for pathologists to seek further fellowship training in a subspecialty of AP.
Anatomical pathology practice settings
Surgical pathology is the most significant and time-consuming area of practice for most anatomical pathologists. Surgical pathology involves the gross and microscopic examination of surgical specimens, as well as biopsies submitted by non-surgeons such as general internists, medical subspecialists, dermatologists, and interventional radiologists. Generally recognized sub-specialties of surgical pathology include the following:
The practice of surgical pathology allows for definitive diagnosis of disease (or lack thereof) in any case where tissue is surgically removed from a patient. This is usually performed by a combination of gross (i.e., macroscopic) and histologic (i.e., microscopic) examination of the tissue, and may involve evaluations of molecular properties of the tissue by immunohistochemistry or other laboratory tests.
There are two major types of specimens submitted for surgical pathology analysis, biopsies, and surgical resections.
A biopsy is a small piece of tissue removed primarily for the purposes of surgical pathology analysis, most often in order to render a definitive diagnosis. Types of biopsies include core biopsies which are obtained through the use of large-bore needles, sometimes under the guidance of radiological techniques such as ultrasound, CT scan, or magnetic resonance imaging. Core biopsies, which preserve tissue architecture, should not be confuse with fine needle aspiration specimens, which are analyzed using cytopathology techniques. Incisional biopsies are obtained through diagnostic surgical procedures which remove part of a suspicious lesion, while excisional biopsies remove the entire lesion, and are similar to as therapeutic surgical resections. Excisional biopsies of skin lesions and gastrointestinal polyps are very common.
The pathologist's interpretation of a biopsy is critical to establishing the diagnosis of a benign or malignant tumor, and can differentiate between different types and grades of cancer, as well as determining the activity of specific molecular pathways in the tumor. This information is important for estimating the patient's prognosis and for choosing the best treatment to administer. Biopsies are also used to diagnose diseases other than cancer, including inflammatory, infectious, or idiopathic diseases of the skin and gastrointestinal tract, to name only a few.
Surgical resection specimens are produced through the therapeutic removal of an entire diseased area or organ (and occasionally multiple organs). These procedures are often intended as definitive surgical treatment of a disease in which the diagnosis is already known or strongly suspected. However, pathological analysis of these specimens is critically important in confirming the previous diagnosis, staging the extent of malignant disease, establishing whether or not the entire diseased area was removed (sometimes intraoperatively through the technique of frozen section), identifying the presence of unsuspected concurrent diseases, and providing information for postoperative treatment, such as adjuvant chemotherapy in the case of cancer.
Surgical pathology workflow
Many pathologists seek fellowship-level training, or otherwise pursue expertise in a focused area of surgical pathology. Subspecialization is particularly prevalent in the academic setting, where pathologists may specialize in an area of diagnostic surgical pathology which is relevant to their research, but is becoming increasingly prevalent in private practice as well. Subspecialization has a number of benefits, such as allowing for increased experience and skill at interpreting challenging cases, as well as development of a closer working relationship between the pathologist and clinicians within a subspecialty area. Commonly recognized subspecialties of surgical pathology include the following:
An autopsy, also known as a post-mortem examination, necropsy, or obduction, is a medical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present. It is usually performed by a specialized medical doctor called a pathologist.
Autopsies are either performed for legal or medical purposes. A forensic autopsy is carried out when the cause of death may be a criminal matter, while a clinical or academic autopsy is performed to find the medical cause of death and is used in cases of unknown or uncertain death, or for research purposes. Autopsies can be further classified into cases where external examination suffices, and those where the body is dissected and an internal examination is conducted. Permission from next of kin may be required for internal autopsy in some cases. Once an internal autopsy is complete the body is reconstituted by sewing it back together.
Necropsy is the term for a post-mortem examination performed on an animal. The prefix 'auto-' means 'self', and so autopsy denotes the human species performing a post-mortem examination on one of its own.
Role of autopsy in medicine
Autopsies are important in clinical medicine as they often shed light on mistakes and can be used to help guide continuous improvement.
A study that focused on myocardial infarction (heart attack) as a cause of death found significant errors of omission and commission, i.e., a sizable number cases ascribed to myocardial infarctions (MIs) were not MIs and a significant number of non-MIs were actually MIs.
A large meta-analysis suggested that approximately one third of death certificates are incorrect and that half of the autopsies performed produced findings that were not suspected before the person died. Also, it is thought that over one fifth of unexpected findings can only be diagnosed histologically, i.e. by biopsy or autopsy, and that approximately one quarter of unexpected findings, or 5% of all findings, are major and can similarily only be diagnosed from tissue.
The term "autopsy" derives from the Greek for "to see for oneself". "Necropsy" is from the Greek for "seeing a dead body".
There are three main types of autopsies:
While dissection of human remains for medical reasons has been practiced irregularly for millennia, the modern autopsy process derives from the anatomists of the Renaissance. The two great nineteenth-century medical researchers Rudolf Virchow and Carl von Rokitansky built on the Renaissance legacy to derive the two distinct autopsy techniques that still bear their names. Their demonstration of correspondences between pathological conditions in dead bodies and symptoms and illnesses in the living opened the way for a different way of thinking about disease and its treatment. In China, the office of coroner and forensic autopsy have a history nearly two thousand years old.
A forensic autopsy is used to determine the cause of death. Forensic science involves the application of the sciences to answer questions of interest to the legal system. In United States law, deaths are placed in one of five manners:
Following an in-depth examination of all the evidence, a medical examiner or coroner will assign a manner of death as one of the five listed above; and detail the evidence on the mechanism of the death.
Clinical autopsies serve two major purposes. They are performed to gain more insight into pathological processes and determine what factors contributed to a patient's death. More importantly, autopsies are performed to ensure the standard of care at hospitals. Autopsies can yield insight into how patient deaths can be prevented in the future.
The body is received at a medical examiner's office or hospital in a body bag or evidence sheet. A brand new body bag is used for each body to ensure that only evidence from that body is contained within the bag. Evidence sheets are an alternate way to transport the body. An evidence sheet is a sterile sheet that the body is covered in when it is moved. If it is believed there may be any significant residue on the hands, for instance gunpowder, a separate paper sack is put around each hand and taped shut around the wrist.
There are two parts to the physical examination of the body: the external and internal examination. Toxicology, biochemical tests and/or genetic testing often supplement these and frequently assist the pathologist in assigning the cause or causes of death.
The person responsible for handling, cleaning and moving the body is often called a Diener, the German word for servant. After the body is received, it is first photographed. The examiner then notes the kind of clothes and their position on the body before they are removed. Next, any evidence such as residue, flakes of paint or other material is collected from the external surfaces of the body. Ultraviolet light may also be used to search body surfaces for any evidence not easily visible to the naked eye. Samples of hair, nails and the like are taken, and the body may also be radiographically imaged.
Once the external evidence is collected, the body is removed from the bag, undressed and any wounds present are examined. The body is then cleaned, weighed and measured in preparation for the internal examination. The scale used to weigh the body is often designed to accommodate the cart that the body is transported on; its weight is then deducted from the total weight shown to give the weight of the body.
If not already within an autopsy room, the body is transported to one and placed on a table. A general description of the body as regards race, sex, age, hair color and length, eye color and other distinguishing features (birthmarks, old scar tissue, moles, etc) is then made. A handheld voice recorder or a standard examination form is normally used to record this information. In some countries e.g. United Kingdom, France, Germany and Canada to name but a few, an autopsy may comprise an external examination only. This concept is sometimes termed a "view and grant". The principles behind this being that the medical records, history of the deceased and circumstances of death have all indicated as to the cause and manner of death without the need for an internal examination.
If not already in place, a plastic or rubber brick called a "body block" is placed under the back of the body, causing the arms and neck to fall backward whilst stretching and pushing the chest upward to make it easier to cut open. This gives the prosector, a pathologist or assistant, maximum exposure to the trunk. After this is done, the internal examination begins. The internal examination consists of inspecting the internal organs of the body for evidence of trauma or other indications of the cause of death. For the internal examination there are a number of different approaches available:
In all of the above cases the cut then extends all the way down to the pubic bone (making a deviation to the left side of the navel).
Bleeding from the cuts is minimal, or non-existent, due to the fact that the pull of gravity is producing the only blood pressure at this point, related directly to the complete lack of cardiac functionality. However, in certain cases there is anecdotal evidence to prove that bleeding can be quite diffuse especially in cases of drowning.
An electric saw dubbed a "Stryker saw" after a common manufacturer of the tool, is most often used to open the chest cavity. However, in some cases, due to the large amount of dust created when the bone is cut by the saw, shears are used to open the chest cavity. It is also possible to utilize a simple scalpel blade. The prosector uses the tool to saw through the ribs on the lateral sides of the chest cavity to allow the sternum and attached ribs to be lifted as one chest plate; this is done so that the heart and lungs can be seen in situ and that the heart, in particular the pericardial sac is not damaged or disturbed from opening. A scalpel is used to remove any soft tissue that is still attached to the posterior side of the chest plate. Now the lungs and the heart are exposed. The chest plate is set aside and will be eventually replaced at the end of the autopsy.
At this stage the organs are exposed. Usually, the organs are removed in a systematic fashion. Making a decision as to what order the organs are to be removed will depend highly on the case in question. Organs can be removed individually, in separate blocks or all together in a single block (from the torso).
One method is described here: The pericardial sac is opened to view the heart. Blood for chemical analysis may be removed from the inferior vena cava or the pulmonary veins. Before removing the heart, the pulmonary artery is opened in order to search for a blood clot. The heart can then be removed by cutting the inferior vena cava, the pulmonary veins, the aorta and pulmonary artery, and the superior vena cava. This method leaves the aortic arch intact, which will make things easier for the embalmer. The left lung is then easily accessible and can be removed by cutting the bronchus, artery, and vein at the hilum. The right lung can then be similarly removed. The abdominal organs can be removed one by one after first examining their relationships and vessels.
Some pathologists, however, prefer to remove the organs all in one "block". Then a series of cuts, along the vertebral column, are made so that the organs can be detached and pulled out in one piece for further inspection and sampling. During autopsies of infants, this method is used almost all of the time. The various organs are examined, weighed and tissue samples in the form of slices are taken. Even major blood vessels are cut open and inspected at this stage. Next the stomach and intestinal contents are examined and weighed. This could be useful to find the cause and time of death, due to the natural passage of food through the bowel during digestion. The more area empty, the longer the victim had gone without a meal before death.
The body block that was used earlier to elevate the chest cavity is now used to elevate the head. To examine the brain, a cut is made from behind one ear, over the crown of the head, to a point behind the other ear. When the autopsy is completed, the incision can be neatly sewn up and is not noticed when the head is resting on a pillow in an open casket funeral. The scalp is pulled away from the skull in two flaps with the front flap going over the face and the rear flap over the back of the neck. The skull is then cut with an electric saw to create a "cap" that can be pulled off, exposing the brain. The brain is then observed in situ. Then the brain's connection to the spinal cord is severed, and the brain is then lifted out of the skull for further examination. If the brain needs to be preserved before being inspected, it is contained in a large container of formalin (15 percent solution of formaldehyde gas in buffered water) for at least two but preferably four weeks. This not only preserves the brain, but also makes it firmer allowing easier handling without corrupting the tissue.
Reconstitution of the body
An important aim of the autopsy is to reconstitute the body such that it can be viewed, if desired, by relatives of the deceased following the procedure. After the examination, the body has an open and empty chest cavity with chest flaps open on both sides, the top of the skull is missing, and the skull flaps are pulled over the face and neck. It is unusual to examine the face, arms, hands or legs internally. The organs are replaced (which are usually poured in) or incinerated, the chest flaps are closed and sewn back together and the skull cap is sewed back in place. Then the body may be wrapped in a shroud and it is common for relatives of the deceased to not be able to tell the procedure has been done when the deceased is viewed in a funeral parlor after embalming.
The principal aim of an autopsy is to discover the cause of death, to determine the state of health of the person before he or she died, and whether any medical diagnosis and treatment before death was appropriate. Studies have shown that even in the modern era of use of high technology scanning and medical tests, the medical cause of death is wrong in about one third of instances unless an autopsy is performed. In about one in ten cases the cause of death is so wrong that had it been known in life the medical management of the patient would have been significantly different.
In most Western countries the number of autopsies performed in hospitals has been decreasing every year since 1955. Critics, including pathologist and former JAMA editor George Lundberg, have charged that the reduction in autopsies is negatively affecting the care delivered in hospitals, because when mistakes result in death, they are often not investigated and lessons learned.
When a person has given permission in advance of their death, autopsies may also be carried out for the purposes of teaching or medical research.
An autopsy is frequently performed in cases of sudden death, where a doctor is not able to write a death certificate, or when death is believed to be due to an unnatural cause. These examinations are performed under a legal authority (Medical Examiner or Coroner or Procurator Fiscal) and do not require the consent of relatives of the deceased. The most extreme example is the examination of murder victims, especially when medical examiners are looking for signs of death or the murder method, such as bullet wounds and exit points, signs of strangulation, or traces of poison.
Forensic pathology is a branch of medicine concerned with determining cause of death, usually for criminal law cases and civil law cases in some jurisdictions. The word forensics is derived from the Latin fore-nsis meaning public or forum. The word pathology literally means study of disease.
The Forensic pathologist:
In an Autopsy, they are often assisted by an autopsy/mortuary technician (sometimes called a Diener in the USA). Forensic physicians (sometimes referred to as 'Forensic Medical Examiners' or 'Police Surgeons' (in the UK until recently)) are medical doctors trained in the examination of, and provision of medical treatment to, living victims of assault (including sexual assault) and those individuals who find themselves in police custody. Many forensic physicians in the UK practice clinical forensic medicine on a part-time basis, whilst they also practice family medicine, or another medical specialty.
Investigation of death
Deaths that are not considered natural are investigated. In some jurisdictions this is done by a coroner and in others by a medical examiner. Terminology is not consistent across jurisdictions. In some jurisdictions, the title of "Medical Examiner" is used by non-physician, elected officials involved in medicolegal death investigation. In others, the title is reserved exclusively for physicians that are appointed. Similarily, the title "Coroner" is applied to both physicians and non-physicians. Historically, coroners were not all physicians. However, in some jurisdictions the title of "Coroner" is exclusively used by physicians.
Coroners and medical examiner in the US
In the United States, a coroner, typically, is an elected public official, in a particular geographic jurisdiction, who investigates and certifies deaths. The vast majority of coroners lack a Doctor of Medicine degree and the amount of medical training that they have received is highly variable, depending on their profession (e.g. law enforcement, judges, funeral directors, firefighters, nurses).
In contrast, a medical examiner, typically, is a physician who holds the degree of Doctor of Medicine. Ideally, a medical examiner has completed both a pathology residency (medicine) and a fellowship in forensic pathology.
He or she may also be board certified by the American Board of Pathology in Anatomic and Forensic Pathology. This entails passing separate examinations in anatomic pathology and forensic pathology. To be eligible for the American Board of Pathology's board examinations, a candidate must demonstrate that he or she has completed training in anatomic pathology and forensic pathology at programs accredited by the Accreditation Council for Graduate Medical Education.
History in United States
Forensic pathology was first recognized in the USA by the American Board of Pathology in 1959.
Becoming a forensic pathologist
Forensic pathology is a subspecialty of anatomical pathology and typically one year of additional training (a fellowship), that is completed after becoming a licensed anatomical pathologist. Becoming an anatomical pathologist requires completing a four or five year residency in anatomical pathology, which is something one does on completing medical school. In Canada and UK, anatomical pathology is a five year residency. In the US, anatomic pathology (as it is called), is a four year residency.
In the United States, all told, the education after high school is typically 13 years in duration (4 years undergraduate training + 4 years medical school + 4 years residency (in anatomical pathology) + 1 year forensic pathology fellowship). Generally, the biggest hurdle is gaining admission to medical school.
Principals of Pathology
A disease is an abnormal condition of an organism that impairs bodily functions. In human beings, "disease" is often used more broadly to refer to any condition that causes discomfort, dysfunction, distress, social problems, and/or death to the person afflicted, or similar problems for those in contact with the person. In this broader sense, it sometimes includes injuries, disabilities, disorders, syndromes, infections, isolated symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts and for other purposes these may be considered distinguishable categories. This article primarily describes human diseases, one of man's greatest enemies.
While many diseases are biological processes with observable alterations of organ function or structure, others primarily involve alterations of behavior. Classifying a condition as a disease is a social act of valuation, and may change the social status of the person with the condition (the patient). Some conditions (known as culture-bound syndromes) are only recognized as diseases within a particular culture. Sometimes the categorization of a condition as a disease is controversial within the culture.
Causes of disease
Many different factors intrinsic or extrinsic to a person (or plant or animal) can cause disease. Examples of intrinsic factors are genetic defects or nutritional deficiencies. An an environmental exposure, such as second-hand smoke is an example of an extrinsic factor. Many diseases result from a combination of intrinsic and extrinsic factors. For many diseases a cause cannot be identified.
There are many different factors that can cause disease. These can be broadly categorized into the following categories like social, psychological, chemical and biological. Some factors may fall into more than one category. Biochemical causes of disease can be considered as a spectrum where at one extreme disease is caused entirely by genetic factors (e.g. CAG repeats in the Huntingtin gene that causes Huntington's Disease) and at the other extreme is caused entirely by environmental factors. Environmental factors include toxic chemicals (e.g. acetaldehyde in cigarette smoke and dioxins released from the breakdown of Agent Orange) and infectious agents (e.g. smallpox virus and poliovirus). In between these extremes genes (e.g. NOD2/CARD15) and environmental factors (e.g. Gut microbiota) interact to cause disease, as seen for example in the inflammatory bowel disease Crohn's Disease (Fig 1, right). Absence of the genetic or environmental factors in this case results in disease not being manifest. Koch's postulates can be used to determine whether a disease is caused by an infectious agent.
To determine whether a disease is caused by genetic factors, researchers study the pattern inheritance of the disease in families. This provides qualitative information about the disease (how it is inherited). A classic example of this method of research is inheritance of hemophilia in the British Royal Family. More recently this research has been used to identify the Apoliprotein E (ApoE) gene as a susceptibility gene for Alzheimer's Disease, though some forms of this gene - ApoE2 - are associated with a lower susceptibility.
To determine to what extent a disease is caused by genetic factors (quantitative information), twin studies are used. Monozygotic twins are genetically identical and likely share a similar environment whereas dizygotic twins are genetically similar and likely share a similar environment. Thus by comparing the incidence of disease (termed concordance rate) in monozygotic twins with the incidence of disease in dizygotic twins, the extent to which genes contribute to disease can be determined. Candidate disease genes can be identified using a number of methods. One is to look for mutants of a model organism (e.g. the organisms Mus musculus, Drosophila melanogaster, Caenhorhabditis elegans, Brachydanio rerio and Xenopus tropicalis) that have a similar phenotype to the disease being studied. Another approach is to look for segregation of genes or genetic markers (e.g. single nucleotide polymorphism or expressed sequence tag)
A large number of SNPs spaced throughout the genome have been identified recently in a large project called the HapMap project. The usefulness of the HapMap project and SNP typing and their relevance to society was covered in the 27th October 2005 issue of the leading international science journal Nature (journal).
A large number of genes have been identified that contribute to human disease. These are available from the US National Library of Medicine, which has an impressive range of biological science resources available for free online. Amongst these resources is Online Mendelian Inheritance in Man - OMIM that provides a very, very comprehensive list of all known human gene mutations associated with, and likely contributing to, disease. Each article at OMIM is regularly updated to include the latest scientific research. Additionally, each article provides a detailed history of the research on a given disease gene, with links to the research articles. This resource is highly valuable and is used by the world's top science researchers.
The terms disease, disorder, medical condition are often used interchangeably. There is no agreed-upon universal distinction between these terms, though some people do make distinctions in particular contexts.
Medical usage sometimes distinguishes a disease, which has a known specific cause or causes (called its etiology), from a syndrome, which is a collection of signs or symptoms that occur together. However, many conditions have been identified, yet continue to be referred to as "syndromes." Furthermore, numerous conditions of unknown etiology are referred to as "diseases" in many contexts. Refractory diseases do not respond to therapy by overcoming the resistance to drugs.
Illness, although often used to mean disease, can also refer to a person's perception of their health, regardless of whether they in fact have a disease. A person without any disease may feel unhealthy and simply have the perception of having an illness. Another person may feel healthy with similar perceptions of perfectly good health. The individual's perception of good health may even persist with the medical diagnosis of having a disease; for example, such as dangerously high blood pressure, which may lead to a fatal heart attack or stroke.
Pathology is the study of diseases. The subject of systematic classification of diseases is referred to as nosology. The broader body of knowledge about human diseases and their treatments is medicine. Many similar (and a few of the same) conditions or processes can affect non-human animals (wild or domestic). The study of diseases affecting animals is veterinary medicine.
Disease can be thought of as the presence of pathology, which can occur with or without subjective feelings of being unwell or social recognition of that state. Illness as the subjective state of "unwellness" can occur independently of, or in conjunction with, disease or sickness (with sickness the social classification of someone deemed diseased, which can also occur independently of the presence or absence of disease or illness (c.f. subjective medical conditions). Thus, someone with undetected high blood pressure who feels to be of good health would be diseased, but not ill or sick. Someone with a diagnosis of late-stage cancer would be diseased, probably feeling quite ill, and recognized by others as sick. A person incarcerated in a totalitarian psychiatric hospital for political purposes could arguably be then said to not be diseased, nor ill, but only classified as sick by the rulers of a society with which the person did not agree. Having had a bad day after a night of excess drinking, one might feel ill, but one would not be diseased, nor is it likely that a boss could be convinced of the sickness.
Transmission of disease
Some diseases such as influenza are contagious or infectious. Infectious diseases can be transmitted by any of a variety of mechanisms, including aerosols produced by coughs and sneezes, by bites of insects or other carriers of the disease, and from contaminated water or food (possibly by feces or urine in the sewage), etc. When micro-organisms that cannot be spread from person to person might play a role, some diseases can be prevented with proper nutrition. Other diseases such as cancer and heart disease are not considered to be caused by infection. The same is true of mental diseases.
Social significance of disease
The identification of a condition as a disease, rather than as simply a variation of human structure or function, can have significant social or economic implications. The controversial recognitions as diseases of post-traumatic stress disorder, also known as "Soldier's heart," "shell shock," and "combat fatigue;" repetitive motion injury or repetitive stress injury (RSI); and Gulf War syndrome has had a number of positive and negative effects on the financial and other responsibilities of governments, corporations and institutions towards individuals, as well as on the individuals themselves. The social implication of viewing aging as a disease could be profound, though this classification is not yet widespread.
A condition may be considered to be a disease in some cultures or eras but not in others. Oppositional-defiant disorder, attention-deficit hyperactivity disorder, and, increasingly, obesity, are conditions considered to be diseases in the United States and Canada today, but were not so-considered decades ago and are not so-considered in some other countries. Lepers were a group of afflicted individuals who were historically shunned and the term "leper" still evokes social stigma. Fear of disease can still be a widespread social phenomena, though not all diseases evoke extreme social stigma.
Sickness confers the social legitimization of certain benefits, such as illness benefits, work avoidance, and being looked after by others. In return, there is an obligation on the sick person to seek treatment and work to become well once more. As a comparison, consider pregnancy, which is not a state interpreted as disease or sickness by the individual. On the other hand, it is considered by the medical community as a condition requiring medical care and by society at large as a condition requiring one's staying at home from work.
An infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host's resources to multiply (usually at the expense of the host). The infecting organism, or pathogen, interferes with the normal functioning of the host and can lead to chronic wounds, gangrene, loss of an infected limb, and even death. The host's response to infection is inflammation. Colloquially, a pathogen is usually considered a microscopic organism though the definition is broader, including bacteria, parasites, fungi, viruses, prions, and viroids. A symbiosis between parasite and host, whereby the relationship is beneficial for the former but detrimental to the latter, is characterized as parasitism. The branch of medicine that focuses on infections and pathogens is infectious disease.
Wound colonization refers to nonreplicating microorganisms within the wound, while in infected wounds replicating organisms exist and tissue is injured. All multicellular organisms are colonized to some degree by extrinsic organisms, and the vast majority of these exist in either a mutualistic or commensal relationship with the host. An example of the former would be the anaerobic bacteria species which colonize the mammalian colon, and an example of the latter would be the various species of staphylococcus which exist on human skin. Neither of these colonizations would be considered infections. The difference between an infection and a colonization is often only a matter of circumstance. Organisms which are normally non-pathogenic can become pathogenic under the right conditions, and even the most virulent organism requires certain circumstances to cause a compromising infection. Some colonizing bacteria, such as Corynebacteria sp. and viridans streptococci, prevent the adhesion and colonization of pathogenic bacteria and thus have a symbiotic relationship with the host, preventing infection and speeding wound healing.
The variables involved in the outcome of a host becoming inoculated by a pathogen and the ultimate outcome include:
As an example, the staphylococcus species present on skin remain harmless on the skin, but, when present in a normally sterile space, such as in the capsule of a joint or the peritoneum, will multiply without resistance and create a huge burden on the host.
An occult infection is medical terminology for a "hidden" infection, that is, one which presents no symptoms. Dr. Fran Giampietro discovered and coined the term "Occult Infection" in the late 1930's.
Inflammation (Latin, inflammatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection it is incorrect to use the terms as synonyms: infection is caused by an exogenous pathogen, while inflammation is the response of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation - swelling, redness, pain, heat, and loss of function - due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis). The first four characteristics have been known since ancient times and are attributed to Celsus. Loss of function was added to the definition of inflammation by Rudolf Virchow in the 19th century.
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation, and the increased blood flow to the area causes the reddened color and increased heat. The blood vessels also alter to permit the extravasation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.
Chronic inflammation is a pathological condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterized by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, especially by Mycobacterium tuberculosis, prolonged exposure to chemical agents such as silica, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated (especially in atheromatous plaques).
The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved via the chemically-induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma. The increased collection of fluid into the tissue causes it to swell (edema).
Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability, and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood - a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
Plasma cascade systems
The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules which damage pathogenic invaders. Leukocytes also release inflammatory mediators which develop and maintain the inflammatory response. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
Neutrophils migrate from blood vessels to the inflamed tissue via chemotaxis, where they remove pathogens through phagocytosis and degranulation Neutrophils migrate from blood vessels to the inflamed tissue via chemotaxis, where they remove pathogens through phagocytosis and degranulation Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be divided up into a number of broad steps:
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.
Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischaemic heart disease.
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise dysregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:
An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever, which is caused by a hypersensitive response by skin mast cells to allergens. Pre-sensitized mast cells respond by degranulating, releasing vasoactive chemicals such histamine. These chemicals propagate an excessive inflammatory response characterized by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. Severe inflammatory response may mature into a systemic response known as anaphylaxis.
Other hypersensitivity reactions (type 2 and type 3) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.
Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte function often result in a decreased capacity for inflammatory defence with subsequent vulnerability to infection. Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chediak-Higashi syndrome), or produce microbicides (chronic granulomatous disease). Additionally, diseases affecting the bone marrow may result in abnormal or few leukocytes.
Certain drugs or chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses, and anti-inflammatory drugs work specifically by inhibiting normal inflammatory components.
The inflammatory response must be actively terminated when no longer need to prevent unnecessary "bystander" damage to tissues. Failure to do so results in chronic inflammation, cellular destruction, and attempts to heal the inflamed tissue. One intrinsic mechanism employed to terminate inflammation is the short half-life of inflammatory mediators in vivo. They have a limited time frame to affect their target before breaking down into non-functional components, therefore constant inflammatory stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include:
An organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial, however in chronic inflammation they can contribute to amyloidosis. These proteins include C-reactive protein, serum amyloid A, serum amyloid P, vasopressin, and glucocorticoids, which cause a range of systemic effects including:
Systemic inflammation and obesity
With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.
High levels of several inflammation-related markers such as IL-6, IL-8, and TNF are associated with obesity. During clinical studies, inflammatory-related molecule levels were reduced and increased levels of anti-inflammatory molecules were seen within four weeks after patients began a very low calorie diet. The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense research.
The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. There are three possible outcomes to inflammation:
Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. When an individual is wounded, a set of events takes place in a predictable fashion to repair the damage. These events overlap in time and must be artificially categorized into separate steps: the inflammatory, proliferative, and remodeling phases (Some authors consider healing to take place in four stages, by splitting different parts inflammation or proliferation into separate steps).In the inflammatory phase, bacteria and debris are phagocytized and removed and factors are released that cause the migration and division of cells involved in the proliferative phase.
The proliferative phase is characterized by angiogenesis, collagen deposition, granulation tissue formation, epithelialization, and wound contraction. In angiogenesis, new blood vessels grow from endothelial cells. In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin.
In epithelialization, epithelial cells crawl across the wound bed to cover it.In contraction, the wound is made smaller by the action of myofibroblasts, which establish a grip on the wound edges and contract themselves using a mechanism similar to that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis.
In the maturation and remodeling phase, collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis.
In the inflammatory phase, clotting takes place in order to obtain hemostasis, or stop blood loss, and various factors are released to attract cells that phagocytise debris, bacteria, and damaged tissue and release factors that initiate the proliferative phase of wound healing.
When tissue is first wounded, blood comes in contact with collagen, triggering blood platelets to begin secreting inflammatory factors. Platelets also express glycoproteins on their cell membranes that allow them to stick to one another and to aggregate, forming a mass.
Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles and prevents further blood loss. This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited. Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors. The clot is eventually lysed and replaced with granulation tissue and then later with collagen.
Platelets, the cells present in the highest numbers shortly after a wound occurs, release a number of things into the blood, including ECM proteins and cytokines, including growth factors. Growth factors stimulate cells to speed their rate of division. Platelets also release other proinflammatory factors like serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, and histamine, which serve a number of purposes, including to increase cell proliferation and migration to the area and to cause blood vessels to become dilated and porous.
Vasoconstriction and vasodilation
Immediately after a blood vessel is breached, ruptured cell membranes release inflammatory factors like thromboxanes and prostaglandins that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area. This vasoconstriction lasts five to ten minutes and is followed by vasodilation, a widening of blood vessels, which peaks at about 20 minutes post-wounding. Vasodilation is the result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine. Histamine also causes blood vessels to become porous, allowing the tissue to become edematous because proteins from the bloodstream leak into the extravascular space, which increases its osmolar load and draws water into the area. Increased porousness of blood vessels also facilitates the entry of inflammatory cells like leukocytes into the wound site from the bloodstream.
Within an hour of wounding, polymorphonuclear neutrophils (PMNs) arrive at the wound site and become the predominant cells in the wound for the first three days after the injury occurs, with especially high numbers on the second day. They are attracted to the site by fibronectin, growth factors, and substances such as neuropeptides and kinins. Neutrophils phagocytise debris and bacteria and also kill bacteria by releasing free radicals in what is called a 'respiratory burst'. They also cleanse the wound by secreting proteases that break down damaged tissue. Neutrophils usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by macrophages.
Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability. T cells also increase the activity of macrophages.
Macrophages are essential to wound healing. They replace PMNs as the predominant cells in the wound by two days after injury. Attracted to the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enter the area through blood vessel walls. Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. Once they are in the wound site, monocytes mature into macrophages, the main cell type that clears the wound area of bacteria and debris.
The macrophage's main role is to phagocytise bacteria and damaged tissue, and it also debrides damaged tissue by releasing proteases. Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wounding days. These factors attract cells involved in the proliferation stage of healing to the area. Macrophages are stimulated by the low oxygen content of their surroundings to produce factors that induce and speed angiogenesis. and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix. Because they secrete these factors, macrophages are vital for pushing the wound healing process into the next phase.
Because inflammation plays roles in fighting infection and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to tissue damage if it lasts too long. Thus the reduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as long as there is debris in the wound. Thus the presence of dirt or other objects can extend the inflammatory phase for too long, leading to a chronic wound.
As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, and numbers of neutrophils and macrophages are reduced at the wound site. These changes indicate that the inflammatory phase is ending and the proliferative phase is underway.
About two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset of the proliferative phase even before the inflammatory phase has ended. As in the other phases of wound healing, steps in the proliferative phase do not occur in a series but rather partially overlap in time.
Also called neovascularization, the process of angiogenesis occurs concurrently with fibroblast proliferation when endothelial cells migrate to the area of the wound. Because the activity of fibroblasts and epithelial cells requires oxygen, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythematous) due to the presence of capillaries.
In order to form new blood vessels and provide oxygen and nutrients to the healing tissue. Stem cells called endothelial cells originating from parts of uninjured blood vessels develop pseudopodia and push through the ECM into the wound site. Through this activity, they establish new blood vessels.
To migrate, endothelial cells need collagenases and plasminogen activator to degrade the clot and part of the ECM. Zinc-dependent metalloproteinases digest basement membrane and ECM to allow cell proliferation and angiogenesis.
Endothelial cells are also attracted to the wound area by fibronectin found on the fibrin scab and by growth factors released by other cells. Endothelial growth and proliferation is also stimulated by hypoxia and presence of lactic acid in the wound. In a low-oxygen environment, macrophages and platelets produce angiogenic factors which attract endothelial cells chemotactically. When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors. Thus, when tissue is adequately perfused, migration and proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die by apoptosis.
Fibroplasia and granulation tissue formation
Simultaneously with angiogenesis, fibroblasts begin accumulating in the wound site. Fibroblasts begin entering the wound site two to five days after wounding as the inflammatory phase is ending, and their numbers peak at one to two weeks post-wounding. By the end of the first week, fibroblasts are the main cells in the wound. Fibroplasia ends two to four weeks after wounding.
In the first two or three days after injury, fibroblasts mainly proliferate and migrate, while later, they are the main cells that lay down the collagen matrix in the wound site. Fibroblasts from normal tissue migrate into the wound area from its margins. Initially fibroblasts use the fibrin scab formed in the inflammatory phase to migrate across, adhering to fibronectin. Fibroblasts then deposit ground substance into the wound bed, and later collagen, which they can adhere to for migration.
Granulation tissue is needed to fill the void that has been left by a large, open wound that crosses the basement membrane. It begins to appear in the wound even during the inflammatory phase, two to five days post wounding, and continues growing until the wound bed is covered. Granulation tissue consists of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, and the components of a new, provisional ECM. The provisional ECM is different in composition from the ECM in normal tissue and includes fibronectin, collagen, glycosaminoglycans, and proteoglycans. Its main components are fibronectin and hyaluronan, which create a very hydrated matrix and facilitate cell migration. Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue. Fibroblasts deposit ECM molecules like glycoproteins, glycosaminoglycans (GAGs), proteoglycans, elastin, and fibronectin, which they can then use to migrate across the wound.
Growth factors and fibronectin encourage proliferation, migration to the wound bed, and production of ECM molecules by fibroblasts. Fibroblasts also secrete growth factors that attract epithelial cells to the wound site. Hypoxia also contributes to fibroblast proliferation and excretion of growth factors, though too little oxygen will inhibit their growth and deposition of ECM components, and can lead to excessive, fibrotic scarring.
One of fibroblasts' most important duties is the production of collagen. Fibroblasts begin secreting appreciable collagen by the second or third post-wounding day, and its deposition peaks at one to three weeks. Collagen production continues rapidly for two to four weeks, after which its destruction matches its production and so its growth levels off.
Collagen deposition is important because it increases the strength of the wound; before it is laid down, the only thing holding the wound closed is the fibrin-fibronectin clot, which does not provide much resistance to traumatic injury. Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.
Even as fibroblasts are producing new collagen, collagenases and other factors degrade it. Shortly after wounding, synthesis exceeds degradation so collagen levels in the wound rise, but later production and degradation become equal so there is no net collagen gain. This homeostasis signals the onset of the maturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once their work is done. At the end of the granulation phase, fibroblasts begin to commit apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen.
The formation of granulation tissue in an open wound allows the reepithelialization phase to take place, as epithelial cells migrate across the new tissue to form a barrier between the wound and the environment. Basal keratinocytes from the wound edges and dermal appendages such as hair follicles, sweat glands and sebaceous (oil) glands are the main cells responsible for the epithelialization phase of wound healing. They advance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in the middle.
Keratinocytes migrate without first proliferating. Migration can begin as early as a few hours after wounding. However, epithelial cells require viable tissue to migrate across, so if the wound is deep it must first be filled with granulation tissue. Thus the time of onset of migration is variable and may occur about one day after wounding. Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.
If the basement membrane is not breached, epithelial cells are replaced within three days by division and upward migration of cells in the stratum basale in the same fashion that occurs in uninjured skin. However, if the basement membrane is ruined at the wound site, reepithelization must occur from the wound margins and from skin appendages such as hair follicles and sweat and oil glands that enter the dermis that are lined with viable keratinocytes. If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.
Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition and by chemicals such as nitric oxide. Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes, which normally anchor the cells by intermediate filaments in their cytoskeleton to other cells and to the ECM. Transmembrane receptor proteins called integrins, which are made of glycoproteins and normally anchor the cell to the basement membrane by its cytoskeleton, are released from the cell's intermediate filaments and relocate to actin filaments to serve as attachments to the ECM for pseudopodia during migration. Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.
Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia and wide processes that look like ruffles. Actin filaments and pseudopodia form. During migration, integrins on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along. The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia.
Epithelial cells climb over one another in order to migrate. This growing sheet of epithelial cells is often called the epithelial tongue. The first cells to attach to the basement membrane form the stratum basale. These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along as well. The more quickly this migration occurs, the less of a scar there will be.
Fibrin, collagen, and fibronectin in the ECM may further signal cells to divide and migrate Like fibroblasts, migrating keratinocytes use the fibronectin cross-linked with fibrin that was deposited in inflammation as an attachment site to crawl across.
As keratinocytes migrate, they move over granulation tissue but underneath the scab (if one was formed), separating it from the underlying tissue. Epithelial cells have the ability to phagocytize debris such as dead tissue and bacterial matter that would otherwise obstruct their path. Because they must dissolve any scab that forms, keratinocyte migration is best enhanced by a moist environment, since a dry one leads to formation of a bigger, tougher scab. To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through. They secrete plasminogen activator, which activates plasmin to dissolve the scab. Cells can only migrate over living tissue, so they must excrete collagenases and proteases like matrix metalloproteinases (MMPs) to dissolve damaged parts of the ECM in their way, particularly at the front of the migrating sheet. Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.
As keratinocytes continue migrating, new epithelial cells must be formed at the wound edges to replace them and to provide more cells for the advancing sheet. Proliferation behind migrating keratinocytes normally begins a few days after wounding and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues. Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.
Growth factors, stimulated by integrins and MMPs, cause cells to proliferate at the wound edges. Keratinocytes themselves also produce and secrete factors, including growth factors and basement membrane proteins, which aid both in epithelialization and in other phases of healing.
Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point contact inhibition causes them to stop migrating. When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane. Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosomes and hemidesmosomes and become anchored once again to the basement membrane. Basal cells begin to divide and differentiate in the same manner as they do in normal skin to reestablish the strata found in reepithelialized skin.
Around a week after the wounding takes place, fibroblasts have differentiated into myofibroblasts and the wound begins to contract. In full thickness wounds, contraction peaks at 5 to 15 days post wounding. Contraction can last for several weeks and continues even after the wound is completely reepithelialized. If contraction continues for too long, it can lead to disfigurement and loss of function.
Contraction occurs in order to reduce the size of the wound. A large wound can become 40 to 80% smaller after contraction.. Wounds can contract at a speed of up to 0.75 mm per day, depending on how loose the tissue in the wounded area is. Contraction usually does not occur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization and alignment of cells with collagen.
At first, contraction occurs without myofibroblast involvement. Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction. Myofibroblasts contain the same kind of actin as that found in smooth muscle cells.
Myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrin in the provisional ECM in order to reach the wound edges. They form connections to the ECM at the wound edges, and they attach to each other and to the wound edges by desmosomes. Also, at an adhesion called the fibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrix like fibronectin and collagen. Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size. In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.
As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract. The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis. The breakdown of the provisional matrix leads to a decrease in hyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating and proliferating. These events signal the onset of the maturation stage of wound healing.
Maturation and remodeling phase
When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun. The maturation phase can last for a year or longer, depending on the size of the wound and whether it was initially closed or left open. During Maturation, type III collagen, which is prevalent during proliferation, is gradually degraded and the stronger type I collagen is laid down in its place. Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines. As the phase progresses, the tensile strength of the wound increases, with the strength approaching 50% that of normal tissue by three months after injury and ultimately becoming as much as 80% as strong as normal tissue. Since activity at the wound site is reduced, the scar loses its erythematous appearance as blood vessels that are no longer needed are removed by apoptosis.
The phases of wound healing normally progress in a predictable, timely manner; if they do not, healing may progress inappropriately to either a chronic wound such as a venous ulcer or pathological scarring such as a keloid scar.
Neoplasia (new growth in Greek) is abnormal proliferation of cells in a tissue or organ. A neoplastic growth is called a neoplasm. Many neoplasms form distinct masses, or tumors, but there are also many examples of neoplastic processes which are not grossly apparent, a commonly diagnosed example being cervical intraepithelial neoplasia, a pre-cancerous lesion of the uterine cervix. It is important to note that the term "neoplasm" is not synonymous with cancer, since neoplasms can be either benign or malignant. Leiomyoma (fibroids of the uterus) and melanocytic nevi (moles) are the most common types of neoplasms - both are benign.
Interestingly, there is not a complete consensus in the biomedical community as to the exact biological definition of a neoplasm, although the statement of the British oncologist R.A. Willis is widely cited:
“ A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues, and persists in the same excessive manner after cessation of the stimulus which evoked the change.”
Neoplastic tumors often contain more than one type of cell, but their initiation and continued growth is usually dependent on a single population of neoplastic cells which are clonal - that is, they are descended from a single progenitor cell. The neoplastic cells typically bear common genetic or epigenetic abnormalities which are not seen in the non-neoplastic stromal cells and blood-vessel forming cells, whose growth is dependent on molecular stimuli from the neoplastic cells. The demonstration of clonality is now considered by many to be necessary (though not sufficient) to define a cellular proliferation as neoplastic.
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