<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Circumvallate placenta and can you explain it in depth? [/INST] Circumvallate placenta is a rare condition affecting about 1-2% of pregnancies, in which the amnion and chorion fetal membranes essentially "double back" on the fetal side around the edges of the placenta. After delivery, a circumvallate placenta has a thick ring of membranes on its fetal surface. Circumvallate placenta is a placental morphological abnormality associated with increased fetal morbidity and mortality due to the restricted availability of nutrients and oxygen to the developing fetus.
Physicians may be able to detect a circumvallate placenta during pregnancy by using an ultrasound. However, in other cases, a circumvallate placenta is not identified until delivery of the baby. Circumvallate placenta can increase the risk of associated complications such as preterm delivery and placental abruption. Occasionally, a circumvallate placenta can also increase the risk of neonatal death and emergency caesarean section. Although there is no existing treatment for circumvallate placenta, physicians can attempt to minimize the effects of complications, if they occur, through frequent fetal monitoring and, if necessary, emergency cesarean section.In a circumvallate placenta, the chorionic plate, which forms the fetal surface of the placenta, tends to be smaller than the basal plate, which forms the maternal surface of the placenta. This results in the elevation of the placental margin and the appearance of an annular shape. The fetal surface is divided into a central depressed zone surrounded by a thickened white ring which is incomplete. The ring is situated at varying distances from the margin, or edges, of the placenta. This thick ring of membranes is composed of a double fold of amnion and chorion with degenerated decidua vera and fibrin in between. Blood vessels, supplying nutrients and carrying waste products to and from the developing fetus, radiate from the umbilical cord insertion to as far as the ring of membranes, and then disappears from view.

Signs & Symptoms
A circumvallate placenta does not always induce associated symptoms during pregnancy, making it extremely difficult to diagnose a circumvallate placenta in asymptomatic mothers. In symptomatic mothers, physicians may be able to detect a circumvallate placenta based on the presentation of the following signs.
Vaginal bleeding: A circumvallate placenta can increase the risk of frequent vaginal bleeding during the first trimester of pregnancy. In a study conducted with 92 women with a circumvallate placenta, it was concluded that incidences of vaginal bleeding were significantly higher in women with a circumvallate placenta during all three trimesters when compared to the control group. However, a noted limitation of the study considered by the researchers was that because the study included such a small number of women, the obtained results may not be fully representative of the general population. Because the chorionic plate is much smaller than the basal plate in a circumvallate placenta, vaginal bleeding tends to occur at this site where the placenta is exposed and uncovered. In mothers presenting with vaginal bleeding, circumvallate placenta should be suspected as a possible cause of the vaginal bleeding.
Inhibited fetal growth: Fetuses tend to develop more slowly when associated with a circumvallate placenta, largely due to the reduced supply of blood and nutrients from mother to fetus. Physicians will order tests to determine the cause of inhibited fetal growth when a developing fetus does not meet growth expectations during the course of the pregnancy.
Premature rupture of membranes (PROM): PROM happens when the protective covering of the amniotic sac ruptures before the onset of labor and delivery. If PROM occurs within the first 37 weeks of pregnancy, it is termed preterm premature rupture of membranes (PPROM). PROM itself has many causes and risk factors. When PROM occurs along with vaginal bleeding in the second trimester of pregnancy, it is suspected that a mother likely has a circumvallate placenta.

Complications
Circumvallate placenta has also been associated with a higher incidence of complications including placental abruption, low birth weight, premature delivery, perinatal death, and fetal abnormalities.

Low birth weight: Lack of proper nutrition and blood flow to the fetus during pregnancy often results in decreased weight of the baby at birth.
Placenta abruption: Placenta abruption, in which the placenta divides from the wall of the uterus prior to birth, can have severe outcomes for a mother and her baby. Such consequences include vaginal bleeding, decreased birth weight, preterm delivery, and stillbirth. Significant vaginal bleeding can induce maternal anemia and dangerously low blood pressure.
Oligohydramnios: Insufficiency of proper volumes of amniotic fluid, a condition called oligohydramnios, can also occur as a result of a circumvallate placenta. Amniotic fluid is essential to normal fetal movement, fetal organ development, and cushioning of the fetus within the mothers uterus. It is also imperative in preventing umbilical cord compression so that the fetus is able to obtain nourishment and oxygenation from its mother.
Premature delivery: Premature birth of the fetus occurs at less than 37 weeks of gestation, compared to full-term delivery at about 40 weeks.
Miscarriage: Loss of a fetus prior to birth via miscarriage can transpire if any of the above complications occur without prompt intervention and treatment.

Cause
Unfortunately, there is no known cause of circumvallate placenta and no major preventative measures that can be taken to minimize the risk of developing a circumvallate placenta. Circumvallate placenta is not a genetic disorder. Some potential causes of circumvallate placenta include reduced amniotic fluid pressure, circumferential hemorrhage, and superficial or deep implantation of the embryo within the uterine wall, although these potential causes are still not well-understood in terms of their relation to circumvallate placenta.High-risk pregnancies are described as pregnancies in which a mother, the fetus, or both are put at a higher risk for developing pregnancy complications before, during, or after birth. Risk factors such as hypertensive medical conditions, maternal age, and substance use are just some of the things that can put a woman at an increased risk for developing circumvallate placenta and/or any other complications.

Risk factors
Hypertensive disorders
Women entering a pregnancy with hypertension are considered to be put at a higher risk for preeclampsia or eclampsia during the course of their pregnancy. Hypertensive disorders, like hypertension, have been found to affect about 10% of pregnancies in the United States and have resulted in about 6.8% of maternal deaths from 2011 to 2015. High blood pressure during pregnancy can potentially damage maternal organ systems such as the liver or the kidneys, which can be life-threatening. To prevent preeclampsia or eclampsia from developing in pregnancy, women with hypertension can be prescribed anti-hypertensive medications during pregnancy and are advised to monitor their blood pressure throughout the course of pregnancy.

Maternal age
Another risk factor for developing any pregnancy complications is maternal age. Advanced maternal age, considered to be when a woman enters pregnancy at age 35 or above, has also been linked to increased risk of maternal mortality, preeclampsia, restricted fetal growth, fetal distress, and a variety of other pregnancy complications. Conversely, teenage pregnancy is also associated with increased risk of endometriosis, postpartum hemorrhage, and mild preeclampsia, when compared with pregnant mothers in their 20s. Genetically, the long period of time between meiotic arrest of the egg gamete as a fetus and each ovulation cycle occurring after the onset of female puberty in teenage years can potentially contribute to the increased risk for pregnancy complications in mothers who are age 35 or older at time of pregnancy.

Substance use
Further, yet another factor inducing adverse complications in pregnancy is substance use status. Nicotine, alcohol, and marijuana are the most common substances used during pregnancies. Substance use in pregnancy is concerning because of its alarming association with other risk factors, such as mental illness. Depression alone has been associated within increased risk for preeclampsia, gestational diabetes, hypertension, premature birth, and low birth weight. Women with substance use disorders tend to live in areas that are unable to provide quality prenatal care or proper management of their psychiatric conditions. As a result of improper management of psychiatric illnesses, substances are abused during pregnancy, potentially causing harm to both the mother and the fetus. Some pregnancy complications that can occur as a result of substance use in pregnancy are fetal alcohol syndrome and neonatal abstinence disorder.Women with these risk factors are recommended additional surveillance during pregnancy to monitor fetal development and to be able to detect fetal, placental, or umbilical cord abnormalities as early as possible.

Pathophysiology/Mechanism
The placenta is a transient organ developed during pregnancy that facilitates nutrient, gas, and waste exchange between a mother and a developing fetus. Placental abnormalities, such as circumvallate placenta, can harm a developing fetus, as normal exchange of materials between a mother and a developing fetus is impaired. With placental abnormalities, a developing fetus is unable to receive the vital materials that it needs for proper development, resulting in the possibility of pregnancy complications, birth defects, and/or death of the fetus.
In a normal placenta, there is a smooth transition from the parenchymal villous chorion to the membranous chorion at the border of the placental plate. Fetal blood vessels subdivide from the umbilical cord and spread diagonally throughout the parenchyma towards the edge of the placental plate.In a circumvallate placenta, the membranes often become restrained due to marginal infarct, hemorrhage, or fibrin depositing. This results in the reduction in size of the chorionic plate of the placenta, further causing the membranes on the fetal side to fold backward on themselves. The parenchymal villous chorion continues to proliferate beyond the tethered membranes and appears to protrude outward. The fetal blood vessels are directed downward and then horizontally in order to provide blood flow to the most peripheral parts of the placental plate extending beyond the tethered membranes.Since a portion of the placenta tends to become exposed in a circumvallate placenta, due to the reduced size of the chorionic plate, vaginal bleeding is more likely to occur at this site of exposure. Likewise, inhibited fetal growth can also ensue due to the decreased exchange of nutrients and waste between mother and fetus, since the fetus is unable to sustain necessary nutritional demands for proper fetal development. Premature rupture of membranes often occurs as a result of infection in the uterus, which can be caused by the occurrence vaginal bleeding. Therefore, placental abnormalities such as circumvallate placenta can be extremely detrimental in causing the onset of associated conditions.

Diagnosis
In some cases, a physician may be able to diagnose a circumvallate placenta via ultrasound during one of many routine ultrasound screenings. In most cases, a circumvallate placenta is not discovered until physical examination of the placenta after delivery of the fetus. For this reason, circumvallate placenta is very difficult to diagnose during pregnancy.
On ultrasound, a normal placenta should appear complete and uniform, with the fetal surface of the placenta appearing slightly shiny and translucent. The appearance of a circumvallate placenta on ultrasound may present with irregular edges, uplifted margins, or placental sheets. In a study conducted in 1994, 62 healthy pregnant women were examined with placental sonography for detection of circumvallate placenta. Of the five experienced sonologists who interpreted the placental ultrasounds, all were unable to properly detect and diagnose circumvallate placenta, revealing the difficult nature of circumvallate placenta recognition. Further, these findings indicate that prenatal sonographic criteria used for detection of circumvallate placenta are not reliable enough for screening purposes.
Complete circumvallate placenta involves morphological abnormality of the entire dimension of the placenta, while partial circumvallate placenta does not involve the entire placenta but rather a portion of the placenta. Complete circumvallate placenta is very rare, occurring within about 1% of pregnancies, and has been noted to increase the risks of associated complications such as placental abruption, premature childbirth, premature rupture of membranes, perinatal death, and congenital abnormalities. Partial circumvallate placenta is more common but is not found to be as clinically significant as complete circumvallate placenta.The accurate diagnosis of circumvallate placenta during pregnancy can have significant implications in the recognition of patients who are at risk of complications. Although the ability of sonography to accurately diagnosis circumvallate placenta during pregnancy is quite limited, research studies continue to emerge at the possibility of doing so.

Treatment/Management
Although there is no cure or specific treatment for restoration of the circumvallate placenta, there are ways to decrease the risks of possible complications prior to birth or attempt to manage complications if they develop. If circumvallate placenta is diagnosed during pregnancy, physicians may offer recommendations to reduce the risks of associated complications such as lower birth weight and placental abruption.Decreased birth weight is a major concern associated with circumvallate placenta. Infants born with birth weights that are lower than expected per their gestational age oftentimes end up requiring extra support in the neonatal intensive care unit (NICU). To assist in the monitoring of appropriate fetal growth, a physician may recommend more frequent growth checks during pregnancy if circumvallate placenta is suspected. If a fetus is not growing satisfactorily, premature delivery, via vaginal delivery or caesarean section, may be recommended, with C-section being more favorable compared to vaginal delivery.In women experiencing a placental abruption associated with circumvallate placenta, physicians will normally advocate for frequent growth checks, hospital bed rest, early delivery, and, if necessary, emergency C-section. Likewise, IV fluids and blood transfusions can also be given to patients with a placental abruption in attempts to increase blood pressure and minimize the effects of severe blood loss.If oligohydramnios occurs as a result of a circumvallate placenta, a treatment called amnioinfusion may be considered to replenish the amount of lost amniotic fluid within the amniotic sac. Amnioinfusion may help in preventing underdevelopment of the lungs.If diagnosed with a circumvallate placenta, consistent fetal monitoring by a licensed physician can help to prevent and/or reduce the effects of associated complications that may occur. Additionally, healthy lifestyle choices, a well-balanced and nutritious diet, adequate rest, and cessation of alcohol and tobacco products can also help to prevent the incidence of a circumvallate placenta and its associated complications. If diagnosed with a circumvallate placenta, in association with other threatening pregnancies complications, emergency cesarean section will most likely be suggested by a physician.

Prognosis
Unfortunately, there is currently not a cure available for circumvallate placenta. While some evidence suggests that a circumvallate placenta can increase the risk of complication during pregnancy, other research suggests this increased risk is marginal. Sadly, circumvallate placenta can occasionally result in infant death depending on the severity of the complications encountered. In other cases, circumvallate placenta can result in premature birth of infants who are otherwise healthy after being monitored in the neonatal intensive care unit for a period of time after birth. Therefore, proper medical care and monitoring are crucial in attempting to minimize the likelihood of complications. In other cases, patients diagnosed with circumvallate placenta are able to carry their babies until term or near-term.

Epidemiology
Circumvallate placenta is a very rare condition affecting pregnant women. This condition is a placental morphological abnormality, with the placenta being formed during the early periods of pregnancy. Women are able to become pregnant with the onset of ovulation and menstruation in early adolescence, with most women becoming pregnant during adulthood. Circumvallate placenta is currently known to affect about 1-2% of pregnancies. It is not virally transmissible to other individuals, nor can it be transferred through contact or respiration.There are no specific racial or ethnic groups that are more predisposed to acquiring a circumvallate placenta during pregnancy, however, as with all pregnancies, there are general risks factors that can put a pregnant woman at risk for complications, including circumvallate placenta. Notably, certain pregnancy complications, such as preeclampsia, tend to be almost three times as fatal in African American women compared to non-Hispanic white women, even though both groups tend to experience preeclampsia at almost the same rates. This is partially thought to be due to inequalities in accessing quality prenatal care in lower socioeconomic neighborhoods and the effect of structural racism within healthcare systems. Any woman residing in an area with a lower socioeconomic status, regardless of race or age, is predisposed to developing pregnancy complications like circumvallate placenta if quality prenatal care is not available.
Women with significant obstetric histories can also be at higher risk for developing any type of pregnancy complication, including circumvallate placenta, and are recommended to be screened for placental abnormalities within their second trimester of pregnancy.

Research Directions
The placenta plays a dominant role in being responsible for a variety of complications within pregnancy and labor. Placental pathological studies have significantly contributed to recent obstetric literature. Many studies have examined the clinical significance of patients with circumvallate placenta compared to patients with a normal placenta. They have revealed that incidences of preterm birth, oligohydramnios, placental abruption, low birth weight, and fetal death were present in significantly higher rates than when compared to control patients with normal placentas. Because circumvallate placenta is such a rare condition, it is difficult to gain significant evidence and data.A case study reported in 2020 observed the correlation between circumvallate placenta and the occurrence of obstetric complications such as battledore insertion. Battledore insertion, abnormal insertion of the umbilical cord into the placenta, occurs in about 7% of pregnancies and can also result in many of the same pregnancy complications as circumvallate placenta; intrauterine growth restriction, fetal distress, and fetal death. This abnormal insertion of the umbilical cord into the placenta can result in a loss of adequate blood flow to the developing fetus due to restriction. The fetus is unable to obtain normal amounts of required oxygen and nutrition through the placenta, and this can further cause other severe complications.
In the study, a 22-year-old woman at 28 weeks and 2 days of gestation, presented for a routine third trimester screening. She was noted to have had 2 prior miscarriages at 17 and 20 weeks. A previous normal second trimester routine screening at 21 weeks of gestation did not identify any structural abnormalities within the placenta, decreased fetal size, or abnormally-appearing umbilical cord insertion. The patient also did not have any episodes of vaginal bleeding during the current pregnancy.Upon presenting for routine screening at 28 weeks and 2 days of gestation, the patient was not exhibiting any signs of active contractions and a cardiotocography was performed as part of routine screening. Cardiotocography is a diagnostic tool used during the third trimester of pregnancy to observe fetal heart rates and presence of uterine contractions. It can also be used to detect signs of any sort of fetal distress. In interpreting the cardiotocography that the 22-year-old pregnant woman had completed, it was noted that the fetus appeared to be much smaller than expected and was exhibiting concerns of decreased amniotic fluid volume, oligohydramnios, and restricted blood flow through the umbilical cord. Cardiotocographic monitoring also noted decreases in fetal heart rate every 25 minutes without contractions. Fetal motion was present, with the placenta appearing enlarged and spherical.Decreases in the fetus heart rate, in addition to the other findings of the cardiotocography, ultimately prompted physicians to deliver the baby via emergency cesarean section without major complications. The newborn, with normal APGAR scores and umbilical cord arterial pH levels, was admitted to the neonatal intensive care unit. Upon examining the placenta after delivery, it was noted that the placenta demonstrated the appearance of a circumvallate placenta, and also showed evidence of abnormal umbilical cord insertion into the placenta. Postpartum, the mother had a good recovery and the newborn was discharged from the neonatal intensive care unit 105 days post-birth.This case study discussed the association of circumvallate placenta and abnormal battledore cord insertion in producing pregnancy complications. Restriction of umbilical cord blood flow from the placenta to the fetus and placental abnormalities like circumvallate placenta may work in conjunction to generate fetal distress. Decreased levels of oxygenation and nutrient absorption resulted in decelerations of fetal heart rate and the decision to deliver the fetus via cesarean section to prevent fetal death by hypoxia. Routine monitoring of fetal growth and development, placental structure, and placental function are recommended with high-risk pregnancies. In patients diagnosed with circumvallate placenta during pregnancy, monthly fetal growth assessments are also recommended. Patients found to have blood flow restrictions to or from the placenta are recommended to undergo weekly ultrasounds with consistent monitoring of fetal heart rate.In a separate case study reported in 2017, a woman at about 35 weeks of gestation presented with preeclampsia and intrauterine fetal demise, or more commonly known as stillbirth </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Brown-Séquard syndrome and can you explain it in depth? [/INST] Brown-Séquard syndrome (also known as Brown-Séquards hemiplegia, Brown-Séquards paralysis, hemiparaplegic syndrome, hemiplegia et hemiparaplegia spinalis, or spinal hemiparaplegia) is caused by damage to one half of the spinal cord, i.e. hemisection of the spinal cord resulting in paralysis and loss of proprioception on the same (or ipsilateral) side as the injury or lesion, and loss of pain and temperature sensation on the opposite (or contralateral) side as the lesion. It is named after physiologist Charles-Édouard Brown-Séquard, who first described the condition in 1850.

Causes
Brown-Séquard syndrome may be caused by injury to the spinal cord resulting from a spinal cord tumor, trauma [such as a fall or injury from gunshot or puncture to the cervical or thoracic spine], ischemia (obstruction of a blood vessel), or infectious or inflammatory diseases such as tuberculosis, or multiple sclerosis. In its pure form, it is rarely seen. The most common cause is penetrating trauma such as a gunshot wound or stab wound to the spinal cord. Decompression sickness may also be a cause of Brown-Séquard syndrome.The presentation can be progressive and incomplete. It can advance from a typical Brown-Séquard syndrome to complete paralysis. It is not always permanent and progression or resolution depends on the severity of the original spinal cord injury and the underlying pathology that caused it in the first place.

Pathophysiology
The hemisection of the cord results in a lesion of each of the three main neural systems:
the principal upper motor neuron pathway of the corticospinal tract
one or both dorsal columns
the spinothalamic tractAs a result of the injury to these three main brain pathways the patient will present with three lesions:

The corticospinal lesion produces spastic paralysis on the same side of the body below the level of the lesion (due to loss of moderation by the UMN). At the level of the lesion, there will be flaccid paralysis of the muscles supplied by the nerve of that level (since lower motor neurons are affected at the level of the lesion).
The lesion to fasciculus gracilis or fasciculus cuneatus (dorsal column) results in ipsilateral loss of vibration and proprioception (position sense) as well as loss of all sensation of fine touch.
The loss of the spinothalamic tract leads to pain and temperature sensation being lost from the contralateral side beginning one or two segments below the lesion.In addition, if the lesion occurs above T1 of the spinal cord it will produce ipsilateral Horners syndrome with involvement of the oculosympathetic pathway.

Diagnosis
Magnetic resonance imaging (MRI) is the imaging of choice in spinal cord lesions.Brown-Séquard syndrome is an incomplete spinal cord lesion characterized by findings on clinical examination which reflect hemisection of the spinal cord (cutting the spinal cord in half on one or the other side). It is diagnosed by finding motor (muscle) paralysis on the same (ipsilateral) side as the lesion and deficits in pain and temperature sensation on the opposite (contralateral) side. This is called ipsilateral hemiplegia and contralateral pain and temperature sensation deficits. The loss of sensation on the opposite side of the lesion is because the nerve fibers of the spinothalamic tract (which carry information about pain and temperature) crossover once they meet the spinal cord from the peripheries.

Classification
Any presentation of spinal injury that is an incomplete lesion (hemisection) can be called a partial Brown-Séquard or incomplete Brown-Séquard syndrome.Brown-Séquard syndrome is characterized by loss of motor function (i.e. hemiparaplegia), loss of vibration sense and fine touch, loss of proprioception (position sense), loss of two-point discrimination, and signs of weakness on the ipsilateral (same side) of the spinal injury. This is a result of a lesion affecting the dorsal column-medial lemniscus tract, well localized (deep) touch, conscious proprioception, vibration, pressure and 2-point discrimination, and the corticospinal tract, which carries motor fibers. On the contralateral (opposite side) of the lesion, there will be a loss of pain and temperature sensation and crude touch 1 or 2 segments below the level of the lesion via the Spinothalamic Tract of the Anterolateral System. Bilateral (both sides) ataxia may also occur if the ventral spinocerebellar tract and dorsal spinocerebellar tract are affected.Crude touch, pain and temperature fibers are carried in the spinothalamic tract. These fibers decussate at the level of the spinal cord. Therefore, a hemi-section lesion to the spinal cord will demonstrate loss of these modalities on the contralateral side of the lesion, while preserving them on the ipsilateral side. Upon touching this side, the patient will not be able to localize where they were touched, only that they were touched. This is because fine touch fibers are carried in the dorsal column-medial lemniscus pathway. The fibers in this pathway decussate at the level of the medulla. Therefore, a hemi-section lesion of the spinal cord will demonstrate loss of fine touch on ipsilateral side (preserved on the contralateral side) and crude touch (destruction of the decussated spinothalamic fibers from the contralateral side) on the contralateral side.Pure Brown-Séquard syndrome is associated with the following:
Interruption of the lateral corticospinal tracts:
Ipsilateral spastic paralysis below the level of the lesion
Babinski sign ipsilateral to lesion
Abnormal reflexes and Babinski sign may not be present in acute injury
Interruption of posterior white column:
Ipsilateral loss of tactile discrimination, vibratory, and position sensation below the level of the lesion
Interruption of lateral spinothalamic tracts:
Contralateral loss of pain and temperature sensation. This usually occurs 2–3 segments below the level of the lesion.

Treatment
Treatment is directed at the pathology causing the paralysis. If the syndrome is caused by a spinal fracture, this should be identified and treated appropriately. Although steroids may be used to decrease cord swelling and inflammation, the usual therapy for spinal cord injury is expectant.

Epidemiology
Brown-Séquard syndrome is rare as the trauma would have to be something that damaged the nerve fibres on just one half of the spinal cord.

History
Charles-Édouard Brown-Séquard studied the anatomy and physiology of the spinal cord. He described this injury after observing spinal cord trauma which happened to farmers while cutting sugar cane in Mauritius.
French physician, Paul Loye, attempted to confirm Brown-Séquards observations on the nervous system by experimentation with decapitation of dogs and other animals and recording the extent of each animals movement after decapitation.

Notes
Sources
Egido Herrero JA, Saldanã C, Jiménez A, Vázquez A, Varela de Seijas E, Mata P (1992). "Spontaneous cervical epidural hematoma with Brown-Séquard syndrome and spontaneous resolution. Case report". J Neurosurg Sci. 36 (2): 117–19. PMID 1469473.
Ellger T, Schul C, Heindel W, Evers S, Ringelstein EB (June 2006). "Idiopathic spinal cord herniation causing progressive Brown-Séquard syndrome". Clin Neurol Neurosurg. 108 (4): 388–91. doi:10.1016/j.clineuro.2004.07.005. PMID 16483712. S2CID 35644328.
Finelli PF, Leopold N, Tarras S (May 1992). "Brown-Sequard syndrome and herniated cervical disc". Spine. 17 (5): 598–600. doi:10.1097/00007632-199205000-00022. PMID 1621163. S2CID 37493662.
Hancock JB, Field EM, Gadam R (1997). "Spinal epidural hematoma progressing to Brown-Sequard syndrome: report of a case". J Emerg Med. 15 (3): 309–12. doi:10.1016/S0736-4679(97)00010-3. PMID 9258779.
Harris P (November 2005). "Stab wound of the back causing an acute subdural haematoma and a Brown-Sequard neurological syndrome". Spinal Cord. 43 (11): 678–9. doi:10.1038/sj.sc.3101765. PMID 15852056.
Henderson SO, Hoffner RJ (1998). "Brown-Sequard syndrome due to isolated blunt trauma". J Emerg Med. 16 (6): 847–50. doi:10.1016/S0736-4679(98)00096-1. PMID 9848698.
Hwang W, Ralph J, Marco E, Hemphill JC (June 2003). "Incomplete Brown-Séquard syndrome after methamphetamine injection into the neck". Neurology. 60 (12): 2015–16. doi:10.1212/01.wnl.0000068014.89207.99. PMID 12821761. S2CID 13491137.
Kraus JA, Stüper BK, Berlit P (1998). "Multiple sclerosis presenting with a Brown-Séquard syndrome". J. Neurol. Sci. 156 (1): 112–13. doi:10.1016/S0022-510X(98)00016-1. PMID 9559998. S2CID 44403915.
Lim E, Wong YS, Lo YL, Lim SH (April 2003). "Traumatic atypical Brown-Sequard syndrome: case report and literature review". Clin Neurol Neurosurg. 105 (2): 143–45. doi:10.1016/S0303-8467(03)00009-X. PMID 12691810. S2CID 37419566.
Lipper MH, Goldstein JH, Do HM (August 1998). "Brown-Séquard syndrome of the cervical spinal cord after chiropractic manipulation". AJNR Am J Neuroradiol. 19 (7): 1349–52. PMID 9726481.
Mastronardi L, Ruggeri A (January 2004). "Cervical disc herniation producing Brown-Sequard syndrome: case report". Spine. 29 (2): E28–31. doi:10.1097/01.BRS.0000105984.62308.F6. PMID 14722422. S2CID 36231998.
Miyake S, Tamaki N, Nagashima T, Kurata H, Eguchi T, Kimura H (February 1998). "Idiopathic spinal cord herniation. Report of two cases and review of the literature". J. Neurosurg. 88 (2): 331–35. doi:10.3171/jns.1998.88.2.0331. PMID 9452246.
Rumana CS, Baskin DS (April 1996) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Thrombotic microangiopathy and can you explain it in depth? [/INST] Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury.  It may be seen in association with thrombocytopenia, anemia, purpura and kidney failure.
The classic TMAs are hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.  Other conditions with TMA include atypical hemolytic uremic syndrome, disseminated intravascular coagulation, scleroderma renal crisis, malignant hypertension,
antiphospholipid antibody syndrome, and drug toxicities, e.g. calcineurin inhibitor toxicity.

Signs and symptoms
The clinical presentation of TMA, although dependent on the type, typically includes: fever, microangiopathic hemolytic anemia (see schistocytes in a blood smear), kidney failure, thrombocytopenia and neurological manifestations. Generally, renal complications are particularly predominant with Shiga-toxin-associated hemolytic uremic syndrome (STx-HUS) and atypical HUS, whereas neurologic complications are more likely with TTP. Individuals with milder forms of TTP may have recurrent symptomatic episodes, including seizures and vision loss. With more threatening cases of TMA, and also as the condition progresses without treatment, multi-organ failure or injury is also possible, as the hyaline thrombi can spread to and affect the brain, kidneys, heart, liver, and other major organs.

Cause
The specific cause is dependent of the type of TMA that is presented, but the two main pathways that lead to TMA are external triggers of vascular injury, such as viruses, bacterial Shiga toxins or endotoxins, antibodies, and drugs; and congenital predisposing conditions, including decreased levels of tissue factors necessary for the coagulation cascade. Either of these pathways will result in decreased endothelial thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, enhanced vascular shear stress, and abnormal vWF fragmentation. The central and primary event in this progression is injury to the endothelial cells, which reduces the production of prostaglandin and prostacyclin, ultimately resulting in the loss of physiological thromboresistance, or high thrombus formation rate in blood vessels. Leukocyte adhesion to the damaged endothelial wall and abnormal von Willebrand factor (or vWF) release can also contribute to the increase in thrombus formation. More recently, researchers have attributed both TTP and HUS to targeted agents, such as targeted cancer therapies, immunotoxins, and anti-VEGF therapy.Bacterial toxins are the primary cause of one category of thrombotic microangiopathy known as HUS or hemolytic uremic syndrome. HUS can be divided into two main categories: Shiga-toxin-associated HUS (STx-HUS), which normally presents with diarrhea, and atypical HUS. The Shiga-toxin inhibits the binding of eEF-1-dependent binding of aminoacyl tRNA to the 60S subunit of the ribosome, thus inhibiting protein synthesis. The cytotoxicity from the lack of protein damages glomerular endothelial cells by creating voids in the endothelial wall and detaching the basement membrane of the endothelial layer, activating the coagulation cascade. Atypical HUS may be caused by an infection or diarrheal illness or it may be genetically transmitted. This category of TMA encompasses all forms that do not have obvious etiologies. Mutations in three of the proteins in the complement cascade have been identified in patients with atypical HUS. Several chemotherapeutic drugs have also been shown to cause damage to the epithelial layer by reducing the ability for the cells to produce prostacyclin, ultimately resulting in chemotherapy-associated HUS, or C-HUS.The second category of TMAs is TTP thrombotic thrombocytopenic purpura, which can be divided into 3 categories: congenital, idiopathic, and non-idiopathic. Congenital and idiopathic TTP are generally associated with deficiencies in ADAMTS13, a zinc metalloprotease responsible for cleaving Very Large vWF Multimers in order to prevent inappropriate platelet aggregation and thrombosis in the microvasculature </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Joint and can you explain it in depth? [/INST] A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animals skeletal system into a functional whole. They are constructed to allow for different degrees and types of movement. Some joints, such as the knee, elbow, and shoulder, are self-lubricating, almost frictionless, and are able to withstand compression and maintain heavy loads while still executing smooth and precise movements. Other joints such as sutures between the bones of the skull permit very little movement (only during birth) in order to protect the brain and the sense organs. The connection between a tooth and the jawbone is also called a joint, and is described as a fibrous joint known as a gomphosis. Joints are classified both structurally and functionally.

Classification
The number of joints depends on if sesamoids are included, age of the human and the definition of joints. However, the number of sesamoids is the same in most people with variations being rare.Joints are mainly classified structurally and functionally. Structural classification is determined by how the bones connect to each other, while functional classification is determined by the degree of movement between the articulating bones. In practice, there is significant overlap between the two types of classifications.

Clinical, numerical classification
monoarticular – concerning one joint
oligoarticular or pauciarticular – concerning 2–4 joints
polyarticular – concerning 5 or more joints

Structural classification (binding tissue)
Structural classification names and divides joints according to the type of binding tissue that connects the bones to each other. There are four structural classifications of joints:
fibrous joint – joined by dense regular connective tissue that is rich in collagen fibers
cartilaginous joint – joined by cartilage. There are two types: primary cartilaginous joints composed of hyaline cartilage, and secondary cartilaginous joints composed of hyaline cartilage covering the articular surfaces of the involved bones with fibrocartilage connecting them.
synovial joint – not directly joined – the bones have a synovial cavity and are united by the dense irregular connective tissue that forms the articular capsule that is normally associated with accessory ligaments.
facet joint – joint between two articular processes between two vertebrae.

Functional classification (movement)
Joints can also be classified functionally according to the type and degree of movement they allow: Joint movements are described with reference to the basic anatomical planes.
synarthrosis – permits little or no mobility. Most synarthrosis joints are fibrous joints (e.g., skull sutures).
amphiarthrosis – permits slight mobility. Most amphiarthrosis joints are cartilaginous joints (e.g., intervertebral discs).
synovial joint (also known as a diarthrosis) – freely movable. Synovial joints can in turn be classified into six groups according to the type of movement they allow: plane joint, ball and socket joint, hinge joint, pivot joint, condyloid joint and saddle joint.Joints can also be classified, according to the number of axes of movement they allow, into nonaxial (gliding, as between the proximal ends of the ulna and radius), monoaxial (uniaxial), biaxial and multiaxial. Another classification is according to the degrees of freedom allowed, and distinguished between joints with one, two or three degrees of freedom. A further classification is according to the number and shapes of the articular surfaces: flat, concave and convex surfaces. Types of articular surfaces include trochlear surfaces.

Biomechanical classification
Joints can also be classified based on their anatomy or on their biomechanical properties. According to the anatomic classification, joints are subdivided into simple and compound, depending on the number of bones involved, and into complex and combination joints:
Simple joint: two articulation surfaces (e.g. shoulder joint, hip joint)
Compound joint: three or more articulation surfaces (e.g. radiocarpal joint)
Complex joint: two or more articulation surfaces and an articular disc or meniscus (e.g. knee joint)

Anatomical
The joints may be classified anatomically into the following groups:

Joints of hand
Elbow joints
Wrist joints
Axillary joints
Sternoclavicular joints
Vertebral articulations
Temporomandibular joints
Sacroiliac joints
Hip joints
Knee joints
Articulations of footUnmyelinated nerve fibers are abundant in joint capsules and ligaments as well as in the outer part of intraarticular menisci. These nerve fibers are responsible for pain perception when a joint is strained.

Clinical significance
Damaging the cartilage of joints (articular cartilage) or the bones and muscles that stabilize the joints can lead to joint dislocations and osteoarthritis. Swimming is a great way to exercise the joints with minimal damage.A joint disorder is termed arthropathy, and when involving inflammation of one or more joints the disorder is called arthritis. Most joint disorders involve arthritis, but joint damage by external physical trauma is typically not termed arthritis.
Arthropathies are called polyarticular (multiarticular) when involving many joints and monoarticular when involving only a single joint.
Arthritis is the leading cause of disability in people over the age of 55 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Nipple discharge and can you explain it in depth? [/INST] Nipple discharge is fluid from the nipple, with or without squeezing the breast. The discharge can be milky, clear, green, purulent, bloody, or faintly yellow. The consistency can be thick, thin, sticky, or watery.Nipple discharge may be normal, such as milk in late pregnancy or after childbirth, and in newborns during the first weeks of life. It may also be normal following squeezing, in women during the reproductive years. It is likely abnormal if it occurs in men, contains blood, is from only one breast, or is associated with a breast lump, swelling, redness or overlying skin changes. Reasons for abnormal discharge include an intraductal papilloma, duct ectasia, blocked milk duct, infected breast (mastitis or breast abscess), breast cancer, certain medications, and conditions that raise prolactin.Milky discharge in a non-pregnant, non-breast feeding women is evaluated differently to other abnormal nipple discharge. Often, the cause can be determined based on symptoms and examination. Blood tests may be done to rule out low thyroid or high prolactin. Other tests may include mammography, breast ultrasound, breast biopsy, or skin biopsy.Treatment depends on the underlying cause. Duct ectasia may be treated with surgical removal of the ducts involved. Infectious causes may require antibiotics or incision and drainage. Nipple discharge is the third most common breast complaint by women, after breast pain and a breast lump. About 3% of breast cancer cases are associated with discharge.

Signs and symptoms
Nipple discharge is fluid from the nipple, with or without squeezing the breast. The discharge can be milky, clear, green, purulent, bloody, or faintly yellow. The consistency can be thick, thin, sticky, or watery.

Causes
Nipple discharge can arise from any one or more of the 15 to 20 milk ducts that each breast contains, and its causes can be divided into normal (physiological) and abnormal (pathological).

Normal
Milky liquid from nipples is normal during the last few weeks of pregnancy, after childbirth and during breastfeeding. Some newborn babies may leak a milky liquid which is usually normal and lasts a couple of weeks.Stimulation of breasts by massage, using a breast pump or after mammography, may induce yellow, milky, or green nipple discharge in many healthy women of reproductive age.

Abnormal
Spontaneous nipple discharge unrelated to pregnancy or lactation is considered abnormal, but mostly have a non-serious cause. Nipple discharge in men is not normal. Discharge from nipples is also more likely to be abnormal (pathological) if it is crystal clear or blood-stained, is from only one breast, or is associated with a breast lump, swelling, redness or overlying skin changes.A blocked or enlarged milk duct can result in nipple discharge.Intraductal papillomas are non-cancerous lesions and commonest in women age 30 to 50. Divided into central and peripheral papillomas, nipple discharge is more frequently observed when they are central. Up to half of women with intraductal papillomas may present with bloody nipple discharge, but it can also be straw-coloured. They are usually too small to feel and have a rare association with breast cancer.15-20% of people with nipple discharge are found to have duct ectasia. This is usually in perimenopausal and menopausal women, who may have associated pain and retraction of the nipple. A lump may also be present.Ductal carcinoma in situ (DCIS) usually presents with abnormal findings on mammography, but can less frequently present with a lump or nipple discharge in women, whereas in men with DCIS, nipple discharge is the common presentation.Infection in a breast, either mastitis or breast abscess may cause a discharge. Eczema of the nipple may result in a discharge with crusting of the nipple skin.Nipple discharge may be due to breast cancer, particularly if there is an accompanying breast lump. A blood-stained discharge may appear in Pagets disease.

Milky
Some condition that cause a raised prolactin can result in a milky liquid appearing from nipples. These include endocrine causes such as pituitary and thyroid disease, and some medications. Such medications include:
Medication for hypertension: Methyldopa, reserpine, verapamil
Gastrointestinal agents: Cimetidine, metoclopramide
Hormones: Estrogen, birth control pill
Opiates: Codeine, heroin, methadone, morphine
Psychotropic drugs: Antipsychotics, monoamine oxidase inhibitors, neuroleptics, selective serotonin reuptake inhibitors, tricyclic antidepressantsSome herbs including anise and fennel have also been implicated as causing leaking of fluid from nipples.

Diagnosis
The evaluation of milky nipple discharge in a non-pregnant, not breast feeding women is different to the assessment of other abnormal nipple discharge. Often, the cause can be ascertained without performing tests.When blood tests are requested, they usually include thyroid tests and prolactin to rule out hypothyroidism and hyperprolactinemia. Other tests that may be considered include mammography, breast ultrasound, CT scan of the head to rule out a pituitary tumour, breast biopsy, x-ray imaging of breast ducts or skin biopsy.The absence of cancerous cells in samples of nipple discharge does not exclude cancer, hence cytology of the nipple discharge is not usually performed </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Crushed and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Therapy and can you explain it in depth? [/INST] A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications.  There are many different types of therapy.  Not all therapies are effective.  Many therapies can produce unwanted adverse effects.
Medical treatment and therapy are generally considered synonyms.  However,  in the context of mental health, the term therapy may refer specifically to psychotherapy.

History
Before the creating of therapy as a formal procedure, people told stories to one another to inform and assist about the world. The term "healing through words" was used over 3,500 years ago in Greek and Egyptian writing. The term psychotherapy was invented in the 19th century, and psychoanalysis was founded by Sigmund Freud under a decade later.

Semantic field
The words care, therapy, treatment, and intervention overlap in a semantic field, and thus they can be synonymous depending on context. Moving rightward through that order, the connotative level of holism decreases and the level of specificity (to concrete instances) increases. Thus, in health care contexts (where its senses are always noncount), the word care tends to imply a broad idea of everything done to protect or improve someones health (for example, as in the terms preventive care and primary care, which connote ongoing action), although it sometimes implies a narrower idea (for example, in the simplest cases of wound care or postanesthesia care, a few particular steps are sufficient, and the patients interaction with that provider is soon finished). In contrast, the word intervention tends to be specific and concrete, and thus the word is often countable; for example, one instance of cardiac catheterization is one intervention performed, and coronary care (noncount) can require a series of interventions (count). At the extreme, the piling on of such countable interventions amounts to interventionism, a flawed model of care lacking holistic circumspection—merely treating discrete problems (in billable increments) rather than maintaining health. Therapy and treatment, in the middle of the semantic field, can connote either the holism of care or the discreteness of intervention, with context conveying the intent in each use. Accordingly, they can be used in both noncount and count senses (for example, therapy for chronic kidney disease can involve several dialysis treatments per week).
The words aceology and iamatology are obscure and obsolete synonyms referring to the study of therapies.
The English word therapy comes via Latin therapīa from Greek: θεραπεία and literally means "curing" or "healing".

Types of therapies
Therapy comes in different forms. These include, cognitive behavioral therapy, dialectical behavior therapy, mindful based cognitive therapy, physical therapy, etc. Therapists are here for use and used daily by many people. Therapist are trained to provide treatment to an individual or group. Therapy was invented in the 1800s and the founder was Franz Mesmer, the "Father of Western Psychotherapy". Sigmund Freud then comes into play and shows us the understanding depth of all the different types included in therapy. Therapy is used in many ways to shape and help reform a person. This type of treatment allows individuals to regain gain goals lost or wanting to accomplish. Many individuals come into therapy looking for ways to cope with issues and to receive an emotional release. For example, healing from trauma, in need of support, emotional issues, and many more. . Allowing yourself to express your thoughts and feelings go a long way in therapy recovery, this is called the therapeutic process.

By chronology, priority, or intensity
Levels of care
Levels of care classify health care into categories of chronology, priority, or intensity, as follows:

Emergency care handles medical emergencies and is a first point of contact or intake for less serious problems, which can be referred to other levels of care as appropriate.
Intensive care, also called critical care, is care for extremely ill or injured patients. It thus requires high resource intensity, knowledge, and skill, as well as quick decision making.
Ambulatory care is care provided on an outpatient basis. Typically patients can walk into and out of the clinic under their own power (hence "ambulatory"), usually on the same day.
Home care is care at home, including care from providers (such as physicians, nurses, and home health aides) making house calls, care from caregivers such as family members, and patient self-care.
Primary care is meant to be the main kind of care in general, and ideally a medical home that unifies care across referred providers.
Secondary care is care provided by medical specialists and other health professionals who generally do not have first contact with patients, for example, cardiologists, urologists and dermatologists. A patient reaches secondary care as a next step from primary care, typically by provider referral although sometimes by patient self-initiative.
Tertiary care is specialized consultative care, usually for inpatients and on referral from a primary or secondary health professional, in a facility that has personnel and facilities for advanced medical investigation and treatment, such as a tertiary referral hospital.
Follow-up care is additional care during or after convalescence. Aftercare is generally synonymous with follow-up care.
End-of-life care is care near the end of ones life. It often includes the following:
Palliative care is supportive care, most especially (but not necessarily) near the end of life.
Hospice care is palliative care very near the end of life when cure is very unlikely. Its main goal is comfort, both physical and mental.

Lines of therapy
Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options can often be ranked or prioritized into lines of therapy: first-line therapy, second-line therapy, third-line therapy, and so on. First-line therapy (sometimes referred to as induction therapy, primary therapy, or front-line therapy) is the first therapy that will be tried. Its priority over other options is usually either: (1) formally recommended on the basis of clinical trial evidence for its best-available combination of efficacy, safety, and tolerability or (2) chosen based on the clinical experience of the physician </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Follicular lymphoma and can you explain it in depth? [/INST] Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles (nodular swirls of various types of lymphocytes) in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures (see adjacent Figure) in the tissues they invade. These structures are usually the dominant histological feature of this cancer.There are several synonymous and obsolete terms for FL such as CB/CC lymphoma (centroblastic and centrocytic lymphoma), nodular lymphoma, Brill-Symmers Disease, and the subtype designation, follicular large-cell lymphoma. In the US and Europe, this disease is the second most common form of non-Hodgkins lymphomas, exceeded only by diffuse large B-cell lymphoma. FL accounts for 10-20% of non-Hodgkins lymphomas with ~15,000 new cases of it being newly diagnosed each year in the US and Europe. Recent studies indicate that FL is similarly prevalent in Japan.FL is a broad and extremely complex clinical entity with a wide range of manifestations which have not yet been fully systematized. It is commonly preceded by a benign precancerous disorder in which abnormal centrocytes and/or centroblasts accumulate in lymphoid tissue. They may then circulate in the blood to cause an asymptomatic condition termed in situ lymphoid neoplasia of the follicular lymphoma type (i.e. ISFL). A small percentage of these cases progress to FL. Most commonly, however, FL presents as a swelling of lymph nodes in the neck, armpits, and/or groin. Less often, it presents as a gastrointestinal tract cancer, a cancer in children involving lymphoid tissues of the head and neck area (e.g. tonsils), or one or more masses in non-lymphoid tissues such as the testes.FL typically has a slow disease course which persists essentially unchanged for years. However, each year 2-3% of FL cases progress to a highly aggressive form often termed stage 3B FL, to an aggressive diffuse large B-cell lymphoma, or to another type of aggressive B-cell cancer. These transformed follicular lymphomas (t-FL) are essentially incurable. However, recent advancements in the treatment of t-FL (e.g. the addition to standard chemotherapy of agents such as rituximab) have improved overall survival times. These newer regimens may also delay the transformation of FL to t-FL. Additional advances in understanding FL may lead to further improvements in treating the disease.

Pathophysiology
Genomic alterations
The serial progressions of in situ FL to FL and FL to t-FL appear to involve the accumulation of increasing numbers of genomic alterations (i.e. chromosome abnormalities and gene mutations) in the formative B-cell precursors to these disorders. At least some of these alterations appear to cause the over-expression or under-expression of the products of genes that regulate these cells susceptibility to develop further genomic alterations, to survive, to proliferate, and/or to spread to other tissues. In consequence, multiple B-cell clones that exhibit increasing genomic alterations and malignant behaviors populate the disorder. No single genomic alteration seems responsible for the development of each of the spectrum of FL disorders. Rather, interactions between multiple genomic alterations appear to underlie this serial progression.

In situ follicular lymphoma
In situ follicular lymphoma is an accumulation of monoclonal B cells (i.e. cells descendent from a single ancestral cell) in the germinal centers of lymphoid tissue. These cells commonly bear a pathological genomic abnormality, i.e.  a translocation between position 32 on the long (i.e. "q") arm of chromosome 14 and position 21 on chromosome 18s q arm. This translocation juxtaposes the B-cell lymphoma 2 (BCL2) gene on chromosome 18 at position q21.33 near to the immunoglobulin heavy chain locus (IGH@) on chromosome 14 at position q21. In consequence, BCL2 overexpresses its product, BCL2 apoptosis regulator (i.e. Bcl2). Bcl2 functions to inhibit programmed cell death thereby prolonging cell survival. The overexpression of Bcl2 in the B-cells of ISFL is thought to be a critical factor in their pathological accumulation and subsequent malignant progression. Small numbers (e.g. 1 in 100,000) of circulating nucleated blood cells bearing this t(14:18)q32:q21) translocation are found in 50-67% of otherwise healthy individuals. The prevalence of this finding increases with age and years of tobacco smoking. Since most individuals with this translocation in their blood cells do not develop ISFL, the t(14:18)(q32:q21) translocation, while prolonging cell survival, must be just one step in the development of ISFN. This translocation is proposed to occur during the early development of immature bone marrow B-cells (i.e. pre-B-cells/pro-B-cells) after which these cells circulate freely and in rare cases accumulate and mature to centrocytes and/or centroblasts in the germinal centers of lymphoid follicles to form ISFL. The mechanism favoring this localization and further accumulation is unclear.Individuals with ISFL progress to FL at a rate of 2-3%/year for at least the first 10 years following diagnosis. This progression likely involves the acquisition of genomic aberrations besides the t(14:18)q32:q21) translocation in the ISFL B-cells. Suspect mutations include those in the following genes: 1) EZH2 (encodes polycomb repressive complex 2 family protein which is involved in maintaining the transcriptional repressive state of various genes and is found in up to 27% of FL cases); 2) CREBBP (encodes CREB-binding protein which contributes to the activation of various genes); 3) TNFSF14 (encodes tumor necrosis factor superfamily member 14, a member of the tumor necrosis factor superfamily which may function as a co-stimulatory factor for the activation of lymphoid cells); and 4) KMT2D (encodes histone-lysine N-methyltransferase 2D, a histone methyltransferase which regulates the expression of various genes). ISFL may also acquire numerous copy-number variations (i.e. duplications and deletions of a portion of a chromosome along with any of the genes contained therein) that may contribute to FL. In all cases, the number of genetic abnormalities acquired in the B-cells of ISFL are much less than those in FL.

Follicular lymphoma
The genomic alterations found in FL include 1) the t(14:18)(q32:q21.3) translocation (85-90% of cases); 2) 1p36 deletions (i.e. deletions in the q arm of chromosome 1 at position 36, [60-70% of cases]) that lead to lose of TNFAIP3 (encodes tumor necrosis factor, alpha-induced protein 3 which inhibits the activation of NF-κB, blocks cell death due to apoptosis, and regulates lymphocyte-based immune responses through its ubiquitin ligase activity); 3) mutations in PRDM1 (encodes the PR domain zinc finger protein which promotes the maturation and proliferation of B-cells); and 4) the same mutations seen in ISFL including KMT2D (85-90% of cases), CREEBP (40-65% of cases), BCL2 (40-65% of cases), and EZH2 (20-30% of cases) as well as other mutations such as those in the histone-modifying gene HIST1H1E (20-30% of cases), the RRAGC gene (~17% of cases) which regulates cell growth, survival, death, and proliferation, and, in ≤15% of cases several other genes including MEF2B, STAT6, EP300, ARID1A, SLC22A2, CARD11, FOXO1, GNA12, B2M (i.e. the gene for beta-2 microglobulin), and SGK1. Except for the t(14:18)(q32:q21.3) translocation and EZH2 mutations which lead to gains in the expression and function, respectively, of their products, the genetic alterations generally lead to a loss in the production or function of the cited genes products. However, the exact roles, if any, of these genomic abnormalities in promoting the progression of ISFL to FL are unclear.

Transformed follicular lymphoma
The transformation of FL to a more aggressive state or other type of aggressive lymphoma is associated with: 1) primarily gene-activating mutations in CREEBP, KMT2D, STAT6, CARD11 (encoding a guanylate kinase which interacts with BCL10 and activates NF-κB to regulate cell survival); 2) changes in the expression of diverse genes; 3) the overproduction of various cell-activating cytokines and CD79B (encoding the Ig-beta protein component of the B-cell receptor); 4) gene-inactivating mutations in TNFAIP3, CD58 (encoding the cell adhesion molecule, lymphocyte function-associated antigen 3, that is involved in activating T-cells), CDKN2A (encoding p16INK4a and p14arf tumor suppressor proteins) or CDKN2B (encoding cyclin dependent kinase inhibitor 2B  multiple tumor suppressor 2) (inactivation of either CDKN2 gene causes genome instability, i.e. increased frequency of other gene mutations), and TNFRSF4 (encoding one type of tumor necrosis factor receptor); and 5) gene-activating or -inactivating mutations in, or other causes for the under- or over-expression of, c-MYC ((encoding the c-Myc proto-oncogene transcription factor that regulates the expression of diverse genes many of which promote cell proliferation).

Tumor environment
The non-neoplastic immune and stromal cells as well as the extracellular matrix in tissues may enable neoplastic follicular cells to survive, proliferate, and avoid surveillance by the immune system. For example, laboratory studies show that: 1) follicular dendritic cells, fibroblastic reticular cells, and T helper cells provide growth and survival signals to neoplastic follicular B-cells; 2) neoplastic follicular B-cells recruit regulatory T cells that act to suppress immune responses to them; 3) the cytotoxic T-cells which normally kill neoplastic cells become dysfunctional in the presence of neoplastic follicular cells that are embedded in this multicellular environment; and 4) bone marrow stromal cells directly support the growth of neoplastic follicular cells. Reduced levels of immune-infiltration has been shown to be strongly associated with early progression of disease.

Presentation and course
In situ follicular lymphoma
FL is commonly preceded by but uncommonly progresses to ISFL, an asymptomatic disorder that usually is discovered in tissues which are biopsied for other reasons. FL lymphoma may be diagnosed in the uncommon  cases in which individuals with ISFL are found to have FL on follow-up examinations. Similarly, individuals with >1 in 10,000 circulating lymphocytes containing the t(14:18)q32:q21) translocation are at increased but still small risk of developing FL and being diagnosed as having FL on follow up examinations.

Follicular lymphoma
FL commonly presents as an otherwise asymptomatic enlargement of lymph nodes in the neck, armpit, groin, femoral canal, or other sites in individuals (median age 65) without a known history of ISFL or abnormal numbers of circulating t(14:18)q32:q21-conatianing lymphocytes. These enlargements may have been present for months to years and during this time waxed and waned in size. Less commonly, FL presents as extra-nodal masses in the skin, thyroid gland, salivary gland, breast, testicles. spleen, liver, and/or lung. Regardless of the type of presentation, FL is usually (~80% of cases) at an advanced stage at diagnosis as indicated by involvement of the bone marrow (50% to 70% of cases), multiple lymph nodes in different parts of the body, and/or other tissues. A minority (<33%) of FL patients present with B symptoms, i.e. recurrent unexplained fevers, recurrent night sweats, and/or weight loss ≥10% in the past 6 months. Generally, the disease has an indolent and prolonged course with a median life expectancy of 15–20 years: a large percentage of patients die from other causes than their FL disease. However, each year, including the early years after diagnosis, some 2-3% of FL cases transform to t-FL; Median survival has been ~4.5 years after the onset of this transformation.There are less common subtypes of FL that differ not only in their presentation but also in their histopathology, genetic abnormalities, and course. These subtypes, which are now (i.e. primary gastrointestinal tract FL) or may in the future (pediatric-type FL) be considered distinctive diseases, are:

Duodenal-type follicular lymphoma
Duodenal-type follicular lymphoma (DFL) was initially considered to be a type of Primary gastrointestinal tract (GI tract) follicular lymphoma (PGTFL), i.e. a follicular lymphoma in which GI tract lesions were prominent parts of the disease. However, a subset of PGTFL cases had lesions that were localized to the duodenum and other parts of the small intestine usually without involving other parts of the GI tract or tissues outside of the GI tract. This contrasts with the other cases of PGTFL which were systemic diseases involving a wide range of GI tract and non-GI tract tissues. Consequently, the World Health Organization (2017) removed the localized disease from the primary gastrointestinal tract follicular lymphoma category, reclassified it as a distinct disease entity, and termed it duodenal-type follicular lymphoma. DFL is most often an asymptomatic disease that is diagnosed on endoscopic examination of the GI tract conducted for other reasons. Less commonly, it presents with vague abdominal symptoms. In one review of former studies, the lesions in 85% of primary duodenal follicular lymphoma were located not only in the duodenum but also other sites in the intestine (i.e. jejunum and/or ileum), with rare cases having lesions in the rectum or cecum PDF is an indolent disease that may spontaneously remit and relapse but only rarely progresses to a more aggressive form.  A watch-and-wait strategy has been a generally recommended method for the initial treatment of the disease.

Primary gastrointestinal tract follicular lymphoma
PGTFL is a follicular lymphoma (which as currently defined excludes cases of duodenal-type follicular lymphoma) that has a prominent component of GI tract involvement. The disease may present with signs and symptoms typical of the common type of  follicular lymphoma. For example, enlargement of lymph nodes in the neck, armpit, groin,  femoral canal, and/or other areas, and/or signs and symptoms of GI tract disease due to lesions in the stomach, small intestine, large intestine or rectum may be seen. These signs and symptoms may include abdominal pain, bowel obstruction, persistent nausea and vomiting, hematochezia (i.e. passage of fresh blood usually on feces through the rectum), or melena (i.e. passage of tarry feces containing blood that has been digested in the stomach or upper intestine). PGTFL is generally treated like cases of common follicular lymphoma: depending on the severity of the disease and its symptoms, patients are  treated with watchful waiting, surgery, chemotherapy, radiation, immunotherapy plus radiotherapy, or combinations of these modalities.

Predominantly diffuse follicular lymphoma with 1p36 deletion
Predominantly diffuse follicular lymphoma with 1p36 deletion is a rare subtype of FL in which involved lymph nodes show infiltrations of centrocytes and centoblasts that generally do not form the nodular, swirling patterns characteristic of most types of FL. In addition, these cells lack the t(14:18)(q32:q21.3) translocation commonly found in other FL types but, similar to many FL cases, have a deletion in the terminal part of the short (i.e. "p") arm of chromosome 1 that encodes the TNFRSF14 gene (see pathophysiology section). Predominantly diffuse follicular lymphoma with 1p36 deletion usually presents with bulky enlargements of inguinal (i.e. groin) lymph nodes but may present with enlargements of the axillary (i.e. armpit) or cervical (i.e., neck) lymph nodes. In rare cases, there may be involvement of the bone marrow. In spite of the evidence of bulky and disseminated disease, predominantly diffuse follicular lymphoma with 1p36 deletion appears to be an indolent disorder that may require long-term observation rather than overtreatment.

Pediatric-type follicular lymphoma
Pediatric-type follicular lymphoma (PTFL) was initially reported to occur in children ages 1–17 years old (median age ~13-14) but more recently has been reported to occur in adults. The disorder was recently defined by the World Health Organization (2016) as a distinct entity that occurs mostly in males and involves swollen lymph nodes in the head (including tonsils and adenoids), neck, or, rarely, axillary, or inguinal areas, or non-lymphoid tissues. Currently, however, patients who had exhibited or are exhibiting involvement of areas or tissues outside of the head, neck, armpit, or groin areas are now regarded as far more likely to have a newly and provisionally defined disease, large B-cell lymphoma with IRF4 rearrangement.The lesions in PTFL consists of infiltrates containing rapidly proliferating centrocytes and centroblasts that lack the t(14:18)(q32:q21.3) translocation but nonetheless often overexpress the BCL2 gene. These cells may show a loss of heterozygosity at 1p36 (20-50% of cases) that results in decreased expression of the TNFRSF14 gene (see Pathophysiology section) as well as mutations in the IRF8 (10-50% of cases), which contributes to the development and function of B cells, and the MAP2K1 gene (10-40% of cases), which regulates activation of the ERK cell signaling pathway. More than 2 dozen other genes have been reported to be mutated in rare cases of PTFL but in general the genetic abnormalities found in this disorder are fewer and less complex than those in other types of FL. PTFL has an indolent, relapsing and remitting course with a 5-year survival rate of >95%. Patients diagnosed with PTFL have been treated with chemotherapy, surgery, and combinations of these treatments. In general, these patients did well (100% survival with <5% of cases relapsing regardless of treatment modality). More recently, 36 patients have been treated with surgical resection alone followed by observation; all these patients survived with only one having a relapse. Thus, PTFL appears to be a highly indolent type of FL in which multiple studies have reported overall and progression-free survival rates of 100% and >90%, respectively, for >2 years and an estimated probability of 5-year event-free survival rate of ~96%. The therapeutic regimens versus follow-up observations that best treat this disorder in children, adolescents, and adults (adults may require different treatments than children and adolescents) requires further study.

Primary follicular lymphoma of the testis
Primary follicular lymphoma of the testis (PFLT), also termed testicular follicular lymphoma, was classified as a distinct form of FL by the World Health Organization in 2016. It is an extremely rare disease that has been recognized as occurring primarily in children and adolescents but also has been reported in 5 adults. PFLT differs from cases of typical follicular lymphoma that involve the testis in that it more often occurs in children and adolescents; involves malignant B-cells that do have the t(14:18)q32:q21) translocation; and  presents with disease that is strictly limited to the testis. While similar to pediatric-type follicular lymphoma in not involving cells that bear the t(14:18)q32:q21) translocation, PFLT differs from the former disease in that it is limited to the testis and involves malignant cells that do not express Bcl2. PFTL is an extremely indolent disease which is manifested by lesions that exhibit a typical FL histology or, more commonly, a mixed FL-diffuse large cell lymphoma histology. It usually involves a 2-4 centimeter lesion in a single testicle. Patients have been treated with removal of the involved testes followed by various standard anti-lymphoma chemotherapy regimens to attain excellent results, i.e. 100% completed remissions with no recurrence of disease in 15 child and adolescent patients observed for 4–96 months. No cases of primary follicular lymphoma of the testis have been reported to progress to t-FL. Surgery followed by less strenuous or even no chemotherapy may prove to be the optimal treatment for this disease.

Transformed follicular lymphoma
FL progresses at a rate of 2-3% per year for at least the first 10 years after diagnosis to a more aggressive form, principally diffuse large B-cell lymphoma (~93% of cases) or Burkitt-like lymphoma (~7% of cases) or in rare cases exhibit the histology resembling precursor B-cell lymphoblastic leukemia, plasmablastic lymphoma, the high grade subtype of B-cell lymphoma, Hodgkin lymphoma of the B-cell type, chronic lymphocytic leukemia/small cell lymphcytic lymphoma, or histiocytic sarcoma. t-FL is almost always diagnosed in patients being followed for FL. These FL patients present with the: fast growth of lymph nodes; formation of extra-nodal lesions in extra-nodal sites such as the central nervous system, liver or bone; the onset of B-symptoms (i.e. fever, night sweats, weight loss); development of hypercalcemia (i.e. high serum levels of calcium); and/or sudden rises in serum levels of the enzyme lactate dehydrogenase. A minority of t-FL patients present without a history of FL. These patients generally present with advanced, bulky disease that may be accompanied by extra-nodal lesions and B-symptoms. Typically, all the various forms of t-FL are aggressive, rapidly progressive diseases with overall media survival times in treated patients of ~4.5 years. The transformation of FL to DLBCL is in over 70% of cases associated with the gain of MYC activity by genetic or non-genetic mechanisms.

Diagnosis
The diagnosis of FL depends on examining involved tissues for histological, immunological, and chromosomal abnormalities that are indicative of the disease. FL usually involves enlarged lymph nodes populated by abnormal follicles (see adjacent picture) that when examined histologically contain a mixture of centrocytes or centroblast surrounded by non-malignant cells, mostly T-cells. The centrocytes, which typically outnumber centroblasts, are small to medium-sized B-cell lymphocytes that characteristically exhibit cleaved nuclei; the centropblasts are larger B-cell lymphocytes without cleaved nuclei. Rare cases of FL may show lesions that contain tissue infiltrations dominated by B-cells with features of precursor (i.e. "blast") cells, monocytes, or malignant mantle cells such as those found in mantle cell lymphoma. Immunochemical analyses reveal that these cells generally express B-cell surface markers including the CD10 (60% of cases), CD20, CD19, CD22, and CD79 but not CD5, CD11c, or CD23 cell surface proteins; genomic analyses reveal that these cells contain t(14:18)(q32:q21.3) translocation (85-90% of cases), 1p36 deletions (60-70% of cases), and with far less frequency the other genomic abnormalities listed in the above sections on Pathophysiology and Presentation and course. None of these protein markers or genomic abnormalities are diagnostic for FL, e.g. the t(14:18)(q32:q21.3) translocation is found in 30% of diffuse large B-cell lymphoma and in a small number of reactive benign lymph nodes. Rather, the diagnosis is made by a combination of histological, immunological, and genomic abnormalities. According to World Health Organization (WHO) criteria, differences in the microscopically determined morphology of these tissues can be used to diagnose and categorized FL into the following 3 Grades with grade 3 having A and B subtypes:

Grade 1: follicles have <5 centroblasts per high-power field (hpf).
Grade 2: follicles have 6 to 15 centroblasts per hpf.
Grade 3: follicles have >15 centroblasts per hpf.
Grade 3A: Grade 3 in which the follicles contain predominantly centrocytes.
Grade 3B: Grade 3 in which the follicles consist almost entirely of centroblasts.Grades 1 and 2 are regarded as low grade FL; Grade 3A is usually also regarded as low grade FL although some studies have regarded it as high grade FL; and Grade 3B is regarded as a highly aggressive FL in the t-FL category.In addition to grade 3B disease, histologic examinations may reveal other evidence of t-FL such as histologic findings consistent with FL and diffuse large cell lymphoma in the same tissue (referred to as composite lymphomas) or in separate tissues (referred to as (discordant lymphomas) or histologic findings similar to those found in Burkitt lymphoma, precursor B-cell lymphoblastic leukemia, plasmablastic lymphoma, the high grade subtype of B-cell lymphoma, Hodgkin lymphoma of the B-cell type, chronic lymphocytic leukemia/small cell lymphocytic lymphoma, or histiocytic sarcoma. Other findings indicating the presence of this transformation include rapid growth in size of lymph nodes, recently acquired or new B symptoms, recent development of FL lesions in non-nodal tissue, rapid rises in serum lactate dehydrogenase levels, and the presence of high levels of serum calcium.

Differential diagnosis
FL may be confused with marginal zone B-cell lymphoma, mantle cell lymphoma, and the small lymphocytic lymphoma variant of chronic lymphocytic leukemia. The malignant cells in marginal zone B-cell lymphoma may form follicular structures but commonly proliferate in the marginal zone rather than germinal center of lymphoid tissues. These malignant cells often show features of monocytes or plasma cells. Mantle cell lymphomas show monotonous, medium-sized lymphocytes, monocytes, and atrophied germinal centers; unlike FL, the malignant lymphocytes in this disease are positive for Cyclin D1 by immunohistochemistry staining. Small lymphocytic lymphomas are composed of nodular structures with small- to medium-sized malignant cells surrounding immature lymphocytes and immunoblasts. The malignant cells in this disease, unlike FL, stain positive for CD5 and CD23.

Treatment and prognosis
FL is typically a slowly growing lymphoma with an overall median life expectancy for treated patients of 10–15 years with many cases of it waxing and waning in the size of their lesions and rare cases of it remitting spontaneously. These considerations favor the use of observation over intervention in patients whose particular form of FL has a favorable prognosis or who are intolerant to aggressive treatments. However, most cases of FL have a less favorable prognosis at some stage of their disease and will therefore require intervention. There is little consensus regarding the guidelines to be used to define the prognosis and treatment for FL at its presentation or during its course.. Currently used indicators for this include the diseases: 1) histology; 2) subtype; 3) predicted indolence and potential for transformation; and 4) extent of disease as measured by clinical examinations, bone marrow biopsy to determine bone marrow involvement, and PET/CT imaging of the chest, abdomen, pelvis, and any areas outside of these regions if physical examination suggests involvement. Some suggested guidelines using these parameters to indicate the prognosis and need for treatment in FL include:
The WHO criteria using histological grade (see previous section): Patients with Grades 1, 2, and 3A disease are predicted to have the same low risk prognosis that is seen in cases of typical FL while patients with grade 3B disease are predicted to have the high risk prognosis typical of t-FL.
The Follicular Lymphoma International Prognostic Index (FLIPI): FLIPI uses the following criteria: age ≥60 years; Ann Arbor disease stage III (i.e. lesions located both above and below the thoracic diaphragm) or IV (i.e. disseminated lesions involving one or more non-lymphatic organs); blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; and involvement of >4 lymph nodes. Patients positive for 0–1, 2, or ≥3 of these factors are classified as in low, intermediate, and high risk group, respectively, and after treatment with regimens that include rituximab have 2 year predicted progression free survivals of 84, 72, and 65%, respectively, and overall survivals of 98, 94, and 87%, respectively.
The FLIP2 index. This modification of FLIP1 uses age ≥60; blood hemoglobin <12 gram/deciliter; serum lactose dehydrogenase level above normal; serum beta-2 microglobulin level above normal; ≥1 lymph node with a diameter >6 centimeters; and bone marrow involvement. The predicted percentage of therapy-treated patients with progression free survival at 5 years for individuals positive for 0, 1–2, and ≥3 of these factors are 80, 51, and 19%, respectively.
CT/PET imaging: This method measures total body tumor volume as detected by tissue uptake of radioactive fludeoxyglucose (F18). Progression free and overall survival at 5 years for patients with estimated tumor volumes above versus below 510 cubic centimeters are reported to be 32.7 and 84.8% versus 65.1 and 94.7%, respectively.
Lugano staging: this method classifies Stage I disease as involving a single lymphatic region or extra-lymphatic site; Stage II disease as involving ≥2 lymphatic sites or 1 lymphatic site plus 1 extralympatic site with all lesions being on the same side of the diaphragm; Stage III disease as involving ≥2 lymphatic regions that are on opposite sides of the diaphragm; and Stage IV disease as disseminated lesions that are found to be in ≥1 non-lymphatic organs.
Response-based prognosis: FL patients whose disease progresses within 24 months of initiating treatment with chemotherapy and immunotherapy versus patients whose disease does not progress within 24 months are predicted to have 5 year survival rates of 50-74% versus ~90%, respectively.The prognosis and treatment for the specific presentations of typical FL cases (see above sections for the prognoses and treatment recommendations for primary gastrointestinal tract FL, predominantly diffuse FL with 1p36 deletion, pediatric-type FL, and primary FL of the testis) that are in common use are as follows:

In situ follicular lymphoma
ISFL is a benign condition that may be reevaluated periodically to detect the rare cases of it which progress to FL; otherwise ISFL is not treated.

Localized follicular lymphoma
In 10-20% of cases, FL appears limited to single radiation field, does not involve the bone marrow, and is therefore regarded as localized early-stage FL. In these cases, which are sometimes classified as Ann Arbor stage I (i.e. disease limited to a single restricted region) or stage II (i.e. disease restricted to two sites that are on the same side of the diaphragm), radiation therapy achieves 10 year overall survival rates of 60-80% and median overall survival times of 19 years. It seems likely that many of the relapses in these cases are due to undetected disease outside of the radiation field at the time of radiation treatment. The use of PET/CT imaging is strongly recommended to insure that the FL is localized. In any case, the excellent results achieved with radiation therapy strongly support its use in localized disease. The use of an immunotherapeutic agent such as Rituximab alone or in combination with a chemotherapeutic regimen such as CVP (i.e. cyclophosphamide, vincristine, prednisone and rituximab) in cases of localized, early-stage disease may be appropriate choices for some of these early-stage patients. However, the latter approach is recommended for cases of localized disease in which the disease extends beyond a single field: 56% of patients treated in this manner had progression-free survival at 10 years while patients treated with other regimens had progression free survivals of 41%. Nonetheless, overall survival did not differ between the two groups.

Asymptomatic follicular lymphoma
Patients with asymptomatic but not localized low grade FL, gastrointestinal tract FL, and pediatric-type follicular lymphoma have been served by careful follow-up without therapeutic intervention. Even high grade, aggressive, relapsed, or transformed FL may also be served with observation in patients who are asymptomatic. Findings in asymptomatic patients who have been recommended as triggers for starting treatment include one or more of the following: tumor size ≥7 cm in diameter; involvement of ≥3 nodes in 3 distinct areas, each of which is ≥3 cm in diameter; organ compression; presence of ascites or pleural effusion (i.e. build-up of fluid in the abdominal or pleural cavities); poor performance status due to the disease; elevated levels of serum lactose dehydrogenase or beta-2 microglobulin; presence of localized bone lesions; kidney involvement; reduced levels of circulating blood platelets or any of the various types of white blood cells; onset of significant pruritus (i.e. itching sensation) or other B symptoms; and enlargement (i.e. ≥50% increase in size over a period of at least 6 months) of lymph nodes, spleen, or other follicular lymphoma-infiltrated organs or tissues.

Symptomatic follicular lymphoma
Symptomatic FL requires treatments directed at relieving symptoms by reducing the load of tumor cells. Various chemotherapeutic regimens have been used for this including combinations of alkylating antineoplastic agents, nucleoside analogues, and/or anthracyclines. Two commonly used chemotherapeutic regimens are CVP (see Localized FL section) and CHOP (i.e. CVP plus the anthracycline adriamycin). Newer agents used to treat FL include monoclonal antibodies such as rituximab, obinutuzumab, galiximab, inotuzumab ozogamicin, or epratuzumab and immunomodulators such as lenalidomide and interferon. The latter medications have been used in combination or alone to treat symptomatic FL. Most such regimens add rituximab (a monoclonal antibody which binds and thereby kills the CD20 cell surface protein on B cells) with CVP or CHOP regimens (termed R-CVP and R-CHOP regimens).
The R-CHOP regimen appears superior to the R-CVP regimen with, for example, one study finding 8-year progression-free survival rates of 57% versus 46% for the two respective regimens. More recently, FL patients have been treated with other regimens including: 1) rituximab combined with the chemotherapeutic alkylating agent bendamustine; 2) rituximab combined with the chemotherapeutic agent fludarabine and the inhibitor of Type II topoisomerase, mitoxantrone; and 3) rituximab combined with another immunotherapeutic agent such as galiximab, epratuzumab (monoclonal antibodies directed respectively against the CD80 or CD22 cell surface proteins on immune cells including B cells), or the immunomodulating medication, lenalidomide. While it is too soon to judge the long-term results of the latter regimens, the regimens have shown similar results when analyzed based on poor treatment responses (~10-20% poor responses). Bendamustine with rituximab may be preferable to R-CHOP or R-CVP for treating low-grade (i.e. Grades 1, 2, and possibly 3A) FL; R-CHOP may be preferred in FL that has high-risk characteristics (e.g. high levels of Beta-2 macroglobulin or bone marrow involvement). The combination of lenalidomide with rituximab has shown good potential in treating indolent cases of FL.Studies indicate that maintenance therapy with rituximab following successful induction therapy prolongs progression-free survival; for example one study found progression-free survival after 6 years of treatment was 59.2% in patients treated with rituximab maintenance and 42.7% without this maintenance; however, overall survival at 6 years was similar in the two groups, 87.4% and 88.7%, respectively. Another study found that prolonged maintenance with rituximab did not have any benefits over an eight-month maintenance period. Finally, surgery and radiation are additional therapies that can be used to relieve symptoms caused by bulky t-FL disease or to treat lesions in patients who cannot withstand other types of treatment.

Transformed follicular lymphoma
Early studies on treating t-FL with various purely chemotherapy regimens gave poor results with median overall survival times of 1–2 years. However, the addition of rituximab to the regimens such as CVP and CHOP as part of induction and maintenance therapies (i.e. R-CVP and R-CHOP) greatly improved overall 5 year survival to rates of 73%. The R-CHOP regimen is a good option for treating such cases. However, these regimens need not be started in people with FL who are asymptomatic and have low tumor burdens: the outcomes in such patients show no difference between early versus delayed treatment. Some recent studies found that the use of rituximab in combination with bendamustine (i.e. the RB regimen) provided better results than R-CHOP: progression-free survival times in one study were 69.5 months for RB and 31.2 months for R-CHOP. Similar results were obtained when RB was compared to R-CVP. These studies also found no overall survival time benefit between the RB and R-CHOP regimens. Other recently examined regimens include 1) the use of obinutuzumab instead of rituximab in the R-CHOP and R-CVP regiments to attain progression-free survival rates at 3 years of 80% for the obinutuzumab-chemotherapy regimen versus 73% for the rituximab-chemotherapy regimen and 2) the combination of rituximab with lenalidomide (no chemotherapy agent) versus various chemotherapy plus immunotherapy (principally rituximab) to achieve similar complete remission and 3 year progression-free survival rates but with rituximab plus lenalidomide causing less toxicity (i.e. severe neutropenia). Many of these studies did use rituximab maintenance therapy after induction therapy.

Prevention
Several studies, while not conclusive, suggest that the early treatment of low risk FL reduces the incidence of the disease progressing to t-FL. The treatments used in these studies include chemotherapy, radiation therapy, and immunotherapy combinations plus rituximab maintenance therapy.

Relapsed follicular lymphoma
Patients who relapse after initial therapy for FL may be followed closely without therapy if asymptomatic. When treatment is required, patients may be treated with the initial treatment regimen when such treatment led to a remission that lasted for at least one year; otherwise an alternative regimen is used. The regimens commonly used in relapsed lymphoma include R-CHOP, R-CVP, RFM (i.e. rituximab, fludarabine, and mitoxantrone), and  RB (Bendamustine plus rituximab) </s>