What is a spleen

The spleen is the largest lymphoid organ and has a crucial function in the immune system. The spleen is responsible for the production and maturation of IgM, B lymphocytes, and opsonins ¹. The spleen most importantly protects against infections from polysaccharide-encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitidis, Escherichia coli, Salmonella, Klebsiella, and group B Streptococci (SHiNE SKiS) ¹. The spleen also acts as the primary reservoir for platelets and as a filter for red blood cells (RBCs), removing damaged or malformed red blood cells from the circulation. In addition, the spleen performs extramedullary hematopoiesis.

The normal position of the spleen is within the peritoneal cavity in the left upper quadrant of the abdominal cavity adjacent to ribs nine through 12, just beneath the left diaphragm. The spleen lies behind and to the left side of your stomach (see Figure 1). The normal sized spleen abuts the stomach, colon, and left kidney The spleen resembles a large lymph node and is subdivided into lobules (see Figure 3). However, unlike the lymphatic sinuses of a lymph node, the spaces in the spleen, called venous sinuses, are filled with blood instead of lymph.

A normal spleen ranges in length from 6 to 13 cm and in weight from 75 to 200 g ². The spleen is not normally palpable except in slender young adults ². When the spleen can be felt below the left costal (rib) margin, at rest or on inspiration, spleen enlargement should be assumed and the explanation sought. Although the normal-size or even the abnormally small, spleen can be involved in pathologic processes, with the exception of rubs associated with splenic infarcts, physical examination is generally not helpful in identifying the problem. Nevertheless, the enlarged and palpable spleen is an important clue to the presence of a variety of illnesses ².

Figure 1. Spleen location

Figure 2. Spleen and the lymphatic system

What does the spleen do ?

The spleen plays a significant role in hematopoiesis and immunosurveillance. The major functions of the spleen include clearance of abnormal erythrocytes, removal of microorganisms and antigens as well as the synthesis of immunoglobulin G (IgG). The spleen also synthesizes the immune system peptides properdin and tuftsin ³. Also, approximately one-third of circulating platelets are stored in the spleen.

The tissues within splenic lobules are of two types (see Figure 3). The white pulp is distributed throughout the spleen in tiny islands. This tissue is composed of splenic nodules, which are similar to the lymphatic nodules in lymph nodes and are packed with lymphocytes (T lymphocyte cells and B lymphocyte cells). The red pulp, which fills the remaining spaces of the lobules, surrounds the venous sinuses. This pulp contains numerous red blood cells, which impart its color, plus many lymphocytes and macrophages.

Without an immune system, a human being would be just as exposed to the harmful influences of pathogens or other substances from the outside environment as to changes harmful to health happening inside of the body. The main tasks of the body’s immune system are:

• Neutralizing pathogens like bacteria, viruses, parasites or fungi that have entered the body, and removing them from the body
• Recognizing and neutralizing harmful substances from the environment
• Fighting against the body’s own cells that have changed due to an illness, for example cancerous cells.

The normal adult spleen contributes to the homeostasis of the body by removing from the blood useless or potentially injurious materials (e.g., abnormal or “wornout” red blood cells and microorganisms) and by synthesizing immunoglobulins and properdin ².

Figure 3. Spleen anatomy

Blood capillaries in the red pulp are quite permeable. Red blood cells can squeeze through the pores in these capillary walls and enter the venous sinuses. The older, more fragile red blood cells may rupture during this passage, and the resulting cellular debris is removed by phagocytic macrophages in the venous sinuses. These macrophages also engulf and destroy foreign particles, such as bacteria, that may be carried in the blood as it flows through the venous sinuses. Thus, the spleen filters blood much as the lymph nodes filter lymph.

Phagocytosis removes foreign particles from the lymph as it moves from the interstitial spaces to the bloodstream. Phagocytes in the blood vessels and in the tissues of the spleen (and the liver and bone marrow) remove particles that reach the blood. Monocytes that leave the bloodstream by diapedesis become macrophages. These large cells may be free, or fixed in various tissues. The fixed macrophages can divide and produce new macrophages. Neutrophils, monocytes, and macrophages constitute the mononuclear phagocytic system (reticuloendothelial system).

Fever is body temperature elevated above an individual’s normal temperature due to an elevated setpoint. It is part of the innate defense because as a result of the fever the body becomes inhospitable to certain pathogens. Higher body temperature causes the spleen (and the liver) to sequester iron, which reduces the level of iron in the blood. Because bacteria and fungi require iron for normal metabolism, their growth and reproduction in a fever-ridden body slows and may cease. Also, phagocytic cells attack more vigorously when the temperature rises. For these reasons, low-grade fever of short duration may be a natural response to infection, not a treated symptom.

T Cells and the Cellular Immune Response

A lymphocyte must be activated before it can respond to an antigen. T cell activation requires that processed fragments of the antigen be attached to the surface of another type of cell, called an antigen-presenting cell (accessory cell). Macrophages, B cells, and several other cell types can be antigen-presenting cells.

T cell activation may occur when a macrophage phagocytizes a bacterium and digests it within a phagolysosome formed by the fusion of the vesicle containing the bacterium (phagosome) and a lysosome. Some of the resulting bacterial antigens are then displayed on the macrophage’s cell membrane near certain protein molecules that are part of a group of proteins called the major histocompatibility complex (MHC). MHC antigens help T cells recognize that a newly displayed antigen is foreign (nonself).

Activated T cells interact directly with antigen-bearing cells. Such cell-to-cell contact is called the cellular immune response, or cell-mediated immunity. T cells (and some macrophages) also synthesize and secrete polypeptides called cytokines that enhance certain cellular responses to antigens. For example, interleukin-1 and interleukin-2 stimulate the synthesis of several other cytokines from other T cells. Additionally, interleukin-1 helps activate T cells, whereas interleukin-2 causes T cells to proliferate. This proliferation increases the number of T cells in a clone, which is a group of genetically identical cells that descend from a single, original cell. Other cytokines, called colony stimulating factors (CSFs), stimulate leukocyte production in red bone marrow and activate macrophages. T cells may also secrete toxins that kill their antigen-bearing target cells, growth-inhibiting factors that prevent target cell growth, or interferon that inhibits the proliferation of viruses and tumor cells. Several types of T cells have distinct functions.

A specialized type of T cell, called a helper T cell, is activated when its antigen receptor combines with a displayed foreign antigen (Figure 9). Once activated, the
helper T cell proliferates and the resulting cells stimulate B cells to produce antibodies that are specific for the displayed antigen.

Another type of T cell is a cytotoxic T cell, which recognizes and combines with nonself antigens that cancerous cells or virally infected cells display on their surfaces near certain MHC proteins. Cytokines from helper T cells activate the cytotoxic T cell. Next, the cytotoxic T cell proliferates. Cytotoxic T cells then bind to the surfaces of antigen-bearing cells, where they release perforin protein that cuts pore like openings in the cell membrane, destroying these cells. In this way, cytotoxic T cells continually monitor the body’s cells, recognizing and eliminating tumor cells and cells infected with viruses. Cytotoxic T cells provide much of the body’s defense against HIV infection.

Some cytotoxic T cells do not respond to a nonself antigen on first exposure, but remain as memory T cells that provide for future immune protection. Upon subsequent exposure to the same antigen, these memory cells immediately divide to yield more cytotoxic T cells and helper T cells, often before symptoms arise.

Figure 4. T-cell (T lymphocyte) activation

Steps in Antibody Production

T Cell (T Lymphocyte) Activities

1. Antigen-bearing agents enter tissues.
2. An accessory cell, such as a macrophage, phagocytizes the antigen-bearing agent, and the macrophage’s lysosomes digest the agent.
3. Antigens from the digested antigen-bearing agents are displayed on the membrane of the accessory cell.
4. Helper T cell becomes activated when it encounters a displayed antigen that fits its antigen receptors.
5. Activated helper T cell releases cytokines when it encounters a B cell that has previously combined with an identical antigen-bearing agent.
6. Cytokines stimulate the B cell to proliferate, enlarging its clone.
7. Some of the newly formed B cells give rise to cells that differentiate into antibody-secreting plasma cells.

Figure 5. B (lymphocyte)-cell activation

B Cell (B Lymphocyte) Activities

1. Antigen-bearing agents enter tissues.
2. B cell encounters an antigen that fits its antigen receptors.
3. Either alone or more often in conjunction with helper T cells, the B cell is activated. The B cell proliferates, enlarging its clone.
4. Some of the newly formed B cells differentiate further to become plasma cells.
5. Plasma cells synthesize and secrete antibodies whose molecular structure is similar to the activated B cell’s antigen receptors.

Antibody Actions

In general, antibodies react to antigens in three ways. Antibodies directly attack antigens, activate complement, or stimulate localized changes (inflammation) that help prevent the spread of pathogens or cells bearing foreign antigens.

In a direct attack, antibodies combine with antigens, causing them to clump (agglutination) or to form insoluble substances (precipitation). Such actions make it easier for phagocytic cells to recognize and engulf the antigen-bearing agents and eliminate them. In other instances, antibodies cover the toxic portions of antigen molecules and neutralize their effects (neutralization). However, under normal conditions, direct antibody attack is not as important as complement activation in protecting against infection.

When certain IgG or IgM antibodies combine with antigens, they expose reactive sites on antibody molecules. This triggers a series of reactions, leading to activation of the complement proteins, which in turn produce a variety of effects. These include:

• coating the antigen-antibody complexes (opsonization), making the complexes more susceptible to phagocytosis;
• attracting macrophages and neutrophils into the region (chemotaxis);
• rupturing membranes of foreign cells (lysis); agglutination of antigen-bearing cells; and
• neutralization of viruses by altering their molecular structure, making them harmless.

Other proteins promote inflammation, which helps prevent the spread of infectious agents.

Immune Responses

Activation of B cells or T cells after they first encounter the antigens for which they are specialized to react constitutes a primary immune response. During such a response, plasma cells release antibodies (IgM, followed by IgG) into the lymph. The antibodies are transported to the blood and then throughout the body, where they help destroy antigen bearing agents. Production and release of antibodies continues for several weeks.

Following a primary immune response, some of the B cells produced during proliferation of the clone remain dormant as memory cells. If the same antigen is encountered again, the clones of these memory cells enlarge, and they can respond rapidly by producing IgG to the antigen to which they were previously sensitized. These memory B cells, along with the memory cytotoxic T cells, produce a secondary immune response.

As a result of a primary immune response, detectable concentrations of antibodies usually appear in the blood plasma five to ten days after exposure to antigens. If the same type of antigen is encountered later, a secondary immune response may produce the same antibodies within a day or two. Although newly formed antibodies may persist in the body for only a few months or years, memory cells live much longer.

Naturally acquired active immunity occurs when a person exposed to a pathogen develops a disease. Resistance to that pathogen is the result of a primary immune response.

A vaccine is a preparation that produces artificially acquired active immunity. A vaccine might consist of bacteria or viruses that have been killed or weakened so that they cannot cause a serious infection, or only molecules unique to the pathogens. A vaccine might also be a toxoid, which is a toxin from an infectious organism that has been chemically altered to destroy its dangerous effects. Whatever its composition, a vaccine includes the antigens that stimulate a primary immune response, but does not produce symptoms of disease and the associated infections.

Specific vaccines stimulate active immunity against a variety of diseases, including typhoid fever, cholera, whooping cough, diphtheria, tetanus, polio, chickenpox, measles (rubeola), German measles (rubella), mumps, influenza, hepatitis A, hepatitis B, and bacterial pneumonia. A vaccine has eliminated naturally acquired smallpox from the world.

Enlarged spleen

Splenomegaly is defined as enlargement of the spleen measured by size or weight ³. The normal sized spleen measures up to 11 cm in length. A length of 11 cm-20 cm indicates splenomegaly and a length greater than 20cm is definitive of massive splenomegaly ³. The normal weight of the adult spleen is 70 g-200 g, spleen weight of 400 g-500 g indicates splenomegaly and spleen weight greater than 1000 g is definitive of massive splenomegaly ³. The normal sized spleen is usually not palpable in adults. However, it may be palpable due to variations in body habitus and chest wall anatomy. Splenomegaly may be diagnosed clinically or radiographically using ultrasound, CT imaging, or MRI. Splenomegaly may be a transient condition due to acute illness or may be due to serious underlying acute or chronic pathology.

Splenomegaly is a rare disease, with estimated prevalence approximately 2% of total US population ³. In adults, there has been no reported predominance in prevalence based on ethnicity, sex, or age.

Spleen enlargement can be associated with decreased or increased function, depending on the cause of the enlarged spleen.

Table 1. Causes of Splenomegaly (enlarged spleen)

When spleen enlargement is associated with a change in splenic function, it is most frequently associated with splenic hyperfunction. This is reflected in the peripheral blood by thrombocytopenia, leukopenia, rapid red blood cell destruction, or a combination of these findings. This clinical syndrome of an enlarged spleen and peripheral cytopenias is often referred to as hypersplenism. When splenic enlargement is secondary to an infiltrative process (i.e., tumors or amyloidosis), splenic hypofunction can result. This is reflected in the peripheral blood by Howell–Jolly bodies and abnormal red blood cell forms. The presence of an enlarged spleen should lead to examination of the peripheral blood by the physician.

It is extremely important to correlate the presence of an enlarged spleen with the clinical history findings, other physical findings, laboratory results, and x-ray findings to identify the cause of splenic enlargement in a particular patient. For example, vascular spiders, red palms, and small testes in a patient with splenic enlargement would strongly suggest liver disease as the etiology. Roth spots and a new heart murmur would suggest endocarditis. Extensive lymphadenopathy, weight loss, night sweats, and an enlarged spleen would suggest a malignant lymphoproliferative disease. By making these correlations, it is possible to utilize the presence of an enlarged spleen to plan a patient’s subsequent evaluation and quickly and efficiently reach the correct diagnosis.

The mechanism underlying splenic enlargement varies based on the etiology. In the case of acute infectious illness, the spleen performs increased work in clearing antigens and producing antibodies and increases the number of reticuloendothelial cells contained within the spleen. These increased immune functions may result in splenic hypertrophy. In the case of liver disease and congestion, underlying illness causes increased venous pressure causing congestive splenomegaly. Extramedullary hematopoiesis exhibited in myeloproliferative disorders can lead to splenic hyperplasia.

Splenic sequestration crisis is a life-threatening illness common in pediatric patients with homozygous sickle cell disease and beta thalassemia ³. Up to 30% of these children may develop splenic sequestration crisis with a mortality rate of up to 15%. This crisis occurs when splenic vaso-occlusion causes a large percentage of total blood volume to become trapped within the spleen. Clinical signs include severe, rapid drop in hemoglobin leading to hypovolemic shock and death ³. Pediatric patients with sickle cell disease and beta thalassemia experience multiple splenic infarcts, resulting in splenic fibrosis and scarring. Over time, this leads to a small, auto infarcted spleen typically by the time patients reach adulthood. Splenic sequestration crisis can only occur in functioning spleens which may be why this crisis is rarely seen in adults. However, late adolescent or adult patients in this group who maintain splenic function may develop splenic sequestration crisis.

Symptoms of enlarged spleen

The most common physical symptom associated with splenomegaly is vague abdominal discomfort ³. Patients may complain of pain in the left upper abdomen or referred pain in the left shoulder.

• Abdominal bloating, distended abdomen, anorexia, and/or early satiety may also occur.

Commonly, patients will present with symptoms due to the underlying illness causing splenomegaly ³. Constitutional symptoms such as weakness, weight loss, and night sweats suggest malignant illness. Patients with splenomegaly due to acute infection may present with fever, rigors, generalized malaise, or focal infectious symptoms. Patients with underlying liver disease may present with symptoms related to alcohol abuse or hepatitis. Symptoms of anemia (lightheadedness, dyspnea, or exertion), easy bruising, bleeding, or petechiae may indicate splenomegaly due to underlying hemolytic process.

Diagnosis of enlarged spleen

A combination of serum testing and imaging studies may definitively diagnose splenomegaly and the underlying cause. Derangement in complete blood (cell) counts and morphology including white blood cell, red blood cell and platelets will vary based on underlying disease state. Abnormalities in liver function tests, lipase, rheumatologic panels, and disease-specific infectious testing aid in the diagnosis of causative disease.

Imaging may be used to diagnose splenomegaly and elucidate its underlying cause. The spleen has a similar attenuation as the liver when measured on CT imaging. In addition to diagnosing splenomegaly (splenic measurement of greater than 10 cm in craniocaudal length), abdominal CT may detect splenic abscess, mass lesions, vascular abnormalities, cysts, inflammatory changes, traumatic injury, intra-abdominal lymphadenopathy, or liver abnormalities.

Ultrasound is a useful imaging modality in measuring the spleen and spares the patient radiation from CT imaging. Normal spleen size measured via ultrasound is less than 13 cm superior to the inferior axis, 6 cm-7 cm in medial to lateral axis and 5 cm-6 cm in anterior to posterior plane.

MRI, PET scans, liver-spleen colloid scanning, and splenectomy and splenic biopsy may be indicated in certain cases.

Treatment and Management of enlarged spleen

Treatment of splenomegaly is targeted at treating the underlying disease and protecting the patient from complications of splenomegaly itself. Patients with splenomegaly from any cause are at increased risk of splenic rupture, and increased attention must be made to protect the patient from abdominal trauma. Treatment ranges from abdominal injury avoidance in the young healthy patient with splenomegaly due to infectious mononucleosis, to splenectomy of a massively enlarged spleen in a patient with Hairy cell leukemia. Likewise, the prognosis is largely dependent on underlying disease state.

Patients who undergo splenectomy are at increased risk of overwhelming infection due to encapsulated organisms such as Haemophilus Influenzae, Streptococcus pneumoniae, and Neisseria meningitidis should receive vaccinations against these organisms. Careful attention must be paid to post-splenectomy patients presenting with febrile illnesses as they may require more aggressive, empiric antibiotic therapy.

Ruptured spleen

Blunt splenic injury which is often times the first or second most commonly injured solid organ in the abdomen along with the liver ⁴. Rupture of the spleen is relatively common both immediately and in a delayed fashion following significant blunt abdominal injury ⁵. Massive hemorrhage commonly occurs from injuries to this friable vascular organ. The mortality rate from simple splenic rupture is 1% ⁶. Delayed diagnosis of a ruptured spleen increases the rate to 10% ⁶. While less common, cases of atraumatic rupture of diseased spleens ⁷, ⁸.

Four types of splenic injuries are recognised namely: intraparenchymal laceration, subcapsular haematoma, and splenic rupture and delayed rupture ⁹.

For many years it was accepted that splenic injury was best managed by splenectomy. However, it has more recently been realized that patients whose spleen has been removed are more liable to life-threatening infection ¹⁰. This is of particular consequence if splenectomy is performed in childhood, with a long life expectancy. The spleen has many functions including filtering or removing old poorly functioning red blood cells, catching bacteria, and producing antibodies. After removal of the spleen, these functions are lost and the patient could be susceptible to an overwhelming post-splenectomy infections from bacteria such as streptococcus pneumoniae, neisseria meningitidis, and hemophilus influenza ⁴. To reduce this risk, patients who undergo surgery to remove their spleen receive vaccines against these bacteria.With greater understanding of the splenic anatomy and function, and natural course of splenic injuries, the management has evolved into a more conservative approach though a splenectomy may still be required in some situations.

Symptoms of ruptured spleen

Most splenic injuries manifest at the moment of injury with symptoms of acute intraperitoneal hemorrhage and shock ¹¹. At this point the patient falls into one of two categories:

• hemodynamically stable or
• hemodynamically unstable based on their vital signs (blood pressure and heart rate).

If the patient has a low blood pressure and/or a high heart rate (unstable), the trauma surgeon must identify the cause, which is often due to bleeding. Next the trauma surgeon determines the location of the bleeding. If it appears that the abdomen is the source, the patient, the patient may need to be taken to the operating room emergently for exploratory abdominal surgery. If a splenic injury with bleeding is found, removal of the spleen (splenectomy) may be required.

Treatment for splenic injury:

• Approximately 70% to 90% of children with splenic injury receive Non-operative management (NOM)
• Approximately 40% to 50% of adult patients with splenic injury receive Non-operative management
• 85% patient receive non-operative management in some centers

If instead the patient’s vital signs are normal (hemodynamically stable), a CT scan of the abdomen/pelvis may be done to evaluate potential trauma to the abdomen. At this point if the patient is found to have a splenic laceration it is graded according to the American Association for the Surgery of Trauma splenic injury scale (Table 1). Other factors such as intravenous contrast extravasation or “blush” can also be identified via the CT scan, which indicates that there may be active bleeding in progress in which case a hemodynamically stable patient may be sent to interventional radiology so that an angiogram can be performed and a potential active bleeding vessel can be embolized or coiled to stop any further bleeding. The patient then may be observed in the ICU/floor depending on severity and other trauma to the patient. Close monitoring of the patient’s condition, vital signs, blood tests and serial abdominal exams are required in order to assess the stability of the bleeding from the injury. The trauma surgeon must be prepared to operate 24/7 in case recurrent bleeding develops after a period of stability. Thus, these patients are best managed at a trauma center, which has the necessary resources to intervene quickly. If the patient remains stable the patient’s diet and activity can slowly be started after 24 hrs or depending on the individual institution’s protocols.

Whether the patient undergoes surgery or is managed non-operatively there are risks and complications associated with either strategy. After surgery there is always a small risk of infection and additionally bleeding from the procedure. If the spleen has been removed, the patient is at risk for certain bacterial infections, as discussed earlier and will require vaccinations. There is also a risk during the procedure of injuring the pancreas or other organs necessitating additional procedures. With the non-operative strategy there is a risk of delayed bleeding which may require an operation to remove the spleen. Also if the patient is selected for nonoperative management there is a chance of a missed associated injury in the abdomen such as a bowel injury.

As a result of understanding the function of the spleen, natural evolution of the splenic injury, improving technology and adjuncts such as angiogram the trauma surgeons are better able to manage blunt spleen injuries nonoperatively more successfully than before. Managing a hemodynamically unstable patient suspected of having an intra-abdominal injury often requires an immediate surgery for abdominal exploration. However, out of the patients managed nonoperatively there still is a set of patients that fail this type of management who will require surgical intervention and it is in those patients that the trauma surgeon must be vigilant. Blunt splenic trauma management has evolved significantly over the last few decades and as our understanding of the injury and its evolution improves so does our ability to manage the splenic injury whether it’s nonoperatively or surgically.

Table 1. Spleen injury scale

1. Hijazi LS, Mead T. Functional Asplenism. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499949
2. Armitage JO. Spleen. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 150. Available from: https://www.ncbi.nlm.nih.gov/books/NBK258/
3. Chapman J, Bhimji SS. Splenomegaly. [Updated 2017 May 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2017 Jun-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430907/
4. Blunt Splenic Trauma. American Association for the Surgery of Trauma. http://www.aast.org/GeneralInformation/BluntSplenicTrauma.aspx
5. Olsen WR, Polley TZ Jr. A Second Look at Delayed Splenic Rupture. Arch Surg. 1977;112(4):422–425. doi: 10.1001/archsurg.1977.01370040074012. https://www.ncbi.nlm.nih.gov/pubmed/849149
6. “Delayed rupture of the spleen” or delayed diagnosis of the splenic injury ? Isr J Med Sci. 1980 Sep-Oct;16(9-10):659-64. https://www.ncbi.nlm.nih.gov/pubmed/7429801
7. Systematic review of atraumatic splenic rupture. Renzulli P, Hostettler A, Schoepfer AM, Gloor B, Candinas D. Br J Surg. 2009 Oct; 96(10):1114-21. https://www.ncbi.nlm.nih.gov/pubmed/19787754/
8. Debnath D, Valerio D. Atraumatic rupture of the spleen in adults. J R Coll Surg Edinb. 2002;47:437–445. https://www.ncbi.nlm.nih.gov/pubmed/11874265
9. Horgan GI. The paediatric Liver and Spleen. In: Rumack CR, Wilson SR, Charboneau J William, editors. Diagnostic ultrasound. Volume 2. Vol. 59. Mosby year Book; 1991. pp. 1175–1176.
10. Conservative management of ruptured spleen. S Afr Med J. 1980 Apr 19;57(16):655-8. https://www.ncbi.nlm.nih.gov/pubmed/7376031
11. Delayed splenic rupture: understanding the threat. J Trauma Nurs. 2002 Apr-Jun;9(2):34-40. https://www.ncbi.nlm.nih.gov/pubmed/15997614
12. Spleen injury scale (1994 revision). American Association for the Surgery of Trauma. http://www.aast.org/Library/TraumaTools/InjuryScoringScales.aspx

What is thymus cancer

The thymus is a small organ in your upper chest, under your breastbone (see Figure 1 and 2). The thymus is in a part of the chest known as the mediastinum, the space in the chest between the lungs that also contains the heart, part of the aorta, the esophagus (the tube that connects the throat to the stomach), part of the trachea (windpipe), and many lymph nodes. The thymus sits just in front of the aorta and above the heart. Before birth and during childhood, the thymus helps the body make a type of white blood cell – T cells (T lymphocytes). These cells help protect you from infections.

Cancer of the thymus is rare. You are more likely to get it if you have other diseases such as myasthenia gravis, lupus or rheumatoid arthritis ¹. Sometimes there are no symptoms. Other times, thymus cancer can cause:

• A cough that doesn’t go away
• Chest pain
• Trouble breathing

Although thymic tumors are the most common tumors in the anterior mediastinum (the front part of the chest cavity), overall they are rare. They occur at a rate of only 1.5 cases for every million people each year in the US. This works out to about 400 cases per year (the exact number diagnosed each year is not known) ².

The thymus is an important part of your body’s immune system. During fetal development and childhood, the thymus is involved in the production and maturation of T lymphocytes (also known as T cells), a type of white blood cell. T lymphocytes develop in the thymus and then travel to lymph nodes (bean-sized collections of immune system cells) throughout the body. There they help the immune system protect the body from viruses, fungus, and other types of infections.

The thymus has different types of cells, each of which can develop into different types of cancer:

• Epithelial cells give the thymus its structure and shape. Thymomas and thymic carcinomas, develop from these cells.
• Lymphocytes make up most of the rest of the thymus. Whether in the thymus or in other parts of the body, these immune system cells can develop into cancers called Hodgkin disease and non-Hodgkin lymphoma.
• Kulchitsky cells, or neuroendocrine cells, are much less common cells that normally release certain hormones. These cells can give rise to cancers called carcinoid tumors.

Figure 1. The location and structure of the thymus

Figure 2. Thymus location

Thymomas and thymic carcinomas

Thymomas and thymic carcinomas are tumors that start from thymic epithelial cells ³. Not all doctors agree about the best way to describe and classify these tumors. In the past, thymomas were sometimes divided into benign (non-cancerous) thymomas and malignant (cancerous) thymomas, based on whether they had grown beyond the thymus into other tissues or organs. Now, most doctors think all thymomas are potentially cancerous and the best way to predict how likely they are to come back after treatment is to describe whether they have grown into tissues beyond the thymus (and if so, how far). This is done by the surgeon who notes whether or not the tumor appears attached to nearby organs and by the pathologist who looks at samples from the margins (edges) of the tumor under the microscope.

World Health Organization classification system for thymomas

Most doctors also classify thymomas by how they look under a microscope and by tests done on the tissue samples. This is called the histologic type. The system used for this classification, which was developed by the World Health Organization (WHO), assigns letters to the different types of thymomas.

Type A: The cells in these tumors are spindle-shaped or oval epithelial cells that appear to be fairly normal looking. This is the rarest type of thymoma, but it seems to have the best prognosis (outlook).

Type AB: This type, also known as a mixed thymoma, looks like type A except that there are also areas of lymphocytes mixed in the tumor.

Type B1: This type looks a lot like the normal structure of the thymus. It has a lot of lymphocytes along with normal-appearing thymus cells.

Type B2: This type also has a lot of lymphocytes, but the thymus epithelial cells are larger with abnormal nuclei (the DNA-containing part of the cell).

Type B3: This type has few lymphocytes and mostly consists of thymus epithelial cells that look pretty close to normal.

Type C: This is the most dangerous form and is also known as thymic carcinoma. It contains cells that have a very abnormal appearance under the microscope. The cells may no longer even look like thymus cells. These tumors have often grown into (invaded) nearby tissues and/or metastasized (spread to distant tissues and organs) at the time they are found. This type of thymoma has the worst prognosis (outlook) ³.

Type AB and type B2 are the most common types of thymoma, and type A is the least common. As you go from A to C, the outlook for survival tends to get worse, with type A having the best outlook, and type C having the worst. Still, for most types of thymoma, the stage (extent of growth and spread) is a better predictor of a person’s outcome.

What Causes Thymus Cancer ?

Not much is known about why thymus cancers develop in some people but not in others ⁴. Researchers have found some DNA changes that occur more often in thymus cancer cells than in normal cells. DNA is the chemical in each of our cells that makes up our genes — the instructions for how our cells function. However, they are still not certain why these changes occur in some people, exactly how the changes occur, and how the changes might cause cancer to form.

• Because we do not know what causes most thymus cancers, it is not yet possible to know how to prevent them.

What Are the Risk Factors for Thymus Cancer ?

A risk factor is anything that affects your chance of getting a disease such as cancer. Different cancers have different risk factors. For example, exposing the skin to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for lung cancer and many others.

But risk factors don’t tell us everything. Having a known risk factor, or even several risk factors, does not mean that you will get the disease. And many people who get the disease may not have had any known risk factors.

No specific inherited, environmental, or lifestyle risk factors have been strongly linked to thymoma or thymic carcinoma ⁵. Some studies have suggested a possible link with exposure to radiation to the upper chest area, but this has not been confirmed. The only known risk factors are age and ethnicity.

Age

The risk of this type of cancer goes up with age. This type of cancer is rare in children and young adults, is seen more often in middle-aged adults, and is most common in those in their 70s.

Ethnicity

In the US, this cancer most common in Asians and Pacific Islanders and least common in Whites and Latinos. It is more common in African Americans than in Whites.

Thymus cancer symptoms

Many thymic tumors are found on an x-ray or scan done for some other reason, before the patient has symptoms ⁶. The rest are brought to the attention of a doctor after a person starts to have symptoms. These may be related to the tumor itself, or they may be part of a paraneoplastic syndrome.

Although these signs and symptoms might be caused by thymus tumors, they can also be caused by other conditions. Still, if you have any of these problems, it’s important to see your doctor right away so the cause can be found and treated, if needed.

Symptoms caused by the thymus tumor

The thymus is in the middle of the chest, near the airways and certain blood vessels. Tumors in the thymus can press on nearby structures, causing symptoms such as:

• Shortness of breath
• Cough (which may bring up bloody sputum)
• Chest pain
• Trouble swallowing
• Loss of appetite
• Weight loss

The thymus is near the superior vena cava, the main blood vessel bringing blood from the head and upper body to the heart. Tumors that press on this vessel can cause symptoms of superior vena cava syndrome, which can include:

• Swelling in the face, neck, and upper chest, sometimes with a bluish color
• Swelling of the visible veins in this part of the body
• Headaches
• Feeling dizzy or light-headed

Paraneoplastic syndromes

These are conditions that are related to the cancer but that are not caused directly by the tumor mass. For example, people with thymomas may develop autoimmune diseases, where the immune system starts to attack the body itself. Part of the normal function of the thymus is to help keep the immune system in check, which may help explain why this happens.

Myasthenia gravis: About 30% to 65% of people with thymomas also have myasthenia gravis. This is by far the most common autoimmune disease associated with thymomas. In this disease, the immune system forms antibodies that block the chemical signals that signal the muscles to move. This causes severe muscle weakness. People with myasthenia gravis tire easily. They may notice problems climbing stairs or walking long distances.

Although patients have decreased muscle strength throughout the body, symptoms caused by weakness of the muscles of the eyes, neck, and chest may be the most troublesome. Weakness of the eye muscles can cause blurred or double vision and drooping eyelids, while weak neck muscles can lead to problems with swallowing. Weakness of the chest muscles and diaphragm can cause problems breathing and shortness of breath.

Many people with thymomas have myasthenia gravis, but most people with myasthenia gravis don’t have thymomas. Many people with myasthenia gravis have other, noncancerous abnormalities of the thymus gland. Myasthenia gravis can be treated by removing the thymus (whether or not a thymoma is present) or with medicines that either strengthen the chemical signals to muscles or weaken the immune attack on the muscles.

Red cell aplasia: Red cell aplasia, in which the body’s ability to make new red blood cells is severely reduced, occurs in about 5% of thymoma patients. Red blood cells carry oxygen from the lungs to other tissues of the body. Reduced red blood cell production causes anemia (low red blood cell counts). Symptoms of anemia can include weakness, dizziness, shortness of breath, and tiring easily. The usual treatment is to remove the thymus gland.

Hypogammaglobulinemia: Hypogammaglobulinemia is a disorder in which the body makes low amounts of infection-fighting antibodies (also known as gamma globulins). This leaves the person susceptible to infections. About 5% to 10% of thymoma patients develop hypogammaglobulinemia. About 10% of patients with hypogammaglobulinemia have a thymoma. Removing the thymus does not help correct this disease.

Other autoimmune diseases: Many other autoimmune diseases have also been linked to thymoma. However, they are much less common than myasthenia gravis, pure red cell aplasia, or hypogammaglobulinemia. Some examples include:

• Systemic lupus erythematosus
• Polymyositis
• Ulcerative colitis
• Rheumatoid arthritis
• Sjogren (Sjögren) syndrome
• Sarcoidosis
• Scleroderma

Most people who have these autoimmune diseases do not have a thymoma ⁶.

Can Thymus Cancer Be Found Early ?

Screening is testing for a disease like cancer in people without any symptoms. Thymus cancers are uncommon, and there are no widely recommended screening tests for them. Still, these cancers can sometimes be found early.

About 4 out of 10 people with thymomas have no symptoms when their tumor is found. In most of these cases the tumor is seen by chance on a test (like a chest x-ray or CT scan) that is done for some other reason ⁷.

Thymomas are often associated with symptoms that are not directly caused by the tumor mass itself. These are called paraneoplastic syndromes (tumor-related conditions). Some of these paraneoplastic syndromes, such as myasthenia gravis, red cell aplasia, and hypogammaglobulinemia. These conditions can be very important in diagnosing some thymomas early because they may be present while the tumor is still at an early stage.

Thymus cancer diagnosis

If there is a reason to think you might have a tumor of the thymus, your doctor will ask you about symptoms and use one or more exams or tests to find out if the disease is really present. Certain signs and symptoms might suggest that a person may have a thymus tumor, but tests are needed to confirm the diagnosis.

Medical history and physical exam

If you have signs or symptoms that suggest you might have a thymus tumor, your doctor will want to take a complete medical history to check for symptoms. You will also be asked about your general health.

A physical exam provides information about possible signs of thymus cancer and other health problems. Patients with thymic cancer will sometimes have a fullness that the doctor can feel in the lower neck area.

Thymomas are often suspected because the patient has signs and symptoms associated with myasthenia gravis, hypogammaglobulinemia, or red cell aplasia.

If symptoms and/or the results of the physical exam suggest a thymus tumor might be present, more tests probably will be done. These might include imaging tests, lab tests, and other procedures.

Imaging tests

Imaging tests use x-rays, magnetic fields, or radioactive substances to create pictures of the inside of your body. Imaging tests may be done for a number of reasons, including to help find a suspicious area that might be cancerous, to learn how far cancer may have spread, and to help determine if treatment has been effective.

Chest x-ray

A chest x-ray may be the first imaging test a doctor orders if he or she suspects a problem in the middle of the chest. It may be able to show if there is a tumor in the chest. In some cases, a chest x-ray may find tumors in people before they cause any symptoms (when the person is having the x-ray done for another reason). However, some thymomas are small or are in certain places that may not show up on a chest x-ray. If your doctor is still suspicious or if an abnormality appears on the chest x-ray, a CT scan may be ordered.

Computed tomography (CT) scan

The computed tomography (CT) scan is an x-ray procedure that produces detailed cross-sectional images of your body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around you while you are lying on a narrow platform. A computer then combines these into images of slices of the part of your body that is being studied.

Before the test, you may be asked to drink 1 to 2 pints of a liquid called oral contrast. This helps outline abnormal areas in the body. You may also receive an IV line through which a different kind of contrast dye (IV contrast) is injected. This helps better outline structures such as blood vessels in your body.

The injection can cause some flushing (redness and warm feeling that may last hours to days). A few people are allergic to the dye and get hives. Rarely, more serious reactions like trouble breathing and low blood pressure can occur. Medicine can be given to prevent and treat allergic reactions. Be sure to tell the doctor if you have ever had a reaction to any contrast material used for x-rays.

A CT scanner has been described as a large donut, with a narrow table in the middle opening. You will need to lie still on the table while the scan is being done. CT scans take longer than regular x-rays, and you might feel a bit confined by the ring while the pictures are being taken.

CT scans can have several uses:

• CT scans of the chest can spot very small tumors and help determine the exact location and extent of the tumors.

• CT scans can be helpful in staging a cancer (determining the extent of its spread). For example, they can show whether the cancer has spread to nearby lymph nodes or to the liver, kidneys, brain, or other organs.

• CT scans can also be used to guide a biopsy needle precisely into a suspected tumor or metastasis. For this procedure, called a CT-guided needle biopsy, the patient remains on the CT scanning table while a radiologist advances a biopsy needle through the skin and toward the location of the mass. CT scans are repeated until the needle is within the mass. A biopsy sample is then removed and looked at under a microscope.

• During or after treatment, CT scans may be used to see whether tumors are shrinking or have recurred (come back) in other parts of the body.

Magnetic resonance imaging (MRI) scan

Like CT scans, MRI scans provide detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into very detailed images of parts of the body. A contrast material called gadolinium is often injected into a vein before the scan to better see details.

MRI scans may be a little more uncomfortable than CT scans. They take longer — often up to an hour. You may be placed inside a large cylindrical tube, which is confining and can upset people with a fear of enclosed spaces (claustrophobia). For people who cannot tolerate a regular MRI machine, there are special, more open MRI machines that can be used instead in some cases. The MRI machine makes buzzing and clicking noises that you might find disturbing. Some places will provide earplugs to help block this out.

MRI of the chest may be done to look more closely at thymus tumors. They are most often used when the patient can’t have a CT scan for medical reasons (like problems with the IV contrast). MRI images are also particularly useful in looking for cancer that may have spread to the brain or spinal cord.

Positron emission tomography (PET) scan

For a PET scan, you receive an injection of a substance that contains a radioactive atom. This is usually glucose (a type of sugar), but other substances that are attracted to thymoma cells may also be used. The amount of radioactivity is very low. The cancer cells in the body absorb large amounts of the radioactive substance. A special camera can then be used to create a picture of areas of radioactivity in the body. The picture is not finely detailed like a CT or MRI scan, but it can provide helpful information about your whole body.

A PET scan can help give the doctor a better idea of whether an abnormal area seen on another imaging test is a tumor or not. If you have already been diagnosed with cancer, your doctor may use this test to see if the cancer has spread to lymph nodes or other parts of the body. A PET scan can also be useful if your doctor thinks the cancer may have spread but doesn’t know where.

Certain machines are able to perform both a PET and CT scan at the same time (PET/CT scan). This lets the doctor compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT. Combined PET/CT is used more often than PET (alone) in looking at thymomas.

Blood tests

Blood tests can’t be used to diagnose thymomas directly, but they may still be helpful in some situations. For example, tests may be done to look for certain antibodies in the blood of people who may have myasthenia gravis or other autoimmune disorders. Other blood tests may be done to make sure a mass in the middle of the chest isn’t a germ cell tumor or part of the thyroid gland.

If a thymoma is diagnosed, blood cell counts and blood chemistry tests are done to get an idea of a person’s overall health, especially if surgery is planned. Also, tests for myasthenia gravis (MG) will be done before any surgery. This is because MG is very common in patients with a thymoma, and, if left untreated, it can cause problems with anesthesia during surgery. People getting chemotherapy also have regular blood tests to make sure the drugs aren’t having unwanted effects on the bone marrow, kidneys, or other organs.

Types of biopsy procedures

Although signs, symptoms, and imaging tests can suggest that a thymic tumor is likely to be present, doctors can’t be certain of the diagnosis without looking at the tumor under a microscope.

For most cancers, removal of a small sample of the tumor (known as a biopsy) is needed to confirm whether a tumor is present and, if so, to determine its type. For thymomas, this is rarely done because doctors can usually tell that the tumor is very likely a thymoma based on how it looks on imaging tests. Because of this, doctors often remove the entire tumor rather than do a biopsy. If the doctor suspects a different type of tumor, a biopsy may be done before surgery. Most often, a needle biopsy is done. A biopsy may also be done to confirm the diagnosis if the tumor can’t be removed completely with surgery. This can allow the cancer to be treated with things other than surgery.

Needle biopsy

Tumors in the chest are sometimes sampled by needle biopsy. A long, hollow needle is passed through the skin in the chest. Imaging tests such as CT scans are used to guide the needle into the tumor so that a small sample can be removed to be looked at under the microscope. This procedure is done without a surgical incision or overnight hospital stay.

A possible downside of this test is that it might not always get enough of a sample to make an accurate diagnosis or allow the doctor to get a good sense of the extent of the tumor.

Surgical biopsy

In most cases, if the doctor believes that the patient has thymoma (based on CT findings and lab tests, especially in a patient with a paraneoplastic syndrome) and it can be removed with surgery, the doctor may operate without any biopsy. This can both provide enough of a sample for a diagnosis and treat the tumor at the same time. The specimen is sent to the lab after surgery to confirm the diagnosis.

How Is Thymus Cancer Staged ?

Staging is the process of finding out if and how far a cancer has spread. Your treatment and prognosis (the outlook for chances of survival) depend, to a large extent, on the cancer’s stage.

Masaoka staging system ⁸

There is no single staging system for thymomas that all doctors agree on, perhaps because these tumors are so uncommon ⁸. The system most often used to stage thymomas is the Masaoka system, although other systems exist. Staging in the Masaoka system is based on:

• The extent of disease as seen on imaging tests such as CT or MRI scans
• Whether the surgeon finds the tumor hard to separate from nearby tissues (indicating the tumor is invasive)
• Whether the doctor sees tumor cells beyond the thymus when looking at the tumor sample under the microscope

The Masaoka system has 4 main stages.

Stage I

The thymoma is non-invasive. That is, it has not spread into the capsule (outer layer) of the thymus.

Stage II, which is divided into IIA and IIB

• Stage IIA: The thymoma is growing into the capsule (the outer layer of tissue of the thymus).
• Stage IIB: The tumor has grown through the capsule into the nearby fatty tissue, and may be stuck to the mediastinal pleura (the thin layer covering the space between the 2 lungs) or the pericardium (the tissue sac containing the heart).

Stage III

The thymoma is growing into nearby tissues or organs of the lower neck or upper chest area, including the pericardium (the tissue sac containing the heart), the lungs, or the main blood vessels going into or exiting from the heart (the superior vena cava and aorta).

Stage IV, which is divided into IVA and IVB

• Stage IVA: The thymoma has spread widely throughout the pleura (lining of the lungs and chest wall) and/or pericardium.
• Stage IVB: The thymoma has spread to distant organs. The most common sites of spread are bone, the liver, and the lungs.

Resectable versus unresectable cancer

The Masaoka staging system divides thymomas into different groups that help give doctors an idea about a person’s prognosis (outlook). But for treatment purposes, doctors often use a simpler system based on whether these cancers are likely to be resectable (where all visible tumor can be removed by surgery) or unresectable.

In general terms, almost all stage I and II thymomas, most stage III thymomas, and even some stage IV thymomas are potentially resectable, but there are exceptions. Resectability is based on whether the tumor appears to have grown into nearby tissues or spread to distant sites, as well as on whether or not a person is healthy enough to have surgery.

Surgery is typically part of the treatment plan whenever possible. In some cases, other forms of treatment such as radiation therapy or chemotherapy may be recommended as well.

Other prognostic factors

The prognosis (the outlook for chances of survival) after treatment of a thymoma depends to a large extent on its stage. But other features are important as well, such as its cellular classification and whether the surgeon is able to remove the entire tumor.

Thymus cancer treatment

Factors important in choosing a treatment include the type and stage of the cancer, whether or not it is resectable (able to be completely removed with surgery), and whether you have any other serious medical problems. Whether or not a thymus cancer is considered resectable (removable by surgery) is one of the most important factors in determining treatment options. The type of tumor is also important. Thymic carcinomas are more likely to grow and spread quickly than thymomas and often require more aggressive treatment. Because thymic cancer is rare, it has been hard to do large studies looking at treatments and comparing one against another. That’s why in many cases the best way to treat this cancer is not always clear

Selecting a treatment plan is an important decision, and you should take the time to think about all of your choices. If time permits, it is often a good idea to seek a second opinion. A second opinion can provide more information and help you feel more confident about the treatment plan chosen.

The main treatments for thymus cancer are:

• Surgery
• Radiation
• Chemotherapy

Surgery

Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. For thymoma, surgery is usually done by a thoracic surgeon, a doctor who specializes in surgery of the chest.

Surgery is the most common treatment for early-stage thymoma ⁹. For early-stage thymoma, it is also often the only treatment needed. The most common type of surgery for thymoma is called a median sternotomy. During a median sternotomy, the breastbone is split, and the thymoma and the tissue surrounding the tumor are removed. Sometimes, for smaller, early-stage tumors, a less invasive type of surgery using smaller incisions and a laparoscope may be an option. A laparoscope is a thin, lighted tube with a small camera on the end. With some laparoscopes, the surgeon can work with small instruments through the tube.

Later-stage thymoma treatment options may include surgery to remove as much of the tumor as possible when the entire thymoma cannot be removed with surgery. This is called debulking surgery and may provide some relief of symptoms. If the thymoma has spread to the lining of the lung, surgery may also include the removal of the lung lining or a portion of the lung.

Radiation therapy

Radiation therapy is the use of high-energy x-rays or other particles to destroy cancer cells. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. The most common type of radiation treatment is called external-beam radiation therapy, which is radiation given from a machine outside the body. A radiation therapy regimen (schedule) usually consists of a specific number of treatments given over a set period of time.

External-beam radiation therapy can be used as the only treatment after surgery. Or, it may be combined with chemotherapy. For patients with later-stage disease, radiation therapy is often recommended after the thymoma has been surgically removed.

Side effects from radiation therapy may include fatigue, mild skin reactions, difficulty swallowing, upset stomach, and loose bowel movements. Most side effects go away soon after treatment is finished.

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by stopping the cancer cells’ ability to grow and divide. Chemotherapy is given by a medical oncologist, a doctor who specializes in treating cancer with medication.

Systemic chemotherapy gets into the bloodstream to reach cancer cells throughout the body. Common ways to give chemotherapy include an intravenous (IV) tube placed into a vein using a needle or in a pill or capsule that is swallowed (orally).

A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a set period of time. A patient may receive 1 drug at a time or combinations of different drugs at the same time. Common drugs for thymoma or thymus carcinoma include ⁹.:

• Carboplatin (Paraplatin)
• Cisplatin (Platinol)
• Cyclophosphamide (Neosar)
• Doxorubicin (Adriamycin)
• Etoposide (Toposar, VePesid)
• Ifosfamide (Ifex)
• Octreotide (Sandostatin)
• Paclitaxel (Taxol)
• Pemetrexed (Alimta)

The common drug combinations for thymoma or thymic carcinoma include:

• Carboplatin and paclitaxel
• Cyclophosphamide, doxorubicin, and cisplatin
• Etoposide and cisplatin

These chemotherapy combinations are sometimes used to shrink the tumor before surgery if the thymoma is found at a later stage ⁹. Chemotherapy may also be used for people who have stage IVB/advanced thymoma or recurrent thymoma that cannot be completely removed with surgery. Recurrent thymoma is thymoma that has come back after treatment.

The side effects of chemotherapy depend on the individual, the type of drug, and the dose used, but they can include fatigue, risk of infection, nausea and vomiting, hair loss, loss of appetite, and diarrhea. These side effects usually go away once treatment is finished.

Targeted therapy

Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells.

Recent studies show that not all tumors have the same targets. To find the most effective treatment, your doctor may run tests to identify the genes, proteins, and other factors in your tumor. This helps doctors better match each patient with the most effective treatment whenever possible. In addition, many research studies are taking place now to find out more about specific molecular targets and new treatments directed at them.

For thymus tumors, anti-angiogenesis therapy may be an option ⁹. Anti-angiogenesis therapy is a type of targeted therapy. It is focused on stopping angiogenesis, which is the process of making new blood vessels. Because a tumor needs the nutrients delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapies is to “starve” the tumor. The 2 targeted therapies used for thymic tumors include ⁹:

• Everolimus (Afinitor, Zortress)
• Sunitinib (Sutent).

Metastatic thymus cancer

If cancer spreads to another part in the body from where it started, doctors call it metastatic cancer. If this happens, it is a good idea to talk with doctors who have experience in treating it. Doctors can have different opinions about the best standard treatment plan. Also, clinical trials might be an option. Learn more about getting a second opinion before starting treatment, so you are comfortable with your treatment plan chosen.

Your treatment plan may include a combination of surgery, radiation therapy, chemotherapy, and targeted therapy. Sometimes, when thymoma is metastatic and growing very slowly, your health care team may recommend no treatment for a period of time. You will be closely monitored during this time. When thymoma has spread to another location in the body, it is unlikely that any of the treatments will make the cancer go away forever. Palliative care will also be important to help relieve symptoms and side effects.

Resectable thymus cancers

For patients with resectable cancers (almost all stage I and II thymus cancers, most stage III cancers, and small number of stage IV cancers), surgery offers the best chance for long-term survival if it can be tolerated. This typically includes removal of the entire thymus and, depending on the extent of the disease, maybe parts of nearby organs or blood vessels as well.

Early stage thymomas (such as stage I and II) do not usually require further treatment after surgery as long as the tumor was removed completely. For early thymomas, radiation therapy may be considered if there is concern that any tumor was left behind.

Patients with more advanced stage thymomas (such as stages III and IV) may be treated with radiation after surgery, even if all of the tumor was removed. If the tumor couldn’t be removed completely, radiation therapy is usually given after surgery. Depending on how much cancer was left behind, chemotherapy (chemo) may be added as well.

Thymic carcinomas are more likely to come back after treatment. Patients with stage I tumors may not need further treatment if the tumor was removed completely. If the tumor is more advanced, or some might have been left behind, patients are typically treated with radiation after surgery. The radiation may be given with chemo as well, especially if some of the cancer is left behind after surgery.

Unresectable thymus cancers

Unresectable cancers are those that cannot be removed with surgery. This group includes cancers that are too close to vital structures or that have spread too far to be removed completely (which includes many stage III and most stage IV cancers), as well as cancers in people who are too ill for surgery.

In some cases, doctors may advise giving chemo, radiation therapy, or both first to try to make the tumor resectable. If it shrinks enough, surgery is done. This is then followed by further treatment with chemo or radiation therapy.

Surgery may be the first treatment for some unresectable cancers, to try to remove as much of the tumor as possible. This is known as debulking. Radiation therapy and/or chemo are then given. The hope is that the surgery may help the other treatments work better and may help people live longer, even if it doesn’t cure the cancer. Studies of this approach have had mixed results.

For patients who can’t have surgery, either because the cancer has spread too far or because they are too sick from other serious medical conditions, chemo and radiation therapy are the main treatment options.

Because unresectable cancers can be hard to treat, taking part in a clinical trial of a newer form of treatment may be a reasonable option.

Recurrent thymus cancer

When cancer comes back after treatment it is called recurrent. Recurrence can be local (in or near the same place it started) or distant (spread to organs such as the liver or bone).

Thymomas most often come back locally. Thymic carcinomas can also come back locally and in nearby lymph nodes, but they may also spread to liver, lungs, and bone.

Treatment for thymus cancer that has recurred (come back) after initial treatment depends on the location of the recurrence and on what the original treatment was. If the recurrence is not too widespread, surgery may be an option and would offer the best chance for long-term survival. But in most cases, the treatment options may be limited to radiation therapy and/or chemo. These treatments can often be effective in controlling the cancer for a time, although they are very unlikely to result in a cure.

Because recurrent cancers can often be hard to treat, clinical trials of new types of treatment may be a good option.

Thymus cancer survival rate

The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed ¹⁰. Of course, many people live much longer than 5 years (and many are cured). Although many patients live much longer than this, it isn’t always an indication that the cancer has been cured, as some thymus tumors are very slow growing, and others may return in some people several years after treatment.

To get 5-year survival rates, doctors have to look at people who were treated at least 5 years ago. Treatment may have improved since then which could result in a more favorable outlook for people now being diagnosed with thymus cancer.

Because thymus cancers are not common, it is hard to find accurate survival rates based on the stage of the cancer. The numbers below come from a large series of patients treated in Japan between 1990 and 1994. They look separately at patients with thymoma (types A, AB, and B) and thymic carcinoma (type C thymoma). Also, these are observed survival rates. People with thymus cancer can die of other things, and these numbers don’t take that into account.

Table 1. Thymoma stages and 5 year survival rate

Table 2. Thymus carcinoma stages and 5 year survival rate

1. Thymus Cancer. Medline Plus. https://medlineplus.gov/thymuscancer.html
2. What Are the Key Statistics About Thymus Cancers ? American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/about/key-statistics.html
3. What Is Thymus Cancer ? American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/about/what-is-thymus-cancer.html
4. What Causes Thymus Cancer ? American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/causes-risks-prevention/what-causes.html
5. What Are the Risk Factors for Thymus Cancer ? American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/causes-risks-prevention/risk-factors.html
6. Signs and Symptoms of Thymus Cancers. American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/detection-diagnosis-staging/signs-symptoms.html
7. Can Thymus Cancer Be Found Early ? American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/detection-diagnosis-staging/detection.html
8. How Is Thymus Cancer Staged ? American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/detection-diagnosis-staging/staging.html
9. Thymoma: Treatment Options. American Society of Clinical Oncology. http://www.cancer.net/cancer-types/thymoma/treatment-options
10. Survival Rates for Thymus Cancer. American Cancer Society. https://www.cancer.org/cancer/thymus-cancer/detection-diagnosis-staging/survival-rates.html

What is thymus

The thymus is a soft, pink, bilobed gland enclosed in a connective tissue capsule and located in front of the aorta and above the heart. It lies behind to the upper part of the sternum (Figure 1 and 2). The thymus is in a part of the chest known as the mediastinum, the space in the chest between the lungs that also contains the heart, part of the aorta, the esophagus (the tube that connects the throat to the stomach), part of the trachea (windpipe), and many lymph nodes.

The thymus is divided into 2 halves, called lobes. It has an irregular shape and a surface that is made up of many small bumps with connective tissues extend inward from the surface of the thymus, subdividing it into lobules (Figure 3). The thymus has 3 main layers:

• The medulla is the innermost part of the thymus.
• The cortex is the layer surrounding the medulla.
• The capsule is the thin covering over the outside of the thymus.

The thymus is usually proportionately larger during infancy and early childhood, reaching its maximum weight of about 1 ounce during puberty, then slowly shrinks after puberty as it is gradually replaced by fatty tissue. In elderly people, adipose (fatty tissue) and connective tissues replace lymphatic tissue in the thymus.

The thymic lobules house many lymphocytes. Most of these cells (thymocytes) are inactive; however, some mature into T lymphocytes (T cells), which leave the thymus and provide immunity. Epithelial cells in the thymus secrete hormones called thymosins, that affect the production, differentiation of certain white blood cells (lymphocytes) and stimulate maturation of T lymphocytes. In this way, the thymus plays an important role in immunity.

Figure 1. The location and structure of the thymus

Figure 2. Thymus location

Figure 3. Thymus anatomy

What does the thymus do

Thymus function

Lymphocyte production begins during fetal development and continues throughout life, with red bone marrow releasing unspecialized precursors to lymphocytes into the circulation. About half of these cells reach the thymus, where they specialize into T lymphocytes or T cells. After leaving the thymus, some of these T cells constitute 70% to 80% of the circulating lymphocytes in blood. Other T cells (T lymphocytes) reside in lymphatic organs and are particularly abundant in the lymph nodes, thoracic duct, and white pulp of the spleen.

Other lymphocytes remain in the red bone marrow until they differentiate into B lymphocytes, or B cells. The blood distributes B cells, which constitute 20% to 30% of circulating lymphocytes.

In addition, the thymus produces a hormone which has an immunotrophic effect, i.e. it endows cells having immunological potential with immunological competence. In humans it has been postulated that the tonsillar tissues may play an analogous role. Animal experiments involving extirpation of the immunotrophic lymphoid tissues have led to a better understanding of immunological deficiency diseases in man.

Figure 4. B Lymphocyte (B cell) and T Lymphocyte (T cell) production

T Cells and the Cellular Immune Response

A lymphocyte must be activated before it can respond to an antigen. T cell activation requires that processed fragments of the antigen be attached to the surface of another type of cell, called an antigen-presenting cell (accessory cell). Macrophages, B cells, and several other cell types can be antigen-presenting cells.

T cell activation may occur when a macrophage phagocytizes a bacterium and digests it within a phagolysosome formed by the fusion of the vesicle containing the bacterium (phagosome) and a lysosome. Some of the resulting bacterial antigens are then displayed on the macrophage’s cell membrane near certain protein molecules that are part of a group of proteins called the major histocompatibility complex (MHC). MHC antigens help T cells recognize that a newly displayed antigen is foreign (nonself).

Activated T cells interact directly with antigen-bearing cells. Such cell-to-cell contact is called the cellular immune response, or cell-mediated immunity. T cells (and some macrophages) also synthesize and secrete polypeptides called cytokines that enhance certain cellular responses to antigens. For example, interleukin-1 and interleukin-2 stimulate the synthesis of several other cytokines from other T cells. Additionally, interleukin-1 helps activate T cells, whereas interleukin-2 causes T cells to proliferate. This proliferation increases the number of T cells in a clone, which is a group of genetically identical cells that descend from a single, original cell. Other cytokines, called colony stimulating factors (CSFs), stimulate leukocyte production in red bone marrow and activate macrophages. T cells may also secrete toxins that kill their antigen-bearing target cells, growth-inhibiting factors that prevent target cell growth, or interferon that inhibits the proliferation of viruses and tumor cells. Several types of T cells have distinct functions.

A specialized type of T cell, called a helper T cell, is activated when its antigen receptor combines with a displayed foreign antigen (Figure 9). Once activated, the
helper T cell proliferates and the resulting cells stimulate B cells to produce antibodies that are specific for the displayed antigen.

Another type of T cell is a cytotoxic T cell, which recognizes and combines with nonself antigens that cancerous cells or virally infected cells display on their surfaces near certain MHC proteins. Cytokines from helper T cells activate the cytotoxic T cell. Next, the cytotoxic T cell proliferates. Cytotoxic T cells then bind to the surfaces of antigen-bearing cells, where they release perforin protein that cuts pore like openings in the cell membrane, destroying these cells. In this way, cytotoxic T cells continually monitor the body’s cells, recognizing and eliminating tumor cells and cells infected with viruses. Cytotoxic T cells provide much of the body’s defense against HIV infection.

Some cytotoxic T cells do not respond to a nonself antigen on first exposure, but remain as memory T cells that provide for future immune protection. Upon subsequent exposure to the same antigen, these memory cells immediately divide to yield more cytotoxic T cells and helper T cells, often before symptoms arise.

Figure 5. T-cell (T lymphocyte) activation

Steps in Antibody Production

T Cell (T Lymphocyte) Activities

1. Antigen-bearing agents enter tissues.
2. An accessory cell, such as a macrophage, phagocytizes the antigen-bearing agent, and the macrophage’s lysosomes digest the agent.
3. Antigens from the digested antigen-bearing agents are displayed on the membrane of the accessory cell.
4. Helper T cell becomes activated when it encounters a displayed antigen that fits its antigen receptors.
5. Activated helper T cell releases cytokines when it encounters a B cell that has previously combined with an identical antigen-bearing agent.
6. Cytokines stimulate the B cell to proliferate, enlarging its clone.
7. Some of the newly formed B cells give rise to cells that differentiate into antibody-secreting plasma cells.

Figure 6. B-cell activation

B Cell (B Lymphocyte) Activities

1. Antigen-bearing agents enter tissues.
2. B cell encounters an antigen that fits its antigen receptors.
3. Either alone or more often in conjunction with helper T cells, the B cell is activated. The B cell proliferates, enlarging its clone.
4. Some of the newly formed B cells differentiate further to become plasma cells.
5. Plasma cells synthesize and secrete antibodies whose molecular structure is similar to the activated B cell’s antigen receptors.

Antibody Actions

In general, antibodies react to antigens in three ways. Antibodies directly attack antigens, activate complement, or stimulate localized changes (inflammation) that help prevent the spread of pathogens or cells bearing foreign antigens.

In a direct attack, antibodies combine with antigens, causing them to clump (agglutination) or to form insoluble substances (precipitation). Such actions make it easier for phagocytic cells to recognize and engulf the antigen-bearing agents and eliminate them. In other instances, antibodies cover the toxic portions of antigen molecules and neutralize their effects (neutralization). However, under normal conditions, direct antibody attack is not as important as complement activation in protecting against infection.

When certain IgG or IgM antibodies combine with antigens, they expose reactive sites on antibody molecules. This triggers a series of reactions, leading to activation of the complement proteins, which in turn produce a variety of effects. These include:

• coating the antigen-antibody complexes (opsonization), making the complexes more susceptible to phagocytosis;
• attracting macrophages and neutrophils into the region (chemotaxis);
• rupturing membranes of foreign cells (lysis); agglutination of antigen-bearing cells; and
• neutralization of viruses by altering their molecular structure, making them harmless.

Other proteins promote inflammation, which helps prevent the spread of infectious agents.

Immune Responses

Activation of B cells or T cells after they first encounter the antigens for which they are specialized to react constitutes a primary immune response. During such a response, plasma cells release antibodies (IgM, followed by IgG) into the lymph. The antibodies are transported to the blood and then throughout the body, where they help destroy antigen bearing agents. Production and release of antibodies continues for several weeks.

Following a primary immune response, some of the B cells produced during proliferation of the clone remain dormant as memory cells. If the same antigen is encountered again, the clones of these memory cells enlarge, and they can respond rapidly by producing IgG to the antigen to which they were previously sensitized. These memory B cells, along with the memory cytotoxic T cells, produce a secondary immune response.

As a result of a primary immune response, detectable concentrations of antibodies usually appear in the blood plasma five to ten days after exposure to antigens. If the same type of antigen is encountered later, a secondary immune response may produce the same antibodies within a day or two. Although newly formed antibodies may persist in the body for only a few months or years, memory cells live much longer.

Naturally acquired active immunity occurs when a person exposed to a pathogen develops a disease. Resistance to that pathogen is the result of a primary immune response.

A vaccine is a preparation that produces artificially acquired active immunity. A vaccine might consist of bacteria or viruses that have been killed or weakened so that they cannot cause a serious infection, or only molecules unique to the pathogens. A vaccine might also be a toxoid, which is a toxin from an infectious organism that has been chemically altered to destroy its dangerous effects. Whatever its composition, a vaccine includes the antigens that stimulate a primary immune response, but does not produce symptoms of disease and the associated infections.

Specific vaccines stimulate active immunity against a variety of diseases, including typhoid fever, cholera, whooping cough, diphtheria, tetanus, polio, chickenpox, measles (rubeola), German measles (rubella), mumps, influenza, hepatitis A, hepatitis B, and bacterial pneumonia. A vaccine has eliminated naturally acquired smallpox from the world.

Autoimmunity

The immune response can turn against the body itself. It may become unable to distinguish a particular self antigen from a nonself antigen, producing  autoantibodies and cytotoxic T cells that attack and damage the body’s tissues and organs. This reaction against self is called autoimmunity.

The specific nature of an autoimmune disorder reflects the cell types that are the target of the immune attack. In type 1 (insulin dependent) diabetes mellitus the target is beta cells in the pancreas. The tissues within the joints are targeted in rheumatoid arthritis. In systemic lupus erythematosus the target is DNA and proteins associated with it in the cell nuclei. About 5% of the population has an autoimmune disorder.

Why might the immune response attack body tissues ?

Perhaps a virus, while replicating inside a human cell, takes proteins from the host cell’s surface and incorporates them onto its own surface. When the immune response “learns” the surface of the virus in order to destroy it, it also learns to attack the human cells that normally bear those particular proteins. Another explanation of autoimmunity is that somehow T cells never learn to distinguish self from nonself. A third possible route of autoimmunity is when a nonself antigen coincidentally resembles a self antigen.

What are lymph nodes

Along with red bone marrow, the lymph nodes are centers for lymphocyte production. Lymphocytes attack viruses, bacteria, and other parasitic cells that are brought to the lymph nodes by lymph in the lymphatic vessels. Lymph nodes are important for the proper functioning of the immune system, acting as filters for foreign particles and cancer cells. Macrophages in the lymph nodes engulf and destroy foreign substances, damaged cells, and cellular debris. Lymph nodes do not have a detoxification function, which is primarily dealt with by the liver and kidneys.

A lymph node or lymph gland is an ovoid or kidney-shaped organ of the lymphatic system that have two primary functions:

1. Filtering potentially harmful particles from lymph before returning it to the bloodstream, and
2. Monitoring body fluids (immune surveillance), a function performed by lymphocytes and macrophages.

A capsule of connective tissue encloses each lymph node and subdivides it into compartments. Lymph nodes contain large numbers of lymphocytes (B cells and T cells) and macrophages that fight invading microorganisms. Masses of B lymphocytes and macrophages in the cortex are contained within lymphatic nodules, also called lymphatic follicles, the functional units of the lymph node. The spaces within a node, called lymphatic sinuses, provide a complex network of chambers and channels through which lymph circulates.

Lymph nodes are generally in groups or chains along the paths of the larger lymphatic vessels throughout the body and each group drains a specific area of your body, but are absent in the central nervous system. Figure 1 shows the major locations of lymph nodes. You may be more likely to notice swelling in certain areas, such as in the lymph nodes in your neck, behind your ears, under your chin, in your armpits and in your groin. The site of the swollen lymph nodes may help identify the underlying cause.

Lymph nodes vary in size and shape, but are usually less than 2.5 centimeters long and somewhat bean-shaped (Figure 2 and 3). Blood vessels join a lymph node through the indented region of the lymph node, called the hilum. The lymphatic vessels leading to a lymph node (afferent vessels) enter separately at various points on its convex surface, but the lymphatic vessels leaving the lymph node (efferent vessels) exit from the hilum.

Figure 1. Locations of major lymph nodes

Figure 2. Functions of lymph nodes in the lymphatic system

Figure 3. Lymph node anatomy

The Lymphatic System

The lymphatic system is a vast collection of cells and biochemicals that travel in lymphatic vessels, and the organs and glands that produce them. The lymphatic system includes a network of vessels that assist in circulating body fluids, so it is closely associated with the cardiovascular system. Lymphatic vessels transport excess fluid away from interstitial spaces in most tissues and return it to the bloodstream (Figure 4). Without the lymphatic system, this fluid would accumulate in tissue spaces. Special lymphatic capillaries, called lacteals, are located in the lining of the small intestine. They absorb digested fats and transport them to the venous circulation.

The lymphatic system has a second major function— it enables you to live in a world with different types of organisms. Some of them live in or on the human body and in some circumstances may cause infectious diseases. Cells and biochemicals of the lymphatic system launch both generalized and targeted attacks against “foreign” particles, enabling the body to destroy infectious agents. This immunity against disease also protects against toxins and cancer cells. When the immune response is abnormal, persistent infection, cancer, allergies, and autoimmune disorders may result.

The larger lymphatic vessels lead to specialized organs called lymph nodes. After leaving the lymph nodes, the vessels merge to form still larger lymphatic trunks.

Figure 4. Schematic representation of lymphatic vessels transporting fluid from interstitial spaces to the bloodstream. Depending on its origin, lymph enters the right or left subclavian vein.

Lymph Movement

Lymph is essentially tissue fluid (interstitial fluid) that has entered a lymphatic capillary. Lymphatic capillaries are microscopic, closed-ended tubes that originate in the interstitial spaces of most tissues. Thus, lymph formation depends upon tissue fluid formation.

The walls of lymphatic vessels are similar to those of veins, but are thinner. Like some peripheral veins, lymphatic vessels have valves that help prevent backflow of lymph.

Filtration from the blood plasma normally exceeds reabsorption, leading to the net formation of tissue fluid. This accumulation of tissue fluid increases the tissue fluid hydrostatic pressure, which moves tissue fluid into lymphatic capillaries, forming lymph. Lymph returns to the bloodstream most of the small proteins that passed through the blood capillary walls. At the same time, lymph transports foreign particles, such as bacteria and viruses, to lymph nodes.

The hydrostatic pressure of tissue fluid drives lymph into lymphatic capillaries. However, muscular activity largely influences the movement of lymph through the lymphatic vessels. Lymph within lymphatic vessels, like venous blood, is under relatively low hydrostatic pressure and may not flow readily through the lymphatic vessels without help from contraction of skeletal muscles in the limbs, contraction of the smooth muscle in the walls of the larger lymphatic trunks, and pressure changes associated with breathing.

Contracting skeletal muscles compress lymphatic vessels. This squeezing action moves the lymph inside lymphatic vessels. Valves in these vessels prevent backflow, so lymph can only move toward a collecting duct. Additionally, smooth muscle in the walls of larger lymphatic trunks contracts rhythmically and compresses the lymph inside, forcing the fluid onward.

Breathing aids lymph circulation by creating a relatively low pressure in the thoracic cavity during inhalation. At the same time, the contracting diaphragm increases the pressure in the abdominal cavity. Consequently, lymph is squeezed out of the abdominal vessels and forced into the thoracic vessels. Once again, valves in lymphatic vessels prevent lymph backflow.

The continuous movement of fluid from interstitial spaces into blood and lymphatic capillaries stabilizes the volume of fluid in these interstitial spaces. Conditions that interfere with lymph movement cause tissue fluid to accumulate within the interstitial spaces, producing edema or swelling. Edema may develop when surgery removes lymphatic tissue, preventing lymph flow. For example, a surgeon removing a cancerous breast tumor may also remove nearby axillary lymph nodes to prevent associated lymphatic vessels from transporting cancer cells to other sites. Removing this lymphatic tissue can obstruct drainage from the upper limb, causing edema.

Figure 5. Lymph Movement

Where are lymph nodes

The body has approximately 600 lymph nodes, but only those in the submandibular (under the jaw), axillary (armpits) or inguinal (groin) regions may normally be palpable in healthy people ¹.

Common areas where the lymph nodes can be felt (with the fingers) include ²:

• Groin
• Armpit
• Neck (there is a chain of lymph nodes on either side of the front of the neck, both sides of the neck, and down each side of the back of the neck)
• Under the jaw and chin
• Behind the ears
• On the back of the head.

Swollen lymph nodes

The term “swollen glands” refers to enlargement of one or more lymph nodes. In general, lymph nodes greater than 1 cm in diameter are considered to be abnormal. The medical name for swollen lymph nodes is lymphadenopathy ³. In a child, a node is considered enlarged if it is more than 1 centimeter (0.4 inch) wide.

There are various classifications of swollen lymph nodes (lymphadenopathy), but a simple and clinically useful system is to classify swollen lymph nodes as “generalized” if lymph nodes are enlarged in two or more noncontiguous areas or “localized” if only one area is involved. Distinguishing between localized and generalized lymphadenopathy is important in formulating a differential diagnosis. In primary care patients with unexplained lymphadenopathy, approximately three fourths of patients will present with localized lymphadenopathy and one fourth with generalized lymphadenopathy.

Swollen lymph nodes by anatomic site:

Localized:

• Head and neck 55 percent
• Inguinal (groin) 14 percent
• Axillary (armpits) 5 percent
• Supraclavicular (above the clavicles) 1 percent

Generalized 25 percent.

Swollen lymph nodes usually occur as a result of exposure to bacteria or viruses ⁴. When swollen lymph nodes are caused by an infection, this is known as lymphadenitis. Rarely, swollen lymph nodes are caused by cancer.

Painful lymph nodes are generally a sign that your body is fighting an infection. The soreness usually goes away in a couple of days, without treatment. The lymph node may not return to its normal size for several weeks.

Superficial lymphatic vessels inflamed by bacterial infection appear as red streaks beneath the skin, a condition called lymphangitis. Inflammation of the lymph nodes, called lymphadenitis, often follows. In lymphadenopathy, affected lymph nodes enlarge and may be quite painful.

Your lymph nodes, also called lymph glands, play a vital role in your body’s ability to fight off infections. They function as filters, trapping viruses, bacteria and other causes of illnesses before they can infect other parts of your body. Common areas where you might notice swollen lymph nodes include your neck, under your chin, in your armpits and in your groin.

In some cases, the passage of time and warm compresses may be all you need to treat swollen lymph nodes. Treatment of lymphadenitis depends on the cause.

Causes of enlarged lymph nodes ⁵

Infections are the most common cause of swollen lymph nodes. Infections that can cause them include:

• Infected (abscessed) tooth or impacted tooth
• Ear infections
• Colds, flu, and other infections
• Swelling (inflammation) of gums (gingivitis)
• Mononucleosis
• Mouth sores
• Tonsillitis
• Strep throat
• Measles
• Skin or wound infections, such as cellulitis

Uncommon infections

• Tuberculosis
• Certain sexually transmitted infections, such as syphilis
• Toxoplasmosis — a parasitic infection resulting from contact with the feces of an infected cat or eating undercooked meat
• Cat scratch fever — a bacterial infection from a cat scratch or bite

Immune or autoimmune disorders that can cause swollen lymph nodes are:

• Human immunodeficiency virus (HIV) — the virus that causes AIDS
• Rheumatoid arthritis (RA) — a chronic inflammatory disease that targets the tissue that lines your joints (synovium)
• Lupus — a chronic inflammatory disease that can target your joints, skin, kidneys, blood cells, heart and lungs

Cancers that can cause swollen lymph nodes include:

• Leukemia
• Hodgkin disease
• Non-Hodgkin lymphoma. Many other cancers may also cause this problem.
• Other cancers that have spread (metastasized ) to lymph nodes.

Certain medicines can cause swollen lymph nodes, including ⁶:

• Seizure medicines such as phenytoin (Dilantin)
• Typhoid immunization
• Preventive medications for malaria.
• Allopurinol (Zyloprim)
• Atenolol (Tenormin)
• Captopril (Capozide)
• Carbamazepine (Tegretol)
• Cephalosporins
• Gold
• Hydralazine (Apresoline)
• Penicillin
• Primidone (Mysoline)
• Pyrimethamine (Daraprim)
• Quinidine
• Sulfonamides
• Sulindac (Clinoril)

Which lymph nodes are swollen depends on the cause and the body parts involved. Swollen lymph nodes that appear suddenly and are painful are usually due to injury or infection. Slow, painless swelling may be due to cancer or a tumor.

Table 1. Clues to the Diagnosis of Swollen Lymph Nodes (Lymphadenopathy)

Complications of swollen lymph nodes

If infection is the cause of your swollen lymph nodes and isn’t treated, these complications might occur:

• Abscess formation. An abscess is a localized collection of pus caused by an infection. Pus contains fluid, white blood cells, dead tissue and bacteria or other invaders. An abscess may require drainage and antibiotic treatment.
• Bloodstream infection (bacteremia). A bacterial infection anywhere in your body can progress to sepsis, which is an overwhelming infection of the bloodstream. Sepsis may progress to organ failure and death. Treatment involves hospitalization and intravenous antibiotics.

Symptoms of swollen lymph nodes

Many lymph nodes are located in your head and neck region. Lymph nodes that frequently swell are in this area, as well as in your armpits and groin area.

Swollen lymph nodes are a sign that something is wrong somewhere in your body. When your lymph nodes first swell, you might notice:

• Tenderness and pain in the lymph nodes
• Swelling that may be the size of a pea or kidney bean, or even larger in the lymph nodes

Depending on the cause of your swollen lymph nodes, other signs and symptoms you might have include:

• Runny nose, sore throat, fever and other indications of an upper respiratory infection
• General swelling of lymph nodes throughout your body — which may indicate an infection, such as HIV or mononucleosis, or an immune disorder, such as lupus or rheumatoid arthritis
• Hard, fixed, rapidly growing nodes, indicating a possible tumor
• Fever
• Night sweats

When to see a doctor

Some swollen lymph nodes return to normal when the underlying condition, such as a minor infection, gets better. See your doctor if you’re concerned or if your swollen lymph nodes ⁸:

• Have appeared for no apparent reason
• Continue to enlarge or have been present for two to four weeks
• Feel hard, irregular, rubbery, or don’t move (fixed in place) when you push on them
• They are red and tender.
• Any node in a child is larger than 1 centimeter (a little less than half inch) in diameter.
• You have persistent fever, night sweats or unexplained weight loss

Seek immediate medical care if you’re having difficulty swallowing or breathing.

Swollen lymph nodes Diagnosis

To diagnose what might be causing your swollen lymph nodes, your doctor may need:

• Your medical history. In addition, your doctor will want to know when and how your swollen lymph nodes developed and if you have any other signs or symptoms.
• A physical exam. Your doctor will also want to check lymph nodes near the surface of your skin for size, tenderness, warmth and texture. The site of your swollen lymph nodes and your other signs and symptoms will offer clues to the underlying cause.
• Blood tests. Depending on what your doctor suspects is causing your swollen lymph nodes, certain blood tests may be done to confirm or exclude the suspected underlying condition. The specific tests will depend on the suspected cause, but most likely will include a complete blood count (CBC). This helps evaluate your overall health and detect a range of disorders, including infections and leukemia.
• Imaging studies. A chest X-ray or computerized tomography (CT) scan of the affected area may help determine potential sources of infection or find tumors.
• Lymph node biopsy. Your doctor may have you undergo a biopsy. He or she will remove a sample from a lymph node or even an entire lymph node for microscopic examination.

When lymphadenopathy is localized, the clinician should examine the region drained by the nodes for evidence of infection, skin lesions or tumors.

Table 2. Lymph Node Groups: Location, Lymphatic Drainage and Selected Differential Diagnosis

If lymph nodes are detected, the following five characteristics should be noted and described:

Size. Nodes are generally considered to be normal if they are up to 1 cm in diameter; however, some authors suggest that epitrochlear nodes larger than 0.5 cm or inguinal nodes larger than 1.5 cm should be considered abnormal ⁹. Little information exists to suggest that a specific diagnosis can be based on node size. However, in one series10 of 213 adults with unexplained lymphadenopathy, no patient with a lymph node smaller than 1 cm2 (1 cm × 1 cm) had cancer, while cancer was present in 8 percent of those with nodes from 1 cm2 to 2.25 cm2 (1 cm × 1 cm to 1.5 cm × 1.5 cm) in size, and in 38 percent of those with nodes larger than 2.25 cm2 (1.5 cm × 1.5 cm). In children, lymph nodes larger than 2 cm in diameter (along with an abnormal chest radiograph and the absence of ear, nose and throat symptoms) were predictive of granulomatous diseases (i.e., tuberculosis, cat-scratch disease or sarcoidosis) or cancer (predominantly lymphomas) ¹⁰. These studies were performed in referral centers, and conclusions may not apply in primary care settings.

Pain/Tenderness. When a lymph node rapidly increases in size, its capsule stretches and causes pain. Pain is usually the result of an inflammatory process or suppuration, but pain may also result from hemorrhage into the necrotic center of a malignant node. The presence or absence of tenderness does not reliably differentiate benign from malignant nodes ¹¹.

Consistency. Stony-hard nodes are typically a sign of cancer, usually metastatic. Very firm, rubbery nodes suggest lymphoma. Softer nodes are the result of infections or inflammatory conditions. Suppurant nodes may be fluctuant. The term “shotty” refers to small nodes that feel like buckshot under the skin, as found in the cervical nodes of children with viral illnesses.

Matting. A group of nodes that feels connected and seems to move as a unit is said to be “matted.” Nodes that are matted can be either benign (e.g., tuberculosis, sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic carcinoma or lymphomas).

Location. The anatomic location of localized adenopathy will sometimes be helpful in narrowing the differential diagnosis. For example, cat-scratch disease typically causes cervical or axillary adenopathy, infectious mononucleosis causes cervical adenopathy and a number of sexually transmitted diseases are associated with inguinal adenopathy (Table 3).

Supraclavicular lymphadenopathy has the highest risk of malignancy, estimated as 90 percent in patients older than 40 years and 25 percent in those younger than age 40 ¹¹. Having the patient perform a Valsalva’s maneuver during palpation of the supraclavicular fossae increases the chance of detecting a node. Lymphadenopathy of the right supraclavicular node is associated with cancer in the mediastinum, lungs or esophagus. The left supraclavicular (Virchow’s) node receives lymphatic flow from the thorax and abdomen, and may signal pathology in the testes, ovaries, kidneys, pancreas, prostate, stomach or gallbladder. Although rarely present, a paraumbilical (Sister Joseph’s) node may be a sign of an abdominal or pelvic neoplasm ¹⁰.

In patients with generalized lymphadenopathy, the physical examination should focus on searching for signs of systemic illness. The most helpful findings are rash, mucous membrane lesions, hepatomegaly, splenomegaly or arthritis (Table 3). Splenomegaly and lymphadenopathy occur concurrently in many conditions, including mononucleosis-type syndromes, lymphocytic leukemia, lymphoma and sarcoidosis.

Table 3. Evaluation of Suspected Causes of Lymphadenopathy

Summary on causes of swollen lymph nodes (lymphadenopathy)

In most patients, lymphadenopathy has a readily diagnosable infectious cause. A diagnosis of less obvious causes can often be made after considering the patient’s age, the duration of the lymphadenopathy and whether localizing signs or symptoms, constitutional signs or epidemiologic clues are present. When the cause of the lymphadenopathy remains unexplained, a three- to four-week observation period is appropriate when the clinical setting indicates a high probability of benign disease.

Treatment swollen lymph nodes

Swollen lymph nodes caused by a virus may return to normal after the viral infection resolves. Antibiotics are not useful to treat viral infections. Treatment for swollen lymph nodes from other causes depends on the cause:

• Infection. The most common treatment for swollen lymph nodes caused by a bacterial infection is antibiotics. If your swollen lymph nodes are due to an HIV infection, you’ll receive specific treatment for that condition.
• Immune disorder. If your swollen lymph nodes are a result of certain conditions, such as lupus or rheumatoid arthritis, treatment is directed at the underlying condition.
• Cancer. Swollen nodes caused by cancer require treatment for the cancer. Depending on the type of cancer, treatment may involve surgery, radiation or chemotherapy.

Home remedies for swollen lymph nodes

If your swollen lymph nodes are tender or painful, you might get some relief by doing the following:

• Apply a warm compress. Apply a warm, wet compress, such as a washcloth dipped in hot water and wrung out, to the affected area.
• Take an over-the-counter pain reliever. These include aspirin, ibuprofen (Advil, Motrin, others), naproxen (Aleve) or acetaminophen (Tylenol, others). Use caution when giving aspirin to children or teenagers. Though aspirin is approved for use in children older than age 2, children and teenagers recovering from chickenpox or flu-like symptoms should never take aspirin. Talk to your doctor if you have concerns.
• Get adequate rest. You often need rest to aid your recovery from the underlying condition.

1. Goroll AH, May LA, Mulley AG Jr. Primary care medicine: office evaluation and management of the adult patient. 2d ed. Philadelphia: Lippincott, 1987.
2. Swollen lymph nodes. Medline Plus. https://medlineplus.gov/ency/article/003097.htm
3. Tower RL, Camitta BM. Lymphadenopathy. In: Kliegman RM, Stanton BF, St Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier; 2016:chap 490.
4. Swollen lymph nodes. Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/swollen-lymph-nodes/home/ovc-20258973
5. Armitage JO. Approach to the patient with lymphadenopathy and splenomegaly. In: Goldman L, Schafer AI, eds. Goldman’s Cecil Medicine. 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 168.
6. Pangalis GA, Vassilakopoulos TP, Boussiotis VA, Fessas P. Clinical approach to lymphadenopathy. Semin Oncol 1993; 20:570–82.
7. Lymphadenopathy: Differential Diagnosis and Evaluation. Am Fam Physician. 1998 Oct 15;58(6):1313-1320. http://www.aafp.org/afp/1998/1015/p1313.html
8. Symptoms and causes of Swollen lymph nodes. Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/swollen-lymph-nodes/symptoms-causes/dxc-20258981
9. Morland B. Lymphadenopathy. Arch Dis Child. 1995;73:476–9.
10. Slap GB, Brooks JS, Schwartz JS. When to perform biopsies of enlarged peripheral lymph nodes in young patients. JAMA. 1984;252:1321–6.
11. Fijten GH, Blijham GH. Unexplained lymphadenopathy in family practice. An evaluation of the probability of malignant causes and the effectiveness of physicians’ workup. J Fam Pract. 1988;27:373–6.