Lymphadenopathy overview

# Overview
Lymphadenopathy (also known as "enlarged lymph nodes") refers to lymph nodes which are abnormal in size, number, or consistency. Common causes of lymphadenopathy are infection, autoimmune disease, or malignancy. Lymphadenopathy may be classified according to distribution into 2 groups: generalized lymphadenopathy and localized lymphadenopathy. The pathogenesis of lymphadenopathy is characterized by the inflammation of lymph nodes. This process is primarily due to an elevated rate of trafficking of lymphocytes into the node from the blood, exceeding the rate of outflow from the node. Lymph nodes may also be enlarged secondarily as a result of the activation and proliferation of antigen-specific T and B cells (clonal expansion). Lymphadenopathy is very common,  the estimated incidence of lymphadenopathy among children in the United States ranges from 35%- 45%. Patients of all age groups may develop lymphadenopathy. Lymphadenopathy is more commonly observed among children. Common complications of lymphadenopathy, may include: abscess formation, superior vena cava syndrome, and intestinal obstruction.  Diagnostic criteria for malignant lymphadenopathy, may include: node > 2 cm, node that is draining, hard, or fixed to underlying tissue, atypical location (e.g. supraclavicular node), associated risk factors (e.g. HIV or TB), fever and/or weight loss, and splenomegaly. On the other hand, diagnostic criteria for benign lymphadenopathy, may include: node < 1 cm, node that is mobile, soft-or tender, and is not fixed to underlying tissue, typical location (e.g. supraclavicular node), no associated risk factors, and palpable and painful enlargement. Laboratory findings consistent with the diagnosis of lymphadenopathy may include elevated lactate dehydrogenase (LDH), mild neutropenia, and leukocytosis. There is no treatment for lymphadenopathy; the mainstay of therapy is treating the underlying condition.

# Historical Perspective

# Classification
Lymphadenopathy may be classified according to distribution into 2 groups localized lymphadenopathy and generalized lymphadenopathy.
Lymphadenopathy may be classified as follows:
- By location:
Tracheobronchial lymph nodes.
Mediastinal lymphadenopathy
Bilateral hilar lymphadenopathy
- Tracheobronchial lymph nodes.
- Mediastinal lymphadenopathy
- Bilateral hilar lymphadenopathy
- Dermatopathic lymphadenopathy: lymphadenopathy associated with skin disease.
- By malignancy: Benign lymphadenopathy is distinguished from malignant types which mainly refer to lymphomas or lymph node metastasis.
- By extent:
Localized lymphadenopathy: due to localized spot of infection
Generalized lymphadenopathy: due to systemic infection of the body. In some cases, it may persist for prolonged periods possibly without an apparent cause
- Localized lymphadenopathy: due to localized spot of infection
- Generalized lymphadenopathy: due to systemic infection of the body. In some cases, it may persist for prolonged periods possibly without an apparent cause
- By size, where lymphadenopathy in adults is often defined as a short axis of one or more lymph nodes is greater than 10mm.

# Pathophysiology
Lymph nodes are part of the immune system. As such, they are most readily palpable when fighting infections. Infections can either originate from the organs that they drain or primarily within the lymph node itself, referred to as lymphadenitis.*The pathogenesis of lymphadenopathy is characterized by the inflammation of lymph nodes. This process is primarily due to an elevated rate of trafficking of lymphocytes into the node from the blood, exceeding the rate of outflow from the node.
- The immune response between the antigen and lymphocyte that leads to cellular proliferation and enlargement of the lymph nodes.
- Lymph nodes may also be enlarged secondarily as a result of the activation and proliferation of antigen-specific T and B cells (clonal expansion).
- On gross pathology, characteristic findings of lymphadenopathy, include:
- Enlarged lymph node
- Soft greasy yellow areas within the capsule
Lymph nodes are a part of the reticuloendothelial (RES) system, which includes lymphatic vessels, the lymphatic fluid found in interstitial fluid, monocytes of the blood, macrophages of the connective tissue, bone marrow, thymus, spleen, bone, and  mucosa-associated lymphoid tissue (MALT) of visceral organs 
Lymphatic fluid moves throughout the lymphatic system and enters lymph nodes for filtration of foreign antigen. Foreign antigens are presented to the lymphoid cells, which lead to cellular proliferation and enlargement. Under microscopy, cellular proliferation in lymphoid follicles may be identified as several mitotic figures. Increased activity leads to stretching of the lymphatic capsule and this may cause localized tenderness.
The development of B-cells originates from pluripotent stem cells from the bone marrow. B cells that successfully build their immunoglobulin heavy chains migrate to the germinal centers to allow for antibody diversification by somatic hypermutation. The current school of thought is that B-cell lymphomas occur as a result of alternations in chromosomal translocations and somatic hypermutation.
T-cell development also begins from pluripotent stem cells, which mature within the thymic cortex.  While they are in the thymic cortex, specific rearrangements occur at the T-cell receptor. It is understood that chromosomal translocations at the level of T-cell receptors lead to T-cell lymphomagenesis.
Lymph nodes follicle necrosis may occur due to inflammatory, infectious, or malignant conditions. The neutrophil-rich infiltrates suggests bacterial infection, while lymphocyte-rich predominance may suggest viral infection. However, clinicians must remember that etiologies may vary; lymphomas, leukemias, tuberculosis, or even systemic lupus erythematosus (SLE) may be more appropriate diagnoses in the appropriate clinical context

# Causes
The most common causes of lymphadenopathy include infections, cancers, and connective tissue disorders.
Lymph node enlargement can be of viral, bacterial, malignant, protozoan origin and can even be caused by live vaccines 
Examples of infections that can cause lymph node enlargement include:
- Viral infections such as Epstein-Barr Virus and cytomegalovirus which cause infectious mononucleosis, and CMV mononucleosis respectively.
as well HHV8 and HIV.
- Yersinia pestis, which causes the bubonic plague, causes lymph node swelling so large that it can be seen under the skin. These lymph nodes are called buboes and may become necrotic.
- Other bacterial infections such as cat-scratch disease, cutaneous anthrax, and tuberculous lymphadenitis
- Protozoal infections including African sleeping sickness, Chagas' Disease,  and toxoplasmosis.
Examples of malignancies that cause lymphadenopathy are:
- Primary: Hodgkin lymphoma and non-Hodgkin lymphoma give lymphadenopathy in all or a few lymph nodes.
- Secondary: metastasis, Virchow's Node, neuroblastoma, and chronic lymphocytic leukemia.
Autoimmune causes include: systemic lupus erythematosus and rheumatoid arthritis may have generalized lymphadenopathy.

## Benign lymphadenopathy
Examples include:
- Reactive Follicular hyperplasia
- Atypical Follicular Hyperplasia
- IgG4-related sclerosing disease-associated lymphadenopathy
- Paracortical hyperplasia/Interfollicular hyperplasia: It is seen in viral infections, skin diseases, and nonspecific reactions.
- Sinus histiocytosis: It is seen in lymph nodes draining limbs, inflammatory lesions, and malignancies.
- Benign lymphadenopathy with extensive necrosis
Axillary lymphadenopathy can be defined as solid nodes measuring more than 15  mm without fatty hilum. Axillary lymph nodes may be normal up to 30  mm if consisting largely of fat.
In children, a short axis of 8  mm can be used. However, inguinal lymph nodes of up to 15  mm and cervical lymph nodes of up to 20  mm are generally normal in children up to age 812.
Lymphadenopathy of more than 1.5  cm - 2  cm increases the risk of cancer or granulomatous disease as the cause rather than only inflammation or infection. Still, increasing size and persistence over time are more indicative of cancer.

# Differentiating Lymphadenopathy from Other Diseases
Lymphadenopathy must be differentiated from syphilis, which may present as fever, myalgias, weight loss, and lymph node enlargement.
After a thorough history and physical examination, lymphadenopathy can be initially categorized as:
Diagnostic: wherein the practitioner has a proximal cause for the lymph nodes and can go on to treat them. Examples would be Strep pharyngitis or localized cellulitis.
The lymphadenopathy pattern history and physical examination can be suggestive an example would be mononucleosis wearing the practitioner has a strong clinic index of suspicion can perform a confirmatory test which if positive he can go on and treat the patient.
Unexplained lymphadenopathy.
Unexplained lymphadenopathy can be generalized into localized or generalized lymphadenopathy.
Unexplained localized lymphadenopathy is further divided into patterns at no risk for malignancy or severe illness in which case the patient can be observed for 3 to 4 weeks and if a response or improvement can be followed. The other alternative is if the patient is found to have a risk formalignancy or serious illness biopsy is indicated
Unexplained generalized lymphadenopathy can be approached after a review of epidemiological clues and medications with initial testing with a CBC with manual differential and mononucleosis serology if either is positive and diagnostic proceed to treatment. If both are negative, the second workup approach would be a PPD, and RPR, a chest x-ray, and ANA, hepatitis BS antigen serology and HIV. Additional testing modalities and lab tests may be indicated depending on clinical cues. If the results of this testing are conclusive, the practitioner can proceed on to diagnosis and treatment of the illness. If the results of the testing are still not clear, proceed to biopsy of the most abnormal of the nodes. The most functional way to investigate the differential diagnosis of lymphadenopathy is to characterize it by node pattern and location, obtained pertinent history including careful evaluation of epidemiology, and place the patient in the appropriate arm of the algorithm to evaluate lymphadenopathy.

# Epidemiology and Demographics
The estimated incidence of lymphadenopathy in children in the United States ranges from 35%- 45%. It is more common in the pediatric population. Race and gender have no predilection in lymphadenopathy incidence.
Generalities can safely be made about the epidemiology of lymphadenopathy. First, both generalized and localized lymphadenopathies are fairly equally distributed without regard to gender.  Second, lymphadenopathy is more prevalent in the pediatric population than in the adult population secondary to the greater number of viral infections. It would follow that the majority of the time, lymphadenopathy in the pediatric population is of less consequence again secondary to the prevalence of viral and bacterial infections in that age group. Three-quarters of all lymphadenopathy observed are localized, and of those three-quarters, half of these are localized to the head and neck area. All remaining localized lymphadenopathy is found in the inguinal area and the remaining lymphadenopathy is found in the axilla in the supraclavicular area. Of note, the differential diagnosis of lymphadenopathy changes significantly with the age of the patient.  Third, the patient's location and circumstance are very revealing and lymphadenopathy. For example, in the developing world (sub-Saharan Africa, Southeast Asia, Indian subcontinent), exposure to parasites, HIV, and miliary TB are far more likely to be causes of generalized lymphadenopathy than in the United States and Europe. Whereas, Epstein-Barr virus, streptococcal pharyngitis, and some neoplastic processes are more likely candidates to cause lymphadenopathy in the United States and the remainder of the localized industrial world. An exposure history is very important for diagnosis.  Exposure to blood and blood-borne products either through transfusion, unsafe sexual practices, intravenous drug abuse, or vocation Exposure to infectious disease whether it be travel, in the workplace, or the home Medication exposure-prescription, nonprescription, or supplements Exposure to animal-borne illness either via pets or the workplace Exposure to arthropod bites

# Risk Factors
Common risk factors in the development of lymphadenopathy may be occupational, environmental, genetic, and viral.

# Screening
There is insufficient evidence to recommend routine screening for lymphadenopathy

# Natural History, Complications, and Prognosis
The natural course of lymphadenopathy depends on the underlying cause. Lymphadenopathy due to infectious causes subsides once the infection is controlled. Common complications of lymphadenopathy depend on the site of involvement, e.g. mediastinal lymphadenopathy include compression symptoms likeTracheal and bronchial obstruction and Dysphagia in Superior vena cava syndrome. Prognosis is generally excellent for infectious causes. Prompt treatment with antibiotics usually leads to a complete recovery. However, it may take weeks, or even months, for swelling to disappear. The amount of time to recovery depends on the cause. Prognosis is poor for malignant tumors.

# Diagnosis

## Diagnostic Criteria

### Malignant Lymphadenopathy
- Node > 2 cm
- Node that is draining, hard, or fixed to underlying tissue
- Atypical location (e.g. supraclavicular node)
- Risk factors (e.g. HIV or TB)
- Fever and/or weight loss
- Splenomegaly

### Benign Lymphadenopathy
- Node < 1 cm
- Node that is mobile, soft-or tender, and is not fixed to underlying tissue
- Common location (e.g. supraclavicular node)
- No associated risk factors
- Palpable and painful enlargement

## History and Symptoms
The hallmark of lymphadenopathy is swollen lymph node. A positive history of a lump in the neck, red, tender skin over lymph node, and swollen, tender, or hard lymph nodes is suggestive of lymphadenopathy. The most common symptoms of lymphadenopathy include a lump in neck or affected part and constitutional symptoms like fatigue, fever, malaise, flu- like illness, nausea and vomiting, night sweats, weight loss, and cachexia.

## Physical Examination
Common physical examination findings of lymphadenopathy include fever and tachycardia in infectious causes. There is an enlargement of different groups of lymph node chains depending upon the site of involvement and underlying causes.

## Laboratory Findings
- CBC with manual differential: This is a foundational test in the diagnosis of both generalized and regional lymphadenopathy. The number and differential of the white blood cells can indicate bacterial, viral, or fungal pathology. In addition, characteristic white blood cell (WBC) patterns are observed with several of the hematological neoplasms producing lymphadenopathy
- EBV serology: Epstein-Barr viral mono is present causing regionalized lymphadenopathy
- Sedimentation rate: A measure of inflammation though not diagnostic, can contribute to diagnostic reasoning
- Cytomegalovirus titers: This viral serology is indicative of possible CMV mononucleosis
- HIV serology: This serology can be used to diagnose acute HIV syndrome-related lymphadenopathy or to infer the diagnosis of secondary HIV-elated pathologies causing lymphadenopathy.
- Bartonella henselae serology: used for the diagnosis of cat-scratch lymphadenopathy
- FTA\RPR: These tests can diagnose syphilis as the cause of lymphadenopathy
- Herpes simplex serology: can determine if the lymphadenopathy is herpes-related. Herpes simplex can produce symptoms that are similar to mononucleosis.
- Toxoplasmosis serology: can be used to diagnose toxoplasmosis
- Hepatitis B serology: Serological tests for hepatitis B to establish it as a contributing factor for lymphadenopathy
- ANA: this is a screening test for SLE that can help establish it as a cause for generalized lymphadenopathy

## Electrocardiogram

## X-ray
Chest X-ray can reveal tuberculosis, pulmonary sarcoidosis, and pulmonary neoplasm.

## Echocardiography and Ultrasound
Ultrasound can help in the diagnosis of lymphadenopathy to define the presence and extent of a lymph node abscess, to differentiate malignant lymph nodes from lymph node enlargement due to infections. On ultrasound, characteristic findings of lymphadenopathy, include increased lymph node size. In the assessment of number, size, form, marginal description, and internal structures in patients with lymphadenopathy, this imaging modality can be used. Furthermore, color Doppler ultrasonography is used to differentiate between older pre-existing lymphadenopathy and newly active lymphadenopathy in the vascular pattern.

## CT scan
A Chest CT scan may be helpful in the diagnosis of hilar adenopathy. Findings on CT scan suggestive of/diagnostic of tuberculosis, sarcoidosis, lymphoma, and other malignancies. Abdominal and pelvic CT scan in combination with chest CT scan can be revealed in cases of supraclavicular adenopathy and the diagnosis of secondary neoplasm.

## MRI
MRI may be helpful in the diagnosis of lymphadenopathy. Findings on MRI suggestive of/diagnostic of lymphadenopathy include negative enhancement that is showed as decreased T1 and T2 signal intensity.

## Other Imaging Findings

## Other Diagnostic Studies

# Treatment
Treatment of lymphadenopathy is based on the etiology. Generally, treatment of lymphadenopathy is as follows:
- Infectious causes of lymphadenopathy can be treated with antibiotic therapy, antiviral therapy, or antifungal therapy.
- Immune therapy, systemic glucocorticoids can be used for autoimmune causes of lymphadenopathy
- For malignancies, any combination of surgery, chemotherapy, and radiation therapy can be used.
- If medication is the suspected cause, discontinue the medication if possible.

## Medical Therapy
The medical therapy depends upon the underlying cause. Appropriate antibiotics are given for infective causes. Glucocorticoids for autoimmune conditions like sarcoidosis, and chemotherapy and radiation for malignant causes.

## Surgery
Surgery is not the first-line treatment option for patients with lymphadenopathy. Surgery is usually reserved for patients with either malignancy and an indication of biopsy. It involves the removal or aspiration of lymph nodes. They are dissected when  cancer is in an advanced stage.

## Primary Prevention
Good general health and hygiene are helpful in the prevention of any infection.

## Secondary Prevention
Effective measures for the secondary prevention of lymphadenopathy include sentinel lymph node biopsy and early treatment if metastasis is detected.