Lymphadenopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2],, Raviteja Guddeti, M.B.B.S. [3]Delband Yekta Moazami, M.D.[4]

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.

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
• 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

• By size, where lymphadenopathy in adults is often defined as a short axis of one or more lymph nodes is greater than 10mm.

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

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.

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 8–12.

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.

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.

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

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

There is insufficient evidence to recommend routine screening for lymphadenopathy

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.

• 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

• 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

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.

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.

• 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

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

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.

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 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.

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.

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 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.

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

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

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2], Raviteja Guddeti, M.B.B.S. [3]Delband Yekta Moazami, M.D.[4] Ogechukwu Hannah Nnabude, MD

Lymphadenopathy may be classified according to distribution into 2 groups localized lymphadenopathy and generalized lymphadenopathy.

Depending upon the involvement of the lymph nodes, lymphadenopathy is classified into 2 groups, generalized and localized:^[1]

• Localized lymphadenopathy: localized adenopathy occurs in contiguous groupings of lymph nodes. In discrete anatomical regions, lymph nodes are distributed, and their enlargement represents their location’s lymphatic drainage. Tender or non-tender, fixed or mobile, and discreet or “matted” together can be the nodes themselves. 75 percent of all lymphadenopathies are localized, with over 50% seen in the region of the head and neck.

• Generalized lymphadenopathy: generalized lymphadenopathy involves lymphadenopathy in 2 or more non-contiguous sites. due to generalized infection all over the body e.g. influenza.
• Persistent generalized lymphadenopathy (PGL): persisting for a long time, possibly without an apparent cause.
• Dermatopathic lymphadenopathy: lymphadenopathy associated with skin disease. Tangier disease (ABCA1 deficiency) may also cause this.

Lymphadenopathy may be classified as follows:

• Location:
  • Tracheobronchial lymph nodes.
  • Mediastinal lymphadenopathy
  • Bilateral hilar lymphadenopathy
• Dermatopathic lymphadenopathy: lymphadenopathy associated with skin disease.
• Malignancy: Benign lymphadenopathy is distinguished from malignant types which mainly refer to lymphomas or lymph node metastasis.

• 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

• Size, where lymphadenopathy in adults is often defined as a short axis of one or more lymph nodes is greater than 10mm.^[2][3]

Upper limit of lymph node sizes in adults

Generally	10 mm[4][5]
Inguinal	10[6] – 20 mm[7]
Pelvis	10 mm for ovoid lymph nodes, 8 mm for rounded[6]
Neck
Generally (non-retropharyngeal)	10 mm[6][8]
Jugulodigastric lymph nodes	11mm[6] or 15 mm[8]
Retropharyngeal	8 mm[8] Lateral retropharyngeal: 5 mm[6]
Mediastinum
Mediastinum, generally	10 mm[6]
Superior mediastinum and high paratracheal	7mm[9]
Low paratracheal and subcarinal	11 mm[9]
Upper abdominal
Retrocrural space	6 mm[10]
Paracardiac	8 mm[10]
Gastrohepatic ligament	8 mm[10]
Upper paraaortic region	9 mm[10]
Portacaval space	10 mm[10]
Porta hepatis	7 mm[10]
Lower paraaortic region	11 mm[10]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Delband Yekta Moazami, M.D.[3] Ogechukwu Hannah Nnabude, MD

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.

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.^[1]

• 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 ^[1]

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.^[2] 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.^[3] 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. ^[4] 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 ^[5]

• On microscopic histopathological analysis, characteristic findings of lymphadenopathy will depend on the etiology.Common findings, include:^[1]

Non-specific reactive follicular hyperplasia (NSRFH)

• Large spaced cortical follicles
• Tingible body macrophages, normal dark/light GC pattern

Lymph node metastasis

• Foreign cell population (usually in subcapsular sinuses)
• +/-nuclear atypia
• +/-malignant architecture

Toxoplasmosis

• Large follicles
• Epithelioid cells perifollicular & intrafollicular
• Reactive GCs
• Monocytoid cell clusters

Cat-scratch disease

• PMNs in necrotic area
• “Stellate” (or serpentine) shaped micro-abscesses
• Presence of granulomas

Dermatopathic lymphadenopathy

• Melanin-laden histiocytes
• Histiocytosis

Systemic lupus erythematosus lymphadenopathy

• Blue hematoxylin bodies
• Necrosis
• No PMNs

Histology can provide more information regarding the cause of lymphadenopathy when etiology is not clear during initial history taking, physical examination, and laboratory evaluation.

Common causes of lymphadenopathy with their associated histological findings include:

• Bacterial lymphadenitis: Neutrophil-rich infiltrate can be found within the sinus and medullary cords. Follicular hyperplasia can be seen as well. ^{[6] [7]}
• Viral lymphadenopathy: Macrophage infiltration and lymphoid hyperplasia. Necrosis can be seen in those who are immunocompromised.^[8]
• Sarcoidosis: non-caseating granulomas that replace the normal architecture of the lymph node
• Non-Hodgkin lymphoma: There is partial or widespread loss of the lymph node by a single cell lineage. Lymphoid cells can either proliferate in a disorderly manner or as those that mimic follicular center structures.
• Hodgkin lymphoma: Can be classified by the histological appearance (from most common to least):^[9]
  • Nodular-sclerosing
  • Mixed cellularity
  • Lymphocyte-rich
  • Lymphocyte-depleted

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2]Raviteja Guddeti, M.B.B.S. [3]Delband Yekta Moazami, M.D.[4] Ogechukwu Hannah Nnabude, MD

The most common causes of lymphadenopathy include infections, cancers, and connective tissue disorders. The enlargement of the lymph nodes may be of infectious, bacterial, malignant, protozoan origin and may also be caused by live vaccines. Viral infections such as Epstein-Barr virus and cytomegalovirus cause infectious mononucleosis. Yersinia pestis causes swelling of the lymph node so large that it can be seen under the skin, which causes the bubonic plague. These lymph nodes can become necrotic and are called buboes. Cat-scratch disease, cutaneous anthrax, and tuberculous lymphadenitis are other bacterial infections. African sleeping sickness, Chagas’ disease, and toxoplasmosis are protozoal infections. Neoplastic causes of lymphadenopathy are primary and secondary. 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.

Common causes of lymphadenopathy may include:

• Acute infections (e.g. bacterial, or viral)
  • Infectious mononucleosis(cervical lymph nodes)
• Chronic infections:
  • tuberculous lymphadenitis
  • cat-scratch disease
  • AIDS – generalized lymphadenopathy^[1]
• Toxoplasmosis, a parasitic disease, gives a generalized lymphadenopathy^[2]
• Cancers:^[2]
  • Hodgkin lymphoma
  • non-Hodgkin lymphoma
  • hairy cell leukemia, ( all or a few lymph nodes )
• Metastasis
• Connective tissue disorders:
  • Sarcoidosis
  • Systemic lupus erythematosus (SLE)
  • Rheumatoid arthritis

Cardiovascular	Apo a-i deficiency
Chemical/Poisoning	Anthrax, Black widow spider venom, Zinc
Dental	Lip cancer
Dermatologic	Aphthous stomatitis, Asymmetric periflexural exanthem , Dermatomyositis, Erysipelas, Erythroderma, Gingivostomatitis, Infantile papular acrodermatitis, Leprosy, Mastitis, Measles, Melanoma, Mumps, Sarcoidosis, Spotted fevers, Yaws
Drug Side Effect	Allopurinol, Atenolol, Bcg vaccine, Captopril, Carbamazepine, Cephalosporins, Certolizumab pegol, Hydralazine, Infliximab, Oxaprozin, Penicillin, Penicillium marneffei, Phenytoin, Pinta, Pneumococcal vaccine 13-valent  , Primidone, Pyrimethamine, Quinidine, Sulfonamides, Sulindac, Tiagabine, Typhoid vaccination
Ear Nose Throat	Aphthous stomatitis, Kikuchi’s disease, Lymphangioma, Lymphangitis, Lymphatic filariasis, Lymphoma, Malignant lymphoma, Mesenteric adenitis, Sinus histiocytosis, Streptococcal pharyngitis, Vincent’s angina
Endocrine	Castleman’s disease, Chediak-higashi syndrome, Hyperthyroidism
Environmental	No underlying causes
Gastroenterologic	Brucellosis, Colorectal cancer, Hemophagocytic lymphohistiocytosis, Stomach cancer, Whipple’s disease
Genetic	Chediak-higashi syndrome, Churg-strauss syndrome, Faisalabad histiocytosis, Familial alphalipoprotein deficiency, Familial hemophagocytic lymphohistiocytosis, Familial histiocytic reticulosis, Griscelli disease, Lipogranulomatosis, Rosai-dorfman disease, Siccardi syndrome, Sphingomyelinase deficiency, Wt limb blood syndrome, X-linked agammaglobulinaemia, X-linked lymphoproliferative syndrome
Hematologic	Acute lymphatic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Addison’s disease, Adult t cell leukemia, Apo a-i deficiency, Autoimmune haemolytic anaemia, Autoimmune lymphoproliferative syndrome type 1, Caspase-8 deficiency, Chancroid, Chronic lymphatic leukemia, Chronic lymphocytic leukemia, Churg-strauss syndrome, Cutaneous t cell lymphoma, Familial alphalipoprotein deficiency, Familial hemophagocytic lymphohistiocytosis, Familial histiocytic reticulosis, Hairy cell leukaemia, Hemoblastosis, Histiocytosis x, Hodgkin’s lymphoma, Hyperimmunoglobulinemia d , Kawasaki disease, Large granular lymphocyte leukemia, Lassa fever, Leukemia, Macroglobulinemia, Myeloproliferative disorder, Non-hodgkin’s lymphoma, Plasma cell leukemia, Primary autoimmune haemolytic anaemia, Pseudolymphoma, Septicaemia, Siccardi syndrome, Sinus histiocytosis, Waldenström macroglobulinemia, Yersinia pestis
Iatrogenic	Bcg vaccine, Pneumococcal vaccine 13-valent  , Radiotherapy, Typhoid vaccination
Infectious Disease	Bacteria: Anthrax, Borrelia burgdorferi, Boutonneuse fever, Brucellosis, Cat scratch disease, Congenital tuberculosis, Erysipelas, Granuloma inguinale, Lepromatous leprosy, Listeriosis, Lymphogranuloma venereum,Mastitis, Moraxella catarrhalis, Mycobacterium avium-intracellulare, Mycobacterium chelonei, Pinta,Plague, Rat-bite fever, Rickettsiae, Scrub typhus, Sennetsu fever, Septicaemia, Spotted fevers,Streptococcal tonsillitis, Syphilis, Three-day fever, Tuberculosis, Tularemia, Typhus fever, Vincent’s angina, Yaws, Yersinia pestis Virus: AIDS, Cowpox, Coxsackie virus, Cytomegalovirus infection, Dengue, German Measles/Rubella, Hepatitis A, Hepatitis B, Herpes simplex, Infectious mononucleosis, Influenza, Lassa fever, Measles, Mumps,Smallpox, Varicella, Western equine encephalitis Fungal: Coccidioidomycosis, Blastomycosis, Histoplasmosis, Sporotrichosis Parasitic: African Sleeping sickness, Chagas’ disease, Congenital Toxoplasmosis, Filaria, Lymphatic filariasis,Onchocerciasis, Opisthorchiasis, Paracoccidioidomycosis, Rhabditida Infections, Toxoplasmosis,Trypanosomiasis, Visceral leishmaniasis /Kala-azar, Wuchereria bancrofti
Musculoskeletal/Orthopedic	Dermatomyositis, Rhabdomyosarcoma, Rheumatoid arthritis
Neurologic	African sleeping sickness, Western equine encephalitis
Nutritional/Metabolic	Lipogranulomatosis
Obstetric/Gynecologic	Breast cancer, Lymphogranuloma venereum
Oncologic	Acute lymphatic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Addison’s disease, Adult t cell leukemia, Breast cancer, Chronic lymphatic leukemia, Chronic lymphocytic leukemia, Colorectal cancer, Cutaneous t cell lymphoma, Cystic hygroma, Epstein-barr virus, Gamma heavy chain disease, Granuloma inguinale, Hemangiopericytoma, Hodgkin’s lymphoma, Inflammatory pseudotumor, Kikuchi’s disease, Leukemia, Lip cancer, Lymphangioma, Lymphoma, Malignant lymphoma, Melanoma, Merkel cell carcinoma, Myeloproliferative disorder, Non-hodgkin’s lymphoma, Pancoast tumor, Plasma cell leukemia, Primary autoimmune haemolytic anaemia, Pseudolymphoma, Reticuloendotheliosis, Rhabdomyosarcoma, Secondary deposits from a local malignancy, Stomach cancer, Systemic mastocytosis, Waldenström macroglobulinemia
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Congenital tuberculosis, Extrinsic allergic alveolitis, Histoplasmosis, Pancoast tumor, Pneumoconiosis, Tuberculosis
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	Amyloidosis, Extrinsic allergic alveolitis, Hemangiopericytoma, Hemophagocytic lymphohistiocytosis, Hemophagocytic reticulosis, Juvenile chronic arthritis, Rheumatoid arthritis, Rheumatoid disease, Still’s disease, Systemic lupus erythematosus
Sexual	Aids, Bejel, Chancroid, Herpes simplex, Herpes virus 2, Hiv-1 disease, Human immunodeficiency virus, Secondary syphilis, Sexually transmitted diseases, Syphilis
Trauma	Snake bite , Spider bite
Urologic	Granuloma inguinale
Miscellaneous	Tang hsi ryu syndrome

• Common causes of lymphadenopathy, include:^[3][4]

• Infections (acute suppurative)

• Fungal
• Mycobacterial
• Viral
• Protozoal (e.g. toxoplasma)
• Bacterial (e.g. chlamydia, rickettsia, bartonella)

• Reactive

• Follicular hyperplasia
• Paracortical hyperplasia
• Sinus histiocytosis
• Granulomatous
• Neoplastic
• Drugs (e.g. cyclosporin, phenytoin, methotrexate)
• Lipid storage diseases
• IgG4-related sclerosing disease

Various causes in alphabetical order:^[5][6]

Acute lymphoblastic leukemia Acute lymphocytic leukemia Adult T cell leukemia African Sleeping sickness[7] AIDS[8] Amyloidosis Angioimmunoblastic lymphadenopathy[9] Anthrax Aphthous stomatitis Apo A-I deficiency[10] Autoimmune lymphoproliferative syndrome type 1[11] BCG vaccine Bejel Black widow spider envenomation Borrelia burgdorferi Boutonneuse fever[12] Breast cancer Brucellosis[13] Caspase-8 deficiency Castleman’s disease[14] Cat scratch disease[15] Certolizumab pegol Chagas’ disease Chediak-Higashi syndrome[16][17] Chronic lymphocytic leukemia Churg-Strauss syndrome Coccidioidomycosis Colorectal cancer Common Variable Immunodeficiency[18] Congenital Toxoplasmosis Congenital tuberculosis Cowpox Coxsackie virus infections Cutaneous leishmaniasis Cutaneous T cell lymphoma Cystic hygroma Cytomegalovirus infection Dengue Drug reaction Erysipelas Erythroderma[19] Extrinsic allergic alveolitis Faisalabad histiocytosis Familial alphalipoprotein deficiency Familial hemophagocytic lymphohistiocytosis[20] Familial histiocytic reticulosis[21] Filaria Fungal blastomycosis Gamma heavy chain disease[22] German Measles Gingivostomatitis Granuloma inguinale Griscelli disease[16] Hairy cell leukaemia

Hemangiopericytoma[23] Hemoblastosis[24] Hemophagocytic reticulosis Hepatitis A Hepatitis B Herpes simplex Histiocytosis X[25] Histoplasmosis Hodgkin’s Lymphoma Hyperimmunoglobulinemia D and periodic fever syndrome Hyperthyroidism Idiopathic Infantile papular acrodermatitis Infectious mononucleosis Infliximab Influenza Juvenile chronic arthritis Large granular lymphocyte leukemia Lassa fever Leishmaniasis Lepromatous leprosy Leukemia Lip cancer Lipogranulomatosis Listeriosis[26] Lymphangioma Lymphatic filariasis Lymphogranuloma venereum[27] Lymphoma Macroglobulinemia[28] Malignant lymphoma Metastasis Mastitis Measles Melanoma Merkel cell carcinoma Mesenteric adenitis Moraxella catarrhalis Mucocutaneous leishmaniasis Mumps Mycobacterium avium-intracellulare[29] Mycobacterium chelonae Mycosis fungoides[19] Myeloproliferative disorder Non-Hodgkin’s Lymphoma Onchocerciasis Opisthorchiasis Oxaprozin Pancoast tumor Paracoccidioidomycosis Penicillium marneffei Phenytoin Pinta Plague Plasma cell leukemia Pneumococcal Vaccine 13-Valent (Prevnar 13): in infants and toddlers Pneumoconiosis

Autoimmune haemolytic anaemia Protozoa Pseudolymphoma Radiotherapy Rat-bite fever Reticuloendotheliosis Rhabditida Infections Rhabdomyosarcoma Rheumatoid arthritis Rickettsiae Rubella Sarcoidosis Scrub typhus Secondary syphilis Sennetsu fever Septicaemia Serum sickness Siccardi syndrome Sinus histiocytosis[30] SLE Smallpox Snake bite (Viperidae) Sphingomyelinase deficiency[31] Spider bite Sporotrichosis Spotted fevers Sexually transmitted diseases Still’s Disease – Juvenile-Onset Stomach cancer Streptococcal tonsillitis Syphilis Systemic lupus erythematosus Systemic mastocytosis Tang Hsi Ryu syndrome[32] Three-day fever[33] Tiagabine Toxoplasmosis Trypanosomiasis Tuberculosis Tularemia Typhus fever Vaccination Varicella Vincent’s angina Visceral leishmaniasis / Kala-azar Waldenström macroglobulinemia[28] Western equine encephalitis Whipple’s disease WT limb blood syndrome Wuchereria bancrofti X-linked agammaglobulinaemia X-linked lymphoproliferative syndrome Yaws Yersinia pestis

• The common causes can divide into the following:
  • Tuberculosis
  • Sarcoidosis
  • Lymphoma
  • Other malignancies

• Less common causes include:
  • Churg-Strauss syndrome
  • Human Immunodeficiency Virus
  • Extrinsic allergic alveolitis
  • Pneumoconiosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[5] Ogechukwu Hannah Nnabude, MD

Lymphadenopathy can be caused by different disease categories include: neoplasms, such as lymphoma; bacterial, viral, and parasite diseases; and inflammatory conditions, such as systemic lupus erythematosus.

Lymphadenopathy can be caused by different disease categories include: neoplasms such as lymphoma; bacterial, viral, and parasites diseases; and inflammatory conditions, such as systemic lupus erythematosus.

Diseases		Clinical manifestations							Para-clinical findings			Pathogonomic finding
		Symptoms
									Lab Findings		Biopsy
		Painless or painful Lymphadenopathy	Generalized or localized Lymphadenopathy	Fever	Weight loss	Night Sweats	Rash	Other symptoms	Immunochemistry	Blood work
NEOPLASMS
Non-Hodgkins lymphoma		Painless	Generalized	+	+	+	+	Presents with “B” symptoms Constant fatigue Shortness of breath and cough Abdominal pain or swelling Constipation Nausea andvomiting.	Coombs test may be positive Hypogammaglobulinemia HIV serology Elevated lactate dehydrogenase Abnormal liver function test Hypercalcemia	Anemia Thrombocytopenia Leukopenia Lymphocytosis	Monomorphic medium to large sized lymphocytes seen	N/A
Hodgkin’s disease[1][2][3][4]		Painless	Generalized	+	+	+	+	Presents with “B” symptoms Constant fatigue Shortness of breath and Cough Abdominal pain or swelling Constipation Nausea andvomiting.	Lactate dehydrogenase (LDH) may be increased. ESR elevated Serum creatinine elevated in nephrotic syndrome. Alkaline phosphatase (ALP) increased Hypercalcemia, hypernatremia, and hypoglycemia.	N/A	Fine-needle aspiration Mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells	Reed-Sternberg cells on microscopic pathology.
Chronic lymphocytic leukemia[5][6][7][8]		Painless	Generalized	+	+	+	–	Recurrent bleeding Muscle wasting Generalized weakness Anorexia Abdominal pain Recurrent infections	Monoclonality of kappa and lambda producing B cells Presence of smudge cells Express CD19, CD20, CD23, and CD5 on the cell surface	CBC Absolute lymphocytosis (>5000 cells/μl) Decreased hemoglobin concentration Decreased platelets count	On microscopic histopathological analysis: Small lymphoid cells Thin cytoplasmic border Dense nucleus Lack of nucleolus Clumped chromatin aggregates The presence of smudge cells The presence of gumprecht nuclear shadows	N/A
Small cell carcinoma of the lung[9][10][11][12][13]		Painless	Localized	–	–	–	–	Syndrome of inappropriate antidiuresis (SIADH) Hypercalcemia Cough (most common symptom) Wheezing Dyspnea Hemoptysis Chest pain	Nearly all SCLC are immunoreactive for keratin thyroid transcription factor 1 epithelial membrane antigen Neuroendocrine and neural differentiation result in the expression of molecules like dopa-decarboxylase calcitonin neuron-specific enolase, chromogranin A CD56 gastrin-releasing peptide insulin-like growth factor 1	N/A	The tumor cells are small and round, but they can sometimes be ovoid or spindle shaped. They have a scantycytoplasm with a high mitotic count and a hyperchromatic nuclei.	N/A
Melanoma[14][15][16]		Painless	Localized	–	–	–	–	Rapid growth of an existing nevus Bleeding nevus Cutaneous nodules Hyper/hypopigmented skin lesion Melanonychia (brown/blue nail discoloration) Non-healing skin ulcer Painful skin lesion Pruritus Bone pain	Positive for CD133+ Positive for CD34+	N/A	An excisional biopsy (either elliptical, punch, or saucerization) of the thickest portion of the lesion with 1-3 mm margins.	Epidermal atrophy and flattening and prominent dermal invasion
Lymphomatoid granulomatosis[17][18][19][20][21][22][23]		Painless	Generalized or localized	+	+	–	+	Cough Dyspnea Chest tightness Malaise Fatigue Headaches Seizures Hemiparesis Ataxia Macules Papules Plaques Subcutaneous nodules Larger ulcerated nodules	N/A	CBC Leukopenia Lymphopenia Low CD4 count Leukocytosis is rare Elevated Hematocrit	N/A	On chest CT scan, Halo sign is seen due to the angioinvasive nature of the disease
Angioimmunoblastic lymphadenopathy[24][25][26][27]		Painless	Generalized	+	+	+	+	Edema Chest pain Abdominal pain Bone pain Fatigue Pale skin color Dark urine Chronic pain and swelling of the joints	Immunophenotyping Positivity for CD2, CD3, CD4, CD5, CD10, CD20, and focal positivity for CXCL13 Negative for ALK1 and CD30 Fluorescence in situ hybridization (FISH)	Complete blood count (CBC) Anemia Eosinophilia	Lymph node or extranodal tissue biopsy is diagnostic of angioimmunoblastic T-cell lymphoma. Characteristic findings on gross pathology, aborization and proliferation of high endothelial venules On microscopic histopathological analysis, CD4+ T-cells, CD8+ T-cells, and polyclonal plasma cells.	Epstein–Barr virus (EBV) has been found in both reactive B-cells and the neoplastic T-cells. Trisomy 3, trisomy 5, and +X are the most frequent chromosomal abnormalities found in cases.
Giant lymph node hyperplasia (Castleman disease)[28]		Painless	Localized	+	+	–	–	Anemia Loss of appetite Cough Chest discomfort Fatigue Weakness	N/A	Complete blood count and differential count – low white blood cell counts, which may to be due to the overproduction of interleukin 6. Erythrocyte sedimentation rate – elevated in 80% cases.	N/A	Hypersecretion of the cytokine IL-6.
Diseases		Lymphadenopathy		Fever	Weight loss	Night sweats	Rash	Other symptoms	Immunochemistry	Blood work	Biopsy Histopathology	Pathogonomical findings
INFECTIONS
Bacteria	Syphilis[29][30][31][32]	Painless	Localized	+	–	–	+	Primary syphilis: Chancer Secondary syphilis: Rash Condylomata lata Patchy alopecia Tertiary syphilis Gumma Organ system involvement	Darkfield microscopy to detect T. pallidum. Nontreponemal tests (e.g., VDRLand RPR ) Treponemal tests (e.g. FTA-ABS, the TP-PA assay	N/A	On microscopic histopathological analysis, characteristic findings of syphilis: Mononuclear leukocytic infiltration, macrophages, and lymphocytes. Swelling and proliferation of small blood vessels.	Painless clean base chancre.
	Brucellosis[33][34][35][36][37]	Painful	Localized	+	–	–	+	Abdominal pain Hepatosplenomegaly Arthritis	Brucella is most commonly isolated from blood cultures Positive titer of anti-brucella antibodies on serological testing	N/A	N/A	Night sweats, often with characteristic smell, likened to wet hay
Viral	Infectious mononucleosis[38]	Painful	Localized	+	–	–	+	Low-grade fever without chills Sore throat White patches on tonsils and back of the throat Muscle weakness Fatigue Petechial hemorrhage	A positive reaction to a mono spot test Direct detection of EBV in blood or lymphoid tissues	A normal to moderately elevated white blood cell count An increased total number of lymphocytes Greater than 10% atypical lymphocytes Presence of atypical lymphocytes (a type of mononuclear cell) on the peripheral blood smear.	N/A	Presence of atypical lymphocytes (a type of mononuclear cell) on the peripheral blood smear.
	CMV[39][40]	Painful	Localized	+	–	–	+	Floaters Scotomata Peripheral visual field defects Odynophagia Nausea Lethargy Confusion Altered mental status	Positive PCR for CMV.	Hemolytic anemia Thrombocytopenia Disseminated intravascular coagulation Pancytopenia	CMV infection demonstrates the presence of intranuclear inclusion bodies. These inclusion bodies stain dark pink on an H&E stain, and are also called “Owl’s Eye” inclusion bodies.	Owl Eye inclusion bodies.
	HIV[41][42][43][44]	Painful or painless	Generalized or localized	–	+	–	–	Fatigue Myalgia Arthritic pain Headache Memory loss, depression and other neurological disorders	ELISA Dot blot Latex agglutination assays Western blot assays P24 antigen assays CD4 T-cell count (CD4 count) Plasma HIV RNA viral load	Anaemia Thrombocytopenia Leukopenia	N/A	Plasma HIV RNA viral load
	Cat scratch disease[45][46][47][48]	Painful	Localized	+	–	–	+	Back pain Headache Sore throat Abdominal pain Vision problems Malaise Alteration of mental status Convulsions	Indirect immunofluorescence or enzymatic immunoassay with titration of IgG or IgM antibodies to detect serum antibody to B henselae. Polymerase chain reaction (PCR) is the most sensitive test	Lymphocytosis is seen in the acute phase. Erythrocyte sedimentation rate – elevated.	N/A	Painful buboes
Mycobacteria	Tuberculosis[49][50][51][52][53]	Painful	Generalized or localized	+	+	+	+	Hemoptysis Chest pain Anorexia Malaise Chills Fatigue Dyspnea	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli Hyponatremia Hypercalcemia Elevated alkaline phosphatase levels Mild elevation of liver enzymes	Mild normocytic anemia may be present in almost half of patients. Increased erythrocyte sedimentation rate (ESR) Mild leukocytosis	Macrophages, other immune cells such as blood monocytes (tissue macrophages) and lymphocytes also migrate to the Ghon focus aiding in the termination of the infection or initiation of a granulomatous containment.	Gohn’s focus
Parasite	Toxoplasmosis[54][55][56][57]	Painless	Generalized or localized	+	–	+	–	Sore throat Muscle aches and pains	IgG, IgM, IgA antibodies against toxoplasmosis seen by ELISA PCR	N/A	Microscopy of the lesions demonstrate periaqueductal and periventricular vasculitis with necrosis. Fetal tissue and placenta can demonstrate t.gondii cysts with the Wright-Giemsa stain and also with immunoperoxidase staining using t.gondii–specific antibodies.	Multiple ring enhancing lesion on CT Brain.
Diseases		Lymphadenopathy		Fever	Weight loss	Night sweats	Rash	Other symptoms	Immunochemistry	Blood work	Biopsy Histopathology	Pathogonomical findings
AUTOIMMUNE
Systemic lupus erythematosus (SLE)[58][59][60][61]		Painless	Generalized or localized	+	+/-	–	+	Fatigue Myalgia Joint tenderness Muscle weakness Abdominal pain Bloating Distension	ANA positive Lupus anticoagulant (LA) IgG and IgM anticardiolipin (aCL) antibodies IgG and IgM anti-beta2-glycoprotein (GP) C3: Vary between varying between normal to slightly reduced C4: Reduced CH50: Reduced	Leukopenia Lymphopenia Mild anemia Thrombocytopenia ESR CRPelevated	Lupus erythematosus (LE) cells can be seen in SLE. LE cells are neutrophils that have engulfed an intact nucleus. LE cells are also known as LE bodies.	Malar rash and photosensitivity
Sjögren’s syndrome[62][63][64][65]		Painless	Generalized or localized	–	–	–	+	Xerosis Scaly skin Annular erythema	Anti-Ro/SSA Anti-La/SSB Presence of rheumatoid factor (RF) Presence of anti–alpha-fodrin antibody (diagnostic marker of juvenile Sjögren’s syndrome)	Elevated erythrocyte sedimentation rate (ESR) Anemia Leukopenia Thrombocytopenia Eosinophilia	N/A	Keratoconjunctivitis sicca Presence of anti–alpha-fodrin antibody
Sarcoidosis[66][67][68]		Painless	Generalized	–	–	–	–	Can involve all organ systems to varying extent and degree.	Serum ACE level Serum chitotriosidase Soluble interleukin-2 receptor Hypercalcemia Kveim test	N/A	Biopsy of lung Non-caseating granuloma	Non-caseatinggranuloma

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