Peripheral lymphadenopathy without an obvious cause after the history and physical examination presents a diagnostic dilemma.
The location of peripheral lymph node groups is shown schematically in the figures (figure 1 and figure 2).
Distinguishing between localized and generalized lymphadenopathy can help to formulate a differential diagnosis.
Cervical — The anterior cervical lymph nodes are often enlarged because of one of a variety of infections of the head and neck or to some systemic infections such as infectious mononucleosis caused by Epstein-Barr virus (EBV), cytomegalovirus infection, or toxoplasmosis. UpToDate, electronic clinical resource tool for physicians and patients that provides information on Adult Primary Care and Internal Medicine, Allergy and Immunology, Cardiovascular Medicine, Emergency Medicine, Endocrinology and Diabetes, Family Medicine, Gastroenterology and Hepatology, Hematology, Infectious Diseases, Nephrology and Hypertension, Neurology, Obstetrics, Gynecology, and Women's Health, Oncology, Pediatrics, Pulmonary, Critical Care, Sleep Medicine, Rheumatology, Surgery, and more.
Metastatic and lymphomatous nodes tend to have sharp borders, whereas reactive and normal nodes usually show unsharp borders [7]. In the evaluation of the vascular resistance (RI and PI) of cervical lymph nodes, the mean, highest and lowest values have been reported [20-22]. The location of a swelling or lump in the neck will often give a good indication of the tissue of origin, and the age of the patient may also help suggest the most likely diagnoses.
Lymph nodes can enlarge in a number of disorders, often because of disease in the local area of drainage, sometimes because of disease affecting the wider lymphoreticular system (lymph nodes, liver and spleen). Enlargement of the cervical lymph nodes alone usually arises because they are involved in an immune response to an infectious agent in the area of drainage and nodes are then often firm, discrete and painful to touch but are mobile (lymphadenitis). Enlargement of cervical lymph nodes alone may also occur when there is reactive increased number of cells to a cancerous tumor in the drainage area, or metastatic infiltration. Tumors of the lymphoreticular system, such as lymphomas, leukemias, and histiocytoses, usually cause enlargement of many or all cervical lymph nodes.
One cannot feel a normal lymph node therefore a palpable one must be abnormal.  The finding of an enlarged node or nodes in children is relatively common and can be reasonable managed by watchful waiting. Routine intra-oral and extra-oral examinations are done to exclude the common causes: apical and periodontal abscesses, pericoronitis, tonsillitis, otitis and others. Supplementary investigations such as full blood count, fine-needle aspiration cytology, magnetic resonance imaging (MRI) and computed tomography (CT) scans may be needed to exclude malignancy.
There are nearly 9 million new cases and 2 million deaths from tuberculosis world wide every year.3 The incidence of mycobacterial lymphadenitis has increased in parallel with the increase in the incidence of mycobacterial infection worldwide. Tuberculous lymphadenitis is a local manifestation of the systemic disease.12 It may occur during primary tuberculous infection or as a result of reactivation of dormant foci or direct extension from a contiguous focus.
In initial stage of superficial lymph node involvement progressive multiplication of the M. Jones and Campbell30 classified peripheral tuberculous lymph nodes into following five stages.
A high index of suspicion is needed for the diagnosis of mycobacterial cervical lymphadenitis. This intradermal test (Mantoux test) is used to show delayed-type hypersensitivity reactions against mycobacterial antigen, in which the reagent is mostly protein purified derivative (PPD). Polymerase chain reaction (PCR) is a fast and useful technique for the demonstration of mycobacterial DNA fragments in patients with clinically suspected mycobacterial lymphadenitis.52,53 The presence of few dead or live microorganisms is enough for PCR positivity. Chest radiograph, ultrasound, CT and MRI of the neck can be performed in mycobacterial lymphadenitis. The treatment of mycobacterial lymphadenitis in HIV infected patients is same as in those without HIV infection. During antituberculous therapy, affected nodes may enlarge or new nodes may appear, representing an immune response to killed mycobacteria. Tuberculosis is a systemic disease and lymphadenitis is the most common extrapulmonary manifestation of the disease. On the one hand, there are countless potential causes, some of which are severe and treatable. Normal lymph nodes are usually less than 1 cm in diameter and tend to be larger in adolescence than later in life.
A clinically useful approach is to classify lymphadenopathy as localized when it involves only one region such as the neck or axilla, and generalized when it involves more than one region [1]. As will be discussed below, some node presentations suggest a specific disease process, and a few diseases present predominantly with lymphadenopathy.
Posterior cervical lymphadenopathy may occur with EBV infection, tuberculosis, lymphoma, Kikuchi disease (see below), or head and neck malignancy (either lymphomas or metastatic squamous cell carcinoma). The sharp borders in malignant nodes are believed to be due to the tumour infiltration and the reduced fatty deposition within the lymph nodes which increase the acoustic impedance difference between the lymph node and the surrounding tissues. However, we found that the repeatability of measurement is higher when the mean value is used [23]. It has been reported the metastatic nodes have a higher RI and PI than reactive nodes [21, 24]. Distribution of nodes, grey scale and power Doppler sonographic features are useful to identify the cause of cervical lymphadenopathy.
Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis.
Vascularity and grey-scale sonographic features of normal cervical lymph nodes: variations with nodal size.
Metastatic cervical nodes in papillary carcinoma of the thyroid: ultrasound and histological correlation. The use of sonography in differentiating cervical lymphomatous lymph nodes from cervical metastatic lymph nodes. The sonographic appearance and significance of cervical metastatic nodes following radiotherapy for nasopharyngaeal carcinoma. Power Doppler Sonography to Differentiate Tuberculous Cervical Lymphadenopathy from Nasopharyngeal Carcinoma. Evaluation of metastases and reactive lymph nodes in Doppler sonography using an ultrasound contrast enhancer.
Usefulness of Doppler spectral analysis and power Doppler sonography in the differentiation of cervical lymphadenopathies.
Differentiation of benign and malignant cervical lymph nodes with color Doppler sonography. Differentiation of benign and malignant cervical lymph nodes: value of B-mode and color Doppler sonography.
Sonographic evaluation of cervical lymphadenopathy: is power Doppler sonography routinely indicated?

Department of Diagnostic Radiology and Organ Imaging, Department of Optometry and Radiography.
Over a quarter of the lymph nodes in the body are connected with cervical lymph nodes (glands in the neck) situated in the head and neck.
The duration of the lesion is also relevant, one that has been present since an early age is likely to be of inborn origin, while a lump appearing in the later life and persisting may be cancerous.
The tonsil is lymphoid tissue located between the pillars of the fauces and there is similar material in the posterior aspect of tongue (lingual tonsil) and the posterior wall of the pharynx (adenoids).
It is important therefore to consider the whole body when dealing with lymph node swellings. The focus of inflammation can usually be found in the drainage areas which is anywhere on the face, scalp and nose, sinuses, ears, pharynx and mouth. Swollen lymph nodes from acute infections are usually painful to touch, soft and obvious, while chronic infections give firm lymph nodes. The latter may cause node to feel distinctly hard and it may bound down to adjacent tissues (‘fixed’), it may not be discrete and may even, in advanced cases, ulcerate through the skin. Undiagnosed cervical lymphadenopathy in adults mandate biopsy-establishing definitive diagnosis. An excision biopsy of the node may be required if the diagnosis still not been established. It remains both diagnostic and therapeutic challenge because it mimics other pathologic processes and yields inconsistent physical and laboratory findings. TB lymphadenitis is seen in nearly 35 per cent of extrapulmonary TB which constituted about 15 to 20 per cent of all cases of TB.
The lymph nodes are usually not tender unless (i) secondary bacterial infection, (ii) rapidly enlarging nodes or (iii) co-existing HIV infection are evident.
A thorough history and physical examination, tuberculin test, staining for acid-fast bacilli, radiologic examination, and fine-needle aspiration cytology (FNAC) will help to arrive at an early diagnosis of mycobacterial lymphadenitis which will allow early institution of treatment before a final diagnosis can be made by biopsy and culture.39,40 The differential diagnosis is extensive and includes infections (viral, bacterial or fungal), and neoplasms (lymphoma or sarcoma, metastatic carcinoma), non-specific reactive hyperplasia, sarcoidosis, toxoplasmosis, cats-scratch fever, collagen vascular diseases and diseases of reticuloendothelial system.
However, a negative culture result should not exclude the diagnosis of mycobacterial cervical lymphadenitis. Associated chest lesions as seen on chest radiography are very common in children but less common in adults, evident nearly 15% cases.9,16,21 Ultrasound of the neck can demonstrate singular or multiple hypoechoic and multiloculated cystic lesions that are surrounded with thick capsule.
Necrotic foci, when present, are more frequently peripheral rather than central, and this together with the soft tissue edema may be of value in differentiating mycobacterial cervical lymphadenitis from metastatic nodes.64 If the cervical mass is necrotic, there will be low and high signal intensity in the center of the mass in T1- and T2-weighted images, respectively. The National Tuberculosis Programmes worldwide follow the World Health Organization’s guidelines, directly observed treatment, short-course (DOTS) approach as intermittent chemotherapy for patients with TB lymphadenitis.
The rifampicin decreases the serum concentrations of anti-retroviral agents to subtherapeutic levels. Patients with TB lymphadenitis especially those who are co-infected with HIV may develop paradoxical reactions while on antitubercular drugs. Their diagnosis and distinction need a high index of suspicion, and application of a variety of diagnostic modalities. Lymphadenitis as a characteristic manifestation of disseminated tuberculosis in intravenous drug abusers infected with human immunodeficiency virus. Fine needle aspiration biopsy diagnosis of tuberculous lymphadenitis in patients with and without the acquired immune deficiency syndrome. Comparison of mycobacterial lymphadenitis among persons infected with human immunodeficiency virus and seronegative controls. Cervical tuberculous lymphadenopathy: changing clinical pattern and concepts in management. Diagnostic imaging of abdominal tuberculosis: gastrointestinal tract, peritoneum, lymph nodes.
Diagnosis, management and surgical treatment of non-tuberculous mycobacterial head and neck infection in children. Computed tomography of esophagomediastinal fistula in tuberculous mediastinal lymphadenitis. Combined use of fine-needle aspiration cytologic examination and tuberculin skin test in the diagnosis of cervical tuberculous lymphadenitis. Efficacy of fine needle aspiration cytology in the diagnosis of tuberculous cervical lymphadenopathy. Atypical mycobacterial lymphadenitis in childhood--a clinicopathological study of 17 cases.
Combined use of fine needle aspiration cytology and polymerase chain reaction in the diagnosis of cervical tuberculous lymphadenitis. Reverse transcriptase in situ polymerase chain reaction in atypical mycobacterial adenitis.
Polymerase chain reaction detection of Mycobacterium tuberculosis from fine-needle aspirate for the diagnosis of cervical tuberculous lymphadenitis.
Comparison of in house polymerase chain reaction with conventional techniques for the detection of Mycobacterium tuberculosis DNA in granulomatous lymphadenopathy. A comparative study of diagnostic tests for tuberculous lymphadenitis: polymerase chain reaction vs histopathology and clinical diagnosis. Detection of mycobacterial DNA in cervical granulomatous lymphadenopathy from formalin-fixed, paraffin-embedded tissue by PCR. Isolated peripheral tuberculous lymphadenitis in adults: current clinical and diagnostic issues. Cervical lymphadenitis due to mycobacteria other than tuberculosis--an emerging problem in children?
Management of non-pulmonary forms of tuberculosis : review of TRC studies over two decades. Nontuberculous mycobacterial adenitis of the head and neck in children: experience from a tertiary care pediatric center. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature.
On the other, severe causes are uncommon and the best way to reach a definitive diagnosis is by biopsy, which is invasive and not justified in most cases. Lymph nodes are often palpable in the inguinal region in healthy people, perhaps because chronic trauma and infection is so common in the lower extremities, and may also be palpable in the neck (particularly submandibular) following head and neck infections. Unsharp borders are common in tuberculous nodes and these are due to the edema and inflammation of the surrounding soft tissue (periadenitis).
With the use of newer transducer, lymphomatous nodes are less likely to have the pseudocystic appearance, whereas they demonstrate a micronodular appearance [14].

However, another study found that there was no significant difference in RI and PI between benign and malignant nodes [25].
Useful grey scale features include size, shape, status of echogenic hilus, echogenicity, micronodular appearance, intranodal necrosis and calcification. It is not surprising then, that many diseases of the lymphoid tissue present primarily in this region.
Nodes that are increasing in size and are hard, or fixed to adjacent tissues may be cancerous. Inhaled droplet nuclei are small enough to pass muco-ciliary defences of bronchi and lodge in terminal alveoli of lungs. This can be followed by inflammation, progressive swelling and matting with other nodes within a group.
Tuberculous lymphadenitis most frequently involves the cervical lymph nodes (Figure 1) followed in frequency by mediastinal, axillary, mesenteric, hepatic portal, perihepatic and inguinal lymph nodes.17,21,22 Mycobacterial infection should be considered in the differential diagnosis of a cervical swelling, especially in endemic areas. The lymph node abscess may burst infrequently leading to a chronic non-healing sinus and ulcer formation. The presence of 10–100 bacilli per cubic millimeter of the specimen is enough for a positive culture result.
It can differentiate between lymphadenitis caused by Mycobacterium tuberculosis and that caused by NTM. According to the DOTS guidelines TB lymphadenitis is categorised under treatment category III.65 Those with smear positive TB lymphadenitis with pulmonary involvement or severely ill are categorised under treatment category I. In those cases rifapentine can be used instead of rifampicin along with INH in continuation phase.65,75,76 The CD4+ and CD8+ T lymphocyte counts must be estimated and highly active antiretroviral treatment (HAART) must be administered when indicated.
A similar phenomenon is also seen in patients with HIV infection who begin concurrent antiretroviral therapy is a result of immune reconstitution.
The approach to diagnosis should be individualized depending on the location of the disease and the clinical evaluation.
Therefore, size of lymph nodes cannot be used as the sole criterion in differential diagnosis. Our studies found that metastatic nodes tend to have a higher RI and PI than reactive nodes, except for the metastatic nodes from papillary carcinoma of the thyroid which show similar RI and PI with reactive nodes [17, 26]. A thorough history and physical examination, staining for acid-fast bacilli, fine-needle aspiration and PCR are helpful in obtaining an early diagnosis. Mycobacterium tuberculosis is the most common causative agent in India.8-10 The incidence of mycobacterial lymphadenitis primarily depends on the endemicity of the of Mycobacterium tuberculosis. Classically, tuberculous sinuses have thin, bluish, undermined edges with scanty watery discharge.
PCR is used as an adjunct to conventional techniques in the diagnosis of mycobacterial infections.55,56 The PCR should only be reserved for problem cases in resource limited countries. Complete surgical excision of all affected tissue can be done when feasible.26 Aspiration, which may result in 50% cure rate, can be performed when surgical excision is limited. Tuberculous adenitis is best treated with antituberculosis medication and in addition surgical treatment is more useful in selected cases. However, in clinical practice, size of lymph nodes is useful when there is an increase in nodal size on serial examinations in a patient with known primary tumour, which is highly suggestive for metastases.
However, in clinical practice, a proven malignant node with unsharp borders indicates extracapsular spread, which helps in the assessment of patient prognosis. Nevertheless, we found that the combination of grey scale sonographic features and vascular pattern of lymph nodes already have a high accuracy in differentiating metastatic and reactive nodes [27]. In the lymphomas particularly, the nodes may be rubbery, matted together and fixed to deeper structures. It is also important to differentiate tuberculous from nontuberculous mycobacterial cervical lymphadenitis because their treatment protocols vary. Lymphadenopathy due to non-tuberculous mycobacterial (NTM) is uncommonly reported from India.4 In nontuberculous adenitis, Mycobacterium avium-intracellulare complex is the most common causative agent. The centre of the enlarging gland becomes soft and caseous material may rupture into surrounding tissue or through skin with sinus formation. Scrofuloderma is a mycobacterial infection of the skin caused by direct extension of tuberculosis into the skin from underlying structures or by contact exposure to tuberculosis. However, several weeks are needed to obtain the culture result, which may prolong the initiation of treatment. Therefore, measurement of the vascular resistance of lymph nodes may not be necessary in routine clinical practice.
In the systemic infective disorders the nodes are usually firm, discrete, painful to touch and mobile. Mycobacterial lymphadenitis most frequently affects patients in their second decade but may afflict patients of any age.
Tuberculous mediastinal lymphadenitis may enlarge and cause compression of major blood vessels, phrenic or recurrent laryngeal nerves or cause compression of major blood vessels, phrenic or recurrent laryngeal nerves or cause erosion of bronchus. Second-line drugs, which are less efficacious and more toxic than the first-line drugs, are capreomycin, kanamycin, ethionamide, thiacetazone, para-aminosalicylic acid and cycloserine. Situation has become worse due to sharp increase in the incidence of atypical mycobacteria, poorly controlled HIV epidemic and rise of drug-resistant TB lymphadenitis.
Tuberculous adenitis is best treated as a systemic disease with antituberculosis medication.
From the regional nodes, organism may continue to spread via the lymphatic system to other nodes or may pass through the nodes to reach blood stream, from where it can spread to virtually all organ of the body. Generally, no modification or prolongation in antituberculosis treatment regimen is indicated.10 In few cases even after treatment FNAC may remain positive for tuberculosis and even for AFB because of dead bacilli. Surgical therapy along with antituberculosis medication can be beneficial in selected patients. Hilar, mediastinal and paratracheal lymphnodes are the first site of spread of infection from the lung parenchyma.
The test may be positive in different conditions, like other infections, metabolic disease, malnutrition, live virus vaccination, malignancy, immunosuppressive drugs, newborns, elderly people, stress, sarcoidosis and inadequate test application.

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