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| POSTGRADUATE FORUM |
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| Year : 2023 | Volume
: 3
| Issue : 2 | Page : 82-86 |
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Tubercular lymphadenopathy for postgraduates – A minireview
Vidushi Rathi, Pranav Ish
Department of Pulmonary and Critical Care Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| Date of Submission | 28-Dec-2022 |
| Date of Acceptance | 02-Feb-2023 |
| Date of Web Publication | 02-May-2023 |
Correspondence Address:
Dr. Pranav Ish
Department of Pulmonary and Critical Care Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, Room No. 638, 6th Floor, Superspeciality Block, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jalh.jalh_41_22
Extrapulmonary tuberculosis (EPTB) remains often ignored by both medical community and authorities. This review attempts to summarize the pathogenesis, clinical presentation, investigations, diagnosis, treatment, and complication of lymph node TB (LNTB) in India. LNTB refers to Mycobacterium tuberculosis infection of the lymph nodes and is the most common form of EPTB in India. Classical symptoms include low-grade fever, weight loss, loss of appetite, night sweats, and painless enlarged lymph nodes in the neck or axilla or groin. Mediastinal lymphadenopathy presents with cough and chest discomfort and uncommonly even with shortness of breath; wherever possible, a pathological and microbiological diagnosis must be attempted by fine-needle aspiration for cytology, histopathology, acid-fast bacilli smear, and molecular tests such as cartridge-based nucleic acid amplification test and culture. For deep nodes, ultrasound/computed tomography/endobronchial ultrasound-guided aspiration can be done. LNTB is primarily requires medical management, and adjunct surgical excision is generally associated with worse outcomes. Six-month antitubercular therapy standard first-line regimen is recommended for peripheral LNTB and can be provided at the nearest local directly observed treatment short-course chemotherapy center in India.
Keywords: Cartridge-based nucleic acid amplification test, lymphadenopathy, treatment, tuberculosis
How to cite this article:
Rathi V, Ish P. Tubercular lymphadenopathy for postgraduates – A minireview. J Adv Lung Health 2023;3:82-6 |
| Introduction | |  |
Lymph node tuberculosis (LNTB, also called TB lymphadenitis) refers to Mycobacterium tuberculosis infection of the lymph nodes and may occur as the sole manifestation of TB infection or alongside pulmonary or miliary TB. LNTB is the most common form of extrapulmonary tuberculosis (EPTB) in India, accounting for around 35% of EPTB cases.[1] Utmost care should be taken to identify patients who need to be investigated for LNTB, as there is multiple differential diagnosis for lymphadenopathy.[2] Among all tuberculous lymphadenitis, cervical adenopathy is most common (45%–75% cases), but inguinal, axillary, mesenteric, and mediastinal involvement have also been described.[3]
| Pathogenesis | | |
Tuberculous lymphadenitis may represent a spread of infection from the tonsils, adenoids, sinonasal, or osteomyelitis of the ethmoid bone. In untreated primary tuberculosis, enlargement of hilar and paratracheal lymph nodes (or both) becomes apparent on chest radiographs. In the initial stage of superficial lymph node involvement, progressive multiplication of M. tuberculosis occurs. The onset of delayed hypersensitivity is accompanied by marked hyperemia, swelling, necrosis, and caseation of the center of the nodes. This can be followed by inflammation, progressive swelling, and matting with other nodes within a group. Adhesion to the adjacent skin may result in induration and purplish discoloration. The center of the enlarging gland becomes soft and caseous material may rupture into surrounding tissue or through the skin with sinus formation.[4]
Tuberculous mediastinal lymphadenitis may enlarge and cause compression of major blood vessels, phrenic or recurrent laryngeal nerves or cause erosion of the bronchus. There is various portal of entries of infection described for acquiring mycobacterium tubercular lymphadenitis:
- Through respiratory tract – hematogenous and lymphatic dissemination. Hilar and mediastinal lymph nodes are usually involved initially
- Through tonsil – spreads through the lymphatics to the draining cervical lymph nodes as a result of TB infection involving the tonsils, adenoids, and Waldeyer's ring, leading to cervical lymphadenopathy
- Abdominal tuberculous lymphadenopathy may occur through ingestion of sputum or milk infected with M. tuberculosis or Mycobacterium bovis.
| Clinical Symptoms | | |
Classical symptoms (seen in 55%–60%) include low-grade fever, weight loss, and loss of appetite along with night sweats with a duration of 1–2 months. Presentation of superficial lymphadenopathy includes enlarged lymph nodes in the neck/axilla/groin which are usually painless (65%–90% of cases), usually unilateral (85% of cases), and uncommonly associated with draining sinus/ulceration or abscess (4%–11% cases).[1] Presentation of deep lymphadenopathy includes mediastinal lymphadenopathy, which usually presents with cough and chest discomfort and uncommonly even with shortness of breath; abdominal lymphadenopathy, which commonly presents with dull aching abdominal pain and rarely with obstructive jaundice or subacute intestinal obstruction.
On local examination, depending on location, size, consistency, etc., approach to a patient of lymphadenopathy is variable. However, the following features of the lymph nodes must be examined:
- Location of lymph nodes: Generalized (>3 groups) can be present in human immunodeficiency virus infection, non-Hodgkin lymphoma, TB, infectious mononucleosis, and systemic lupus erythematosus
- Size of lymphadenopathy: Significant lymphadenopathy is present if >2 cm diameter in the inguinal region and >1 cm at the rest of the sites
- Consistency of lymph node – LYMPH nodes are often hard in malignancy/metastasis/chronic infection, firm/rubbery in lymphoma/chronic leukemia, and soft in acute leukemia
- Fixation: Fixed lymphadenopathy seen in malignancy/inflammation whereas matted (group of nodes are conglomerated) generally seen in tuberculosis
- Tenderness: Generally seen in acute viral/bacterial infection
- Organomegaly: All patients must be examined for enlarged liver/spleen.
| Investigations | | |
In patients with deep lymphadenopathy, all peripheral lymph nodes must be assessed for the presence of lymphadenopathy and preferred for sampling. Wherever possible, a pathological and microbiological confirmation must be attempted. This often requires sampling by fine-needle aspiration (FNA) for cytology, histopathology, acid-fast bacilli (AFB) smear, and molecular tests such as cartridge-based nucleic acid amplification test (CBNAAT) and culture. If samples are insufficient, in case of high clinical suspicion, CBNAAT testing may be given priority as it helps detect mycobacterium along with rifampicin resistance. As per the clinician's suspicion, samples may also be sent for bacterial/fungal culture and microscopy.
Sampling from superficial lymph node can be done directly by FNA. For deep nodes, USG/computed tomography (CT)/endobronchial ultrasound (EBUS)-guided aspiration can be done. Biopsy can be done where FNA is not diagnostic in the setting of strong clinical suspicion of TB, or alternate diagnosis is suspected. Excisional biopsy is preferred over incisional biopsy as excisional biopsy has the highest diagnostic yield, and incisional biopsy may later be associated with sinus tract formation. M. tuberculosis can be cultured in 70%–90% of cases in an excisional biopsy.[5] Mediastinal lymph node biopsy is done with the help of bronchoscopy/mediastinoscopy/EBUS. Advantages of taking a biopsy include the highest diagnostic yield along with adequate samples, which can be sent for AFB, microscopy, culture, molecular test, and immunohistochemistry marker for lymphoma/carcinomas in cases of diagnostic dilemma. However, it requires experience and has a risk of local complications such as infection and sinus tract formation.[1]
The finding of caseating granuloma on histopathology with constitutional symptoms is highly suggestive of tuberculosis; antitubercular therapy (ATT) may be initiated in such cases even in the absence of microbiological evidence. Zeihl–Neelson stain to detect AFB can be done in FNA/biopsy/local discharge/sputum sample. It has the advantage of being easily available, having high specificity (>90%), and uses in response assessment. However, sensitivity is low and a negative result does not rule out tuberculosis.
The molecular method (CBNAAT) is the first-line test to be done along with microscopy, culture, and histopathology. It is a rapid (requires 90 min), automated, easy test to interpret having high sensitivity (72%–92%) and specificity (80%–97%), and also identifies rifampicin resistance. However, a negative result does not rule out tuberculosis and it cannot be used to monitor response to therapy.
Microbiological culture methods include Lowenstein–Jensen (LJ) media and an automated BACTAC system (MGIT 960).[6] LJ is the selective medium, which is used for the cultivation and isolation of Mycobacterium species. It is used for the diagnosis of mycobacterial infections, antibiotic susceptibility of isolates, and for differentiating different species of mycobacterium (by colony morphology, growth rate, biochemical characteristics, and microscopy). The limitation of these tests is cost, availability, and, most importantly, the long incubation period. However, they have a high yield in smear-negative specimens and eventually clarify for drug resistance phenotypically. Automated cultures are advantageous in giving results faster within 4 weeks.
The importance of radiological imaging in the diagnosis of TB lymphadenopathy is immense. It helps in diagnosis in relatively inaccessible site, assesses the extent of disease, evaluates response to therapy, detects residual infection after completion of therapy, and helps in guided procedures such as FNA and biopsy. Associated chest X-ray findings include pulmonary infiltration, right paratracheal or hilar opacity, obliteration of costophrenic angles, and miliary mottling. Ultrasonography can differentiate reactive, malignant, and tubercular lymph node, aid in FNA from deeper nodes, and is safe for pregnant women. Sonographic features that help to identify abnormal nodes include shape (round), absent hilus, intranodal necrosis, reticulation, calcification, matting, soft-tissue edema, and peripheral vascularity.[7],[8] Tuberculous nodes tend to be hypoechoic, round, and without echogenic hilus and tend to show intranodal cystic necrosis, nodal matting, and adjacent soft-tissue edema.
EBUS transbronchial needle aspiration (TBNA) is a minimally invasive technique allowing sampling of mediastinal lymph nodes through FNA under direct sonographic visualization. It has a low rate of morbidity and has demonstrated utility in the diagnosis of mediastinal lymphadenopathy secondary to malignancy, lymphoma, and sarcoidosis.[9] EBUS-TBNA has been shown to have a sensitivity of 85% and a diagnostic yield of 92%. CT provides knowledge not only of the site and extent of tuberculous lymphadenitis but also of the status of affected lymph node. CT is more sensitive than plain radiography in detecting tuberculous lymphadenopathy. CT reveals lymph nodes often measuring more than 2 cm, with characteristic, “rim enhancement sign” that consists of a low-density center, representing caseous necrosis, surrounded by a peripheral enhancing rim due to granulomatous inflammatory tissue.[10]
CT in TB lymphadenopathy can present as – (1) peripheral enhancement with hypodense centers which is secondary to caseous and/or liquefactive necrosis, (2)conglomerate lymph node masses secondary to perinodal inflammation, (3) increased number of enlarged nodes of homogeneous density, or (4) simply as calcified lymph nodes only.[11] Magnetic resonance imaging (MRI) is radiation-free and can be used in follow-up cases of mediastinal tuberculosis. MRI tuberculous lymphadenopathy is mostly hyperintense on T2-weighted images. Central hyperintensity on T2-weighted images corresponding to liquefaction necrosis. Obliteration of the perinodal fat, characterized by increased signal intensities on T2-weighted images, has been suggested to reflect capsular disruption. MRI often shows peripheral enhancement of the tubercular lymph nodes which is visible as a uniform complete or incomplete rim. Sometimes, conglomerate group of nodes show peripheral and central areas ofenhancement in MRI.
18F-fluorodeoxyglucose Positron emission tomography CT (18-FDG PET/CT) is anoninvasive imaging method that has been used widely for the differentiation of malignant from benign lesions. However, 18F-FDG uptake is also observed in PTB, tuberculoma, and other TB-related lesions. During anti-TB treatment, some bacillus-negative tuberculomas do not decrease in size and may even increase, making it difficult for the physician to decide whether to modify treatment. 18F-FDG PET/CT imaging may help, as the changes in glycolytic activity within the inflammatory lesion, measured by 18F-FDG uptake, correlate well with the clinical markers of response. The value of 18F-FDG PET/CT in the follow-up and evaluation of the treatment response, especially in patients with extrapulmonary involvement and when drug resistance is prevalent.[10]
The differential diagnosis for LNTB is summarized in [Table 1] and the current national diagnostic and treatment guidelines are in [Table 2]. | Table 2: Index-tuberculosis guidelines for treating lymph-node tuberculosis
Click here to view |
| Treatment | | |
The treatment of LNTB is summarized in [Figure 1]. Diagnostic definitions used for LNTB include:
Microbiologically confirmed LNTB case is defined if there are symptoms and signs of LNTB plus at least one of the following – positive microscopy for AFB, positive culture for M. tuberculosis, or positive validated polymerase chain reaction (PCR)-based test (e.g., GeneXpert MTB/RIF).[12]
Clinically diagnosed LNTB is when there are symptoms and signs of lymph node tuberculosis plus negative microscopy, negative culture, and PCR-based test, no other diagnosis explains signs and symptoms, radiological evidence suggestive of LNTB with/without histological finding and clinical feature suggestive of tuberculosis.[12]
LNTB is primarily requires medical management, and adjunct surgical excision is generally associated with worse outcomes.[13] Six-month ATT standard first-line regimen is recommended for peripheral LNTB and can be provided at the nearest local directly observed treatment short-course chemotherapy center in India. Initial 2 months as intensive phase – four-drug regimen which includes isoniazid (INH), rifampicin, pyrazinamide, and ethambutol. Continuation phase from 2nd month onward, up to 4 months (total 6 months of therapy) which includes three-drug regimens (INH, rifampicin, and ethambutol).
Assessment of response to ATT is done at 4 months. Possible treatment failure should be considered in patients who have worsened or deteriorated after initial improvement. Such cases require further investigation to look for drug resistance and alternate diagnosis which should be followed by an appropriate change of treatment. Deterioration in the first 3 months may be due to paradoxical reaction – this does not require repeat diagnostic tests or change of treatment.[12] The current expert opinion on when to stop ATT in patients with persistently enlarged mediastinal lymph nodes is to stop when there is documentation of the absence of interval change in CT/MRI of mediastinal lymph nodes for more than 4 months, with resolution of all other signs and symptoms.[12]
Difficulties in managing lymph-node tuberculosis apart from difficulties encountered in the diagnosis of lymph-node tuberculosis mentioned earlier, and certain problems may be encountered during its treatment such as the appearance of new lymphadenopathy, enlargement of the existing nodes, development of fluctuation, sinus tracts formation, residual lymphadenopathy after completion of treatment, or relapse. Possible explanations for this suboptimal response of therapy in lymph-node tuberculosis include poor patient compliance to treatment, unidentified drug resistance, poor drug penetration into the lymph node/absorption, unfavorable local milieu, nontuberculous mycobacterial infection, enhanced delayed hypersensitivity reaction in response to mycobacterial antigens released during medical treatment of the disease, superadded infection, drug resistance (INH mono-resistance/ Multidrug resistant TB), or alternative underlying diagnosis.
| Prognosis and Complications | | |
Some patients with LNTB have residual lymphadenopathy at the end of treatment. This is not usually due to continued active TB infection where the largest node is <1 cm in size. Some patients have residual nodes more than 1 cm in size, and these patients are classified as partial responders. There is uncertainty about whether continuing ATT in these patients is beneficial. The INDEX TB guidelines suggested these patients should receive an additional 3 months of Rifampicin, isoniazid and ethambutol (RHE), followed by a biopsy sent for histology and TB culture.[10]
For mediastinal TB, progress on ATT can be monitored with chest X-ray, but a CT scan may be indicated if lymph nodes do not reduce in size after 4 months. In patients who fail to improve on ATT, the alternative diagnoses of lung cancer, lymphoma, sarcoidosis, and fungal infection should be considered. The appearance of fluctuation in one or more lymph nodes calls for aspiration under all aseptic precautions. Any secondary bacterial infection should be dealt with appropriately that may include incision and drainage.[12],[13] Worsening after 8 weeks of therapy may call for en bloc resection of the involved lymph node chain to avoid the appearance of ugly sinus tracts. Nonhealing sinus tracts may need resective surgery. All efforts should be made to isolate the causative agent and to obtain prompt sensitivity testing, particularly in relapsed cases/nonresponders and chemotherapy modified accordingly.[14]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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| 12. | Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD, Mohan A, et al. Index-TB guidelines: Guidelines on extrapulmonary tuberculosis for India. Indian J Med Res 2017;145:448-63. [ PUBMED] [Full text] |
| 13. | Campbell IA, Dyson AJ. Lymph node tuberculosis: A comparison of various methods of treatment. Tubercle 1977;58:171-9. |
| 14. | Gupta PR. Difficulties in managing lymph node tuberculosis. Lung India. 2004;21:50. |
[Figure 1]
[Table 1], [Table 2]
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