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Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 7  |  Issue : 6  |  Page : 255-262
Cytomorphological tissue reaction patterns in lymph node tuberculosis and their correlation with bacterial density


1 Department of Pathology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Department of Pathology, University College of Medical Sciences, Guru Tegh Bahadur Hospital, Delhi, India

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Date of Web Publication14-Apr-2015
 

   Abstract 

Background: The diagnosis of extrapulmonary lymph node tuberculosis (TB) is made by the demonstration of different cytomorphological tissue reaction patterns on fine needle aspirations (FNA) smears; however, definitive diagnosis is made by demonstration of AFB by culture or Ziehl-Neelsen (ZN) stained smears. This procedure is technically demanding and time consuming, and is liable to fail on occasion for unexplained reasons. If the identification of cytomorphological patterns could predict bacterial density, it would help to improve diagnostic accuracy and also serve as a control on the acid-fast staining procedure. Therefore this study was being undertaken to determine the correlation between bacterial density and cytomorphological patterns in lymph node TB. Materials and Methods: FNA was performed on 505 clinically-suspected lymph node TB patients. May Grunwald Giemsa stained smears were used to analyze cytomorphological patterns and ZN stained smears for acid-fast bacilli (AFB) detection. Bacterial density (BI) was calculated by utilizing Ridley's logarithmic scale. Results: Seven distinct cytomorphological tissue reaction patterns were observed. Pattern 1 was predominantly an exudative response, comprising of neutrophils and mononuclear phagocytes and was the most common tissue reaction pattern, seen in 160 out of 505 patients (31.6%). Pattern 4, epithelioid cell granulomas with necrosis, was the second most common and seen in patients (29.3%). This study showed that multibacillary lesion (BI>1) was more often associated with pattern 1. Although the BI varied significantly across different cytomorphological tissue reaction patterns (P value = 0.004), no specific trend was observed as both paucibacillary as well as multibacillary lesions were noticed with different proportions among all tissue reaction patterns. Conclusion: The present study showed that multibacillary disease is more frequently associated with pattern 1 compared to pattern 4. However, more studies are needed to establish a trend among different cytomorphological tissue reaction patterns.

Keywords: Bacterial density, cytomorphological tissue reaction patterns, lymph node tuberculosis

How to cite this article:
Afrose R, Singh N, Bhatia A, Arora VK. Cytomorphological tissue reaction patterns in lymph node tuberculosis and their correlation with bacterial density. Ann Trop Med Public Health 2014;7:255-62

How to cite this URL:
Afrose R, Singh N, Bhatia A, Arora VK. Cytomorphological tissue reaction patterns in lymph node tuberculosis and their correlation with bacterial density. Ann Trop Med Public Health [serial online] 2014 [cited 2019 Dec 5];7:255-62. Available from: http://www.atmph.org/text.asp?2014/7/6/255/155019

   Introduction Top


Tuberculosis (TB) still represents a threat and a challenge to humanity, as it has done throughout history. The World Health Organization (WHO) declared TB a global emergency in 1993. [1] It is estimated that 95% of the world's TB cases and 98% of the TB deaths occur in the developing world. [2]

India has the highest burden of TB in the world and accounts for nearly one-fifth (20%) of the global burden of the disease. [3] In India extrapulmonary tuberculosis (EPTB) comprises 20% of all TB cases and its prevalence in the country varies between 8.3-13.1% in different districts. [4] Lymph node involvement is the most common extrapulmonary manifestation. [5]

The diagnosis of TB, based on clinical features, alone can be erroneous. [6] Soluble antigen fluorescent antibodies, [6],[7] indirect hemagglutination, [6],[7] kaolin agglutination [8] and enzyme-linked immunosorbent assay (ELISA) [9] are cumbersome and time consuming tests. Antibodies to mycobacterium TB (Mtb) are not definitive evidence of active TB because false-positive results are seen in high prevalence areas. [9]

Fine needle aspiration cytology (FNAC) provides an inexpensive, quick, and safe alternative to histopathology. [10] EPTB is diagnosised by demonstrating different cytomorphological tissue reaction patterns on smear, due to easy accessibility of lymph nodes by fine needle aspiration (FNA). However, definitive diagnosis depends on demonstration of acid-fast bacilli (AFB) by culture or smear. The morphological manifestations exhibit a specific spectra of tissue reaction patterns, which is similar to other granulomatous inflammations; best exemplified by the Ridley-Jopling classification of leprosy. [11] Other examples of granulomatous inflammations manifested in a morphological spectrum are Cutaneous leishmaniasis, Cysticercosis, Lymphatic filariasis, and other infections. [12]

The morphological spectrum in tuberculosis is highly variable but has been broadly classified as: [13]

  1. Epithelioid granuloma without necrosis
  2. Epithelioid granuloma with necrosis
  3. Necrosis only
The rate of AFB positivity in cytological smears varies widely in different studies [10],[14] and is found to be highest in purulent aspirates, followed by caseous aspirates, and least often in aspirates with blood mixed particles. [14]

AFB demonstration can be done either by the conventional Ziehl-Neelsen (ZN) method or by using auramine and rhodamine separately or in combination. The ZN stain is the special stain requisitioned most frequently in most of the laboratories. This procedure is technically demanding and time consuming, as has been shown by different studies. [15] Whatever the method adopted, it is liable to fail on occasion for unexplained reasons.

Granulomatous inflammation is a manifestation of many chronic inflammatory diseases like TB, sarcoid, leprosy, syphilis, and various mycosis. Yet, in regions of high endemicity, such as India and Srilanka, [16] granulomatous inflammations are largely considered to be of tuberculous origin, unless proven otherwise. In this setting demonstration of AFB, although not diagnostic of infection by M. TB, improves the diagnostic accuracy.

If identification of cytomorphological patterns could predict bacterial density, it would help to improve diagnostic accuracy and also serve as a control on the acid-fast staining procedure. Therefore this study is being undertaken to determine the correlation between bacterial density and cytomorphological patterns in lymph node TB.


   Materials and Methods Top


Study setting

This was a hospital-based prospective observational study conducted in the Department of Pathology at the University College of Medical Sciences (UCMS) and Guru Teg Bahadur (GTB) Hospital, Delhi.

Clearance was obtained from the ethical committee of the institution. Written informed consent was obtained from patients or family members. The study was conducted over a period of one year from 2009-2010.

Sample size

The study was carried out in aspirated material of lymph nodes from 505 patients having clinical diagnosis of tuberculous lymphadenitis. Out of which:

  • All AFB positive cases regardless of cytomorphology were included. When AFB was not demonstrable, but the tissue reaction pattern showed granulomatous inflammation with necrosis, the case was also included in this study.
  • All AFB negative cases with granulomatous inflammation but without necrosis, purulent exudates, acellular necrosis, or in which the patient was on anti-tubercular therapy, were excluded from the study.
Methodology

FNA was carried out using 20 ml disposable plastic syringes and 23-gauge needles. Air-dried smears were stained by May Grunwald Giemsa (MGG) for cytomorphological analysis. Modified ZN staining was done for AFB detection.

Bacteriological index was calculated by applying Ridley's logarithmic scale: [17]

0 No bacilli in any of the 100 oil- immersion fields.

1 + 1-10 bacilli, on average, in 100 oil-immersion fields.

2 + 1-10 bacilli, on average, in 10 oil-immersion fields.

3 + 1-10 bacilli, on average, in each oil-immersion field.

4 + 10-100 bacilli, on average, in each oil-immersion field.

5 + 100-1000 bacilli, on average, in each oil-immersion field.

6 + More than 1000 bacilli, on average, in each oil-immersion field.

Chi-square test was used for statistical analysis.


   Results and Observations Top


Seven cytomorphological tissue reaction patterns were identified on MGG stained smears.

Pattern 1 (160 cases): predominantly exudative response comprising of neutrophils and mononuclear phagocytes [Figure 1]. This group was found to be the largest group. AFB positivity was found to be 90.6%. BI ranged from 1+ to 4+.
Figure 1: Pattern 1: Exudative response, MGG ×400

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Pattern 2 (10 cases): predominantly reactive lymphoid cells with few scattered or clusters of histiocytes or focal necrosis [Figure 2]. AFB positivity was 50%. BI in this group ranged from 1+ to 2+.
Figure 2: Pattern 2: Necrosis with reactive lymphoid cells, MGG ×400

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Pattern 3 (114 cases): Epithelioid cell granulomas without necrosis [Figure 3] AFB positivity was 22.8%. BI ranged from 1+ to 2+.
Figure 3: Pattern 3: Granuloma in a reactive background, MGG ×400

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Pattern 4 (148 cases): Epithelioid cell granulomas with necrosis [Figure 4]. This group was the second largest group with AFB positivity 70.3% and BI ranged from 1+ to 3+ [Figure 8] and [Figure 9].

Pattern 5 (39 cases): Predominantly acellular necrosis [Figure 5]. AFB positivity was 61.5% and BI ranged from 1+ to 3+ [Figure 8] and [Figure 9].

Pattern 6 (22 cases): Pattern 4 or 5 with preserved stromal fragments containing blood vessels [Figure 6]. AFB positivity was the highest (95.4%). BI ranged from 1+ to 2+.

Pattern 7 (12 cases): Histiocytic granuloma or foam cells [Figure 7]. All cases were positive for the human immunodeficiency virus (HIV), and showed 91.7% AFB positivity. BI ranged from 3+ to 6+ [Figure 9] and [Figure 10]. In this group all cases except 1 (AFB negative) were multibacillary.

[Table 1] depicts correlation of cytomorphological tissue reaction patterns with bacterial density.
Figure 4: Pattern 4: Necrosis with epithelioid granuloma, MGG ×400

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Figure 5: Pattern 5: Acellular necrosis, MGG ×400

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Figure 6: Pattern 6: Necrosis with vascular fragments (arrow), MGG×200

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Figure 7: Pattern 7: loose aggregates of histiocytes, MGG ×400

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Figure 8: AFB (marked), B.I. 1+, ZN ×400

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Figure 9: AFB, B.I. 3+, ZN ×400

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Figure 10: Globi within macrophages, B.I. 6+, ZN ×400

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Table 1: Correlation of AFB positivity with tissue reaction patterns in 505 patients with lymph node tuberculosis (TB)

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The data for [Table 2] are derived from [Table 1] and pertains to 380 patients, who met the inclusion criteria of this study.
Table 2: Correlation of AFB positivity with tissue reaction patterns in 380 patients with lymph node tuberculosis

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Of these 380 cases, 336 (88.4%) were AFB positive. All 44 (11.6%) AFB negative cases belong to pattern 4, i.e., granulomatous inflammation with necrosis.

Analysis of [Table 2] reveals that the AFB positivity in the different group varied from BI 1+ to BI 6+. Since more than 25% cells in the grid are blank, statistical analysis for test of significance would not have been possible. To overcome this problem it was decided to carry out subsequent statistical analysis by reclassifying the cases in two groups namely BI = 1+ (paucibacillary, [Figure 8]) and BI > 1+ (multibacillary, [Figure 9] &10), as in the leprosy model. Also the 11 cases belonging to pattern 7 were not considered for further statistical analysis because pattern 7 was a small percentage (2.9%) of cases and to avoid the possibility of high BI due to HIV interfering with the analysis.

[Table 3] shows the breakup of the remaining 325 AFB positive cases and their tissue reaction patterns.
Table 3: Correlation of paucibacillary and multibacillary cases with tissue reaction patterns in 325 patients with lymph node TB

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   Discussion Top


The high burden of tuberculosis in our hospital is reflected in the annual turnover of the cytopathology section. In the year 2010-2011, the turnover of patients referred for FNAC was 10514. Of them 2,243 (21.3%) were tuberculosis cases. Therefore, the ZN stain is the most frequently requisitioned stain after the MGG stain in our laboratory.

In our cytopathology set up, the smears are first screened by the residents prior to sign out by the faculty on the next day. A large proportion of time is spent in searching for AFB in ZN smears. An earlier study [15] has attempted to rationalize the laboratory procedure in order to achieve higher AFB pickup rates. It has been demonstrated that selection of smears for ZN staining on the basis of screening MGG slides for foci of necrosis improves the pickup rate of AFB from 42% to 92%. [15]

The literature reports AFB positivity rates in patients with tuberculosis varying from 37.4% to 59.4%. [10],[14],[18] The highest AFB positivity has been found in smears associated with necrosis without granulomas, followed by epithelioid cell granuloma with necrosis/abscess and epithelioid granuloma in reactive lymphoid background. [10],[18] None of these studies attempted systematic analysis of tissue reaction patterns in relation to AFB positivity. There have been sporadic reports in the literature describing tissue reaction patterns; these patterns are thought to be limited to three main types: [5],[13]

  1. Epithelioid granuloma without necrosis
  2. Epithelioid granuloma with necrosis
  3. Necrosis only
On the other hand, another mycobacterial disease, leprosy, has a fairly well defined spectrum of tissue reaction patterns, ranging from epithelioid granuloma at one end to histiocytic granuloma at the other with the addition of necrosis being seen in lesions in the nerves. Compiling these patterns in the literature we were able to identify seven tissue reaction patterns in our study.

To ensure the validity of frequency with which these tissue reaction patterns occurred, it was proposed to include only AFB positive cases and only those AFB negative cases in which granulomatous inflammation was accompanied by necrosis. The latter group was included because granulomatous inflammation with necrosis has a high probability of being tuberculous in origin. Using this approach we are able to identify 325 cases in a period of approximately 14 weeks.

Cytomorphological spectrum in lymph node tuberculosis

The most common tissue reaction pattern 145/336 was predominantly exudative response, pattern 1 [145/336] comprising of neutrophils and mononuclear phagocytes. BI in this pattern ranged from 1+ to 4+ [Table 2]. Influx of polymorphs in more advanced lesions is believed to occur as a secondary complication of softening or liquefaction. [19] The liquefaction of the caseous centers of tubercles is one of the most harmful host responses in tuberculosis. Like caseation, it is associated with delayed type of hypersensitivity (DTH). Liquefaction seems to be due to hydrolysis of the protein, lipid, and nucleic acid components of caseous tissue by the hydrolytic enzymes of macrophages and granulocytes [20] with a resultant exudative response. A gradual decrease in enzyme inhibitors within the caseous focus may also contribute to liquefaction. In adults a tuberculous lesion is usually well controlled until its caseous center liquefies. The liquefied caseum is an excellent culture medium for the tubercle bacillus along with a possible increase in blood supply. In this menstruum, the bacillus extensively multiplies extracellularly for the first time and attains large numbers. This large antigenic load is toxic to tissues because of the presence of DTH. In this study, we also found that pattern 1 occurred more frequently with multibacillary lesion [Table 2].

The second most common pattern was granuloma with necrosis, pattern 4 (104/336). BI in this group ranged from 1+ to 2+. After being ingested by macrophages, the Mycobacteria continue to multiply slowly, with bacteria cell division occurring every 25 to 32 h. [21] Regardless of whether the infection becomes controlled or progresses, the initial development involves production of proteolytic enzymes and cytokines by macrophages in an attempt to degrade the bacteria. [22] Released cytokines attract T lymphocytes to the site, the cells that constitute cell-mediated immunity. Macrophages then present mycobacterial antigens on their surface to the T cell. [22] This initial immune process continues for 2 to 12 weeks; the microorganisms continue to grow until they reach sufficient numbers to fully elicit the cell-mediated immune response, which can be detected by a skin test. [22],[23] For persons with intact cell mediated immunity, the next defensive step is formation of granulomas around the M. TB organisms. [24] These nodular-type lesions form from an accumulation of activated T lymphocytes and macrophages, which creates a microenvironment that limits the replication and spread of the mycobacteria. [23] This environment destroys macrophages and produces early solid necrosis at the center of the lesion; however, the bacilli are able to adapt to survive. [25] In fact, M. TB organisms can change their phenotypic expression, such as protein regulation, to enhance survival. By 2 or 3 weeks, the necrotic environment resembles soft cheese, often referred to caseous necrosis, and is characterized by low oxygen levels, low pH, and limited nutrients. This condition restricts further growth and establishes latency. Lesions in persons with an adequate immune system generally undergo fibrosis and calcification, successfully controlling the infection so that the bacilli are contained in the dormant, healed lesions. [25] We observed that this pattern was more frequently associated with paucibacillary, i.e., BI = 1+ [Table 3].

The third-most common tissue reaction pattern 26/336 was pattern 3, epithelioid granuloma without necrosis. BI in this group ranged from 1+ to 2+ [Table 2]. This may be a manifestation of early disease before necrosis occurred. Literature [26] documents that with relatively low doses of bacillary antigen(s), and with intact immunity a compact proliferative type of accumulation of lymphocytes and macrophages occurs. This pattern in FNA smears may also occur due to the focal sampling of the node or when necrosis is limited to a small region.

The fourth-most common tissue reaction pattern was pattern 5, Acellular necrosis (24/336) [Figure 5]. BI in this group ranged from 1+ to 3+ [Table 2]. No granuloma formation or epithelioid cells were noted in these cases. Macrophages cannot penetrate very far into the caseous center. Caseum is avascular, and adjacent blood vessels are thrombosed. [27] It has a moderately acidic pH, a relatively low oxygen tension, and usually a relatively high concentration of bacillary components that are toxic to the cells of the hypersensitive host. Thus, macrophages cannot eliminate the tubercle bacilli within the caseous focus. Our study demonstrated areas of necrosis showed not only high positivity rate but bacterial density was also high, i.e., BI>1+ [Table 3].

The fifth-most common tissue reaction pattern we found was pattern 6 (21/336) i.e. Pattern 4 or 5 with preserved stromal fragments containing blood vessels. BI in this group ranged from 1+ to 2+ [Table 2]. Mycobacterium is an obligate aerobe and hence the bacilli tend to localize close to preserved as well as degenerated or necrosed blood vessels in the necrotic areas. [28] At times the centre of granulomas may undergo liquefied necrosis, acquiring a more fluid, pus-like consistency. It is now that oxygen creeps in and AFB multiplies. [28] Therefore, the numbers of organisms within the necrosis are variable.

The least common pattern observed was pattern 7 (11/336), in which loose histiocytic granulomas or foam cells were noted. BI ranged from 1+ to 6+ [Table 2]. In this group most patients (10/11) were HIV positive. In people with acquired immunodeficiency syndrome (AIDS), there are qualitative and quantitative defects in Th-1 (CD4+) cells. Hence, macrophages do not get activated. Non-activated macrophages release certain chemokines IL-1, TNF-α, and lytic enzymes which contribute to local tissue destruction and caseous necrosis and continuous proliferation of bacilli takes place within macrophages [Figure 1]0]. [29] Normally in immuno-competent persons, macrophage activation response takes place in response to T helper cells (Th-1) that activate macrophages to become bactericidal by release of IFN-g and IL-2, which stimulates formation of phago-lysosome and nitric oxide synthesis. These activated macrophages differentiate into epithelioid histiocytes and effectively neutralizes tubercle bacilli. [29]

Correlation of tissue reaction patterns with bacterial density

The initial estimation of BI was done using the 7-point (0 to 6+) Ridley-Jopling classification scale used for BI estimation in leprosy. The Ridley-Jopling classification scale was chosen for this study because it is highly standardized and has been widely used for the estimation of BI in all mycobacterial disease. In contrast in TB several modifications [30] of BI are used ranging from subdividing cases into AFB positive and AFB negative through low and high AFB positivity to a 5-point scale (0 to 4+). The intention in choosing the Ridley-Jopling classification scale was to achieve closer coordination of tissue reaction patterns with BI, should such coordination emerge. The correlation of AFB positivity with tissue reaction patterns in 380 patients with lymph node TB is shown in [Table 2].

Of 380 cases included in the study group only in two patterns, pattern 1 (predominantly exudative response comprising of neutrophils and mononuclear phagocytes) and pattern 4 (epithelioid cell granulomas with necrosis), were the number was large enough for statistical comparison. It was found that multibacillary disease more frequently occurs with pattern 1 (53.9%), compared to pattern 4 where it was only 23.4%. Although the BI varied significantly across different cytomorphological tissue reaction patterns (P value = 0.004), no trend was observed as both paucibacillary as well as multibacillary was seen with various proportions with all patterns.


   Conclusion Top


In conclusion seven distinct cytomorphological tissue reaction patterns were observed in AFB-positive lymph node TB, with the most common being pattern 1 followed by pattern 4. The present study showed that multibacillary disease is more frequently associated with pattern 1 compare to pattern 4. However, more studies are needed to establish a trend among different cytomorphological tissue reaction patterns.

Limitations of the study

Excluding AFB-negative cases from the study could be a limiting factor. However, the decision to include only AFB-positive cases was taken to ensure maximal confidence in the diagnosis of tuberculosis.

Further studies are needed to identify tissue reaction patterns that may predict low or high rates of AFB-positivity.

 
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Correspondence Address:
Ruquiya Afrose
Department of Pathology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.155019

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    Figures

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    Tables

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