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Peripheral Tuberculous Lymphadenitis

Epidemiology, Diagnosis, Treatment, and Outcome

Polesky, Andrea MD, PhD; Grove, William MD; Bhatia, Gulshan MRCP(UK)

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doi: 10.1097/
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Mycobacterial lymphadenitis, also known as scrofula, has been recognized for at least 3000 years. Hippocrates described scrofula in ancient Greece31. In medieval Europe, scrofula was known as the "King's Evil" because certain monarchs would touch patients to "cure" the disease31,53. In the 19th century, after Koch demonstrated mycobacteria in lymph nodes, scrofula was finally recognized to be a consequence of tuberculosis (TB)31. For most of the 20th century, lymphadenitis was treated with wide excision and prolonged antituberculous therapy1,11,15,16,24,35-37,40,49,60,80,88. Only in the modern era, with the introduction of effective short course rifampin-containing chemotherapy, has tuberculous lymphadenitis become an easily treatable medical disease12,14,20,48,54,76,83,94.

Although the total number of cases of TB continues to decline within the United States, the number of exclusively extrapulmonary cases of TB is declining much less rapidly and currently accounts for approximately 20% of all cases17. Thirty to 50% of all extrapulmonary cases of TB involve the peripheral lymph nodes17,25,38,71,73 making this a common entity in areas in the United States with a high incidence of TB. In Santa Clara County, California, the annual TB case rate between 1994 and 1999 averaged 16.3/100,000 population, in comparison to 7.8/100,000 population in the United States as a whole, with tuberculous adenitis accounting for 9% of all Santa Clara County cases17,73.

To better define the epidemiology of tuberculous adenitis within our community, we reviewed our single institution experience between 1994 and 1999 at the Santa Clara County Tuberculosis Clinic (SCCTBC) where we followed a large cohort of patients with TB adenitis. The SCCTBC follows all patients diagnosed with active TB through the Santa Clara County Health and Hospital System and its outpatient clinics as well as referrals from the community. Most of the diagnostic procedures, treatment, and follow-up were supervised by the authors. We were interested in evaluating the utility and efficacy of fine needle aspiration (FNA) versus excisional biopsy and comparing the relative contributions of cytology and histopathology in the diagnostic evaluation of patients with suspected tuberculous lymphadenitis. Treatment outcomes, complications, and relapse rates were recorded for this group of patients, 82% of whom received directly observed therapy for the entirety of their treatment. We present a diagnostic algorithm based on our experience for evaluating patients with suspected TB lymphadenitis.


We reviewed records to identify patients evaluated and treated in the clinic for peripheral TB lymphadenitis between June 1994 and June 1999 and identified 110 patients. In addition, we reviewed all the charts of patients who received a final diagnosis of active TB in 1999 and identified 123 patients who did not have peripheral TB adenitis as a comparison group. The charts of these patients were retrospectively reviewed for clinical presentation, management, and outcome. All patients underwent a medical history and physical examination on presentation to the clinic. Each patient either had a chest radiograph at the clinic or brought the radiograph ordered by the referring physician. Tuberculin skin tests (TSTs) of 5.0 tuberculin-units (Aplisol, Parkedale Pharmaceuticals, Rochester, MI) were placed, recorded, and interpreted according to United States guidelines23,85.

Most diagnostic procedures were performed at Santa Clara Valley Medical Center (SCVMC). The pathologist (most often WG) performed FNAs with a minimum of 4 passes of a 23-gauge needle in order to obtain adequate samples for culture and cytology. Cytology specimens were processed and stained with Diff-Quik (Dade Behring, Newark, DE) and Papanicolaou stains. Histology specimens were stained with hematoxylin-eosin. Ziehl-Neelsen stains were used to identify mycobacteria. Where possible, the histopathology and cytology slides were re-reviewed for all available cases by WG and every attempt was made to obtain pathologic specimens and reports from the other referring institutions. Re-review of the pathology and cytology slides was carried out to obtain a consistent evaluation and description of the cytologic and pathologic findings.

Microbiology specimens were processed according to guidelines and stained for mycobacteria using an auramine-rhodamine (fluorochrome) stain23. Specimens were inoculated into Bactec 460 12B (Becton Dickinson Microbiology Systems, Sparks, MD, before 1998) or BactT/Alert MP (Biomérieux Inc, Durham, NC) bottles and held for 42 days. All patients with cultures positive for Mycobacterium tuberculosis in the SCVMC microbiology lab were referred to the TB Clinic. Susceptibility testing on positive M. tuberculosis cultures was performed for isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin.

Antituberculous treatment was initiated with isoniazid (10-15 mg/kg in children and 300 mg in adults), rifampin (10-20 mg/kg up to 600 mg) or rifabutin (300 mg), ethambutol (15-20 mg/kg), and pyrazinamide (25 mg/kg) by mouth daily8,9. Therapy was directly observed 5 times a week for daily therapy and for all doses during intermittent therapy9.

Two-tailed p values were calculated using a chi-square, Fisher exact test, or a z statistic as appropriate.


Patient Characteristics

Between June 1994 and June 1999, we cared for 940 cases of TB at the SCCTBC; 110 patients were evaluated for peripheral TB lymphadenitis. Following detailed chart review, 4 patients were excluded from analysis. Of the 4 excluded, 3 patients received none of their treatment in the clinic and 1 patient was diagnosed with nasopharyngeal carcinoma and never received antituberculous medication.

Of the 106 patients evaluated and treated for TB included in the analysis, 77 patients were referred from within the Santa Clara County Health and Hospital System, 21 patients were referred by private physicians in the community, 4 patients were transfers from other county health departments, and 4 patients were new immigrants arriving in Santa Clara County with abnormal chest films. Ninety-one (86%) patients were followed in the clinic throughout their course and 15 (14%) had more than a month of treatment outside of the clinic.

Table 1 shows the characteristics of the patients with peripheral TB lymphadenitis compared with those of all TB patients without lymphadenitis in 1999. The lymphadenitis cohort included 70 female patients and 36 males with a female to male ratio of 1.9:1. The average age at diagnosis was 34.2 years (median, 29 yr; range, 2.3-77 yr). On average, 21 patients were diagnosed during each full year of the study.

Patient Characteristics

Ninety-eight of 106 (92%) patients were foreign born. Sixty-three patients emigrated from Vietnam to the United States, and 11 patients emigrated from Mexico. Twenty-four patients emigrated from at least 10 other countries. Six of 8 United States-born patients were of Hispanic ethnicity. The mean number of years of residence in the United States for foreign-born patients was 5.2 years (median, 4 yr; range, 0.8-23 yr).

Ninety-seven of 106 patients had no additional medical problems that would increase their risk for progression to active TB. Of the remaining 9 patients, 5 were human immunodeficiency virus (HIV) seropositive, 1 patient had had a renal transplant, 1 patient had dermatomyositis treated with methotrexate, 1 patient had had a Whipple procedure, and 1 patient had adult-onset diabetes mellitus.

TST status was known for 96 patients. Ninety of 96 patients (94%) had a positive skin test. Six of 96 (6%) patients had a negative skin test, 4 of whom were HIV seropositive. TST sizes were recorded in 59 of 96 (61%) patients with an average size of 17.9 mm (range, 0-35 mm).

Forty-four of 90 patients (49%) had positive TSTs for a year or more before the diagnosis of TB adenitis. Sixteen (15%) patients had received therapy for latent TB infection. Of the 16 patients who had received therapy, 14 received isoniazid. Eleven of 16 patients previously treated for latent TB had positive cultures for M. tuberculosis, and isoniazid-resistance was documented in only 1 of these cases.

Thirteen patients (12%) of 106 were treated for active TB previously (6 in the United States). Eight patients had prior lymph node disease, 4 had pulmonary TB, and 1 patient had pulmonary TB and lymphadenitis. Five patients with prior TB were treated with an effective and monitored regimen. Eight of 13 patients previously treated for TB did not receive appropriate therapy, could not recall the therapy received, or were noncompliant. For the 13 patients treated previously, 11 cultures were performed and 5 were positive.

Symptoms and Presentation

Table 2 shows the symptoms of the patients with peripheral TB lymphadenitis compared with those of patients without lymphadenitis. One hundred four of 106 patients (98%) presented with an enlarging mass. A history of fever and cough occurred in 19% and 18% of patients, respectively. A single initial temperature was available for 92 (87%) of 106 patients, and 88 patients were afebrile. Three HIV-seropositive patients and the renal transplant patient had documented fever at presentation (temperature > 38.5 °C). Other symptoms reported by patients were weight loss (16%), night sweats (13%), fatigue (12%), and anorexia (8%). Eight percent of patients (9/106) had draining lymph nodes at presentation (see Table 2).

Symptoms of Tuberculosis

The head and neck region was the most common location of adenopathy (Table 3). Cervical nodes were enlarged in 60 (57%) patients and supraclavicular nodes in 28 (26%) patients. Fourteen patients (13%) had submandibular adenopathy and 13 (12%) had axillary adenopathy. Other enlarged lymph nodes were less common (see Table 3). Adenopathy was bilateral in 18 (17%) cases. Eighty-three (78%) patients had between 1 and 3 nodes involved, 19 (18%) patients had 3-5 nodes involved, and 4 (4%) patients had more than 5 nodes involved. Ninety-four patients for whom there were adequate data had symptoms for an average of 23 weeks before diagnosis (median, 8 wk; range, 1-312 wk).

Signs and Extent of Tuberculosis


The diagnosis of TB was made by clinical presentation, biopsy with histopathology and culture of enlarged lymph nodes, chest radiograph, and sputum culture. Of the 106 patients treated for TB lymphadenitis, 101 patients had 120 initial biopsies for the purpose of diagnosis: 79 FNAs, 36 excisional biopsies, and 5 incisional biopsies. Five patients had no initial biopsy performed.

Eighty-four of 101 patients had a single biopsy (60 FNAs, 24 surgical biopsies) and 17 patients (12 in the FNA group and 5 in the surgical biopsy group) had 19 additional biopsies. Follow-up biopsies in the 17 patients were performed for the following reasons. In 3 patients, the initial biopsy showed granulomas, but no cultures were sent. In 6 patients, pathology showed granulomas but the biopsies were culture negative. In 6 patients, the initial pathology was nondiagnostic. In each case, repeat biopsy showed granulomas. In 2 patients, initial lymph node cultures obtained were positive, but the second biopsy was performed before the availability of final culture results. Follow-up biopsies provided additional diagnostic information in 12 patients (9 additional positive cultures, 2 additional acid-fast bacilli (AFB)-positive stains, and 1 biopsy with granulomas).

Forty (38%) of 106 patients had abnormal chest radiographs consistent with TB (see Table 3). Overall 15 (14%) patients had culture-positive pulmonary TB. Five of the culture-positive patients were immunosuppressed (1 renal transplant and 4 HIV-seropositive patients). The yield of sputum cultures with abnormal films (34/40 patients tested) was 14 of 34 (41%).

Ten (9%) patients had TB diagnosed in other locations including intrathoracic lymph nodes (3 patients) and breast, skin, and pleura in 1 patient each. Four patients had disseminated TB (TB involving more than 2 sites), 3 of whom were immunosuppressed.

Pathology and Microbiology Results by Biopsy Type

Ninety-five of the 120 (79%) biopsies used for initial diagnosis were performed at SCVMC and were interpreted by a single group of pathologists. To compare FNA to surgical biopsy, we looked at the pathologic and microbiologic diagnostic yield of both types of specimens.

As shown in Table 4, the pathology results were grouped into specimens that showed granulomas with necrosis, granulomas without necrosis, acute neutrophilic inflammation and necrosis, and other pathology. Granulomas (with and without necrosis) were seen on 62% (47/76) of FNAs compared to 88% (36/41) of surgical biopsies (p < 0.01). Furthermore, granulomas with necrosis were much less common in FNA specimens than in excisional biopsies (28% versus 71%, p < 0.01). On the other hand, the combination of acute inflammation and/or necrosis without granulomas was reported more often for FNAs than for excisional biopsies (28% versus 10%, p < 0.05), and this finding in an FNA specimen correlated with both a positive fluorochrome stain (10/21, 48%) and positive culture (16/21, 76%).

Interpretation of Initial Biopsies

Ziehl-Neelsen stains were performed on 39/41 surgical specimens and were positive in 15 (38%). Because of the small amount of material obtained by FNA, Ziehl-Neelsen stains were typically performed on FNA specimens when the fluorochrome stain in the microbiology lab was negative and adequate material was available to restain slides. Only 19 of 76 (25%) FNA specimens submitted for cytology were stained, and 5/19 (26%) were positive.

Comparing the microbiologic performance of FNA to excisional biopsy, the yield of fluorochrome stains performed on FNAs and excisional biopsies was similar (21% versus 26%, p = 0.5). Samples submitted for culture from FNAs and excisional biopsies also had an equivalent rate of culture positivity (62% versus 71%, p = 0.4).

Comparing the Ziehl-Neelsen and fluorochrome stains without regard to biopsy type revealed additional information. Not surprisingly, positive Ziehl-Neelsen and fluorochrome stains predicted a positive culture with 83% of Ziehl-Neelsen-positive specimens and 73% of fluorochrome-positive specimens growing M. tuberculosis (data not shown). On the other hand, the results of Ziehl-Neelsen and fluorochrome stains were not concordant, but rather additive. Because not all pathology specimens were stained for AFB and not all specimens were sent for microbiology, only 52 samples had both AFB stains performed. The Ziehl-Neelsen stain was positive in 10 specimens that were fluorochrome negative and the fluorochrome stain was positive in 2 Ziehl-Neelsen-negative specimens (data not shown).

Biopsies During Treatment

Eighteen of 106 (17%) patients had 23 biopsies and or drainage procedures during therapy (14 with 1 biopsy, 3 with 2 biopsies, and 1 with 3 biopsies). The 4 patients with multiple procedures were either immunosuppressed or children. Biopsies during therapy were performed an average of 4.9 months into therapy (median, 4.1 mo; range, 0.4-16 mo). Of the 18 patients, 9 (50%) patients had positive cultures initially. Biopsies and drainage procedures were repeated to confirm the diagnosis (especially in immunosuppressed patients and culture-negative patients) or for the comfort of the patient.

Fifteen of 23 biopsies during therapy showed granulomas and 2 showed inflammation and/or necrosis. One specimen was Ziehl-Neelsen positive and 4 additional biopsies were fluorochrome positive. All cultures were negative. Three excisional biopsies led to alternative diagnoses.

Results by Patient and Empiric Treatment

Table 5 shows the pathology and microbiology results by patient. One hundred two of 106 (96%) patients had biopsies done. (One patient's first biopsy was performed 3.5 months into therapy when she first transferred to clinic.) Ninety-nine of 102 (97%) patients had their specimens sent to pathology and granulomas were present in at least 1 specimen in 79 of 99 (80%) patients. A positive Ziehl-Neelsen stain was present in 21 of 53 (40%) patients for whom it was performed. Ninety-eight of 106 (92%) patients had lymph node cultures. Twenty-seven of 98 (28%) patients had positive fluorochrome smears and 70 of 98 patients (71%) had positive lymph node cultures (69 M. tuberculosis and 1 Mycobacterium avium complex). Two patients with negative lymph node cultures had sputum cultures positive for M. tuberculosis.

Results of Lymph Node Biopsies by Patient

Of the 34 culture-negative patients, 30 patients improved on antituberculous therapy and received a diagnosis of TB lymphadenitis. In addition to improvement on therapy, the diagnostic criteria for TB in 25 patients were the presence of a positive AFB stain and/or the presence of compatible pathology (granulomas and/or inflammation and necrosis). Eleven patients had a positive AFB stain on at least 1 specimen during treatment. Thirteen patients were treated on the basis of granulomas, and 1 patient on the basis of inflammation and necrosis.

Four TST-positive children (ages 3, 7, 9, 10 yr, respectively) newly arrived in the United States from areas of high TB endemicity with abnormal chest films were treated without a biopsy. Two of the children had prior partial inadequate treatment overseas. All responded to antituberculous treatment. Three children's chest films improved by the end of treatment (2 with hilar/mediastinal adenopathy and 1 with parenchymal disease) and the fourth child's peripheral lymphadenopathy improved. A fifth patient with an inadequate biopsy was also treated empirically, and her adenopathy resolved.

Three patients, with granulomas on initial biopsy, had other diagnoses made with additional biopsies (2 lymphomas and 1 pilomatrixoma). A fourth patient's initial biopsy was delayed and he received 5 weeks of therapy before the diagnosis of nasopharyngeal carcinoma.

Figure 1 shows how final diagnoses were made by patient and biopsy type, incorporating the results of biopsies during therapy. The diagnosis of TB was made with the use of a single FNA in 58/73 (79%) patients, a single surgical biopsy in 24/29 (83%) patients and a combination of procedures in 14 patients. Five patients (3 with improved pulmonary infiltrates or adenopathy on chest radiography) were treated without a diagnostic biopsy. Five patients had other definite diagnoses made with either an initial (2 patients) or second (3 patients) procedure. Thus 101/106 (95%) patients received a final diagnosis of TB (see Table 5).

Outcome of patients started on antituberculous medication by biopsy type. *TB diagnostic criteria include a positive culture; a positive AFB smear in patients with a positive culture; or pathologic findings of granulomas, granulomas with necrosis, and inflammation and necrosis in patients without a positive culture or AFB smear. This group includes 1 patient with a nondiagnostic initial biopsy and 2 patients with initial biopsies consistent with TB who had a positive AFB stain during treatment. Abbreviations: Pt = patient; Bx = biopsy; Dx = diagnosis; FNA = fine needle aspirate; MAC = Mycobacterium avium complex; NPC = nasopharyngeal carcinoma; Tx = treatment; c/w = consistent with; Nondx = nondiagnostic; CXR = chest radiograph; Cx = culture; AFB = acid-fast bacilli; Path = pathology; Micro = microbiology; TB = tuberculosis.

Expansion of and Drainage from Lymph Nodes During Therapy

Paradoxical expansion due to TB during monitored therapy was seen in 20 of 101 patients (20%). Paradoxical expansion involved the initially enlarged nodes (11 patients) or a new site (9 patients). Ten patients' initial lymph node biopsies were culture positive for M. tuberculosis. Lymph node expansion occurred, on average, 3.5 months after therapy was initiated (range, 0.5-16.75 mo). New and expanding lymph nodes took an average of 3.9 months to resolve (range, 1.0-8.5 mo). Paradoxical expansion was common in HIV-seropositive (3/5) and immunosuppressed (2/4) patients, although the number of patients is small.

Patients presented with complaints of new lymph node enlargement (20 patients), fluctuance (14 patients), pain (12 patients), erythema (12 patients), and spontaneous drainage (12 patients). Only 1 HIV-seropositive patient and the patient with a renal transplant had constitutional symptoms. Patients were treated with antituberculous medication and aspiration (5 patients). Eight patients had FNAs performed. Excisional biopsy was used to treat 2 culture-negative children and 2 immunosuppressed patients. No patient received steroids. All cultures of aspirates or repeat biopsy material were negative. Granulomas and/or a positive AFB stain were present in 11 of 12 biopsies.

During therapy, 17 of 101 patients (16%) developed draining nodes an average of 2.1 months (range, 0.25-9.25 mo) after therapy started. Development of drainage was associated with initially expanding and fluctuant nodes in 5/17 patients and paradoxical expansion of lymph nodes in 12/17 patients. Ten patients' initial lymph node biopsies were culture positive. All lesions healed spontaneously with antituberculous treatment in an average of 2.5 months (range, 1-4.25 mo). Development of drainage was not temporally associated with biopsy procedures. Although the majority of patients (13/17, 76%) with drainage had an FNA initially, a similar percentage of all patients had an initial FNA (72/101, 71%, p = 0.4).


There were 13 TST-positive patients under the age of 18 years. The 4 children with abnormal chest films who responded to empiric antituberculous therapy have been described above. All had bilateral cervical and in 2 cases bilateral axillary adenopathy. Three patients, with cervical adenopathy and normal chest films, ages 15-16 years, had positive lymph node cultures for M. tuberculosis.

Differentiating between adenitis due to TB and nontuberculous mycobacteria was most difficult in 6 young children (aged 2.25-6 yr) with normal chest films and unilateral adenopathy. M. avium complex grew from a lymph node excised from a child with cervical and posterior auricular adenopathy, and his antituberculous therapy was discontinued. Five children were treated with a combination of excisional biopsy and antimycobacterial therapy. Three of these 5 children, with submandibular area adenopathy and FNA as the initial diagnostic procedure, had a prolonged course of adenopathy and spontaneous drainage, despite repeated excisions and combined therapy for M. avium complex and M. tuberculosis.

HIV-Seropositive Patients

The 5 HIV-seropositive patients in the cohort had a mean CD4 cell count of 50 μl/L (range, 10-130 μl/L). TB was the presenting acquired immunodeficiency syndrome (AIDS)-defining diagnosis in 4 patients. Four of 5 patients had negative TSTs. All patients presented with constitutional symptoms (fever 100%; cough 80%; weight loss 60%; night sweats, anorexia, and fatigue 40%). Mycobacterial sputum cultures were performed in 4 patients and all had concurrent active pulmonary TB, including 1 patient with a normal chest film. Two patients had disseminated TB.

The diagnosis of TB lymphadenitis was made by FNA in 3 patients, by excisional biopsy in 1 patient, and by a combination of FNA and excisional biopsy in the remaining 2 patients. Granulomas were present in all 5 patients, and a positive AFB smear in 4. Lymph node cultures were positive in all 5 patients.

Treatment included both antituberculous treatment and antiretroviral therapy in all patients. Three of 5 patients had paradoxical expansion of lymph nodes during therapy, and 2 were rebiopsied and showed granulomatous changes. In 2 cases, paradoxical expansion occurred within 2 months of starting antiretroviral therapy in association with a rising CD4 cell count and falling HIV viral load. The third patient had been on antiretroviral therapy with a stable CD4 cell count for 6 months. There were no deaths, treatment failures, or relapses in this group of patients.

Therapy and Response to Therapy

Treatment lasted an average of 7.2 months and a median of 6 months. Of the 71 cultures positive for M. tuberculosis (including 2 sputum samples), 64 isolates were susceptible to all primary drugs tested (isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin) and 7 (10%) were resistant to at least 1 drug. One isolate was resistant to isoniazid and 1 to pyrazinamide. Two isolates were resistant to streptomycin, and 2 were resistant to isoniazid and streptomycin. One isolate was resistant to isoniazid, pyrazinamide, and streptomycin. Eighty-seven patients (82%) had directly observed therapy and 17 (16%) were followed by a combination of directly observed therapy, weekly pill count, and self-administered therapy. Two of 106 patients received only self-administered therapy.

Ninety-four of 106 (89%) patients completed treatment in clinic. Of the 12 patients not completing treatment in clinic, 5 patients had other diagnoses made, 2 patients were lost to follow-up, and 4 patients moved to another county. One patient's therapy was discontinued during retreatment and her lymphadenitis resolved off therapy.

Drug toxicity occurred in 16 of 106 (15%) patients. In 15 patients, antituberculous medication was successfully restarted following sequential rechallenge. Rechallenge led to the discontinuation of a single medication in 12 patients. Three patients discontinued no medications. One patient discontinued all medications secondary to hepatitis during retreatment.

All patients who completed treatment in clinic had improvement of adenopathy on therapy. Twenty-four of 94 patients (26%) had palpable nodes less than 1 cm at the end of therapy. No patient required excision of adenopathy after therapy was complete. Sixteen of 80 (20%) adult patients, for whom data are available, had documented weight gain at the end of treatment of at least 4.5 kg. These 16 patients included an overlapping group of patients with AIDS (4/5), other immunosuppression (2/4), disseminated TB (4/4), and pulmonary TB (6/16).

Patient Follow-up, New Adenopathy After Therapy, and Relapse

Patients were followed for an average of 9.8 months (range, 0-93 mo) after the end of therapy. Eight of 94 (9%) patients with available follow-up had 12 episodes of increased adenopathy after therapy was completed. Posttherapy lymphadenopathy occurred on average 27 months (range, 2.25-93 mo) after therapy was completed, with 5 episodes occurring at an old site and 7 occurring at a new site. Seven patients were rebiopsied. Granulomas were seen in 5 of the 6 samples analyzed, and a positive AFB stain was present in 3 patients. One patient had a positive lymph node culture sensitive to all primary antituberculous medications 8 years after initial treatment. This is the only culture-positive relapse in the cohort to date.

Two patients were retreated for 6 months and a third patient's therapy was discontinued when she developed drug-induced hepatitis. Five patients were followed. All of the patients with recurrent adenopathy who were followed without treatment or excision had resolution of their adenopathy within 3 months.


Peripheral tuberculous adenitis remains an important cause of adenopathy globally. It is a common manifestation of extrapulmonary TB in the developed world and accounts for approximately half of the annually reported cases of extrapulmonary disease in Santa Clara County72,73. The pathogenesis of this disease has been the subject of much debate as it is not clear if TB lymphadenitis represents local disease or is part of a generalized process40,45,57,60,80,88,90. While most cases in adults reflect reactivation or postprimary TB, there are reports in the literature suggesting that the enlargement of the nodes in the head and neck are representative of primary local infection of the tonsils or nasopharynx57,80,86,88,93.

Although TB lymphadenitis is thought of as a disease of young children in areas where TB is highly endemic, in areas of the world where TB is less common it is most often seen in young healthy adults1,15,36,40,62,83. In agreement with previous data, the incidence of tuberculous adenitis in our cohort was highest among women, and a positive TST was noted in 90% of cases1-3,15,16,20-22,29,36,47-49,52,62,64,68. TB patients without peripheral lymphadenitis in our clinic were older and had a higher male predominance, but were equally likely to have a positive TST (see Table 1).

Most of our patients were foreign born, consistent with the epidemiology of TB in Santa Clara County (83%-94% of patients foreign born)73. It is noteworthy that Vietnamese patients made up 60% of the case patients but only 32% of patients in our comparison cohort (see Table 1). The propensity of TB lymphadenitis to occur in immigrants from Asia has been noted previously25,52,64,67,71, and may be related in part to the age at immigration67. TB lymphadenitis in the United States has been reported disproportionately in Asian immigrants aged 15-44 years67,71, and this observation explains the different representation of Asian countries in the lymphadenitis and non-lymphadenitis cohorts. Patients from the Philippines in the clinic are on average older than patients from Vietnam, although they have been in the United States for a similar period of time (data not shown).

Nine percent of lymphadenitis patients had medical diagnoses associated with an increased risk of progression to active TB85. HIV infection was the most common underlying condition74. Diabetic patients, who are at significant risk for pulmonary TB44,61 and currently account for 17% of our caseload, were notably few in the lymphadenitis cohort (see Table 1).

In agreement with most series1,2,5,16,21,22,40,48,62,80, tuberculous lymphadenitis occurred in an insidious manner with a minority of patients having constitutional symptoms. There is a small group of series, however, where constitutional symptoms are reported in a majority of patients20,29,41,92. An explanation of these differences is probably multifactorial; it is likely that these cohorts contain more immunosuppressed patients, hospitalized patients, or patients with delayed presentations. Our patients were mostly outpatients, and only 5% were HIV seropositive (see Table 2).

Active pulmonary TB occurs infrequently in immunocompetent patients with TB lymphadenitis1,15,20,21,36,48,49,52,62,80,93. However, all patients presenting with adenopathy should have a chest radiograph performed as part of the initial evaluation. Fifteen percent of patients in the cohort overall had concurrent active pulmonary TB, but 41% of patients with abnormal films suggestive of TB had culture-positive pulmonary TB.

In immunocompromised patients, symptomatic pulmonary disease and disseminated disease are the norm74,78,87. Five of the 6 most immunosuppressed patients (5 HIV-seropositive patients and 1 renal transplant recipient) had active pulmonary disease, and 3 of the 4 patients with disseminated disease were immunocompromised. Since HIV-seropositive patients with normal chest films can have active pulmonary TB30,66, mycobacterial sputum cultures should be performed in this group of patients regardless of chest film results.

Most of our patients started therapy based on pathology results while waiting for culture results. To review how pathology results correlated with procedure type and diagnosis, we divided the histopathology results into granulomas with necrosis, granulomas without necrosis, necrosis and neutrophilic inflammation, and other32,33.

Granulomas (with and without necrosis) provided an immediate presumptive diagnosis for patients with positive TSTs and a compatible clinical syndrome48. Because of the amount and type of material obtained by excision, granulomas were seen in 88% of surgical biopsies compared with 62% of FNAs (see Table 4). The yield of FNAs for granulomas is consistent with the 55%-85% yield of FNA for granulomas in immunocompetent patients cited in the literature3,6,20,32,48,56. Granulomas with necrosis, which are more specific for TB, were more common in excisional biopsy specimens compared with FNA specimens (71% versus 28%, respectively).

On the other hand, necrosis and acute inflammatory changes were more common in FNA specimens than in surgical biopsies (28% versus 10%, respectively). This is in agreement with published data4,7,26,28,29,32,33,56,70 and may be related to the fact that fluctuant lesions are ideally approached with needle aspiration. AFB smear positivity and a positive culture are commonly seen in samples showing necrosis (see Table 4)4,7,26,28,32,33,56,68,70.

Selection bias does not entirely account for the observation that samples with inflammation and necrosis had a high yield of smear and culture positivity. Although the number of patients with TB not referred to clinic with culture-negative lymph node biopsies showing necrosis and inflammation is unknown, we think this number was small because the pathologist obtaining the sample was an important part of the referral process. Even though inflammatory changes in FNAs are not specific for TB10, the presence of necrosis and acute inflammatory changes in a biopsy sample should highlight the need for mycobacterial staining and culture of the sample in the young foreign-born patient with a positive TST4,7,10,26,28,33,56,68,70.

Ziehl-Neelsen stains should be performed whenever TB is considered part of the differential diagnosis on excisional biopsies. On cytology specimens, Ziehl-Neelsen stains should be performed when the fluorochrome is negative. Although labor intensive, Ziehl-Neelsen stains of pathologic material provide additional information to the fluorochrome stain.

In the current series, cultures were positive in 65% of biopsies overall: 62% of FNA specimens versus 71% of excisional biopsy specimens. The yield from FNA for positive cultures in the literature is quite variable (17%-82%)7,20,29,33,46-48, and the few direct comparisons of FNA and surgical biopsy show a significantly higher percentage of positive cultures from surgical biopsy material46-48. These differences may reflect a variety of confounding variables including sampling error and inadequate sampling, poor laboratory handling of the specimen, and misdiagnosis5. In this series, the pathologist (usually WG) performed the FNA and coordinated the handling of microbiology and cytology specimens, perhaps increasing the yield in both areas.

It is possible that in patients with equivocal results on FNA there may be an increasing role for the use of PCR when the suspicion of TB adenitis is high6,65,79,92. Unfortunately this still does not replace the need for culture and sensitivity data with which to guide therapy65,79,92.

We found that a single FNA led to a diagnosis in 58 of 73 (79%) patients (see Figure 1). The indications for most repeat biopsies at the initiation of therapy were a negative culture and a nondiagnostic biopsy. Surgical biopsies were repeated in 5 of 29 (17%) cases. Most initial surgical biopsies performed were at other institutions (20 of 29), and the reason for a second biopsy in many of these patients was failure to consider TB in the initial diagnosis leading to a failure to send samples for culture25.

Patients who underwent subsequent biopsies during therapy were those patients who did not respond to therapy within the first 2 months or who had expanding and draining nodes. Excisional biopsies during therapy were performed in a minority of patients. In culture-negative patients, excisional biopsy led to alternative diagnoses in 3 cases with granulomas present on initial FNA. It is noteworthy that 2 of the patients with granulomas on initial FNA (1 sample with necrotizing granulomas) were subsequently diagnosed with lymphoma. The differential diagnosis of granulomas is broad, and in rare cases malignancy can present with granulomas26,42,95. Among culture-positive patients, 1 HIV-seropositive patient and the transplant patient had excisional biopsies during treatment because of their risk of multiple coexisting infections and lymphoma.

There are few direct comparisons of FNA to surgical biopsy in the same patient from which true sensitivities and specificities of cytologic changes consistent with TB can be calculated. Lau et al46 reviewed 1349 FNAs and found 90 FNAs followed by surgical biopsies revealing changes consistent with TB. Retrospectively, FNAs showed granulomas in 70% of samples and granulomas and/or AFB in 77%46. A follow-up prospective study of FNA followed by excisional biopsy in 74 patients with suspected TB lymphadenitis showed that 77% of FNAs had granulomas47. Shariff and Thomas75 compared the results of 46 FNAs followed by excisional biopsies and found that the surgical biopsy confirmed the diagnosis of TB in 87% of patients, but provided an alternative diagnosis, including 1 lymphoma and 3 necrotizing metastatic carcinomas, in 13% of patients.

In summary, FNA has played an increasing role in the evaluation of persons presenting with adenopathy, as it is easily performed and eliminates the need for surgery. The complication rate following FNA is small20,28,47,48 compared to surgical biopsy3,35,80,81, and we observed no complications in this series. While excisional biopsy has been the traditional procedure of choice16,18,80, our experience and that in the literature support the use of FNA as the initial method of evaluation in immunocompetent patients3,7,20,29,46-48,69. However, granulomas are present less often in FNAs, and inflammation and necrosis are not specific for TB. Therefore, FNA interpretation requires the physician to take into account the clinical and epidemiologic characteristics of the patient. Nondiagnostic FNAs can be easily repeated and excisional biopsies can be performed in the small group of patients in whom the diagnosis remains in doubt.

The choice of diagnostic procedure in HIV-seropositive patients and other immunosuppressed patients is more difficult. FNA in HIV-seropositive patients has a lower sensitivity for granulomas and the presence of granulomas is less specific26,50. FNA was quite helpful in our cohort when the AFB smear was positive, when the lymph node was fluctuant, and when confirmation that lymph nodes were tuberculous was needed in patients with TB at other sites.

Empiric therapy was given to 30% of our patients. Every attempt was made to ensure that adequate initial biopsy material was obtained, mycobacterial stains were performed on all specimens, and an initial chest radiograph and sputum cultures were performed if appropriate to increase the certainty of the diagnosis before therapy. The diagnosis of TB in the absence of a positive culture requires a combination of epidemiologic and histopathologic criteria as well as a trial of antituberculous medication. Granulomas or inflammation and necrosis with a positive AFB stain in a TST-positive foreign-born patient was highly suggestive of TB in this series. In the 17 patients with pathology consistent with TB and negative stains and cultures, TB was still likely and 14 patients were considered to have TB based on their clinical response to therapy.

Our experience with children was mostly favorable. Nine of 13 children with epidemiologic risk factors for TB either had culture-proven disease or clearly responded to medical therapy. One child's biopsy specimen grew M. avium complex, and 3 culture-negative children younger than 6 years of age with normal chest films and unilateral submandibular adenopathy had a poor response to combined antituberculous and M. avium complex therapy after initial FNA. Their courses were also consistent with atypical mycobacterial adenitis64,81. Consideration should be given to performing an excisional biopsy as the initial diagnostic procedure early in therapy in this group for both diagnostic and therapeutic reasons19,27,34,51,64,81,82,84,89,91.

Therapy for tuberculous adenitis is uniformly successful with the current standard multidrug antituberculous regimen. In a series of prospective studies by the British Thoracic Society12-14,76,77, medical therapy was shown to be highly efficacious. Current short course rifampin-containing medical therapy after initial diagnostic biopsy12,13,20,21,48,83,94 has made the need for radical surgical excision and surgical excision with prolonged drug therapy obsolete1,11,15,16,24,35-37,40,49,60,80,88. Treatment duration is typically 6 months, and this duration has been shown to be as effective as regimens of 9-18 months 12,54,76,77,94. Cure rates of 95%-99% have been reported for patients treated with 6-month regimens5,14,48,54,94.

The British Thoracic Society studies documented that paradoxical expansion during therapy occurred in 23%-25% of patients12-14,25,29,77. Paradoxical expansion was noted in 20% of patients in the current study. Immunosuppressed patients had higher rates of paradoxical expansion in this cohort. The HIV-seropositive patients received antiretroviral therapy, which in 2 cases was associated with paradoxical expansion of lymph nodes as part of a well-recognized immune reconstitution syndrome58,59,63.

Seventeen percent of patients had spontaneous drainage of lymph nodes. The timing of drainage, the association with expanding lymph nodes (sometimes at sites distant from the original node), the response to antituberculous therapy, and the fact that drainage was independent of biopsy type suggest that drainage is part of the natural history of TB lymphadenitis.

Residual palpable adenopathy after cessation of therapy has been reported in 5%-30% of patients12,14,39,77. Less than 1 cm residual nodes were palpable in 26% of our patients overall, and no patient required excision at the end of therapy.

Lymphadenopathy occurring after therapy is a difficult problem in that relapse must be differentiated from posttherapy paradoxical expansion, which may occur in 4%-11% of patients12,14,55,76,77. Why patients develop enlarging lymph nodes that are culture negative and often resolve spontaneously is unclear, but the process may be immunologically mediated12. Nine percent of the cohort developed recurrent adenopathy after adequate monitored therapy. As our experience in treating patients with this disease entity grew, our inclination to consider retreatment in the absence of a positive culture diminished. Only 1 patient with new adenopathy had a documented culture-positive relapse.

Based on our extensive and ongoing experience with tuberculous adenitis in the setting of an urban developed community with a large foreign-born population at risk for TB, we have developed a diagnostic algorithm for the evaluation of peripheral lymphadenopathy in our clinical practice (Figure 2). We recommend that all patients found to have palpable adenopathy undergo a clinical assessment, TST, and chest radiograph. If the patient is at high risk for tuberculous adenopathy, the next step should be an FNA. If the FNA contains an adequate sample and is consistent with TB, empiric therapy can be started pending culture data. Patients who have equivocal results on the initial FNA should have a repeat FNA or an excisional biopsy. Depending on the clinical situation, we have a lower threshold for excisional biopsy in HIV-seropositive and other highly immunosuppressed patients. In the event of a poor clinical response and a negative culture, an excisional biopsy should be performed.

Diagnostic and treatment algorithm for patients with suspected tuberculous adenitis. *Other tests including serologies for Bartonella, Coccidioides immitis, and Toxoplasma and the Histoplasma capsulatum urine antigen should be ordered depending on patient characteristics. Cytology results consistent with TB include granulomas with or without necrosis and inflammation and necrosis. Patients with fluctuant nodes can usually be drained in clinic. §These lymph nodes may resolve with observation. Abbreviations: TST = tuberculin skin test; FNA = fine needle aspirate; CXR = chest radiograph; HIV = human immunodeficiency virus; Dx = diagnosis; TB = tuberculosis.

Immunocompetent patients with positive initial cultures presenting with recurrent or new nodes on therapy should undergo repeat FNA to confirm the initial diagnosis and to exclude the presence of another diagnosis if the lymph nodes fail to resolve quickly. In immunosuppressed patients where lymphoma remains in the differential diagnosis, an excisional biopsy should be performed if the lymph nodes are not fluctuant. Excisional biopsies are rarely necessary for fluctuant lymph nodes; however, repeated aspiration may be required for the comfort of the patient.

New lymphadenopathy after therapy should be re-evaluated based on the adequacy and monitoring of the initial therapy. A follow-up FNA and/or excisional biopsy should be performed to confirm the diagnosis of granulomatous disease. The lymph node should be followed for resolution. We are currently not retreating patients with negative cultures and documented compliance with initial therapy.


We thank William Jensen, MD, for critically reviewing the manuscript.


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