Pictorial essay: PET/CT in tuberculosis

In routine practice, oncologic workup is responsible for the majority of referrals for whole-body FDG-PET/CT. The indications in oncology include staging, restaging, assessment of therapy response, and detection of recurrence. In spite of the great success achieved by FDG-PET imaging in the evaluation of malignant disorders, the modality is not specific for the diagnosis of cancer.[1] It has been noted that processes such as infection and inflammation, and particularly granulomatous diseases, also cause increased FDG uptake in the affected tissues.[2–6] 
 
Tuberculosis (TB) is a chronic granulomatous inflammation caused by Mycobacterium tuberculosis. India accounts for nearly a third of the global burden of tuberculosis, with approximately 1.8 million new cases of tuberculosis reported every year.[7] Although it involves the thorax most frequently, any organ system in the body can be infected. The clinical and radiological features of tuberculosis are known to mimic those of many other diseases. The role of FDG PET and PET/CT in TB and other inflammatory diseases is evolving and is not as yet clearly defined. 
 
At the same time, there is a considerable increase in PET/CT referrals for patients with fever of unknown origin (FUO), generalized lymph node (LN) enlargement, and mediastinal or abdominal lymphadenopathy, especially when other investigations are inconclusive. The aim of such referrals is generally to rule out an underlying malignant disease or to detect an inflammatory pathology. Infections remain the most frequent cause of FUO, followed by neoplasms and noninfectious inflammatory diseases.[8,9] In India, TB is known to be the commonest infection to present as FUO.[10] ′The high sensitivity of FDG PET in detecting malignant lesions, infections, and other inflammatory processes alike, makes it an important tool that has the potential to play a role in the diagnostic protocol and management of patients with FUO.′[11,12] 
 
While performing FDG PET/CT for oncologic workup, we found TB to be a common cancer mimic, producing uptake patterns that are indistinguishable from that of cancer. Many studies have documented increased FDG uptake in active TB in diverse anatomical locations, mimicking malignant processes.[5,6,13–17] Though a high standardized uptake value (SUV), greater than 2.5, is attributed to malignant lesions,[18] we have encountered high values of peak SUV, upto 21.0 (range 2.2-21.0), in tuberculous lesions Figures [​[11–7]. 
 
 
 
Figure 1 (A-E) 
 
Mediastinal lymphadenopathy in a patient of carcinoma colon who, post-hemicolectomy and post-chemotherapy was detected to have raised tumor marker (CEA) levels. Coronal plain CT (A), PET (B), PET/CT (C) with axial plain CT (D), and PET/CT (E) images of ... 
 
 
 
 
 
Figure 7 (A-D) 
 
Disseminated TB with multifocal hepatic and diffuse splenic uptake. Coronal plain CT (A) and PET (B) with axial PET/CT (C, D) images in a patient with FUO show diffuse increased FDG uptake in an enlarged spleen and multifocal uptake in the liver, mediastinal ... 
 
 
 
 
 
Figure 6 (A-D) 
 
Repeat axial CT (A), PET/CT (B) images of the thorax, and axial (C) and coronal (D) PET/CT abdomen images of the same patient described in Figure 5 show complete resolution of the liver lesion and a considerable reduction in the size of the left hilar ...

Tuberculosis (TB) is a chronic granulomatous infl ammation caused by Mycobacterium tuberculosis.India accounts for nearly a third of the global burden of tuberculosis, with approximately 1.8 million new cases of tuberculosis reported every year. [7]Although it involves the thorax most frequently, any organ system in the body can be infected.The clinical and radiological features of tuberculosis are known to mimic those of many other diseases.The role of FDG PET and PET/CT in TB and other infl ammatory diseases is evolving and is not as yet clearly defi ned.
At the same time, there is a considerable increase in PET/CT referrals for patients with fever of unknown origin (FUO), generalized lymph node (LN) enlargement, and mediastinal or abdominal lymphadenopathy, especially when other investigations are inconclusive.The aim of such referrals is generally to rule out an underlying malignant disease or to detect an infl ammatory pathology.Infections remain the most frequent cause of FUO, followed by neoplasms and noninfectious infl ammatory diseases. [8,9]In India, TB is known to be the commonest infection to present as FUO. [10]The high sensitivity of FDG PET in detecting malignant lesions, infections, and other infl ammatory processes alike, makes it an important tool that has the potential to play a role in the diagnostic protocol and management of patients with FUO.' [11,12] While performing FDG PET/CT for oncologic workup, we found TB to be a common cancer mimic, producing uptake patt erns that are indistinguishable from that of cancer.Many studies have documented increased FDG uptake in active TB in diverse anatomical locations, mimicking malignant processes.[5,6,[13][14][15][16][17] Though a high standardized uptake value (SUV), greater than 2.5, is attributed to malignant lesions, [18] we have encountered high values of peak SUV, upto 21.0 (range 2.2-21.0), in tuberculous lesions [Figures 1-7].PET/CT att enuation correction was done.Images were reconstructed using a standard iterative algorithm and reformatt ed into transaxial, coronal, and sagitt al views.Fusion images of PET and CT were obtained.The PET/CT images were evaluated by one radiologist and one nuclear medicine physician in all cases.Focal accumulation of FDG above the background muscle uptake in an abnormal location was considered a positive fi nding. Areas oncreased uptake were evaluated qualitatively and quantitatively using standard methods.[19] The peak SUV (SUV max ) of the abnormal areas was noted.

Case Material
All studies were performed on an integrated PET/CT scanner (Biograph 2, Siemens Medical Solutions, Erlangen, Germany).A whole-body PET/CT study, from the skull base to the mid-thigh level, was performed 1 h aft er intravenous injection of 370 MBq of FDG.Nonenhanced CT scan images were obtained, using 130 KV and 100 mAs.CT-based Patients with a diagnosis of tuberculosis were identifi ed from the database.A large number of these were referred for workup of FUO or lymphadenopathy [Figures 5-9

Role of Accompanying CT Scans
CT images of PET/CT were helpful in characterizing the lesions morphologically and in some instances, especially in lung and bone lesions, were indicative of a tuberculous etiology.We did not use intravenous contrast enhancement for our CT scans.However, the use of intravenous contrast  brain abscess should be considered when FDG accumulates at the periphery of a ring-enhancing lesion in a chronically ill or immunocompromised patient.' [20] FDG-PET shows intense tracer uptake at the periphery of the lesion in a ring-like or 'doughnut' patt ern, with low uptake within the abscess cavity [Figure 2].

Thorax
Intense FDG uptake is usually noted in active tuberculous lesions involving the lung parenchyma [6,21] [Figure 3].This is att ributed to the presence of a large number of activated macrophages which have a high glycolytic rate.The CT images in PET/CT may add useful morphological information in defi ning the nature of the lung lesions.PET may help in determining the activity in the lesions, define the extent of disease, and aid in assessing the response to therapy.High FDG uptake has been reported in tuberculomas [16] [Figure 4].
A common dilemma faced during oncologic workup with FDG-PET/CT is the presence of FDG-avid mediastinal or hilar nodes in cases of extrathoracic malignancies (e.g., carcinoma colon, renal cell carcinoma, or carcinoma cervix).In these entities, isolated mediastinal nodal metastases are uncommon and tuberculosis may be the cause of FDG-avid mediastinal or hilar adenopathy [Figure 1].

Lymphoreticular system
[23] We found FDG-avid tuberculous nodes in may increase the specifi city of diagnosis in some instances, by more accurately demonstrating the presence of necrosis in enlarged lymph nodes or the presence of typical focal lesions in the liver and spleen.  .Also, disseminated TB can variably involve the liver and spleen.In proven cases of disseminated TB, we found varied patt erns of increased FDG uptake in the liver and spleen, some showing diff use and others focal uptake [Figures 7 and 8].

Skeletal system
Osteomyelitis: Tuberculous osteomyelitis is a common entity in Asian countries, with frequent involvement of the spinal column.This entity classically involves contiguous dorsal or lumbar vertebral bodies and the intervening discs, oft en associated with abscess formation and granulation tissue.FDG-PET has a high sensitivity for the detection of chronic osteomyelitis. [24]Tuberculous lesions are found to have increased FDG uptake in the active regions of granulomatous infl ammation, with cold areas that represent necrosed tissue (pus) [25] [Figures 9 and 13].

Abdomen
Although TB can involve any part of the gastrointestinal tract, from the esophagus to the anal canal, the most commonly involved regions are the distal ileum and cecum.The lesions may be ulcerative, proliferative, or ulceroproliferative.The latt er type may present as a bowel mass, indistinguishable from bowel cancer on routine imaging modalities and may exhibit intense uptake on FDG-PET imaging [14] [Figures 10 and 11].Involvement of the adrenal gland may also present with FDG avidity [Figure 12].The role of FDG-PET in assessing the urinary system is limited because of the interference caused by the high concentration of the excreted FDG in urine, which masks FDG-avid lesions.

Dual time point imaging
Studies have documented the value of additional delayed images, obtained 90-120 min after FDG injection, in diff erentiating benign from malignant lesions.On delayed images, inflammatory lesions show increased FDG washout, whereas cancerous lesions usually exhibit further accumulation of tracer. [26,27]However, in our experience, in 15 TB patients, we found equivocal results with dual time point imaging at 45 and 120 min post-FDG injection; a majority of the tuberculous lesions showed no reduction, a few showed mild reduction (up to 20%), and many showed an increase (varying from 10-40%), in peak SUV.

The future
FDG-PET has a high sensitivity for infection and infl ammation but poor specifi city.One approach that may increase the diagnostic accuracy of PET for tuberculosis includes the combined use of F-18 FDG and C-11 acetate, as the latt er accumulates in tumors but not in infl ammatory lesion. [28]hus, C-11 acetate may help diff erentiate infl ammation from neoplasms.In the future, labeling antituberculous drugs like isoniazid and rifampicin with positron emitt ing isotopes may culminate in the development of TB-specifi c PET radiopharmaceuticals.

Conclusion
Due to the high prevalence of tuberculosis in India, false positive cases during oncologic workup with FDG-PET are commonly encountered in practice.Though FDG PET/CT is not specifi c for tuberculosis, it plays an important role in the evaluation of known or suspected TB cases.FDG PET/CT can determine the activity of lesions, guide biopsy from active sites, assess disease extent, detect occult distant foci, and evaluate response to therapy.Active tuberculous lesions oft en exhibit a high degree of FDG uptake, though this can vary, depending upon the grade of infl ammatory activity.No characteristic patt ern has been identifi ed as yet that will defi nitely diff erentiate them from cancerous lesions.
With FDG-PET imaging per se, based on semiquantitative analysis using SUV and the dual time point imaging technique, it is currently not possible to differentiate malignant lesions from active tuberculosis consistently.However, with an integrated PET/CT technique, the CT scan images may help diff erentiate tuberculosis from malignant lesions, using morphologic criteria.The use of intravenous contrast increases this ability.In future, new, more specifi c radiotracers, like positron-emitt er labeled antituberculous drug molecules may help to diff erentiate TB from cancer and nontuberculous inflammatory processes.

Figure 1 (
Figure 1 (A-E): Mediastinal lymphadenopathy in a patient of carcinoma colon who, post-hemicolectomy and post-chemotherapy was detected to have raised tumor marker (CEA) levels.Coronal plain CT (A), PET (B), PET/CT (C) with axial plain CT (D), and PET/CT (E) images of the thorax show FDG-avid mediastinal nodes (SUV 6.7) (arrows).No pulmonary lesion was detected on the CT images.The patient underwent mediastinoscopy and lymph node biopsy, which revealed tuberculosis

Figure 3 (Figure 4 (Figure 5 (Figure 6 (
Figure 3 (A-D): Pulmonary tuberculosis.A sputum positive case of pulmonary TB with clinically poor response to 2 months of antituberculous therapy.Coronal plain CT (A) and PET/CT (B) with axial plain CT (C) and PET/CT (D) images reveal extensive FDG-avid pulmonary parenchymal lesions.The superior segment of the left lower lobe shows consolidation with central cavitation (arrows) with an SUV max of 10.1.These fi ndings suggest active disease, indicating an inadequate response to therapy ]. Others included suspected cases of malignancy that turned out to have tuberculosis [Figures 2 and 10-12] and followup cases of cancer found to have associated TB [Figure 1].A few patients had established TB and were referred for evaluation of the extent of disease or to monitor response to treatment [Figures 3 and 13].

Figure 7 (
Figure 7 (A-D): Disseminated TB with multifocal hepatic and diffuse splenic uptake.Coronal plain CT (A) and PET (B) with axial PET/CT (C, D) images in a patient with FUO show diffuse increased FDG uptake in an enlarged spleen and multifocal uptake in the liver, mediastinal nodes, and patchy lung lesions (arrows).Transbronchial sampling from the subcarinal nodes revealed tuberculosis.PET in this case guided the tissue sampling from an active lesion in an accessible site, using the least invasive route

Figure 8 (
Figure 8 (A-C): Disseminated TB with focal splenic lesions, sparing of the liver and with extensive lymph node involvement.Coronal CT (A), PET (B), and PET/CT (C) images in a patient with cervical lymphadenopathy show large FDG-avid cervical, supraclavicular, and abdominal nodes.FDG-avid focal lesions are seen in the spleen (arrows).The differential diagnoses included lymphoreticular malignancy (lymphoma), metastases from an unknown primary, and tuberculosis.A supraclavicular lymph node biopsy confi rmed tuberculosis.Note the relative sparing of the liver

Figure 11 (
Figure 11 (A-E): Tuberculosis of the cecum.Coronal PET/CT (A), sagittal plain CT reconstruction (B), sagittal PET/CT (C), axial plain CT (D), and axial PET/CT (E) images of the abdomen in a 36-year-old man with generalized lymphadenopathy shows increased FDG uptake in the cecum (arrows), with irregularly thickened walls (SUV 16.8) and multiple enlarged supraclavicular and abdominal lymph nodes.Disseminated carcinoma of the cecum was suspected.Colonoscopic biopsy of the cecal lesion and cervical lymph node biopsy, both revealed tuberculosis.The patient responded well to antituberculous therapy

Table 1
lists all the cases described here.