**2.3 FDG-PET**

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

ies are demonstrating some opposite results.

carbon monoxide (DLCO).

(ARDS and infections).

pulmonale.

normal as follows:

• TLC decrease;

• RV decrease;

• FEV1 decrease;

• FVC decrease;

• DLCO decrease; and

• compliance decrease.

• carbon dioxide output (VCO2);

• anaerobic threshold (lactic acid).

angiotensin converting enzyme (ACE) in the blood [1].

• minute ventilation; and

exchange abnormalities.

function tests is found.

• FEV1/VC is equal to or more than 70%;

plethysmography, and a carbon monoxide diffusion capacity test of the lungs for

Restrictive disorders (infiltrative) are characterized by a reduction in lung volume, with difficult in taking air inside the lungs and decreased total lung capacity. Other restrictive disorders are chest wall disorders (neuromuscular, e.g., polio, kyphoscoliosis, pleural disease, and severe obesity); chronic interstitial and infiltrative disease (pulmonary fibrosis, pneumoconioses, granulomatous diseases, pulmonary eosinophilia, and pulmonary alveolar proteinosis); Acute diseases

Typical symptoms are dyspnea, tachypnea, end inspiratory crackles without airway obstruction, honey-comb lung, secondary pulmonary hypertension, and cor

In restrictive pulmonary disease, lung volume is decrease, but flow rate is

Usually, a significant correlation between radiological stage and pulmonary

Cardiopulmonary exercise testing (CPET) is another useful tool to identify and quantify the extent of pulmonary involvement and also may suggest cardiac involvement that otherwise is not evident [2]. It provides an integrative assessment of involving the pulmonary, cardiovascular, muscular, and cellular oxidative

• primarily oxygen uptake (VO2): VO2 at maximal exercise (peak VO2) is considered the best index of aerobic capacity and cardiorespiratory function;

In patients who have normal gas exchange at rest, CPET unmasks the gas

Laboratory tests can identify some serum abnormalities as high blood calcium with a normal parathyroid hormone level and hypercalciuria, or elevated levels of

systems and involves measurements of gas exchange as follows:

Sarcoidosis is commonly considered a restrictive disorder, but more recent stud-

**34**

FDG-PET is a metabolic imaging technique and provides an insight into metabolism of this disease. It relies on the principle of increased accumulation and metabolism of glucose by the malignant or inflammatory areas. FDG is a radioactive analog of glucose that enters cells through the same receptors that are involved in glucose uptake and gets converted into FDG 6 phosphate by the enzyme hexokinase, similar to glucose metabolism by the glycolytic pathway. FDG 6 phosphate is not metabolized further and gets entrapped in the cell. Tissues with high glucose metabolism such as brain tissue gray matter, cancer cells, and inflammatory changes show increased fluorine – 18 fluorodeoxyglucose ((18) F-FDG) accumulation on PET imaging.

As a key component of the inflammatory process, inflammatory cells consume glucose at a much higher level than peripheral noninflammatory cells, leading to higher glucose metabolism and increased uptake of (18) F-FDG within inflammatory foci. Therefore, the level of FDG uptake is proportional to the level of glycolysis in the tissue. This explains the mechanism of increased uptake of FDG in malignancy, inflammatory, and infectious processes [3].

The role of fluoro-deoxy glucose-positron emission tomography (FDG-PET) scanning in assessing the extent of disease spread or metastasis and its utility in assessing response to treatment in the form of chemotherapy or radiotherapy is well defined in many neoplastic conditions, and its utility has also been recognized in certain inflammatory conditions, like sarcoidosis.

During the last years, FDG-PET imaging has been shown to have a central role to detect inflammation activity and has become a novel fundamental tool, playing also an increasingly important role in the management of patients with any inflammatory conditions. FDG-PET can afford precious information in patients with pulmonary and extrapulmonary sarcoidosis and has become a centerpiece for testing the efficacy of different therapies [5]. In difficult clinical cases, it can also be useful to plan the site of biopsy in order to determinate a histopathological diagnosis.

A combined modality using FDG-PET and CT scanning (FDG-PET/CT) has been found to be more sensitive than PET in diagnosing. FDG-PET and a combination of this procedure with computed tomography scanning (FDG-PET/CT) has gained prominent attention in patients with sarcoidosis over the last two decades as a means to assess disease activity and response to therapy. Radionuclide imaging techniques have increasingly been used in the evaluation of organ involvement in sarcoidosis. F-FDG-PET/CT scanning has received increasing attention in last several years [3].

The usefulness of F-FDG-PET/CT is to identify the disease activity and the extent of organ involvement in patients affected by sarcoidosis; F-FDG-PET/CT is still useful to determinate its utility in the evaluation of response to drug treatment, comparing the agreement between clinical, radiological (with chest radiography and/or HRCT of lungs), and metabolic indices (FDG-PET/CT) of disease activity.

*Monitoring disease activity* in sarcoidosis still remains a clinical goal as there is no gold standard. The term "activity" in sarcoidosis means ongoing inflammation that necessitates appropriate drug therapy [3]. PET imaging is a new tool to assess the metabolic activity, but there is still limited data on the role of serial PET scans in monitoring the sarcoidosis activity [6].

*Conventional imaging techniques* used in sarcoidosis are chest radiography and CT. Even though chest radiography and HR-CT are still the fundamental for diagnosing pulmonary involvement, F- FDG PET appears to be superior to both techniques to identify active sites of disease. F- FDG- PET also correlates well with serum biomarkers, such as soluble interleukin-2 receptor in symptomatic patients, and in lung parenchyma correlates with decrease of lung function values over time. Moreover F-FDG-PET even visualizes active lesions (in pulmonary and extrapulmonary sites) in the context of normal serum biomarkers. Also in cardiac involvement in sarcoidosis, FDG-PET is a promising tool associated or complementary to magnetic resonance imaging, especially in planning treatment [7].

*Magnetic resonance imaging* (MRI) is the main imaging method for diagnosis and follow-up of neurosarcoidosis and for evaluation of cardiac involvement. However, these mentioned methods are unable to identify active inflammation; instead, FDG-PET/CT has an important advantage in the detection of reversible, inflammatory, active granulomatous disease in patients with sarcoidosis [8].

*PET* provides high-resolution three-dimensional images of the whole body that facilitates precise localization of abnormalities. Localization is enhanced with PET/ CT. Fluorodeoxyglucose is extremely sensitive with a high negative predictive value; however, the limiting factor of the test is specificity [9, 10]. (18) F-FDG PET/CT allows to obtain a complete morphofunctional cartography of inflammatory active localizations and to follow treatment efficacy in patients with sarcoidosis, particularly in atypical, complex, and multisystemic forms.

Disseminated lesions should alert clinician to consider sarcoidosis-lymphoma syndrome (SLS) or tuberculosis in the differential diagnosis. However, histological confirmation with biopsy will be required in such complex cases.

#### *2.3.1 Pulmonary sarcoidosis*

Pulmonary sarcoidosis is the main localization site in the majority of patients (>90% cases) typically with bilateral mediastinal (hilar) lymphadenopathy diagnosed on chest radiography; and its severity ranges from asymptomatic involvement of mediastinal lymph nodes (mostly hilar) to progressive pulmonary fibrosis and chronic respiratory failure that is unresponsive to therapy. The most common clinical presentations of pulmonary involvement are cough and dyspnea.

The diagnosis of pulmonary sarcoidosis requires a compatible clinical picture supported by radiologic (X-rays chest and/or HRCT of lungs) and pathologic data (pulmonary functional tests and laboratory tests). A recent innovation in diagnosing of pulmonary sarcoidosis is endobronchial ultrasound that increases the yield of transbronchial needle aspiration of hilar and/or mediastinal lymph nodes. F-FDG-PET is highly sensitive in detecting occult sites of disease and is very useful in guiding biopsies of these sites. A combined imaging modality using both FDG-PET and CT scan is more sensitive than PET alone and is now the main proceeding of care in patients needing biopsies of active lesions [11].

For staging of pulmonary disease on chest radiograph, Scadding stages (**Figure 1**) are still widely used depending on the presence of hilar lymph node enlargement and pulmonary opacities on chest radiography as follows:


**37**

*2.3.2 Cardiac sarcoidosis*

*Early Diagnosis of Sarcoidosis*

**Figure 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.90523*

occult sites of disease at the chest CT scan.

*Chest X-rays: reticulonodular pattern with perihilar distribution.*

*HRCT*, however, is still the gold standard imaging modality for primary diagnosis of sarcoidosis and is more accurate than chest X-rays, which is the first imaging level, in identifying the different manifestations of pulmonary sarcoidosis as well its complications. F-FDG-PET, instead, is a new highly sensitive tool in detecting

HRCT most common signs are: micronodules (*miliary sarcoidosis*) and macronodules with perilymphatic distribution, for the most part, symmetrically in the middle zones of the lungs; rarely solitary opacity (*alveolar sarcoidosis*) and with a mass-like presentation (1–4 cm in diameter) may mimic consolidation containing air bronchograms, from confluence of many smaller nodules with irregular margins and presenting as *sarcoid galaxy sign* (mass-like region from confluence of numerous smaller granulomas with a central core and multiple peripheral nodules; central cavitation may occur, and the lesion can be surrounded by ground-glass opacity), more frequent in patients older than 50 years of age of presentation; linear opacities, mostly, in the upper and middle parts of the lungs, most common of stage II or III of disease; and ground glass opacities represent interstitial sarcoid granulomas under resolution rather than alveolitis, above all, located in the lower zones of the lungs [12] (**Figures 2–6**). Functional imaging of sarcoidosis nowadays is performed with (18) F-FDG PET-CT, which improves anatomical localization of sites of abnormality and has a relatively short delay time between radiotracer injection and image acquisition. (18) F-FDG PET-CT can identify disease activity better than conventional makers in a large proportion of patients (very high sensitivity about 80–100%). In patients with positive HRCT but no parenchymal fluorodeoxyglucose F18 uptake, pay attention to

initiation or intensification of immunosuppressive treatment [1, 13].

Cardiac involvement in sarcoidosis is uncommon (5%) and is associated with very poor prognosis [1], because of many complications of cardiac as follows: ventricular tachycardia, conductional abnormalities, congestive heart failure, and sudden cardiac death. Moreover, cardiac sarcoidosis (CS) is an important prognostic factor in patients with this disease. However, early diagnosis of CS in still


*Sarcoidosis and Granulomatosis - Diagnosis and Management*

and in lung parenchyma correlates with decrease of lung function values over time. Moreover F-FDG-PET even visualizes active lesions (in pulmonary and extrapulmonary sites) in the context of normal serum biomarkers. Also in cardiac involvement in sarcoidosis, FDG-PET is a promising tool associated or complementary to

*Magnetic resonance imaging* (MRI) is the main imaging method for diagnosis and follow-up of neurosarcoidosis and for evaluation of cardiac involvement. However, these mentioned methods are unable to identify active inflammation; instead, FDG-PET/CT has an important advantage in the detection of reversible, inflammatory,

*PET* provides high-resolution three-dimensional images of the whole body that facilitates precise localization of abnormalities. Localization is enhanced with PET/ CT. Fluorodeoxyglucose is extremely sensitive with a high negative predictive value; however, the limiting factor of the test is specificity [9, 10]. (18) F-FDG PET/CT allows to obtain a complete morphofunctional cartography of inflammatory active localizations and to follow treatment efficacy in patients with sarcoidosis, particu-

Disseminated lesions should alert clinician to consider sarcoidosis-lymphoma syndrome (SLS) or tuberculosis in the differential diagnosis. However, histological

Pulmonary sarcoidosis is the main localization site in the majority of patients

The diagnosis of pulmonary sarcoidosis requires a compatible clinical picture supported by radiologic (X-rays chest and/or HRCT of lungs) and pathologic data (pulmonary functional tests and laboratory tests). A recent innovation in diagnosing of pulmonary sarcoidosis is endobronchial ultrasound that increases the yield of transbronchial needle aspiration of hilar and/or mediastinal lymph nodes. F-FDG-PET is highly sensitive in detecting occult sites of disease and is very useful in guiding biopsies of these sites. A combined imaging modality using both FDG-PET and CT scan is more sensitive than PET alone and is now the main proceeding of

For staging of pulmonary disease on chest radiograph, Scadding stages (**Figure 1**) are still widely used depending on the presence of hilar lymph node

• Stage I: bilateral mediastinal lymphadenopathy (hilar lymphadenopathy);

• Stage II: bilateral mediastinal lymphadenopathy (hilar lymphadenopathy) and

enlargement and pulmonary opacities on chest radiography as follows:

• Stage III: infiltrates alone, parenchymal disease only; and

(>90% cases) typically with bilateral mediastinal (hilar) lymphadenopathy diagnosed on chest radiography; and its severity ranges from asymptomatic involvement of mediastinal lymph nodes (mostly hilar) to progressive pulmonary fibrosis and chronic respiratory failure that is unresponsive to therapy. The most common clinical presentations of pulmonary involvement are cough and

magnetic resonance imaging, especially in planning treatment [7].

active granulomatous disease in patients with sarcoidosis [8].

confirmation with biopsy will be required in such complex cases.

larly in atypical, complex, and multisystemic forms.

care in patients needing biopsies of active lesions [11].

• Stage 0: normal chest radiographic findings;

infiltrates with parenchymal lesion;

• Stage IV: pulmonary fibrosis.

*2.3.1 Pulmonary sarcoidosis*

dyspnea.

**36**

**Figure 1.** *Chest X-rays: reticulonodular pattern with perihilar distribution.*

*HRCT*, however, is still the gold standard imaging modality for primary diagnosis of sarcoidosis and is more accurate than chest X-rays, which is the first imaging level, in identifying the different manifestations of pulmonary sarcoidosis as well its complications. F-FDG-PET, instead, is a new highly sensitive tool in detecting occult sites of disease at the chest CT scan.

HRCT most common signs are: micronodules (*miliary sarcoidosis*) and macronodules with perilymphatic distribution, for the most part, symmetrically in the middle zones of the lungs; rarely solitary opacity (*alveolar sarcoidosis*) and with a mass-like presentation (1–4 cm in diameter) may mimic consolidation containing air bronchograms, from confluence of many smaller nodules with irregular margins and presenting as *sarcoid galaxy sign* (mass-like region from confluence of numerous smaller granulomas with a central core and multiple peripheral nodules; central cavitation may occur, and the lesion can be surrounded by ground-glass opacity), more frequent in patients older than 50 years of age of presentation; linear opacities, mostly, in the upper and middle parts of the lungs, most common of stage II or III of disease; and ground glass opacities represent interstitial sarcoid granulomas under resolution rather than alveolitis, above all, located in the lower zones of the lungs [12] (**Figures 2–6**).

Functional imaging of sarcoidosis nowadays is performed with (18) F-FDG PET-CT, which improves anatomical localization of sites of abnormality and has a relatively short delay time between radiotracer injection and image acquisition. (18) F-FDG PET-CT can identify disease activity better than conventional makers in a large proportion of patients (very high sensitivity about 80–100%). In patients with positive HRCT but no parenchymal fluorodeoxyglucose F18 uptake, pay attention to initiation or intensification of immunosuppressive treatment [1, 13].
