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Positron Emission Tomography (PET) Jann Mortensen Department of Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark. E-mail: jannmortensen@rh.dk. 8th Annual Congress, Thoracic imaging in lung diseases, April 30th 2005. annihilation photon. g. electron/positron annihilation. b -.

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Positron Emission Tomography (PET)

Jann Mortensen

Department of Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark

E-mail:

jannmortensen@rh.dk

8th Annual Congress, Thoracic imaging in lung diseases, April 30th 2005


annihilation

photon

g

electron/positron

annihilation

b-

b+

g

annihilation

photon

Decay with positron

emission

Princip of Positron Emission Tomography

Radioactive glucose ligand:

18Fluoro-Deoxy-Glucose

1+

0.0

(109.77m)

EC1,

0+

0.0

(stable)


Positron Emission tomography (PET)


Normal cells use glucose

GLU

GLU

GLU-6-phoshate

CO2+H20

hexokinase

FDG

FDG-6- phoshate

FDG

Glut 1 & 3


(Warburg O. 1930, 129-169)

Cancer cells use much glucose

*

Also high amino acid

and nucleic acid use

GLU

GLU

GLU-6-phoshate

CO2+H20

FDG

FDG-6- phoshate

FDG

Metabolic trapping

Glut 1 & 3


Physiology of FDG tumor uptake

FDG signal in tumor is dependent on 1) delivery (blood flow),

2) transport into the cells, and 3) phosporylation

FDG tumor uptake ~ number of viable cancer cells


Normal FDG-PET

  • Visual assessment


Physiologic and patologic FDG metabolism

  • SUV (standard uptake value) = tumor uptake in relation to mean body uptake

    • Correlates with degree of malignancy

    • (Cut-off value > 2.5 SUV ~ malignancy)

MIP 3-D projection

Colour scale ~SUV


Prognostic information from

tumor metabolism

PET predicts survival

SUV Median survival

low uptake < 10 2 yr

high uptake > 101 yr

+ large mass >3 cm½ yr

Ahuja et al. Cancer 1998; 83 ; 918-24

In multivariate analysis,the SUV was independently predictive

of disease-free and overallsurvival

Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Lancet Oncol 2004; 5: 531–40


Performing a PET study

  • Patient preparation: > 4 h fast, drink (but no sugar)

  • Blood sample for glucose (no hyperglycaemia)

  • 400 MBq 18-F FDG i.v., rest ½-1 h

  • Scan time:

    • PET: regional ~ 15-30 min, whole body scan 60 min

    • PET/CT:regional < 15 min, whole body scan <30 min

PET

CT


Low dose CT

PET

Fused PET + CT


CT

PET

Fused PET + CT

Anato-metabolic imaging


Cancer

Infection & inflammation

Indications: PET in pulmonary disease


Cancer @

Pulmonary nodules

Staging (NSCLC)

Relaps and re-staging

Treatment monitoring

SCLC

Mesothelioma

[Radiation field planning]

Indications: PET in pulmonary disease

@ PET costs covered by US Medicare


Cancer @

Pulmonary nodules

Staging (NSCLC)

Relaps and re-staging

Treatment monitoring

SCLC

Mesothelioma

[Radiation field planning]

Infection & inflammation*

Localisation and monitoring of activity:

Sarcoidosis

AIDS (opportunistic infections and malignancy)

Fever of unknown origin

Lung abscess

Tuberculosis, Actinomycosis, Histoplasmosis, Invasive aspergillosis

Vasculitis (Wegener, Takayasu..)

Radiation induced inflammation

Indications: PET in pulmonary disease

@ PET costs covered by US Medicare

* = Sem Nucl Med 2002 ;32: 293-321


Main indication: FDG-PET in SPN

  • Single pulmonary nodule/mass on CT which is borderline for malignancy

  • cannot be easily biopsied or inconclusive biopsy

    • Malignant or benign ?

  • Indication supported by > 16 studies in > 1000 patients with histologic/long-term follow-up

  • Sensitivity 0.96

  • Specificity 0.78

  • PPV and NPV >0.90

    • Size: 1-4 cm

    • 1474 nodules (JAMA 2001; 285: 914-24)

      • Only 8 nodules <1 cm: 3 TP, 2 TN, 3 FN

      • Diagnostic value in < 1 cm small nodules ?

Lancet Oncol 2001;2:659-66


Case 1: 57 y-o-m with COPD

9 mm nodule found on high-resolution CT

18F-FDG PET


Case 1: 57 y-o-m with COPD

transaxial coronal saggital

Diagnosis and staging

(PET suggests T1 N0 M0)

attenuation corrected

RH - PET / jm (ap)


FDG PET in small nodules (<10 mm)

  • The interpretation of FDG-PET findings in subcentimetric nodules is at present unsolved.

    • [Vansteenkiste JF. Lung Cancer 2004; 45: 29-30].

  • 4 new studies on > 100 SPN in the litterature

    • 3 positive and 1 negative about the value of FDG PET

  • [Lung Cancer 2004; 45:19—27] [Nucl Med Commun 2004; 25: 3-9]

  • [Am J Respir Crit Care Med. 2005 (in press)][Lancet 2003;362:593-79]

  • Studies in progress on value of PET in low-dose CT screening


    FDG PET in large nodules

    • FDG-PET can discriminate between malignant / benign ≥ 10 mm solid pulmonary nodules !

    • FDG-PET has a high negative predictive value, can correctly exclude malignancy in the vast majority of nodules seen in daily practice.

    • A surgical procedure can be avoided,

    • A repeat CT after 3-12 months can be used to confirm the absence of growth (ie. benignity).

    Lancet Oncol 2001; 2: 659-66

    Lung Cancer 2004; 45: 29-30.


    Main indication : Staging in NSCLC

    T NM status (in one exam.)

    • Conventional staging is inaccurate. After presumably radical treatment, 20% develop an early distantrelapse.

    • [Lancet 1996;347:649–653].

    Indication supported by studies in

    > 1500 patients

    with histologic/long-term follow-up

    Lancet Oncol 2001;2:659-66


    Impact of PET in lung cancer

    • PET changes stage in 35% of patients (N=894, 16 studies)

      • Usually the PET stage is higher than with usual work-up incl. CT

        • Due to local (N2 eller N3) metastasis or extra-pulmonary metastasis

      • ie. operation is unnecessary

      • change in therapy to chemotherapy and / or radiation treatment

        • Semin Nucl Med 2002, 32:240-71

    • PET is cost effective in lung cancer

      • Both for diagnosis of single pulmonary nodules and for Staging

      • References: (Gambhir J Clin Oncol 1998; 16: 2113-2125) (Dietlein Eur J Nucl Med 2000; 27: 1441-56) (Gould ARRDCCM 2001) (Plus study)


    Randomised study of PET staging

    • Effect parameter: no. unneccesary thoracotomy´s

    • 188 ptt. usual work-up +/- PET, 1 yr follow-up

    • 9 Deutch hospitals (1 dedicated PET center)

    • PET reduced the no. unneccesary thoracotomy´s:

      • PET 32 (41%) , + PET 18 ptt (21%)

    • For each 5 PET scans one unneccesary thoracotomy was avoided

      • reduced cost per patient with PET: > 1.000 EURO

    (PLUS study. Lancet 2002; 359: 1388-92)


    Prospective study of preoperative staging with PET vs. standard staging (CT, ultrasound, bone scanning)

    • 102 patients with resectable NSCLC, 6 months follow-up,

    • histopathological reference.

  • (N) metastasisSensitivitySpecificity

  • PET 91 %86 %

  • CT 75 %66 %

  • (M) metastasis: PET identified distant metastases not found

    by standard methods in 11 of 102 patients:

    PET identified a different stage in 62 patients:

    stage was lowered in 20 and raised in 42

    Pieterman et al. N Engl J Med 2000;343:254-61


    FDG PET for extrathoracic metastasis

    • 40% with NSCLC have distantmetastases at presentation, most often in the

    • adrenal glands,bones, liver, or brain [Ann Thorac Surg 1996;62:246–250].

    • Adrenal glands: 10% of NSCL have enlarged adrenal glands on CT, 2/3 being benign.

    • PET has high sensitivity (>92%) and specificity (80%–100%) -> reduces number of unnecessary adrenal biopsies.

    • Bone: Bone scintigraphy good sensitivity (90%), low specificity (±60%),

    • PET good sensitivity (90%), but higher specificity (98%)and accuracy (96%).

    • Liver:US and/or CT remain thestandard imaging techniques for the liver. No good comparisons studies. Additional diagnosticinformation by PET combined with CT, in thedifferentiation of hepatic lesions that are indeterminate onconventional imaging.

    • Brain:PET low sensitivity (60%) not suited for the detection of brain metastases.

    The Oncologist 2004; 9 (6): 633-43


    FDG PET for extrathoracic metastasis

    • 40% with NSCLC have distantmetastases at presentation, most often in the

    • adrenal glands,bones, liver, or brain [Ann Thorac Surg 1996;62:246–250].

    • Adrenal glands: 10% of NSCL have enlarged adrenal glands on CT, 2/3 being benign.

    • PET has high sensitivity (>92%) and specificity (80%–100%) -> reduces number of unnecessary adrenal biopsies.

    • Bone: Bone scintigraphy good sensitivity (90%), low specificity (±60%),

    • PET good sensitivity (90%), but higher specificity (98%)and accuracy (96%).

    • Liver:US and/or CT remain thestandard imaging techniques for the liver. No good comparisons studies. Additional diagnosticinformation by PET combined with CT, in thedifferentiation of hepatic lesions that are indeterminate onconventional imaging.

    • Brain:PET low sensitivity (60%) not suited for the detection of brain metastases.

    The Oncologist 2004; 9 (6): 633-43


    PET/CT in lung cancer

    ”PET/CT will improve staging in 20- 40 % of lung cancer patients”

    Lardinois D et al.

    N Engl J Med 2003; 348: 2500-7

    Cerfolio RJ et al. Ann Thorac Surg 2004; 78: 1017–23

    A randomised study in progress in Copenhagen


    Bone metastasis with normal CT


    Value of PET in lung cancer

    • Sensitivity ~ 96 % (SPN); ~ 73% (N staging)

    • Specificity ~ 78 % (SPN), ~ 93% (N staging)

    • Reasons for false negative

      • Small size (resolution 6 mm, movement)

      • Well-differentiated tumors:

        • Adenocarcinoma

        • Carcinoids (Neuroendocrine tumors)

        • Broncioalveolar carcinoma (BAC)

      • Dysregulated diabetes, insufficient fast

    • Reasons for false positive

      • Infection / inflammation (Indication per se)


    Increased FDG-PET uptake can be seen inbenign pulmonary conditions

    • Infections

      • Lung abscess

      • Tuberculosis (and M avium intracellulare)

      • Bacterial pneumonia, Actinomycosis, Histoplasmosis, Invasive aspergillosis, aspergilloma, blastomycosis

    • Inflammatory lesions

      • Sarcoidosis

      • Vasculitis: Wegeners granulomatosis, takayasu arteritis, etc

      • Pneumoconiosis (silicosis, coal workers-, fibrosis)

      • Rheumatoid arthritis, sclerosing mediastinitis

      • Amyloidosis, Idiopathic pulmonary fibrosis

      • Bronciolitis oblitarative organising pneumonia (BOOP),etc

    • Benign neoplasm (-chondrohamartoma)

    • Iatrogenic disorders

      • Radiation induced pneumonitis, biopsy, rib fractures, etc

    Case stories

    Sem Nucl Med 2002;32(4):246 & 293-321


    Increased FDG-PET uptake can be seen inbenign mediastinal adenopathies(Z)

    • Granulomatosis and silicosis (Inflammation)

      • Sarcoidosis

      • Anthrasilicosis

    • Infections

      • Histoplasmosis,

      • Tuberculosis (and M avium intracellulare)

      • Actinomycosis, etc.

    • Benign neoplasm (-thymoma, teratoma, swannoma)

    • Iatrogenic disorders (Radiation related changes)

    Case stories

    (Z) Yet, only a minority with these conditions have a high FDG uptake

    Sem Nucl Med 2002;32(4): 293-321


    FDG PET in active tuberculosis

    • TB in a 58-year-old man. (A) chest radiograph shows two nodules (b) coronal FDG PET scan shows increased uptake (solid arrow) in the left upper lobe nodules (SUV 4).

    • Radiology 2000 6:117-21


    Sarcoidosis

    Monitoring:

    Localisation of activity

    in- and outside lungs:

    Before treatment:

    After inhaled steroid:

    After prednisolone:

    • Milman N, Mortensen J, Sloth C. Respiration. 2003;70:408-13.


    Newer indications for PET in lung cancer

    PET predicts survival

    SUVmedian survival

    < 10 2 yr

    > 10 1 yr

    + mass >3 cm½ yr

    Ahuja et al. Cancer 1998; 83 ; 918-24

    • Prognostic information from SUV

    • Evaluation of treatment effect ->

    • PET/CT for planning of radiation field

    • Staging and monitoring SCLC ->

    • Staging and diagnosis of Mesothelioma


    Newer indications for PET in lung cancer

    • Prognostic information from SUV

    • Evaluation of treatment effect ->

    • PET/CT for planning of radiation field

    • Staging and monitoring SCLC ->

    • Staging and diagnosis of Mesothelioma


    Newer indications for PET in lung cancer

    • Prognostic information from SUV

    • Evaluation of treatment effect ->

    • PET/CT for planning of radiation field

    • Staging and monitoring SCLC ->

    • Staging and diagnosis of Mesothelioma

    • PET/CT guided RT improves radiation dose to the tumor

    • and metastases and reduces dose to adjacent normal tissue

      • No studies with patient outcome yet


    Newer indications for PET in lung cancer

    • Prognostic information from SUV

    • Evaluation of treatment effect ->

    • PET/CT for planning of radiation field

    • Staging and monitoring SCLC ->

    • Staging and diagnosis of Mesothelioma


    Newer indications for PET in lung cancer

    • Prognostic information from SUV

    • Evaluation of treatment effect ->

    • PET/CT for planning of radiation field

    • Staging and monitoring SCLC ->

    • Staging and diagnosis of Mesothelioma

    J Nucl Med. 1999 Aug;40(8):1241-5.

    Semin Oncol. 2002 Feb;29(1):26-35.

    • FDG PET for:

    • Guiding of biopsy

    • Staging (extrathoracic or contralateral metastasis)


    Help from a PET-scan

    • A positive PET focus indicates malignancy

      • but needs histological proof (to avoid false positive)

      • PET or PET/CT guided biopsy possible

  • A negative PET focus indicates benignancy

    • A solitary pulmonary nodule is either benign or very slowly growing cancer (no or CT control 6-12 months for growth)

    • Staging, no metastasis found, refer to operation.


  • Conclusion

    • Single Pulmonary Nodules

      • Differentiate between benign/malignant indeterminate SPN

        • if biopsy is difficult / nondiagnostic

        • confirm benignity with CT follow-up

      • the uptake predicts prognosis (high metabolism -> bad prognosis)

    • StagingRegional (N) and distant (M) metastases:

      • Addition of PET improves conventional staging (CT+US+ bone scintigraphy)

      • PET changes stage and treatment in ~35 % of patients

        • Detects unexpected distant metastases in ~14 %

        • Exclusion of malignancy in ~5 % (can be operated)

        • Usually a higher stage is found

        • Avoids unneccesary thoracotomy (in 10-20 %)

        • Mediastinoscopy can be avoided if PET + CT are normal (in non-central tumors)

    • Other indications:

      • Restaging and treatment monitoring, radiation field planning, SCLC, Mesothelioma

      • Localisation & monitoring of infections & inflammatory disorders


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