1. در مرکز پزشکی هسته ای دکتر دباغ – دکتر صادقی در خدمت شما هستیم مشهد، ملاصدرا 11 ، پلاک 1/4 www.DSNMC.ir Tel:+98(51) 38411524; +98(51)38472927

2. www.DSNMC.ir Lymphoma V. R. Dabbagh Kakhki, M.D. Nuclear Medicine Specialist Associate Professor DSNMC Nuclear Medicine Research Center (NMRC; MUMS)

3. Nuclear Medicine in Lymphoma Introduction Of Lymphoma Tc99m-MIBI Scan Thallium (Tl-201) Scan Gallium Scan (GS; 67 Ga Scan) FDG-PET V.R.Dabbagh; DSNMC; www.DSNMC.ir Somatostatin Receptor Imaging (Octreotide Scan

4. Gallium Scan was a cornerstone in functional imaging of lymphoma However : - Gallium may not be available -physicians usually refuse to perform Gallium scan due to logistic problems -Several days for imaging First Nuclear Medicine in Lymphoma in 4 slides

5. FDG-PET is a promising functional imaging of lymphoma However : -may not be available -Its expensive First Nuclear Medicine in Lymphoma in 4 slides

6. Somatostatin Receptor Imaging (Octreotide Scan) is also a useful functional imaging of lymphoma -Available -Reasonable cost (cost effective) -Easy imaging in one day (less than 4 hours) -Labeling with Tc99m: available and cheap First Nuclear Medicine in Lymphoma in 4 slides

7. Somatostatin Receptor Imaging (Octreotide Scan+SPECT): is useful and can be recommended:  First: baseline before beginning the treatment  In follow-up  For assessment of response to therapy  For assessment of relapse First Nuclear Medicine in Lymphoma in 4 slides

8. Lymphoma: Pathology Classification The Working Formulation Classification: –Low grade –Intermediate grade –High grade REAL Classification: –B-cell neoplasms –T-cell/putative NK-cell neoplasms –HD Within each groups : disease types based on : cytology, immunophenotype, genetic and clinical features WHO classification of hematopoietic and lymphoid tumors: standard B-cell T-cell

10. Introduction to NHL A heterogeneous group of >25 subtypes of malignancies of the lymphatic system NHLs can be grouped clinically according to their behaviour: –Aggressive (high-grade): grow rapidly, have in general rapidly developing symptoms, but are potentially curable 65% of NHLs –Indolent (low-grade) : grow slower, have in general slower developing symptoms, most patients relapse after treatment 35% of NHLs Armitage et al. N Engl J Med 1993;328:1023–1030 Bastion et al. J Clin Oncol 1997;15:1587–1594 Harris et al. Ann Oncol 2000;11(suppl 1):S3–S10

11. Introduction to Non Hodgkin’s Lymphoma Diffuse large B-cell lymphoma is the most common aggressive NHL –(31% of all NHLs) Follicular lymphoma is the most common indolent NHL – (22% of all NHLs) Armitage et al. N Engl J Med 1993;328:1023–1030 Bastion et al. J Clin Oncol 1997;15:1587–1594 Harris et al. Ann Oncol 2000;11(suppl 1):S3–S10

12. Survival Patterns are Different for Indolent and Aggressive NHL Probability of survival (%) Years Indolent NHL (e.g. Follicular lymphoma) Aggressive NHL (e.g. Diffuse large B-cell lymphoma) The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:3909–3918

13. Epidemiology of NHL Incidence increased steadily in recent decades in the western world Incidence of NHL is greater in men than in women Age-standardised incidence of NHL in 1997 was: –Men 14.03 per 100 000 –Women 9.19 per 100 000 Median age 65 years Hagenbeek et al. Martin Dunitz 1999 Ferlay et al. IARC CancerBase No.4. IARC Press, 1999 Parkin et al. CA Cancer J Clin 1999;49:33-64

14. Frequency of NHL Subtypes in Adults Follicular (22%) Diffuse large B-cell (31%) Small lymphocytic (6%) Mantle cell (6%) Peripheral T-cell (6%) Marginal zone B-cell, MALT (5%) Other subtypes with a frequency <2% (9%) Marginal zone B-cell, nodal (1%) Lymphoplasmacytic (1%) Composite lymphomas (12%) Armitage et al. J Clin Oncol 1998;16:2780–2795

15. Staging Modified Ann Arbor system

16. Staging in Lymphoma PE Haematological analyses –CBC –ESR –LDH CT: neck, thorax, abdomen and pelvis GS BMB MRI: specific sites: CNS, Bone

17. Prognostic Tools International Prognostic Index –0-5 Age>60 ECOG performance≥2 LDH>normal Stage III-IV Extranodal involvement>1

18. Current Treatment Watchful waiting External-beam radiation High-dose chemotherapy with transplantation support Combination chemotherapy Purine analogue: –Fludarabine phosphate Monoclonal antibody therapy: –Rituximab Radioimmunotherapy: –Zevalin ® Witzig et al. J Clin Oncol 1999;17(12):3793–3803 Vose. Ann Oncol 1996;7(suppl 6):S13–S19 Horning. Semin Oncol 1993;20(suppl 5):75–88

19. Nuclear Medicine Imaging in Lymphoma

20. Diagnostic questions 1)Determine the clinical stage at initial presentation 2) Characterize a residual mass after treatment as scar or viable tumor (restaging) 3) Evaluate whether or not the neoplasm responds to the selected therapeutic regimen 4) Assess whether the tumor has shown a complete response to treatment and follow the disease over time

21. Investigations in management decisions Anatomical imagings:CT,MRI Histological assessment of the BM Specific blood indices (CBC, ESR, LDH, absolute lmyphocyte count, renal and liver profiles,…) BS Limitations of CT: –Based on size alone –Spleen,Liver, BM –Extra-nodal involvement –Assess residual masses Because of early and late toxicity, treatment should be limited to a minimum, without compromising the clinical outcome.

22. Management is dependent upon Accurate Staging Histological evaluation –Primary mass –BM Other risk factors –CBC –ESR –LDH Scored together in IPI

23. Ga-67; a cornerstone in functional imaging of lymphoma Role; Diagnostic and prognostic data –Staging –Monitoring response to treatment –Differentiate between fibrotic or necrotic tissues from viable lymphoma in a residual mass –Early diagnosis of recurrence –Predicting outcome Other tumor agents: – 99m Tc-MIBI – 201 Tl – 111 In octreotide –Radioimmunoscintigraphy – 18 F-FDG PET; gradually replacing GS

24. Gallium Scintigraphy (GS) 67 Ga is a tumor viability agent A baseline examination before treatment –The main goal of GS at diagnosis : determine the 67 Ga avidity –May be value in the initial staging –Use of GS for staging mainly in lymphoma subtypes with intense Ga avidity: small, non-cleaved cell lymphoma (lesion sens:89%) Periodic examination during treatment and after its conclusion

25. GS Detection depends on –Tumor type –Size –Location –Histologic feature –Technical factors A close relationship between transferrin receptors expression, 67 Ga uptake and high risk subgroups of lymphoma High grade lymphoma was associated with both higher CD71 values and a higher degree of 67 Ga uptake Low sensitivity in low-grade NHL and MALT lymphoma: –Baseline GS – 201 Tl –Sensitivity of GS in the more common subtypes ( FSC, FM) was similar to that in HD and high grade NHL.

26. GS GS in extranodal lymphoma –Sensitivity in the skin, GI and testis :low –Overall sensitivity was 88% similar in nodal disease –Non-Ga-avid extra nodal lymphoma (skin) ; 201 Tl and FDG-PET

27. GS Bone involvement: up to 10-15% –Bone scan Diagnostic Can not assess its response to therapy –GS Sensitivity:93%, Specificity: 91% Assessing non-osseous disease Monitoring bone lymphoma response to treatment Primarily for follow-up BM involvement: –Biopsy: sampling errors, and false negative results –GS: poor results –FDG & MRI

28. GS Hepatic and splenic involvement –Diffuse physiological uptake of Ga-67 –CT is also suboptimal SPECT ; improved –Sensitivity – Specificity – Anatomical localization

29. GS in monitoring lymphoma response to treatment Characterising a residual mass after treatment –Residual active disease Poor prognosis Further second-line regimens should be initiated as early as possible CT & GS GS: Longterm successful outcome : NPV<PPV NPV of post-therapy GS : patients with limited HD > Advanced HD No difference in NPV (CT, GS) PPV of GS (73-80%) > PPV of CT(29-35%) High false positive rate of follow-up CT Disease free survival : –In patients with negative follow-up GS was significantly better than that of Ga-positive patients

30. –Reversion of a positive scan to a negative study and the rapidity of response : prognostic indicator –GS after one course and at mid-treatment was a significant variable in predicting 5-year failure free survival (FFS) and a better indicator than other risk factors variables( stage, performance status, IPI) –Results of GS after only one cycle of therapy are more predictive of prolonged remission than GS after completion an entire regimen Pts who achieved an early CR: longer disease free period and lower relapse rate (20% vs 60%) than Pts with late CR Prediction of response to therapy and of long- term outcome

31. –Early detection of relapse may increase the chances of long- term survival (salvage therapy) Periodic GS in remission –Detection of sites of early recurrence on 8.6 months before the symptoms, PE, and other diagnostic tests –67% recurrences in both original and new sites –27% of recurrences occurred only at new sites –Sensitivity : GS:90%> PE:80%> LDH:65% A 2-3 weeks interval between the last chemo course and GS : avoid false negative scans Prediction of response to therapy and long-term follow-up

32. Normal GS Diffuse lung Ga-67 uptake after chemo NHL

33. Clinical History: 20-year-old, three weeks post partum with anterior mediastinal mass. Findings: Gallium scan at shows mediastinal adenopathy and bilateral breast uptake. Diagnosis: Hodgkin's Lymphoma.The breast uptake represents benign uptake secondary to lactation.

34. Ga-SPECT/CT in a patient with showing a residual mass on CT after treatment. Abnormal 67 Ga uptake is demonstrated in the corresponding residual CT abnormality, indicating the presence of residual viable tumor tissue

35. Baseline GS GS after one cycle of chemotherapy Rapid Response to treatment

36. Rebound thymic hyperplasia in a 6-year- old patient with HD, in complete remission after treatment

37. Tl-201 and Tc99m-MIBI Tumor agents: Brain, bone, chest, thyroid, lymphoma 201 Tl: –ATP-ase system, Co-transport system (K, Na, Cl), Calcium ion channel systems, Blood flow –Taken up Mainly by viable tumor cells Inflammatory lesions –Not taken up by necrotic tissue –Sensitivity for staging of lymphoma varies between different histological types HD, low & intermediate grades NHL: 100%, High grade NHL: 75% Uptake higher in low-grade NHL>aggressive NHL and HD –Benign thymic hyperplasia after chemotherapy: Positive 67 Ga and negative Tl-201(quantitative)

38. Tc99m-MIBI A lipophilic cation Relationship between cellular uptake and mitochondrial activity or density Tc99m-MIBI was similar Tl-201: low grade lyphoma Washout: MDR P-gp

39. Mitochondria Nucleus MIBI ΔΨm ΔΨc 99mTc Passive diffusion + + + + + - - - - - - - - -

40. Factors influencing uptake of MIBI Perfusion: Increased blood flow of the tumor Electrical gradient: Passive influx Early stage of apoptosis: reduction of MIBI uptake

41. Factors influencing retention of MIBI in drug- resistant tumor cells Membrane cell transporters :efflux pump –MDR1: P-gp –MRP Altered tumor cell mitochondria –Anti-apoptotic protein Bcl-2

42. Mitochondria Nucleus MIBI ΔΨm ΔΨc 99mTc Passive diffusion + + + + + - - - - - - - - - MDR Proteins Active Efflux

43. Pretherapeutic MIBI Scintigraphic prediction of tumor response to treatment Poor responders –Less MIBI accumulation –Rapid washout of MIBI P-gp MRP Bcl-2

44. PEPTIDE RECEPTOR IMAGING Tumor cells, despite their seemingly uncontrolled metabolism and growth are in fact modulated by various endogenously peptides that interact with receptor on the tumor surface –Somatostatin – Tumor necrosis factor – Angiogenesis factor –Vasoactive intestinal peptide

45. Tumor with somatostatin receptors fall into three categories 1- Neuroendocrine Tumors (NETs) such as pituitary adenoma, gastrinoma ̗ insolinoma pheochromocytoma, medulary thyroid cancer and carcinoid 2- CNS tumors : Astrocytomas, menangioma and neuroblastoma 3- Other tumors, including lymphoma, breast lung (SCLC) and renal cell cancer

47. A unique feature of NETs is their overexpression of somatostatin receptors on the tumor cells: – imaging –peptide receptor radionuclide therapy (PRRT) In the European consensus guidelines of ENETS from 2012, Octreotide Scan is an important part of the diagnostic work-up of patients with NETs. –Localization of NETs primary tumors and unknown metastases in approximately 90% of patients. Somatostatin Receptor Scintigraphy

48. can image many other human tumors expressing somatostatin receptors, including malignant lymphomas and thymomas. The sensitivity of SRS to image somatostatin receptor- positive tumors is very high The sensitivity of somatostatin receptor scintigraphy for Hodgkin’s lymphoma is 95%-100%, whereas for non- Hodgkin’s lymphoma it is around 80%. Somatostatine Receptor Scintigraphy (SRS) in Other Tumors: Lymphoma

49. Somatostatin Receptor High SR expression –Neuroendocrine tissues and tumors – Benign and malignant lymphocytes, during the prolifrative active stage of the cell cycle Inverse correlation between the expression of SRs and degree of lymphoma differentiation

50. Thorax of Patient 5. (A) 4-hr scintigram shows pericardial infiltration (arrows), bulky mediastinal disease (bold ar row) and a right supraclavicular lymph node (arrow-head). (B) Corresponding x-ray with mediastinal mass.

51. Somatostatin Receptor Imaging (Octreotide Scan+SPECT) is useful and can be recommended :  First: baseline before beginning the treatment  In follow-up  For assessment of response to therapy  For assessment of relapse

52. FDG PET in oncology: General aspects( 18 FDG) Cell membrane 18 FDGGlucose 18 FDGGlucose hexokinase 18 FDG-6-PGlucose-6-P Metabolites of Glucose Glucose 6 phosphatase Warburg’s initial observation Increased glycolysis GLUT 1-5 Hexokinase Accumulation in: Tumor cells Macrophages Neutophils Muscle cells

53. FDG PET The most accurate currently available functional imaging for lymphoma In contrast to GS –FDG imaging is a 1-day procedure –Higher resolution –Better dosimetry(10 mSv vs 44 mSv) –Improved lesion delectability (staging) –Higher tumor-to-background ratios for FDG –FDG a good solution for non-Ga- avid lymphomas (low-grade NHL) –Assessment of focal BM involvement –More accurate in spleen –Extranodal lymphoma, benign skeletal involvement, benign parahilar uptake –More sensitive : nodal and extranodal

54. Grade and Prognostic stratification Aggressive NHL: higher FDG uptake A relationship between glucose utilization, proliferative activity and histologic grade In a study:On the basis of the clinical outcome: –Uptake: Not achieve a remission> CR with no relapse or CR with relapse

55. Grade and Prognostic stratification –Potentially no FDG uptake MALT-type lymphomas Small lymphocytic type –Variable Uptake: Follicular lymphoma Marginal-zone lymphoma –SUV: aggressive>indolent; Overlap SUV<10: correctly identified 81% of indolent lymphoma SUV>13: virtually indicative of aggressive lymphoma. Higher SUV: Higher specificity of aggressive disease –More recent reports: High sensitivity: 98% in indolent NHL

56. Staging in malignant lymphoma Identify extension of disease: overt & occult The ideal staging test : –Sensitive and specific –Safe & atraumatic –Available in a timely fashion –Cost-effective Basic staging tool; CT MRI: BM, pelvis, CNS and musculoskeletal The accuracy of FDG-PET for staging suffers from the absence of a reference criterion. –Pathology Ethical Practical

57. PET: Initial Staging Ability of PET to detect disease not suspected from conventional staging (equivocal) Finding an increased number of site of disease (Overal sens: 15%> sens of CT) More accurate for detecting LN involvement than CT Whole body imaging technique: superior to conventional staging Higher accuracy in evaluating BM involvement than CT as well as an accuracy comparable to BM biopsy PET and CT : additional involved nodal sites compared with each modality alone A small number of patients may have their staging changed(10-40%) and about half of them led to modifications in subsequently applied therapy An FDG –PET diagnostic approach decreases costs compared with the conventional staging approach with similar or higher accuracy PET dose not replace conventional staging techniques but should be performed routinely in initial diagnosis

58. PET: Initial Staging Several Studies: –PET changes the management Median: 10.5% 0-62% –Median Sensitivity PET: 93% CT: 81% 67 Ga : 73% –Median Specificity: PET: 99% CT: 93% 67 Ga: 76% Isasi(2005) systematic review: FDG PET –True positive rate: 91% –False positive rate ; 10% –Accuracy: 88%

59. PET: Initial Staging –Diagnostic accuracy, sensitivity and FP rate of PET May be higher in HL than NHL –But NHL is a more heterogeneous disease

60. PET: Initial Staging : HL –PET has a higher sensitivity than conventional imaging for peripheral and thoracic LNs as well as for extra- nodal disease

61. PET: Initial Staging : NHL –PET may be useful in diagnosis of transformation of low grade to high grades (15-20%): more intense than previously: biopsy –More accurate assess LNs involvement and number sites of involvement (IPI)

62. Initial Staging : BM –BMB in all patients –Focal involvement –HL: BM : 6.5% –NHL: 30-50% –FDG PET; Sen & Spec> BS –FDG : higher accuracy : BMA or CT or both –MRI: Accurate : whole body? –Change in staging and treatment

63. Initial Staging : BM –A meta-analysis(Pakos;2005) Better sensitivity in HL and aggressive NHL PET and BMB are complementary techniques No replacement –Missed some BM involvements –Sometimes diffuse uptake : reactive myeloid dysplasia (HL)

64. HL and a negative initial BMB but pathological focal marrow FDG uptake in the mid- and lower lumbar spine, sacrum and left ischium (arrows).

65. BM: Normally mild to moderate uptake, similar to liver activity, This distribution can change with any process that changes normal marrow distribtution or activity. Common causes for altered marrow distibution/activity: Activation of hematopoeisis secondary to anemia or therapy GCSF- Granulocyte colony stimulating factor therapy (common in lymphoma patients) Bone marrow metastasis BM hyperplasia in HL

66. A grade 3 follicular lymphoma and a negative initial bone marrow biopsy of the iliac crest. PET slices show pathological marrow uptake in the sternum (small arrows). which was confirmed histologically. There is also lymph node involvement of the right hilum (large arrow).

67. Splenic Involvement –A single study(Rini;2003): 7 Pts (5 pts with spleen involvement) PET was –True positive for all splenic involvements –True negative for all noninvolvement's –Accuracy: 100% CT: –True positive : 4 –False positive : 2 –Accuracy: 57% –Specificity was similar to GS but PET was twice as sensitive

68. As a lymphoid organ, the spleen normally demonstrates diffuse homogenous uptake above blood pool, but usually below that seen in the liver.

70. GS in a patient with high grade NHL and BM transplantation. He presented with a palpable spleen, fever, dyspnea and pancytopenia. The MRI showed findings most consistent with multiple peripheral splenic infarcts, increasing splenomegaly and no change in multiple small retroperitoneal LNs.

72. PET also can detect focal splenic deposits, even in the absence of structural abnormality. As well as uptake in non- enlarged lesser curve and splenic hilar nodes, several focal splenic nodules are clearly apparent, particularly on fused PET/CT images.

73. Bone PET: similar sensitivity but higher specificity as compared to the BS

74. Lymphoma (Staging) Focal osseous involvement of the spine was identified in this patient with lymphoma. Conventional images were negative.

75. Anatomical regions PET: sensitivity: –Thoracic LNs(91%)>Peripheral LNs(83%)>Abdomen and Pelvis(75%)

76. Staging : Cost-effectiveness –Klose(2000): Incremental cost effectiveness ratio: 3100 euros per patient PET as compared to the CT Cost savings accrued through better planning of further diagnostic procedures and subsequent treatment\ –Another Study; total saving US 30000 dollars using PET FDG-PET : noninvasive, efficient and cost-effective whole body imaging with high Sens, Spec and Acc for staging of lymphoma

77. HD involving: LNs, Ribs, Spine, Right Femur, BM, Spleen

78. PET and CT in a patient with HD involving the supraclavicular and infraclavicular sites, the mediastinum and the lung hilum bilaterally

79. On conventional staging this patient with low-grade (follicular) NHL. CT demonstrated left lower cervical and mediastinal lymphadenopathy. There was no splenomegaly, and bone marrow biopsy was negative. FDG PET/CT demonstrated abnormal uptake in non-enlarged axillary and para-aortic nodes and intense splenic uptake, upstaging the patient and changing our treatment to chemotherapy.

80. Male patient with history of NHL and a normal abdominal CT

81. Epigastric mass with abdominal para-aortic lymphadenopathy and splenomegaly on CT. Biopsy of the mesenteric mass was inconclusive, and bone marrow biopsy was negative. FDG PET confirmed known sites of abnormality and additional focal liver (horizontal arrows), bone (vertical arrow and other sites not displayed in these coronal planes), and left supraclavicular nodal disease (oblique arrow). The patient was subsequently confirmed to have stage IV NHL with focal bone lesions on MRI.

82. In cases with multifocal bone involvement FDG PET, as demonstrated in this case, sampling error may yield a false-negative bone marrow biopsy result. In such cases, PET and particularly PET/CT can be used to guide biopsy.

83. PET/CT images for restaging of HD. Intense FDG uptake in cervical (upper arrow), mediastinal (lower arrow), axillary (arrow at the left axilla) and iliac (lowest arrow) lymph nodes as well as an FDG-avid lesion in the spleen (short arrow). There are multiple lesions with FDG uptake in the bones (arrow- heads; left humerus, pelvis, both proximal femora). Bone window of the axial CT image at the level of the upper thorax shows enlarged axillary lymph nodes (arrow) but normal bone structure of the scapula (arrow- heads). Corresponding axial PET image (c) and fused PET/ CT image (d) demonstrate intense FDG uptake in enlarged axillary lymph nodes (arrow) and the scapula (arrowheads). BMB was negative in this patient

84. Assessment of response to therapy PE, Biochemistry (LDH,…) Cross-sectional imaging: based on nodal size –Can not differentiate between fibrosis or disease in a residual mass(85% in HD & 40% in NHL). identify disease relapse differentiate enlarged reactive nodes from infiltrated nodes identify disease in normal-sized node Functional imaging : helpful – 67 Ga –PET

85. PET; Early prediction of response to primary treatment Around 85% of Pts will respond to their primary chemotherapy satisfactorily Early PET response after 2 cycles of chemo –predict ultimate outcome –Stronger prognostic factor than IPI Enable us to identify those –Who may requires less intensive treatment with early good response to PET –Who should be taken out of conventional chemo and moved into high dose treatment at earlier stage –Who are in complete remission after 4-6 cycles of chemo do not actually require any further treatment (spared of toxicity) 100% relapse rate for the interim PET positive scan compared with 8% for the negative group in HD. Predictive results from PET scanning would supersede conventional scanning

86. PET; Early prediction of response to primary treatment Persistently Positive PET scans after 3 cycles of chemotherapy –Sensitivity> Ga67 for the prediction of subsequent relapse PET scans after 2 cycles of chemotherapy –PPV for relapse > Ga67 Interim PET scanning: –Predict response –PFS –OS –Stronger predictor for PFS and OS than IPI However the clinical utility of this information is yet to be evaluated and there is no form evidence to date to suggest that early change in therapy in poorly responding patients improves survival.

87. Complete response and good prognosis of HL. (A)Baseline PET: Abnormal FDG uptake in sites of lymphadenopathy in the left supra- clavicular region, the right axilla, the mediastinum bilaterally, the left lung hilum, and the porta hepatis region. (B)Repeat FDG-PET, performed after one cycle of chemotherapy, is negative. (C)CR at a follow-up of 15 months.

88. NHL: Assessment of partial response, prediction of poor outcome, and detection of recurrence. (A)Baseline : multiple areas of abnormal FDG uptake in sites of mesenteric and retroperitoneal adenopathy. (B) Repeat FDG-PET performed after two cycles of chemotherapy shows residual but less prominent abnormal FDG uptake in abdominal sites indicating partial response. (C)FDG-PET at the end of treatment is negative indicating that complete response was achieved. (D)Routine follow-up FDG-PET at 4 months of remission shows recurrent disease inabdominal sites.

89. Stage IIA high-grade NHL. Baseline:Highly hypermetabolic lymph nodes in the left axillary and cervical areas PET performed after 3 courses of chemotherapy shows a complete metabolic response. The patient is in complete clinical remission 6 months after completing the treatment.

90. HD : A: Baseline FDG PET:Multiple foci of increased activity in cervical and mediastinal areas as well as right hilar and lung infiltration. B: FDG PET performed after 2 cycles of polychemotherapy indicates residual 18F-FDG uptake in a right cervical lymph node. C: Treatment failure was observed at the end of treatment.

91. PET : Definitive response to primary chemotherapy (residual mass) After completion of 6 or 8 conventional cycles of chemo: complete remission? Uncertain complete response (uCR) –Tiny remnant on CT or MRI –Normal-sized lymph nodes at previous pathological LNs region Residual mass: PET : greatest utility: to determine the presence or absence of active cells within residual radiological abnormality Some patients may be spared the late effects of radiotherapy if it can be demonstrated the residuum not contain active disease Early identification of pts who have not been cured –A major impact on the out come of treatment –Allow treatment at an early stage with a lower cellular burden: higher probability of cure from further treatment

92. PET : Definitive response to primary chemotherapy (residual mass) PET is more accurate than CT Accuracy of PET is high enough to become a standard method of remission assessment in addition to CT or with increasing use of PET/CT for it replace CT in this setting End of treatment PET dose not add prognostic information to an early interim PET that was clearly positive or negative( except for interim PET with MRU)

93. PET : Definitive response to primary chemotherapy (residual mass) Persistent uptake in NHL: –In sites that were initially involved : highly: residual disease –Abnormal uptake outside the initially involved sites : First: excluded: infectios/inflammatory lesions Thymic hyperplasia –A negative results: can not exclude MRD: late relapse : possible Prognostic value of PET will depend on the pre-test likelihood of relapse: OVERALL: CT+ PET: CT-defined residual mass but negative PET: no further treatment PET positive residual masses : further treatment preferably after histological confirmation

94. Best time for end of treatment evaluation Unknown Suggest: at least 1 month after chemotherapy 3 moths after radiotherapy

95. Lymphoma (Residual mass post-therapy) A patient received chemotherapy for lymphoma. There was a residual left neck mass following completion of therapy. A FDG PET exam revealed persistent metabolic activity within the mass concerning for residual tumor.

96. Diffuse large B-cell NHL : Baseline FDG PET shows several foci of increased activity in the right cervical and infraclavicular areas, as well as in the spleen (arrows in A). 18 F-FDG PET performed after completion of induction chemotherapy (4 courses) shows a normal distribution of the tracer (B). No relapse was observed (follow-up: 1 year).

97. PreChemotherapy PostChemotherapy - August 24, 1996PostChemotherapy - August 24, 1996 Non-Hodgkin's Lymphoma - Chemotherapy response Non-Hodgkin's Lymphoma - Chemotherapy response PostChemotherapy Non-Hodgkin's Lymphoma - Chemotherapy response

98. Normal Thymus S/P: Right calf melanoma resected Right groin lesion (long arrow), a lesion at inferior margin of liver and FDG uptake in thymus (short arrow).

99. PET : Definitive response to primary chemotherapy (residual mass) and relapse False positive; Post-treatment PET : Better prognosis in HL Relapse is rare in HL NPV : HL> NHL PPV: HL<NHL Overall Accuracy : comparable Pts selection criteria: High suspicion relapse: improve PPV

100. PET : Definitive response to primary chemotherapy (residual mass) and relapse Early stage of HL: PET: PPV <NPV Advanced stage of HL and aggressive NHL : higher relapse, higher PPV. –A PET- : does not exclude MRD and should not be used therefore as the sole indicator of disease eradication. ( but longer PFS) Different algorithms; Differential interpretation of PET after therapy in different types of Lymphomas may improve the correct estimation of treatment response. NHL and high stage HL: –PET +: highly suggestive of disease: requires intensive confirmatory investigations –PET- : does not exclude the presence of MRD and future relapse: close follow-up Early stage of HL: –PET-: CR with favorable prognosis even in the presence of residual masses on CT –PET+: especially in a different site: caution: exclude the benign lesions

101. Follow-up  Regular out patient visits, symptoms, PE, CXR, CT  Non-site-specific tests: GS, PET, LDH: may be better at identifying relapse  Earlier identification using PET of Pts who are destined to relapse would have considerable value in allowing earlier institution of salvage therapy  PET can detect recurrent disease before clinical symptoms, signs Labs, CT ; salvage chemotherapy with minimal disease rather than overt relapse  However, despite the high PPV, histological or other evidence of disease recurrence should be sought prior to salvage therapy: significant FP

102. Lymphoma (Recurrent tumor) A patient with history of submandibular lymphoma. CT imaging revealed evidence of recurrent lymphoma, but failed to identify the lesion in the right psoas muscle (black arrow on FDG PET exam)

103. Patients with relapse but remain chemosensitive HDT/ASCT: the treatment of choice for patients who relapse after conventional chemotherapy but who remain chemotherapy sensitive The most important prognostic factors to predict favorable outcome after HDT/ASCT are: – the duration of remission prior to progressive disease – the chemosensitivity of the tumor to salvage therapy prior to ASCT

104. Patients with relapse but remain chemosensitive PET –Predict outcome –Prediction of response at earlier time during chemotherapy –Accurate in the prediction of relapse –PPV: 79%, NPV: 80% and accuracy 79% –Co-existing inflammatory disease is more frequently seen in this population : FP –Correlations of PET, clinical and morphological imaging data are essential –Negative PET after induction: better prognosis –But chemosensitive PET positive Pts: : should not be excluded from ASCT: median estimated risk of relapse for all PET positive Pts: 20% –Some patients with residual uptake will have a good out come after HCT/ASCT –PET should be used together with IPI –PET: important prognostic factor –Not perfect –Not all patients with a negative PET have favorable outcome –Not all patients with a positive PET will relapse –But stronger predictor factor than IPI –No change the management of chemosensitive Pts for HCT/ASCT

105. PET: Radiotherapy planning Wide-filed radiotherapy (acute and late effects on normal tissues) Involved field radiotherapy –Decreases acute and late effects including second malignancies –An enlarged LN on CT or MRI is likely to underestimate the extent of disease: adjacent microscopic disease – PET: could have an important role: Involved-node irradiation: only CT and PET positive areas are treated Exciting developments: registration PET images with radiotherapy planning CT images

106. Mediastinal HL: was planned for chemotherapy followed by radiotherapy. Focal liver lesions were considered equivocal for disease on CT with hepatic cysts being a differential diagnosis. PET confirmed low metabolic activity in the hepatic lesions (vertical and horizontal arrows). The extent of metabolically active disease in the mediastinum lower right neck and left axilla was used to guide radiotherapy. The left axillary nodes (oblique arrow) were not clinically or radiologically involved.

107. FDG PET Ultimate aim: improve management, higher cure rates, lower toxicity rates, PET-CT scanners: combined morphological and functional information: may provide optimal disease assessment –A single Study (Allen-Auerbach, 2004): –Overall Staging was accurate: PET/CT: 93% PET:84%

108. Timing of PET in relation to chemotherapy Interim scan: ? Romer1998: –Rapid decrease in FDG uptake as early as 7 days –However FDG uptake at 42 days correlated better with long-term outcome Two other studies: –Reduction in SUV as early as 24 hours –Increased macrophage uptake :7-10 days –Ideally≥ 14 days TIMING:?

109. FDG-PET or PET/CT at diagnosis Negative No more follow-up scans Positive Repeat PET or PET/CT during therapy Positive scan HD and NHL Negative scan,NHL,HD stage ΙΙΙ and ΙV Negative scan HD stage Ι and ΙΙ Consider more aggressive therapy 1 year follow-up scans mandatory Follow-up scans only within clinical suspicion Repeat scan after secondary treatment and before transplantation Negative: Further installed treatment and repeat scan at the end of therapy

110. Limitations of FDG PET FDG is not a very tumor-specific substance –Anti-inflammatory cells show FDG avidity; infection, inflammation, granulomatous disease –Thymic hyperplasia Post-radiation inflammation changes Limited spatial resolution to 5-8 mm. May have lower uptake in low grade NHL, MALT and small lymphocytic lymphoma Physiological uptake may occur –Bowel –Myocardium –Brain –Urinary tract –Muscle –Salivary glands –Lymphoid tissue Thus, tumor may be Missed Masked Mimicked by other pathology

111. Brown fat

113. Methods to circumvent limitations Performing baseline scans at presentation for comparison with post-treatment scans Simple maneuvers: lasix, diazepam, Caffeine, Indral Considering the clinical data PET/CT

114. This patient presented with abdominal pain, and bulky para-aortic lymphadenopathy was identified on CT. FDG PET demonstrated high uptake in multiple abdominal nodes as well a several discrete foci with slight elongation, suggesting small bowel involvement. Coregistered PET images and CT with oral contrast obtained contemporaneously on hybrid PET/CT demonstrate intense uptake corresponding to mural thickening of small bowel.

115. Despite relatively high uptake of FDG in the normal brain, very intense FDG uptake in most primary cerebral lymphomas renders PET a useful technique for therapeutic monitoring. New tracers like FLT that have low uptake in the normal brain may be more sensitive for small lesions and possibly for leptomeningeal disease.

121. V.R.Dabbagh; DSNMC; www.DSNMC.ir