Molecular and Whole-body MR Imaging in Lymphomas
Condition: Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin
MeSH terms: Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin
Study type: Interventional

Summary: 
      Lymphomas are classified as Hodgkin's or non-Hodgkin's lymphomas, of which especially the
      latter represent a heterogeneous group with varying patterns of prognosis, biological
      behaviour and response to treatment. 18F-FDG PET/CT is useful for staging and response
      monitoring but has the disadvantage of associated radiation exposure which may not be
      desirable for young patients. Advanced MRI techniques including diffusion weighted imaging
      (DWI) are increasingly used for improved lesion detection and characterisation of lymphomas
      and in the whole-body mode offer a promising radiation-free alternative to CT. Molecular
      imaging in turn is important in theranostics medicine where detection of therapeutic target
      is essential. The concept of theranostics has been successfully adapted to management of
      neuroendocrine tumors (NET) where peptide receptor radiotherapy (PRRT) is offered to patients
      progressing on treatment with long-acting somatostatin analogues.

      Recently in the investigator's hospital a case of diffuse large B-cell lymphoma (DLBCL) was
      initially misdiagnosed as NET because of high uptake of 68Ga-DOTANOC in pancreatic tumor at
      PET/CT. A PubMed search revealed a similar case report in bronchial tumor which turned out to
      be DLBCL (Jain et al. Clin Nucl Med 2014;39:358-359). Bearing these two cases in mind the
      investigators now aim to systematically study somatostatin receptor status (ssr) by measuring
      uptake of 68Ga-DOTANOC with PET/CT in patients with newly diagnosed non-Hodgkin's and
      Hodgkin's lymphoma. The imaging findings will be compared to immunohistochemically determined
      ssr-subtypes 2,3 and 5 obtained from pre-treatment fresh tumor samples and 18F-FDG PET/CT
      which is part of standard diagnostic evaluation. Furthermore, whole-body MRI with DWI will be
      performed before, during and after chemotherapy to define the most sensitive and specific
      imaging method appropriate for routine diagnosis and follow-up. This study has potential
      implications for future response monitoring and follow-up imaging techniques in patients with
      malignant lymphoma and provides additional biologic characterization which may be useful for
      novel therapeutic approaches such as PRRT.
    

Detailed description: 
      Lymphomas are malignant tumours of the immune system. Lymphomas are classified as Hodgkin's
      or non-Hodgkin's lymphomas with several subtypes. In Finland the amount of newly diagnosed
      Hodgkin's lymphomas is 120-150 new cases per year and it accounts for 12 % of all lymphomas.
      Non-Hodgkin's lymphoma is the sixth most common cancer in men and the eight most common
      cancer in women in Finland. There are approximately 1200 new cases per year and the incidence
      has been increasing during the last decade. (1, 2)

      Etiology of lymphomas is mostly unknown but many risk factors have been identified.
      Diagnostics and classification to different subgroups is based on clinical, pathological,
      molecular, and radiological studies. Some of lymphoma's subtypes can be cured with current
      treatment methods, however, many of them remain still incurable. (1) Clearly, more accurate
      diagnostic tools with subsequent targeted therapies against lymphomas are needed.

      Somatostatin receptors (SSTs) are expressed by a wide variety of different tumour cell types,
      including malignant lymphomas. (8, 9, 10, 11) Somatostatin receptor imaging by octreotide
      scintigraphy has showed a sensitivity of 95-100 % in Hodgkin's lymphoma and 80 % in
      non-Hodgkin's lymphoma. However, somatostatin receptor scintigraphy does not appear to have a
      significant role in diagnostic process because of the relatively low uptake of the used
      somatostatin analogue (octreotide) and limited sensitivity of the single photon emission
      computed tomography (SPECT) acquisition to detect and localise small involved nodes. (11, 25)
      Hence, somatostatin receptor imaging has been further developed with the advent of hybrid
      SPECT and positron emission tomography (PET) and computed tomography (CT) scanners. Several
      other radioligands have been studied to improve the binding affinity (15). This has also
      offered a new target for tumor cell-specific therapy using different somatostatin analogs
      labelled with therapeutic radionuclides such as 90Y-DOTATOC, a somatostatin receptor subtype
      2 (SST2) -specific ligand. Clinical studies of peptide receptor radionuclide therapy (PRRT)
      have extensively focused on neuroendocrine tumors as a palliative treatment modality (12, 13,
      14). Another new candidate for SST based imaging and treatment is 68Ga-DOTANOC, a
      high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 (SST2, SST3, SST5) (16).
      Neuroendocrine tumors are known to express SST2 and they show high uptake of radiolabeled
      somatostatin analogs on PET. However, lymphomas may mimick NETs on DOTANOC PET/CT as was
      shown in a recent case report (17). Therefore, further studies on SST2 status and DOTANOC
      uptake are in order to establish the role of peptide based imaging in diagnosis and possible
      PRRT in lymphomas.

      The aim of the study is to determine tumor uptake of 68Ga-DOTANOC in patients with
      non-Hodgkin's and Hodgkin's lymphoma to characterize the SST2, SST3 and SST5 receptor status
      of the tumour in vivo with 68Ga-DOTANOC PET/CT. In addition, immunohistochemical analysis of
      SST2, SST3 and SST5 subtype status will be made of the tumor specimens obtained in routine
      diagnostic biopsy resection. Furthermore, PET findings will be correlated with advanced MRI
      techniques, such as diffusion weighted imaging (DWI) in an attempt to find methods which
      limit radiation exposure especially in young patients. Hence, PET/CT will be performed with
      68Ga-DOTANOC and 18F-FDG and compared with whole-body MRI (including DWI) to define the most
      sensitive and specific imaging method appropriate for routine diagnosis and follow-up of
      patients with lymphoma.

      To the investigators knowledge, no prospective studies comparing octreodite analogue based
      PET/CT imaging with standard diagnostic procedures have been published until now. PET/CT
      offers a clear advantage over scintigraphy in terms of sensitivity and resolution which
      should be helpful in determining the SST status of various histologic forms of lymphomas The
      investigators hypothesize that a positive 68Ga-DOTANOC PET/CT scan correlates with the
      overexpression of all or some SST subtypes in lymphomas, which is possibly linked to a more
      indolent behavior of the disease. Furthermore, it is hypothesized that 68Ga-DOTANOC PET/CT
      imaging provides a valid method to select patients with lymphoma for radionuclide therapy
      with 177Lu-DOTATATE. Third, differential diagnosis with NETs may also improve after receiving
      information on SST status in lymphomas. Thus findings in this study may be useful not only
      for biologic characterization but also for diagnosis and management of these heterogenous
      diseases originating in the lymphatic system
    

Intervention name(s): 68Ga-DOTANOC PET/CT; Diffusion weighted MRI
Intervention type(s): Other
Intervention description(s): PET/CT: Radionuclide imaging using short-lived isotope Ga-68; MRI imaging w/o gadolinium contrast
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Lymphoma; 68Ga-DOTANOC PET/CT; Somatostatin receptor; MRI; Diffusion weighted imaging; Early treatment response