PET/CT in malignant bone disease

The most commonly used positron emission tomography (PET) tracer in clinical practice, fluorine-18 fluorodeoxyglucose ( (18)F-FDG) is a glucose analogue that directly gains entry in excess into tumor cells. It is therefore sensitive for the detection of early bone marrow involvement prior to any identifiable bone changes. The introduction of (18)F-FDG-PET in the imaging algorithms of various malignant diseases often obviates the need to perform a separate assessment of malignant bone involvement with conventional bone scintigraphy. After therapy, disappearance of (18)F-FDG accumulation indicates success even when the bone remains morphologically abnormal. Novel hybrid systems composed of PET and computed tomography (CT) allow for acquisition of both modalities in the same clinical setting and the generation of fused functional-anatomical images. This technique has been found to improve the diagnostic accuracy of PET in detecting malignant bone involvement. This article discusses the role of PET/CT, primarily (18)F-FDG PET/CT, in the assessment of malignant bone involvement in patients with primary bone sarcomas, common solid malignancies, lymphoma, and multiple myeloma.     

Knochenmarkbeteiligung bei hämatologischen Neoplasien und soliden Tumoren

Bone marrow involvement is often observed in patients with hematological malignancies and solid tumors. Sensitive immunological and molecular biological methods allow the detection of isolated transformed cells in bone marrow samples. Like normal hematopoietic cells, tumor cells interact with bone marrow stroma through adhesion molecules. Since adhesion molecules play an essential role in the invasion and proliferation of malignant cells, new therapeutic approaches involving the inhibition of cell-cell and cell-matrix interactions are conceivable.     

Magnetic resonance imaging in diffuse malignant bone marrow diseases

Twenty-four patients with malignant bone marrow involvement or polycythemia vera, 8 patients with reactive bone marrow and 7 healthy individuals were examined with spin-echo magnetic resonance imaging at 0.35 T and 0.5 T. Signs of an increased longitudinal relaxation time, T1, were found when normal bone marrow was replaced by malignant cells, polycythemia vera or reactive marrow. A shortened T1 was indicated in 4 patients in bone marrow regions treated by radiation therapy; the marrow was most likely hypocellular in these cases. The estimated T1 relaxation times were highly correlated to the cellularity of the bone marrow as assessed by histology. Among patients with close to 100 per cent cellularity neither T1 nor T2 discriminated between the various malignancies or between malignant and reactive, non-malignant bone marrow. Characterization of tissues in terms of normalized image intensities was also attempted, the motive being to avoid approximations and uncertainties in the assessment of T1 and T2. The normalization was carried out with respect to the image of highest intensity, i.e. the proton density weighted image. The results were in agreement with those for T1 and T2. It was concluded that MRI is valuable for assessing bone marrow cellularity, but not for differentiating between various bone marrow disorders having a similar degree of cellularity.     

The role of positron emission tomography in skeletal disease

The role of positron emission tomography (PET) in the evaluation and management of skeletal disorders is increasing. A number of reports are available in both benign and malignant disease with a variety of tracers. The bone agent 18F-fluoride can be used to evaluate bone metastases both qualitatively and, for a number of focal and systemic skeletal disorders, quantitatively. 18-Fluorodeoxyglucose is used as a tumor agent in both primary and metastatic bone and bone marrow malignancies; its use has also been described in the evaluation of infection within the skeleton. A possible role for the use of the hypoxia selective tracer 18F-fluoromisonidazole in skeletal infection also exists. This article summarizes the current role of PET in the skeleton with regard to these tracers and diseases.     

Imaging of malignant bone involvement by morphologic, scintigraphic, and hybrid modalities.

Detection of bone involvement is essential for optimal therapy of oncologic patients. The purpose of imaging is to identify early bone involvement, to determine the full extent of the skeletal disease, to assess the presence of accompanying complications-such as fractures and cord compression-and to monitor response to therapy. Detection of bone involvement by various imaging modalities is based on either direct visualization of tumor infiltration or detection of the reaction of bone to the malignant process. MRI can identify early involvement of bone marrow. CT, which depends mainly on bone destruction, provides detailed bone morphology. In nuclear medicine, uptake of (18)F-FDG is directly into tumor cells, thus allowing for early detection and monitoring the response to therapy of tumor sites in the marrow, bone, and soft tissue, whereas increased uptake of (18)F-fluoride and (99m)Tc-methylene diphosphonate reflects the osteoblastic reaction of bone to the presence of tumor cells. The hybrid techniques SPECT/CT and PET/CT, recently introduced into clinical practice, provide a better anatomic localization of scintigraphic findings and may improve the diagnostic accuracy of SPECT and PET in detecting malignant bone involvement. The current review discusses the basis for the detection of malignant bone involvement by various morphologic and scintigraphic imaging modalities and the advantages and the limitations of each. Special emphasize is placed on the newer integrated technique of PET/CT. The role of imaging in identifying bone involvement in different malignant diseases is also discussed.     

Diffuse bone marrow involvement of Hodgkin lymphoma mimics hematopoietic cytokine-mediated FDG uptake on FDG PET imaging

Whole-body fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) has been useful in the management of a variety of malignancies. In patients with chemotherapy followed by bone marrow stimulants such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, the bone marrow will have diffuse, increased FDG accumulation. Therefore, diffuse bone marrow FDG uptake is commonly attributable to the effect of hematopoietic cytokines. However, diffuse bone marrow FDG uptake can also be caused by bone marrow involvement by malignancy. The authors report a patient with diffuse bone marrow involvement of Hodgkin disease that appears indistinguishable from hematopoietic cytokine-mediated FDG bone marrow uptake.     

Prospective study of bone marrow infiltration in aggressive lymphoma by three independent methods: whole-body MRI, PET/CT and bone marrow biopsy

PURPOSE: Initial lymphoma staging requires bone marrow assessment in aggressive lymphomas. Bone marrow lymphoma infiltration is routinely assessed by bone marrow biopsy (BMB), considered as the "gold standard". The aim of this study was to compare the performance of BMB, whole-body MRI and PET/CT for evaluation of BM infiltration. METHODS: Patients with newly diagnosed aggressive lymphoma were evaluated by BMB, MRI and PET/CT. Two radiologists, two nuclear medicine physicians and one pathologist independently assessed the results of the three modalities. Bone was considered as involved if BM was positive or if PET/CT or MRI was positive and if there was a resolution of the abnormal image shown on PET/CT or MRI halfway or at the end of therapy. RESULTS: Both MRI and PET/CT detected bone marrow lesions in the 9/43 patients, but two patients with multiple lesions had more lesions detected by PET/CT compared to MRI. Among these nine patients, two with an iliac crest lesion detected by both MRI and PET/CT had bone marrow involvement with large-cell lymphoma on histological examination. The other seven patients had focal MRI and PET/CT lesions in areas other than the iliac crest, where the blind BMB was done. The other patients had bone marrow without large-cell lymphoma involvement. In all cases, after lymphoma therapy bone marrow involvement regressed on histological examination, PET and MRI. CONCLUSION: These preliminary results suggest that non-invasive morphological procedures could be superior to BMB for bone marrow assessment in aggressive lymphomas. Ongoing study is underway to validate these results.     

Malignant lymphoma: bone marrow imaging versus biopsy

In 107 patients with malignant Hodgkin and non-Hodgkin lymphoma, bone marrow was evaluated with scintigraphy, magnetic resonance (MR) imaging, and biopsy to detect bone marrow infiltration. Imaging and biopsy results were classified as normal (class 0), suggestive of reactive changes (class 1), or suspicious for infiltration (class 2). About one-half of biopsy and imaging results agreed completely. In patients with chronic lymphocytic leukemia, false-negative findings were frequent with both imaging techniques. Although a positive biopsy result is usually accepted as proof of bone marrow infiltration, results indicate that negative biopsy findings do not exclude tumor involvement. When suspected infiltration was found with MR imaging or scintigraphy but results were normal or suggestive of reactive changes in the first blind biopsy, repeat blind or guided biopsy helped confirm the imaging results. Autopsy findings in two patients completely confirmed previous results with MR imaging and scintigraphy, although findings at antemortem biopsy were different. Scintigraphy and MR imaging should be included routinely in the staging of malignant lymphoma as an adjunct to blind biopsy in the complete evaluation of bone marrow status.     

Can [18F]fluorodeoxyglucose positron emission tomography imaging complement biopsy results from the iliac crest for the detection of bone marrow involvement in patients with malignant lymphoma?

OBJECTIVES: To assess the usefulness of [18F]fluorodeoxyglucose positron emission tomography in the detection of bone marrow involvement in malignant lymphoma, and its impact in clinical management. METHODS: One hundred and six consecutive patients with a confirmed diagnosis of lymphoma, referred for staging or restaging of Hodgkin's lymphoma (n=18) or non-Hodgkin's lymphoma (n=88), were reviewed retrospectively. A positron emission tomography scan and bone marrow biopsy of the iliac crest were performed in all patients. The assessment of bone marrow involvement by lymphoma was confirmed by histology and/or progression of bone marrow lesions in clinical follow-up. RESULTS: In 28 of 106 patients, bone marrow involvement was found. Positron emission tomography was more sensitive (86%) than bone marrow biopsy (57%). Positron emission tomography and bone marrow biopsy were concordant by positive correlation in 12 of 28 cases (43%) and by negative correlation in 77 of 78 cases (99%). Ten cases of non-Hodgkin's lymphoma and two cases of Hodgkin's lymphoma with positive positron emission tomography results and an initial negative bone marrow biopsy showed clinical progression of the bone marrow lesions and/or subsequent positive histology. These were considered as false-negative results for bone marrow biopsy. In seven of the 12 positive cases with negative bone marrow biopsy, positron emission tomography uptake distant from the site of the biopsy was seen. In four cases of follicular lymphoma, the bone marrow biopsy was positive and the positron emission tomography scan was normal. CONCLUSIONS: Positron emission tomography and bone marrow biopsy are complementary in assessing the presence of bone marrow involvement in patients with malignant lymphoma. In our series, positron emission tomography was more sensitive than bone marrow biopsy in Hodgkin's and non-Hodgkin's lymphoma, except in follicular lymphoma.     

The evolving role of MRI in oncohaematological disorders

Magnetic resonance imaging (MRI) has opened new possibilities to current diagnostic radiology in the evaluation of bone marrow. Compared with other imaging modalities, MRI is the only technique able to directly visualise bone marrow with its different components of red and yellow marrow. Other advantages of MRI are high-contrast resolution and multiplanar view, as well as extensive coverage of the skeleton with whole-body MRI (WBMRI). However, specificity of signal alterations of bone marrow is low. Therefore, MRI findings need to be integrated with clinical and laboratory findings as well as with haematological and oncological evaluation. MRI provides information that effectively aids diagnosis, staging and follow-up of various bone marrow disorders. There is increasing interest in the capabilities of MRI in the evaluation of bone marrow, in particular of haematological malignancies. According to some authors much work remains to be done to improve sensitivity and specificity of MRI in order to define the real clinical value of this imaging modality in the multidisciplinary management of patients with a haematological malignancy. This article presents recent developments and perspectives in the use of MRI in oncohaematological diseases.     

Imaging of metabolic bone disease and marrow disorders in children

There are a wide variety of metabolic and infiltrative diseases that involve the bones. Conventional radiography is the primary imaging examination for the initial evaluation of most of these disorders. MR imaging, however, provides detailed information about the bone marrow and is gaining an increasingly important role in the management of disorders of bone marrow infiltration.     

The evaluation of the bone marrow accumulation of Ga-67 citrate

The bone marrow distribution of Ga-67 citrate may be influenced by various elements in serum. In order to make these points clear, 1,955 whole body images were reviewed on the relationship between the accumulation of bone marrow and laboratory examination data of each patients. Increasing accumulation in the bone marrow was determined as positive when the bones of lower extremities were deposited on the images, because these bones was not visualized in normal gallium image. Laboratory data of 20 patients without having bone marrow accumulation was used as control. The positive findings of bone marrow accumulation was observed in 38 patients (2%) including 23 malignancies and 15 benign disease. The malignant tumor infiltration to the bone marrow was demonstrated by bone marrow aspiration biopsy in 2 out of 7 patients with bone marrow accumulation of Ga-67. Seven out of 15 patients with benign disease were collagen disease such as aortitis syndrome or SLE. The values of hemoglobin, hematocrit, serum iron and creatinine clearance were significantly lower in the patients with positive findings in comparison with control. These results suggest that the lower level of serum iron and anemia may cause increasing bone marrow accumulation of Ga-67 citrate.     

Diffusion-weighted imaging of bone marrow: current status

Diffusion-weighted imaging allows for measurement of tissue microstructure and reflects the random motion of water protons. It provides a new method to study bone marrow and bone marrow alterations on the basis of altered water-proton mobility in various diseases. Different diffusion-weighted methods have proved to be capable of differentiating between benign edema and tumorous involvement of bone marrow. It is especially useful for the distinction of acute benign osteoporotic and malignant vertebral compression fractures. Diagnosis is based on the contrast to normal bone marrow. Hypo- or isointensity reflects acute benign collapse, whereas hyperintensity is indicative of the tumorous nature of a fracture. Apparent diffusion coefficients (ADC) are significantly lower in metastatic disease than in bone marrow edema. Furthermore, bone marrow cellularity can be estimated by ADC measurements. Diffusion-weighted imaging might be helpful for monitoring response to therapy in metastatic disease.     

The current status of bone scintigraphy in malignant diseases

For the past few decades, planar bone scintigraphy has been the most frequently performed imaging study in the evaluation of metastatic bone disease. Although scintigraphic findings alone are often nonspecific for skeletal pathologies, this technique reportedly has an exquisite sensitivity. However, recently accumulated data on the efficacy of positron emission tomography with fluorine-18 fluorodeoxyglucose and fluorine-18 sodium fluoride as well as magnetic resonance imaging for evaluating skeletal metastatic disease now indicate that conventional planar bone scintigraphy is not very sensitive in the detection of metastatic bone lesions in selected malignancies. Nevertheless, bone scintigraphy still remains the primary imaging modality for evaluation of metastatic bone disease owing mainly to its cost effectiveness and wide availability. In addition, recently introduced hybrid imaging systems combining single-photon emission computed tomography and spiral computed tomography, although not widely available yet, increase considerably both the sensitivity and specificity of bone scintigraphy. This article focuses primarily on the current role of bone scintigraphy and its strengths and weaknesses in assessing different types of malignant diseases relative to other imaging modalities in selected malignancies.     

Role of 99mTc-hexakis-2-methoxyisobutylisonitrile for detecting marrow metastases in childhood solid tumours

AIM: To evaluate the role of 99mTc-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) for detecting bone marrow metastases in childhood solid tumours, including lymphomas. METHODS: Twenty-six children (18 males, eight females) were studied. They all had proven malignant solid tumours [Hodgkin's lymphoma (5), non-Hodgkin's lymphoma (3), neuroblastoma (9), Ewing's sarcoma (3), Langerhans cell histiocytosis (4), rhabdomyosarcoma (1) and germ cell tumour (1)] with suspected bone marrow metastases. All patients underwent computed tomography and/or magnetic resonance imaging, 99mTc-MIBI and Tc-methylene diphosphonate bone scans and bone marrow aspiration and/or biopsy. The scintigraphic evaluation of 99mTc-MIBI scans was performed according to the visual assessment of the extent and intensity of uptake. The scintigraphic score, which is the sum of the extent and intensity of uptake, was calculated for each patient. Scores of more than 2 were considered to be positive for bone marrow involvement. RESULTS: Twenty-seven 99mTc-MIBI scans were studied for 26 patients. Twenty-two 99mTc-MIBI scans were accepted as normal bone marrow. Bone scans were also normal in these patients. Five of the 27 99mTc-MIBI scans had scores of more than 2. Bone marrow cytology revealed bone marrow metastases in these patients. CONCLUSION: Abnormal 99mTc-MIBI uptake correlated extremely well with bone marrow aspiration/biopsy cytology results. Non-invasive 99mTc-MIBI imaging in children with malignant solid tumours appears to be promising for the evaluation of bone marrow metastases.     

Distribution of technetium-99m-labeled multilamellar liposomes in patients with Hodgkin's disease

The distribution of 99mTc-labeled multilamellar liposomes composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a molar ratio of 7:3, administered intravenously, was studied in ten patients with Hodgkin's disease (HD). The dose of lipid was 150 mg/m2 and the mean dose of radioactivity injected per patient was 8.1 mCi (range 6.7-9.8). Whole-body imaging techniques were used, and for each organ an uptake index was calculated as the percent photographic density (PD) relative to the PD of the liver. Results were compared to those in a group of six patients with other malignancies. Increased liposome uptake in several skeletal areas was observed in one patient with HD with diffuse bone involvement and in the bone marrow of two patients with HD with bone marrow involvement. No definite liposome uptake was observed in lymph nodes involved by HD or in tumor areas of patients with other malignancies. Patients with HD had a significantly higher uptake by bone marrow (23.8% compared with 10.2% at 4 hr p = 0.02), and lungs (59.6% compared with 25.0% at 4 hr, p = 0.01) than patients with other malignancies. Among patients with HD, the uptake by bone marrow and lungs were higher in those with constitutional symptoms (bone marrow at 4 hr 31.4% compared with 16.2%, p = 0.02; lungs at 4 hr 68.8% compared with 50.4%, p = 0.19) and with liver involvement (bone marrow at 4 hr 30.8% compared with 16.8%, p = 0.03; lungs at 4 hr 73.6% compared with 45.6%, p = 0.03). These results suggest that patients with HD have a different pattern of distribution of multilamellar liposomes which may be related to a combination of nonspecific stimulation of the reticuloendothelial system and tumor uptake. It does not appear that liposomal 99mTc is capable of adequately imaging HD for clinical diagnosis.     

Three-dimensional images of contrast-enhanced MDCT for preoperative assessment of musculoskeletal masses: comparison with MRI and plain radiographs

PURPOSE: To evaluate the diagnostic capability of contrast-enhanced multidetector computed tomography (MDCT) for the preoperative assessment of musculoskeletal masses, in comparison with magnetic resonance imaging and plain radiographs (MRI+X-p). MATERIALS AND METHODS: Sixty-eight patients with musculoskeletal masses underwent plain radiography, MRI, and contrast-enhanced MDCT. The following five items were evaluated for all images: histological properties, vascularity, neurovascular involvement, calcification/ossification, and cortical/marrow involvement. The MDCT images with three-dimensional reconstruction were retrospectively compared with MRI+X-p. RESULTS: In 32 bone lesions, MDCT was superior/equal/inferior to MRI+X-p regarding histological properties in 4/10/18, vascularity in 0/11/21, neurovascular involvement in 0/26/6, calcification/ossification in 15/17/0, and cortical/marrow involvement in 29/3/0 cases, respectively. In 36 soft-tissue lesions, MDCT was superior/equal/inferior to MRI+X-p with histological properties in 1/18/17, vascularity in 0/12/24, neurovascular involvement in 1/24/11, calcification/ossification in 8/28/0, and cortical/marrow involvement in 7/29/0 cases, respectively. The MDCT evaluation of both calcification/ossification and cortical/marrow involvement in bone lesions was superior to that in soft-tissue lesions (p<0.05). There were no statistically significant differences between benign and malignant lesions in the evaluation of each of the five items. CONCLUSION: MDCT provided additional and more comprehensive information than MRI+X-p for the preoperative assessment of musculoskeletal masses, especially for calcification/ossification and cortical/marrow involvement. Three-dimensional contrast-enhanced MDCT images can be adopted equally to MRI for the preoperative evaluation of neurovascular involvement.     

Verlaufsbeurteilung des malignen Lymphoms

CLINICAL/METHODICAL ISSUE: A proven criterion for assessing tumor response is the increase in tumor size. Unlike most tumors, lymph nodes are normal anatomical structures and can be measured even when benign. The International Working Group (IWG) criteria for lymphomas therefore combine morphological with functional (positron emission tomography PET) and biopsy (bone marrow biopsy) parameters. The IWG criteria have been established as the standard in clinical trials and take nodal involvement, spleen, liver involvement as well as bone marrow involvement into account, which makes the response evaluation complex. STANDARD RADIOLOGICAL METHODS: This involves an investigator-dependent, non-standardized and poorly reproducible estimation of tumor response to therapy. METHODICAL INNOVATIONS: The formulation of standardized response categories for malignant lymphomas. PERFORMANCE: The aim was to produce uniform and standardized criteria for application in medication studies. ACHIEVEMENTS: Established as the standard for medication studies but too time-consuming for practical application. PRACTICAL RECOMMENDATIONS: An improved practicability can be achieved by incorporating a computer-assisted evaluation program.     

Bone marrow investigation with technetium-99m microcolloid and magnetic resonance imaging in patients with malignant myelolympho-proliferative diseases

In 63 patients with primary extramedullary malignant lymphoma or plasmacytoma, a study was performed in order to evaluate bone marrow involvement. All patients underwent a 99mTc microcolloid bone marrow whole body imaging (scintigraphy), using a gamma camera interfaced with a computer, followed by nuclear magnetic resonance bone marrow imaging (MRI), (1.5 Tesla). MR images were made of the lumbosacral region, the pelvic region, both femoral and other parts of the skeleton, according to focal lesions in the scintigraphy. A posterior iliac crest bone marrow biopsy was used as a standard reference. In the present study, both scintigraphy and MRI showed a dissiminated or focal involvement or a combination of both. In 53 of the 63 patients (84%) the results were in accordance. Pathological MR signals or pathological findings in scintigraphy did not always correspond to tumorous bone marrow involvement, and were shown to reflect reactive changes in the central part of the skeleton in combination with a periphery radionuclide extention interpreted as a periphery compensatory hematopoietic proliferation. The negative predictive value of scintigraphy and MRI was 92% and 100%, respectively. When combining the results of both examinations, the positive predictive value increased from 49% to 58%, if the bone marrow biopsy is accepted as gold standard. The results indicate that bone marrow investigation performed simultaneously using scintigraphy and MRI is superior both to the use of either of the methods alone and to the traditional iliac crest bone marrow biopsy.     

Malignant lymphoma of the gingiva: MR evaluation.

PURPOSEOur purpose was to document the MR imaging findings of malignant lymphoma of the gingiva.METHODSFive patients with histologically proved malignant lymphoma of the gingiva were studied by MR imaging. The MR images were analyzed for tumor size, extent, and signal characteristics, bone involvement, and associated cervical lymph node enlargement.RESULTSClinical examination tended to underestimate the size of lymphomatous lesions. The signal intensity of the lesions was isointense to hyperintense relative to muscle on noncontrast T1-weighted images and showed variable contrast enhancement patterns. On T2-weighted images, signal intensity was isointense to hypointense relative to the oral mucosa. In one case, the mass extended to the submandibular space; in the remaining cases, the masses were limited to the gingiva and the adjacent bone. MR imaging revealed that gingival lymphomatous masses were broad-based along the mandible or maxilla and eroded through the cortex into the marrow space, but the cortex was still recognizable. No nodal involvement was noted in any of the patients with malignant lymphoma.CONCLUSIONThe signal characteristics of gingival lymphoma overlap those of other tumors. The cortex separating marrow involvement from the broad-based gingival mass generally appears to be permeated with small erosions but is still recognizable.