Diagnosis of bone metastases in urological malignancies – an update

C H A P T E R

45 Diagnosis of bone metastases in urological malignancies – an update Nathan Lawrentschuk1, Nieroshan Rajarubendra2, Damien Bolton2 1

University of Melbourne, Department of Surgery and Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Melbourne, Australia 2 Department of Urology, Austin Hospital, University of Melbourne, Department of Surgery, Heidelberg, Melbourne, Australia

INTRODUCTION Bone is a common site for spread of cancer. Prostate cancer as a urological malignancy has the highest incidence of bony metastatic spread, up to 70%1. Other malignancies such as kidney and bladder also metastasize to bone (Table 45.1). Bone metastases complications can be debilitating for patients, resulting in severe pain, pathological fractures, spinal cord compression, hypercalcemia, and nerve compression syndromes. The presence of bony metastases is a survival predictor. Half the prostate cancer patients with bony metastases detected will succumb within 30 months of detection2. Figures show that in excess of 350,000 people with a variety of malignancies in the United States die with bone metastases3. Given the high blood flow in areas of red marrow, bone is a preferred site for the spread of cancer. Adhesive molecules produced by tumor cells bind to marrow stromal cells and bone matrix. Furthermore, there is a large reservoir for immobilized growth factors1,4. It is difficult to determine the tendency of tumors to spread to bone because patients who succumb to cancer early from an aggressively growing malignancy do not have enough time for metastases to develop. Bone metastases can be osteoblastic (bone forming) or osteolytic (bone destructive) (Table 45.1). The majority of cancers are a combination of the two. At the extreme end of the spectrum, multiple myeloma is purely lytic, while prostate cancer is predominately osteoblastic5. Prevention of complications caused by bony metastases through early detection can reduce patient morbidity and cost to the community. As part of the assessment and surveillance of malignancies, clinical assessment, bone markers, radiological imaging and tissue biopsies are vital tools used in the diagnosis of bony spread. It will allow the implementation of treatment strategies such as surgical fixation, radiotherapy or bisphosphonate therapy to improve quality of life6. A proactive role has been taken in detecting and then treating bone metastases with benefit to the patient as well as potentially reducing costs. A seminal report by Saad and colleagures looked at men with hormone resistant prostate cancer with bone metastases7. These men were divided into two groups, those who were symptomatic and those without symptoms of bony lesions. Participants were given the bisphosphonate, zoledronic acid, and compared to a control group. The results showed that there was a 39% relative reduction in bone metastatic complications in the asymptomatic group and 19% relative reduction in the symptomatic group when compared to untreated patients. This indicates that bisphosphonate therapy has a valuable role in the early treatment of metastatic disease and paved the way for the bone health focus now taken in prostate cancer. Building upon this paradigm are studies that now consider men with hormone-naïve disease whereby those with oligometastatic disease potentially have benefit from radiation treatment to an isolated site in the hope of delaying disease progression8. A clinical suspicion of possible bony spread is ascertained with history and examination. This will guide and rationalize the array of investigations available to gather further evidence of metastases. Bone Cancer. DOI: 10.1016/B978-0-12-416721-6.00045-5 Copyright © 2015 Elsevier Inc. All rights reserved

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TABLE 45.1 Incidence of metastatic spread to bone and their common metastatic nature. Mixed = both lytic and blastic60,61 Order of frequency

Whole population

Metastatic nature

1

Breast

Mixed

2

Prostate

Blastic

3

Bronchial

Lytic

4

Colonic

Mixed

5

Gastric

Lytic

6

Bladder

Blastic

7

Uterine

Lytic

8

Rectal

Mixed

9

Thyroid

Lytic

10

Renal

Lytic

11

Ovarian

Mixed

Rare

Testicular

Mixed

Rare

Adrenal

Lytic

HISTORY AND EXAMINATION A physician should be able to determine a level of suspicion of metastatic spread of a malignancy by the clinical assessment of a patient. Using the fundamentals of history and examination, as well as disease tempo, investigations can be rationalized to answer the clinical question.

History The main symptom indicating possible bony spread is pain. Pain can be attributed to many causes such as arthritis, disc prolapse, and musculoskeletal strain or even referred pain, all of which should be considered as a differential diagnosis. Pain specific questions that should be elicited are: Intensity (scale 0–10) Location and radiation Onset and character over time Quality Constant or intermittent pain Exacerbating and relieving factors Associated symptoms, especially neurological, e.g. pain and altered sensation Impact of patient’s daily activities Current pain relief medications and its effectiveness Typically, metastatic bone pain is slow in onset and gradually increases in severity over time. However, sometimes patients can present with a sudden onset of pain. This can be due to a crush fracture of a vertebral body containing metastases. Pain can be characterized as an ache, whereas nerve root entrapment, usually associated with vertebral metastases, is a burning or radiating type of pain. If pain is described as being distal to the knees or elbows, it is less likely to be due to metastatic spread because active marrow is found proximally and centrally. Constitutional symptoms such as lethargy, loss of appetite and weight are symptoms of possible metastatic disease. These symptoms are not specific to bony spread but to distant manifestation of the malignancy.

Examination During patient examination, signs of cachexia and spinal contour, such as kyphosis, should be reviewed. Observing patient posture and gait can identify possible restriction of movement or pain triggers. In order to perform this examination, the vertebral column is palpated, with a moderate amount of pressure applied on the individual III.  BONE METASTASES



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spinous process to elicit pain. Lateral compression should be applied to spring the rib cage and pelvis. Proximal long bones are also palpated, while asking the patient to indicate if pain is produced. Assessment of the abdominal and respiratory systems is needed to complete the examination.

SERUM AND BONE MARKERS FOR BONE METASTASES Bone undergoes regular remodeling. It is a balance between bone resorption, which is controlled by osteoclasts and bone formation governed by osteoblasts. These two processes are tightly coupled together to maintain bone mass. However, metabolic bone diseases including bone metastases alter this balance. When cancer cells enter into the bone marrow, they disrupt normal bone cell turnover by releasing local cytokines and growth factors. This eventually leads to the net result of osteolysis or osteosclerosis. Some malignancies secrete factors that stimulate osteoclasts, such as parathyroid hormone-related protein, tumor necrosis factor a or b, and other cytokines such as interleukins 1 and 6. For sclerotic lesions, cancer cells commonly secrete factors such as epidermal growth factor, transforming growth factor a and b, and insulin-like growth factors that stimulate osteoblast activity9,10. Different malignancies secrete mixed number factors, resulting in net bone resorption or formation. This can be evaluated by gauging prominent enzymatic activity of bone forming or resorbing cells, or by measuring bone matrix breakdown products released into circulation during bone formation or resorption. These bone turnover markers are grouped into bone formation or bone resorption.

Serum calcium Hypercalcemia is an elevation in total serum calcium concentration, that may produce neurologic, gastrointestinal, renal, and cardiovascular disturbances; it may also cause calcification in extraskeletal tissue11. Measuring serum calcium is not routinely conducted as part of urological malignancy assessment, with the one exception being in renal cell carcinoma, where hypercalcemia is more likely related to a paraneoplastic syndrome rather than bone metastases. In one study of over 7600 patients with a variety of malignancies, severe hypercalcemia was present in 0.5%, most often in RCC patients at 1.4%12. It is important to acknowledge that hypercalcemia may be present due to hyperparathyroidism even in the setting of malignancy. Consequently, measuring parathyroid hormone concentration estimation is essential in patients with malignancy and hypercalcemia when bone secondaries are not evident13. Finally, there is no role for serum calcium in bladder cancer or germ cell tumors. In prostate cancer patients, studies have shown that men with higher levels of serum calcium have a four to fivefold elevated risk of metastatic prostate cancer14,15. However, no routine recommendations exist regarding measuring of serum calcium considering pain and or a raised PSa with or without a bone scan are likely to find metastases. This may be changing in the future, as men commencing androgen deprivation are now often being placed on vitamin D, calcium supplements and alendronate, but this is not the subject of this review.

Bone formation The bone formation markers include the enzyme alkaline phosphatase and byproducts of bone matrix synthesis such as osteocalcin and procollagen extension peptides. Alkaline phosphatase Alkaline phosphatase is found in osteoblasts. Total alkaline phosphatase (tALP) is commonly used as a test for bone metastases, but it lacks specificity. This is because it is also found in liver, intestine and placenta which contribute to the total serum level. As a result an elevated tALP can be attributed to many factors (Table 45.2). Specificity of detecting alkaline phosphatase from bone has been improved by the development of monoclonal antibodies recognizing the bone isoenzyme bone alkaline phosphatase (bALP), which determines osteoblast cell activity. However, there is some cross-reactivity ranging between 15 and 20% between bALP and liver alkaline phosphatase9. This is because the structural differences between the isoforms of alkaline phosphatase are minor due to them originating from a post-translational modification of the same gene product. The currently accepted markers for the detection of bony metastases from urological malignancies by the National Comprehensive Cancer Network (NCCN) and the European Association of Urology are shown in Table 45.316–21. 2.  Pre-clinical and clinical aspects

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TABLE 45.2 Physiological and pathological causes of an elevated ALP Normal physiological elevation

Pathological elevation

Age: increases in first three months of life and at puberty

Hepatobiliary disease: biliary obstruction, primary biliary cirrhosis, malignancy, medication

Sex: Men between ages 20 and 50 is higher and women post-­ menopausal higher

Bone disease: Paget’s disease, osteomalacia, hyperparathyroidism, metastatic bone disease, Vitamin D deficiency

Hormonal status: puberty, pregnancy (placental isoenzyme) and post-menopausal

Other cases: resolution phase of cardiac, pulmonary, renal, gastrointestinal or splenic infarction, ulceration in gastrointestinal tract, autosomal dominant familial inheritance

Blood type: type O and B Other causes: tobacco use, increased blood sugar, increasing weight

TABLE 45.3 Summary of bone markers commonly used in urological malignancies Malignancy

Recommended markers

Prostate

ALP

Renal

ALP,  serum calcium

Bladder

ALP

Testicular

ALP

Newer markers not yet in clinical practice Osteocalcin Osteocalcin is a non-collagenous protein found in bone and dentin. It is rich in glutamic acid (GLA) and is also known as bone GLA protein. It is made by osteoblasts and is integrated into bone extracellular matrix. However some of the osteocalcin that is not incorporated into the matrix is released into circulation and can be measured using radioimmunoassay9. Procollagen extension peptides These are by products of extracellular breakdown of procollagen released into circulation, which were synthesized by osteoblasts during bone collagen synthesis. These by products of type I collagen synthesis are the aminoand carboxy-terminal procollagen I extension peptides (PINP and PICP)22. They are raised in metastatic bone disease and can indicate aggressive bone metastases phenotype with an increased PICP/PINP ratio23. However, non-skeletal sites such as skin and muscle can elevate both these markers.

Bone resorption There are numerous markers for bone resorption, and they can be assessed using urine and serum tests. These markers include the enzyme tartrate-resistant acid phosphatase (TRAP), products of bone breakdown like calcium and products of bone matrix degradation for example hydroxyproline, pyridinium cross-links and telopeptides. Tartrate-resistant acid phosphatase This is a lysosomal enzyme found in bone, prostate, platelets, erythrocytes and spleen. It is measured using electrophoresis and immunoassay. Fasting urinary calcium and hydroxyproline Fasting urinary calcium is measured in the mornings and is corrected with creatine excretion. It is able to detect large changes in bone resorption, but it has poor sensitivity and specificity. Hydroxyproline, a degradation product of collagen, has a limited value in detecting bone metastases. It has been reported that only 50% of the urinary hydroxyproline is attributed to bone resorption because it is derived from nonskeletal collagen sources such as cartilage and skin23. It is also influenced by dietary intake of collagen-containing foods. III.  BONE METASTASES



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Pyridinium cross-links Pyridinoline (Pry) and deoxypyridinoline (D-Pyr) are cross-linking amino acid derivatives that stabilize mature bone. Pyr is found in type I collagen of bone and in type II collagen of cartilage and connective tissue. D-Pyr is mainly found in type I of bone collagen. Of the released pyridinium cross-links, 40% is released in free form while 60% circulate in peptide bound form23. This test has limited value, due to sampling errors as it is excreted via a circadian rhythm (peak in early morning and trough in afternoon) and needs correction for urinary creatine. Telopeptides Some of the products of bone collagen products have their amino and carboxyl terminals cross-linked to telopeptides. There are two telopeptides, N-telopeptides (NTx) and C-telopeptides, which are both found in urine. Commercial assays are currently available.

IMAGING MODALITIES The most commonly used methods in analyzing and assessing bone metastases are: plain radiography, computed tomography, bone scintigraphy, position emission tomography (PET/CT), and magnetic resonance imaging.

Plain radiography With this methodology an X-ray beam is projected through a patient. Different structures within the body absorb this beam in varying degrees, thereby allowing an image to be detected. Plain radiography allows the final result of bone destruction and repair to be seen, predominantly lysis or sclerosis. Lytic lesions are most commonly found in the following malignancies: breast, lung, thyroid, kidney, and myeloma. Lytic lesions can be identified through thinning of trabeculae and ill-defined margins that indicate regions of destroyed trabeculae between the central destruction and the radiological normal bone (Figure 45.1).

FIGURE 45.1  Forty-eight-year-old male diagnosed with multiple myeloma. (A) Skull showing multiple lesions “pepper pot” skull appearance. (B) Distal right femur with multiple lytic lesions.

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45.  Diagnosis of bone metastases in urological malignancies – an update

FIGURE 45.2  Eighty-two-year-old male was diagnosed with metastatic prostate cancer. (A) and (B) Plain radiographs of the right hip and pelvis show multiple sclerotic lesions.

Sclerotic lesions are predominately found in prostate cancer; however, they also exist in breast and carcinoid tumors. Radiologically, they appear nodular, rounded, and fairly well circumscribed due to the thickened, coarse trabeculae (Figure 45.2). Plain radiography requires 30–75% of normal bone mineral content to be lost before they become apparent. Hence, it may take several months before detection. Plain radiography is less sensitive, ranging from 44 to 50% (level II–II evidence) than bone scintigraphy24.

Computed tomography This operates by rotating a continuous fan beam of radiation through a patient and measuring the transmission at thousands of points. The exact exposure of radiation at a given location is calculated. This is then reconstructed as three-dimensional images or segmental slices. Conventional scanners (spiral or helical) work by rotating the X-ray tube around the patient on a moving table. The multidetector CT, which is a new scanner, has multiple rows of detectors, and can obtain up to 16 slices at once. This allows for results to be obtained faster and at high spatial resolution25,26. However, radiation exposure is high with the use of CT, hence it is recommended that careful thought be given prior to patient selection and benefits of the use of CT compared to unnecessary radiation exposure be assessed. In the 1990s, the Royal College of Radiologists in the UK compared CT with conventional X-ray and found that a CT of the abdomen was equivalent to the radiation exposure to 500 chest X-rays27. The principal benefit of CT is the detailed images produced (Figure 45.3). CT shows both osteolytic and osteoblastic lesions as well as soft tissue extension. The visualization of bone structure and tumors in bone marrow allows for the detection of potentially small bone marrow metastases early. CT sensitivity ranges from 71 to 100% (level II–III evidence)24. The principle drawback of this modality is that the entire vertebral column cannot be scanned, due to limitations with the CT table movement. Hence, CT is better employed to assess suspicious lesions identified by other imaging modalities.

Bone scintigraphy A gamma camera records the distribution of radioactivity caused by the administration of a radionucleotide, usually Tc-methylene diphosphonate (99mTc-MDP). The radionucleotide circulation is influenced by increased local blood flow and osteoblastic activity (Figure 45.4). The radionucleotide is absorbed onto the calcium of hydroxyapatite in the bone. 99m

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FIGURE 45.3  Conventional CT imaging of spinal column with the presence of bony metastases is seen in (A). Bony windows in (B) shows greater detail in the bone structure and the lesions are seen with more definition in comparison to the conventional window.

FIGURE 45.4  A staging bone scintigraphy was performed on a 77-year-old male with prostate cancer. Metastases are seen in the left 6th rib posteriorly, the right 5th and 6th ribs laterally, T6, spinous process of L2, scarum and both ilia adjacent to sacroiliac joints and in the right superior acetabulum.

Bone scintigraphy has poor specificity but high sensitivity of 95% in detecting metastatic bone disease28. False positives maybe created with this methodology due to degenerative changes, infections and fractures (Figure 45.5). Therefore, further imaging is required to make a conclusive diagnosis. A plain radiograph is taken initially, however, if a suspicion of metastasis persists, further imaging in the form of CT or MRI is warranted. False-negative results have also been reported with bone scintigraphy (Figure 45.6). This may occur where there are purely osteolytic metastases that are aggressively developing the bone turnover is labile or if the site is avascular (cold spot). 2.  Pre-clinical and clinical aspects

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45.  Diagnosis of bone metastases in urological malignancies – an update

FIGURE 45.5  Bone scintigraphy of a patient with prostate cancer showed increased uptake in the lumbosacral spine and sternum (A). However, with CT evaluation of these sites, images B and C, proved that there were no evidence of metastatic lesions but of degenerative changes.

FIGURE 45.6  Bone scintigraphy in a patient with prostate cancer shows the presence of bone metastases in L4 vertebra (A). However, further imaging with MRI shows the presence of other bony lesions in T8 as seen in image B and also in T3, L1 and L2.

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Positron emission tomography PET commonly uses a radiopharmaceuticals such as 2-deoxy-2-[18F]-fluoro-d-glucose (18F-FDG), which behave as a glucose analog. Malignant tumors exhibit increased glucolysis due to upregulation of intracellular hexokinase activity29. PET allows for the assessment of a lesion as being benign or malignant, providing qualitative and quantitative metabolic information. In the follow-up of patients after chemotherapy or surgical resection, PET is useful as scarring or fibrosis does not affect its results and it allows the functional capacity of the tumor to be measured. Given that PET is a whole-body technique it detects disease in regions not routinely included in anatomical studies but it does not provide exact anatomical location of the lesion (Figure 45.7). This inadequacy can be addressed with its fusion with CT (see below). Tumor metabolism and early tumor formation in marrow is visualized by PET. Bone metastases detection sensitivity ranges from 62 to 100% and specificity from 96 to 100% (level II–III evidence)24. Going forwards, whole-body PET can be used to stage for nodal and visceral disease as well as bony metastases. In PET imaging, another radionucleotide marker, 18F-fluoride has been shown to be more sensitive in detecting bone lesions than 18F-FDG PET30,31, and newer agents such as 18F-fluoromethylcholine (FCH) are also being utilized and will be discussed in the next section.

PET/CT Combining a PET camera and a CT scanner allows for functional and anatomical studies to be done together. It can facilitate for rapid and accurate anatomical localization of an abnormal uptake33. Stand-alone PET is rarely if ever conducted. A further advance is PET-MRI, which is now being used in many studies; however, few are ready for bone disease identification and this will not be discussed further. A study by Nakamoto and coworkers with patients identified as having bone metastases using PET indicated that CT only showed morphological changes in half the patients34. However, combining PET and CT allows for precise locations of bone metastases to be identified for targeted treatment (Figure 45.8).

FIGURE 45.7  A 61-year-old male with right sided RCC presented with lower back pain. Reverse bone scintigraphy (A) shows a bony lesion at the L4 level. The group of images in B were performed with PET, which shows increased activity at the L4 level. Note increased activity is seen in the upper pole of the right kidney, depicting the RCC

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CT not only reduces scanning time by 40% but also provides noiseless attenuation-correction of standard PET transmission measurements35. Table 45.4 depicts the improvements of sensitivity and specificity of PET when combined with CT. Furthermore, in differentiating between benign and malignant bony lesions, PET/CT has been shown to be superior. The other advantage of this modality is the ability to detect lesions not found on standard bone scintigraphy (Figure 45.9). This modality may also detect nodal and even visceral metastases (Figure 45.9) and thus, like wholebody MRI (see below), the advantage of staging beyond bones makes it an attractive modality.

FIGURE 45.8  Metastatic RCC in a 59-year-old female. A metastatic lesion is seen in T8 and T9 extending into the left pedicle and left 9th rib. One third of the spinal canal is encroached upon by the malignancy.

TABLE 45.4 Sensitivity and specificity of PET and PET/CT20 Modality

Sensitivity (%) [P < 0.05]

Specificity (%)

PET

88

56

PET/CT

Up to 100

88

FIGURE 45.9  Standard bone scintigraphy (A) in a 66-year-old with prostate cancer failed to diagnose a metastatic deposit. However, fluorocholine PET-CT diagnosed a rib metastasis in the second rib (B) as well as a nodal metastases (C), both seen easily on CT alone. III.  BONE METASTASES



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Magnetic resonance imaging MRI uses radiofrequency radiation in a carefully controlled magnetic field to produce, high quality cross-sectional images of the body. It does not use ionizing radiation, nor is it invasive. Like CT, MRI is useful in assessing suspicious lesions found by other modalities. Bone metastases are detected through the difference in the magnetic signal intensity between the tumor tissue and normal bone marrow. Plain radiography and bone scintigraphy visualize indirect changes to identify metastases, MRI however, visualizes metastatic tumor directly. Hence it can detect an intramedullary lesion before any cortex destruction and before any osteoblastic reaction is detected on a bone scan36. For cord compression, it is the technique of choice. MRI produces wide sagittal views, allowing the entire spine to be imaged (Figure 45.10) providing more information on the spine for patients with spinal symptoms in comparison to bone scintigraphy. MRI, like CT, facilitates early detection of tumors before structural changes in cortical bone are seen as it visualizes bone marrow37.

FIGURE 45.10  The formation of a PET/ CT image is by the combination of a PET image with a CT scan. Image (A) shows the PET of the patient seen above with metastatic RCC. The CT image in (B) is able to show the anatomical location of the lesion in L4. The final product, image (C), shows PET/CT depicting the L4 lesion. It shows the metabolic activity as well as the anatomical location of the lesion.

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45.  Diagnosis of bone metastases in urological malignancies – an update

MRI images of bone marrow are of better resolution than CT. Bone marrow produces a high intensity signal in comparison to metastases, which replaces the fat in the marrow, with CT imaging. Cortical bone does not produce a signal hence MRI is unable to depict destruction of bone structure as well as plain radiography and CT. Whole body MRI Whole body MRI (WB-MRI) with or without diffusion-weighted images (DWI) for detecting bone metastases has gained interest in the literature regarding prostate cancer38–40. The obvious advantage is that WB-MRI may be utilized for staging of bone and nodal disease. In one study it appears as a modality to outperform traditional bone scintigraphy in detecting bone metastases and performs as well as CT for enlarged lymph node evaluation40. The question remains whether WBMRI can replace the current multimodality metastatic work-up for the concurrent evaluation of bones and lymph nodes in high-risk PCa patients. More data will be required.

BONE BIOPSY Histological diagnosis of a lesion is the most accurate method of confirming pathology. A bone biopsy is performed when there is a need to confirm the diagnosis of metastatic disease prior to definitive treatment such as radiation or chemotherapy. Tissue samples can be obtained via an open technique or needle biopsy. The procedure needs to be planned so that adequate tissue samples are obtained without compromising the outcome. Some factors to consider are41–43: Completing staging studies so that the most accessible lesion can be sampled easily and safely. Extracting the biopsy so that the tract can be easily excised if definitive surgery is considered. Achieving hemostasis, as the bony environment is highly vascular and there is a high chance of local spread or wound infection if a hematoma develops. Open biopsies are performed with general or local anesthesia depending on the location and amount of tissue needed from the lesion. The advantage of this procedure is that the lesion can be visualized directly and adequate tissue obtained for a histological diagnosis. Hemostasis can be achieved minimizing the risk of local spread. Needle biopsies are usually conducted with the assistance of radiological imaging. This has allowed for biopsies to be taken in most areas of the body adequately and safely. Most are conducted with local anesthesia and are generally less expensive, as they do not require an operating room. However the disadvantage with this technique is that a limited amount of tissue is obtained and sampling errors can occur44. There is also no immediate method to stop bleeding with this technique apart from direct pressure to the area. Two types of needle biopsies are available, fine needle aspiration (FNA) and core biopsy. FNA can be performed with or without imaging and it is valuable in detecting bone metastases. It is useful in diagnosing the primary disease, however it is unable provide sufficient information on tissue architecture or tumor grade (Figure 45.11). Core biopsies are mainly performed with image guidance unless the lesion is large, palpable and homogeneous throughout. With radiological guidance, specific sites of lesions can be accurately sampled. The main imaging modalities used are fluoroscopy, ultrasound, CT and MRI45,46. The effectiveness of making a diagnosis using needle biopsy is higher in metastatic bone lesions in comparison to primary malignancy. Furthermore, needle biopsy has lower complications in comparison to the open technique. However, it has the usual problems with bleeding, infection and injury to nearby tissues. Performing a biopsy of a bone lesion is the most accurate method of diagnosing metastatic spread. However its use should be rationalized, as it is the most invasive and costly technique used in diagnosing bone metastases.

UROLOGICAL MALIGNANCIES – RECOMMENDATIONS Prostate The common site for the spread of prostate cancer is bone; it accounts for up to 80% of all metastases47. Spread occurs via the hematogenous route to well-vascularized areas of the skeleton; red bone marrow of the axial skeleton is the preferred site. Prostate cancer cells invade Batson’s plexus, which is a low-pressure, high-volume communication venous network between the pelvis and vertebral veins. For this reason, the vertebral column is the initial site for prostate cancer spread47. III.  BONE METASTASES



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FIGURE 45.11  A 66-year-old female diagnosed with metastatic breast cancer. Image (A) shows widespread disease involving. Mixed lytic and sclerotic lesions measuring upto 1 cm in the lumbar vertebrae are seen on CT using bony windows (B and C).

In detecting bone metastases from prostate cancer, bone scintigraphy is recommended as the first line modality in the European Association of Urology guidelines, published in 2007. The probability of detecting prostate cancer bone metastases is increased when an elevated prostate specific antigen (PSA) >20 mg/L, is identified (grade B recommendation)19. Locally advanced disease or Gleason score 8 or greater increase the detection rate of bone metastases48. The cut-off for PSA of 20 remains controversial as some clinicians believe it should be 1049–53 or whenever radical treatment is planned32. Due to the limitations of specificity, imaging modalities such as a plain radiography, CT or MRI are needed to clarify equivocal lesions (Figure 45.12). Bone scintigraphy assesses osteoblastic reaction rather than tumor proliferation, and as a result early metastases can be missed. When assessing for microscopic or marrow-infiltrate-only disease or osteolytic lesions (which are uncommon in prostate cancer), the sensitivity of bone scintigraphy is limited32. The site of metastases in reference to axial or appendicular distribution in the skeleton can be determined by bone scintigraphy. This assists determination of a patient’s prognosis; given axial metastases have a better prognosis than appendicular metastases2. 2.  Pre-clinical and clinical aspects

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45.  Diagnosis of bone metastases in urological malignancies – an update

FIGURE 45.12  A patient diagnosed with hormone refractory prostate cancer shown here to have widespread osseous metastatic disease involving the axial and appendicular skeleton (A). The images B and C show multiple sclerotic lesions in the lumbar spine.

Current data strongly favor bone scintigraphy over PET as the first line imaging modality for prostate cancer54,55. Importantly, recent data suggest no bone metastases were observed in patients with PSA of <10 ng/mL, independently of the clinical T stage and Gleason score (n = 212) and PSA of <20 ng/mL if T stage is less than T3 and Gleason score is less than 8 (n = 97). Approximately 50% of the patients enrolled in this study met these criteria56. This appears to be the first prospective trial to demonstrate that BS can be avoided in patients with low-risk PCa. PET-CT could have a role in detecting local recurrence and distant spread after treatment failure55,57. Choline based radiopharmaceuticals are attracting most interest (Figure 45.9) for lymph node disease and also biochemical recurrence58,59. Over time, choline-based PET-CT will improve and may challenge bone scintigraphy, but further studies are needed60. This is increasingly being recognized in international guidelines61. As PET-CT is evolving, another ­radiotracer investigated, 18F-fluoride-PET, has been shown to be more sensitive than bone scintigraphy at specifically targeting bony lesions. However, the supportive evidence for this is limited and further research is required to justify its use routinely31,60,62. Computer tomography should be used as a complementary investigative tool for assessing suspicious regions determined by bone scintigraphy or plain radiography. PET/CT has been put forward as being a useful modality in re-staging prostate cancer after radical prostatectomy. Again, further supportive data is needed before implementation of this technique as best practice63. Due to the limited availability, costs, and supportive data, MRI is not used as a first line imaging modality64. However, studies have shown MRI as having a higher sensitivity and specificity in detecting prostate cancer bone III.  BONE METASTASES



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metastases in the vertebral bodes than bone scintigraphy in high-grade prostate cancer65,66. Early bone metastases, before osteoblastic reactions appear visible on bone scintigraphy or plain radiography, are seen initially on MRI. Whole-body MRI has already been discussed and may evolve to a bony, lymph node and visceral modality for prostate cancer. In one study, 100 consecutive prostate cancer patients at high risk for metastases prospectively underwent WBMRI, CT, and BS completed with targeted X-rays (BS/TXR) in case of equivocal BS. Overall, 68 patients had metastases. The sensitivity of BS/TXR and WBMRI for detecting bone metastases was 86 and 98–100% respectively (p < 0.04), and specificity was 98 and 98–100% respectively. Recommendations Staging process History and examination. Bone marker ALP checked for elevation. Bone scintigraphy used if T1-T2 disease with PSA >20 ng/ml or Gleason score ≥8 or T3, T4 or symptomatic. Follow-up Mainstay of surveillance is PSA every 6–12 months and DRE annually. History and examination. ALP and bone scintigraphy are employed when PSA reaches >20 ng/ml or symptomatic in patients who have not had treatment. For patients who have had definitive treatment such as radiotherapy or surgery, failure for PSA to fall to undetectable levels post-treatment or PSA rising on two or more consecutive readings. Future prospects PET/CT has shown great potential and future research is needed for it to be used as a single imaging modality. Choline and fluoride-based radiopharmaceuticals offer current best data.

Renal In primary renal tumors, 90% is accounted for by renal cell carcinoma (RCC)67. There are over 50,000 new cases of renal tumors reported in the United States3. Distant metastases have been found in 30–60% of patients, initially diagnosed with RCC, and these lesions are predominantly osteolytic68. The indication for the use of bone scintigraphy for detection of bone spread should only be utilized in high-risk patients, e.g. raised alkaline phosphatase or bone pain (grade A recommendation)21. It has no role as a screening modality in RCC. As discussed earlier, other imaging techniques are required to confirm diagnosis of suspect lesions questioned by bone scintigraphy (Figure 45.13). The detection of metastases in RCC using 18F-FDG-PET has been shown to have sensitivity ranging as high as 63– 100%69–73. However, with respect to bone metastases from RCC; PET was reported to be less sensitive than conventional imaging70. Due to the lack of convincing evidence it is difficult to justify its use in routine assessment of metastatic RCC. Post-treatment re-staging of RCC using 18F-FDG-PET has been reported to have sensitivities ranging between 87 and 100%69. Again, further high-level evidence is needed prior to establishing this as a follow-up tool. A recent paper compared PET/CT with conventional methods and found it to have 89.5% specificity, 83.3% sensitivity, and comparable levels of accuracy in detecting metastases while having the advantage of examining all organs with the one procedure74. Recommendations Staging process History and examination. Bone marker ALP and serum calcium. Bone scintigraphy is used only if bone markers are elevated or the patient complains of bone pain. Follow-up Usually every 6 months for 2 years then annually for 5 years. History and examination. ALP is assessed at each surveillance visit. Bone scintigraphy if bone markers are elevated or patient has signs and symptoms of bony spread. 2.  Pre-clinical and clinical aspects

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FIGURE 45.13  Fifty-seven-year-old female with NSCLC noted to have increased tracer uptake in multiple regions on bone scintigraphy (A). Tracer uptake is seen in left mandible, right humeral head, sternum, spinal column and right sacroiliac joint. An OPG and CT (B and C respectively) show a lytic lesion in the mandible highlighting the presence of mixed lesions occurring in lung cancer.

Future prospects Again, PET/CT needs further evidence before being implemented.

Bladder A large lymphatic network drains the bladder and therefore transitional cell carcinoma (TCC) preferentially spreads via the lymphatic system as opposed to the hematogenous route. Hematogenous spread does occur to some extent to bone, lung, liver and directly to the retroperitoneum75. The incidence of the subtypes of bladder cancer is demonstrated in Table 45.5. One-third of patients with bladder cancer due to TCC will have muscle invasive or metastatic disease. Furthermore, patients who have superficial TCC, 30% will progress to an invasive tumor20.

TABLE 45.5 Classes of bladder cancer52,62 Type

Incidence (%)

Transitional cell carcinoma

>90

Squamous cell

5–10

Mixed transitional and squamous

<5

Adenocarcinoma

2–3

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Urological Malignancies – Recommendations

553

Predominantly lytic lesions are produced by TCC, but occasionally osteoblastic lesions can be seen. Autopsy reports of patients who succumbed to bladder cancer show 25% have bone metastases. Currently the accepted imaging modality used for detecting bone metastases in patients with TCC is bone scintigraphy (Figure 45.13). The European Association of Urology guidelines and the National Comprehensive Cancer Network recommend the use of bone scintigraphy for muscle invasive bladder carcinoma in patients with symptoms of bone involvement or elevated alkaline phosphatase18,20. As a result, bone scintigraphy should not be used as a screening tool in muscle invasive TCC76–80. There are no satisfactory reports on the use of PET in evaluating bony metastases of bladder cancer. It is able to demonstrate local recurrence and stage lymph nodes81. Other studies using 11C-methionine-PET have been shown to be advantageous over conventional PET as it is not renally excreted and therefore not obscuring the bladder and the surrounding regions82. Recommendations Staging process History and examination. Bone marker ALP is used. Bone scintigraphy is indicated if ALP is elevated or the patient complains of bone pain. Follow-up Three monthly reviews. History and examination. Yearly ALP check. Bone scintigraphy if ALP elevation or patient complains of bone pain. Future prospects Possible role for 11C-methionine-PET.

Testicular Testicular tumors are rare and affect males between the ages of 15–35. In 95% of patients, the malignant tumors arising from the testis are germ cell tumors. The incidence of bony metastases is low; this is due to the high cure rate with this tumor. Ninety percent of patients with germ cell tumors are cured either with surgery or chemotherapy83. Serum tumor markers, alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG) are used in the diagnosis and follow-up of recurrence. However, if these markers are elevated, they do not indicate the location of the metastases during the surveillance process. Apart from bony marker, the indication for assessing bone metastases is when the patient has signs or symptoms of bone involvement. Hence, bone metastases are not routinely assessed in staging or surveillance. Bone scintigraphy is the modality used when bony spread is suspected. PET is not used routinely in the examination of bone metastases82,84. They are recommended for follow-up of seminoma post-chemotherapy residual masses85. Recommendations Staging process History and examination. ALP with the tumor markers. Bone scintigraphy if the patient has clinical evidence of bony spread or elevated ALP. Follow-up History and examination. Bone scintigraphy and ALP are used if suspicion of bony spread is suspected. Future prospects PET as a single imaging modality. 2.  Pre-clinical and clinical aspects

554

45.  Diagnosis of bone metastases in urological malignancies – an update

TABLE 45.6 Summary of investigations used to assess for bony metastases in urological malignancies. ALP= alkaline phosphatase, BS = bone scintigraphy, PR = plain radiography and PET = positron emission tomography Malignancy

Bone markers

Symptoms

Screening

Follow-up

Future role

Prostate

ALP

PR, BS

BS

BS, PET

PET

Renal

ALP, serum calcium

BS

–

If symptomatic

PET

Bladder

ALP

BS

–

If symptomatic

PET

Testicular

ALP

BS

–

If symptomatic

PET

Adrenal Low incidence of spread of malignancy to bone but similar protocol and approaches to detection should be used. Investigations should be followed when a high index of clinical suspicion exists. A similar protocol to renal tumors should be used to assess for bony spread.

CONCLUSION The detection of bone metastases in patients with urological malignancies will alter the treatment plan. It allows for appropriate measures to be taken to prevent complications and improve quality of life. The use of clinical suspicion, bone markers, radiological imaging, and histological sampling; increases the yield of detecting metastatic spread. The utilization of these investigations depends on many factors such as accuracy, timing, cost-effectiveness and availability. With ongoing research, other bone markers and imaging techniques will supersede current standards. PET-CT and whole-body MRI may offer some advantages being able to look at visceral and bony metastases in a whole-body fashion. Especially in the case of positron emission tomography in combination with computer tomography, it has been shown to detect and localize lesions not only in bone but also in the entire body allowing for precise treatment planning. It can be used as the only imaging modality but further evidence is required to support its use and its costs need to be addressed. With evolving technology, detection rates are improving and early and appropriate measures can be instituted to obtain better patient outcomes. Current recommendations are shown in Table 45.6.

Acknowledgment We would like to acknowledge the Nuclear Medicine Department and the Centre for PET at Austin Hospital, Melbourne, Australia for providing the images; Dr Alan Wong from the Austin Department of Pathology for assisting with photographing the histology slides.

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