Contemporary Tumor Imaging: Optimizing Treatment Decisions

Margaret C. McEntee, DVM, DACVIM (oncology), DACVR (radiation oncology)
Cornell University

Imaging of cancer patients is pivotal to many aspects of oncology including diagnosis, staging, treatment planning, and evaluation of response to therapy. Diagnostic imaging tests have greatly extended the physical examination by displaying the structure and function of sites not evaluable by palpation, or auscultation. It is important to have an appreciation for the range of imaging modalities that are available. It is equally important to understand the limitations as well as advantages of different imaging techniques to optimize use of this information in patient management. It is possible that in specific instances appropriate imaging may obviate the need for an "exploratory" surgery. At times multiple imaging tests are used to evaluate an organ or anatomic region, and there may or may not be a consensus as to which test is superior. It is possible that the various images may provide complementary or different information. It is also possible that despite imaging an exploratory surgery and further investigation will ultimately be necessary. If you stop and think about it for a moment, it should not be surprising that many tumors cannot be fully characterized on the basis of imaging studies. Pathologists, with the specimen in hand, can have difficulty arriving at a definitive diagnosis. A final histopathologic report may indicate what the lesion is most likely, but may also provide a list of other differentials. Another critical point is that a negative imaging study does not eliminate the possibility of for instance micrometastasis which in actuality represents an already large colony of viable cancer cells. A case based discussion will be the focus of this presentation.

The choice of a specific imaging modality is based on a number of different factors. It is important to consider the following questions.

1)  What information is being sought ?

2)  Is this for initial screening, staging, assessment of response to treatment or to monitor freedom from relapse ?

3)  Is the intent to just detect disease or to more precisely and accurately delineate the extent of involvement for treatment planning purposes ?

4)  What is the availability and quality of the imaging technology to be used ?

5)  And last but perhaps most importantly, what is the level of familiarity and expertise with the imaging tool to be used by the radiologist ?

Radiography

The most commonly utilized imaging tool in oncology is three-view thoracic radiography to assess patients for evidence of pulmonary metastasis. Owners are often reluctant to repeat studies that have been done previously. Significant changes, i.e., the development of pulmonary metastasis, can occur over a 2-4 week time period. The most current and up-to-date information should be available to us as clinicians and for the owner to assist in making appropriate therapeutic decisions. The question also arises as to how frequently imaging studies should be repeated, and what if anything can be done based on the resultant information. An intensive recheck schedule would entail appointments at 1,2,3,5,7,9,12 months and every 3-6 months thereafter. Close observation of patients after treatment provides a more accurate assessment of the efficacy of therapy. However, if there is not an action step that can be taken based on the information obtained then there may not be an acceptable cost to benefit ratio. There has been limited assessment of the impact of various imaging tests on patient management and outcome in veterinary medicine. Thoracic radiographs are frequently repeated during a course of chemotherapy to monitor for metastasis and/or disease progression. If pulmonary metastasis develops during a course of chemotherapy the treatment course is typically altered or discontinued. In this setting the cost associated with the thoracic radiographs is warranted if the outcome is identification of progressive disease and this results in the discontinuation of therapy that may be costly and is ineffective.

Thoracic radiographs may also be obtained in patients with tumors that do not metastasize or only rarely metastasize to the thorax as a screening tool to evaluate the heart and lungs. In this setting thoracic radiographs are utilized as a part of the routine health screen that also includes complete blood work.

If an abnormality is identified then it can be helpful to compare to previous studies. Baseline imaging studies are more than appropriate and should be obtained even if there is a low expectation of a positive finding during the initial evaluation.

In both the evaluation of patients, and discussion with owners it is important to be familiar with the specific biologic behavior of the primary tumor. It is also important to remember that tumor behavior can vary based on tumor location, species and a number of other factors. An appendicular osteosarcoma in the dog will have already metastasized to the lung in up to 85% of cases but typically will not be evident on the initial thoracic radiographs. This is an important distinction, as even though it is assumed that most dogs have pulmonary metastasis at presentation, dogs that have obvious metastatic disease have not been shown to benefit from adjuvant chemotherapy. Feline appendicular osteosarcoma is associated with a much lower rate of metastasis, closer to 20%, and treatment is usually limited to amputation alone. It is worth repeating, that in consideration of cancer patients it is important to take into account not only the tumor histology, but also the tumor grade, tumor site as well as species to more accurately predict behavior and determine the appropriate imaging studies and diagnostic tests to be performed.

Conventional radiography for tumor imaging can provide a useful screening tool. It has specific utility in the imaging of primary and metastatic bone tumors particularly of the appendicular skeleton. The main disadvantage of radiography results from the superimposition of overlying structures. For instance, imaging of nasal tumors using conventional radiography can provide information regarding areas of involvement and may show bony or turbinate lysis. However, imaging of nasal tumors is better suited to cross-sectional imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI).

Good quality radiographs are obtained routinely. Other imaging studies (CT, MR, ultrasound) can show significant variation in quality based on the level of technology available, level of technical skill of the operators, and the level of expertise in interpreting images.

Ultrasonography

Ultrasonography is used routinely in staging cancer patients. It provides information on the internal structure of organs based on differences in acoustic impedance. Sonography provides useful information not attainable with routine radiography because tissues with different acoustic impedances often have the same radiographic opacity. Ultrasonographic examination of patients with pleural or peritoneal effusion can be useful both for imaging and ultrasound guided aspiration or biopsy. In such patients routine radiography may provide only limited information due to the presence of fluid and resultant degradation of image quality. Ultrasonography has largely replaced abdominal radiography. Ultrasonographic identification of bowel-associated masses has also replaced barium studies. Ultrasound guided fine-needle aspiration biopsy can be useful in the diagnosis of gastro-intestinal disease, and for example with lymphoma may obviate the need for an exploratory surgery and biopsies. This is particularly useful for a disease that is managed primarily with systemic chemotherapy. However, one pitfall with abdominal ultrasound is that if a mass in the liver is isoechoic to the liver then the mass will not be identified unless there is alteration of the contour of a liver lobe. In this situation a contrast enhanced CT scan may more useful. In the evaluation of dogs with bladder tumors, ultrasonography is more sensitive for mass detection than either intravenous urography or double-contrast cystography.

It is important to remember that ultrasonography is sensitive for lesion detection but it is not specific for disease etiology. There may be a high level of confidence as to the nature of the lesion but it is inappropriate to diagnose disease processes based on sonographic appearance. A definitive diagnosis requires cytologic and/or histopathologic confirmation.

Ultrasonography in particular raises the issue of the problem of detection of what have been termed "incidentilomas", which can represent a diagnostic dilemma and challenge. Two examples encountered relatively frequently are adrenal masses and splenic nodules.

Ultrasonography can have a therapeutic role. For instance the identification of an abnormal parathyroid gland in a dog with primary hyperparathyroidism, or an enlarged thyroid gland in a cat with a thyroid adenoma or hyperplasia can provide direction for application of therapy. Ultrasound-guided ethanol injection in both of these situations has been investigated and has shown utility.

Ultrasonography may also be of some utility in patients with pleural or pericardial effusion to help localize the fluid for thoracocentesis. This procedure may be both diagnostic as well as therapeutic.

Computed Tomography

Computed tomography (CT) has two main advantages over conventional radiography. Images are tomographic which refers to the "slices" obtained of the patient. Superimposition, which limits the utility of conventional radiography, is not considered to be a problem with CT. Also, because the images are computer generated the contrast between structures is significantly enhanced. Appropriate assessment of findings from CT imaging requires a basic knowledge of cross-sectional anatomy and necessitates a different way of thinking about images. CT imaging of brain and nasal tumors has attained widespread use, and radiologists as well as clinicians are familiar with interpretation. CT imaging of other sites can be problematic. It can be difficult to identify abnormalities when there is a limited familiarity with the normal anatomy on CT images. There is always a learning curve and with experience it should be possible to demonstrate whether or not CT imaging has utility as a diagnostic tool in a wider range of settings.

CT imaging is more expensive than routine radiography but it can provide a substantial amount of information and direct treatment planning. For example, an accurate assessment of the extent of disease in a cat with a vaccine-associated sarcoma may prevent one cat from undergoing a surgery that has little chance of success, and for another cat it may direct the surgeon to resect the appropriate muscles and tissue planes which will successfully effect local tumor control.

Even with state-of-the-art equipment it is important to tailor a study for the specific patient to maximize the information obtained. It is important to consider slice thickness to optimize image quality and in closer assessment of specific regions. In the evaluation of nasal tumors, thin slices at the level of the cribriform plate may show evidence of cribriform involvement not appreciated on thicker slices. More accurate assessment may in turn allow for more precise prognostication. The WHO staging system for nasal tumors has not been shown to be of prognostic significance. This could change with more precise evaluation of the extent of local disease.

It is also important to communicate with the radiologist as to the goals of the study. Is the CT scan being done to assess osseous as opposed to soft tissue involvement, or both ? The window settings will need to be altered based on the focus of the study. Has a previous surgery been done and the interpretation of the images would be aided by identification of the surgical scar on the CT images ? This can be easily accomplished by placing a small amount of barium paste along the incision. Other markers (thin wire, hollow catheter, etc.) can be used to assist in identification of landmarks on patients for subsequent planning for surgery and/or radiation therapy. Appreciation of the normal anatomy in CT imaging of pelvic tumors is enhanced by the placement of contrast material in the urethra and the use of a red rubber catheter or other hollow tubing in the rectum for delineation of the position of these normal structures on the images.

CT-guided percutaneous biopsy of tumors in number of different anatomic locations has been described including the retrobulbar space, cranial mediastinum, pulmonary masses, brain tumors, and hilar lymph nodes. Fluoroscopy and ultrasound guided biopsies and/or aspirates have been typically done in the past, but the benefit of CT-guided biopsies is the additional information provided regarding the location of a mass in relationship to the surrounding anatomic structures.

CT's performed in the post-operative setting or after radiation therapy can be difficult to assess. A mass seen on a post-operative CT scan may represent scar tissue, necrotic tumor, or residual viable tumor. Neither radiography nor CT imaging can accurately predict which is present. Monitoring of the site may reveal persistent stable disease or slowing regressing disease, both potentially indicative of tumor control. A second surgery and/or surgical biopsy may be indicated. The additional problem that then arises is that if the biopsy is diagnostic for tumor, then does it represent viable clonogenic tumor cells that can lead to local regrowth, or non-clonogenic cells. If there is no obvious sign of disease progression this may be a difficult question to answer.

If the study is going to be used for radiation treatment planning then the patient will need to be positioned as for therapy. CT images can then be directly downloaded into the radiation treatment-planning computer for use in determination of the radiation treatment field number, size and position. The optimal approach is to use repositioning devices, such as vac-lok positioners, at the time of the initial CT scan such that the patient can be reproducibly positioned for daily radiation treatments.

The use of intravenous contrast enhancement can markedly increase the ability to delineate the extent of local disease, e.g., vaccine-associated sarcomas in cats. Also, precise timing of contrast administration may allow visualization of vasculature. In each instance a decision should be made as to the use of intravenous contrast and whether or not there may be benefit in obtaining both pre- and post-contrast images.

Image quality with CT is constantly improving and the use of spiral CT scanners is significantly decreasing image acquisition time. It is not inconceivable that in the future we may be performing whole body CT imaging in the diagnosis, staging, and follow up of cancer patients. Spiral CT allows acquisition of a volume of data over 20-40 seconds as opposed to a single slice every 5-10 seconds as occurs with standard CT. This allows rapid data acquisition, optimal timing of contrast administration, and the effect of motion due to breathing is minimized.

Magnetic Resonance Imaging

MR is used extensively in the diagnosis of brain tumors. It also provides more information on the extent of disease in soft tissue sarcomas in dogs and cats wherein CT imaging even with contrast may not adequately differentiate between normal soft tissues and tumor. MR is the dominant imaging modality for musculoskeletal tumors in humans because of the superior soft tissue definition as well as in evaluation of bone marrow. MR can be used in the assessment of residual disease. Mature scar tissue is acellular or hypocellular and contains very little water compared to viable tumor cells. T2-weighted images of persistent tumor will have a high signal compared with the low signal of mature scar tissue. However, early in the process of fibrosis the tissue will be more cellular and have a higher water content and will be difficult to differentiate from tumor on MR imaging. In human oncology the differentiation of tumor versus fibrosis on MR images is considered useful only 6-9 months after the end of treatment.

MR provides exquisite detail for tumors in the neck region in dogs and is recommended for imaging of thyroid tumors prior to surgery and/or local radiation therapy. It is possible to identify the vasculature, the tumor and relationship to the surrounding tissues to better understand the likelihood of a successful outcome from surgical resection.

Radionuclide Imaging

The most common application is in the evaluation of thyroid disease, and both local and metastatic bone tumors. In nuclear medicine radiotracers and radiation detectors (e.g., gamma camera) are used to create functional images of physiologic and pathophysiologic processes occurring in patients.

Bone scans are usually done with planar gamma camera imaging using technetium-99m labeled phosphonate compounds. Metastases to bone and primary bone tumors typically provoke an osteoblastic reaction. In regions of new bone production, the Tc-99m phosphate compound is laid down in the hydroxyapatite crystal. In primary bone tumors radiography often underestimates the extent of bone involvement whereas nuclear imaging often overestimates the extent of bone involvement. For the purposes of limb sparing surgery for appendicular osteosarcoma in dogs it is more appropriate to resect the tumorous bone based on a bone scan. Bone scans are considered sensitive for detecting bone metastasis and are considerably more sensitive than conventional radiography. In some instances a bone scan may fail to identify bone lesions. For instance in multiple myeloma, with a purely lytic lesion, the areas of bone involvement may not be evident on a bone scan and radiography or CT may be more sensitive. Another problem is that a number of non-neoplastic lesions may be identified, e.g., dental disease, or arthritis, and further investigation may be necessary to determine the significance of sites of activity detected.

Thyroid scintigraphy can be done using either sodium ^99mTc pertechnetate (^99mTcO₄-) or radioiodine (¹³¹I). ^99mTc pertechnetate is usually used for thyroid imaging. The distribution of pertechnetate is similar to iodine in the body with accumulation in the thyroid glands, salivary glands, gastric mucosa, and choroid plexus. Radioiodine is more suitable for quantitative thyroid uptake studies and may be more sensitive for the detection of differentiated thyroid metastases. Imaging allows the assessment of hyperactivity of the thyroid, whether one or both thyroid glands are involved, presence of ectopic tissue or metastatic disease, and some estimation of size and relative activity. In a normal patient the activity visualized in the thyroid glands should be similar to that seen in the salivary glands. Canine thyroid tumors are typically not functional and a thyroid scan will commonly identify one normal thyroid, and the involved gland may be less distinct.