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I. Miguel, M.A., M.D., Ph.D.
Assistant Professor, University of Oklahoma School of Community Medicine
These conditions consist of diminished speech and can include emotional lability, hypotonia, long-tract signs, bulbar dysfunction, decreased respiratory drive, urinary retention, and ataxia. These changes can be seen in up to 25% of patients who have undergone a resection of a midline posterior fossa tumor. Chemotherapy Chemotherapy has been used in medulloblastomas with the dual goals of reducing the radiation dose while maintaining optimal disease-free survival rates in average-risk patients and improving disease-free survival in high-risk patients. Based on these results, the routine use of chemotherapy for "high"-risk medulloblastomas has become standard. The 2 Ч 2 randomization also compares boosting the entire posterior fossa versus a local boost. Current approaches for high-risk medulloblastomas focus on chemotherapy dose intensification. High-dose cyclophosphamide with autologous stem cell rescue is feasible and provided a 5-year event-free survival of 70% in patients with high-risk disease. Because the risk of cognitive deficits increases with decreasing patient age, extensive effort has been made to develop regimens that can delay or potentially eliminate the need for radiation in patients younger than 3 years of age. The avoidance of radiation has proved to be more feasible for patients with M0 disease. Neurodevelopmental assessments did not show a decline in cognitive or motor function. The peak incidence of germ cell tumors is in the 2nd decade, and few present after the 3rd decade. Germ cell tumors commonly involve the two midline sites, suprasellar and pineal regions, and occasionally are found in other areas such as the basal ganglia, ventricles, cerebral hemispheres, and the spinal cord. Germinomas can occur bifocally or, rarely, even multifocally; the most common bifocal presentation is synchronous involvement of the suprasellar region and the pineal gland. A quarter of the intracranial germ cell tumors have more than one histologic component and are known as mixed germ cell tumors. Alpha-fetoprotein (elevated in yolk sac tumors) and -human chorionic gonadotropin (elevated in choriocarcinoma, and to a modest extent in germinoma) are generally secreted by these tumors. Neurologic signs and symptoms are caused by obstructive hydrocephalus and involvement of ocular pathways. Long-term effects from treatment can be categorized as neurocognitive, neuropsychiatric, neuroendocrine, and growth retardation. Hypothalamic and pituitary endocrinopathies such as delayed hypothyroidism and decreased growth hormone secretion may occur. Growth retardation can also be secondary to delayed or reduced bone growth, leading to a reduction in sitting height. Neurocognitive deficits have long been recognized secondary to surgery, radiotherapy, and chemotherapy. Calcification and fat may be seen in teratomas or mixed malignant germ cell tumors. Germinomas tend to surround a calcified pineal gland, whereas pineal parenchymal tumors tend to disperse the calcification into multiple small foci. The potential for leptomeningeal dissemination requires imaging of the neuraxis before surgery. Determination of histology, tumor markers, and extent of disease is critical for the optimal management of pineal region tumors. The prognosis varies depending on the histologic type, the size of the tumor, and the extent of disease at presentation. Surgery Because pineal tumors are often near the center of the brain, they are among the most difficult brain tumors to remove. Having said that, there is no role for cytoreductive surgery in the treatment of germinoma, which requires only a biopsy from the neurosurgeon followed by radiation, chemotherapy, or both. The application of modern surgical technology with superb illumination, magnification, surgical guidance, and neuroanesthesia has made this region much more accessible. Whenever possible, the tumor is completely excised, except when a germinoma is found at open surgery; a biopsy suffices in this situation because germinomas respond well to radiation. The place of stereotactic biopsy in the diagnosis of pineal region tumors is unclear.
When using fluoroscopic simulation, one must be certain that the field size and shape adequately encompasses the target volume. Without detailed knowledge of the true extent of the tumor volume, fluoroscopically determined treatment portals may result in inadequate coverage. In order to be able to consistently reproduce the treatment set up established at the simulation, three or more laser beams are used to establish fiducial marks often called triangulation points on the patient. The data acquired at the time of simulation can also be directly captured into a Record & Verify system (R&V), obviating the need for manual entry with the potential of transcription error. At completion of the simulation, a set of simulation films that show the field size, field isocenter, and projected anatomy from the chosen beam direction and distance is obtained. These films are used as the standard by which the future port films in the treatment room will be measured for set-up accuracy and to assess patient movement. Acceptance testing and commissioning of a treatment planning system provides the benchmark by which the system will be evaluated during the periodic quality assurance testing. Acceptance testing is performed after installation but prior to clinical use of the system. The ability to properly transfer imaging data is confirmed by scanning phantoms of known geometry with internal markers and transferring the imaging data to the treatment planning system. The transferred data is then compared with film images to validate orientation, measurement, and fiducial positioning. System commissioning involves extensive testing of the dosimetric algorithms for a variety of clinical scenarios. Data such as percent depth-dose tables, off-axis profiles, and output factors are acquired using a computer-controlled water phantom for each treatment beam on each treatment unit to be used in the planning system. Phantoms with known geometric target volumes are used to simulate common clinical scenarios and treatment plans are evaluated to verify calculated dose distributions. Although anthropomorphic phantoms (that are shaped like the human body) are well-suited to test clinical treatment techniques, geometric phantoms (that are cylindrical or cubic) have more reliable ionization chamber positioning (15). These numbers are plotted versus electron density to derive the calibration curve for that scanner. Although the most accurate form of dose calculations are Monte-Carlo-based, these calculations are computationally intensive and cannot currently be used for routine planning. All other dose calculation algorithms used in treatment planning systems have limitations, and it is essential to understand where these limitations manifest, for example, in areas where electronic equilibrium does not exist, such as lung-tissue interfaces. Routine periodic quality assurance testing of the planning system consists of daily, monthly, and annual tests. Daily tests validate the performance of input devices such as point digitizers and the accuracy of output devices such as printers. Monthly tests can involve calculating computer checksums for the treatment planning software executables and machine data, to ensure the program and data has not been modified. This set of standard plans are used for testing whenever software upgrades, either patches or version changes, are applied. This delineation can be the major contributor to overall uncertainty in the treatment planning chain, as many factors exist that contribute to this uncertainty. It is imperative that the treating physician and the radiation treatment planner share a common vocabulary regarding the tumor volume and the additional margins necessary to account for organ motion and set-up inaccuracies. Prescribing and designing a treatment plan to a target without correcting for geometric uncertainties will result in a substantially different delivered dose than the intended one. These margins are determined based on the extent of uncertainty caused by patient and tumor movement as well as the inaccuracies in beam and patient setup. Several margin recipes based on geometrical uncertainties and coverage probabilities have been published; however, their clinical impact remains to be proven (17). Internal margin uncertainty that is caused by physiological changes such as respiratory movement cannot be easily modified without using respiratory gating techniques. In contrast, set-up margin uncertainty can be more readily minimized by proper immobilization and improved machine accuracy. In order to avoid significant radiation toxicity and to maintain post treatment quality of life, the planning physician must be vigilant when considering avoidance structures. Even with a common terminology and attention to detail when delineating the anatomical structures, several uncertainties exist that are related to the imaging modality used for data acquisition. When the scan time is protracted, the artifact can be significant enough to render the reconstructed images unrecognizable in relation to its stationary counterpart (20).
The synthetic pathway involves multiple intermediate hormones that can sometimes mimic the activity of mature hormones if produced in sufficient quantity by tumors of the adrenal cortex. The majority are functionally silent, but these tumors can produce steroid hormones, which in excess may cause typical clinical syndromes. These tumors typically produce a combination of epinephrine, norepinephrine, and rarely dopamine. Those of sympathetic origin are typically mediastinal or abdominal and can produce norepinephrine, whereas those of parasympathetic origin are found in the head and neck and are functionally silent. In recent years, international collaboration and increasingly sophisticated biologic techniques have elucidated many genes that appear to be important in the pathogenesis of these diseases. The vast majority of adrenal incidentalomas are benign, but up to 15% can be functional, autonomously secreting adrenal hormones leading to clinical or subclinical hormone excess, making clinical exam and biochemical evaluation for hormone excess mandatory. As such, screening should only be considered for patients with a known or suspected familial syndrome that predisposes to adrenal neoplasia. Demonstration of a genetic mutation allows for identification of other affected family members and disease-specific screening and surveillance for adrenal neoplasms and other associated tumors in all gene carriers. Cortisol is the most commonly produced hormone in both benign and malignant functional cortical neoplasms. Basic laboratory evaluation of a patient presenting with an adrenal mass or syndrome of hormone excess includes a complete blood count and comprehensive metabolic panel with liver enzymes. Those presenting with an incidental adrenal mass require comprehensive hormonal evaluation including tests for hypercortisolism, androgen excess, hyperaldosteronism in hypertensive patients, and catecholamine production in all patients. Benign cortical lesions tend to be small, fat-containing, and homogeneous, with smooth borders. Functional imaging can be useful in evaluating both cortical and medullary tumors of the adrenal gland. After infusion of intravenous contrast (absolute percentage washout = 75%, relative percentage washout = 49%). However, no validated quantitative criteria exist for reliably predicting whether a lesion that is indeterminate by anatomic imaging in a patient without a known primary cancer will be benign or malignant. Percutaneous biopsy of adrenal tumors is almost never indicated because cytology is unhelpful in characterizing adrenal neoplasia, and biopsy has significant risk of complications including hemorrhage and pneumothorax. Histopathologic criteria established by Weiss predict malignancy in adrenocortical neoplasms when three or more of nine criteria are present. The Pheochromocytoma of the Adrenal Gland Scaled Score system has been proposed for assessing malignant potential by using 12 histopathologic criteria,106 but validation studies have produced conflicting results. The introduction of -blockade and volume repletion has reduced mortality to 0% to 3% in contemporary series. Selective 1-blockade has been used to avoid some undesirable 2-mediated side effects including reflex tachycardia, hypoglycemia, and somnolence, but these agents are less well studied compared with nonselective agents. Dosage can be titrated on an outpatient basis for adequate blockade, which often takes 2 weeks or longer. During this time, salt- and fluid-loading are recommended for volume optimization to minimize postoperative hypotension. Aggressive preoperative control of hypercortisolism is advocated but should not delay surgery. However, most endocrine neoplasia groups suggest that all patients receive some form of long-term follow-up. Postoperative biochemical testing at 2 to 6 weeks and 6 months is appropriate, and chromogranin A may be useful if elevated preoperatively. Recurrences were malignant in half of all cases and more commonly occurred in patients with familial syndromes or larger tumors. Quality of life must be considered because in some cases observation and supportive medication alone is the best option. Similar to any surgery, these procedures require sufficient preparative -blockade. Subsequently, this can be reduced to biannually until 5 years and annually thereafter.
Two techniques have been used; the first being the use of plastic scintillators as a detector system themselves, using optical coupling through a light pipe assembly to a video detector. Significant difficulties still exist with the spatial resolution of these systems. Light emitted by the scintillator can travel some distance, in any direction, before reaching the light detector. Unless the plastic scintillator is thin, the resolution of the image will be degraded considerably. Some efforts have been to quench the light by adding dyes to the scintillator, to reduce the distance traveled by the light obliquely through the scintillator. Until this problem is resolved, the quality of the imaged dose distribution will not be adequate for radiation dosimetry. A second technique involves the use of plastic scintillators to enhance the response of another detector, such as radiographic film (38). In this technique, radiographic film is sandwiched between sheets of organic plastic scintillator. Several investigators have noted that radiographic film has a tendency to overrespond to low energy photons (39,40). The use of an organic plastic scintillator has been proposed to enhance the response of radiographic film to higher energy photons, thus making the energy response of the film detector system more uniform. Again, film itself is not a 3D dosimeter, but stacks of film have been used to measure dose distributions in 3D. The difficulties with film are well known; energy dependence, requirements for processing, variations from one batch to the next, dose rate dependence, positional dependence, and other issues have been discussed by a number of investigators (41). Radiochromic film requires no processing, has very little energy dependence, no known dose rate dependence, and requires minimal special handling techniques (42,43). Its use has been limited principally to point measurements, because the dosimeter is provided either as extruded rods or chips, or as a powder that is encapsulated for use. Thermoluminescent dosimetry has a number of limitations, among them energy dependence, but most notably a requirement for delay between irradiation and processing. In addition, an expensive piece of equipment is required for readout of the material. The film can be irradiated in much the same manner as conventional radiographic film, and may be immersed in a water phantom as necessary. After irradiation, and following the requisite delay, the film is inserted into a readout device that selectively heats the individual dosimeter regions using a laser. Through an automated operation, a matrix of data can be obtained quickly and efficiently. However, due to the cost of the reader, this dosimetry system is presently available only as a service (Inovision, Inc. For many years, positioning has been verified through the use of conventional radiographic film, or through the use of video imaging techniques (45,46). Video imaging permits only a check of the relative position of external landmarks. Radiographic film permits verification of the patient position through the visualization of internal boning anatomy, but requires a delay while the film is processed. The introduction of electronic portal imaging has brought to the clinic the possibility of immediate verification of patient position. The failure or incorrect programming of a multileaf collimator can result in a completely unacceptable dose distribution. With on-line portal imaging, such errors may be detectable promptly, even during treatment (4752). A further improvement has been the introduction of transmission flat-panel detectors up- and downstream from the patient. These allow the measurement of photon beam fluence entering and exiting the patient, and the estimation of dose within the patient. During the last two decades, however, the number of investigators has increased rapidly, and the body of knowledge regarding gel dosimetry has expanded considerably (55,56). Gel dosimetry is still considered by some to be a research project, and the introduction of this tool into clinical use is proceeding slowly. However, the interest in, and potential of, gel dosimetry for clinical use is demonstrated by the level of participation in three successful international workshops held to date on this subject (5759). This section reviews the development of gel dosimetry, several of the formulations that have been investigated intensively, the characteristics of gel dosimetry that make it desirable for clinical use, the postulated and demonstrated applications of gel dosimetry, and some complications, setbacks, and failures that have contributed to the slow introduction into routine clinical use.
Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Primary thyroid lymphoma: a review of recent developments in diagnosis and histology-driven treatment. Prognosis of primary thyroid lymphoma: demographic, clinical, and pathologic predictors of survival in 1,408 cases. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. Thompson inciDence anD etiology Parathyroid tumors are one of the most common endocrine neoplasms. A total of 85% of the cases are caused by a parathyroid adenoma, parathyroid hyperplasia involving the four glands (10%), double parathyroid adenoma (2% to 5%), and parathyroid cancer in <1% of the cases. The epidemiology of this disease has shown significant changes over the last several decades, with the majority of the patients remaining relatively asymptomatic with only mild hypercalcemia, being diagnosed by routine calcium measurements instead of symptoms. It is more common in women (1 in 500) than in men (1 in 1,000) and occurs in approximately 0. Based on some of these studies, which capture approximately 60% to 80% of all cancer diagnoses in the United States, between 30 and 50 cases of parathyroid carcinoma occur annually. The clinical behavior of parathyroid cancer is quite variable but usually the tumor is very aggressive, and most patients develop locoregional recurrence; distant metastasis to lung, bone, and liver occur late. Most patients with parathyroid cancer succumb to uncontrollable hypercalcemia, not to direct tumor burden. Different than the benign parathyroid tumors (female-to-male ratio of 3 to 4:1), parathyroid cancer occurs with equal frequency in men and women. More than 75% of patients will present after the age of 45 where the median age of presentation is 55 years old. At the time of neck exploration, malignant tumors are often large (usually >3 cm), weighing between 2 and 10 g (the combined weight of all four normal parathyroid glands is approximately 150 mg). They are often hard, firm, and whitish-gray, and with invasion or adherence to the adjacent tissues such as the strap muscles, thyroid gland, recurrent laryngeal nerve, trachea, or esophagus. In 1973 after 70 cases of parathyroid cancer were examined, Schantz and Castleman25 reported histologic criteria 1189 Practice of oncology 1190 Practice of oncology / Cancer of the Endocrine System that are still commonly used. This includes the presence of fibrous bands intersecting the tumors forming trabecular architecture, along with capsular invasion, vascular invasion, and increased mitotic activity. These features are not unique to parathyroid carcinoma and can also be found in benign parathyroid tumors (adenoma, atypical adenoma, parathyromatosis, and hyperplasia). Overall, there is not one histopathologic sign that can distinguish between parathyroid cancer and benign disease; definitive diagnosis can be made only with the presence of loco regional invasion or distant metastases. Electron microscopy does not add proof of malignancy when compared to light microscopy. Identification of the molecular markers associated with parathyroid carcinoma will prove to be an important tool for the improvement of the often difficult diagnostic dilemma. P27kip1 (cell-cycle progression regulator) is also downregulated in parathyroid cancer cells. Concomitant renal and bone involvement can be seen in half of the patients and can lead to chronic renal insufficiency. Manifestations of bone disease include osteitis fibrosa cystica, subperiosteal bone resorption, and "salt and pepper" skull. The overall symptoms can be exactly the same for benign parathyroid disease, and the challenge for the physician remains to differentiate between hyperparathyroidism due to benign disease versus parathyroid cancer. On the physical examination, a neck mass is palpable in >40% of patients, while in benign parathyroid disease this is much less frequent15 (Table 83. DiagnoSiS It is often difficult to diagnose parathyroid cancer prior to surgery as the clinical features are very similar with benign disease. Shaha and Shah50 have proposed a staging system in the past taking in consideration the size of the tumor, invasion to adjacent tissues, lymph node involvement, and distant metastases (Table 83.
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