General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > Volume I - The Lung, Pleura, Diaphragm, and Chest Wall > Section III - Thoracic Imaging > Chapter 13 - Radionuclide Studies of the Lung

Chapter 13

Radionuclide Studies of the Lung

Vicente J. Caride

Radionuclide imaging of organs and diseases should not be equated with the strictly anatomic rendition of other imaging modalities. Abnormalities in function and anatomy are manifestations of disease that are important for appropriate clinical management decisions. Clinically relevant functional imaging depends on the right choice of tracer, the use of modern imaging equipment and imaging processing, and the correlation with complementary anatomic imaging and other diagnostic tests.

Selective targeting of imaging agents can be as simple as the introduction of a radiotracer into an accessible organ or anatomic space. Pioneering work by West (1962), Ball and colleagues (1962), Dollery and Gillam (1963), and Milic-Emili and associates (1966) was done with the radioactive inert gas xenon 133 (¹³³ Xe) to obtain fundamental physiologic measurements of regional pulmonary ventilation and perfusion. Pulmonary perfusion is more commonly studied by embolizing the pulmonary artery precapillary arterioles with radioactive macroaggregates of albumin (MAA).

Colloidal particles 1 m or smaller injected intravascularly are cleared from the blood by phagocytes in the liver, spleen, and bone marrow. Colloidal preparations injected intradermically or in the interstitium of organs or tumors are removed by the lymphatics, allowing lymph node identification and evaluation of lymphedema, lymphoceles, and chylous extravasation. Other radiotracers that remain circulating in the bloodstream after injection, combined with fast imaging, provide effective strategies to evaluate cardiovascular and peripheral vascular abnormalities.

The use of radioactive tracers allows easy detectability for diagnostic imaging, but the radiolabeled compound may not behave the same as the natural substance. Improved targeting can be expected with the use of radiolabeled antibodies or molecules that have affinity for receptors expressed by specific cells. The nature of the interactions between the radiocompound and the living organism may result in nonspecific distribution of radioactivity, a fact to be borne in mind when interpreting images. Monoclonal antibodies directed to tumor-associated antigens face several barriers before interacting with the target. There are unwanted interactions between the antibody and cells and other molecules in the bloodstream, loss of the radioactive labeling, impediments for the large molecule to travel to the target cells, and further interactions with the peritumoral environment. The expected antibody antigen attachment depends on the presence of the antigen in the target cells, antigen accessibility, and the uniqueness of the antigen antibody affinity that prevents cross-reactivity. The monoclonal antibody technology has been applied for diagnostic imaging in colorectal and prostate cancer and other tumors and is making great strides for treatment of lymphomas refractory to other therapies. Monoclonal antibodies against lung tumors were briefly used without gaining a place in the diagnosis or staging of the disease.

Targeting specific receptors with small peptidic molecules has a promising future. Somatostatin (SST) receptor imaging is based on receptor targeting with small SST analog peptides. SST receptors are expressed in neuroendocrine tumors, other tumors, and nonneoplastic conditions. The use of radiolabeled SST analogues extends to therapy of neuroendocrine tumors.

A radiolabeled peptide that binds to the glycoprotein IIb/IIIa receptors in activated platelets has replaced radiolabeled platelets for detecting active thrombosis. Radiolabeled leukocytes for diagnosing and localizing infections and red blood cells for the diagnosis of hemangiomas, evaluation of cardiac function, detection of active gastrointestinal bleed, and occasionally bronchial bleeds remain the best example of the use of radiolabeled cells for imaging.

Selverstone and associates (1949) located brain tumors at the time of craniotomy with the aid of phosphorus P-32 and a Geiger-M ller detector. Tracer methodology has returned to the surgical suites with the use of specially designed, handheld detectors to search for radiolabeled lymph nodes or tumors using more advanced and more specific radiotracers.

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VENTILATION AND PERFUSION STUDIES OF THE LUNGS

The ventilation study is performed with radioactive gases: ¹³³ Xe, xenon 127 (¹²⁷ Xe), or krypton 89 (⁸⁹ Kr), or with radioaerosols of technetium 99m (^99m Tc) diethylenetriaminepentaacetic acid (DTPA). Intravenous injection of macroaggregates of albumin labeled with ^99m Tc MAA are use for imaging the pulmonary perfusion. The total number of particles injected should not exceed 500,000 to limit safely the embolization to 1 in every 1,000 precapillary arterioles. The number of particles should be reduced in patients with extensive lung disease, postpneumonectomy, or severe pulmonary hypertension; in pediatric patients; and in patients with known large right-to-left shunts. Reduction of radioactivity from 4 to 2 mCi (128 to 72 MBq) is advisable in pregnant women and pediatric patients. The macroaggregates clear the lungs with a biological half-life of 3 hours.

Acute and chronic pulmonary embolism (PE) (Fig. 13-1), lung tumors, radiation therapy, congenital pulmonary artery anomalies (Fig. 13-2), chronic obstructive lung disease, lymphangitic spread of cancer and tumor emboli (Fig. 13-3), fibrosing mediastinitis, vasculitis, pneumonia, bronchial obstruction, pleural effusions, and chest wall deformation result in diverse perfusion defects. Therefore, lung perfusion studies should be interpreted with knowledge of the clinical findings and compared with ventilation scan and a chest radiograph obtained within 4 hours. The lung scan interpretation considers whether the perfusion defects follow a segmental distribution, the degree of hypoperfusion, the number and location of perfusion defects, and whether there are matching ventilation defects. Extensive literature exists on the various presentations and pitfalls of lung scan in the diagnosis of PE.

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Acute and Chronic Pulmonary Emboli

The PIOPED study (1990) validated the use of probability estimates for PE based on the ventilation-perfusion scintigraphy and chest radiographic findings. PIOPED confirmed that a lung scan without perfusion defects effectively rules out PE and that a high probability scan, defined as one with two or more segmental perfusion defects, a normal ventilation, and a clear chest radiograph, is diagnostic for PE with a specificity of 97% and a sensitivity of 41%. In subjects that had prior PE, the high probability lung scan has a specificity of 88%, compared with 98% for patients without prior PE. Other scintigraphic presentations fall under the low probability range (less than 20% probability), where perfusion abnormalities are nonsegmental or small, with matched ventilation or with chest radiographic abnormalities larger than the perfusion defects. The intermediate probability is reserved for scans that do not fit in the high or low probability categories.

Lung scintigraphy is an alternative to computed tomography (CT) pulmonary angiography in patients with contrast intolerance or poor renal function, individuals that are obese or claustrophobic, pediatric patients, and during pregnancy. It has been suggested that lung scintigraphy may be the first choice when there is low clinical suspicion for the disease. Triaging these patients with noninvasive perfusion lung scans may be cost-effective, reserving more invasive studies for patients whose lung scans are abnormal. The triage should start with a pointed clinical evaluation to establish the likelihood of PE. In an attempt to provide a structured clinical selection of patients, Wicki and co-workers (2001) identified conditions that are significant predictors for PE (recent surgical procedure, thromboembolic disease, older age, hypocapnia, hypoxemia, tachycardia, band atelectasis or elevation of the diaphragm on the chest radiograph) to obtain a clinical score. A low clinical score, in this study, had 10% probability for PE. Intermediate score and high score carried 38% and 81% probabilities for PE, respectively.

Miniati and collaborators (1996) triaged prospectively 890 patients by combining clinical evaluation, chest radiographs, and perfusion lung scans. Four hundred thirteen of 670 patients with abnormal lung scans consented to have a pulmonary angiogram. The perfusion lung scans were interpreted as consistent or not consistent with PE, resulting in a sensitivity of 92% and specificity of 87%. The prevalence of PE in this study was 44%.

In populations with a low prevalence of PE (<20%), triaging with scintigraphy can be even more valuable because it will avoid subjecting individuals that do not have the disease to an unnecessary iodinated contrast study. Triaging, by selecting a subpopulation with higher prevalence of PE, allows better use of resources and improves the positive predictive value of spiral CT.

Pulmonary hypertension is characterized by insidious progressive exertional dyspnea, exercise intolerance, and scant findings on physical examination. Establishing the

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Detection of Right-to-Left Shunt

Perfusion lung scintigraphy can detect right-to-left shunts and provide information on the degree of shunting. The diagnosis is suspected when the lung scan shows extrapulmonary activity and is confirmed by demonstrating brain uptake of ^99m Tc MAA (see Fig. 13-1C). In patients with unexplained hypoxemia and a negative lung scan, additional images of the head may be useful to exclude significant right to left shunting of blood.

Aerosol images are an attractive alternative to ¹³³ Xe ventilation studies because of their simplicity and because the lungs can be imaged in multiple projections. The aerosol study requires submicron aerosolized radiotracer to reach the alveoli. As part of the ventilation-perfusion study, after quiet tidal volume breathing of the aerosolized ^99m Tc DTPA, multiple projections of the lungs are acquired. A perfusion scan follows the aerosol study.

Evaluation of Integrity of the Alveolocapillary Membrane

For evaluation of the integrity of the alveolocapillary membrane after inhalation of the aerosol, the lungs are imaged continuously for 10 to 30 minutes, and the clearance of the radioaerosol is then calculated. Clearance rates have been reported from 0.5% to 2% per minute, with a clearance half-time of about 60 minutes. Fast clearance rates are seen in smokers, after inhalation injuries, after radiation therapy, and in alveolitis, sarcoidosis, immunosuppression, and pneumonitis of any etiology.

RADIONUCLIDE EVALUATION OF NEOPLASTIC AND NONNEOPLASTIC LUNG DISEASES

Gallium 67 (⁶⁷ Ga) citrate, thallium 201 (²⁰¹ Tl) chloride, and ^99m Tc sestamibi are agents that accumulate in viable tumors. The clinical value of these agents for lung tumors, however, is limited.

Gallium 67 Scintigraphy

After intravenous administration, the iron analog ⁶⁷ Ga circulates in blood mostly associated to transferrin. The cellular uptake of ⁶⁷ Ga is mediated by the transferrin receptors found in many normal cells and in Hodgkin's and non Hodgkin's lymphomas, squamous cell and adenocarcinomas of the lung, hepatomas, and adenocarcinomas and anaplastic thyroid cancers, as reported by Tsuchiya and colleagues (1992).

De Meester (1976, 1979), Alazraki (1978), and Richardson (1980) and their colleagues reported ⁶⁷ Ga sensitivities for lung cancer ranging from 80% to more than 90%. Hatfield and co-workers (1986) reviewed 111 patients after lung cancer resection and concluded that gallium scintigraphy may be useful to detect recurrent tumor even in the presence of radiation changes. In 20% of 55 patients with recurrent tumor, gallium was the only test indicating recurrence. Thirteen percent of 175 gallium scans performed in 56 patients who did not have recurrent disease were false-positive results. MacMahon and co-workers (1989) reviewed 100 patients with lung tumors studied with ⁶⁷ Ga and CT and concluded that gallium scintigraphy adds little additional information to the clinical assessment or information provided by CT. In their study, gallium was superior to CT in 16% of cases. However, in most cases, the lesions discovered by ⁶⁷ Ga were either suspected clinically (i.e., patient with neurologic symptoms and brain metastases seen on gallium, or back pain and abnormal accumulation of tracer in the spine) or were located outside the area covered by the CT exam. ⁶⁷ Ga imaging largely missed hepatic metastases and adrenal involvement. In a recent review of this topic, Schuster and Alazraki (2002) reiterated that to evaluate posttherapy residual tumor, gallium scintigraphy might be an alternative to positron emission tomography (PET) when this modality is not available.

The clinical use of ⁶⁷ Ga is well documented for Hodgkin's disease and non Hodgkin's lymphomas. Gallium scintigraphy adds information of tumor viability to the CT anatomic findings. Front and co-workers (1997) used ⁶⁷ Ga during the initial evaluation of lymphoma with the purpose of confirming that the disease is gallium avid and also to evaluate body regions not included in standard CT examination. Gallium-positive patients can then be followed with gallium scintigraphy to evaluate response to therapy or recurrent disease. Salloum and colleagues (1997) reviewed 101 Hodgkin's lymphoma patients and found that 16.5% of patients with negative posttherapy gallium scans relapsed during the follow-up. Of 16 patients who relapsed, 11 were stage III/IV, suggesting that in stage III/IV patients, gallium scintigraphy is a poor predictor of disease eradication.

In high-grade non Hodgkin's lymphoma, gallium scintigraphy complements cross-sectional imaging to detect recurrent disease and to evaluate areas that are not routinely covered by CT. Janicek and associates (1997) showed early

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Optimal gallium scintigraphy should include single-photon emission computed tomography (SPECT) as well as multiple planar images of the whole body. Shortcomings of gallium scintigraphy result from the lack of disease-specific uptake and from the limited spatial resolution of the study. Gallium accumulates physiologically in bowel, salivary glands, liver, bone, and soft tissues and in nonneoplastic conditions, including granulomatous diseases, infections, iatrogenic pneumonitis, and surgical wounds. Nonspecific hilar uptake is a well-recognized false-positive finding and is largely ignored by the radiologist when the uptake is limited to and of equal intensity in both hila.

Thymic rebound, usually seen in children and young adults after chemotherapy or radiation therapy, and thymic hyperplasia are also gallium avid. In the immune-deficient patient, intercurrent infections are gallium active. Gallium scintigraphy has been used for the early detection of Pneumocystis carinii pneumonitis and is positive in mycobacterial infections.

Kaposi's sarcoma is characteristically gallium negative. In effect, a negative gallium scan in an immunosuppressed patient with abnormal chest radiograph or chest CT is almost diagnostic of Kaposi's sarcoma. Instead, ²⁰¹ Tl chloride accumulates in Kaposi's sarcoma. Lee and collaborators (1991) reported that a positive ²⁰¹ Tl scan with negative ⁶⁷ Ga scan favors the diagnosis of Kaposi's sarcoma.

Thallium 201 and Technetium 99m Sestamibi Scintigraphy

²⁰¹ Tl and ^99m Tc sestamibi, primarily used for cardiac imaging, also have affinity for neoplastic tissues and some other nonneoplastic conditions. ²⁰¹ Tl, a potassium analogue, distributes in tissues following regional blood flow and is taken up by cells through the Na⁺ -K⁺ ATPase pump. Therefore, accumulation of this tracer reflects cell viability and regional blood perfusion. Breast, lung, and differentiated thyroid cancer, thymomas, lymphomas, some bone tumors, as well as parathyroid adenomas and sarcoidosis, have been reported as ²⁰¹ Tl-avid lesions. Thallium, in contrast to gallium, accumulates in viable tumors with minimal uptake in inflammatory and necrotic tissue.

Higashi and co-workers (2001) compared ²⁰¹ Tl with FDG PET and found a similar detection rate and similar differentiation of benign from malignant lung nodules in lesions larger than 0.8 cm. False-negative results, however, are expected with small lesions and lesions that are located near the heart or lung bases. The authors suggested that ²⁰¹ Tl may be better than FDG in detecting slow-growing bronchioloalveolar tumors, although the difference was not statistically significant. If FDG PET is not available, the use of ²⁰¹ Tl to evaluate lung nodules in patients who refuse biopsy or are at risk for complications may be justified. A lung nodule that is positive with ²⁰¹ Tl should be excised or resected. Negative nodules or nodules that, because of their location or size, cannot be optimally evaluated should be followed clinically and with CT.

^99m Tc sestamibi is a lipophilic cation that passively accumulates in the cytoplasm and mitochondria driven by differential transmembrane potentials, as reported by Maublant and colleagues (1993). ^99m Tc sestamibi is a substrate for the transmembrane p-glycoprotein (Pgp) encoded in the multidrug resistance (MDR1) gene. The p-glycoprotein is found in adrenal glands, kidneys, luminal epithelium of colon, and sometimes lung. The Pgp is overexpressed in certain tumor cell lines and is responsible for the resistance to chemotherapy of tumors. This characteristic of ^99m Tc sestamibi received the attention of researchers hoping to develop a test to identify patients whose tumors are resistant to chemotherapeutic drugs that are also substrate of Pgp. A multidrug resistance-associated protein (MRP) was demonstrated in cells that do not express the MDR1 gene. The MRP is expressed in lung, testis, and peripheral mononuclear cells and in small cell lung cancer (SCLC) as well as non small cell lung cancer (NSCLC)-resistant cell lines.

Zhou and colleagues (2001) studied 34 lung cancer patients with ^99m Tc sestamibi SPECT and, after resection, analyzed the tumors by immunohistochemistry to assess the expression of Pgp, MRP, and lung resistance protein (LRP). The washout rate of ^99m Tc sestamibi in tumors expressing Pgp was higher than in the Pgp-negative tumors. The authors did not find a relation between the washout rate of ^99m Tc sestamibi and the expression of MRP or LRP.

Clinical studies by Dirlik and collaborators (2002) failed to provide definitive evidence that imaging studies can select out patients whose lung tumors expressed the multidrug resistance gene. This failure is expected in patients with SCLC who do not express the transmembrane glycoprotein whose substrate is ^99m Tc sestamibi. ^99m Tc sestamibi has limited use in evaluating patients with lung cancer, and at this time, the potential of this agent to select patients for alternative therapies has not been demonstrated.

Parathyroid adenomas can be readily identified using ²⁰¹ Tl or ^99m Tc sestamibi scintigraphy. Although most parathyroid adenomas can be localized at operation without the aid of imaging, preoperative localization of the lesion reduces the length of the procedure and on occasion detects adenomas in aberrant locations. It also allows the selection of patients for selective surgical intervention. Preoperative parathyroid imaging is advantageous for patients who had recurrent or persistent hyperparathyroidism after parathyroidectomy.

The study can be performed by obtaining images of the neck and mediastinum 15 minutes after injection followed by delayed 2 hours images, or by using thyroid subtraction with simultaneous iodine 123 (¹²³ I) thyroid imaging. Normal

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Scintigraphy cannot determine whether the adenoma originates from the superior or inferior parathyroid gland, but it can indicate the adenoma location in relation to the thyroid gland. SPECT is important for the detection and localization of mediastinal adenomas (Fig. 13-4). In these cases, correlation with magnetic resonance (MR) imaging is desirable before proceeding with operation. The use of gamma handheld probes during the surgical procedure can be helpful in certain cases of recurrent hyperparathyroidism and for small aberrant lesions whose location is unclear. If the patient had implantation of parathyroid tissue, in addition to evaluation of the neck and chest, the site of implantation should be imaged to determine the viability of the implant.

Active accumulation of the ^99m Tc sestamibi is also found in benign and malignant thyroid nodules, lung tumors, metastatic lymph nodes, sarcoid, and other active granulomas. Extravasated ^99m Tc sestamibi at the injection site accounts for visualization of normal axillary lymph nodes. Persistent tracer retention along the venous tracks is a common occurrence and may mimic a mediastinal abnormality. To avoid these pitfalls, the radiotracer should be injected in a foot vein.

False-negative studies happen with small lesions or lesions located near another radioactive structure and in suboptimal studies in which no delayed images or SPECT were obtained. Kao and co-workers (2002) evaluated 47 patients with parathyroid adenomas larger than 1.5 g. In 8 patients, ^99m Tc sestamibi scintigraphy failed to detect parathyroid adenomas. All the nonvisualized adenomas expressed Pgp or MRP, responsible for the extrusion of ^99m Tc sestamibi. The other 39 detected adenomas did not expressed Pgp or MRP.

Somatostatin Receptor Scintigraphy

SST, a 14 or 28 amino acid peptide found in the hypothalamus, cerebral cortex, brainstem, gastrointestinal tract, and pancreas, is a neurotransmitter in the central nervous system and in the gastrointestinal tract with inhibitory hormonal actions on growth hormone, insulin, glucagon, gastrin, serotonin, and calcitonin. SST has an antiproliferative effect on tumors by inhibiting growth and the release of growth factors, hormones, and angiogenesis. It also has an inhibitory effect on inflammatory cells and acts as an immunomodulator. There are at least five SST receptors subtypes, variously expressed in normal tissues and neuroendocrine tumors. These receptors are also present in other nonneuroendocrine tumors in the brain, breast, lungs, lymphomas, and activated lymphocytes.

Octreotide is an 8 amino acid analog of SST that has affinity for the SST receptor subtype 2 and less so for subtypes 3 and 5 and no significant affinity for types 1 and 4. A radiolabeled form of octreotide, indium 11 (¹¹¹ In) octreotide, is used for imaging of neuroendocrine tumors. ¹¹¹ In octreotide planar and SPECT scintigraphy is performed 4, 24, and 48 hours after the administration. The tracer accumulates in organs that express SST receptor, including the pituitary, thyroid, spleen, and excretory organs and the liver, kidneys, and bladder. Octreotide is partially reabsorbed in the kidneys, explaining the often obtrusive intense persistent renal activity. The hepatobiliary excretion results in bowel activity and occasionally gallbladder visualization. Nonspecific activity of ¹¹¹ In octreotide is seen in wounds, in healing surgical incisions, and after radiation therapy.

To date, no significant clinical advantage for lung tumor detection or staging has been demonstrated with depreotide, another SST analog labeled with ^99m Tc that has affinity for the subtype STT receptor 3, thus enabling imaging of tumors that do not express the subtype 2 receptor.

Some nonneuroendocrine tumors, Hodgkin's and non Hodgkin's lymphomas, breast and thyroid cancers, and sarcomas express STT receptors and are detectable with radioactive octreotide, whereas others tumors, such as glioblastomas, NSCLC, exocrine pancreatic tumors, and squamous cell cancer, lack SST receptors. Reubi and collaborators (1996) investigated the expression of SST and vasoactive intestinal peptide (VIP) receptors in mesenchymal tumors. SST receptors were consistently found in cells derived from bone and vessels, particularly highly cellular, poorly differentiated osteosarcomas, but not in osteoid-forming, highly differentiated tumors. SST receptors are also present in angiosarcomas and hemangiopericytomas, in some muscle tumors, and in synovial sarcomas. No receptors were

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Kwekkeboom and colleagues (1994) reported that despite the lack of SST receptors in NSCLC cells, ¹¹¹ In octreotide scintigraphy was positive in 40 patients due to activated lymphocytes and leukocytes around the tumor. Granulomatous and autoimmune conditions express SST receptors and are detectable by SST analogue scintigraphy, accounting for false-positive results in the investigation of malignancies.

The value of imaging tumors with this agent resides not only in the actual localization of the tumor and metastases but also in the ability to evaluate therapeutic response and to select patients for receptor-based therapy. Moertel and colleagues (1994) reported that demonstration of STT receptors might have prognostic value in patients with lung tumors or metastatic neuroendocrine, epithelial, and mesenchymal tumors.

Lung tumors with neuroendocrine characteristics include typical and atypical carcinoids (low- and intermediate-grade carcinomas), large cell carcinomas (high-grade carcinomas), and SCLC. The value of octreotide imaging is to locate, diagnose, stage, and plan therapy for these tumors (Fig. 13-5). Although the tumors are often treated surgically and with chemotherapy or radiation therapy, therapy with octreotide and other SST analogues is becoming more frequent for advanced disease. The demonstration of STT receptors by imaging is therefore important before considering therapy with radioactive STT analogs.

¹¹¹ In octreotide scintigraphy detects more than 80% of the primary SCLC tumors. Kwekkeboom and co-workers (1994) reported that 25 of 26 cases of SCLC were detected by octreotide. In their experience, mediastinal lymphadenopathy and brain metastases were consistently identified. However, lesions in the liver, bone marrow, and adrenals were missed in 14 of 20 patients, owing to the high accumulation of tracer in the kidneys and liver. Octreotide scintigraphy upstaged 5 of 14 nontreated patients from limited to extensive disease.

The role of STT analogue scintigraphy in staging lung cancer is limited owing to the poor spatial resolution common to most gamma imaging procedures. Ongoing research by Ugur and colleagues (2002), using STT analogue labeled with the positron emitters ⁶⁸ Ga or ⁶⁶ Ga, is intended to combine the specificity of STT with the higher spatial resolution of PET.

Iodine 123 Metaiodobenzylguanidine Scintigraphy

The use of ¹²³ I metaiodobenzylguanidine (MIBG) scintigraphy in the evaluation of patients with paragangliomas and pheochromocytomas of the mediastinum is discussed in full in Chapter 191.

RADIONUCLIDE EVALUATION OF THE THYMUS

The thymus is rarely visualized during scintigraphic studies. Benign thymic enlargement or thymic rebound in children and young adults has been reported with ⁶⁷ Ga, ²⁰¹ Tl, and with FDG following radiation therapy or chemotherapy. It may be seen with hyperthyroidism and was also reported by Michigishi and co-workers (1993) to occur after large doses of radioiodine in patients with thyroid cancer.

Higuchi and co-workers (2001) compared ²⁰¹ Tl scintigraphy in 46 myasthenia gravis patients with histopathologic results after thymectomy. All 11 patients with thymoma had accumulation of ²⁰¹ Tl in the tumors both early on and with delayed imaging. Fifteen of 16 patients with lymphoid follicular hyperplasia had positive scans on delayed images; in only 6 patients was there early tumor uptake. Of the 19 patients with normal thymus, 3 had minimal ²⁰¹ Tl uptake on delayed images. Thallium scintigraphy cannot differentiate benign thymic enlargement from thymomas.

Taking into consideration that normal thymus expresses SST receptors, Lastoria and co-workers (1998) used ¹¹¹ In octreotide to detect thymomas. The study was positive in all thymomas, in one thymic carcinoid, and a thymic carcinoma. The authors concluded that since ¹¹¹ In octreotide does not accumulate in thymic hyperplasia, it should be ideal to differentiate between benign hyperplasia and malignancies.

RADIONUCLIDE EVALUATION OF THE THYROID

Evaluation of thyroid tissue should be performed always with radioactive iodine, preferable ¹²³ I, which has ideal

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Surgical removal of large compressive multinodular goiters with or without retrosternal extension is frequently offered for immediate relief of symptoms. An alternative to achieve size reduction for this condition is radioactive ¹³¹ I therapy. The beneficial effect of the radioiodine is not evident for several months, but significant size reduction can be obtained. Patients who refuse surgical removal, elderly and other high-risk patients, and those that had a previous thyroid resection and have recurrent goiter enlargement and symptoms may benefit from this therapy.

Discovery of a nonfunctioning (cold) dominant nodule should alert one to the possibility of malignancy. A biopsy may be then indicated, and thyroidectomy should be performed if the nodule is malignant. Iodinated contrast should be avoided during the preoperative evaluation of thyroid patients because the resulting iodine overload interferes with the diagnostic and therapeutic use of radioiodine. If the patient received iodinated contrast, the radioiodine procedure should be postponed for 4 to 6 weeks.

Huysmans and co-workers (1994), studying a small group of patients with substernal goiters, reported reductions of 26% to 65% in the pretherapy size. Symptomatic relief was achieved about 3 months after therapy. There were no instances of exacerbation of compressive symptoms during the immediate posttherapy follow-up. The most common side effect of radioiodine therapy is hypothyroidism. In this study, the patients were treated with thyroid hormone replacement after radioiodine, and the authors did not report the actual incidence of hypothyroidism.

The therapeutic doses of ¹³¹ I, ranging from 20 to 100 mCi (74 to 370 MBq), are calculated based on the goiter size and the degree of iodine uptake. Hyperthyroidism is not a contraindication for radioiodine treatment but an effort to control hyperthyroidism before therapy is advisable. Patients receiving therapeutic doses of radioiodine should be medicated with a -blocker for symptomatic control of thyrotoxicosis induced by radiation thyroiditis. Poor radioactive iodine uptake by the goiter may be a limitation of the use of radioiodine if the resulting calculated dose of ¹³¹ I is exceedingly high. In these cases, stimulation of radioiodine uptake using recombinant human thyroid-stimulating hormone may have a role.

SURGICAL APPLICATIONS OF RADIONUCLIDE TRACER METHODOLOGY

Preoperative Lung Scintigraphy

It is accepted that perfusion scans closely reflect lung function and can replace ¹³³ Xe or ^81m Kr to predict residual lung function after pneumonectomy. Olsen (1974), Boysen (1977), Ali (1980), Wernly (1980), and Corris (1987) and their co-workers have found good correlation between the scintigraphic prediction of postoperative lung function and the postsurgical patient performance. The predictive value, however, is less accurate in patients undergoing lobectomy because of the anatomic limitations in estimating the contribution of individual pulmonary lobes to the overall lung perfusion.

The procedure requires an anterior and posterior image of the lungs after injecting ^99m Tc MAA. Regions of interest are drawn around each lung, the total combined lung activity is recorded, and the contribution of each lung is expressed as a fraction of the total lung activity (Fig. 13-7). The calculated

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Scintigraphy of the lungs is useful to select regions with poor perfusion and prolonged retention of radioactive gas for surgical resection. Quantitative lung studies before lung volume reduction surgery (LVRS) for emphysema are performed with both ventilation and perfusion scintigraphy. Scintigraphy can differentiate upper lung centroacinar and panacinar emphysema preferentially affecting the lower lobes from diffuse lung involvement (Fig. 13-8). Wang and collaborators (1997) evaluated the prognostic value of perfusion scintigraphy and found that the scintigraphic study

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INTRAOPERATIVE PROCEDURES

The rapid acceptance of intraoperative handheld gamma detectors for sentinel lymph node localization in breast cancer and melanoma has stimulated the use of this survey technique for other indications. The handheld probe detector is sensible to gamma rays, and specially designed probes can also detect beta emissions. The solid-state scintillation detector probe is connected through a flexible fiberoptic cable to the photomultiplier tube and appropriate electronics, including a digital display and an audible signal that changes pitch according to the intensity of the radioactivity. The probe should be selected according to the intended clinical use, the type of radiotracer [i.e., ^99m Tc, ¹¹¹ In, ¹²⁵ I, fluorine 18 (¹⁸ F)], the type of emission (gamma rays vs. beta particles), and the accessibility of the area of interest. The radioactivity detected by the probe, expressed in number of counts per second (cps) or minute (cpm), is corrected by the background radioactivity. Spots with net count rates higher than 3 standard deviations of background activity are considered true findings.

Gamma rays can be detected at a distance from the source of radioactivity. Therefore, the radioactivity deposited at the injection site can interfere with the survey of less active targets if it is seen by the detector. To avoid this problem, the probe should be shielded from gamma rays coming at undesirable angles, and when in use, the face of the detector should always be directed away from the injection site. Accurate detection is obtained when the face of the probe is perpendicular to the source of activity and at close range. Sweeping movements of the probe are ineffectual because fewer counts will be recorded and the origin of the radioactivity cannot be accurately determined.

Raylman and Wahl (1994) designed and built a positron-sensitive surgical probe with high sensitivity for positron detection at nanocurie levels (10-26 millicurie). Daghighian and co-workers (1994) tested in phantoms a dual-detector probe selectively sensitive for beta radiation and insensitive to gamma rays (Fig. 13-9; see Color Fig. 13-9). The study showed good sensitivity for ¹³¹ I and ¹⁸ F. During the operative procedure, the use of beta-particle emitters (electrons or positrons) can be more accurate for detection of lesions with almost no significant interference from other sources of radioactivity thanks to the short distance that electrons travel in biological tissues. However, the short range of beta particles (maximum positron range in tissue for ¹⁸ F is 2.6 mm) requires that the detector probe be in close contact with the tissue being surveyed and is better fitted for superficial lesions. Essner and collaborators (2001) successfully evaluated the intraoperative use of an ¹⁸ F-sensitive probe in patients with melanoma and colorectal cancer, 2 hours after injection of FDG.

The tracer can be introduced by direct tumor injection, subcutaneous injection, or intravascular administration. Subdermic injection of radiocolloids is widely used in breast cancer to detect sentinel lymph nodes and in melanoma to determine the draining basin for lymph nodes removal. Waddington and collaborators (2000) reported the radioactivity in sentinel nodes to be 0.96% 1.33% of the dose injected in the breast. This fraction may be different for other conditions but illustrates the small level of radioactivity that the surgeon will be tracking with the probe.

Bethune and co-workers (1978) reported scintigraphic studies in 43 patients after bronchoscopic mediastinal injection of colloidal gold 198 (¹⁹⁸ Au; particle size, 0.01 to 0.05 m), ^99m Tc sulfur colloid (particle size, 2.0 to 0.2 m) or ^99m Tc antimony sulfide (particle size, 0.005 to 0.015 m). The best results were obtained with the smaller particles of antimony sulfide. The study reports ipsilateral ascending clearance to regional lymph nodes in 47.5% of cases, contralateral

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Detecting the pattern of lymphatic drainage from the tumor should improve the staging of lung cancer and offer a functional, as opposed to anatomic, definition of target lymph nodes. Limited research has been done in the use of intraoperative probes in lung cancer for lymph node detection. The expected spread of disease from intralobar to hilar to ipsilateral mediastinal lymph nodes may not always be seen. Investigating 110 NSCLC patients, Yoshino and co-workers (1996) found that 23% patients had skip metastases. The 5-year survival rate for these patients was better than for patients with the expected sequential pattern of lymph node involvement. (See Chapter 6 for a detailed discussion of lymphatic drainage and skip metastasis.)

Liptay and collaborators (2002) demonstrated the value of intraoperative detection of sentinel lymph nodes in NSCLC patients. These authors studied 100 patients with NSCLC after peritumoral injection of ^99m Tc sulfur colloid during the operative procedure. The migration of the colloid from the tumor to the lymph nodes station took a minimum of 10 to 30 minutes. In their original report on 52 patients, however, Liptay and associates (2000) had noted an average delay of 63 minutes (range, 23 to 170 minutes). This discrepancy may be explained by the eventual improvement in injection technique and the better use of the probe to detect early signs of radioactivity in the lymph nodes.

Delayed clearance of the injected radiocolloid depends on the volume of tracer injected, the injection site (i.e., peritumoral or intratumoral), and the size of the radiocolloid particles. Another likely factor in the study of Liptay and co-workers (2002) was the reduction of the total amount of radioactivity injected (2,000 Ci vs. 250 Ci) in the second group of patients. As the authors pointed out, the large doses of radioactivity injected in the initial group of patients interfered with the detection of early radioactivity in the lymph nodes. Successful migration of the tracer was seen in 86% of the cases. Lack of tracer migration may be related to the presence of necrosis, extensive tumor involvement of lymphatics, or replacement of lymph nodes by tumor. Finally, the failure to recognize a radioactive lymph node can result from improper background determination or wrong detector settings.

Liptay and co-workers (2002) found the mapping technique accurate for the detection of the first line lymph node. They found 20.5% skip metastases in subcarinal, paratracheal, and aortopulmonary window lymph nodes. In 9 of 21 skip nodes with metastases, the sentinel node was the only metastatic lymph node. More significant in their study was the finding of micrometastases in 7 of the 9 lymph nodes or 9% of the 78 sentinel lymph nodes detected.*

Specific targeting of tumors using monoclonal antibodies, octreotide, or other SST analogues or even less specific agents helps to select good candidates for intraoperative localization. The intravenous administration of these tracers the day before surgery allows for preoperative scintigraphic evaluation. Higher background activity can be limiting near organs that excrete or retain the tracer, for example, liver, bowel, and kidneys.

Rodriguez and collaborators (2002) used ¹¹¹ In octreotide and a handheld detector to locate intraoperatively a bronchial carcinoid and to survey the operative bed for residual tumor tissue after removal of the tumor. This approach can be used for lesions that express SST receptors and are visualized during octreotide scintigraphy. The intraoperative detection can be done using the residual radioactivity in the lesion 2 days after scintigraphy. The time delay allows for better target-to-background ratios and facilitates accurate detection of the tumor.

Medullary thyroid cancer metastases can be seen with variable success with ¹³¹ I or ¹²³ I MIBG and with octreotide scintigraphy. At the time of the procedure, however, it may be difficult to ensure that all the lesions shown on the scintigraphic study are removed. Handheld gamma probes in these cases could be useful to mapping the area where scintigraphy showed lesions and to locate other lesions not detected by external imaging.

Radioiodine scintigraphy is not helpful when the metastases from differentiated thyroid cancers fail to accumulate radioiodine. In those cases, ²⁰¹ Tl, ^99m Tc sestamibi, or FDG is used for imaging. Because these tumors respond poorly to chemotherapy, surgical excision is the preferred therapy whenever possible. Intraoperative radioguided detection with any of these agents can facilitate tumor localization and allow the survey of the area for other unsuspected hot spots.

RADIATION ISSUES

The surgeon and other operating room personnel will be exposed to low levels of radiation. At the injection site, the maximum exposure rate to the surgeon's fingers, assuming 1 mCi of ^99m Tc injected 4 hours prior surgery, would be 50 mrem/h. The surgeon's body, at 30 cm distance, would receive 0.5 mrem/h. Other personnel may be exposed to levels equal to or lower than the surgeon. The significance of these exposure estimates is better appreciated when compared with the maximum allowable exposures recommended by the U.S. Nuclear Regulatory Commission,

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Control of operating room contamination is done by monitoring the level of contamination with radiation detectors and segregating heavily contaminated items. These items could be stored to allow radioactive decay before they are released for cleaning. Specimens for pathology should be labeled as caution radioactive material. Samples containing high radioactivity should be let decay for 8 physical half-lives of the radioisotope before processing or disposal. Samples contaminated with ^99m Tc (half-life or 6 hours), for example, should be stored for 48 hours before processing. Heavy contamination, however, is unlikely for most radio-guided applications requiring radioactivity in the microcurie range.

POSTOPERATIVE USES

Bone Scan

Nuclear medicine procedures are requested to evaluate infections, PE, metastatic disease, and recurrent tumor. Bone scans using ^99m Tc diphosphonates, are routinely requested during the follow-up of cancer patients. Early metastatic involvement can at times be difficult to establish with bone scintigraphy, and MR imaging should then be considered for diagnosis. Solitary bone lesions can be difficult to characterize and require additional imaging, preferably with MR or a biopsy.

Air Leaks

Ventilation scintigraphy with ¹³³ Xe has been used in the detection of air leaks, as Unterreiner and Weiss (2001) reported in a patient with emphysema. The use of radioaerosols has been proposed in the postoperative period to evaluate early signs of alveolocapillary membrane damage by performing a baseline study to be followed with repeated studies at later times for comparison.

Lymphoscintigraphy and Chylothorax

Lymphoscintigraphy using radiocolloids is occasionally needed for evaluation of lymphedema, lymphoceles, and other chylous collections. Chylothorax can result from surgical or nonsurgical injury of the thoracic duct or lymphatics, from obstruction at the thoracic duct jugular subclavian vein confluence, or from other neoplastic, inflammatory, or congenital causes. In patients with acquired immunodeficiency syndrome (AIDS), chylothorax may be a complication of Kaposi's sarcoma or tuberculosis.

Evaluation of these patients for the presence of chylous collections is commonly done with CT. However, the level of injury may be impossible to determine even with lymphangiography, CT, or MR imaging. Sun and co-workers (2000), using ^99m Tc sulfur colloid lymphoscintigraphy, localized the level of lymphatic leakage and the subsequent resolution after thoracic duct ligature in traumatic chylothorax. Ogi and collaborators (2002) used ^99m Tc human serum albumin-DTPA injected in the dorsum of both feet to demonstrated chylothorax after transthoracic esophagectomy. Lymphoscintigraphy requires careful, prolonged imaging of the body after subdermic injection of a radiocolloid in the extremities. Injections in the lower extremities drain into the thoracic duct. The study can be complemented with a radionuclide venogram of both arms to evaluate the left jugular subclavian confluence. Thoracic duct scintigraphy with radiocolloids may be useful for the noninvasive diagnosis of lymphatic leakage and to document resolution. Octreotide has been proposed and used in the treatment of postsurgical chylothorax.

Long-chain fatty acids or fatty acid analogues administered orally are absorbed from the intestine directly into the lymphatics and thoracic duct and are potential agents for thoracic duct scintigraphy. Qureshy and co-workers (2001)

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Acute Infections

Acute infections can be localized with ¹¹¹ In-labeled leukocytes, ^99m Tc labeled-leukocytes, or ⁶⁷ Ga citrate (see Fig. 13-10), whereas lower-grade and chronic recurrent infections are better studied with ¹¹¹ In leukocytes or with ⁶⁷ Ga citrate. Whole-body imaging should be performed in all cases, followed by SPECT of the suspicious areas. In these cases, as in any other diagnostic use of radionuclides, the study should be approached with the necessary clinical knowledge and complete understanding of the physiopathology and of radiotracers and instrumentation.

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*It should be noted that the significance of the presence of occult micrometastatic disease in bronchopulmonary or mediastinal lymph nodes in patients with lung cancer remains controversial. Whether its presence represents true N₁ and N₂ disease remains to be determined. (See section on Occult Micrometastatic Disease in Chapter 101.) TW Shields, Senior Editor