Modern diagnostic methods in endocrinology
The widely used diagnostic methods used in modern medicine, such as computed tomography (CT) and nuclear magnetic resonance (NMR), have now become routine. A new, promising diagnostic method that has appeared recently. is positron emission tomography (PET).
PET is one of the newest methods for diagnosing diseases in modern medicine. The principle of PET is based on the registration of two gamma-quantum particles with an energy of 511 keV, emitted in opposite directions, as a result of the annihilating interaction of a positron and an electron. The simultaneous registration of these particles triggers the trigger mechanism of the matching signals. These coincidences are converted into tomographic images using mathematical reconstruction techniques, forming a three-dimensional quantitative map of the distribution of the radioactive indicator in the human body. The PET procedure includes two types of scans. The emission scan reflects the emission of a gamma-quantum from the body after injection of a radiopharmaceutical (RFP). Weak scan, resembling a low-resolution tomographic scan, used to correct gamma-ray distribution within organs.
Modern PET scanners have a theoretical resolution of 3-4 mm. In clinical practice, the minimum resolution is 5-10 mm. Diagnosis of smaller lesions is unreliable.
For PET examinations, radiopharmaceuticals labeled in the cyclotron with positronactive isotopes are used. Some radiopharmaceuticals penetrate cells through transporters and are involved in cell metabolism (type 18P). Other positron-emitting radionuclides (type 11C) are included without changing the molecular structure of the cell. All radiopharmaceuticals are subdivided into short-lived (11C-, 15O-, 13K-labeled drugs), requiring immediate use after synthesis, and drugs with a longer half-life (type 18P) that do not require mandatory isotope production the day before. The advantage of short-lived isotopes compared to other radiopharmaceuticals is that their use even in relatively large doses is safe for patients. In addition, radiopharmaceuticals are synthesized with high specific activity, and therefore the compositions of these drugs can be used in doses that do not have pharmacological effects.
The most frequent radiopharmaceuticals used in PET are ^ labeled 2-Aiogo ^ eohu-P ^ 1so8e (18P-REO). Penetration of 18P-RES into the cell occurs via the glucose transfer mechanism. After phosphorylation, the further metabolism of the radiopharmaceutical is stopped, because 18R-REO is not a substance for the next stage of the exchange. This leads to the accumulation of radiopharmaceuticals inside the cell ("metabolic trap"). The rate of excretion of phosphorylated 18P-REO is very low, therefore, in tumor cells (due to the increased need for glucose) it accumulates to a greater extent than in healthy ones, which is a differential diagnostic criterion. Other approaches to "visualize" tumors with PET are based on pathophysiological features common to most malignant tumors, such as: local blood flow (15O-labeled water, 13K-labeled ammonia), cell proliferation or DNA synthesis (11C-choline, 11C- thi-midine, 18P-fluorinated thymidine), protein synthesis (11C-alpha-amino-gamma-methylthiobutyric acid, 11C-tyrosine), hypoxia (18P-fluoromezonidazole), angiogenesis (18P-galacto-arginine-glycine-aspartic acid) and apoptosis (18P-annexin). However, none of the approaches allows for the specific diagnosis of endocrine tumors. Recently developed methods for diagnosing pheochromocytoma and carcinoid tumors with PET are based on sensitivity to the amine precursor and the decarboxylation pathway characteristic of these tumors. Thus, 6-18P-fluorodopamine enters the pheochromocytoma cell through catecholamine transporters, then concentrates in vesicles of the reticular network. Similarly, 11C-hydroxytryptophan is captured by carcinoid tumor cells, decarboxylated and accumulated as 11C-serotonin. Another possibility for the "visualization" of endocrine tumors using PET is the combination of radiopharmaceuticals with cell receptors. So 11C-estradiol is attached to nuclear receptors, and 1111n-octreatid - to cell membrane receptors. The presence of certain nuclear receptors provides the potential for the development of PET in the diagnosis of endocrine tumors.
Compared with CT and NMR, PET has advantages, allowing you to explore the physiological and pathophysiological mechanisms of cell metabolism, tissue perfusion, protein and DNA synthesis, and in endocrinology - a study of the synthesis, storage, metabolism of hormones and receptors to them.
Topical diagnostics of endocrine tumors. cancer of the thyroid gland
An important problem in modern thyroidology is the detection of relapses and metastases of differentiated thyroid cancer (RSD) after primary and ablative therapy. The main role in the diagnosis of postoperative recurrence and metastasis HERCHZH belongs to the whole body scintigraphy (SVT) from 1311 or 1231. However, only 60-80% of the total number of relapses are visualized using scintigraphy 1311. The use of other methods of examination (radionuclide tumor-specific scintigrams we) until they became mandatory due to their different sensitivity. In a direct comparison of these methods, PET showed much better diagnostic results than CBT with 99Tc-MIBI. This has been confirmed in studies of many of the world's leading centers for the treatment of CHR.
Serum thyroglobulin (TG) values in patients with PCA after thyroidectomy carry important information in the diagnosis of cancer recurrence or metastasis. Patients with baseline or stimulated TSH with a TG level of less than 2 ng / ml do not require CBT with radioactive iodine and remain under regular dynamic control. Patients with a TG level above 2 ng / ml, as well as patients whose TG level cannot be adequately interpreted, are shown to undergo scintigraphy with 131I or 123I.
Postoperative relapses or metastases in the cervical lymph nodes are detected in about 20% of patients with TPTTX. Radioactive iodine CTB in 1/3 of cases does not allow detecting a tumor due to lack of susceptibility to RFP or small size of the tumor. Anatomical deformation of the tissue prior to surgery may lead to incorrect interpretation of the results of CT and NMR. The use of PET with 18F-FDG in such patients allows detecting residual tumor, relapse or metastasis in 82-95% of cases. In addition, PET with 18F-FDG makes it possible to detect recurrences and metastases of cancer from Hurthle cells that are difficult to diagnose using radioactive iodine scintigraphy.
PET studies using 18F-FDG in patients with PChD are not without problems. So, it is not clear whether tumor capture 18F-FDG improves with elevated TSH compared to depressed. Sisson et al described an increased 18F-FDG accumulation by a tumor in a patient with confirmed PCA metastasis during stimulation of TSH compared with no accumulation without it (with euthyresis). Other works, in particular, Grunwald et al. and Wang et al., were unable to detect significant differences in the results of PET with TSH stimulation and suppression in the same patient. Petrich et al. it has been shown that 18F-FDG accumulates better in a tumor during exogenous stimulation with recombinant TSH. Moog et al described the best accumulation of 18F-FDG in 3 patients in a group of 10 patients with endogenous stimulation, suggesting it for PET. These examples show that the question of the dependence of the sensitivity of PET on the level of TSH in patients with TPTTX remains unsolved.
There is no data on primary diagnosis using PET with 18F-FDG after a histologically detected PChD according to the results of TAB for the detection of primary metastasis before the operation and PHr currently. However, works describing randomly found "hot" 18F-FDG-foci in the thyroid gland (TG) (incidentalomas), with the beginning of widespread use of PET in oncology, appear quite regularly. For the first time such data were published by Van den Bruel et al. In this work, 8 incidents were investigated, which were subsequently recorded as thyroid nodes during ultrasound. All of them were punctured and seven of them were deemed suspicious by the results of a preliminary analysis, which led to surgical treatment. The final tests confirmed malignant tumors in 5 of them: 2 medullary and 3 papillary thyroid carcinomas. In two patients, a final histological examination of "hot" 18F-FDG foci revealed benign growths.
These results suggest that increased accumulation of 18F-FDG is not always associated with tumors, but it happens with local thyroiditis, active adenomas, lymphadenitis, fetal fat, and even physiologically reduced neck muscles can lead to increased accumulation. With a suspicious analysis of the TAB of the thyroid gland and ambiguous results obtained by other methods, the final diagnosis can still be obtained only with the help of surgical intervention.
Thus, summing up the above, the General Conference of Endocrinologists and Radiologists recommends the use of PET with 18F-FDG as a routine study for detecting radioiodine-negative DRS metastasis, and for radioiodine-recurrent relapses as a clinically appropriate study. The use of PET for staging RSD in risk patients with relapses / metastases that do not accumulate 131I with an elevated TG level in the case of the "Shr-Aor" phenomenon (mismatch between accumulation of 131I and 18F-FDG tumor foci) was detailed in detail by U. Feine . The findings of this survey allowed us to consolidate the indications for the use of PET in high-risk patients over the age of 40 years with progressive or metastatic PCA, as well as with a primary low tumor differentiation. The indications for PET include control after adjuvant therapy with 13-cis-retinolic acid (for the purpose of redifferentiation of the tumor), which is carried out and constantly modified in the leading centers of the Federal Republic of Germany for the treatment of thyroid cancer. This method pays great attention to the publications of research groups Simon D. and Grunwald F. This treatment leads to an increase in the ability of tumor tissues to capture iodine, which makes it possible to subject them to usual RIT sessions.
PET scan with 18F-FDG is carried out with other thyroid malignant neoplasms. Data on PET scanning in anaplastic cancer are rare and there are no complete studies yet. Medullary thyroid cancer due to hypermetabolic state of the tumor is promising in the diagnosis using PET scan, especially in patients after surgery with high levels of basal and / or stimulated calcitonin.
Most adrenocortical tumors detected by CT or NMR performed for other reasons (incidentalomas) are benign. However, adrenocortical cancer and metastases of malignant tumors of other organs are not uncommon. In the diagnosis of adrenocortical tumors, laboratory methods, ultrasound, CT and NMR always precede radioisotope research methods.
CT based on calculated data on tissue density allows differentiation of adrenal adenomas from metastases. Tumor density less than 10 HU without contrast is most likely to indicate an adrenal gland rich in lipids. If the tumor is non-homogenous or has a density of more than 10 HU - the diagnosis is questionable. It is most likely an adenoma, but it is necessary to differentiate from other tumors of the adrenal gland or metastases from other organs. In this connection, the next step is the study with contrast. The standard is a CT image of the adrenal glands, obtained 60 seconds after the introduction of contrast. Adenomas lose contrast faster than non-adenomas. If 15 minutes after the injection of the contrast, the tumor density is less than 30-40 AI, or the tumor loses more than 60% of the contrast from the initial accumulation, then it is most likely adenomas.
NMR also helps to differentiate adrenal gland adenomas from metastases. The method is based on the different intensity of the signals of hydrogen atoms in the molecules of lipids and water. The intensity of the signals is low for tissues containing both water and lipids, compared with tissues that do not contain lipids at all.
Scintigraphy with 1311-6 / 3-iodomethylcholesterol is used to study adrenocortical tumors. RFP interacts with low-density lipoproteins and receptors of adrenal cortex cells and specifically accumulates in fat droplets inside adrenocortical cells. Scintigraphy with 1311-6 / 3-iodomethylcholesterol has almost 100 percent specificity and acceptable sensitivity (70%) in the diagnosis of benign functioning adrenal adenomas from other adrenocortical tumors, for formations of 2 cm or more. The use of this method in the study of the adrenal incident requires further study. The main limitations in the use of this method are long waiting periods (4-7 days) to obtain an adequate display of the adrenal tumor.
1111p-octreatide scintigraphy is highly sensitive for detecting adrenal tumors that cause hypercorticism (Cushing's syndrome). In addition, scintigraphy with 1111p-octreatide is used to localize tumors with ectopic production of ACTH. The feasibility of the study aldosterom 1111p-octreatide has not been studied.
Some radiopharmaceuticals used for PET can detect hyperactive adrenal cortex tumors more specifically than other methods. So, PS-e! O ^ a! E and 11C-sh! O ^ a! E allow differentiation of adrenocortical tumor from cancer metastasis of a different etiology. These radiopharmaceuticals interact with 11/3-hydroxylase, which is a key enzyme in the synthesis of aldosterone and cortisol. However, a study with IC-e! Oce and IC-te! O1c1a! E does not allow differentiation of benign and malignant formations of the adrenal cortex. This requires PET with 18P-GOO, which differentiates benign and malignant neoplasms with 95% accuracy.
Adrenocortical cancer is prognostically unfavorable due to the prevalence of the tumor in approximately 80% of cases. Anatomical deformities after surgical treatment make it difficult to interpret topical research methods. In this case, PET with 18P-RES displays hypermetabolic lesions, however, there are still no full-scale studies on large groups of patients.
Thus, in the study of tumors of the adrenal cortex, laboratory research, ultrasound, CT and NMR remain a priority. PET is mainly used for the differential diagnosis of malignant tumors and the search for metastatic lesions or continued growth after surgical treatment. PET examinations of the adrenal cortex with the help of other radiopharmaceuticals are still under study.
Diagnosis of chromaffin tumors of the adrenal and extra-adrenal localization is based on clinical and laboratory data. CT and NMR are generally accepted for the initial localization of these tumors. The sensitivity of these methods ranges from 75 to 100%, with extremely low specificity. NMR is more sensitive than CT in detection of paragangliomas.
A more specific diagnostic method is scintigraphy with 1311-metaiodobenzylguanidine (MIBG). MIBG does not bind to postsynaptic adrenergic receptors, therefore it can be used in relatively large doses. However, due to the slow elimination from non-muffle organs, adequate imaging is recorded within 48 hours. The interaction of MIBH with the cells of other organs (salivary glands, heart, liver, pancreas, spleen, gall bladder, kidneys and bladder) can cause difficulties in visualizing the tumor. Malignant chromaffinnom accumulate MIBG less benign, which, apparently, is associated with a reduced number of transporters of norepinephrine in less differentiated tumor cells. Less sensitive 1111n-octreatide and PET with 18P-REO can improve the detection of malignant chromaffin. 1111p-oct-reatide, as an analogue of somatostatin, interacts with somatostatin receptors of the tumor cell membrane.
The use of catecholamine transport specific for chromaffin tumors is based on the use of PET in the diagnosis of chromaffin. Radiopharmaceuticals such as 11C-hydroxyephedrine, 11C-adrenaline, 11C-phenylephedrine and 6-18P-fluorodopamine used in PET work the same as MIBG. The advantage of PET is that it allows you to "visualize" the tumor within a few minutes after the injection of radiopharmaceuticals with excellent resolution. In a recent study, PET with 6-18P-fluorodopamine showed 100% specificity in the diagnosis of chromaffin. Accumulations have been detected even in patients with negative MIBH scanning. One of the drawbacks of PET with 6-18P-fluorodopamine is the complexity of the preparation of the study, which significantly limits the use. The sensitivity of PET with 18Р-ГОО for solitary benign and malignant pheochromocytes was about 70%, PET with 18Р-fluoro-dihydrophenylalanine reached 100%, however all these results were obtained on a small number of patients and require additional study.
Summarizing the above, we can say that the use of PET in the diagnosis of chromaffin is used only in dubious and difficult diagnostic cases. Priority remains clinical, laboratory methods, CT, NMR and scintigraphy with MIBG.
Carcinoids and endocrine tumors of the pancreas
Carcinoids are tumors from enterochromaffin tissue cells. In a broad sense, under the carcinoids understand all endocrine tumors of the pancreas and gastrointestinal tract (apudoma), both functionally active and without hormonal secretion. Carcinoids are often difficult to diagnose, due to their small size and wide variety.
At the first stage of the diagnostic search, laboratory, endoscopic methods, ultrasound, CT and NMR are used. More than 70% of carcinoids contain somatostatin receptors. Using scintigraphy with 1111p-octreatide allows you to "visualize" these tumors. However, the small size of the tumors, as well as the absence of receptors in some carcinoids, leads to difficulties in the diagnostic search. The use of an intraoperative 1111p-octreatid scan using a u-probe is limited by the high-background RFP susceptibility of the liver, kidneys and spleen.
Scintigraphy with MIBH is even less sensitive compared to 1111p-octreatide, 50% and 67%, respectively, and for pancreatic tumors - 9% and 91%.
Carcinoids synthesize serotonin, therefore, PET imaging methods are based on radiopharmaceuticals - serotonin precursors. 11C-5-girdoxitryptophan is the best radiopharmaceutical, especially for tumors with localization in the jejunum. 18E-fluoro-dihydroxyphenylalanine, another precursor of amine, is also used in PET for the diagnosis of carcinoids. Its sensitivity is greater than 18E-EEC used to detect primary tumors and metastases.
The greatest difficulties are caused by the diagnosis of poorly differentiated carcinoids. PET in such patients often leads to negative or false positive results. For diagnosis, 18E-EEC is used, which is not able to visualize the majority of differentiated carcinoids. In addition, the diagnosis of metastatic carcinoid PET with 18E-EEC does not have great advantages over scanning with 1111p-octreatide.
In 90% of patients, solitary adenomas are the cause of primary hyperparathyroidism. Much less frequently, multiple adenomas and hyperplasia of the thyroid glands (OSS) occur. An important fact is the occurrence of primary hyperparathyroidism in syndromes of multiple endocrine neoplasias.
Pre-operative studies include laboratory methods, ultrasound with a sensitivity of just over 75% or CT / NMR with a sensitivity of about 70%. Preoperative detection of a tumor reduces the time of surgery and anesthesia, the size of the incision, tissue injury and the postoperative period.
Among scintigraphic methods for pre-operative diagnosis, a study with 99mTc-MIBI is used, with sensitivity ranging from 25-98%. The accumulation of 99mTc-MIBI is based on the local blood flow of OSS and seizure of radiopharmaceuticals in the cytoplasm and cell mitochondria. OXYL adenomas contain a large number of mitochondria in cells, so 99mTts-MIBI actively accumulates in adenomatous tissue, compared with the surrounding thyroid gland. The combination of ultrasound and scintigraphy improves diagnosis, but not always scintigraphy reveals all OCHD tumors.
A few hours after scintigraphy with 99tTs-MIBI, the intraoperative examination technique using a-probe makes it possible to detect an adenoma during surgery, and the combination with intraoperative ultrasound corrects multiple false positive results. Intraoperative monitoring of parathormone (PTH) before and after removal of the tumor adds a complete diagnostic approach.
PET scan allows to detect and localize primary adenomas of OCH. 11C-a-amino-y-methylthio-butyric acid - radiopharmaceuticals for PET with high specificity for paraadenes. 18E-EEC is also used. However, the use of these techniques is limited to cases of negative diagnosis using topical methods and scintigraphy. Studies comparing scinti-graphy with 99tTs-MIBI and PET were not conducted.
In cancer of OSS, good PET results with 18E-EES have been identified. This aggressive endocrine tumor actively captures 18E-EEC, indicating lesions not detected by other techniques.
Treatment of hypophysis
PET ligands used to diagnose pituitary tumors can detect pathology based on the metabolism of glucose by a tumor (18 E-EEC), protein synthesis (11C-tyrosine), and interaction with receptors (11C-deprenyl, ICC-TeShukr_reg-Ope, ). Such ligands are used to "visualize" various types of pituitary adenomas, to differentiate viable tumor tissue from fibrosis, necrosis, cystic degenerations, tumor recurrences from postoperative changes, to identify hormone-active sellary and extracellular tumors. However, none of the methods became widespread. NMR remains the method of choice for evaluating pituitary tumors. However, there are prospects for the use of PET in patients with pituitary adenomas to control the effectiveness of drug treatment with unchanged tumor sizes, as well as for the differential diagnosis of pituitary adenomas from other tumors of the chiasmically-related region.
Despite the significant cost of research, many insurance companies around the world compensate for the cost of PET scans for various types of cancer. American Pharmaceutical Committee approved the use of 18E-EEC for the diagnosis of all types of malignant tumors. The Nuclear Medicine Society recommends PET scanning with 18E-EEC to detect unknown primary tumors, differentiate malignant and benign neoplasms, determine staging of the disease, detect relapses and differentiate them from postoperative changes, and monitor treatment.
In the future, such approaches to the use of PET will become common in the diagnosis of endocrine tumors. So, now PET scan in patients with radioiodine-metastasis is a routine examination. For other endocrine tumors, such as pheochromocytoma, carcinoids, PET offers excellent visualization, but prospective studies have not yet verified diagnostic efficacy. The most important in these studies will be the comparison of PET with other methods of visualization of endocrine tumors, which ultimately should lead to improved diagnosis of diseases.
Future projects are aimed at continuing the study of the functional features of cells of endocrine organ tumors, and allow us now to "visualize" transporters, cell membranes, nuclear receptors, enzymes, and even gene expression. The use of functionally determined radiopharmaceuticals reflects a clearer clinical use of these substances in the diagnosis of diseases. A functionally defined approach in PET is a real, but still underdeveloped potential for diagnosing endocrine tumors, studying the characteristic features of cells, determining the likelihood of recurrence and metastasis, as well as determining methods of treatment and monitoring their effectiveness.