Clinical and morphological features of nodular thyroid lesions and tactical approaches to their surgical treatment

The dissertation is devoted to the clinical and morphological features of nodular thyroid lesions and to the substantiation of tactical approaches to their surgical treatment. On the basis of a retrospective analysis of twenty years of work at a surgical hospital, the dissertation examines changes in surgical tactics, the structure of morbidity, and the ratio of benign and malignant forms of nodular pathology. It explores the possibilities of preoperative verification by means of fine-needle aspiration biopsy, ultrasound examination of cervical lymph nodes, and determination of thyroglobulin in needle washout. A morphological analysis of genetically damaged thyrocytes using the micronucleus test was carried out, and the long-term results of the application of radioiodine therapy in the comprehensive treatment of thyroid diseases were evaluated.

The problem of diagnosis and treatment of patients with benign and malignant thyroid diseases is one of the most pressing issues in modern medicine. According to WHO data, the number of patients with this pathology is progressively increasing. The expected positive results of programmes aimed at eliminating iodine deficiency and micronutrient imbalance have not led to a significant decrease in the number of people with diffuse and nodular goiter. At present, the increase in the number of patients is largely due to nodular forms of goiter and differentiated cancer (V.G. Aristarkhov et al., 1997, 1998; T.D. Yevmenova, 2001; N.P. Volodchenko et al., 2003; V.I. Semikov, 2004). A number of researchers report a 4-5-fold increase over recent years in the number of patients with nodular thyroid diseases (L.A. Baranov et al., 1999; N.S. Gorbacheva, N.M. Amirova, 2002). In Moscow, within just two years the growth in the number of patients with nodular goiter amounted to 66% (M.B. Antsiferov et al., 1997). The rapid increase in the number of patients with nodular focal lesions of the thyroid gland requires, in view of the current situation, the development of new approaches aimed at addressing the emerging problem.

It must be acknowledged that the increase in the number of patients with thyroid nodules is due not only to a true rise in morbidity but also to improved diagnostics resulting from the widespread introduction of modern methods of investigation into medical practice. The detection rate of nodular lesions by ultrasound in patients examined for preventive purposes reaches 11% - 50% (N.S. Kuznetsov et al., 2003; S. Ezzat et al., 1994; A. Brander et al., 2000; B. Burguera, H. Gharib, 2000). Modern diagnostic methods and diagnostic systems have become widely disseminated and have prompted a reconsideration of the approach to choosing diagnostic and therapeutic tactics both for nodular goiter and for thyroid cancer (M.F. Zarivchatsky, 2001).

However, improvements in diagnostic imaging techniques do not resolve all the problems of thyroid pathology. The acute nature of the problem lies in the fact that malignant thyroid tumors, especially at early stages, masquerade as benign nodular diseases (R.V. Aristarkhov, 2002). According to pooled studies, cancer in nodular forms of goiter is diagnosed at a frequency ranging from 2.8% to 54.2% (E.A. Troshina, 2001). The relationship between malignant and benign processes in the thyroid gland remains the subject of ongoing debate, and the role of benign diseases in the genesis of cancer continues to be discussed (A.I. Paches, R.M. Propp, 1995; L.P. Kotelnikova et al., 1997; S.O. Podvyaznikov, 1999; S.V. Yaitsev, 2000; B.M. Anokhin et al., 2001; P.A. Kuznetsov et al., 2002; S.K. Grebe et al., 1995; F. Russo et al., 1997; E. Papini et al., 1998). The complexity and ambiguity of the scientific data published over the last twenty years do not allow the problem to be viewed simplistically. The attitude of physicians of various specialties toward nodular thyroid diseases remains ambiguous and sometimes opposing. There is no single universally accepted protocol for the examination and treatment of patients with nodular thyroid diseases. This is clearly confirmed by the results of questionnaire surveys of members of the European and American Thyroid Associations (F.N. Bennedbaek et al., 1999; S.J. Bonnema et al., 2000, 2002), as well as a recently conducted survey of Russian endocrinologists (G.A. Melnichenko, V.V. Fadeyev, 2003). To the question concerning diagnostic and therapeutic tactics in nodular thyroid diseases, numerous conflicting answers were obtained.

The greatest controversies concern the diagnosis and treatment of nodular goiter (E.A. Troshina, 2001). This is particularly significant now, when convincing evidence has emerged of an increase in the frequency of thyroid cancer in multinodular goiter. The pathological process in the thyroid gland is increasingly of a multinodular nature, and even when a solitary nodule is detected by palpation, a more thorough investigation often reveals smaller multiple lesions. The previously widespread belief in the low oncological risk of multinodular goiter is in fact not confirmed. Non-palpable ("occult") carcinomas exist, measuring no more than 1 cm in diameter, which may follow an aggressive course, manifesting in rapid metastasis. Such tumors are frequently concealed among numerous benign nodules in one or both lobes of the thyroid gland (A.M. Shulutko et al., 2002). Recognition of the existence not only of thyroid cancer against the background of multinodular goiter but also of multifocal growth of thyroid cancer is reflected in the introduction of the corresponding form of the disease into the WHO classification (TNM).

Studies of recent years have shown that conditions have now arisen (iodine deficiency, technogenic influences, the stimulating effect of goitrogens, reduced immunity) leading to the occurrence of cellular-level damage in the thyroid gland, the ultimate stage of which is disruption of the genome stability of thyrocytes and the formation of thyroid cancer (D.L. Learoyd et al., 2000; F. Moretti et al., 2000). Genome damage is often accompanied by chromosome breaks and can be visualized using the cytogenetic method of micronucleus analysis (W. Schmid, 1975; A.D. Durnev, S.B. Seredenin, 1998). It has previously been demonstrated experimentally that the micronucleus test on a model of rat follicular thyrocytes prestimulated for proliferation in vivo is an informative method for assessing the intensity of the effect of genotoxic agents on the thyroid parenchyma, allowing the cumulative effect of subthreshold doses of mutagens to be revealed (M.A. Gansburgsky, 2005; A.V. Pavlov et al., 2006). With regard to the further development of these studies, great interest is attached to evaluating the informativeness of counting thyrocytes containing micronuclei as one of the possible morphological criteria for the early detection and differential diagnosis of nodular thyroid lesions.

The early recognition of thyroid cancer, especially against the background of multinodular goiter, presents considerable difficulties. None of the existing methods of investigation reliably differentiates between benign and malignant thyroid diseases. The solution is seen in a comprehensive assessment of the changes occurring in the body as a whole. In thyroid cancer, changes first occur in the nearby organs and tissues. It is changes on the part of the trachea, esophagus, lymphatic vessels and nodes that are often the first signals of trouble in the thyroid gland.

Changes in cervical lymph nodes in thyroid diseases are noted by many researchers, primarily specialists in ultrasound diagnostics (V.S. Parshin, 2002). The descriptive nature of most studies does not permit clear recommendations to be given on the use of ultrasound diagnostic data of the cervical lymphatic apparatus. At the same time, on the basis of examination of the cervical lymph nodes alone, clear verification of recurrent thyroid cancer or a metastatic process is possible. The capabilities are significantly enhanced when a set of complementary diagnostic techniques is used (V.A. Goldobin, 2004).

The choice of treatment method for nodular thyroid diseases and thyroid cancer represents one of the most complex issues. Some surgeons consider early surgical removal of both single and multiple nodular lesions necessary, approaching the question from the standpoint of oncological vigilance (A.F. Romanchishen et al., 2001; A.I. Paches, R.M. Propp, 2004; R.A. Galkin et al., 2000; S.V. Ivanov et al., 2002; E.M. Blagnitko et al., 2003; A. Rojlla, 1995). Others regard multinodular goiter as a compensatory reaction aimed at maintaining a constant concentration of thyroid hormones under conditions of iodine deficiency (P.S. Gusev et al., 2003). In this connection, calls are being made to reduce surgical activity. The main difficulties arise in choosing the method of treatment for colloid goiter. Although regarding the extent of surgery for thyroid cancer there are also differing opinions. A substantial change in approaches to the treatment of thyroid diseases has been observed in Russia over the last 10 years in connection with attempts at a wider use of radioactive iodine. The pathogenetic nature of the treatment makes it possible to significantly reduce the aggressiveness of treatment and improve the quality of life of patients after surgery. Despite its promise, the radioiodine therapy method in Russia is used only at the MRRC of the RAMS, and the treatment of patients from other regions presents certain organizational and tactical difficulties. Analysis of the resolution of this problem on the example of medical institutions located far from Obninsk may serve as a subject of study and be of practical interest.

The aim of the study is to develop a system of measures aimed at improving the results of treatment of patients with thyroid diseases on the basis of an in-depth study of the features of etiopathogenesis, expansion of the range of diagnostic methods, and optimization of the postoperative period.

Objectives of the study:

1. To analyze the changes in surgical tactics in the treatment of patients with thyroid diseases over 20 years.

2. To study the capabilities of modern methods of preoperative verification in the selection of patients for surgical treatment with multinodular goiter and thyroid cancer.

3. To study the echosemiotics of cervical lymph node lesions in various thyroid diseases.

4. To evaluate the specificity of the test for thyroglobulin in needle washout in benign thyroid diseases and thyroid cancer.

5. To study the extent of genotoxic damage to thyrocytes in various thyroid diseases.

6. To study the long-term results of the use of radioiodine therapy in the treatment of patients with thyroid diseases. The work was carried out at the Railway Clinical Hospital at Yaroslavl Station of the Northern Railway of JSC «Russian Railways» at the Department of Surgical Diseases of the Pediatric Faculty and the Department of Histology, Cytology and Embryology of the Yaroslavl State Medical Academy within the framework of a programme for improving medical care for patients with thyroid pathology.

Scientific novelty of the research results. For the first time in the clinical setting, the phenomenon of the formation of thyrocytes with micronuclei has been quantitatively studied in patients with nodular goiter and malignant thyroid tumors. In papillary cancer, the multifocal nature of the enhanced formation of aberrant thyrocytes predominantly in the tissue outside the nodule throughout the gland has been demonstrated.

For the first time, a statistical analysis of ultrasound signs of lymphadenopathies in patients with thyroid diseases has been performed. On the basis of criteria for the echolocation of cervical lymph nodes, a system for the comprehensive assessment of their involvement has been proposed.

Practical significance of the work. Based on an analysis of 20 years of results of the surgical hospital, the influence of the changed diagnostic tactics on approaches to the surgical treatment of patients with thyroid diseases has been proven. The echosemiotics of cervical lymph nodes in various thyroid pathologies has been systematized according to ultrasound data. The high specificity of the test for thyroglobulin in needle washout in detecting metastases of differentiated thyroid cancer has been proven. A system of comprehensive treatment with the use of radioactive iodine and monitoring of patients with thyroid cancer under the joint supervision of two medical institutions has been developed. The phenomenon of an increased frequency of aberrant thyrocytes in cytological examination may serve as:

• one of the prognostic criteria indicating an increased risk of malignant neoplastic transformation of the thyroid parenchyma;

• a reason for an in-depth examination of the patient and exclusion of a malignant process in the thyroid gland;

• a theoretical substantiation of the expediency of the radical nature of operations for papillary thyroid cancer.

Main propositions for defence:

1. Among patients operated on for thyroid diseases, the leading trend over the past two decades has been an increase in the proportion of cases with thyroid tumors and a decrease in cases with autoimmune thyroiditis and thyroid cysts.

2. Assessment of the state of cervical and upper mediastinal lymph nodes should be a mandatory part of the examination of patients with benign nodules and thyroid cancer.

3. A marked increase in the frequency of genetically damaged thyrocytes, identified by the presence of micronuclei or nuclear fragmentations, is characteristic only of thyroid cancer. The content of micronucleated cells increases to the greatest extent predominantly in the tissue outside the nodule throughout the gland.

4. The use of radioiodine therapy after adequate surgical intervention helps prevent the development of local recurrences, the progression of regional disease, and the development of distant foci of thyroid cancer.