Angiography effectively supports the diagnosis of hepatic metastases in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) belongs in the group of neuroendocrine tumors with early lymphatic and hepatic dissemination. A high rate of undetectable metastases is hypothesized to be responsible for the frequent mismatch between the apparent relatively small tumor burden and the elevated plasma tumor marker level. METHODS: Thirty-six MTC patients with residual/recurrent biochemical signs (elevated basal calcitonin level) and/or characteristic general symptoms (diarrhea and/or flushing) were systematically examined by conventional radiology, whole-body 18F-deoxyglucose positron emission tomography (PET), dynamic liver computed tomography and magnetic resonance imaging, and hepatic angiography. RESULTS: Conventional diagnostic imaging revealed lymph node (LN) involvement in the cervical, mediastinal, supraclavicular, and axillary regions (16 cases), and multiple pulmonary (3 cases), bony (1 solitary and 1 multiple case), and breast (1 case) metastases. (18)F-deoxyglucose PET identified all these extralymphatic metastatic lesions (except 2 cases with multiple pulmonary metastases), and also supradiaphragmatic LN involvement in 34 (94%) patients. In 32 (89%) cases, multiple small (generally < or = 1 cm) hypervascular, hepatic metastases undetectable by other imaging methods were localized angiographically. Of the 23 original pathologic specimens investigated, 18 (78%) exhibited LN involvement. The smallest primary tumor in patients with hepatic metastases was 1 cm. CONCLUSIONS: Hepatic angiography is recommended for primary staging in MTC patients with a primary tumor measuring 1 cm or larger, and/or pathologically proven LN involvement, and also during restaging for suspected recurrences to avoid unnecessary extensive surgical LN dissection in the neck and mediastinum.

[Current diagnostic method, prognosis estimation and therapy of papillary thyroid cancer: recommendations of the medical universities and the National Oncologic Institute of Budapest]. / A papillaris pajzsmirigy-carcinoma korszerü kivizsgálása, prognózisbecslése és kezelése: az orvostudományi egyetemek és az Országos Onkológiai Intézet ajánlása.

Physical examination, cervical ultrasonography (US) and aspiration cytology are the mainstays of the preoperative diagnostics of papillary thyroid carcinoma. For the staging of suspected malignant cases, cervical and mediastinal CT (MRI for inconclusive results) is indicated before any surgery. The end-result of primary treatment is assessed by total-body iodine scintigraphy and the serum human thyroglobulin (hTG) level. For long-term follow-up, physical examination and the serum hTG level are the most reliable tools (6-monthly), supplemented by cervical US and chest X-ray (yearly), and total-body iodine scintigraphy (2-yearly). If these furnish positive results, further examinations may be indicated. In suspected relapses of hTG non-producing and iodine non-accumulating papillary carcinomas, 201thallium chloride or 99mTc-sesta-MIBI (methoxy-isobutyl-isonitrile) scintigraphy, and positron emission tomography with 18fluoro-deoxyglucose or 11C-methionine may be of help. For estimation of the prognosis (cause-specific survival) of the patients, the MACIS score system of the Mayo Clinic is widely accepted, the patients being divided into low-risk and intermediate/high-risk categories. The recommended standard surgical intervention is near-total thyroidectomy (2-4 g residual glandular tissue left at the upper pole of the less-involved lobe), with a central cervical lymph node dissection for diagnostic purposes. In cases of lymph node dissemination, dissection (radical, modified radical, selective or microdissection) of any of the involved compartments (central, right or left cervical, or upper mediastinal) is indicated for therapeutic reasons, the method of which is depending on the extent of the metastatic involvement. Following adequate surgical intervention, no adjuvant radioiodine therapy is indicated for low-risk cases with a tumour of less than 1 cm diameter. For other low-risk or intermediate/high-risk patients, radioiodine ablation (R0N0M0) or a therapeutic radioiodine dosage (R2N1M1) is indicated. In cases at high-risk of local/regional relapse and in radioiodine non-accumulating tumorous cases, external radiotherapy may be applied. Thyroid hormone medication in a TSH suppressive dose is indicated during the first 5 postsurgical years: the goal is to achieve a TSH level below 0.1 (determined by a 3rd generation assay). If no relapse occurs or the case is a low-risk one, following the 5 years, it is enough to maintain the TSH level in a subnormal range (0.1-0.3).

[The role of intraoperative gamma-probe-guided sentinel lymph node biopsy in the treatment of malignant melanoma and breast cancer]. / Az intraoperatív gamma-próba által vezérelt örszem nyirokcsomó-biopszia jelentösége a melanoma malignum és az emlörák kezelésében.

In the treatment of malignant tumors regional lymphadenectomy is used for two purposes. It is used partly for staging the regional lymph nodes which is a significant and independent prognostic factor and determines the need for adjuvant oncologic treatment and partly for achieving locoregional disease control. Removal of tumor-free lymph nodes by regional lymph node clearance is unnecessary according to our current knowledge. Since the sensitivity and specificity of non-invasive clinical examinations are insufficient in predicting the nodal status the histological study of the regional lymph nodes cannot be abandoned. A new and minimally invasive surgical procedure, the mapping and removal of the first tumor draining lymph node, the sentinel node provides the possibility of pathological nodal staging without performing formal lymphadenectomy. Mapping of the sentinel node can be performed by the use of a radioisotope and intraoperative hand-held gamma-probe or a vital blue dye or a combination of these two. This latter method was used by the authors in 73 patients (25 with malignant melanoma and 48 with breast cancer). Sentinel lymph node biopsy was performed successfully in 92% of patients with melanoma and 90% of patients with breast cancer. In three breast cancer patients the sentinel node inaccurately predicted the axillary status as negative, but is was in 93% accurate in predicting the histologic nodal state. According to our preliminary experiences intraoperative gamma-probe guided sentinel lymph node biopsy is considered a feasible procedure in both malignant melanoma and breast cancer. More experiences are needed before introducing this method in the routine clinical practice.

[Multiple endocrine neoplasia-type medullary thyroid carcinoma in three generations of a family]. / Multiplex endokrin neoplasia típusú medullaris pajzsmirigy-carcinoma egy család három generációjában.

The familial accumulation of a multiple endocrine neoplasia (MEN) type 2a medullary thyroid carcinoma, is described based on the retrospective analysis of a family history. The proband was characterized by medullary carcinoma (MC) combined with phaeochromocytoma, her child had been shown to suffer from MC. In the third generation of the family C-cell hyperplasia and bilateral adrenal hyperplasia occurred. It is shown that in order to arrive at a correct decision as regards the therapy to be used, modern laboratory tests (serum calcitonin, CEA-analysis) and diagnostic imaging methods (ultrasound, computer tomography, magnetic resonance imaging, positron emission tomography, metaiodobenzylguanidine scintigraphy) should be used. It is emphasized that the available therapeutic means (surgery, radiotherapy, nuclear medicine) have to be carefully selected and, if necessary, combined. In medullary thyroid carcinoma associated tumours in other endocrine organs should be expected to occur. Family screening using blood chemical and genetic tests are recommended in asymptomatic cases, since their surgical treatment can in this way lead to complete recovery.

[Cytogenetic study of thyroid patients treated with external irradiation or radioiodine]. / Külsó sugárforrással, vagy radiojóddal kezelt pajzsmirigybetegek citogenetikai vizsgálata.

Where clinically permitted, either external irradiation or radioiodine therapy is usually recommended for the treatment of differentiated thyroid cancer patients. This paper describes an attempt to clarify the radiation burden and the distribution of radiation doses on the lymphocytes in consequence of these two therapeutic modalities, and the circumstances of the applicability of biological dosimetry. Thyrotoxic patients with intact thyroid glands underwent 131I therapy were also analysed for this purpose. An analysis was made of the extent to which exposure to local neck irradiation (50 Gy) or radioiodine therapy (1734-2600 MBq) causes chromosomal aberrations in the lymphocytes of thyroid disease patients after total or subtotal thyroidectomy, or thyrotoxic patients with intact thyroid glands (185-595 MBq). The irradiated volume of lymphatic tissues played the most important role in the formation of chromosomal aberrations. External irradiation caused 10-times more aberrant cells than 131I therapy did in cancer patients. In thyrotoxic patients the lower therapy doses of radioiodine caused a significantly higher frequency of aberrations than that observed in thyroid cancer patients. Selective radiosensitivity of lymphocytes was supported by the analysis of the Poisson distribution of aberrations, which suggested a homogeneous dose distribution only in 131I-treated and thyroidectomized cancer patients. In conclusion, we suggest that the results of studies of the genetic alterations in the lymphocytes exposed to radioiodine, under well-defined circumstances should not be ignored before the mode of radiation treatment is chosen. On the other hand, in the modelling of accidental environmental radioiodine exposure, only thyrotoxic patients with an intact thyroid gland and heterogeneous dose-distribution are a suitable group.

Survival chance in papillary thyroid cancer in Hungary: individual survival probability estimation using the Markov method.

PURPOSE: The typically benign, but occasionally rapidly fatal clinical course of papillary thyroid cancer has raised the need for individual survival probability estimation, to tailor the treatment strategy exclusively to a given patient. MATERIALS AND METHODS: A retrospective study was performed on 400 papillary thyroid cancer patients with a median follow-up time of 7.1 years to establish a clinical database for uni- and multivariate analysis of the prognostic factors related to survival (Kaplan-Meier product limit method and Cox regression). For a more precise prognosis estimation, the effect of the most important clinical events were then investigated on the basis of a Markov renewal model. The basic concept of this approach is that each patient has an individual disease course which (besides the initial clinical categories) is affected by special events, e.g. internal covariates (local/regional/distant relapses). On the supposition that these events and the cause-specific death are influenced by the same biological processes, the parameters of transient survival probability characterizing the speed of the course of the disease for each clinical event and their sequence were determined. The individual survival curves for each patient were calculated by using these parameters and the independent significant clinical variables selected from multivariate studies, summation of which resulted in a mean cause-specific survival function valid for the entire group. On the basis of this Markov model, prediction of the cause-specific survival probability is possible for extrastudy cases, if it is supposed that the clinical events occur within new patients in the same manner and with the similar probability as within the study population. RESULTS: The patient's age, a distant metastasis at presentation, the extent of the surgical intervention, the primary tumor size and extent (pT), the external irradiation dosage and the degree of TSH suppression proved to be statistically significant and independent prognostic factors with regard to cause-specific survival in multivariate studies. During follow-up, 14, 14, 9 and 12% of the patients underwent local/regional/distant relapses or thyroid cancer-related death, respectively. Through use of the above six independent clinical variables and the parameters relating to the four clinical events and their interrelations, mean cause-specific survival probabilities of 88, 83 and 78% were determined at 10, 20 and 30 years, respectively. The survival-predicting software (PATHYPRE) written on the basis of the biostatistical model is available through Internet connections on the home page of the National Institute of Oncology, Budapest (www.oncol.hu). CONCLUSION: Prediction of the individual survival probability for extrastudy cases affords a rationale for individualization of the treatment of papillary thyroid cancer patients.

Cytogenetic study of radiation burden in thyroid disease patients treated with external irradiation or radioiodine.

Where clinically permitted, either external irradiation or radioiodine therapy is usually recommended for the treatment of differentiated thyroid cancer patients. The choice depends on the treatment philosophy of the responsible physician. This paper describes an attempt to clarify the radiation burden on the lymphocytes in consequence of these two therapeutic modalities. An analysis was made of the extent to which exposure to local neck irradiation (25 x 2 Gy) or radioiodine therapy (1734-2600 MBq) causes chromosomal aberrations in the lymphocytes of thyroid disease patients after total or subtotal thyroidectomy. External irradiation caused many more chromosomal aberrations than 131I therapy did, but analysis of the distribution of the aberrations suggested a homogeneous dose distribution only in 131I-treated and thyroidectomized cancer patients. In thyrotoxic patients with intact thyroid glands, the lower therapy doses (185-595 MBq) caused a significantly higher frequency of aberrations than that observed in thyroid cancer patients, and the dose distribution in the lymphocytes was inhomogeneous. Thus, in the modelling of accidental environmental radioiodine exposure, thyroid patients with small if any residual thyroids are not a suitable group.

[Survival potentials of patients with papillary carcinoma of the thyroid gland in Hungary]. / A papillaris pajzsmirigyrákos betegek túlélési esélyei Magyarországon.

The typically benign, but occasionally rapid fatal clinical course of papillary thyroid cancer has raised the need for individual survival probability estimation, to tailor the treatment strategy exclusively to the given patient. A retrospective study was performed on 400 papillary thyroid cancer patients, with a mean follow-up time of 10.3 years, to establish a clinical database for uni- and multivariate analysis of the survival probability-related prognostic factors (Kaplan-Meier product limit method and Cox regression). For a more precise prognosis estimation, in the next step the most important clinical events were investigated and survival functions for each patient were calculated on the basis of a Markov renewal model. The basic concept of this approach is as follows: each patient has an individual disease course, which (besides the initial clinical categories) is affected by special events, e.g. internal covariates (local/regional/distant relapses), that a patient experiences throughout the course of the disease. On the supposition that these events and the cause-specific death are influenced by the same biological process, the parameters of transient survival probability characterizing the speed of the course of the disease for each sequence of clinical events were determined. The individual survival curves for each patients were calculated by using the former parameters and the independent, significant clinical variables, summation of which resulted in an overall cause-specific survival function valid for the entire group. The patient's age, a distant metastasis at presentation, the extent of the surgical intervention, the primary tumour size, the dosage of the external irradiation and the degree of the TSH suppression proved to be statistically significant (in that sequence) and independent prognostic factors as concerns cause-specific survival in multivariate studies. During follow-up 14%, 14%, 9% and 12% of the patients underwent local/regional/distant relapses and thyroid cancer-related death. Through use of the above six independent clinical variables and the parameters relating to the interrelations of the four clinical events, mean cause-specific survival probabilities of 88%, 83% and 78% were determined at 10, 20 and 30 years, respectively. The 30-year individual survival probability prediction for these study cases showed that no cancer-related death occurred > or = 92% (low-risk group), while the tumour-related deaths were considerable (31%) < or = 78% (high-risk group), and there were only 6% deaths in the intermediate-risk group. The constructed survival function permits a prediction of the individual survival probability of extra-study cases under the given treatment conditions and within the given population, and thus affords a rationale for individualization of the treatment of papillary thyroid cancer patients.

Clear cell thyroid cancer--undifferentiated type--an immunohistochemical and electron microscopical study.

Two cases of clear cell thyroid cancer are described. In both tumors immunohistochemical methods detected the presence of intracytoplasmic thyroglobulin that confirmed the follicular origin. Simultaneously performed electron microscopic studies visualized the accumulation of smooth surfaced, membrane coated vesicles of varying size in the cytoplasm. Bad prognosis predicted on the base of undifferentiated histological structure was confirmed by extended hematogenic metastases.

Cyclodextrin-stabilized volatile substances for inhalation therapy.

Diapulmon (Chinoin) which comprise camphor, 1-menthol, eucalyptus oil and quinine dissolved in sunflower oil (Oleum helianthi) is marketed in ampoules of 2 ml but utilized almost exclusively for inhalation therapy. Complexing the active ingredients of Diapulmon with beta-cyclodextrin (beta-CD) a stable non hygroscopic microcrystalline substance is obtained. When this powder sprinkled on hot water, the included volatile compounds are gradually released and the desired pharmacological effect can be brought about.

Enhancement by drugs of metastatic lung nodule formation after intravenous tumour cell injection.

In studies on a model of induced pulmonary metastasis in mice a tumour host system was analysed which was not affected by immunogenicity of the tumour for the host; neither intensive immunosuppression nor immunization caused a significant change in the quantity of pulmonary metastatic nodules. In contrast the application of cytostatic drugs and of Corynebacterium parvum could modify the pulmonary resistance to the formation of tumour nodules by a factor greater than 100 in either direction. This finding confirms the observation of others that major modification of the resistance to metastatic tumour formation can occur independently of classical immunological mechanisms. Special attention is drawn to the fact that cyclophosphamide enhances the formation of metastatic nodules in this model by factors of 100 to more than 1,000 whereas other cytostatic drugs including the cyclophosphamide congeners iphosphamide and trophosphamide are active only factors between 2 and 12. The possible practical significance of these findings is discussed.