Ultrastructural features of solid/trabecular areas in differentiated thyroid carcinoma

The presence of areas exhibiting a solid/trabecular pattern of growth within an otherwise differentiated thyroid carcinoma represents a source of controversy as regards its proper classification and biologic and prognostic significance. The aim of the current study was to investigate the ultrastructural features of solid/trabecular areas in differentiated thyroid carcinoma and to compare those features with the submicroscopic profile of differentiated, poorly differentiated (insular), and undifferentiated (anaplastic) variants of thyroid cancer. The study series included differentiated carcinoma with solid/trabecular areas (3 cases), conventional papillary carcinoma (4 cases), follicular variant of papillary carcinoma (4 cases), poorly differentiated (insular) carcinoma (3 cases), and undifferentiated (anaplastic) carcinoma (3 cases). It was found that the solid/trabecular areas in differentiated carcinoma and poorly differentiated (insular) carcinoma share similar ultrastructural features and overall retain, even if attenuated, many of the submicroscopic attributes of differentiated carcinomas. In particular, nests of neoplastic cells were observed showing a highly developed cytosecretory apparatus and the presence of numerous abortive/rudimentary follicles, and intercellular and intracellular (intracytoplasmic) lumina/canaliculi of variable morphology. The study supports the hypothesis that the solid/trabecular areas do not merely represent an architectural pattern but rather should be regarded as the expression of a process of reduced differentiation similar to that of poorly differentiated (insular) carcinoma.     

Molecular pathology of well-differentiated thyroid carcinomas

The newly discovered molecular features of well-differentiated thyroid carcinomas derived from follicular cells are reviewed, within the frame of the 2004 WHO classification of thyroid tumours, under the following headings: “Follicular carcinoma”, “Papillary carcinoma”, “Follicular variant of papillary carcinoma” and “Hürthle cell tumours”. A particular emphasis is put on the meaning of PAX8–PPARγ rearrangements, RAS and BRAF mutations, and deletions and mutations of mitochondrial genes and of nuclear genes encoding for mitochondrial enzymes, for thyroid tumorigenesis.     

Mutations of thyrotropin receptor gene

 Thyrotropin is the primary pituitary hor- mone which stimulates the growth and differentiation of thyroid cells. TSH binds a specific receptor present in the plasma membrane of thyroid cells and signals the G protein transducers, which activate different effec- tors, mainly adenyl cyclase and phospholipase C. The TSH receptor belongs to a broad class of receptors known as seven-loop receptors because they contain a long stretch of amino acids which cross the plasma membrane seven times. Mutations in the TSH receptor gene have been found in hyperfunctioning thyroid adenomas. These mutations are: (a) somatic (present only in the tumor), (b) dominant (only one copy of the gene is affected), and (c) lead to the constitutive activation of the cAMP signaling cascade. Most mutations which have been identified occur in the intracellular loop III and in the transmembrane domain VI. Germline mutations in the same regions of the receptor have been found in congenital nonautoimmune hyperthyroidism. In addition, germ line mutations have been described in the extracellular domain of the receptor leading to increased TSH levels. The clinical implications of these findings are discussed. Received: 15 January 1996 / Accepted: 8 March 1996     

细胞角蛋白19、galectin-3、HBME-1在甲状腺病变上的表达及鉴别诊断意义

目的 研究细胞角蛋白(CK)19、galectin(Gal)-3、HBME-1在甲状腺不同病变表达的特点及鉴别诊断中的应用价值。方法 应用免疫组织化学EnVision法检测了21例结节性甲状腺肿(结甲)、14例毒性甲状腺肿(甲亢)、15例甲状腺滤泡性腺瘤(腺瘤)、13例滤泡性癌、13例滤泡型乳头状癌及48例经典型乳头状癌中单克隆抗体CK19、Gal-3、HBME-1的表达。结果 甲状腺病变中3种标记表达均位于细胞质;CK19、Gal-3、HBME-1的表达在甲状腺良性病变(结甲、甲亢、腺瘤)大多为弱阳性或阴性,而滤泡性癌阳性明显增加、乳头状癌(滤泡型及经典型)大多为中、强阳性,3种标记在甲状腺不同病变的阳性表达率结甲为52．4％(11／21)、9．5％(2／21)、19．0％(4／21),甲亢为50．0％(7／14)、7．1％(1／14)、7．1％(1／14),腺瘤为60％(9／15)、13．3％(2／15)、13．3％(2／15),滤泡性癌为76．9％(10／13)、61．5％(8／13)、53．8％(7／13),滤泡型乳头状癌为：100％(13／13)、84．6％(11／13)、92．3％(12／13),经典型乳头状癌为100％(48／48)、93．8％(45／48)、95．8％(46／48);在甲状腺良性病变(结甲、甲亢、腺瘤)与恶性病变(滤泡性癌、乳头状癌)间3种标记差异均有显著性(P均=0．000);同时3种标记在滤泡样病变即腺瘤、滤泡性癌和滤泡型乳头状癌间亦有显著差异(CK19：P=0．038,Gal-3：P=0．001,HBME-1：P=0．000)。结甲有9例,甲亢有7例,腺瘤有6例3种标记均不表达,滤泡性癌仅有1例,而乳头状癌(滤泡型及经典型)没有病例3种标记均不表达,同一病例有2种以上阳性表达在结甲、甲亢、腺瘤、滤泡性癌、滤泡型乳头状癌和经典型乳头状癌中分别为14．2％(3／21)、21．4％(3／14)、20．0％(3／15)、69．2％(9／13)、92．3％(12／13)、100．0%(48／48),在甲状腺良性病变与恶性病变间以及滤泡样病变间差异亦有显著性(P=0．000)。结论 CK19、Gal-3、HBME-1的检测尤其是联合检测对甲状腺病变的诊断、鉴别诊断具有较高的实用价值。     

The RET proto-oncogene in medullary and papillary thyroid carcinoma

 The evolution of cancer is a multistep phenomenon, and multiple cellular genetic lesions are involved in the emergence of the malignant neoplasm. Several early events have been implicated in the neoplastic transformation of thyrocytes, and recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms: ras point mutations are frequently observed in tumours with follicular histology, gsp – the mutated form of the alpha subunit of the Gs-protein – is encountered in up to 73% of papillary or follicular thyroid carcinomas, and a high prevalence of p53 point mutations has been found in anaplastic thyroid carcinomas but not in differentiated follicular tumours. More recent studies revealed that the RET proto-oncogene is involved in the oncogenesis of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) by activation of its tyrosine kinase either by point mutation or rearrangement. In this review the most important recently published data on alterations of the RET proto-oncogene in heritable and sporadic MTCs and in PTCs will be summarized. Emphasis will be directed to the pathophysiological mechanisms of tumour initiation, the indications and limitations of DNA testing, and the clinical implications of identified RET defects in thyroid lesions. Received: 9 January 1997 / Accepted: 17 February 1997     

Nocturnal hormonal responses to resistance exercise

The effects of resistance exercise on the nocturnal responses of cortisol (CO), testosterone (TEST), human growth hormone (hGH), and thyroid hormones (T₃, T₄) were examined in eight trained weight lifters. Each subject completed two trials using a counterbalanced design: a control, no exercise trial (CON) and a heavy resistance exercise session of three sets of six exercises to exhaustion (RE). The exercise session took place between 1900 and 2000 hours. Blood was sampled prior to and at 20-min intervals after RE. For both trials blood was sampled at hourly intervals from 2100 hours until 0700 hours. The hGH and CO concentrations were increased up to 40-min post-exercise (P < 0.05), but returned to resting levels 1 h post-exercise. Nocturnal hGH concentration was not affected by RE (P > 0.26) and peaked at 0200 hours and declined until 0700 hours. Similarly, the CO responses were similar between the trails (P > 0.14). This CO concentrations declined from 2200 hours until 0100 hours, then increased steadily until 0700 hours. The TEST concentrations during both trials rose steadily from 2200 hours until 0700 hours; however, the rise in TEST from 0500–0700 hours during RE was greater than during the CON trails (P = 0.059). The T₃ concentrations were unchanged by exercise and were similar at all times between trails. The T₄ concentrations were elevated for 20 min after RE; however nocturnal T₄ concentrations were lower after RE than during CON. These results would suggest that bGH and CO may have limited nocturnal reactivity to resistance exercise. However, the nocturnal alterations of TEST and T4 after resistance exercise, although small, may have implications for muscle anabolism.     

Multiple endocrine cell types in thyroid medullary carcinoma

Summary 10 cases of thyroid medullary carcinoma (TMC) have been studied ultrastructurally and histochemically. Well differentiated calcitonin-producing C cells were present in all tumours, being prevalent in 9 cases. 5-Hydroxytryptamine (5HT) storing cells were found in two cases, somatostatin immunoreactive cells in at least 5 cases and ACTH-immunoreactive cells in 4 cases. Ultrastructurally, at least 3 types of apparently non-C cells were observed. Type 1 cells with large, poorly osmiophilic granules resembling those of gastroenteropancreatic D cells, were present in 6 cases; they appeared to correlate well with somatostatin immunoreactive cells. Type 2 cells with large osmiophilic granules were found in 5 cases; they resembled ACTH-MSH cells of the human pituitary and may correspond to the ACTH-immunoreactive cells of light microscopy. Type 3 cells with small granules and an unknown function were found in 6 cases, always in scarce number. It is concluded that TMC, although mainly made up of C cells, usually contains large proportions of other endocrine cell types.Supported in part by grant N. 75.00630.04 from the Italian National Research Council (C.N.R.). P.F. is a fellow of the Fondazione Anna Villa Rusconi, Varese     

Glucose-6-phosphate dehydrogenase activity in monolayer cultures of thyroid epithelial cells: TSH and inhibition of nitrogen oxide synthase affect the enzyme activity and the oxygen sensitivity of the histochemical assay

The objective was to investigate glucose-6-phosphate dehydrogenase (G6PD) activity in monolayer cultures of thyroid epithelial cells and to examine whether inhibition of nitric oxide synthase affects activity of G6PD or oxygen sensitivity of the assay. Primary cultures without TSH addition prior to experiments demonstrated a TSH-dependent increase in G6PD activity. G6PD activity was higher in F12 medium than in a serum-free physiological medium. Secondary cultures grown in F12 medium demonstrated a diminished activity of G6PD and a lack of response to TSH. In the serum-free physiological medium, G6PD activity was comparable to that found in primary cultures and a response to high concentrations of TSH was maintained. In primary cultures grown in F12 medium devoid of TSH, G6PD activity decreased dose-dependently when nitric oxide synthase activity was inhibited. The oxygen sensitivity of the assay was comparable to that reported previously in malignant cells and correlated with the activity of G6PD in primary cultures. We suggest that thyroid epithelial cells may be an appropriate system to investigate oxygen sensitivity of the G6PD assay as the cells demonstrate a reduced oxygen sensitivity which can be influenced by culture conditions.     

血清抗甲状腺球蛋白抗体和抗甲状腺过氧化物酶抗体检测在甲状腺疾病诊断及甲亢预后判断中的价值

采用放免法检测甲状豚疾病患者抗甲状腺球蛋白抗体（ＴＧＡｂ）和抗甲状腺过氧化物酶抗体（ＴＰＯＡｂ）、并对部分Ｇｒａｖｅｓ病患者停药后随诊一年的结果进行分析。结果显示：（１）自身免疫性甲状腺疾病患者ＴＧＡｂ和ＴＰＯＡｂ活性及阳性率明显高于非ＡＩＴＤ，尤以桥本甲状腺炎为然。（２）ＧＤ治疗前及停药时ＴＧＡｂ和ＴＰＯＡｂ均阴性者与均阳性者停药一年内的复发率分别为０．５８３和０．２３１。（３）ＴＧＡｂ和ＴＰＯＡｂ均阴性，而停药时甲状腺刺激抗体（ＴＳＡｂ）阳性者，停药时ＧＤ复发的机率最大（０．９０９），提示ＴＧＡｂ和ＴＰＯＡｂ检测在ＡＩＴＤ诊断，鉴别诊断以及ＧＤ预后判断中具有重要的临床意义。     

IgG-KAPPA-PRODUCING PRIMARY PLASMACYTOMA OF THE THYROID GLAND WITH PREOPERATIVE SERUM M PROTEIN

A case of primary plasmacytoma of the thyroid gland which occurred in a 63-year-old woman is reported. Histologic and ultramicroscopic examination revealed that the excised thyroid tumor was plasmacytoma superimposed on lymphocytic thyroiditis. Immunohistological study showed that the tumor cells produced intracytoplasmic immunoglobulin (IgG-kappa). Electropho-retic and immunoelectrophoretic studies disclosed the presence of monoclonal immunoglobulin (IgG-kappa) in samples of the patient's serum which had been obtained preoperatively. After completion of irradiation therapy to the neck following tumor removal, the serum monoclonal immunoglobulin disappeared. The patient is currently alive and well without any evidence of the tumor three years after surgery.