John S. Carruthers

Papillary and follicular thyroid cancer: impact of treatment in 1578 patients.

We report the experience from 13 Canadian radiotherapy centres concerning the treatment and outcome for 1074 papillary and 504 follicular thyroid cancer patients followed for 4-24 years. Surgical resection was carried out in almost all patients; there was no correlation between the type of operation and recurrence or survival. Treatment with external irradiation (201 patients) radioiodine (214 patients), or both (107 patients) was used more often in poor prognosis patients than in those with good prognostic factors, and was effective in reducing local recurrences and improving survival, especially in patients with microscopic residual disease postoperatively. Treatment complications were common but rarely fatal. Thyroid cancer was the cause of death in over half of the papillary cancer deaths and in two-thirds of the follicular cancer deaths.

Malignant lymphoma of the thyroid gland

Abstract We reviewed the records of 20 patients with malignant lymphoma presenting in the thyroid gland who were seen at The Princess Margaret Hospital between 1958 and 1977. The disease predominantly affected females of an older age group and clinically was characterized by a rapidly enlarging neck mass associated with obstructive symptoms. Seventeen of the patients (85 %) had histiocytic lymphoma. Eighteen patients (90 %) either were clinically Stage IE or Stage HE disease (Ann Arbor classification). All patients were treated with radiotherapy. Adjuvant chemotherapy was used in only three patients. Overall survival rate at 5 years was 35%. All recurrences but one occurred within 6 months. Survival rate at 5 years from time of recurrence was 7%. Postmortem examination of eight patients showed widespread lymphoma in all; the lung, G.I. tract, liver and kidney were the most frequently affected distant sites. The long term survival group (A) was composed of three patients with Stage I and four with Stage II disease. The failure group (B) included live patients with Stage I, six with Stage II and two with Stage IV disease. Group A patients had “localized” disease and all but two patients received radiation treatment to the neck and mediastinum. Group B patients with Stage I disease received radiation to the neck only and none survived 5 years. All six Stage II patients in group B (five patients with “extensive” disease and one with “localized” disease) received radiation to the neck only; none survived 5 years. We conclude that radiotherapy to the neck and mediastinum is an adequate form of treatment in patients with lymphoma of the thyroid gland with Stage I or localized Stage II disease. More advanced disease should be managed with radiation and chemotherapy.

The ductular cell reaction of rat liver in extrahepatic cholestasis. I. Proliferated biliary epithelial cells.

Abstract The ductular cell reaction in the liver of rats during the second to sixth weeks following ligation of the common bile duct is in part an organized proliferation of ductular (biliary epithelial) cells. The cells show an invariable tendency to surround lumina. Thin ( I 2μ ) sections exmined in the light microscope assist in the understanding of the behavior of ductular cells since the lumina of the penultimate bile-conduction channels can be more clearly visualized than in routine sections. Biliary epithelial cells from proliferated ductules in rats killed two to six weeks after the ligation, show by electron microscopy a persistence of some of the changes noted as occurring during the first 14 days of their proliferation, a paucity of microvilli, edema of microvilli, an increase of the endoplasmic reticulum, and an increase of free ribosomes. Additional abnormalities develop in ductular cells after day 14 of cholestasis. The Golgi zones multiply and become prominent. Smooth-surfaced vesicles increase in number. Some cells become increasingly electron-opaque, and have been designated as ‘dark’ cells. Other cells may acquire a unique one-centriole type of cilia which have an abnormal 7 + 1 doublet filament arrangement. The functional effectiveness of these cilia could not be assessed, owing to the absence of information about any other comparable cilia with a known motility. It was suggested that the prominent ER and RNP granules may signify an increased protein production by proliferating cells rather than evidence of elaboration of a protein-rich secretion. The prominence of Golgi zones and of smooth-surfaced vesicles was interpreted as possible evidence of secretory activity involving water and electrolytes. ‘Dark’ biliary epithelial cells may form as a result of a sudden discharge of such secretion into ductular lumina.

Experimental Extrahepatic Biliary Obstruction: Fine Structural Changes of Liver Cell Mitochondria

Summary This paper records observations of disturbances of mitochondrial morphology in parenchymal liver cells of rats after ligation of the common bile duct. The changes observed include an apparent increase in number of mitochondria in some areas of cells, focal disturbances of the size and density of the matrix of mitochondria, and changes in the relative and absolute length of the cristae mitochondriales. These observations could not be related to any specific type of cell degeneration as seen in the light microscope. No explanation can be offered at present f or their occurrence beyond a general statement that they represent, at an electron microscopic level of observation, evidence of cell injury.

The role of external radiation in the management of papillary and follicular thyroid cancer.

Review of 137 patients with differentiated thryroid carcinoma (82 papillary and 55 follicular) demonstrates that external radiation in moderate dosage eradicates microscopic disease. Its use could lead to a decrease in surgical complications by avoiding unnecessarily radical attempts at removing all potential microscopic disease. Gross tumor also responds favorably to external radiation, but its very slow regression rate has led to the misconception that external radiation is ineffective in the treatment of these cancers. Both radioiodine and thyroid hormone play an important role in the management of differentiated thyroid cancers, but their effectiveness should not be overestimated.

Observations on the fine structure of rat liver cells in extrahepatic cholestasis.

With 12 Figures in the Text (Received June 16th, 1962) The more recent light microscopic studies of the lesions which occur in the liver of rats after ligation of the common bile duct dwelt mainly upon the changes in the biliary system which are the most prominent features of these lesions (CAMERON and 0AKLEY 1932; CAMERO~ and MUZAFFER HASAN 1958; Koc~W]~SER, MEY]~R, u and POPPER 1952; Ri~TT~ER and STOFEI~ 1960; STEIN~ and MARTINEZ 1961; TRAMS and SY~O~IDIS 1957). Electron microscopists have also paid much attention to the changes which occur in the bile eanalieuli (GoLDFISCttER, ARIAS, ESSNER and NOVIKOFI~ 1962; KALIFAT, CARRUTH]~RS and STEIN]~R 1962; ROUILLER 1956; SCHAFFN]~R and PO]~PER 1959) and in the bile ductules and the ducts of Hering (CARRUTHERS and STEIN~R 1961 ; STEINER and CARRUTHERS 1962 ; STEI~E~, CARRU~HERS and KALIFAT 1962), but attention had also been given to the vascular granulation tissue which forms a mantle around the newly-formed ductular channels (CARRUTHERS, KALI]~AT and STEIN~, 1962, STEINER and CAR~CTHERS 1961; STEINE~, CAR~CTHERS and KALIFAT 1962). Considerable discussion has been also devoted to the nature and pathogenesis of the focal, coagulative and cytolytie necroses which occur in the parenchyma of the liver (CAMEROn and Hou 1962). Much less attention has been paid to the more widespread degenerative alterations which affect single hepatocytes, scattered here and there throughout the liver, perhaps because they are less prominent, and more subtle. We know from the work of CA~E~ON and OAKL~,Y (1932), STEINW~ and MAR~INWZ (1961) and TRAMS and SYMEOI~IDIS (1957) that these degenerative changes make their appearance as early as one hour after ligation of the common bile duet, and that they persist to a variable degree throughout the remaining life of the animal. The change consists of a loss of cytoplasmic basophilia with glycogen depletion, mild fat ty metamorphosis and cytoplasmic vacuolation, together with enlargement of the nuclei, and prominence of nucleoli. Mitotic activity is found in cells adjacent to portal tracts. Electron microscopic studies have demonstrated an increase of pericanalicular lysosomes (GOLDFISCHER, ARIAS, ESS~ER and NOVIKOFF 1962), and the development of cytoplasmic vacuoles, some of which are

The ductular cell reaction of rat liver in extrahepatic cholestasis: II. The proliferation of connective tissue☆

Abstract Fibrosis is an invariable accompaniment of the ductular cell reaction following ligation of the common bile duct of rats. Inflammatory cells aggregate around the proliferating ductules and may penetrate between their lining cells. Others are found in close apposition to aberrant microvilli of parenchymal liver cells which are in contact with the peri-ductular connective tissue. Only neutrophils undergo necrobiosis and they are phagocytosed by numerous macrophages. The stimulus to fibrogenesis and the cause of the inflammation are unknown. It is suggested that a phlogistic nonlipid material is excreted into ductules and gains access to the connective tissue where its chemotactic effects can be assessed morphologically. The migration of monocytes and their conversion into phagocytic macrophages are thought of as a response to the presence of degenerating neutrophils. Four types of capillary channels are found in the ductular cell reaction: fenestrated and nonfenestrated blood capillaries, lymphatics and stranded parenchymal sinusoids.

Vascular alterations in the liver of rats with extrahepatic biliary obstruction. An electron and fluorescent microscopic study.

Abstract In the 6 weeks which follow the induction of total extrahepatic cholestasis in rats, vascular lesions develop in capillaries, lymphatics, and sinusoids in the granulation tissue around the newformed ductules and in the adjacent peripheral parts of lobules. The lesions correspond in distribution to the biliary necroses which are found in rats after ligation of the common bile duct. The principal change is a disturbance of endothelial and Kupffer cell hydration, which leads to a narrowing vascular of lumina and is followed by stasis, hyperplasia, and hypertrophy of Kupffer cells and by secondary alterations of parenchymal liver cells. We have suggested that the necrosis may be the result of the ischaemia, perhaps in association with regurgitation of bile constituents into the interior of hepatocytes because of disturbance of the selective permeability of their cell membranes. The development of a prominent endoplasmic reticulum in Kupffer cells after ligation of the common bile duct, was related to the presence of a material staining positively with rabbit anti-rat gamma globulin both in the Kupffer cells and in biliary epithelial cells. Further investigations are required to probe the nature of this material, and its significance in the evolution of the biliary necroses.

Disturbances of hydration of cells of rat liver in extrahepatic cholestasis

Livers of rats were examined during a period of 39 days after ligation of the common bile duct. A widespread disturbance of cell hydration was noted. There was oedema of some of the microvilli of biliary epithelial cells in ductules, and of some of the microvilli of parenchymal liver cells. In other cases, a condensation or oedema affected the hyaloplasm of entire biliary epithelial, endothelial or Kupffer cells. Retrograde intrabiliary injections of colloidal mercuric sulphide showed that these particles came in contact not only with cell surfaces lining biliary lumina, but that they also penetrated between biliary epithelial cells, and traversed their basement membranes to reach the lumina of capillaries and sinusoids. The particles also were found within biliary ductular cells and hepatocytes. These observations led us to suggest that bile constituents with detergent and protein denaturing properties may escape by these routes, and so cause the alterations in hydration. It has also been suggested that the mode of regurgitation of bile in extrahepatic cholestasis is by diffusion across natural barriers rather than by rupture of the bile conduction pathways. Die Leber von Ratten wurde bis 39 Tage nach einer Unterbindung des Gallenganges elektronenmikroskopisch untersucht. Dabei konnte eine ausgesprochene Veränderung des Wassergehaltes der Zellen beobachtet werden. Einige der Mikrovilli der Gallengangsepithelien und manche Mikrovilli der Leberzellen waren ödematös geschwollen; in anderen Fällen hatte Kondensierung oder Ödem, das Hyaloplasma einer ganzen Gallengangsepithelzelle, Endothelzelle oder Kupfferschen Sternzelle erfaßt. Retrograde Injektion von kolloidalem Quecksilbersulfid in den Gallengang zeigte, daß diese Partikel nicht nur mit der Oberfläche der die Gänge auskleidenden Epithelzellen in Berührung kommen, sie dringen vielmehr auch zwischen die Epithelzellen ein, durchqueren die Basalmembran, um schließlich die Lichtung der Capillaren und der Sinusoide zu erreichen. Auch in den Zellen der Ductuli und den Leberzellen selbst wurden Partikel gefunden. Auf Grund dieser Beobachtungen erscheint die Annahme berechtigt, daß Gallenbestandteile mit der Fähigkeit, detergent zu wirken und Eiweiß zu denaturieren, auf diesem Wege austreten und so die Veränderungen im Wassergehalt der Zellen verursachen könnten. Dies würde mit der Anschauung übereinstimmen, nach der die Galle bei extrahepatisch bedingter Cholostase eher infolge einer Diffusion durch die natürlichen Barrieren, als infolge einer Ruptur aus den Gängen austrete.