Pathologic study and clinical significance of Hürthle cell papillary thyroid carcinoma.

Hürthle cell papillary thyroid carcinoma is a variant of papillary thyroid carcinoma (PTC). Its pathologic and clinical significance has not been well documented. The authors studied the relative incidence of Hürthle cell PTC and the relationship of Hürthle cell PTC to other variants of thyroid carcinoma. Three hundred eighty consecutive cases of thyroid carcinoma were reviewed to identify cases with focal or extensive areas of Hürthle cell PTC, classic PTC, Hürthle cell carcinoma (ie, non-Hürthle cell PTC), and follicular carcinoma. In addition, the status of lymphoid infiltrate in the tumor, stromal invasion with desmoplastic reaction, vascular invasion, and distant and lymph node metastasis were noted by microscopic examination, review of clinical charts, or both. A total of 24 (HCs) and 42 PTCs with Hürthle cells were identified. The latter category was divided into pure Hürthle cell PTC or extensive Hürthle cell (HPTC) (28 cases) and PTC or Hürthle cell carcinoma with focal areas of Hürthle cell PTC (14 cases). The Hürthle cell PTC/Hürthle cell carcinoma ratio was lower than that of PTC/follicular carcinoma (39:289) (P = 0.001). Follicular or solid structures were present in all HPTCs. HPTCs were associated with frequent stromal intrathyroid and extrathyroid invasion, but they tended to have a lower rate of lymph node metastasis (8/28) compared with classic PTC with stromal invasion (108:200) (P = 0.12) and a lower rate of distant metastasis (2:28) compared with Hürthle cell carcinoma (15:24) (P = 0.02) or follicular carcinoma (13:39) (P = 0.04). Warthin-like Hürthle cell PTC (10 cases) was associated with extrathyroid invasion in five cases. In Hürthle cell PTC associated with tall cell variant (10 cases), areas of gradual transition between Hürthle cell PTC and tall cell variant were identified. The latter variant showed the highest rate of extrathyroid stromal and vascular invasion with distant metastasis and patient death compared with all Hürthle cell PTCs and classic PTCs. In conclusion, Hürthle cell PTC is frequently associated with tall cell variant. It has a higher potential for extrathyroid invasion than classic PTC and has vascular invasion and distant metastasis characteristics intermediate between those of classic PTC and Hürthle cell carcinoma with or follicular carcinoma. Hürthle cell PTC tends to show a greater likelihood of extrathyroid invasion when associated with Warthin-like features and tall cell variant PTC, and higher vascular invasion and distant metastasis when associated with tall cell variant.     

Evidence for coexistence of enkephalin and glutamate in axon terminals and cellular sites for functional interactions of their receptors in the rat locus coeruleus

The authors previously showed that a subset of axon terminals in the locus coeruleus (LC) contains methionine5-enkephalin (ENK) and gamma-aminobutyric acid (GABA) immunoreactivities. However, numerous ENK-labeled terminals lacked GABA and exhibited synaptic specializations that were characteristic of excitatory-type transmitters. To determine whether ENK coexists with glutamate in the LC, preembedding immunoperoxidase detection of ENK or immunogold-silver was combined with postembedding identification of glutamate using a gold marker. Indeed, 28% of the ENK-labeled axon terminals examined (n = 250 axon terminals) also contained glutamate. To define further sites for functional interactions between opiate ligands and excitatory amino acid receptors, the ultrastructural localization of the mu-opioid receptor (MOR) was examined with respect to either the kainate receptor (KAR) or the R1 subunit of the N-methyl-D-aspartate (NR1)-type glutamate receptor in the LC. Gold-silver labeling for MOR and peroxidase labeling for either KAR or NR1 indicated that the MOR often was localized to the plasma membrane of dendrites that also exhibited immunolabeling for either glutamate receptor subtype. In contrast to the KAR, which was identified primarily in somata and dendrites, NR1 immunoreactivity also was found frequently in axon terminals as well as in glial processes. Glial processes containing NR1 occasionally exhibited immunolabeling for MOR and sometimes were directly apposed to MOR-containing dendrites in the LC. Furthermore, NR1-labeled receptors in axon terminals sometimes were presynaptic to MOR-labeled dendrites. The authors concluded that ENK and glutamate may be cotransmitters in LC afferents. Moreover, ligands at the KAR may modulate directly MOR-containing neurons in the LC, whereas actions at NR1 receptors may affect opioid-sensitive neurons through multiple cellular mechanisms, i.e., through presynaptic, postsynaptic, or glial actions.     

Phosphorylation of factor Va and factor VIIIa by activated platelets

Platelet activation leads to the incorporation of 32[PO4(2-)] into bovine coagulation factor Va and recombinant human factor VIII. In the presence of the soluble fraction from thrombin-activated platelets and (gamma-32P) adenosine triphosphate, radioactivity is incorporated exclusively into the M(r) = 94,000 heavy chain (H94) of factor Va and into the M(r) = 210,000 to 90,000 heavy chains as well into the M(r) = 80,000 light chain of factor VIII. Proteolysis of the purified phosphorylated M(r) = 94,000 factor Va heavy chain by activated protein C (APC) gave products of M(r) = 70,000, 24,000, and 20,000. Only the intermediate M(r) = 24,000 fragment contained radioactivity. Because the difference between the M(r) = 24,000 and M(r) = 20,000 fragments is located on the COOH-terminal end of the bovine heavy chain, phosphorylation of H94 must occur within the M(r) = 4,000 peptide derived from the carboxyl-terminal end of H94 (residues 663 through 713). Exposure of the radioactive factor VIII molecule to thrombin ultimately resulted in a nonradioactive light chain and an M(r) = 24,000 radioactive fragment that corresponds to the carboxyl-terminal segment of the A1 domain of factor VIII. Based on the known sequence of human factor VIII, phosphorylation of factor VIII by the platelet kinase probably occurs within the acidic regions 337 through 372 and 1649 through 1689 of the procofactor. These acidic regions are highly homologous to sequences known to be phosphorylated by casein kinase II. Results obtained using purified casein kinase II gave a maximum observed stoichiometry of 0.6 mol of 32[PO4(2-)]/mol of factor Va heavy chain and 0.35 mol of 32[PO4(2-)]/mol of factor VIII. Phosphoamino acid analysis of phosphorylated factor Va by casein kinase II or by the platelet kinase showed only the presence of phosphoserine while phosphoamino acid analysis of phosphorylated factor VIII by casein kinase II showed the presence of phosphothreonine as well as small amounts of phosphoserine. The platelet kinase responsible for the phosphorylation of the two cofactors was found to be inhibited by several synthetic protein kinase inhibitors. Finally, partially phosphorylated factor Va was found to be more sensitive to APC inactivation than its native counterpart. Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II- like kinase may downregulate the activity of the two cofactors.     

Factor V Quebec revisited

Factor V Quebec has been described as a bleeding disorder that exhibits an autosomal dominant inheritance pattern and presents severe bleeding after trauma. Two members of a fourth-generation (IV.13 and IV.15) Canadian family have been studied in detail and are the subject of this report. Their clinical presentations and histories have been described previously (Tracy et al: J Clin Invest 74:1221, 1984). Persistent abnormalities include mild thrombocytopenia and defective platelet factor V. Plasma factor V is present at near normal concentration and is fully functional. Thus, the bleeding diathesis appears to reflect the absence of platelet factor V activity. The recent report (Hayward et al: Blood 84:110a, 1994 [suppl, abstr]) of multimerin deficiency in these individuals led us to reevaluate these patients. Western blot analyses of platelet lysates developed with a variety of monoclonal antibodies show that the alpha-granule proteins, fibrinogen, von Willebrand factor, factor V and osteonectin are decreased in concentration and significantly degraded in the platelets of these patients. Thrombospondin, while not degraded, is substantially decreased. In contrast, platelet factor 4 and beta-thromboglobulin do not appear to be affected. These observations suggest that the alpha- granules are correctly assembled but the contents are subsequently subjected to proteolytic degradation. The results indicate that factor V Quebec disorder is probably associated with a generalized defect that leads to degradation of most proteins of the alpha-granules.     

The relationship of human platelet density to platelet age: platelet population labeling by monoamine oxidase inhibition

The relationship between platelet density and platelet age appears to vary between species with relatively few labeling studies in humans reported. In this study, irreversible monoamine oxidase (MAO) inhibitors were used to biochemically label the circulating platelet population in 15 humans. Platelet samples were then isolated during the 15 days after drug ingestion. The platelets were separated by density on continuous linear Percoll gradients and the density distributions were divided into five fractions containing approximately equal numbers of platelets. Baseline MAO activity was strongly correlated with platelet density. Twenty-four hours after a single dose of tranylcypromine, platelet MAO activities in the density subpopulations were reduced to 14% to 17% of the baseline values. During the first five days after inhibition, the rates of recovery of MAO activity (percentage per day) were inversely proportional to platelet density. The recovery rates in the two most dense fractions were initially slow but increased after five days. Percentage recovery of MAO activity in the least dense fraction was significantly greater than the percentage recovery in the most dense fraction on days 2, 3, 5, and 8 (P less than .01, sign test). These results support the hypothesis that normal human platelets show a small increase in density with age, but they do not exclude the additional possibility that human platelet lifespan is positively correlated with platelet density.     

Cardiac neoplasms at the Canadian Reference Centre for Cancer Pathology

OBJECTIVE: To review the Canadian Reference Centre for Cancer Pathology's experience with cardiac neoplasms by reviewing all cases with tumours involving the heart referred to the Centre from 1949 to 1995. Referred patient records, panel and consensus statement submissions and glass slides were reviewed in all cases. In selected cases additional immunohistochemical stains were obtained from paraffin block tissues. SETTING: National referral centre for difficult or interesting cancer pathology-related cases. PATIENTS: All cases were derived from referral of autopsy material and/or surgically resected neoplasms. Material was referred from 35 patients during 1949 to 1995. The group consisted of 17 males, 17 females and one infant patient in whom the sex was not specified. The patient age ranged from infancy to 85 years. RESULTS: The neoplasms referred consisted of 12 myxomas, 10 sarcomas, five lymphomas, two carcinomas, two papillary fibroelastomas and one each of rhabdomyoma, mesothelioma of the atrioventricular node, lipomatous hypertrophy of the intra-atrial septum and fibroma. The sarcomas were difficult to classify even with the use of additional immunohistochemical stains. All the lymphomas were of non-Hodgkin's type and were not of primary cardiac origin. CONCLUSIONS: The series of neoplasms referred to the Canadian Reference Centre for Cancer Pathology reflects changes in cardiac surgery, cardiac imaging and cardiac pathology as disciplines. Even with modern pathological techniques some cases, especially sarcomas, are still difficult to diagnose. The clinical presentation often reflects the chamber of origin of the neoplasm rather than being indicative of a specific tumour type.