Henry Johansson

Clinical characteristics in sporadic and familial medullary thyroid carcinoma: a nationwide study of 249 patients in Sweden from 1959 through 1981

All patients with medullary thyroid carcinoma (MTC) diagnosed in Sweden during 1959 through 1981 were recruited for study from the Swedish Cancer Registry. Among a total of 249 patients, 66 were diagnosed in 1959 through 1969 and 183 from 1970 through 1981. Apparently sporadic MTC was present in 186 patients and familial MTC in 63. Twenty‐seven patients with familial MTC were diagnosed from clinical symptoms and 36 by screening. In both the sporadic group and the symptomatic familial group, approximately 80% of the patients had palpable thyroid tumors. Lymph node metastases were present in 44% of the sporadic group and in 37% of the group with symptomatic familial MTC, and distant metastases in approximately 20% of the patients in each of these groups. The patients detected by screening differed significantly from the two groups of symptomatic cases by having a lower frequency of palpable thyroid lesions (50%), smaller tumors, and lower frequencies of cervical lymph node metastases (14%) and distant metastases (0%). Multivariate analyses revealed no significant differences between sporadic cases and symptomatic familial cases regarding tumor size or stage. Large tumors (>3 cm) were more frequently accompanied by palpable cervical lymph nodes and were associated with an approximately four times higher risk of distant metastases than tumors smaller than 1 cm. Women had significantly smaller tumors and a more favorable stage distribution than age‐related men.

Complex Co-localization of Chromogranins and Neurohormones in the Human Gastrointestinal Tract

Co-localization of chromogranin (Cg) A, B, and C has been studied in different neuroendocrine cell types in histologically normal mucosa from human gastrointestinal tract (corpus, antrum, duodenum, ileum, and colon) using single-, double-, and triple-immunofluorescence stainings. Virtually all enterochromaffin (EC) cells contained CgA, and those in the luminal two thirds of the antral mucosa and villi of small intestine often also contained CgB. A few EC cells in the duodenal crypts contained CgC. Most gastrin cells harbored both CgB and CgA, although rather more CgB than CgA, but some gastrin cells contained all three types, i.e., also CgC. Some CCK cells also contained all three chromogranins. Enteroglucagon cells in the duodenal villi contained CgA and some CgB. CgA (but not B or C) was found in some secretin, GIP, enteroglucagon/peptide YY, and neurotensin cells. A few somatostatin cells contained CgA but neither CgB nor CgC. CgA and C were found mainly in the basal cell region, whereas CgB occurred more diffusely throughout the cytoplasm. This varying distribution suggests that not all secretory granules contain CgA, or that CgB may occur in a nongranular form. The varying composition of the different chromogranins may reflect their complex functional roles in the widespread neuroendocrine system.

Patients with primary hyperparathyroidism operated on over a 24-year period: Temporal trends of clinical and laboratory findings☆

Temporal trends of clinical and laboratory data of 441 patients operated upon for primary hyperparathyroidism (HPT) during 1956-1979 were analysed retrospectively. There was a marked increase in the number of operations for HPT during that time period, from 32 during 1956-1964 to 326 in 1970-1979. In parallel there was a decrease in the proportion of patients with classical manifestations of HPT such as renal stones or bone disease, the latter being on the whole rarely seen in this population. The increased number of operations was instead largely attributable to the more frequent diagnosis of HPT in patients with vague psychiatric or neuromuscular symptoms or with no clinical manifestations; the majority of these persons were older women, the proportion of operations in women 45 years of age or older, increasing from 56% during 1956-64 to 71% during 1970-79. The increased number of operations for HPT during the last decades should be mainly the consequence of a greater awareness of the disease.

Chromogranin A in human neuroendocrine tumors. An immunohistochemical study with region-specific antibodies.

Antibodies to six specific regions of the chromogranin A (CgA) molecule were used to study their immunoreactivity in human neuroendocrine (NE) tumors. Tissue specimens from endocrine pancreatic tumors (n = 14), duodenal carcinoids (n = 2), bronchial carcinoids (n = 5), ileal carcinoids (n = 5) appendix carcinoids (n = 2), medullary thyroid carcinomas (n = 6), parathyroid adenomas (n = 2), and pheochromocytomas (n = 8) were analyzed. The results showed that the NE tumor types expressed varying numbers of CgA fragments. A variation in frequency of the expression of immunoreactive cells was sometimes seen also within the same tumor type. The midportion fragment CgA 176–195 (chromacin) was the only fragment expressed in all tumors. Benign and malignant tumors expressed different patterns, being especially true of insulinomas and pheochromocytomas. These findings suggest that region-specific antibodies to CgA fragments can be used as a diagnostic tool for the characterization of NE tumors.

Malignant and benign human mammary disease: Estrogen binding in relation to clinical data

The estrogen binding capacity (EBC) of biopsies from human mammary carcinoma, benign mammary disease, and from “normal” tissue surrounding the tumors was measured. The biopsies were classified following a statistical criterion as positive (having EBC) or negative. Of 105 cases of breast carcinoma, 49% were positive and 51% were negative. Only 5 of 35 cases of benign disease were positive; no positive case of normal tissue was observed. There was no significant correlation between the presence of EBC in a tumor and tumor histology, differentiation, or cellularity, nor between EBC and the menopausal age of the patient or the clinical stage of the disease. On die other hand, the magnitude of the EBC was significantly higher in tumors of medium than of low differentiation and higher with high than with medium cellularity. Ductal carcinomas had higher EBC than adenocarcinomas. In a limited number of cases, EBC values were determined in primary and secondary tumors in the same patient. Provided differences in cellularity were taken into account, the assignment of EBC of the secondary tumor coincided with that of the primary tumor in 6 cases out of 8.

Abdominal surgery in patients with midgut carcinoid tumors.

In patients with midgut carcinoid tumors a curative, radical tumor removal should be attempted when possible. As these tumors are generally malignant, irrespective of size, the radical surgery implies that intestinal resection for excision of a primary tumor should be combined with an extended mesenteric resection. When the patients present with the carcinoid syndrome the disease is, with few exceptions, too advanced for curative surgery. However, surgery often has to be performed also in patients with the advanced carcinoids. Patients with more extensive disease may thus benefit from surgical debulking of large mesenteric or hepatic metastases. Moreover, when the patients present with abdominal symptoms it is important to exclude a threatening major abdominal complication, such as intestinal obstruction or ischemia. As these complications may cause malnutrition and deterioration, it is important to treat them properly, sometimes by repeated surgery.

Cyclic AMP raises cytoplasmic calcium in pancreatic α2-cells by mobilizing calcium incorporated in response to glucose

The cytoplasmic Ca2+ concentration ([Ca2+]i) was monitored in individual guinea-pig pancreatic alpha 2-cells exposed to modulators of glucagon release. Addition of the stimulatory amino acid arginine resulted in a sustained increase in [Ca2+]i, whereas the inhibitor glucose had the opposite effect. Epinephrine, the beta-adrenergic agonist isoproterenol, the adenylate cyclase activator forskolin and 8-bromo-cAMP transiently raised [Ca2+]i provided that the cells had been pretreated with glucose. However, simultaneous presence of glucose was not required and the effect occurred even in the absence of extracellular Ca2+. Carbachol, the alpha 2-adrenergic agonist clonidine and the sulfonylurea tolbutamide lacked effects on [Ca2+]i. In addition to providing support for the concept that glucagon release is positively modulated by [Ca2+]i, the results demonstrate that cAMP raises [Ca2+]i in the alpha 2-cells by mobilizing calcium incorporated in response to glucose.

Detection of apoptotic cells and expression of Ki-67 antigen, Bcl-2, p53 oncoproteins in human parathyroid adenoma.

Presence of apoptotic cells and immunoreactivity to Ki‐67, bcl‐2 and p53 were studied in 20 cases of parathyroid adenoma. To determine apoptosis, the DNA nick end labeling method was used. 85% of the parathyroid adenomas were found to harbor apoptotic cells. All of the 20 adenomas contained Ki‐67 immunoreactive cells. Proliferative activity was not more confined to nodular than to diffuse areas, but there was a highly significant difference in Ki‐67 immunoreactivity between adenomatous tissue and the residual rim of normal tissue outside the adenoma. No Ki‐67 immunoreactive cells were found in two normal parathyroid glands used as controls. All but one of the adenomas (95%) demonstrated immunoreactivity to bcl‐2, but expression of p53 was detected in only a few adenomas (15%). There was a significant relationship between the adenoma weights and both Ki‐67 and bcl‐2. This study suggests that parathyroid adenomas contain cell populations with proliferative activity (clonal proliferation), but the weak immunoreactive expression of p53 combined with the relatively strong expression of bcl‐2 might contribute to a slow glandular growth.

Cytoplasmic Ca2+ concentration of single normal human and bovine parathyroid cells measured by dual wavelength microfluorometry

Dual wavelength microfluorometry was utilized to measure the cytoplasmic calcium concentration (Cai2+) of single parathyroid cells loaded with the indicator fura-2. The method enabled the first registrations of Cai2+ of normal human parathyroid cells, available only in minute numbers. At 0.5 mM extracellular Ca2+, the Cai2+ levels were similar in normal human and bovine cells. Both cell types responded with an initial Cai2+ transient followed by a sustained increase when raising extracellular Ca2+ to 3.0 mM. The sustained effect exhibited a sigmoidal relation to extracellular Ca2+ in the 0.5–3.0 mM range. Although the increase was somewhat greater in the human cells, the half maximal responses were obtained at almost identical extracellular Ca2+ concentrations. Whereas K+ depolarization decreased Cai2+, the Cai2+ channel blocker D-600 had dual actions, raising Cai2+at 0.5 mM Ca2+ and decreasing it at 3.0 mM Cai2+, and the effects were similar in the bovine and human cells. The present experimental approach verified the validity of utilizing bovine cells as controls in studies of human parathyroid tissue and it appears suitable for analysis of the role of different subpopulations of parathyroid cells in the abnormal parathyroid tissue of patients with hyperparathyroidism.

PARATHYROID PATHOLOGY IN HYPERPARATHYROIDISM SECONDARY TO CHRONIC RENAL FAILURE

Weights and histopathological changes in parathyroid glands were evaluated in relation to clinical and biochemical parameters in 42 patients who underwent parathyroidectomy for hyperparathyroidism (HPT) secondary to chronic renal failure. There was a positive relation (r = 0.71, p less than 0.01) between duration of renal insufficiency and total parathyroid glandular weight. The glandular weight was also closely related to the serum levels of parathyroid hormone (r = 0.67, p less than 0.01). No correlation was found between total parathyroid glandular weight or histopathological findings and clinical symptoms, serum levels of calcium, phosphate, alkaline phosphatases, calcium X phosphorus product or radiological evidence of bone disease. The enlargement of the glands was mostly uniform in the individual patient and all patients showed multiple gland involvement. This indicates that when parathyroid surgery is performed in patients with uraemia and secondary HPT, a radical approach, i.e. total parathyroidectomy with autotransplantation or subtotal parathyroidectomy, should always be used. In smaller glands only diffuse hyperplasia of parenchymal cells was generally found; fat cells were present in near-normal amounts. With increasing glandular weight, fat cells were more sparse and nodularity was common. In general, the proportion of oxyphil cells increased parallel with the total glandular weight, suggesting that this cell type is sensitive to stimulation. As a group, patients undergoing conservative renal treatment had suffered longer with renal disease, had larger parathyroid glands with more nodularity, and had more oxyphil cells than those undergoing parathyroidectomy while on haemodialysis.