Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome.

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumours, which are frequently carcinomas, and ossifying jaw fibromas. In addition, some patients may develop renal tumours and cysts. The gene causing HPT-JT, which is referred to as HRPT2 and is located on chromosome 1q31.2, encodes a 531 amino acid protein called PARAFIBROMIN. To date 42 mutations, of which 22 are germline, have been reported and 97% of these are inactivating and consistent with a tumour suppressor role for HRPT2. We have investigated another four HPT-JT families for germline mutations, searched for additional clinical phenotypes, and examined for a genotype-phenotype correlation. Mutations were found in two families. One family had a novel deletional-insertion at codon 669, and the other had a 2 bp insertion at codon 679, which has been reported in four other unrelated patients. These five unrelated patients and their families with the same mutation were not found to develop the same tumours, thereby indicating an absence of a genotype-phenotype correlation. An analysis of 33 HPT-JT kindreds revealed that affected women in 13 HPT-JT families suffered from menorrhagia in their second to fourth decades. This often required hysterectomy, which revealed the presence of uterine tumours. This resulted in a significantly reduced maternal transmission of the disease. Thus, the results of our analysis expand the spectrum of HPT-JT-associated tumours to include uterine tumours, and these may account for the decreased reproductive fitness in females from HPT-JT families.

Fine needle aspiration in plastic surgery outpatients: a retrospective study.

A survey suggested that fine needle aspiration cytology of masses in plastic surgery outpatient clinics was suboptimal. A cytopathologist gave training in the technique and the effectiveness of this intervention was audited. A total of 236 aspirates were taken from 147 patients in the earlier time period and 215 from 149 in the later period. The overall inadequate aspirate rate remained constant at 43%. The most common reasons for poor aspirates were excess blood, unrepresentative adipose tissue and insufficient cellular material. When the specimen was adequate after training, the sensitivity and specificity of the investigation were 96% and 100%, respectively. We present methods for sample optimization. Alternative strategies may be to limit aspiration to one clinician or to refer the patient to a cytopathologist experienced in the technique.

Histopathological assessment of metastasis.

In spite of advances in the fields of immunohistochemistry and molecular biology, in clinical practice much of the assessment of metastases still relies on light microscopy using conventional histological stains. This is not so much a reflection of a reluctance by histopathologists to adopt new techniques, but more an indication that for most malignancies an enormous amount of useful prognostic data can be gained from relatively unsophisticated assessment of tissues, and that many of the strongest studies of prognostic factors in malignancy predate the era of molecular diagnostics. Although it is undoubtedly true that newer techniques have added prognostic information in the assessment of many tumors, and many, such as the measurement of estrogen receptor status in breast cancer, could be considered routine, a skilled assessment of the morphology of the tissues still provides the fundamental basis of assessing prognosis in the vast majority of cases.

An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration.

The sequestration of parasitized erythrocytes in the microvasculature of vital organs is central to the pathogenesis of severe Plasmodium falciparum malaria. This process is mediated by specific interactions between parasite adherence ligands and host receptors on vascular endothelium such as intercellular adhesion molecule-1 (ICAM-1) and CD36. Using immunohistochemistry we have examined the distribution of putative sequestration receptors in different organs from fatal cases of P. falciparum malaria and noninfected controls. Receptor expression and parasite sequestration in the brain were quantified and correlated. Fatal malaria was associated with widespread induction of endothelial activation markers, with significantly higher levels of ICAM-1 and E-selectin expression on vessels in the brain. In contrast, cerebral endothelial CD36 and thrombospondin staining were sparse, with no evidence for increased expression in malaria. There was highly significant co-localization of sequestration with the expression of ICAM-1, CD36, and E-selectin in cerebral vessels but no cellular inflammatory response. These results suggest that these receptors have a role in sequestration in vivo and indicate that systemic endothelial activation is a feature of fatal malaria.

Measuring proliferation in routine fine needle aspirates. Immunocytochemical detection of bromodeoxyuridine incorporation and Ki-67 expression in breast aspirates.

Two simple quantitative means of measuring tumour proliferation which can be applied to cytological material are described. One method involves immunocytochemical staining of cytological smears prepared from breast aspirates with the monoclonal antibody Ki-67. The other method involves incubation of aspirated material with 5-Bromo-2-deoxyuridine (BrdU). Direct measurement of the S phase of the cell cycle is feasible in breast fine needle aspirates by Bromodeoxyuridine incorporation and subsequent immunocytochemical detection. The proliferation indices obtained correlate with those derived from Ki-67 staining. This technique is suitable for routine use in the assessment of tumour proliferation.

Immunocytochemical staining of serous effusions with the monoclonal antibody Ber-EP4.

Cytospin preparations were made from 102 serous effusions for immunocytochemical staining using a panel of monoclonal antibodies including a new monoclonal antibody Ber-EP4. On cytological examination, 32 fluids were reported to contain tumour cells consistent with metastatic adenocarcinoma; 66 contained benign cells only and three were reported to contain cells suspicious of malignancy. One effusion contained tumour cells consistent with malignant mesothelioma. Positive staining of the tumour cells with Ber-EP4 was observed in the 32 effusions (100%) which contained adenocarcinoma cells. No staining of the mesothelial cells in these 32 specimens was observed. Carcinoembryonic antigen, epithelial membrane antigen Ca2 and CD15 staining of tumour cells was noted in 53%, 50%, 50% and 9% of these cases, respectively. None of the mesothelial cells in the benign effusions stained with Ber-EP4. Nor did the malignant mesothelial cells in the only case of malignant mesothelioma. These findings suggest that Ber-EP4 is a valuable addition to antibodies available for the differential diagnosis of mesothelial cells and adenocarcinoma cells in serous effusions.

Medullary carcinoma of the thyroid: management of persistent hypercalcitonaemia utilizing [99mTc] (v) dimercaptosuccinic acid scintigraphy.

Whole body scintigraphy with [99mTc] (v)dimercaptosuccinic acid (pentavalent DMSA) was performed in seven patients with histologically confirmed medullary carcinoma of the thyroid (MCT). Six of these patients had undergone previous thyroid resections for MCT and, although asymptomatic at the time of pentavalent DMSA scintigraphy, had persistent and serial elevations in their plasma calcitonin levels. One additional patient was scanned before and after total thyroidectomy for MCT. The pentavalent DMSA scintigram demonstrated either local neck recurrence (three patients) or distant metastases (two patients) in five of the six asymptomatic patients. In one asymptomatic patient only equivocal neck uptake was demonstrated. Since he had only minimal calcitonin elevations, repeat neck exploration was not performed. The one patient studied before thyroid resection for MCT demonstrated neck uptake before, but not after, total thyroidectomy. The results of the scintigrams had significant impact on patient care and resulted in neck re-exploration (three patients), neck biopsy (one patient), and lumbar spine biopsy and subsequent radiotherapy (one patient). These data demonstrate pentavalent DMSA to be a sensitive localizing agent in the evaluation of asymptomatic MCT patients with hypercalcitonaemia. Accurate targeting of treatment may be shown in due course to have a beneficial impact on survival.

Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes.

Morphometric analysis of the endocrine and exocrine pancreas was done on immunoperoxidase stained post-mortem tissue from 15 Type 2 diabetic and 10 age-matched control subjects. Thirteen of the 15 Type 2 diabetic patients had islet amyloid deposits (mean, 6.5% islet area) in the corpus (body, tail and anterior part of the head) but not in the caput (the "pancreatic polypeptide rich" part of the head) whereas none was seen in control subjects. In the corpus in diabetic subjects, the pancreatic area density of B-cells was decreased by 24% (p = 0.005) and A-cells increased by 58% (p less than 0.001) compared with control subjects. The mean A/B-cell ratio increased in the corpus from 0.27 in control subjects to 0.57 in Type 2 diabetic patients. Positive immunoreactivity for the amyloid constituent peptide, Diabetes Associated Peptide, was demonstrated in islet amyloid of diabetic subjects and in B-cells of control and diabetic subjects. The increase in A-cells may contribute to the hyperglucagonaemia and hyperglycaemia of Type 2 diabetes. The impaired insulin secretion in Type 2 diabetes may be due to a decrease in B-cells and to disruption of the islet structure by amyloid. Exocrine fat was similar in the control and diabetic subjects with both groups having more in the corpus than the caput. Diabetic subjects had increased exocrine fibrosis in the corpus region (p less than 0.001), but not in the caput. Exocrine fibrosis may be secondary to disordered islet cell function.

Granular cell tumours revisited. An immunohistological and ultrastructural study.

Twenty-five granular cell tumours were stained with a panel of antibodies to histiocytic, muscle, neural, neural crest, epithelial and endothelial markers. Electron microscopy was also performed in six cases. Twenty-four of the cases were similar morphologically and immunocytochemically. One case with features of an endothelial origin is described. The present study strongly supports the viewpoint that granular cell tumours are a distinct entity rather than being the common appearance of a group of lesions of differing histogenesis. Origin from a neural crest-derived peripheral nerve-related cell is favoured.

Expression of intermediate filament proteins in normal and diseased thyroid glands.

A total of 67 samples from normal and pathological thyroid glands were stained (as formalin fixed paraffin sections) with a panel of monoclonal antibodies directed against intermediate filament proteins. The study confirmed previous reports of cytokeratin and vimentin coexpression in primary thyroid carcinomas, but coexpression was also detected in normal thyroid and in a range of benign conditions including follicular adenomas, Hashimoto's thyroiditis, and diffuse hyperplasia (thyrotoxicosis). Prekeratin expression was found (using antibodies recognising higher molecular weight cytokeratins) predominantly in areas of squamous change, independent of the underlying thyroid pathology. This study does not therefore support previous findings that prekeratin expression provides a reliable means of distinguishing follicular pattern papillary carcinoma from follicular carcinoma with its poorer prognosis or that it helps distinguish benign from malignant papillary lesions. No evidence of desmin or neurofilament expression was seen, and in particular, neurofilaments could not be detected in any of the cases of medullary carcinoma studied.

Autoimmunity to insulin receptor and hypoglycaemia in patient with Hodgkin's disease.

A 76-year-old man with fasting hypoglycaemia had impaired in-vitro binding of insulin to erythrocyte receptors. The immunoglobulin fraction of his plasma inhibited binding of insulin to normal donor erythrocytes in vitro. Autoantibodies may have stimulated the insulin receptor and produced hypoglycaemia. Hodgkin's disease developed and may have induced the autoimmunity. The hypoglycaemia did not respond to plasmapheresis or azathioprine alone, but it remitted after the addition of prednisolone, and the erythrocyte receptor binding of insulin became normal.