Nassif B.N. Ibrahim

Extrapulmonary oat cell carcinoma

Primary extrapulmonary tumors with histologic features indistinguishable from bronchogenic oat cell carcinoma are appearing with increasing frequency in the literature. These tumors have been described in the esophagus, stomach, pancreas, larynx, hypopharynx, salivary glands, nasal cavity and paranasal sinuses, thymus, small and large bowel, uterine cervix, endometrium, breast, prostate, urinary bladder, and skin. It is now widely believed that oat cell carcinoma is a poorly differentiated counterpart of carcinoid tumor and that both originate from an endocrine cell system. In this article, the authors review all cases of extrapulmonary oat cell carcinomas, which they were able to find in the English literature, and report personally studied examples of these tumors, occurring in the esophagus, stomach and urinary bladder. A closely related, if not identical, tumor arising in the skin is also described. It is emphasized that a wider recognition of these tumors is likely to lead to their more frequent diagnosis and possible treatment.

Expression of the C-terminal peptide of human pro-bombesin in 361 lung endocrine tumours, a reliable marker and possible prognostic indicator for small cell carcinoma.

Small cell carcinoma of the lung is a highly malignant tumour. Its known biological products which include bombesin, do not allow the prediction of tumour behaviour. Molecular biology has revealed the amino acid sequence of human pro-bombesin, which consists of a signal peptide, the bioactive bombesin molecule and a C-terminal peptide. We have raised a rabbit antiserum to the first (N-terminal) 21 amino acids of the predicted C-terminal peptide. A total of 505 (361 neuroendocrine) surgically resected pulmonary tumours were evaluated for the presence of immunoreactive bombesin and C-terminal peptide. Strong immunostaining was obtained with the antiserum to the C-terminal peptide of human probombesin in 70% of the small cell carcinomas (175/250), in 63% of atypical (aggressive) carcinoids (31/49) but only in 16% of benign carcinoids (10/62). In contrast, bombesin immunostaining was focal and only moderately strong and the relative proportion of positive cases was quite evenly distributed amongst the neuroendocrine tumours: 35% of carcinoids (22/62), 22% of atypical carcinoids (11/49) and 25% of small cell carcinoma (62/250). None of the squamous, adeno, or large cell undifferentiated carcinomas were immunoreactive for bombesin or the C-terminal peptide. Radioimmunoassay and chromatography of extracts of tumours recovered from wax blocks revealed high concentrations of C-terminal peptide immunoreactivity (241±66 pmol/g of tissue) in all 12 small cell carcinomas studied, moderate concentrations in carcinoid tumours (50±7 pmol/g) and none in non-small cell carcinomas. Patients with tumours showing immunoreactivity to the C-terminal peptide of human pro-bombesin had a significantly shorter survival time than those without immunoreactive peptide (185±16.49 days, mean± SEM, and with 1128±226 days, respectivelyP> 0.02). The apparent presence of the C-terminal peptide of human pro-bombesin in higher concentrations than bombesin in the more malignant class of endocrine tumours, mainly small cell carcinomas associated with the poorest prognosis, suggests that the antiserum to this C-terminal peptide is not only a useful pathological marker but may prove to be of value in investigating the biological behaviour of small cell carcinomas and predicting the clinical course of the disease.

Experience of thin cutaneous melanomas (< 0.76 mm and < 0.85 mm thick) in a large plastic surgery unit: a 5 to 17 year follow-up

The detailed histological findings of 728 melanoma patients treated at Frenchay Hospital during the period 1967 to 1978 have been fully reviewed and analysed. Of these, 75 patients with lesions less than 0.76 mm thick and 15 with lesions greater than 0.75 mm and less than 0.85 mm thick have been identified using a computerised data base. The general practitioners of all the patients in the series have been approached and the clinical histories found in nearly every case (69/75 and 15/15) thus providing a follow-up period of 5 to 17 years. A number of fatal melanomata have been found in these two groups. The histopathological features have been related to the known prognosis in an attempt to characterise the lethal lesions. No statistically significant relationship could be found between prognosis and any histological feature, including specifically the amount of regression within the lesion. However, it was found that assessment of the ratio of the uninvolved dermis beneath the tumour to tumour thickness itself might prove helpful in future case evaluation.

Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury

BackgroundThe properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.MethodsVEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.Measurements and Main ResultsVEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05).ConclusionThese data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.

Abnormal p53 expression in lung neuroendocrine tumors. Diagnostic and prognostic implications.

The diagnostic and prognostic implications of p53 immunostaining have been investigated in 59 pulmonary neuroendocrine tumors, including typical carcinoids (n = 15), so-called “atypical carcinoids” (n = 22), and small cell lung carcinomas (SCLCs; n = 22). Immunocyto-chemistry was performed on formalin-fixed, paraffin-embedded samples using the monoclonal antibody PAM801. which has been shown to be suitable for staining fixed and embedded tissue sections. p53 immunore-activity was restricted to atypical carcinoids (45% of the cases being immunoreactive) and to SCLCs (which were positively stained in 59% of the cases), whereas it was consistently lacking in typical carcinoid tumors. When the group of the so-called “atypical carcinoids” was further reclassified, p53 immunostaining was strictly confined to those cases belonging to the histologically more aggressive subsets (well differentiated neuroendocrine carcinoma subsets II and III). Within the same tumor type, however, p53 immunoreactivity did not correlate with the clinical outcome of the disease and was not predictive of the length of survival. The data indicate that abnormal p53 expression (which is strictly dependent on structural abnormalities of the p53 gene) is detectable in the majority of neuroendocrine carcinomas of the lung and might represent a useful adjunct in the differential diagnosis of pulmonary neuroendocrine neoplasms, particularly in routinely fixed and embedded small bronchoscopic biopsies.

Perivascular Nerves of the Human Basal Cerebral Arteries: I. Topographical Distribution

In the present study the topographical distribution of the intrinsic nerve plexuses of the basal cerebral arteries in humans was quantified and the relation between vessel diameter and nerve density was investigated. Whole-mount preparations of various segments of the basal cerebral arteries from middle-aged patients were stained for protein gene product (PGP) 9.5. The deep nerve plexuses, located at the adventitial–medial border, were quantified by image analysis. Confocal scanning laser microscopy was used to study nerve plexuses throughout the adventitia. Transverse cryostat sections were stained for PGP 9.5, tyrosine hydroxylase and neurofilament, and quantified. The results showed a three-layered configuration of the adventitial nerves. Measurements on whole-mounts demonstrated that nerve densities were highest in the posterior communicating artery (PCom), and next highest in the proximal parts of the posterior cerebral artery (PCA) and anterior choroidal artery. There appeared to be no clear relation between nerve density and vessel diameter. The measurements on sections confirmed the high nerve densities in the PCom and PCA. Tyrosine hydroxylase- and neurofilament-immunoreactivities appeared to demonstrate separate subpopulations of the overall nerve plexuses, representing sympathetic and, possibly, sensory fibers, respectively. Densities of both subgroups generally followed those of PGP 9.5-immunoreactive nerves. Transmission electron microscopy suggested motor function of the deep nerve plexuses. The results indicate a stronger neuronal influence on this part of the cerebral circulation than hitherto reported. It is concluded that human basal cerebral arteries display a topographical distribution of deep perivascular nerves, and that nerve density is determined by locality rather than by vascular diameter.

Vascular endothelial growth factor receptor and coreceptor expression in human acute respiratory distress syndrome

Background Acute respiratory distress syndrome (ARDS) is characterized by the development of noncardiogenic pulmonary edema, which has been related to the bioactivity of vascular endothelial growth factor (VEGF). Vascular endothelial growth factor receptors and coreceptors regulate this bioactivity. We hypothesized VEGF receptors 1 and 2 (VEGFR1, VEGFR2) and coreceptor neuropilin-1 (NRP-1) would be expressed in human lung tissue with a significant change in expression in ARDS lung. Methods Archival “normal” (no lung pathology and non-ARDS), “early” (within 48 hours), and “later” (after day 7) ARDS lung-tissue sections (n = 5) were immunostained for VEGFR1, VEGFR2, and NRP-1 from human subjects (n = 4). Staining was assessed densitometrically using Histometrix software. Results VEGFR1, VEGFR2, and NRP-1 were expressed on both sides of the alveolar-capillary membrane in both normal and ARDS human lung tissue. In later ARDS, there was a significant up-regulation of VEGFR1 and VEGFR2 versus normal and early ARDS (P < .0001). Neuropilin-1 was down-regulated in early ARDS versus normal lung (P < .05), with normalization in later ARDS (P < .001). Conclusion Differential temporal VEGFR1, VEGFR2, and NRP-1 up-regulation occurs in human ARDS, providing evidence of further functional regulation of VEGF bioactivity via VEGFR2 consistent with a protective role for VEGF in lung injury recovery. The mechanisms behind these observations remain to be clarified.

Extraadrenal paragangliomas: An immunocytochemical and ultrastructural report

Although the majority of extraadrenal paragangliomas are nonfunctional, some of these tumors are associated with hormone production and clinical symptoms, notably hypertension. The authors have investigated 22 paragangliomas, five of which were diagnosed as clinically functional in a light microscopic immunocytochemical and electron microscopic study (nine cases). Histologically, all the paragangliomas exhibited similar features, with a “Zellballen” pattern of polygonal cells. All 22 cases were strongly immunoreactive to protein gene product 9.5 (PGP 9.5) antisera and moderately reactive to antineuron‐specific enolase (NSE) sera. Ten cases (five functional) were focally immunoreactive to antichromogranin sera. Seven cases (four functional) were immunoreactive to neuropeptide Y and enkephalin antisera, and six (five functional) to tyrosine hydroxylase antisera. The clinically functional tumors expressed at least two of the antigens, enkephalin, neuropeptide Y, or tyrosine hydroxylase, whereas none of the 17 nonfunctional possessed more than one of these. Electron microscopic study revealed cells from all the nine cases studied to contain secretory granules. Granule sizes ranged from 100 to 280 nm and the morphologic examination of the secretory granules generally showed a dense core with a membrane‐bound halo of variable size. Secretory granules were observed in the five functional cases and these were larger (220–280 nm) than those seen in the nonfunctional tumor cells (100–180 nm). Also, tumor cells from the functional cases contained numerous dilated mitochondrial profiles.

A melanoma registry based on a computer-run word and data processing system

A Melanoma Register, previously organised on a filing card system, has been largely transferred to a computer which utilises both word and data processing programs. This transfer has revolutionised not only the analytical potential of the material, but the follow up of all patients, both old and new. The system is applicable to many other tumours and diseases.

Gynaecomastia: A decade of experience

BACKGROUND Gynaecomastia is the most common benign condition of the male breast and accounts for up to 80% of male breast referrals. We sought to identify any changes in the number of patients referred with the condition and assess its impact on clinical practice. METHODS Patients were identified from two prospectively maintained databases. Diagnosis of gynaecomastia was based on clinical findings, ultrasound scan (USS) assessment and/or histology. RESULTS There was a significant increase in the number of men referred to a specialist unit and diagnosed with gynaecomastia. Gynaecomastia was more prevalent in the under twenties age group. Core biopsy (CB) became the histological investigation of choice for men with unilateral disease and there was no change in the percentage of men undergoing surgery. CONCLUSION Most men are looking for reassurance that their condition is benign and that no intervention is required. Thus it is important to offer these men psychological support as part of their treatment.