Large cell neuroendocrine carcinoma of the ovary.

Large cell neuroendocrine carcinoma of the ovary is a recently described tumour entity that is now included in the WHO classification of primary ovarian neoplasms. Although mostly in stage I at diagnosis, this tumour shows an aggressive clinical behaviour with subsequent metastases and mean survival is less than one year. In addition to the neuroendocrine carcinoma, most cases also have a malignant surface epithelial tumour component. I here report a 64-year-old woman who was operated on for a right-sided ovarian large cell neuroendocrine carcinoma without a surface epithelial component, which constitutes only the second reported tumour of this "pure" kind. Histological and immunohistochemical findings are described and a review of the literature is presented. The patient was treated postoperatively with chemotherapy. She developed bleomycin-induced lung fibrosis that responded well to treatment with steroids. There have been no signs of local tumour recurrence or metastases at follow-up examinations during the first 9 months after the operation.

Carcinosarcoma of the prostate.

We report the case of a 66-year-old man who was diagnosed as having prostatic adenocarcinoma with widespread skeletal metastases. After treatment with a luteinizing hormone-releasing hormone analog for one year, a second biopsy revealed transformation of the tumour into a carcinosarcoma with heterogeneous and unusual findings in the carcinomatous as well as the sarcomatous component. Among others, these included a papillary growth pattern and a liposarcomatous differentiation. The patient died 5 months after the diagnosis of carcinosarcoma.

Xanthoma of the urinary bladder.

Xanthomas of the urinary bladder are rare lesions of reactive nature. They present as yellow-white mucosal plaques that may be mistaken for a neoplastic process. A biopsy displays stromal accumulation of lipid macrophages without accompanying inflammatory component. This article presents a 78-year-old woman who had a tumour-suspect xanthoma of the urinary bladder occurring subsequent to several resections of non-invasive carcinomas.

Prognostic significance of Ki-67/MIB-1 proliferation index in meningiomas.

Even though tumor grade, subtype, and extent of resection are strong prognostic factors in human meningiomas, the growth of this tumor is still unpredictable, and additional prognostic markers are needed. Thus, immunohistochemical determination of proliferative activity using the Ki-67 equivalent antibody MIB-1 has gained increased attention. However, the reported prognostic significance of this marker in meningiomas is not fully clarified. The aim of this study was to investigate the prognostic role of MIB-1 proliferation index (PI) in a series of meningiomas comprising 23 benign, 17 atypical, and 9 anaplastic tumors. MIB- 1 PI increased with increasing tumor grade and discriminated significantly benign from atypical and anaplastic meningiomas whereas no difference was found between the latter two grades. However, due to the considerable overlap of PI values between the various grades, one should be circumspect before using this criterion for tumor grading. Furthermore, MIB-1 PIs were significantly higher in recurrent tumors compared with non-recurrent and a reliable MIB-1 PI cut-off value of 10% was established. This value, however, cannot automatically be adapted by other laboratories and must be regarded just as a guideline. In conclusion, MIB-1 PI appears as an important prognostic factor and should be used in combination with traditional histological criteria for malignancy in order to identify meningiomas with increased risk of recurrence.

Adenoma of the esophagus with intracytoplasmic mucoid bodies.

We report a tubular adenoma of the esophagus in a 79-year-old man. The tumour had progressed to an intramucosal carcinoma at follow-up 6 months later. The adenoma displayed a peculiar and heterogeneous histological picture with non-dysplastic and cystic areas alternating with those of a typical tubular adenoma. The tumour revealed a strong and diffuse expression of cytokeratin 7 and basal cell cytokeratin, whereas cytokeratin 20 was focally positive only. The most remarkable finding, however, was the demonstration of intracytoplasmic inclusion-like mucoid bodies of the epithelial cells in a small area of the adenomatous component. These inclusions stained PAS positive and alcian blue negative, and electron microscopy revealed a homogeneous structure without viral-like particles.

Brain weight: what does it mean?

The weights of the whole and various parts of 8 unfixed normal adult brains were determined at autopsy, and the relative weight of each part as compared with the total brain weight was calculated. On the average, the cerebrum accounted for 87% of the total brain weight, the cerebellum and brain stem for 13%, whereas the contribution of the attached upper spinal cord was negligible (< 2 g). The removed leptomeninges had a mean weight of 34.2 g (2.5% of the total brain weight), but they may reach 50 g. The slices of the cerebrum with removed leptomeninges weighed only 79.2 - 84.4% of the total brain weight. It is concluded that all scientific papers reporting brain weights should state whether the recordings are based upon fresh or fixed specimens and, in the latter case, the fixation procedures must be described accurately. Furthermore, it is of equal importance to indicate exactly the anatomic structures that have been weighed.

Determination of proliferation index in neoplasms using different Ki-67 equivalent antibodies.

Paraffin sections from 23 tumours were immunohistochemically stained with the following four Ki-67 equivalent antibodies: monoclonal MIB-1 (DAKO), monoclonal MM1 (Novocastra), polyclonal NCL-Ki-67p (Novocastra), and polyclonal Rah Ki-67 (DAKO). Ki-67 labelling indices were determined by counting in exactly the same area in each case. MIB-1 showed the highest labelling index in 21 of the 23 cases, and the mean MIB-1 index was approximately 30% higher than that of the other antibodies. The differences between MM1, NCL-Ki-67p and Rah Ki-67 were small and non-significant. There was a positive correlation between each of the four antibodies. As these findings may be of importance when the Ki-67 labelling index is used as a criterion for tumour grading or for clinical prognostication, this necessitate identification of the antibody used in every case.

Comparison of Ki-67 equivalent antibodies.

AIMS: To compare commercially available Ki-67 equivalent antibodies with regard to qualitative and quantitative immunohistochemical staining characteristics. METHODS: The following antibodies were used: monoclonal MIB-1 (Immunotech), monoclonal MM1 (Novocastra), polyclonal NCL-Ki-67p (Novocastra), and polyclonal Rah Ki-67 (Dako). All immunostainings were evaluated in squamous epithelium from formalin fixed and paraffin wax embedded pharyngeal tonsils. Labelling indices (LIs) were recorded twice to test their reproducibility. RESULTS: By application of all four antibodies the nuclear staining could be either diffuse, granular, or a combination of both (classified as granular in this study). The diffuse pattern generally showed a strong or moderate staining intensity, whereas the granular pattern displayed a continuum from strong to very weak, making it difficult to discriminate between positive and negative nuclei. The diffuse staining pattern was seen in approximately 59% of the nuclei with the MIB-1 antibody and in 35-45% when the other antibodies were used. The following mean LIs were recorded: MIB-1, 31%; NCL-Ki-67p, 21%; Rah Ki-67, 17%; and MM1, 14%. The reproducibility was excellent for all four antibodies, with the mean of differences between the two runs of counts ranging from 1.1% to 1.5%. CONCLUSIONS: The four tested Ki-67 equivalent antibodies revealed differences in qualitative and quantitative staining characteristics, which resulted in considerable variations in registered LIs. The MIB-1 antibody appears to have a higher sensitivity for detecting the Ki-67 antigen than the other three tested antibodies. These differences are important to consider when proliferative activity is determined by the Ki-67 LI.

The prevalence of human intestinal spirochetosis in Norway.

The prevalence of human intestinal spirochetosis (HIS) was determined histologically in 402 subjects from South Norway (Kristiansand) who had undergone colorectal resections during the period June 1991-June 1996. The figures were compared with those from a previous mid-Norwegian study (Trondheim) comprising 1205 patients with large bowel resections as well as colonoscopic mucosal biopsies examined in 1990. The studies showed a prevalence of HIS of 2.5% in mid-Norway and 3.0% in South Norway, and in both regions there was a considerable male predominance of HIS (70% and 75%, respectively). Furthermore, HIS was more often diagnosed by the pathologists in South Norway (25%) than in mid-Norway (6.5%).

Comparative investigation of proliferation markers and their prognostic relevance in human meningiomas.

OBJECTIVE: In human meningiomas, histology alone does not always predict the clinical outcome. Proliferative activity has therefore, become a potential tool in the histopathological grading of these tumors. The aim of this study was to investigate different Ki67 antibodies on meningiomas, to compare their proliferation indices (PI) and with other proliferation markers, such as S-phase fraction and mitotic activity, and to see whether these factors correlate with histological tumor grade. MATERIAL AND METHODS: The study included 43 meningiomas graded according to the criteria of WHO and Jääskeläinen et al. [1985, 1986]. Paraffin sections were used for immunohistochemical detection of Ki67 antigen and flow-cytometric determination of S-phase fraction. RESULTS: The PIs displayed an overall increase with increasing histological grade, however, the range of values for benign, atypical and anaplastic meningiomas were wide, resulting in considerable overlap between the groups. There were for the most significant correlations between the different proliferation markers. CONCLUSIONS: Ki67-equivalent antibodies and S phase fraction have no advantage over counting mitoses to assess the proliferative activity in meningiomas. Thus, mitotic activity justifies its role in meningioma grading.

Diagnostic examination of human intestinal spirochetosis by fluorescent in situ hybridization for Brachyspira aalborgi, Brachyspira pilosicoli, and other species of the genus Brachyspira (Serpulina).

Human intestinal spirochetosis, characterized by end-on attachment of densely packed spirochetes to the epithelial surface of the large intestines as a fringe has been associated with the weakly beta-hemolytic spirochetes Brachyspira aalborgi and Brachyspira (Serpulina) pilosicoli. In this study, fluorescent in situ hybridization with oligonucleotide probes targeting 16S or 23S rRNA of B. aalborgi, B. pilosicoli, and the genus Brachyspira was applied to 40 sections of formalin-fixed, paraffin-embedded intestinal biopsy specimens from 23 Danish and 15 Norwegian patients with histologic evidence of intestinal spirochetosis. Five biopsy specimens from patients without intestinal spirochetosis and three samples from pigs with experimental B. pilosicoli colitis were examined as well. In addition, the 16S ribosomal DNAs of two clinical isolates of B. aalborgi were sequenced, and a PCR procedure was developed for the identification of B. aalborgi in cultures. The genotypic characteristics of the two clinical isolates showed very high (99.5%) similarity with two existing isolates, the type strain of B. aalborgi and a Swedish isolate. Hybridization with the Brachyspira genus-specific probe revealed a brightly fluorescing fringe of spirochetes on the epithelia of 39 biopsy specimens, whereas 1 biopsy specimen was hybridization negative. The spirochetes in biopsy specimens from 13 Danish and 8 Norwegian patients (55.3%) were identified as B. aalborgi. The spirochetes in the biopsy specimens from the other 17 patients hybridized only with the Brachyspira probe, possibly demonstrating the involvement of as-yet-uncharacterized Brachyspira spirochetes in human intestinal spirochetosis.

Familial mydriasis, cardiac arrhythmia, respiratory failure, muscular weakness and hypohidrosis.

OBJECTIVES: To describe a family with some sort of progressive autonomic failure in one generation (2 affected of a sibship of 7 sisters). The main features were: mydriasis, cardiac arrhythmia, cardiomegaly, hypohidrosis, respiratory failure, and muscular weakness. METHODS: Pupillometry, evaporimetry, and isokinetic power measurements were carried out. RESULTS: The autonomic dysfunction pattern (mainly cardiac abnormalities, mydriasis) seems to differ somewhat from that of progressive autonomic failure (Shy-Drager syndrome). "Lewy body-like" inclusions were present, in particular in substantia nigra, but also in locus ceruleus and raphe nuclei (cell loss only in locus ceruleus). There were no oligodendroglial, cytoplasmatic inclusions, apparently a marker in multiple system atrophy. Proper Lewy bodies were also present. Differences seemed to prevail vs the Shy-Drager syndrome. Various traits: muscular weakness pattern (e.g. preferential peroneal distribution), minor elbow contractures, and arrhythmia were reminiscent of Emery-Dreifuss muscle dystrophy (E-D). Distinguishing features included: hereditary pattern, mydriasis, and hypohidrosis. CONCLUSION: Conceivably, this disorder is close to, but still not identical with E-D.

PCR amplification from fixed tissue indicates frequent involvement of Brachyspira aalborgi in human intestinal spirochetosis.

PCR procedures amplifying portions of the 16S rRNA and NADH oxidase genes of Brachyspira aalborgi and Serpulina pilosicoli were applied to DNA extracted from paraffin-embedded human colonic or rectal tissues from 30 Norwegian, Australian, and U.S. patients, 16 of whom had histologic evidence of intestinal spirochetosis (IS). B. aalborgi-specific sequences were identified by PCR in 10 of the IS patients (62.5%) but none of the others, while S. pilosicoli sequences were not detected in tissues from any patient. Direct sequencing of products from three of the positive samples provided further confirmation of the presence of B. aalborgi. B. aalborgi may be a more common cause of intestinal spirochetosis than has been previously thought.

Synchronous occurrence of carcinoid tumour of the appendix and T-cell lymphoma of the ileum. A case report with review of the literature.

Carcinoid tumours of the gastrointestinal tract are often associated with other tumour types at various sites. However, only rarely has a lymphoma constituted the second tumour. In the present paper, we report the case of a 62-year-old woman who was operated on for a perforated T-cell lymphoma of the ileum and in whom an appendicular carcinoid tumour was incidentally discovered at surgery. It was possible to completely remove both tumours and postoperatively the patient underwent CHOP treatment. Ten months after surgery the patient is well, with no tumour manifestations. We also discuss problems concerning classification of the lymphoma on account of loss of the T-cell antigen CD45RO (UCHL-1).

Epiperikaryal synaptophysin reactivity in the normal human central nervous system.

An epiperikaryal synaptophysin immunoreactivity has been regarded as an indicator of neoplastic or otherwise abnormal neurons and this staining property serves as an important criterion to distinguish between normal and abnormal neurons. In the present study we have investigated the epiperikaryal synaptophysin reactivity in various regions of the normal human central nervous system by using autopsy materials from 11 subjects aged 3 months-86 years. We found a definite but variable staining of the brainstem and spinal cord motor neurons as well as the cerebellar Purkinje cells. A particular strong and consistent reactivity was seen in neurons of the cerebellar nuclei in which also axons and dendrites were labelled to a variable extent. This type of neuronal staining was never observed in the cerebrum. We therefore conclude that the employment of this staining property as a criterion for abnormal neurons should be used with caution in the cerebellum, brainstem, and spinal cord whereas it may be used more safely in the cerebrum.

The frequency of Lewy bodies in a consecutive autopsy series.

In a consecutive autopsy series comprising 284 subjects > or = 50 years, 22 cases (7.7%) revealed Lewy bodies (LBs) of whom 21 had LBs in substantia nigra and/or locus ceruleus and 9 (3.2%) in the cerebral cortex. Only one case had cortical LBs without concomitant inclusions in the brain stem. The mean age of subjects with LBs was significantly higher than in those without (78.0 vs. 72.3 years). Cortical LBs had not been demonstrated in routine HE stains in any case and their identification necessitated the use of staining for ubiquitin. Although great care was taken not to interpret globose neurofibrillary tangles (NFTs) as LBs, anti-tau staining revealed that many of the suspected LBs were in fact NFTs. Thus, we recommend to apply both anti-ubiquitin and anti-tau staining for the demonstration of cortical LBs. In this material 21 of the 22 cases with LBs (95.5%) also revealed Alzheimer type of pathology as compared with 187 of 262 cases without LBs (71.4%). This difference may be explained by the higher age of subjects with LBs. Altogether 96 of the 284 cases (33.8%) had cerebrovascular lesions. None of the 9 cases with cortical LBs were clinically demented, and our results do not support the assertion that Lewy body-associated dementias should outnumber those of vascular origins.

Leptomeningeal lipomatous hamartoma overlying a midline cleft of the ventral pons.

Intracranial lipomatous hamartomas (lipomas) are of maldevelopmental nature and have a predilection for the midsagittal plane. They are often associated with malformations of the CNS and other organ systems. It is reported an asymptomatic lipomatous hamartoma of the ventral pontine leptomeninges and a midline cleft of the subjacent pons discovered incidentally at autopsy of an 80-year-old man. Review of the literature shows that this type of lesion at the ventral pons has not been reported previously.

Sudden, unexpected death in subjects with undiagnosed gliomas.

We report two cases in which a medicolegal autopsy disclosed small and previously undiagnosed gliomas. The first case was a 38-year-old woman who was found dead in bed; her autopsy revealed a 1.3-cm low-grade astrocytoma in the right subthalamic area. The second case involved a 32-year-old man who drowned in shallow water after his canoe capsized. A 0.5-cm oligoden-droglioma of the left temporal lobe and a 0.1-cm ganglionic hamartoma of the hypothalamus were found. In both cases the tumors may, directly or indirectly, have been the underlying cause of death. We emphasize the importance of a thorough neuropathological examination for all cases of sudden unexpected death in which no extracerebral cause of death has been found.

Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.

Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region and three mutations were detected in patients with Cowden disease. We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and, by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.

Sequence analysis of HIV-1 group O from Norwegian patients infected in the 1960s.

Three Norwegians, a couple and their daughter, died from AIDS in 1976 after up to 10 years of clinical manifestations of HIV infection (Lindboe et al., 1986, Acta Pathol. Microbiol, Immunol. Scand. 94, 117-123; Frøland et al., 1988, Lancet i, 1344-1345). We here demonstrate the presence of HIV DNA in autopsy materials from the father and the daughter. In phylogenetic analysis, the obtained sequences of the HIV pol and vif genes clustered with the HIV-1 group O clade. The genotyping was confirmed by detection of antibodies against HIV-1 group O in blood samples from the father and the mother. That these and other early isolates of HIV-1 are very similar to the presently circulating viruses and not intermediates between the present subtypes, verifies that the latest common ancestor of HIV-1 existed long before the emergence of the present epidemic. The presence of HIV-1 group O 30 years ago suggests that the limited spread of these viruses, compared to HIV-1 group M viruses, is not due to a later emergence of the group O viruses.