Increased incidence of Kaposi sarcoma in Sweden before the AIDS epidemic.

Clinical factors of possible importance for the greater than two-fold rise in the incidence of Kaposi sarcoma of the elderly in Sweden before the AIDS epidemic were reviewed in 63 regional patients. 5 patients had lymphoproliferative disease before or at the time of Kaposi sarcoma, and 4 patients had been receiving steroids (including 1 with lymphoma) at diagnosis. 2 of these 9 patients plus 2 additional patients had received blood transfusions 1-9 years before diagnosis. None of 17 patients tested was positive for HIV-1, and none had signs of an unexplained progressive immune defect. Of the evaluable cases, 27% had diabetes mellitus and 7% had had previous myocardial infarction. However, only the frequency of congestive heart failure (47%) was significantly greater than that of an ambulatory control group (P = 0.001) in the age group 75-84 years. Exposure to cytomegalovirus (CMV) was not more common in 15 Kaposi sarcoma patients than in an age and sex matched control group. No single factor could account for increased Kaposi sarcoma among the elderly. If the classical form has an infectious aetiology, the tumour could arise after effective transmission of the agent (as by a transfusion), especially combined with some degree of immune deficiency or perhaps congestive failure late in life.

Alpha-1-antitrypsin in a malignant mixed mesodermal tumor of the ovary.

A malignant mixed mesodermal tumor of the ovary was found to contain multitudinous clusters of eosinophilic hyaline globules in both its epithelial and mesenchymal components. These periodic acid-Schiff-positive, diastase-resistant globules revealed typical positive ring-like staining for alpha-1-antitrypsin (AAT) using an indirect immunoperoxidase technique. Similar findings have previously been reported in certain germ cell and liver tumors and hepatocytes of patients bearing the Z-allele for AAT. The globules also stained with antisera against kappa and lambda immunoglobulin light chains, indicating the presence of surface immunoglobulin. In the electron microscope, the inclusions appeared granular and may have been derived from flocculent material in the dilated rough endoplasmic reticulum. These observations suggest a structural change in the tumor AAT analogous to that proposed for hereditary AAT deficiency. As a histogenetic marker, the presence of AAT in both epithelial and stromal cells suggests their origin from a common precursor cell.U

Myofibromatosis-like hemangiopericytoma metastasizing as differentiated vascular smooth-muscle and myosarcoma. Myopericytes as a subset of "myofibroblasts".

A thyroid hemangiopericytoma that was resected in a 5-year-old boy recurred insidiously in the larynx 8 years later. Marked cicatricial mucosal inflammation prevented a definitive pathologic diagnosis of recurrence until a nodule grew to obstruct the airway 15 years after initial surgery. After excision of the nodule, a larger sarcomatous metastasis was discovered in the upper esophagus and resected, but the patient eventually succumbed to widespread disease at the age of 20 years. The original tumor contained atypical pericytes and bundles of hyalinizing smooth muscle abutting on "staghorn vessels," a pattern similar to infantile myofibromatosis. Desmin immunostaining was negative in the pericytes but positive in smooth-muscle cells dispersed singly as well as in bundles. Both elements reacted strongly for vimentin and the alpha-isoform of actin (alpha-SMA) found in normal smooth muscle and pericytes. A third cell type showing dendritic processes and immunoreactivity for all three antigens was interpreted as a myopericyte. Spindled cells in multiple subsequent mucosal biopsy specimens stained retrospectively also positive for these antigens. Large bundles of vascular smooth muscle surrounded by radiating myocytes characterized the occluding laryngeal nodule. In the esophageal metastasis, which showed no histologic features typical of hemangiopericytoma, numerous mitotically active, small, vimentin+, desmin+, alpha-SMA+ cells often maintained shortened processes and tended to form nodular aggregates about capillaries. Single rows of pericytes accreted to endothelial tubes. Ultrastructurally, some cells contained myofilaments and irregular dense material or showed rare cell junctions and variable investment by a basal lamina.(ABSTRACT TRUNCATED AT 250 WORDS)

K-ras mutations in sinonasal adenocarcinomas in patients occupationally exposed to wood or leather dust.

Of 39 males diagnosed with sinonasal adenocarcinomas over 30 years in the Lund University Hospital catchment area (1.5 million inhabitants), archival tumor tissue was available from 29. Of these, 16 had been exposed to wood dust and three had been exposed to leather dust. The intestinal-type and papillary adenocarcinomas were more common in the exposed patients (P = 0.0002, Fisher's exact test). The tumors from all but one of the 29 sinonasal adenocarcinomas could be analyzed for point mutations at codons 12, 13 and 61 of the K-ras gene. Four mutations were detected in the 28 tumors. The three mutations in the patients exposed to wood and leather dust were all G:C --> A:T transitions, with two at position 2 of codon 12 and one at position 2 of codon 13. The high proportion of G:C --> A:T mutations in this rare tumor may reflect a genotoxic agent in wood and leather dust.

Ovarian malignant mixed mesodermal tumor: the occurrence of hyaline droplets containing alpha 1-antitrypsin.

Twenty-one of 22 cases of malignant mixed mesodermal tumor (including carcinosarcoma) of the ovary were found to contain periodic acid-Schiff(PAS)-positive, diastase-resistant hyaline droplets ranging in diameter from less than 1 micrometer to approximately 50 micrometers. Droplets were located both inside and outside undifferentiated mesenchymal cells, predominantly within myxomatous areas. In 13 cases, droplets also occurred in epithelial structures, including areas mimicking ovarian carcinoma. Immunoperoxidase staining for alpha-fetoprotein was consistently negative, but droplets and cell cytoplasm reacted strongly with anti-alpha 1-antitrypsin. Analysis of the structure of droplet antitrypsin may be necessary to determine the origin of the droplets themselves and the possible usefulness of serum alpha 1- antitrypsin as a tumor marker in ovarian carcinoma and malignant mixed mesodermal tumor.

Abnormal B-cell proliferation associated with combined immunodeficiency, cytomegalovirus, and cultured thymus grafts.

A male infant in whom multiple recurrent multiorgan infections developed during the first six months of life was found to have combined immunodeficiency. Progressive pulmonary disease developed at age two years; cytomegalovirus (CMV) was isolated from the respiratory tract and urine. Three separate intramuscular grafts of cultured thymus fragments did not produce change in the course of the illness. Soon after age three years, IgG lambda appeared in the serum as an M-component. The patient died at age three and one-half years, with respiratory insufficiency due to pulmonary fibrosis. At autopsy, a malignant plasma cell infiltrate was limited to the retroperitoneum. The infiltrate replaced lymph node structures and surrounded nerve fascicles, which appeared necrotic, and contained CMV inclusions in ganglion cell nuclei. The plasma cells showed strong monoclonal staining for IgG lambda. Also noted was positive staining for J-chain, which has been reported previously in malignant plasma cells producing IgG. CMV could be responsible for abnormal B-cell proliferation in patients with defective immunoregulation who receive immunotherapy, as in lymphoid abnormalities associated with Epstein-Barr virus.

Abnormal cell cycle regulation in malignancy.

The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), and mitosis (M), after which the cell may differentiate or enter the resting state (G0). The cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events, involving protein kinases, protein phosphatases, cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors, that ultimately impinge on the activity of transcription factors. Unreplicated or damaged DNA blocks the progression of the cell cycle at checkpoints, including a late G1 checkpoint regulated by the dephosphorylated retinoblastoma protein and a late G2 checkpoint regulated by the phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell cycle regulator genes may be considered proto-oncogenes or tumor suppressor genes, and point mutations, amplifications, deletions, or rearrangements involving their loci, particularly those in the "RB pathway," are associated with various tumors. A number of molecular techniques may be used to detect genomic alterations or posttranscriptional modifications, but immunohistochemistry remains the most common method to determine expression levels of a regulatory protein. Multivariate analysis of the usefulness in prognosis has been applied most often for the general proliferation antigen Ki-67.

In situ hybridisation in herpetic lesions using a biotinylated DNA probe.

In situ hybridisation was performed with a biotinylated DNA probe for herpes simplex virus (HSV) using high temperature denaturation on formalin fixed, paraffin wax sections of lung, brain, ganglion and keratinising and non-keratinising squamous epithelia. Eosinophilic viral nuclear inclusions or characteristically moulded multiple nuclei with altered chromatin, which were present in two cases of HSV encephalitis and one case of viral pneumonitis, all showed complete hybridisation visualised by an alkaline phosphatase/nitroblue tetrazolium detector system. HSV encephalitis and trigeminal ganglionitis, which were confirmed serologically or clinicopathologically but lacked nuclear changes, also gave positive dense nuclear signal in neurons, glias and satellite cells. No staining was present in the ganglion cells in trigeminal zoster, the glia in progressive multifocal leucoencephalopathy, or in a variety of cells in a lung coinfected with cytomegalovirus. In 10 herpetic blisters of squamous epithelia, infected cells hybridised strongly, while morphologically similar herpes zoster lesions remained negative. In neural tissues non-hybridisation staining was most obtrusive in corpora amylacea and seemed to reflect nonspecific probe adherence. In squamous epithelium, major non-hybridisation staining was caused by probe and antibody possibly adhering to intracellular keratin. The HSV probe permits specific detection of virus in the absence of characteristic nuclear changes and allows varicella zoster virus to be differentiated from HSV, provided that the aforementioned problems with non-hybridisation staining are borne in mind.

Malignant mixed mesodermal tumor of the ovary: a report of 22 cases.

Clinicopathologic data are presented for 22 cases of malignant mixed mesodermal tumors of the ovary of both homologous and heterologous types. The results substantiate previous reports of low parity in the almost exclusively postmenopausal women with this tumor. Symptoms were the same as for ovarian malignancy in general. More than half the patients presented with stage III or IV disease, according to the International Federation of Gynecology and Obstetrics (FIGO) classification. Only four (19%) of 21 patients were alive at 18 months and had survived from three to more than 13 years. Their survival was associated strictly with stage I or II disease and with the purely homologous stromal pattern. Two tumors were contiguous with remnants of ovarian endometriosis. Differentiated malignant epithelium was most often of the serous/endometrioid type, frequently with squamous zones, and was of the mucinous type in only one case. Whereas spindle cell stroma was present in many tumors of both stromal types, atypical cartilage was the predominant heterologous element.

Tetraploidization and progressive loss of 6q in a squamous cell carcinoma of the parotid gland.

Cytogenetic analysis of short-term cultures from a squamous cell carcinoma (SCC) of the parotid gland revealed one clone with loss of the Y chromosome only, as well as three related subclones: 91,XXYY,add(6)(q21), -11,t(11;22)(q13;q11),ins(15;?)(q22;?)[cp5+ ++]/91,XXYY,add (6)(q21), -11,add(11)(p11), ins(15;?)(q22;?),der(22)t(11;22)(p11;q11)[2]/91,XXYY,add(6)(q11), -11,add(11)(p11),ins(15;?)(q22;?),der(22) t(11;22)(p11;q11) [cp4]. The finding of only one copy of all structurally rearranged chromosomes in a near-tetraploid karyotype indicates that tetraploidization was an early event in tumorigenesis. Rearrangements, in particular deletions, of 6q have previously been associated with adenoid salivary gland malignancies. Our finding of progressive 6q loss with clonal evolution, combined with the fact that 6q deletions were also seen in the two previously reported SCCs of the salivary glands, indicate that loss of genetic information from this chromosome arm is characteristic for most types of salivary gland carcinomas, irrespective of their histologic differentiation.

Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue.

Angiosarcomas are rare malignant vascular tumors, most commonly found in the skin or superficial soft tissue. We found clonal chromosome aberrations in four short-term cultured angiosarcomas. Two cases were diagnosed as epithelioid angiosarcomas, and one as postmastectomy angiosarcoma. Two of the tumors were deep-seated and two were superficial. Angiosarcomas from deep, soft tissue are extremely rare and have never been cytogenetically investigated before. The chromosome number ranged from hypodiploid to hypertriploid. When the results from the present study were combined with data on the four previously reported cytogenetically aberrant angiosarcomas, the most frequently rearranged chromosomes were 5, 7, 8, 13, 15, 20, 22, and the Y chromosome. Recurrent changes, each found in three of these eight angiosarcomas, were gains of 5pter-p11, 8p12-qter, and 20pter-q12, losses of 7pter-p15 and 22q13-qter, and -Y in two of three men.

Correlation between p53 mutation and cyclin D1 amplification in had and neck squamous cell carcinoma.

Mutations in the p53 tumour suppressor gene and amplification of the cyclin D1 (CCND1) oncogene have been commonly reported in various malignancies. In the present study of 39 squamous cell carcinomas of the head and neck, p53 mutations were manifest in 11 (28%) of the cases, whereas CCND1 amplification was seen in 6 (16%) of 37 analysed tumours. The 10 mutations occurring in coding sequences of p53 were found in exon 5 (4 cases), exon 6 (3 cases),f and exon 8 (3 cases). No mutation was found in exon 7. Eight of the 10 exon nucleotide substitutions were missense mutations and two were nonsense mutations. All six tumours with CCND1 amplification also had p53 mutations, while an additional five tumours manifested p53 mutations in the absence of CCND1 amplification. There was a statistically significant positive correlation between these two gene alterations. This raises the possibility that mutation of p53 precedes CCND1 amplification in carcinogenesis.

Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma.

Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the incidence among young patients is increasing. The aim of this study was to reveal the correlation between cyclin D1 (CCND1) expression and clinical and histologic features. We performed an immunohistochemical study on the level of CCND1 expression in tumor specimens obtained from 94 patients with tongue squamous cell carcinoma. The relationship between the expression and the following features such as age, sex, smoking and alcohol intake history, T, N, histologic grade, and multiple primary cancer was analyzed. Eighteen patients (19%) showed CCND1 overexpression (tumor cell nuclei positivity >/=50%). The 5-year survival rate of high CCND1 expressors was 39%, which was significantly poor (p=0.04). N classification correlated with CCND1 expression. CCND1 overexpression is associated with poor survival associated with progression of lymph node spread in patients with tongue squamous cell carcinomas. CCND1 expression may be a useful biologic marker for prognosis.

Determination of nonendemic nasopharyngeal carcinoma by in situ hybridization for Epstein-Barr virus EBER1 RNA: sensitivity and specificity in cervical node metastases.

After time-consuming and costly investigations, patients with neck metastases from an occult primary often receive unnecessarily large radiation volumes to treat a possible origin in the nasopharynx. In this study a colorimetric antisense Epstein-Barr early ribonucleoprotein 1 (EBER1) oligonucleotide probe specific for Epstein-Barr virus RNA was hybridized in situ to metastatic tissue obtained from 18 nasopharyngeal, 54 oral and pharyngeal, and 12 occult carcinomas derived from an unselected population. All 16 nonkeratinizing nasopharyngeal carcinomas (NPCs) were positive for EBER1. Both cases of keratinizing NPC and all 54 other metastases were negative. A single positive case of occult carcinoma indicated its origin from NPC. In retrospect, 7 patients with occult carcinoma had received unnecessary treatment with irradiation to the nasopharynx. Nasopharyngeal carcinoma appears to be a less common origin of occult carcinoma than previously considered. In the proper clinicopathologic context EBER1 in situ hybridization (EBER1-ISH) allows exclusion of NPC with a high degree of accuracy. Thus unnecessarily large radiation volumes and their adverse sequelae may be reduced in the treatment of occult carcinoma. Conversely, a positive result of ISH allows exclusion of further extensive diagnostic procedures.

Moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the supraglottic larynx. A report of two cases including immunohistochemistry and aspiration cytology.

Moderately differentiated neuroendocrine carcinoma of the larynx is morphologically distinct from the classic carcinoid and small-cell carcinoma. It is composed of medium to large polyhedral cells with an insular, trabecular, or acinar growth pattern, variable pleomorphism, and a tendency to metastasize to skin and bone. We describe the clinicopathological features of the tumor in two patients in whom tumor dissemination resulted in death 13 and 33 months after diagnosis. Both tumors occurred above the glottis and metastasized to bone but not to regional tissues. In one case, the diagnosis was confirmed when the aspiration cytological specimen from a rib lesion suggested a neuroendocrine carcinoma resembling medullary thyroid cancer (triangular cytoplasm, double nuclei, and fine red cytoplasmic granules on May-Grünwald-Giemsa staining). Both tumors were originally misdiagnosed as squamous cell carcinoma, as acinic cell cancer, or as suggesting metastasis of melanoma. Immunohistochemistry gave strong reactivity in both for chromogranin A and calcitonin, although the serum level of calcitonin, determined in one case, was normal.

Kaposi's sarcoma: a trifactorial model.

To explain the epidemiology of Kaposi's sarcoma, including its predominance in men, I present a theory based on three concurrent factors: immunodeficiency, exposure to a specific viral agent, and a recessive, highly prevalent X-linked regulatory gene. The X-linked locus is inferred from comparing the aberrant lymphaticovenous nature of immature lesions with absence of lymphaticovenous connections in XO karyotypes. The theory predicts that for heterosexual populations without sex differences in viral exposure or degree of immunodeficiency, the male-to-female ratio of Kaposi's sarcoma will equal the inverse of the lesion's frequency causative virus. In addition, an increased incidence of Kaposi's sarcoma is expected outside of the context of the acquired immunodeficiency syndrome as the causative virus is transmitted separately from the human immunodeficiency virus.

Biological treatment of gold ore cyanidation wastewater in fixed bed reactors.

The treatment of a cyanidation effluent containing thiocyanate, free cyanide, and complexed cyanide was continuously performed for a period of 6 months. Activated carbon, pozzolana, and a mixture of pumice stone and zeolite were tested as supports in fixed bed reactors. Activated carbon adsorbed the different forms of cyanide. In contrast, the other supports did not remove any pollutants from the effluent during an adsorption experiment. All supports successfully allowed fixation of bacteria. More than 90% of the thiocyanate was biologically decomposed into NH4+, CO2 and SO4(2-), even when increasing the feed flow-rate and the pollutant concentrations. Free and complexed cyanides were eliminated, probably through a combination of precipitation and biological degradation. The oxidation of ammonium into nitrate was only performed by the activated carbon-containing column and with the more diluted feeding. The nitrification process was inhibited in all reactors when the cyanide concentrations and feed flow-rates were increased.

Human herpesvirus 8 and Kaposi's sarcoma.

In the last 2 years, the discovery that the suspected causative agent of Kaposi's sarcoma (KS) is a new gamma-herpesvirus, called human herpesvirus type 8 (HHV8) or Kaposi's sarcoma-associated herpesvirus (KSHV), has been followed by studies showing it to be a sine qua non of all clinical forms of KS and a specific marker for KS in the differential diagnosis of angioproliferative lesions. Reports that the virus is ubiquitous have been based on the polymerase chain reaction and appear to be contradicted by serological studies of blood donors and patients with acquired immunodeficiency syndrome (AIDS)-related and classical KS. Further serological surveys and the application of molecular probes in histological sections should resolve the issue. The recent descriptions of KSHV RNA molecules and several viral mimickers of human cytokines offer the chance to map the viral latent-lytic cycle and will change the direction of cytokine research in KS. These discoveries suggest that the increase of endemic classical KS noted in Nordic countries before the AIDS epidemic was due to spread of KSHV by unknown routes. The aggregate data should force a paradigm shift away from the notion that human immunodeficiency virus infection has a necessary role to play in AIDS-KS other than as a cause of progressive immunodeficiency.

Endothelial transdifferentiated phenotype and cell-cycle kinetics of AIDS-associated Kaposi sarcoma cells.

The nature of Kaposi sarcoma (KS) (vascular malignancy vs. discordant angiogenesis) and lineage of the progenitor cell remain unclear. Therefore, AIDS-KS enzyme isolate cultures were prepared from excised skin lesions. Endothelial marker positivity for Factor VIII related antigen (F8RAg), Ulex europaeus agglutinin (UEA), and angiotensin-converting enzyme (ACE) were determined by fluorescence microscopy (FM) and flow cytometry (FCM). DNA cell-cycle analysis was performed using FCM. KS lesions showed large thick-walled channels (F8RAg and UEA strongly +), narrow vascular slits and thin-walled lakes (F8RAg and UEA weakly +), and non-prominent spindle cells (F8RAg and UEA almost uniformly negative). KS cultures yielded heterogenous populations of spindle, stellate, and flattened endothelial-like cells, displaying positivity for F8RAg (64 +/- 3%; mean +/- SE), UEA (40 +/- 9%), and ACE (81 +/- 9%). When injected subcutaneously in the nude mouse these cells failed to produce tumors. During contact inhibition induced quiescence, KS cultures exhibited a high G2M (18 +/- 3%) compared to non-KS (7 +/- 4%; p < 0.04), evidence of an altered proliferative potential consistent with a transdifferentiated or transformed phenotype.