[Dumbbell-shaped spinal epidural cavernous angioma. Case report and review of the literature]. / Cavernoma raquídeo epidural en reloj de arena. Presentación de un caso y revisión de la literatura.

Spinal epidural cavernous angiomas are rare vascular malformations that exceptionally present with dumbbell-shape morphology. When it happens, preoperative misdiagnosis is the rule, because the clinicoradiological picture is quite similar to the nerve sheath tumours one. Spinal epidural cavernomas complete resection can be achieved with surgical treatment and scarcely morbi-mortality, and excellent outcome can be expected. We report a case of a 57 year-old woman carrying a dumbbell-shaped epidural cavernoma located at C7 and D1 levels that was surgically removed. Special diagnostic features of this kind of lesions are discussed and treatment options currently available are reviewed.

Cavernoma raquídeo epidural en reloj de arena. Presentación de un caso y revisión de la literatura / Dumbbell-shaped spinal epidural cavernous angioma. Case report and review of the literature

Los cavernomas raquídeos epidurales son malformaciones vasculares muy poco frecuentes que, excepcionalmente, pueden adquirir una morfología en “reloj de arena”. En estos casos, el diagnóstico preoperatorio es habitualmente erróneo debido a su similitud clínico radiológica con los tumores de la vaina nerviosa. Con el tratamiento quirúrgico se puede realizar una extirpación completa de estas lesiones sin apenas morbimortalidad, y conseguir en consecuencia un excelente pronóstico .Se presenta el caso de una mujer de 57 años a quien se le extirpó quirúrgicamente un cavernoma epidural en reloj de arena localizado en los segmentos C7 y D1.Se discuten las peculiaridades diagnósticas de este tipo de lesiones y se revisan las opciones terapéuticas disponibles en la actualidad

Spinal epidural cavernous angiomas are rare vascular malformations that exceptionally present with dumbbell-shape morphology. When it happens, preoperative is diagnosis is the rule, because the clinic radiological picture is quite similar to the nerve sheath tumours one. Spinal epidural cavernomas complete resection can be achieved with surgical treatment and scarcely morbi-mortality, and excellent outcome can be expected. We report a case of a 57 year-old womancarrying a dumbbell-shaped epidural cavernoma located at C7 and D1 levels that was surgically removed. Special diagnostic features of this kind of lesions are discussed and treatment options currently available are reviewed

Molecular analysis of the EGFR gene in astrocytic gliomas: mRNA expression, quantitative-PCR analysis of non-homogeneous gene amplification and DNA sequence alterations.

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine kinase activity. This report investigates the presence of mutations, amplification and/or over-expression of the EGFR gene in 86 glial tumours including 44 glioblastomas, 21 anaplastic astrocytomas, and 21 WHO grade II astrocytomas, using polymerase chain reaction/single-strand conformation polymorphism, semiquantitative reverse-transcription-polymerase chain reaction (RT-PCR) and Southern Blot techniques. Gene amplification values were found in 34 tumours. Amplification levels were not uniform, as the transmembrane region presented lower amplification rates than extra- and intracellular domains. For the 19 samples with sufficient available tumour tissue we found over-expression in 11, and no EGFR mRNA expression in three. Ten cases showed deletion transcripts, and EGFR VIII was identified in all of these cases. One of the cases with EGFR vIII also presented a truncated form, C-958, while another showed an in frame tandem duplication of exons 18--25. We found 14 cases with sequence/structure gene alterations, including seven on which genomic novel DNA changes were identified: a missense mutation (1052C > T/Ala265Val), an insertion (InsCCC2498/Ins Pro748), three intronic changes (E6+72delG, E22--14C>G and E18--109T>C), a new polymorphic variant E12+ 22A > T, and one case that presented a 190 bp insertion, that was produced by the intron-7-exon-8 duplication and generated a truncated EGFR with intact exons 1--8 followed by an additional amino acidic sequence: Val-Ile-Met-Trp. These findings corroborate that EGFR is non-randomly involved in malignant glioma development and that different mutant forms participate in aberrant activation of tyrosine kinase pathways.

Aberrant methylation of multiple genes in neuroblastic tumours. relationship with MYCN amplification and allelic status at 1p.

Aberrant hypermethylation occurs in tumour cell CpG islands and is an important pathway for the repression of gene transcription in cancers. We investigated aberrant hypermethylation of 11 genes by methylation-specific polymerase chain reaction (PCR), after treatment of the DNA with bisulphite, and correlated the findings with MYCN amplification and allelic status at 1p in a series of 44 neuroblastic tumours. This tumour series includes five ganglioneuromas (G), one ganglioneuroblastoma (GN) and 38 neuroblastomas (six stage 1 tumours; five stage 2 tumours; six stage 3 cases; 19 stage 4 tumours, and two stage 4S cases). Aberrant methylation of at least one of the 11 genes studied was detected in 95% (42 of 44) of the cases. The frequencies of aberrant methylation were: 64% for thrombospondin-1 (THBS1); 30% for tissue inhibitor of metalloproteinase 3 (TIMP-3); 27% for O6-methylguanine-DNA methyltransferase (MGMT); 25% for p73; 18% for RB1; 14% for death-associated protein kinase (DAPK), p14ARF, p16INK4a and caspase 8, and 0% for TP53 and glutathione S-transferase P1 (GSTP1). No aberrant methylation was observed in four control normal tissue samples (brain and adrenal medulla). MYCN amplification was found in 11 cases (all stage 4 neuroblastomas), whereas allelic loss at 1p was identified in 16 samples (13 stage 4 and two stage 3 neuroblastomas, and one ganglioneuroma). All but one case with caspase 8 methylation also displayed MYCN amplification. Our results suggest that promoter hypermethylation is a frequent epigenetic event in the tumorigenesis of neuroblastic tumours, but no specific pattern of hypermethylated genes could be demonstrated.

Cutaneous metastases from Ewing's sarcoma: report of two cases.

Ewing's sarcoma is a malignant osseous neoplasm that affects mostly children and young adult males. Clinically, the neoplasm presents with oedema, swelling, and pain of the involved area. Histopathologically, Ewing's sarcoma consists of solid sheets of small round cells, with vesicular nuclei and scant cytoplasm, arranged in irregular masses separated by strands of fibrous tissue, with areas of necrosis en masse intermingled with intratumoural haemorrhage. Ewing's sarcoma is an extremely aggressive neoplasm and metastases to sites such as lung, pleura, other bones, central nervous system, liver, and regional lymph nodes frequently develop in early stages of the disease. Surprisingly, despite the highly aggressive biological behaviour of this neoplasm, cutaneous metastases from Ewing's sarcoma are very uncommon. We report two patients with Ewing's sarcoma of the bone who developed cutaneous metastases. As in other internal malignancies, the onset of cutaneous metastases in patients with Ewing's sarcoma indicates a poor prognosis.

Analysis of p73 gene in meningiomas with deletion at 1p.

The p73 gene has been mapped to 1p36.33, a chromosome region that is frequently deleted in a wide variety of neoplasms including meningiomas. The protein encoded by p73 shows structural and functional similarities to p53 and may thus represent a candidate tumor suppressor gene. To determine whether p73 is involved in the development of meningiomas, we examined 30 meningioma samples with proven 1p deletion for mutations of p73. Sequence analysis of the entire coding region of the p73 gene revealed previously reported polymorphisms in eight cases. A tumor-specific missense mutation as a result of an A-to-G transition with an Asn204Ser change was found in one meningioma that nevertheless retained the normal allele. These results suggest that if p73 plays a role in meningioma carcinogenesis, it must be in a manner different from the Knudson two-hit model.

Mutation analysis of the p73 gene in nonastrocytic brain tumours.

Loss of heterozygosity (LOH) involving the distal chromosome 1 p36 region occurs frequently in nonastrocytic brain tumours, but the tumour suppressor gene targeted by this deletion is unknown. p73 is a novel gene that has high sequence homology and similar gene structure to the p53 gene; it has been mapped to 1 p36, and may thus represent a candidate for this tumour suppressor gene. To determine whether p73 is involved in nonastrocytic brain tumour development, we analysed 65 tumour samples including 26 oligodendrogliomas, 4 ependymomas, 5 medulloblastomas, 10 meningiomas, 2 meningeal haemangiopericytomas, 2 neurofibrosarcomas, 3 primary lymphomas, 8 schwannomas and 5 metastatic tumours to the brain, for p73 alterations. Characterization of allelic loss at 1 p36-p35 showed LOH in about 50% of cases, primarily involving oligodendroglial tumours (22 of 26 cases analysed; 85%) and meningiomas (4 of 10; 40%). PCR-SSCP and direct DNA sequencing of exons 2 to 14 of p73 revealed a missense mutation in one primary lymphoma: a G-to-A transition, with Glu291Lys change. 8 additional cases displayed no tumour-specific alterations, as 3 distinct polymorphic changes were identified: a double polymorphic change of exon 5 was found in one ependymoma and both samples derived from an oligodendroglioma, as follows: a G-to-A transition with no change in Pro 146, and a C-to-T variation with no change in Asn 204: a delG at exon 3/+12 position was identified in 4 samples corresponding to 2 oligodendrogliomas, 1 ependymoma and 1 meningioma, and a C-to-T change at exon 2/+10 position was present in a metastatic tumour. Although both LOH at 1 p36 and p73 sequence changes were evidenced in 4 cases, it is difficult to establish a causal role of the p73 variations and nonastrocytic brain tumours development.

Chromosomal abnormalities in pituitary adenomas.

Cytogenetic studies were conducted on 30 pituitary adenomas, using both direct and/or short-term in vitro culture methods. An apparently normal chromosome complement was found in 14 tumors; 5 adenomas were characterized by hyperdiploid or near-triploid modal chromosome numbers. Recurrent numerical deviations were identified in 12 samples, which primarily involved gains of chromosomes 4, 7, 8, 9, 12, and 20 by gains, and losses of chromosomes 10, 14, 19, and 22. Four adenomas were shown to have structural chromosome rearrangements with no apparent recurrent pattern of involvement.

Extramedullary plasmacytoma of the orbit.

PURPOSE: To report a case of extramedullary plasmacytoma of the orbit. METHODS: A 71-year-old patient presented with diplopia eyelid fullness and limitation of ocular motility in the left eye. Visual acuity was counting fingers, intraocular pressure 34 mmHg and fundus eye examination showed choroidal folds in the involved eye. RESULTS: CT scan showed a mass filling the superior and external left orbit without bone destruction. A biopsy was performed revealing that the tumour was composed of plasmacytoid cells positive with immunohistochemical stains for Kappa light chains and epithelial membrane antigen. Systemic work up was negative. The diagnosis of extramedullary orbital plasmacytoma was made. The patient was treated with external beam radiotherapy (40 Gy) and has remained disease free for four years (49 months). CONCLUSION: Extramedullary plasmacytomas of the orbit are extremely rare tumours. Accurate and early diagnosis is essential for the therapeutic approach. Extensive medical work up to rule out multiple myeloma or other malignant lymphoproliferative conditions involving the orbit is needed when the diagnosis of orbital extramedullary plasmacytoma is suspected because treatment and prognosis are very different.

A MELAS phenotype and a paternal inherited inversion of chromosome 10 in a female patient.

A MELAS phenotype and a paternal inherited inversion of chromosome 10 in a female patient: We describe a patient suffering from encephalomyopathy with overlapping symptoms, including MELAS and Kearn-Sayre syndrome features. Mutations in tRNA LEU (UUR) were not found in mtDNA of blood cells, suggesting a different genetic defect. Cytogenetic studies revealed a paternal inherited pericentric inversion of chromosome 10 (p13;q22) pat. Although the presence of the same inversion in the father and in the apparently asymptomatic sister does rather suggest that the concurrence of the mitochondrial disease in the patient was due to chance, some alternative explanations to associate both events might be proposed.

High-resolution analysis of chromosome arm 1p alterations in meningioma.

Loss of heterozygosity (LOH) for loci on chromosome arm 1p is a relatively common event in human meningioma, and this anomaly has been proposed to be associated with the development of grade II or grade III forms (atypical and anaplastic meningiomas). Nevertheless, the limited data available do not allow the establishment of the frequency and the extent of the affected 1p regions. To determine the status of chromosome 1p in meningiomas, we have performed a comprehensive analysis of LOH on 1p in 100 meningiomas using a high density of 1p-marker loci. Allelic loss was found in 35% of tumors, most corresponding to nontypical meningiomas that also displayed losses for loci on chromosome 22. Although some tumors displayed complex rearrangements leading to distinct 1p deletions, the patterns of loss indicated two main target regions: 1p36 and 1p34-p32, which represent the most frequently involved regions, whereas 1p22 and 1p21.1-1p13 regions appeared deleted in some tumors. These results suggest that there may be several putative tumor suppressor genes on 1p, the inactivation of which may be important in the pathogenesis of meningiomas, as well as in other tumor types.

Use of a long-acting gonadotrophin-releasing hormone analogue in a postmenopausal woman with hyperandrogenism due to a hilus cell tumour.

OBJECTIVE: The aim of this study was to prove the utility of GnRH analogues for the suppression of androgen secretion in a postmenopausal woman with a suspected virilizing ovarian tumour. DESIGN AND METHODS: We present a case of a 72-year-old woman with virilization of recent onset. Hormonal studies revealed a fourfold increase in serum testosterone levels, normal dehydroepiandrosterone sulphate concentrations and high levels of serum 17-hydroxyprogesterone levels. Computed axial tomography scan of the ovaries was normal and the adrenal glands showed a discrete enlargement. The long-acting GnRH analogue, triptorelin, was injected initially (3.75mg i.m.) and serum hormone levels were measured weekly throughout one month. RESULTS: GnRH produced a decrease in serum testosterone levels to normal values, in parallel with the suppression of serum LH and FSH concentrations. The patient was treated for three months with triptorelin and she experienced an amelioration of the hyperandrogenic symptoms. In order to achieve a diagnosis, the patient was submitted to a laparotomy that revealed a small hilus cell tumour in the left ovary. CONCLUSION: GnRH analogues may offer a good therapeutic option in some states of gonadotrophin-dependent hyperandrogenism of ovarian origin.

hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas.

The hRAD54 protein belongs to a superfamily of DNA helicases, and mutations in genes with DNA helicase function have been found to be responsible for cancer-prone syndromes (xeroderma pigmentosum, Bloom syndrome, Werner syndrome). hRAD54 thus could be a candidate modifier gene in tumors characterized by allelic imbalance at 1p32, the chromosome region in which this gene is located. Using a panel of 38 1p and five 1q markers, we therefore performed deletion-mapping analysis on a series of 35 oligodendrogliomas, which were also studied for mutations in the hRAD54 gene. Deletions of the short arm of chromosome 1 were evidenced in 26 tumors, mostly involving 1p36-1p13; all thus displayed loss of the 1p32 region. We used PCR/SSCP to examine all 18 exons of the hRAD54 gene for mutations in 25 tumors, but the mobility shifts detected corresponded to previously identified polymorphic changes: T-to-C transition at nucleotide 2865 (with no amino acid change) and at nucleotide 3008, at the 3' untranslated region. We conclude that hRAD54 gene alterations are not required for malignant transformation of oligodendrogliomas.

Search for mutations of the hRAD54 gene in sporadic meningiomas with deletion at 1p32.

The hRAD54 gene is related to a family of genes involved in DNA recombination and repair and encodes a protein with DNA helicase activity. hRAD54 has been mapped to 1p32, a region frequently involved in deletions in a variety of tumor types, including atypical and anaplastic meningiomas. To determine whether alterations of hRAD54 are a common event in meningeal tumors, by means of polymerase chain reaction-single-stranded conformation analysis we examined 29 tumor samples characterized by 1p deletions for hRAD54 mutations. Although 18 tumors displayed allelic loss at the gene region (1p32) as determined by microsatellite marker analysis, the sole coding-sequence alteration detected corresponded to a T-->C transition, with no amino-acid change. The genotype distribution was 10.34% TT, 44.8% TC, and 44.8% CC, whereas in the normal controls it was 3.77% TT, 13.2% TC, and 83.01% CC, and most meningiomas with 1 p32 deletion retained allele C. Another polymorphism due to a T-->C change was evidenced at nt 3008, in the 3' untranslated region. This change was evidenced in all cases we sequenced. These results appear to exclude the involvement of the hRAD54 gene in the pathogenesis of the nontypical meningiomas, although a detrimental effect of the hRAD54 polymorphisms cannot be ruled out.

NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas.

Formation of meningiomas and their progression to malignancy may be a multi-step process, implying accumulation of genetic mutations at specific loci. To determine the relationship between early NF2 gene inactivation and the molecular mechanisms that may contribute to meningioma tumor progression, we have performed deletion mapping analysis at chromosomes 1, 14 and 22 in a series of 81 sporadic meningiomas (54 grade I (typical), 25 grade II (atypical) and two grade III (anaplastic)), which were also studied for NF2 gene mutations. Single-strand conformational polymorphism analysis was used to identify 11 mutations in five of the eight exons of the NF2 gene studied. All 11 tumors displayed loss of heterozygosity (LOH) for chromosome 22 markers; this anomaly was also detected in 33 additional tumors. Twenty-nine and 23 cases were characterized by LOH at 1p and 14q, respectively, mostly corresponding to aggressive tumors that also generally displayed LOH 22. All three alterations were detected in association in seven grade II and two grade III meningiomas, corroborating the hypothesis that the formation of aggressive meningiomas follows a multi-step tumor progression model.

Allelic status of 1p, 14q, and 22q and NF2 gene mutations in sporadic schwannomas.

Schwannomas are common benign tumours of schwann cell origin, frequently found in patients with neurofibromatosis type 2 (NF2). Inactivation of the NF2 tumour suppressor gene appears to be a molecular event responsible for the development of up to 60% of cases, but no data are available on other superimposed secondary or alternative molecular abnormalities in those schwannomas lacking NF2 gene inactivation. We analysed 23 sporadic schwannomas for mutations in the NF2 gene and for the allelic status at 1p, 14q and 22q, as alterations of these genomic regions appear to be related to tumour progression in meningiomas, another NF2-associated neoplasm. Nine samples displayed allelic losses for markers on chromosome 22, and deletions at 1p were detected in two. No case showed losses for 14q. Three tumours displayed NF2 gene mutations, at exons 2, 7 and 12. Our results confirm that inactivation of the NF2 gene is a primary event in schwannoma development, and provide data suggesting that allelic loss at 1p may contribute to the pathogenesis of a small subgroup of this histological tumour type.

[Expression of CD44 variant v6 in breast carcinoma and its relationship with other parameters of tumor biology]. / Expresión de la variante v6 de CD44 en carcinomas de mama y su relación con otros parámetros de la biología tumoral.

BACKGROUND: The variant v6 of CD44 has been associated with metastatic behaviour in neoplasms such as lymphoma, colon carcinoma and breast carcinoma. The expression of CD44v6 in breast carcinoma by flow cytometry and its relationship with other tumor markers is studied in this paper. MATERIAL AND METHODS: The expression of CD44v6 was studied in 46 fresh tissue specimens by flow cytometry using a monoclonal antibody which recognizes the variant v6. Ploidy and cell cycle were also studied by flow-cytometry using propidium iodide labelling. p 53, c-erbB-2 and estrogen receptor expression as well as cell proliferation by Ki-67 staining were performed by immunohistochemistry. RESULTS: Nineteen out of 46 tumors were CD44v6 positive, without correlation with other tumor markers. Levels of CD44v6 in 19 positive samples sligtly correlates with S-phase and hystological grade. CONCLUSIONS: In the present study there was not a correlation among the presence of the variant v6 of CD44 on tumor cells from breast carcinoma and the aggressivity of the tumor. The expression of CD44v6 by flow cytometry does not seem to be a good prognostic marker.

Acquired hypertrichosis lanuginosa: case report and review of the literature.

Acquired hypertrichosis lanuginosa is a rare cutaneous disorder usually associated with internal malignancy that consists of the development of abnormal hair growth of the lanugo type, often confined to the skin of the face and neck, although other areas also may be involved. We report on a 66-year-old woman with a metastatic ductal infiltrating carcinoma of the breast who developed growth of fine lanugo type hair on her face and progressive growth of the hair of eyebrows and eyelashes. We review the literature on this uncommon paraneoplastic cutaneous disorder emphasizing the pathogenic mechanisms that have been proposed to explain the striking overgrowth of lanugo type hair.