Biomedical subjects
Publications and source records attributed to M Kujas.
We report two cases of papillary glioneuronal tumour. Both patients underwent gross total resection of their tumour. One of them was also treated by radiotherapy. Neither tumour had recurred, 19 and 2 years after treatment, thus confirming the good prognosis commonly associated with this tumour.
INTRODUCTION: Cushing's syndrome has a very low incidence (1-10 cases/million/year), and familial cases are even more rare. We report on two situations involving different causes of Cushing's syndrome. CASES: In the first case, we describe the case of a patient with an adrenal adenoma 20 years before the occurrence of Cushing's disease related to the pineal gland. In the second case, two members of the same family were diagnosed almost simultaneously with adrenal cortical adenoma (mother) and Cushing's disease (daughter). DISCUSSION: These cases lead us to consider the known causes of familial Cushing's syndrome, which were not found here.
The expression of Olig2, a basic helix-loop-helix (bHLH) transcription factor involved in oligodendroglial specification, was investigated by immunohistochemistry in a series of 146 tumours and control samples. Olig2 expression was restricted to glial tumours and nontumoral oligodendrocytes. It was higher in oligodendrogliomas as compared to astrocytomas and oligoastrocytomas, and in grade III as compared to grade II tumours. Olig 2 was absent or weakly expressed in glioblastoma (GBM), whereas strong expression was found in the oligodendroglial foci of GBM with oligodendroglial component (GBMO). Double labelling was performed on a subset of the most typical tumours, according to the WHO classification. It showed a mutual exclusion, at cell level, of Olig2 and GFAP expression. In pure oligodendrogliomas, tumour cells were Olig2+/GFAP-. In contrast, two main tumour populations, Olig2+/GFAP- and Olig2-/GFAP+, were found in both oligoastrocytomas and astrocytomas. Based on these data from selected samples, two separate entities can be established, corresponding to 'pure oligodendrogliomas' and 'astrocytomas and oligoastrocytomas'. The relevance of this subdivision is further supported by the association with 1p loss and a trend to better survival for pure oligodendrogliomas and with p53 expression and a trend to shorter survival for astrocytomas and oligoastrocytomas. Combined testing of Olig2, 1p status, GFAP and p53 expression may therefore be helpful in refining current classification and providing more homogeneous sets of gliomas for clinical studies.
Myopericytoma is a benign tumour generally arising in the subcutaneous and superficial soft tissues of the extremities. Very few cases have been reported in other locations and intracranial examples are exceptional. We now report on three cases of primary intracranial myopericytoma and review the literature on that rare entity. The patients were women in their fifties who presented with decreased visual acuity in two cases and raised intracranial pressure in one case. The tumour involved, respectively, the anterior cranial fossa, the orbital apex and the pineal region. Gross total resection was achieved in all three cases. Histological analysis revealed oval-to-spindle shaped myoid-appearing cells with a striking tendency for concentric perivascular growth. The lesional cells showed apparent differentiation towards perivascular myoid cells as witnessed by smooth muscle actin expression. In one case, an epithelioid differentiation was also present. None of the patients received adjuvant therapy. One patient died of unrelated causes 6 months after surgery. The other two are alive and well at 9 and 12 month follow-up respectively. Myopericytoma is a recently described neoplasm, and it is likely that reappraisal of intracranial haemangiopericytoma with which it shares many histopathologic features will lead to more case reports of primary intracranial myopericytoma.
OBJECTIVE: To investigate possible correlations between tumor location and genetic alterations in a series of oligodendrogliomas. METHODS: A series of 158 consecutive oligodendrogliomas were retrospectively reviewed. In each case, the radiologic picture and the chromosome 1p (chr 1p) status of the tumor detected by the loss of heterozygosity technique were analyzed. Correlation between tumor location and molecular profile was made by chi2 tests. RESULTS: Eighty-eight of the 158 patients had low-grade oligodendrogliomas, and 70 had anaplastic oligodendrogliomas. Overall, oligodendrogliomas with chr 1p loss were located preferentially in the anterior part of the brain, whereas tumors with intact chr 1p affected mainly the posterior part of the brain (p = 0.0038). In terms of lobar involvement, a preferential location of oligodendrogliomas with chr 1p loss was found in the frontal lobes as compared with the temporal, parietal, and occipital tumors (p < 0.01). CONCLUSION: There is a significant correlation between loss of heterozygosity on chromosome 1p and tumor location in oligodendrogliomas, suggesting that subtypes of oligodendrogliomas could derive from site-specific precursors.
PURPOSE: To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS: Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS: Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION: TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.
In order to develop preclinical models of malignant astrocytomas and oligodendrogliomas, a series of 54 resected gliomas (37 from oligodendroglial lineage and 17 from astrocytic lineage) were xenografted subcutaneously into nude mice. Molecular alterations commonly observed in gliomas subtypes, including LOH 1p and 1q, LOH 19q, LOH 10p and 10q, LOH 9p, TP53 and PTEN mutations, EGFR amplification, CDKN2A homozygous deletion and telomerase reactivation were systematically screened in the original and xenografted tumours. In all, 23 gliomas grew in nude mice. The most anaplastic tumours were selected as shown by pathological and molecular studies of the original tumour as well as shorter survival in patients whose tumours were successfully grafted. Comparison between the two growth profiles showed that 10q LOH and EGFR amplification gave a tumorigenic advantage. With a few exceptions, the genetic pattern was remarkably stable before and after growth in nude mice. These results suggest that subcutaneous xenografts are useful and reproducible models to analyse the molecular profile of malignant astrocytoma and oligodendroglioma. This represents the first step to improve our understanding of the correlations between molecular alterations and response to standard or experimental therapies.
An inhibitor of telomerase activity maps to chromosome 10p15.1. A series of 51 high-grade gliomas was analyzed for loss of heterozygosity (LOH) on chromosome 10 and for telomerase activity. In univariate analysis, LOH10p (59%) and LOH10q (61%) were associated with telomerase activity (55%; p < 0.0001 and p = 0.0006). In multivariate analysis, only LOH10p remained statistically related to telomerase activity, suggesting that the telomerase repressor gene located on 10p15.1 is inactivated in high-grade gliomas.
INTRODUCTION: Less than 2 per 1,000 meningiomas are complicated by extra-cranial metastases. These are most often found in the lung parenchyma, liver or lymph nodes. They almost always occur in anaplastic meningiomas (grade III according to OMS) and much more rarely in atypical meningiomas (grade II). CASE REPORT: We report a case of pleural metastases from a primary frontal atypical meningioma with no other extra-cranial spread. CONCLUSION: Poorly differentiated meningioma presents many morphological and immuno-histochemical similarities to malignant mesothelioma. For this reason the diagnosis of pleural metastase from a meningioma cannot be made without knowledge of the primary meningeal tumour and its histological type.
Pituitary carcinomas are exceptional tumors and constitute 0.1 to 0.2% of pituitary tumors. Their definition includes well-established criteria but distant metastasis is the hallmark required for diagnosis. We report the fourth case of gonadotropic pituitary carcinoma described in the literature. This case illustrates the dramatic outcome of these tumors. The most interesting feature of our case was the loss of differentiation with time, established by retrospective analysis of the primary tumor surgically treated 15 years earlier. Most of the previously reported cases exhibited a majority of adrenocoticotropin and non-functioning pituitary tumors. However, the frequency of non-functioning tumors seems smaller than previously believed. In the discussion, we stress the need to detect these very aggressive tumors as early as possible and identify treatments to improve the dramatic course of these carcinomas.
Forty-four patients (22 males and 22 females) were admitted to our institution for an intracranial epidermoid cyst between 1980 and 2000. Their mean age was 39.9 years. The duration of the disease at admission varied between a few days and 30 years. CT-scan was performed in all cases, MRI in 33 cases with a diffusion sequence in 3. Most of the 26 patients with posterior fossa lesions were treated surgically in the sitting position, with resection of the tonsils in four cases in order to minimize cerebellar retraction. The other supratentorial tumors were operated using a fronto-temporo-pterional approach in 13 cases (with temporo-polar lobectomy in 6 cases), or a parietal transparenchymal approach in the parieto-occipital lesions (2 cases). The resection was total or subtotal (residual capsule) in 79.5% of cases. Post-operative morbidity was 13.6% and mortality 8.9%. The median follow-up was 8 years, with a recurrence rate of 4.5%. Epidermoid cysts are benign, slowly but ineluctably growing tumors which require surgical treatment. Their diagnosis has become easier, especially with the development of MRI diffusion sequences. Morbidity and mortality (morbi-mortality) reported in the literature as well as found in our series seems to be unrelated to classical aseptic meningitis (22.7% in our series) or hydrocephalus (2 cases in our series). For many authors, it may be the consequence of systematic resection of the tumor capsule. This does not seem to be the case in our series in which only 25% of the patients underwent a complete resection. Prolonged cerebral retraction could be one of the responsible factors. One of the technical proposals could be to perform a transparenchymal approach in selected patients.
OBJECTIVE: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance. METHODS: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses. RESULTS: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS. CONCLUSION: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.
OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.
Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.
Enlargement of the pituitary gland is a frequent cause of incidentaloma and of referrals to endocrinologists for hormonal evaluation and therapeutic advice. In neuroradiological series, 25-50% of healthy women who are 18-35 yr old have a convex superior pituitary contour, but pituitary height exceeds 9 mm in less than 0.5% of cases. This study was performed to provide thorough clinical and hormonal data and long-term endocrinological and imaging follow-up data on subjects with incidentally discovered pituitary hypertrophy (height > 9 mm). Seven eugonadal nulliparous women, 15-27 yr old, referred between 1989 and 1998 with incidentally diagnosed pituitary gland enlargement (height > 9 mm) and a suspected pituitary tumor, were studied. At presentation and at yearly intervals, PRL plasma levels and corticotropic, somatotropic, and thyrotropic pituitary function were measured; and pituitary dimensions and signal on magnetic resonance imaging (MRI), before and after iv gadolinium-diethylene-triamine-pentaacetic acid injection, were assessed. PRL plasma levels were normal; and corticotropic, somatotropic, and thyrotropic pituitary function was considered normal in all cases. In all the women, the upper boundary of the pituitary was convex, on MRI, and touched the optic chiasm in four cases. The width and anteroposterior diameter of the gland were normal. The pituitary itself seemed normal, with a homogeneous signal, on plain and dynamic studies with iv contrast injection. Despite normal initial hormone values, two women underwent surgery, by the transsphenoidal approach, in another center. During surgery, the pituitary seemed normal in both cases, with no evidence of tumoral or inflammatory processes. Biopsy specimens showed the morphologic characteristics of a normal, nonhyperplastic pituitary gland. All seven women were seen at yearly intervals for 2-8 yr (median, 4 yr). Clinical and hormonal status remained stable, as did the structure and size of pituitary, on serial MRI. No tumor formation occurred, supporting the diagnosis of physiologic hypertrophy of the pituitary gland. In conclusion, these observations suggest that careful examination of MRI results may help to distinguish physiologic pituitary hypertrophy from pituitary tumors and infiltrating lesions. The former diagnosis is confirmed by normal baseline pituitary function in extensive hormonal tests. Correct identification of such patients is important to avoid unnecessary pituitary surgery and costly MRI surveillance.
Human pituitary adenomas are benign neoplasms composed of hormonal adenohypophyseal cells. They arise in the sella turcica, and are characterized by a wide range of biological behavioral related not only to hormonal but also to proliferative activities. In the past, pituitary adenoma studies have mainly been devoted to histological and ultrastructural classification improved by immunohistochemical techniques. Molecular biology, cytogenetic studies, associated to experimental animal models, transgenic and knockout mice technologies, have allowed new approaches, especially concerning pathogenesis and progression. It became obvious that tumorigenesis has to be considered as a multistep event, inasmuch as different factors share numerous homologies. On the other hand, it could be supposed that the knowledge of the biological aggressiveness could led to an appropriate follow-up as well as specific therapy.
P18INK4C is a good candidate to be the tumor suppressor gene involved in oligodendrogliomas on 1p32. Loss of heterozygosity on 1p, mutation(s), homozygous deletion(s), and expression of p18 in 30 oligodendroglial tumors were investigated. Loss of heterozygosity on 1p was found in 15 tumors. A p18 mutation was found at an recurrence of an anaplastic oligodendroglioma, but not in the primary, low-grade tumor. No homozygous deletions were found and p18 was expressed in all cases. These results show that p18 alteration is involved in tumor progression in a subset of oligodendrogliomas.
STUDY DESIGN: The authors report the ninth case in the literature of a primary intradural extramedullary ependymoma of the spinal cord. OBJECTIVE: To discuss surgical treatment and the physiopathologic hypothesis of this localization on the basis of the results of the present study and a review of the literature. SUMMARY OF BACKGROUND DATA: Ependymoma is a glial tumor known to arise in the central nervous system. Intradural extramedullary location of this neoplasm has been exceptionally described previously. METHODS: A 43-year-old woman was admitted to the authors' institution with an history of progressive paraplegia. Neurologic examination showed sensory loss below T1 and bladder disturbances. Magnetic resonance imaging revealed an enhanced thoracic intradural extramedullary tumor, extending from T1-T8. No other lesion in the central nervous system was found. Emergency surgical resection was performed. RESULTS: Surgery gave confirmation of an encapsulated extramedullary tumor without attachment to the spinal cord or to the dura mater. Total removal was achieved under microscope. The postoperative course was uneventful, with complete neurologic recovery 3 months later. The patient has been well for 24 months of follow-up evaluation, without evidence of recurrence on magnetic resonance images. Histologic examination revealed the tumor as a benign ependymoma. CONCLUSION: The encapsulated feature, the lack of attachment to the central nervous system, and the absence of other neoplastic processes within the brain or the spinal cord suggested that this lesion is a primary tumor developed from ectopic ependymal cells.