Biomedical subjects
Publications and source records attributed to W M Molenaar.
The cytogenetic study of a case of cardiac myxoma revealed a 46,XY,der(7)t(7;17) (p21;p11),+der(10)t(10;?)(q22;?),+der(12)t(12;?)(p12;?),del(17)(p11) chromosomal pattern. This case adds a new example of chromosomal abnormalities in benign neoplasms.
Juvenile xanthogranuloma (JXG) is considered to represent a lesion originating from histiocytes. Three cases of deeply located JXG and one case of cutaneous JXG were studied. One case with extensive mesenteric involvement presented with hypercalcemia and one case with liver involvement had hypergammaglobulinemia. Immunohistochemistry, electron microscopy, karyotyping, and DNA flow cytometry were used to determine the phenotype of the cells involved and to find further clues as to the histogenesis of these lesions. Immunohistochemically, all lesions studied expressed the CD1a antigen but showed no labeling for S-100 protein. The cells did not contain Birbeck granules. From these data it is suggested that the cells involved are of indeterminate dermal histiocyte lineage and that occurrence of deep located lesions of JXG may be due to migration of CD1 a-positive histiocytes.
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Magnetic resonance (MR) imaging was performed in 116 patients in whom a parotid mass lesion was clinically suspected. Eighty-six patients had benign disease. The 30 patients in whom a malignant tumor was found were further evaluated. To determine which features are characteristic of malignant parotid tumors, spin-echo T1- and T2-weighted images of malignant lesions in the parotid gland were compared with those of benign disease. In our series, tumor margins, homogeneity, or signal intensity were not discriminative factors to correctly predict benign or malignant disease. Infiltration into deep structures (eg, the parapharyngeal space, muscles, and bone) was observed only in malignant tumors. Infiltration into subcutaneous fat was noticed in malignant as well as in inflammatory disease. No statistically significant correlation was found between tumor grade and MR imaging features in malignant disease. MR imaging is useful in delineating malignant tumors but is unreliable in correctly predicting the histologic nature of a mass lesion in the parotid gland.
To study mechanisms involved in evolution of soft tissue sarcomas, we compared DNA ploidy and karyotypes at different stages of their disease in two patients with myxoid liposarcomas (MLS), one with a fibrosarcoma (FS), and two with rhabdomyosarcomas (RMS). None of the MLS samples revealed clearcut histologic changes in later samples as compared to their primaries, and the DNA ploidy in all samples was diploid. In one patient karyotypes at four different times during the 19 yr of his disease all revealed a t(11;12) (p15;q13), but additional clonal chromosomal abnormalities occurred only in later recurrences. In another patient the karyotypes obtained in the 26th and 28th yr of his disease were similar and included the t(12;16) (q13;p11), characteristic of MLS. A comparison with karyotypes of six other MLS patients at different disease stages suggests that the presence of a t(12;16) may correlate with less aggressive clinical behavior. The histology of the FS remained low-grade and the DNA ploidy diploid. The karyotype, however, showed evolution. In both MLS and FS, chromosomal changes thus seem to be a more sensitive marker for tumor progression than histologic changes or DNA ploidy. In one embryonal RMS, karyotypes obtained 7 and 11 yr after the primary diagnosis were different but clearly had a common "progenitor." In one alveolar RMS, the primary and the synchronous lung and lymph node metastases all revealed a t(2;13). The findings in RMS suggest that polyploidization is an early event in tumor evolution, especially in the alveolar subtype, which may be followed by additional chromosomal changes. In addition, DNA ploidy was measured in eight other RMSs. Among the RMSs the embryonal subtype was characterized by DNA aneuploidy, whereas three of the alveolar cases were in the tetraploid range and one was peridiploid. In local recurrences and in metastases changes in DNA index were observed in half the cases.
The current study describes the presence of neuroendocrine antigens of peripheral and central neural tumors using eight monoclonal antibodies raised to small cell lung carcinoma (SCLC), which recognize "neural/neuroendocrine" or "neural" antigens, as defined by their reaction pattern in normal tissues and tumors. At least five of them recognize different epitopes of the neural cell adhesion molecule (N-CAM). It was found that all of 12 neuroblastomas, 2 ganglioneuroblastomas and 4 ganglioneuromas as well as 23 central primitive neuroectodermal tumors, 13 astrocytomas and 4 ependymomas share "neural/neuroendocrine" antigens (as defined by the anti-N-CAM antibodies Moc-1, -21, -32, -52 and -191) with SCLC. The "neural/neuroendocrine" antigen defined by Moc-171 was also found in all peripheral tumors, but only in further differentiated central tumors. Non-N-CAM related "neural" antigens (as defined by Moc-51 and -172) were found only in better-differentiated peripheral and central tumors, but they could be demonstrated in all three medulloblastoma cell lines studied. In addition, the antigen defined by Moc-51 was demonstrated in an immunoblot of a neuroblastoma cell line. Antibodies recognizing "epithelial" antigens of SCLC and other epithelia and their tumors (Moc-31 and -181) were non-reactive. It was concluded that these findings give further support for a relation between neural and neuroendocrine tumors and that some of the antibodies may be useful for the detection of differentiation in neural tumors. Antibodies with an "epithelial" recognition pattern may serve to distinguish neural from neuroendocrine tumors.
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Nerve growth factor (NGF) is important to the survival, development, and differentiation of neurons. Its action is mediated by a specific cell surface transmembrane glycoprotein, nerve growth factor receptor (NGFR). In this study, NGFR expression by human fetal and adult adrenal medullary tissue, peripheral nervous system (PNS) neuroectodermal tumors (neuroblastoma, ganglioneuroblastoma, ganglioneuroma), pediatric primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS), and CNS gliomas was examined by an immunohistochemical technique. Sixty-nine tumors in total were probed in this manner. Nerve growth factor receptor immunoreactivity was confined to nerve fibers and clusters of primitive-appearing cells in the fetal adrenal, and to nerve fibers and ganglion cells of the adult adrenal medulla; adrenal chromaffin cells were negative. In PNS neuroectodermal tumors, there was NGFR expression in tumor cells of 6 of 11 neuroblastomas and 6 of 6 ganglioneuroblastomas or ganglioneuromas. Thirteen of thirty-five CNS PNETs showed NGFR positivity. In most CNS PNETs, NGFR was restricted to scattered single or small groups of cells, but two tumors with astroglial differentiation showed much more extensive immunoreactivity. Most astrocytomas (11 of 14) and all ependymomas (3 of 3) were intensely NGFR positive.
The case history is reported of a patient with an invasion of the inferior vena cava by metastases of a non-seminomatous testicular tumour. He was treated with combination chemotherapy, followed by laparotomy and resection of residual tumour tissue. Fourteen months after this operation he is in good health. For every retroperitoneal lymph node dissection it is necessary to be on the look-out for invasion of the vena cava, because of the risk of a sudden pulmonary embolism.
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A follow-up study, based on clinical, radiological and pathological information was performed of 20 patients who had suffered from an osteoid osteoma and of three patients who had been treated for an osteoblastoma in the period 1978-1988. 50% of the patients mentioned both pain at night and a good reaction to salicylates. In 87% of the cases a correct diagnosis was made with the aid of conventional radiography, tomography and bone scanning. Primary treatment consisted of intracapsular (mostly piecemeal) excision in all cases. A local recurrence was observed in one patient with osteoid osteoma and in two with osteoblastoma. At the time of this follow-up study none of the 23 patients had complaints. Histopathological examination did not reveal any difference between the two types of bone tumour.
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Pigmented villonodular synovitis is a benign disease of the synovial membrane of joints, tendon sheaths, or bursae, which nevertheless can cause marked local destruction. Its diagnosis is often delayed because complaints and symptoms are nonspecific. Familiarity with the disease may ensure an earlier diagnosis and consequently early onset of therapy, which may prevent serious damage. This paper describes 18 patients suffering from localized or diffuse pigmented villonodular synovitis. Findings possibly suggestive of pigmented villonodular synovitis include hemarthrosis, soft tissue swelling, radiological evidence of cyst formation at a distance from the weight-bearing area of a joint, an increased triglyceride concentration, and a positive bone scan. A normal appearance on arthroscopy does not rule out the disease. Therapeutic results are better in the localized than in the diffuse form of the disease.
The development of chromaffin and neuronal features in the adrenal medulla was studied in normal human fetuses with gestational ages (GAs) of 6-34 weeks. Monoclonal antibodies specific for chromogranin A, synaptophysin, and tyrosine hydroxylase; for different subunits and phosphoisoforms of neurofilament (NF) proteins; and for microtubule-associated proteins were applied. Morphologically, two major cell types could be distinguished, i.e., "large" cells with pale nuclei and ill-defined cytoplasm, which were present from 9 weeks GA on, and clusters of "small," primitive appearing cells, present from 14 weeks GA on. The large cells were immunoreactive for chromogranin A, synaptophysin, tyrosine hydroxylase, and NF proteins, similar to adult chromaffin cells. In contrast, small cells expressed NF proteins and tyrosine hydroxylase, but not chromogranin A or synaptophysin, more resembling ganglion cells in the adult adrenal medulla. At the latest developmental stages large cells were observed in the center of the clusters of "small" cells, which morphologically resembled immature ganglion cells and expressed NF proteins in their perikarya. These observations indicate that chromaffin and ganglion cells establish their immunophenotype early in embryogenesis. They suggest that "large" and "small" cells are progenitors of the chromaffin and the ganglion cells, respectively, of the mature adrenal medulla.
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Myopathy accompanying familial hypokalaemic periodic paralysis (HPP) is much less well documented than the paralytic attacks from which the disease derives its name. Eleven affected members of a large kinship with HPP were studied clinically and radiologically for the presence of myopathy. In 4 patients muscle biopsies were also performed and in 1 of them the histological findings obtained at autopsy were compared with the CT scans of various muscles. In another patient not previously biopsied, the specimens of both amputated legs were examined histologically. The age of the studied individuals ranged from 33 to 74 yrs. The 4 youngest patients showed no clinical signs of myopathy. However, in 2 of them CT scans demonstrated discrete hypodense lesions in the leg muscles, whereas in the other 2, muscle biopsies showed a vacuolar myopathy. The other 7 patients, all older than 50 yrs, presented both clinical and CT evidence of myopathy of proximal and distal muscles ranging from very mild to very severe, males being slightly more affected than females. In all 11 patients a mean CT grading was made that was based on the abnormalities found in the different muscle groups. The myopathy appeared to be unrelated to the history of paralytic attacks, but a strong correlation was found between age and mean CT grading. It was concluded that HPP is a myopathy with permanent muscle weakness of late onset in all the patients. The expression of the paralytic attacks is variable.
To establish the neuroendocrine and neural features of peripheral neuroblastic tumors, a prospectively collected group of 12 neuroblastomas (NB), 2 ganglioneuroblastomas (GNB), and 4 ganglioneuromas (GN) was probed with a panel of monoclonal antibodies (MAbs) to neuroendocrine and neural antigens. All tumors expressed the pan-neuroendocrine markers synaptophysin and chromogranin A. They also showed extensive expression of neuronal antigens, ie, of each of the neurofilament (NF) triplet proteins and of the microtubule-associated proteins (MAPs) MAP2 and tau-protein. However, only in the GNBs and GNs was the pattern of NF phosphoisoforms relatively mature. In the latter tumors glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) could be demonstrated as well, suggesting the presence of nonmyelinating and myelinating Schwann cells, respectively. The glial markers did not colocalize with the neural markers. On the basis of these data, it was concluded that all peripheral neuroblastic tumors manifest molecular characteristics of neuroendocrine cells and of neurons. The latter were most developed in GNBs and GNs, in which they were accompanied by Schwann cell differentiation in a separate population of cells. The above-outlined neuronal profile of peripheral neuroblastic tumors, including NBs, distinguishes this group of tumors from the much-less neuronally differentiated primitive neuroectodermal tumors of the central nervous system.
Snap-frozen samples from 22 primitive neuroectodermal tumors (PNETs) primary in the central nervous system were studied with antibodies to synaptophysin, bombesin, somatostatin, substance P, vasoactive intestinal polypeptide, all classes of intermediate filaments, and desmoplakins I and II. Frozen sections were immunostained by the avidin-biotin peroxidase complex and indirect immunofluorescence microscopy methods. Selected cases were also studied by double and triple label immunofluorescence microscopy, and by two-dimensional gel electrophoresis and immunoblot analysis. We found that all 22 PNETs expressed synaptophysin extensively. Focal expression of 2 or more neuropeptides was noted in 10 samples studied. All PNETs expressed vimentin, 21 of 22 expressed glial filament protein (GFP), 16 of 22 expressed neurofilament proteins (NFP), 4 of 22 expressed desmin, and 3 of 22 expressed cytokeratins. In only one case were focal and questionable reactions with desmoplakin antibodies seen. Immunoblots confirmed the presence of desmin. Double and triple immunofluorescence revealed a number of antigenic coexpressions in individual cells including: synaptophysin with vimentin, GFP, NFP and desmin, vimentin-GFP, vimentin-NFP, vimentin-cytokeratin, vimentin-desmin and desmin-NFP; similarly, combinations of vimentin-GFP-NFP, vimentin-GFP-desmin, and vimentin-GFP-cytokeratin were found. The consistent expression of synaptophysin and 2 or more neuropeptides indicates that central nervous system PNETs have significant phenotypic features in common with neuroendocrine tumors. Their complex and variable intermediate filament complement patterns combined with their consistent expression of specific neuroendocrine differentiation markers, suggest that central nervous system PNETs comprise a distinct, albeit heterogeneous group of neoplasms.