Lucien J. Rubinstein

The association of embryonal tumors originating in the kidney and in the brain. A report of seven cases

This report documents, in seven infants younger than 2 years of age, a previously unrecognized association of a renal embryonal neoplasm (malignant rhabdoid tumor in six patients and a Wilms tumor in one) with an embryonal primary tumor originating in the central nervous system. The neuroepithelial tumors included three cerebellar medulloblastomas, one pineoblastoma, one primitive neuroepithelial tumor (probably cerebral neuroblastoma), one malignant subependymal giant cell astrocytoma, and one cerebellar medulloepithelioma with divergent glial and neuronal differentiation. There is no evidence that this association is based on the selective neoplastic transformation of embryonal cells of similar histogenetic or cytogenetic origin. The relationship between these dissimilar, embryologically unrelated tumors remains enigmatic.

Subependymal giant cell astrocytoma

SummaryTwenty-two cases of subependymal giant cell astrocytoma (SGCA), five of which associated with tuberous sclerosis, were reviewed by conventional neurohistological stains and by peroxidase-antiperoxidase (PAP) immunohistochemistry for glial fibrillary acidic (GFA) protein, the 68 Kd neurofilament subunit (68 Kd-NF), and neuron-specific enolase (NSE). Neurohistological stains confirmed the presence of PTAH-positive fibrils and the absence of Nissl bodies and of neurites originating from the tumor cells. GFA protein-positive cells were present in all tumors not associated with tuberous sclerosis. However, the number of positive cells in each tumor was highly variable. GFA protein-positive cells were rare in the two SGCA accompanying tuberous sclerosis and absent in the remaining three. Neurohistological stains showed no differences between GFA protein-positive and negative cells. 68 Kd-NF-positive cells were found in six tumors. In one tumor, associated with tuberous sclerosis, it was present in the large ganglion-like cells only. NSE-positive cells were found in 13 of 18 tumors examined, including four of the five SGCA associated with tuberous sclerosis. The significance of NSE-positivity in central neuroepithelial neoplasms in respect of their possible neuronal origin remains open.This study suggests that the SGCA, especially those associated with tuberous sclerosis, include cells that are apparently unable to express GFA protein. Some of the tumor cells express the 68 Kd-NF, but this expression falls short of the complete expression of neuronal differentiation. The unique morphological appearances of the SGCA and the discrepancies reported in electron-microscopic and immunohistochemical studies suggest that the cell of origin of these tumors is the product of a dysgenetic event in early development. As a result, the potential of that cell for astrocytic or neuronal differentiation may be incompletely or aberrantly expressed, in particular when the stigmata of tuberous sclerosis are also present. No evidence of obvious ganglionic differentiation and no inference of a neuronal origin of the tumor cells in SGCA could be adduced from the present histochemical findings. This study supports the general interpretation of these tumors as a variant of astrocytoma.

Immunohistochemical recognition of human neuroepithelial tumors by anti-Leu 7 (HNK-1) monoclonal antibody.

SummaryThe immunoreactivity of the anti-Leu 7 (HNK-1) monoclonal antibody, a marker for natural killer cells, was evaluated with the peroxidase-antiperoxidase (PAP) method on sections of human paraffin-embedded tissues from 135 tumors of the central nervous system and five esthesioneuroblastomas. As shown independently by others, the antibody was found to react with most types of neoplastic neuroepithelial cells. Our findings indicate that the reaction is most often localized on the cytoplasmic membranes. The immunoreactive cell membranes were generally those of well-differentiated tumor cells and of neoplastic cells found in tumors that usually were not embryonal in nature. Parallel immunostaining either of the same or of successive sections with an anti-glial fibrillary acidic protein serum was of considerable assistance in discriminating between different immunoreactive cells, e.g., between astrocytes and cells presumed to be oligodendrocytes.Despite its cross-recognition of cells of various histogenesis, the anti-Leu 7 monoclonal antibody can, in well-defined circumstances, elucidate specific differential diagnostic problems involving neurogenic neoplasms that cannot be resolved with routine staining techniques.

Astroblastomas: A pathological study of 23 tumors, with a postoperative follow-up in 13 patients

Astroblastomas are rare, usually circumscribed, supratentorial tumors of young subjects and are characterized by a perivascular arrangement of the tumor cells. Their clinical behavior is unpredictable and their prognosis has been regarded as intermediate between that of astrocytomas and glioblastomas. A personal series of 23 astroblastomas was reviewed, adequate postoperative follow-up being available in 13 patients. Two distinct histological types were encountered: low-grade and high-grade. The low-grade type comprised tumors with better differentiated and more benign-appearing microscopical features. Five of the 8 patients with tumors of this type who were available for follow-up have survived from 3 to 20 years after treatment; in 1 patient the tumor converted into a fatal glioblastoma after 4 1/2 years. The high-grade type consisted of tumors with more anaplastic features. Three of the 4 patients with tumors of this type available for follow-up died after 1 1/2 to 2 1/2 years, the astroblastomas in 2 of them having converted into a glioblastoma and a gliosarcoma, respectively. One patient, however, has had an unexpected length of postoperative survival of 11 1/2 years. The best clinical results were obtained after total or subtotal resection of the tumor, followed by radiotherapy. The role of chemotherapy is still uncertain. This form of glioma illustrates the discrepancies that may sometimes be apparent between histopathological features and length of postoperative survival. The prognosis is also further complicated by the potential of the astroblastoma to convert into a more malignant type of glioma.

Immunohistochemical characterization of oligodendrogliomas: an analysis of multiple markers

SummaryTwenty-eight oligodendrogliomas and seven oligoastrocytomas were immunotested by the peroxidase-antiperoxidase (PAP) method with antiglial fibrillary acidic protein (GFAP) serum, anti-Leu 7 monoclonal antibody (Mab), anti-myelin-associated glycoprotein (MAG) Mab, anti-myelin basic protein (MBP) serum, anti-carbonic anhydrase C (CA C) serum and anti-neuron-specific enolase (NSE) serum. The immunoreactivity of their vascular pattern was studied withUlex europaeus type I lectin (UEA I). According to their morphology and distribution GFAP-positive cells were respectively interpreted as reactive astrocytes, neoplastic astrocytes and neoplastic oligodendrocytes. Reactive astrocytes were found in the tumor, around the tumor and surrounding the supporting blood vessels. Neoplastic astrocytes were mainly found in the oligoastrocytomas and usually closely intermingled with neoplastic oligodendrocytes. GFAP-positive neoplastic oligodendrocytes were found in the typical oligodendrogliomatous areas. They had central nuclei and GFA positivity was mainly found in the perinuclear cytoplasm. They correspond to the “gliofibrillary oligodendrocytes” described by Herpers and Budka [11]. Of the oligodendrogliomas 91% displayed Leu 7 positivity, but anti-Leu 7 cannot be considered as a specific marker for oligodendrogliomas since other neuroepithelial tumors have been reported to react with this antibody [20]. MAG-, CA C- and NSE-positivities were found in a number of tumor cells in a few oligodendrogliomas. All the tumor cells were MBP-negative, but myelin sheaths and fragments of myelin in the infiltrated white matter were clearly demonstrated by this antiserum. UEA I strikingly demonstrated the vascular pattern of the tumors, and its usefulness as a discriminating marker for the supportive endothelial cells was confirmed.

Histopathological features of recurrent pleomorphic xanthoastrocytomas: further corroboration of the glial nature of this neoplasm

SummaryPleomorphic xanthoastrocytoma (PXA), a tumor most often presenting superficially over the cerebral hemisphere of young subjects, has certain morphological similarities to fibrous histiocytoma (or fibrous xanthoma) of the meninges and brain, namely the occurrence of lipid-laden neoplastic cells and, frequently, a dense reticulin fiber network. The detection of glial fibrillary acidic (GFA) protein in the tumor cells helped to establish its astrocytic derivation, but it has been advanced that, in spite of this agreed observation, the tumor should still be regarded as a fibrous xanthoma of meningeal origin. Although many patients have a long symptom-free postoperative survival, local recurrences at varying intervals after surgery have been noted in some instanvals after surgery have been noted in some instances. Weldon-Linne et al. first reported that such a recurrence had the morphology of a small-cell glioblastoma. We are reporting three further examples of locally recurrent neoplasms in patients whose original meningocerebral tumors had the typical features of PXA; the recurrences (developing 7 months, 7 years and 15 years, respectively, after surgery) were small-cell glioblastomas. The rich reticulin network present in the initial tumor was mostly lost in the recurrences. This anaplastic evolution further confirms the astrocytic nature of the PXA.

Expression of epithelial membrane antigen in perineurial cells and their derivatives

SummaryParaffin-embedded surgical pathology specimens from skin (5) and muscle (2) biopsies, from Mortons neuromas (3), traumatic neuromas (8), schwannomas (21), neurofibromas (12), and from one perineurioma and one neurothekeoma were studied by immunoperoxidase histochemistry and antibodies against epithelial membrane antigen (EMA), Leu 7 epitopes (Leu 7), S-100 protein (S-100) and cytokeratins. Normal, reactive and neoplastic perineurial cells stain consistently for EMA, whereas Schwann cells express Leu 7 and/or S-100 positivity. None of the immunoreactive cells stained for cytokeratin. Our findings indicate that perineurial and Schwann cells can easily be distinguished by their different patterns of immunoreactivity with the above markers.

Ependymoblastoma. A reappraisal of a rare embryonal tumor

This article reviews the clinicopathologic features of 12 ependymoblastomas, including those of 7 previously unreported cases. The histologic charateristics included a high density of small to medium‐sized neuroepithelial cells with a uniform cytologic appearance, frequent mitotic figures, and numerous diagnostic ependymal rosettes and tubules. Differentiation was restricted to glial precursor cells and to cells with the differentiating features of ependymal cells. Cytogenetically, the tumor cells with the differentiating hallmarks of ependymal cells but which have retained their mitotic activity were considered to be ependymoblasts. Many of the rosettes in the tumors were of the ependymoblastic type, but ependymal rosettes were also present. The absence of pleomorphism, giant cells, multinucleation and pseudopalisades, and the scanty proliferation of vascular endothelial cells are additional features that delineate this tumor from an anaplastic (malignant) ependymoma. The median age of the patients was 2 years. After surgical treatment the median survival time was 12 months. Because of the frequency of leptomeningeal involvement, whole neuraxis radiation should be considered.

The Malformative Central Nervous System Lesions in the Central and Peripheral Forms of Neurofibromatosis

The neuropathological features of 22 autopsied cases of NF have been reviewed, with special reference to the malformative and proliferative lesions implicating the intracranial and intraspinal neural structures. Eleven cases represented examples of the central form of the disease, and 11 examples of the peripheral form. The central form is defined by the association and multiplicity of cranial and spinal meningeal, nerve-sheath, and glial neoplasms (astrocytomas and ependymomas). Bilateral acoustic schwannomas are a frequent, but not invariable, component of the disease. Central NF is also characterized by the very frequent incidence (9 out of 11 cases) of distinctive malformative CNS lesions, which included intramedullary and perivascular schwannosis, meningioangiomatosis, discrete ependymal ectopias, atypical glial cell nests in the grey matter, and, less frequently, syringomyelia. Many of these hamartomatous changes were closely associated topographically with florid neoplastic lesions. Five of the 11 cases of peripheral NF showed involvement of the CNS by cellular proliferative changes that included subependymal gliofibrillary nodules in 3 cases (causing aqueduct stenosis in 2, with resulting hydrocephalus in 1); hyperplastic meningioencephalic gliosis involving the pons and the cerebellum in 1 case; and micronodular capillary and arteriolar proliferations typical of the vascular form of NF in 1 case. Whereas some of the glial proliferations are probably hamartomatous in nature, others may represent an abnormal productive neuroglial response to adjacent pathological conditions, such as antecedent cerebral hemorrhage or infarct, known to stimulate a proliferative gliosis. Such a response may exhibit morphological features that are indistinguishable from those of an astrocytoma, including leptomeningeal and perivascular invasion. The incidence of proliferative CNS lesions in both the central and the peripheral form of NF indicates that the spectrum of tissues implicated extends beyond those derived solely from the neural crest.

S-Antigen immunoreactivity in human pineal glands and pineal parenchymal tumors. A monoclonal antibody study

SummaryUsing a four-step immunoperoxidase (PAP) method and the monoclonal antibody MAbA9-C6 (MAbA9-C6), which defines an epitope of the retinal S-antigen (S-Ag), we investigated the S-Ag immunoreactivity in human fetal, newborn, infantile and adult pineal glands and in 13 human pineal parenchymal tumors. S-Ag immunoreactivity was demonstrated in a few cells in one of the four fetal and in both infantile glands. Eight of nine adult pineal glands contained isolated MAbA9-C6-positive cells. In two of seven pineocytomas showing neuronal or gangliogliomatous differentiation a few scattered cells displayed S-Ag positivity; two of four pineoblastomas contained small groups of strongly immunoreactive neoplastic cells; two malignant pineocytomas did not demonstrate any S-Ag immunoreactivity. Our results indicate that isolated cells in human pineal gland retain some of the cytochemical characteristics of photoreceptor cells recognized by the MAbA9-C6, and that S-Ag immunoreactivity may be occasionally expressed in pineal parenchymal tumors.