F. Stephen Vogel

Glioblastoma multiforme and anaplastic astrocytoma: Pathologic criteria and prognostic implications

A total of 1440 malignant astrocytic gliomas from three Phase III trials of the National Brain Tumor Study Group were studied to document the clinical usefulness of subclassifying these lesions as either an anaplastic astrocytoma or a glioblastoma multiforme. As defined by a previous “blind” pathology review, the two groups of patients were compared as to mean age, mean duration of preoperative symptoms, and postrandomization survival. In addition, 10 histologic variables were studied in 150 patients with the anaplastic astrocytoma to establish internal correlations, and to relate specific histologic variables to patient age and postrandomization survival. There were highly significant differences in the age, duration of preoperative symptoms, and post randomization survival between the two groups. Internal correlations between histologic variables in the anaplastic astrocytoma disclosed statistically significant associations between the presence of lymphocytes and gemistocytic astrocytes. It is concluded that the subclassification of malignant gliomas into the anaplastic astrocytoma and the glioblastoma multiforme defines groups of patients that are significantly different in regard to age, duration of symptoms, and length of survival. The problems of tissue sampling are recognized, however, the assignment, by a blind pathology review, to two such different groups indicates that the classification has utility for large randomized clinical trials. The analysis of histologic variables in the anaplastic astrocytomas confirms previous suggestions that lymphocytes and gemistocytes frequently coexist in malignant gliomas, but in this study these inflammatory cells did not appear to influence survival. The study reemphasizes the association between advancing age and shorter survivals in patients with malignant gliomas.

Increasing incidence of primary brain lymphoma in the US

There have been a number of clinical reports suggesting an increasing incidence of primary brain lymphoma unrelated to acquired immune deficiency syndrome (AIDS) and organ transplantation. To investigate this issue, the US incidence of this rare lymphoma was assessed using data from the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) program (1973 through 1984). Never‐married men, a relatively high risk group for AIDS, were excluded from the analyses. Brain lymphoma incidence increased from 2.7 in 1973 through 1975 to 7.5 cases per ten million population in 1982 through 1984 (chi‐square trend, 15.25; P < 0.001), and it increased among both men (chi‐square trend, 6.74; P = 0.009) and women (chi‐square trend, 10.48; P = 0.001). Increases in incidence also were observed among persons younger than 60 years of age (chi‐square trend, 4.10; P = 0.04) and persons 60 years of age and older (chi‐square trend, 9.16; P = 0.002). This increased incidence of brain lymphoma appears to be real: It antedates the AIDS epidemic and does not appear to be related to organ transplantation, another cause of increased risk of brain lymphoma. Although part of the increase may be an artifact of improvements in diagnostic technology and practice, most of the observed increase antedates the widespread use of such technologies. Finally, the increase in incidence of brain lymphoma does not appear to be related to overall trends in the incidence of brain tumors and non‐Hodgkins lymphoma, and it is not related to time trends in nosology.

The morphologic effects of radiation administered therapeutically for intracranial gliomas: a postmortem study of 25 cases.

To investigate the pathologic consequences of therapeutic radiation, this morphologic study evaluated the brains of 25 patients with intracranial gliomas treated both with and without this form of therapy. Although beneficial effects of radiation such as the retardation of tumor growth were evident in these studies, among the seventeen patients who received from 5000–6000 rads for malignant gliomas, four developed “late delayed” radiation necrosis. The strong predilection of this tissue response for the white matter adjacent to the neoplasm suggests a local sensitivity which may have been engendered or enhanced by cerebral edema. A fifth case disclosed focal demyelination in the mid‐brain suggesting “early delayed” radiation necrosis, and an additional case had distinctive foci of necrosis within the brain stem. Changes of diffuse cerebral edema were noted in many of the radiated brains. It is concluded that radiation therapy in commonly employed dosages for malignant gliomas carries a risk of injury to surrounding cerebral tissues.

Chordoid meningeal tumors in young individuals with peritumoral lymphoplasmacellular infiltrates causing systemic manifestations of the Castleman syndrome. A report of seven cases.

Seven young patients ranging in age from 8 to 19 years had surgically removed meningeal neoplasms with a peculiar myxoid‐chordoid pattern. The tumors were surrounded by massive polyclonal lympho‐plasmacellular infiltrates with follicles and germinal centers. The patients preoperatively manifested iron‐resistant hypochromic microcytic anemia, and one of them had dysgammaglobulinemia and stunted growth. After the masses were removed, the blood picture of the patients normalized, and the adolescent with retarded somatic development resumed normal growth, but two patients developed local recurrence with identical histology and again became anemic. It appears that the peritumoral lymphoplasmacellular infiltrates, which in these instances may be regarded as reactive rather than primary cell proliferations, nevertheless brought about the type of systemic manifestations known as the Castleman syndrome, characteristically seen in patients with angiofollicular lymphoid hyperplasia (hamartoma) of soft tissues, or Castlemans tumor. In one of our patients the inflammatory infiltrate extended far into the surroundings of the meningioma, resulting in the erroneous initial diagnosis of “encephalitis” from a needle biopsy of the brain near the tumor.

Leukodystrophy with diffuse rosenthal fiber formation

SummaryPeculiar filamentary deposits, present diffusely and abundantly throughout the central nervous system of a child with a leukodystrophy, raised the following considerations about their origin and concerning the pathogenesis of the disease process:1.Rosenthal (1898) described peculiar filamentary formations in the glial substance in a case of syringomyelia that he viewed as “pistonlike degenerations of glial fibers”.Benda looked upon them as an “attempt at new myelin fiber formation”, whileBielschowsky (1920), considered them to be the debris of immature glial cells that during the formation of myelin did not contact an axon. The deposits have been termedRosenthal fibers.2.The answer to whether they originate from the degeneration of glia or from the malformation of myelin is contingent, in part, upon the question of whether the myelin fibers are formed by the glia, by the axon cylinders, or by both. While it was previously thought that the lipids which are necessary for the formation of myelin are derived from the blood stream, it has been clearly shown that the specific lipids, cerebrosides and sphingomyelins, as well as the albumins and other proteins are synthesized in the brain itself (Sperry andWaelsch 1940–1941). At the time of myelinization, a prodigious increase in metabolism occurs, as chemical analyses have shown.2.Concomitantly, there is a prolific multiplication of glial cells, which, as spongioblastic myelinization-glia, align themselves to the axons and show vivid signs of activity (Spatz 1918). After the maturation of the myelin, these cells differentiate into oligodendroglia and astrocytes (Roback andScherer 1934). The oligodendroglia remain intimately related with the myelin fibers and are thereafter engaged in their nourishment and preservation.4.Elecron microscopic observations (Geren 1952;Robertson 1952–1957;de Robertis 1958) indicate the myelin formation in the peripheral nerves is possible only when the axon makes contact with the cytoplasm of aSchwann cell. The same obtains with the myelinization-glia in the central nervous system.5.If myelinization-glia do not contact with an axon, they, and subsequently their metabolic products, degenerate. The cells lose their nuclei and transform within the tissues into filamentary and granular slag, termedRosenthal fibers.6.Rosenthal fibers appear not only in association with disturbed development of the central nervous system, but can arise also from undifferentiated cells in the subependymal glia (Opalski), if this glia is stimulated to proliferate by chronic inflammation or neoplasia. Thus, they appear in spongioblastomas, as well as in central neurofibromatosis, as very characteristic, but not obligatory, parts of the alterations.7.Independently ofRosenthal fibers we know an ameboidal degeneration of abundantly proliferated astrocytes and their processes, clasmatodendrosis with crumb-like disintegration products. Morphologically, these are similar toRosenthal fibers, as is well shown in the patient ofAlexander (1949) with megalencephaly and cerebral edema, and, similarly, in more recent observations such as byWohlwill, Bernstein andYakovlev (1951).8.In summary, the case herein reported provides an example of a leukodystrophy evidently caused by a genetic defect that manifested itself during or shortly after the time myelinization, presumably as an enzymatic disturbance in myelin metabolism. This, in turn, stimulated a protracted proliferation of spongioblastic myelinization-glia and astrocytes, which upon degeneration and clasmatodendrosis resulted in massive accumulations about the glial boundaries of the central nervous system, of cellular debris, that in structure, staining characteristics, and distribution resembledRosenthal fibers.ZusammenfassungEigenartige faserige Ablagerungen, die sich diffus in reichlicher Menge im gesamten ZNS eines an Leukodystrophie leidenden Kindes vorfanden, gaben Anlaß zu den folgenden Überlegungen über ihren Ursprung und über die Pathogenese des Krankheitsprozesses:1.Rosenthal beschrieb 1898 eigenartige faserige Gebilde in der Glia bei einem Fall von Syringomyelie; er bezeichnete diese Gebilde als “kolbenähnliche Gliafaserdegenerationen”.Benda hielt sie für einen “Versuch einer neuen Markfaserbildung”, währendBielschowsky (1920) sie als Überreste unreifer Gliazellen betrachtete, die während der Markbildung mit keinem Axon in Kontakt gekommen waren. Die Ablagerungen wurden Rosenthalsche Fasern benannt.2.Zum Teil hängt die Antwort auf die Frage, ob es sich dabei um Degenerationsprodukte von Gliazellen oder um eine Markmißbildung handelt, davon ab, ob die Markfasern von der Glia, von den Achsencylindern oder von beiden gebildet werden. Während man früher annahm, daß die für die Markbildung notwendigen Lipoide aus dem Blute stammen, ist in neuerer Zeit eindeutig bewiesen worden, daß die Synthese der spezifischen Lipoide, Cerebroside und Sphingomyeline, ebenso der Albumine und anderen Proteine im Gehrirn selbst stattfindet (Sperry u.Waelsch 1940–1941). Wie chemische Analysen ergeben haben, kommt es bei der Markbildung zu einer beträchtlichen Erhöhung des Stoffwechsels.3.Gleichzeitig erfolgt eine Vermehrung der unreifen Gliazellen, die sich als “Spongioblasten-ähnliche Bemarkungsglia” an die Axone anlegen und rege Aktivitätszeichen bieten (Spatz 1918). Nach der Markreifung differenzieren sich diese Zellen in Oligodendroglia und Astrocyten (Roback u.Scherer 1934). Die Oligodendroglia bleibt in inniger Verbindung mit den Markfasern und beteilight sich in der Folgezeit an deren Ernährung und Erhaltung.4.Elektronenoptische Beobachtungen (Geren 1952;Robertson 1952–1957;de Robertis 1958) weisen darauf hin, daß die Markbildung in den peripheren Nerven nur möglich ist, wenn das Axon mit dem Cytoplasma einer Schwannschen Zelle in Kontakt kommt. Dasselbe gilt für die Bemarkungsglia im ZNS.5.Kommen die markbildenden Gliazellen mit keinem Axon in Kontakt, dann degenerieren sie selbst und in der Folge auch ihre Stoffwechselprodukte. Die Zellen verlieren ihre Kerne und wandeln sich im Gewebe zu faserigen und granulären Schlacken um, die als Rosenthalsche Fasern bezeichnet werden.6.Rosenthalsche Fasern treten nicht nur in Verbindung mit Entwicklungs-störungen des ZNS in Erscheinung, sondern können auch später aus undifferenzierten Zellen der subependymalen Glia (Opalski) entstehen, wenn diese Glia durch chronische Entzündung oder durch Neubildungen zur Proliferation angeregt wird. Sie treten daher in Spongioblastomen wie auch bei zentraler Neurofibromatose als sehr charakteristische, jedoch nicht obligatorisch anzutreffende Veränderungen auf.7.Unabhängig von den Rosenthalschen Fasern gibt es eine amöboide Degeneration der reichlich gewucherten Astrocyten und ihrer Fortsätze, die Clasmatodendrose in Form krümeliger Zerfallsprodukte. Diese ähneln morphologisch den Rosenthalschen Fasern, wie dies bei den Patienten vonAlexander (1949) mit Megalencephalie und Hirnödem und ebenso in den neueren Beobachtungen, z. B. auch beiWohlwill, Bernstein undYakovlev (1959) deutlich wird.8.Zusammengefaßt ist der von uns mitgeteilte Fall ein Beispiel einer offensichtlich durch einen genetischen Defekt ausgelösten Leukodystrophie, die sich während oder kurz nach der Markbildungsperiode, wahrscheinlich als eine enzymatische Störung des Markstoffwechsels, manifestierte. Dies wieder regte eine protrahierte Wucherung von spongioblastenähnlicher Bemarkungsglia und von Astrocyten an, die durch Degeneration und Clasmatodendrose zu massiven Ansammlungen von Zerfallsprodukten um die Gefäße und um die gliösen Randgebiete des ZNS führte, wobei diese Überreste in Struktur, Färbecharakteristik und Verteilung den Rosenthalschen Fasern gleichen.

Subacute diencephalic angioencephalopathy--report of an additional case.

The following report presents an additional example of subactue diencephalic angioencephalopathy. The patient, a 68-year-old man, unexplicably withdrawn and asocial throughout his life, presented with an altered mental status of relatively recent onset. His illness was marked by progressive dementia and ended in death within 7 weeks. The neuropathologic findings were essentially identical to those described in the previous case in both their histology and topographic localization within the thalamus. The etiology, pathogenesis, and reason for the localization of this entity are unknown. Nevertheless, the lesion underscores the major role of the thalamus in cognitive function, emotional behavior, and awareness.

Hemorrhagic white matter infarction in three critically ill patients

Extensive areas of hemorrhagic softening developed in the cerebral white matter in three critically ill patients. The anatomic peculiarities of the vasculature of this region, as well as the possible roles of edema and vasospasm, are weighed as factors in the pathogenesis of these unusual lesions.

Superiority of PCNU over AZQ in the treatment of primary brain tumors: results of a prospective randomized trial (81-20) by the Brain Tumor Study Group.

SummaryPurposeA two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment ofde novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies.MethodsDuring 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75–100 mg/m2 intravenously (IV) every 8 weeks or AZQ 15 mg/m2 IV once a week for 4 weeks, every 6–8 weeks. All patients who had not received ‘full dose’ radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review.ResultsMedian survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p=0.01) and the VSG (p=0.02). Lifetable analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p=0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.

Phase II evaluation of fludarabine phosphate in patients with central nervous system tumors: A Southwest Oncology Group trial

SummaryTwenty-three patients with malignant central nervous system tumors were treated with fludarabine phosphate (2-FAMP) on a 5 day bolus schedule. One brief partial response was observed in 20 malignant astrocytoma patients. 2FAMP as given in this protocol is inactive in previously treated patients with recurrent malignant astrocytomas.

A modification of Hortega's silver impregnation method to assist in the identification of astrocytes with electron microscopy.

Neural tissues were impregnated en bloc with silver by a modification of Hortegas method customarily used to stain astrocytes in thin tissue sections for light microscopy. The tissue blocks were then embedded in methacrylate and sectioned at 1 micron and 25 millimicrons for light and electron microscopy. The former regularly showed the silver deposited selectively and in great quantities within the perikaryon and fine neuroglial processes of astrocytes. In electron micrographs, the argentophilic neuroglia had moderately abundant osmiophilic cytoplasm from which numerous argentophilic processes arose, forming a dense reticulum, but rarely ending perithelially. When considered together with observations upon neural tissues prepared by conventional methods for electron microscopy, the findings provide cogent evidence that astrocytes possess much osmiophilic, rather than water-clear periknryon and, although attached by foot-processes to blood vessels, do not ensheath the cerebral vasculature.