Sep 1, 1985 - several of these tumors were of guarded prognosis due to location, degree of .... mimicking ependymoma and meningeoma by location,.
Cerebral Pilocytic Astrocytoma GARY 6. CLARK, COL, MC, USA,*.t JAMES M. HENRY, COL, MC, USA,' AND PAUL E. MCKEEVER, MD, PHDS
Cerebral pilocytic astrocytoma is a known intracranial tumor, but its biological characteristics are less well documented. The authors report 30 patients with cerebral pilocytic astrocytoma who were accessioned by the Armed Forces Institute of Pathology between 1970 and 1980. Histological appearance of the tumor was correlated with clinical characteristics. Mean age of onset was 22.15 years, mean preoperative duration of symptoms was 3.77 years, and mean postoperative survival was 5.91 years, with 20 of 23 (87%) known to ultimately survive surgery. These cases of cerebral pilocytic astrocytoma exhibited histologic characteristics consistent with that of a low-grade tumor. Although several of these tumors were of guarded prognosis due to location, degree of infiltration or cyst recurrence, they generally demonstrated a natural course of a relatively low-grade neoplasm. Cancer 56:1128-1133, 1985.
P
also known in the literature as spongioblastoma, is a relatively common glioma. This neoplasm frequently presents as a cystic lesion. It has been found at all levels of the central nervous system (CNS) axis, including the optic nerve, hypothalmus, cerebellum, brainstem and spinal cord. Although occasional examples of this neoplasm have been described in the cerebral hemispheres, they remain completely documented and characterized as a nosological entity. This study was undertaken to document and describe the cerebral pilocytic astrocytoma in detail, particularly in regard to its clinical and biological characteristics, including histologic appearance and prognosis. Our observations emphasize a favorable prognosis for morbidity and mortality in association with modern diagnostic technology, early intervention, and extensive surgical removal. ILOCYTIC ASTROCYTOMA,
Materials and Methods This study of 30 patients comprises the total number of patients with cerebral pilocytic astrocytoma available
From the Departments of *Neuropathology and ?Pediatric Pathology, Armed Forces Institute of Pathology, Washington, D. C. and $Surgical Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. Address for reprints: Gary B. Clark, MD, FCAP, COL, MC, Chief, Department of Pathology and Area Laboratory Services, Walter Reed Army Medical Center, Washington, D. C. 20307. The authors are gratefully indebted to Amy Lou Haymes for her extraordinary skills in the preparation of the manuscript. The opinions or assertions herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Accepted for publication October 17, 1984.
from the files of the Armed Forces Institute of Pathology (AFIP) for the period of 1970 to 1980. All material was reviewed by two of us (G.B.C., J.M.H.) in order to confirm the histologic diagnosis of cerebral pilocytic astrocytoma. Each case was characterized by age, sex, presenting signs and symptoms, anatomic location, gross and histological appearances and postoperative morbidity and mortality. Clinical follow-up was obtained by contacting each respective attending physician and, when possible, each patient. Immunohistologic study was performed by one of us (P.E.M.) on material derived from selected cases. Tissue sections were stained for glial fibrillary acid protein (GFAP) using the immunoperoxidase bridge method on deparaffinized tissue sections. The sections were stained with anti-GFAP and counterstained with hematoxy1in.g Comparison control sections of tumor were stained with anti-GFAP without hematoxylin. Other controls were utilized for substitution of normal serum for anti-GFAP, deletion of anti-GFAP and assessment of endogenous peroxidase activity.
Results
Demography and Clinical Presentation At the onset of symptoms, the 16 males and 14 females included in this series ranged in age from 6 months to 59 years. Retrospectively, the mean age of 4 The GFAP antiserum was provided through the generosity of Dr. Lawrence F. Eng, Veterans Administration Hospital, Stanford University, Palo Alto, CA, and Dr. Eugene Quindlen, University of South Carolina, School of Medicine, Columbia, SC.
CEREBRAL PILOCYTIC ASTROCYTOMA
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TABLE1. Presurgical Demography Male
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Clark et al.
TABLE3. Sites of Occurrence in 30 Cerebral Pilocytic Astrocytoma Patients
Female
Overall Lobe
No. of cases histologically confirmed in this study Mean years of age at symptom onset (n) Mean years of duration of symptoms before surgery (n) Mean years of age at clinical diagnosis (n)
16
14
30
22.32 (16)
21.96 (14)
22.15 (30)
4.83 (16)
2.75 (13)
3.77 (25)
27.06 (16)
24.43 (14)
25.83 (30)
symptom onset was 22.3 1 years for males and 2 1.96 for females (Table 1). Two male cases without significant background clinical histories for intracranial tumor presented as incidental findings during physical examination or autopsy for problems unrelated to their intracranial tumors. The mean duration of clinical symptoms antedating clinical diagnosis and surgical exploration was 4.83 years for males and 2.75 years for females. The longest duration of clinical findings associated with cerebral pilocytic astrocytoma extended over nineteen years prior to diagnosis. The mean age at time of confirmed surgicalpathology diagnosis was 27.06 years for males and 24.43 years for females. The major presenting signs and symptoms are listed in Table 2. The most common presenting complaints included progressive headache, seizure, hemiparesis, ataxia and nausea-vomiting. The most common acute physical sign was papilledema with rapid onset of increased intracranial pressure at the time of end-stage crisis. Site of Occurrence
The neoplasm occurred in the right cerebral hemisphere of 22 patients and in the left hemisphere of 8 TABLE2. Major Presenting Signs and Symptoms in 30 Patients With Cerebral Pilocytic Astrocytoma Symptom
No. of cases and frequency
Headache Seizure disorder Papilledema hemi paresis-ataxia Nausea-vomiting Cranial nerve paresis Mental retardation Blurred vision-diplopia Gustatory aura Dysphasia Behavior disorder Visual field cut
14 (47%) 13 (43%) 9 (30%) 6 (20%) 5 (17%) 2 (7%) 2 (7%) 2 (7%) 2 (7%) 2 (7%) 1(3%) 1(3%)
Nofr.Two patients (7%)were asymptomatic and diagnosed, incidentally, at unrelated surgery or autopsy.
1129
Right
Left
Temporal Parietal Frontal Occipital
patients. Major hemispheric sites are listed in Table 3. It is of interest that seven lesions were located in the paraventricular area while four were submeningeal, mimicking ependymoma and meningeoma by location, respectively.
Gross Characteristics The lesions were characterized by color, size and consistency in surgical and/or autopsy reports. Generally yellow in color, they ranged in size from 2 cm to 10 cm in diameter. Thirteen cases were documented as consisting of fluid-filled cysts containing up to 100 ml of clear yellow fluid, while mural nodules were described in four instances. The gross surgical descriptions in eight cases indicated that there was a distinct tumor margin, or encapsulation, and that the tumor was easily shelled out. Ten cases were described surgically with diffise, infiltrative margins.
Histologic Features Representative hematoxylin and eosin (H & E) sections were evaluated for significant histologic parameters (Table 4) which were assigned an arbitrary indicator of intensity ranging from 0 to 3+. The subject neoplasms were characterized by a low grade of malignancy based on standard histologic criteria. A biphasic pattern of an equal composition of both adult and juvenile types was noted in 12 cases. In these cases the juvenile variety was easily recognizable as a mixture of dense astroglial tissue and abundant neuropile admixed with loose, reticulated, microcystic areas (Fig. 1). A predominant pattern of the TABLE4. Histologic Features of 30 Cerebral Pilocytic Astrocytomas
Features of pilocytic astrocytoma Vascularity Rosenthal fibers Microcysts Calcification Features of anaplasia Cellular density Cellular pleomorphism Endothelial hyperplasia Mitoses
I+
2+
14 13
9 6
13 II 6 2
14
16
14 7
15
6
3+
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CANCERSeptember 1 1985
FIG. 1. Juvenile type of cerebral pilocytic astrocytoma. Notice the disruption of the dense astroglial adult pattern by vacuolation of astrocytes and microcyst formation ( X 125).
adult variety comprised of dense sheets of astroglial cells with monotonous uniformity was seen in 18 cases (Fig. 2). The biphasic pattern was noted in an age group averaging 20.3 years of age, whereas the predominantly adult pattern occurred in an age group averaging 29.9 years of age. These cases sporadically demonstrated excessive degrees of focal hypercellularity, pleomorphism and neovascularity with endothelial hyperplasia. The frequent presence of focal calcification, cystic degeneration and Rosenthal fiber formation reinforced a common clinical impression of indolent growth potential. Rosenthal fibers were particularly prominent in the denser areas of the neoplasm. There was complete lack of mitotic activity.
Immunohistology
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FIG. 3. Cerebral pilocytic astrocytoma contains GFAP in astrocytic processes including the processes which touch the gliovascularjunction (arrows). Cells and fibers within the thick wall of the vessel do not stain for GFAP (immunoperoxidase bridge with anti-GFAP, hematoxylin counterstain, X500).
This immunohistologic characteristic was dramatically emphasized at the interface of astrocytoma and vascular wall (Fig. 3). Normal serum and primary antibody deletion controls confirmed the specificity of the staining technique for astrocytoma cells and Rosenthal fibers. As noted by others,'-3 Rosenthal fibers contained stainable GFAP, particularly at the peripheral, outer surface of the fiber, while the central portion stained less intensely (Fig. 4). The periphery of the Rosenthal fibers frequently stained with greater intensity than even the other surrounding GFAP-positive structures. This selective staining facilitated identification of Rosenthal fibers even under low magnification. Small foci of
The perikaryon and cell processes of the neoplastic astrocytes contained immunologically detectable GFAP.
FIG. 2. Adult type of histologic pattern characterized by dense sheets of astrocytic cells associated with a thick, hair-like neuropile of astrocytic processes. Several small vessels are present (X 125).
FIG. 4. Rosenthal fiber (arrow) in a cerebral pilocytic astrocytoma stains intensely for GFAP except in its center. Surrounding astrocytic processes stain moderately with small foci of intense reactivity (immunoperoxidase bridge with anti-GFAP, X750).
CEREBRAL PILOCYTIC ASTROCYTOMA *
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TABLE5. Preoperative Differential Diagnoses in 30 Cerebral Pilocytic Astrocytoma Patients Nonspecific Avascular mass Calcified mass Cystic mass Vascular mass Hydrocephalus Cerebral atrophy Specific Meningioma Astrocytoma Ependymoma Angiomatous malformation Trauma Infarct Encephalomalacia Polio
20 (67%) 7 (23%) 3 (10%) 2 (7%) 1(3%) 1(3%) 4 (13%) 3 (10%) 3 (10%) 2 (7%) 2 (7%) I(3%)
Clark et al.
1131
TABLE 6. Postoperative Contributors’ Pathologic Diagnoses in 30 Cerebral Pilocytic Astrocytoma Patients 9 (30%) 8 (27%) 3 (10%) 3 (10%) 1(3%) 1(3%) 1(3%) 1(3%) 1(3%)
Astrocytoma, low-grade No diagnosis Pilocytic astrocytoma Gliosis Astrocytoma, high-grade Glioblastoma multiforme Meningioma Infarction Encephalomalacia Ependymoma Oligodendroglioma
1(3%)
1(3%) 30
Total
1(3%)
1(3%)
intense GFAP staining further suggested incipient Rosenthal fiber formation. Normal serum and deletion controls showed no specificity for astrocytes or Rosenthal fibers. Preoperative Diagnoses The major preoperative diagnoses were obtained by diagnostic techniques which were common at the respective times of diagnosis. Those techniques included ventriculography, pneumoencephalography, angiography and computerized tomography. The most frequent preoperative diagnoses are listed in Table 5. Postoperative Diagnoses Major contributor diagnoses based on histologic examination are listed in Table 6. The diagnosis of cerebral pilocytic astrocytoma was usually not considered. In over one third of the cases, the tumor was not recognized as a glial neoplasm. Postoperative Follow-up Clinical Information Of the 30 histologically confirmed cases of cerebral pilocytic astrocytoma, follow-up clinical information is available for 27 cases (Table 7). In one case the neoplasm was discovered incidentally at autopsy performed for chronic renal failure. Of the remaining 26 patients, 3 died during the perioperative period. Subsequently, 23 patients survived the immediate operative period for a known mean of 6.63 years and 5.14 years for 12 males and 1 1 females, respectively. The total duration of post-onset survival, as calculated from the earliest known onset of clinical symptoms to the last recorded follow-up clinical visit, provides an appreciation of the protracted natural history of cerebral pilocytic astrocytomas. Of the 23 postoperative survivors, the total duration of post-onset survival was 1 1.96 years
for males and 7.86 years for females, ranging from 6 months to 27 years. Of the 23 overall postoperative survivors, 5 received radiation therapy, one of those receiving chemotherapy, as well. Four of the five were in the ultimate survivor
TABLE7. Postsurgical Demography Male No. of cases histologically confirmed in the study No. of cases lost to follow-up No. of cases incidental at unrelated autopsy No. of perioperative deaths No. of cases surviving surgery Mean years of duration of immediate postoperative survival (n) Mean years of duration of immediate postonset survival (n) No. of postoperative deaths Due to unrelated cause Due to tumor recurrence Ultimate number of known living survivors Mean years of duration of ultimate known survival (n) Mean years of duration of ultimate postonset survival (n)
Female
Overall
16
14
30
2
1
3
-
1
1
1
2
3
12
11
23
6.63 (12)
5.14 ( 1 1 )
11.96 (12)
7.86 (1 1)
-
2
II
10.0 (23)
2
-
1
5.91 (23)
9
1
20
6.95 (1 1)
5.17 (9)
6.15 (20)
12.73 ( I 1)
8.28 (9)
10.73 (20)
CANCERSeptember 1 1985
I132
TABLE8. Residual or Postoperative Sequelae in 23 Cerebral Pilocytic Astrocytoma Patients with Postoperative Follow-Up 12 (57%) 7 (33%) 5 (24%) 3 (14%) 3 (14%) 2 (10%)
Seizure disorder Hemiparesis Recurrent cyst fluid Asymptomatic Blind/field defect Dysphasia Mental retardation Headache Personality change
1(5%) 1 (5%)
1(5%)
group. There was no known evidence of complications attributable to the radiotherapy and the mean postoperative survival follow-up span was 5.4 years for the group of five ranging from 2 to 12 years. Most major, long-term residual problems (Table 8) were associated with the initial damage done by the original space-occupying lesions and the result of the surgery. Recurrence of cyst fluid was documented in four patients, representing an indication for shunting and/or re-excision. As further noted in Table 7, of the 23 postoperative survivors, two died of causes unrelated to tumor recurrence while 1 died with sequelae suggestive of recurrent cerebral pilocytic astrocytoma. One female died of unrelated chronic pyelonephritis 7 years after craniotomy for cerebral pilocytic astrocytoma; there were minimal postoperative sequelae but there was no autopsy. One female patient, who underwent early repeat craniotomy for removal of recurrent cyst fluid, had severe hemipoiesis and died 2 years later of pneumonia with no evidence of tumor at autopsy. The third patient died 3 years after initial craniotomy due to a clinically presumed recurrence of the original cerebral pilocytic astrocytoma. This latter case is remarkable in that the patient had personal and familial stigmata of neurofibromatosis. Even in light of that
TABLE9. Percentage of Survival in Five Year Increments of 20 Ultimate Survivors
Postsurgical survival Less than 5 years (n) Less than 5-10 years (n) Less than 10-15 years (n) Less than 15-20 years (n) Post-onset survival Less than 5 years (n) Less than 5-10 years (n) Less than 10-15 years (n) Less than 15-20 years (n) 20+ years (n)
Male percentage
Female percentage
Overall percentage
54.5 (6)
66.7 (6) 11.1 ( I )
60.0 ( I 2) 20.0 (4)
22.2 (2) - (0)
10.0 (2) 10.0 (2)
55.6 (5) 22.2 (2) 11.1 (I) - (0) 11.1 ( I )
45.0 (9) 15.0 (3) 15.0 (3) 5.0 ( 1 ) 20.0 (4)
27.3 (3) - (0) 18.2 (2) 36.4 (4) 9.0 ( I )
18.2 (2) 9.1 (1) 27.3 (3)
Vol. 56
history, review of the original brain biopsy material revealed typical features of cerebral pilocytic astrocytoma with no evidence of anaplasia or histologic aggressiveness. However, since no autopsy was performed, the nature of the tumor at death remains unknown. It should be emphasized that 20 of 23 known postoperative survivors were alive and were being actively followed at the time this study was terminated. Among that group of 20 ultimate survivors, the mean length of postoperative survival was 6.95 and 5.17 years for males and females, respectively. Furthermoe, the range of total duration of male post-onset experience was from 3.5 to 28 years and from 0.5 to 29 years for females. Survival is further described in terms of 5 year increments in Table 9. The presence or absence of a diffuse tumor margin the the surgical description of the gross specimen was documented in 18 cases. Of the ten cases described with diffuse margins and the 8 with sharply demarcated margins, postoperative survival was 3.3 t 2.31 SD and 8.25 years f 6.76 SD respectively, at the time of the last known clinical follow-up. Three patients with diffuse tumors died, of which two were intraoperative deaths while the third had the history of neurofibromatosis. Only one patient with an encapsulated tumor died 2 years postoperatively with a history of hemiparesis and recurrent pneumonia, as cited above.
Discussion The degree of malignant potential associated with pilocytic astrocytomas has been a source of understandable clinical concern. This study documents the nosological entity of cerebral pilocytic astrocytoma and demonstrates that the natural history of this cerebral tumor can be relatively long, indicating a generally low degree of biological aggressiveness, but not without inherent dangers. The protracted clinical course, a bland histologic appearance and nonaggressive proclivity of the cerebral pilocytic astrocytoma, as also described in other CNS locations, has led some observers to consider the pilocytic astrocytoma possibly as a hamartomatous l e ~ i o nThat .~ the cerebral pilocytic astrocytoma (or a pilocytic astrocytoma at any other location) may be actually hamartomatous is unsupported by any evidence in this study. We confirm, in fact, that the subject tumor appears clinically and histologically to be a bana jide neoplasm, albeit often slow in growth. We have demonstrated that the pattern of stainable GFAP in cerebral pilocytic astrocytomas is similar to the pattern observed in the other low-grade astro~ y t o m a s ~and - ~ pilocytic astrocytomas located in other
No. 5
CEREBRAL PILOCYTK ASTROCYTOMA
CNS sites.'-1° Whereas anti-GFAP reactivity decreases with increased anaplasia,' ' , I 2 biochemical or histologic assays for GFAP could be useful in the diagnosis of lowgrade tumors such as the subject cerebral pilocytic astrocytomas. This study confirms that stains for GFAP can be used to distinguish a low-grade astrocytoma, such as cerebral pilocytic astrocytoma, from nonastrocytic and nonependymal neoplasms by frozen section at ~ u r g e r y . l ~A - ' ~review of the differential diagnoses as submitted by the contributors of the subject cases indicates the advantage of utilizing anti-GFAP in order to distinguish this neoplasm from meningioma or oligodendroglioma. Maximal surgical extirpation followed by clinical reevaluation at appropriate intervals is encouraged since reaccumulation of cyst fluid is a common postoperative complication. Occurrence of the juvenile histological pattern with concomitant micro- and macrocyst formation is noted to occur in the average age group of 20 years. The increased incidence of the juvenile type may suggest an increased propensity in this younger age group for pre- and postoperative cyst formation. This review of 30 documented cases of cerebral pilocytic astrocytoma indicates that the lesion is often of indolent nature. The margin is noted often to have been sharply demarcated which facilitated easy removal in at least one third of the cases reviewed. However, surgical inaccessibility of the tumor and resultant incomplete sampling may often dictate ancillary treatment. Although radiotherapy and chemotherapy are of questionable advantage, further study of the reaction of tumor cell cultures to modes of ancillary treatment may lend further indication for such postoperative treatment. Malignant transformation would be considered unusual.
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Clark et al.
1133
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