Late Recurrence of Primitive Neuroectodermal Tumor/Medulloblastoma
ILENE 6. LEFKOWITZ, MD, ROGER J. PACKER, MD,*vts* STEPHEN G. RYAN, MD,$ NARlN SHAH, MD, JANE ALAVI, MD,\( LUCY 8. RORKE, MD,**T LESLIE N. SUTTON, ME),*# AND LUIS SCHUT, MD*#
The period of risk for recurrence of primitive neuroectodermal tumor/medulloblastoma (PNET/MB) is not clearly defined. With current treatment since more than 50% of children with PNET/MB can be expected to survive for at least 5 years after diagnosis, determining the evidence of late recurrence is of increasing concern. Collins has stated that patients with embryonal tumors who survive, disease free, for a period of time equal to the age at diagnosis plus 9 months can be declared cured. This, so-called Collins law has been applied to patients with PNET/MB. To determine the incidence of late recur- rence, factors which impact on recurrence and applicability of Collins law, the authors studied all patients diagnosed with PNET/MB at the Childrens Hospital of Philadelphia, Hospital of the Uni- versity of Pennsylvania, Philadelphia, and Geisinger Medical Center, Danville, Pennsylvania, between 1970 and 1984. For the 44 patients in this study, the disease-free survival at 5, 10, and 12 years was 54%,41% and 30%, respectively. For children surviving 5 years, the actuarial survival at 10 years was 75% and at 12 years, 51%. Age, sex, dose of radiotherapy, chemotherapy, or extent of surgery were not predictive of late relapse. Recurrence in three of seven patients (43%) occurred outside the period of risk as predicted by Collins. It appears that the period of risk for recurrent central nervous system tumors after PNET/MB is as yet undefined and probably indefinite.
HE PRIMITIVE neuroectodermal tumor/medullo- T blastoma (PNET/MB) is an embryonal neoplasm which accounts for approximately 20% of pediatric brain tumors. It is most commonly found in the cere- bellar vermis, where it is also known as the medullo- blastoma.
Controversy concerning the cell of origin and there- fore the nomenclature, of similarly appearing tumors in other central nervous system locations exists. In a recent review, it was suggested that until the cell of origin of these tumors can be better established and specific markers can be identified, that all such tumors, indepen- dent of their location whether the neuro-axis, be classi- fied as primitive neuroectodermal tumors (PNET/
Presented in part at the Child Neurology Society, Boston, October 1986.
From the Neuro-Oncology Program, Childrens Hospital of Phila- delphia; Departments of ?Pediatrics, $Neurology, lINeuro-pathology, #Neurosurgery, and I( Medicine, University of Pennsylvania, Philadel- phia; and Weisinger Medical Center, Danville, Pennsylvania.
Supported in part by the Forerder Fund for Excellence, Neuro-On-
The authors thank Linda Cella for secretarial assistance. Address for reprints: Roger J. Packer, MD, Division of Neurology,
Childrens Hospital of Philadelphia, 34th & Civic Center Boulevard, Philadelphia, PA 19 104.
Accepted for publication January 22, 1988.
MB). The dismal prognosis formerly associated with PNET/MB has improved considerably with improve- ments in surgery and postoperative care and the intro- duction of local and craniospinal radiation the rap^.^,^ More recently, the use of adjuvant chemotherapy in certain high-risk patients appears to have further en- hanced ~urvival.~ With current therapy, as high as 50% to 70% of patients with PNET/MB can be expected to survive, disease free, for 5 years after De- spite these encouraging trends, sporadic late recurrences of PNET/MB have been well documented both in indi- vidual case reports and in several longitudinal stud- ies?,6,o*2,16 Some authors have contended that patients who survive beyond the period of time of predicted re- lapse for embryonic tumors described by Collins (Col- lins law) have a high likelihood of c ~ r e . ~ , ~ , ~
We examined the records of patients at our institu- tions who survived at least 5 years after the diagnosis of PNET/MB in order to determine more precisely the incidence of late recurrence and to identify any clinical and histologic features which might be associated with late relapse.
Materials and Methods The medical records of all patients at The
Childrens Hospital of Philadelphia, Geisinger Medical
No. 4 RECURRENT PNET Lefkowitz et a[. 827
TABLE 1. Clinical-Histoloeic Features of Patients With Late Relaase
Initial treatment Relapse
Age at Initial Rad, local Rad, CS Chemo- Time after Histologic diagnosis Sex Tumor site histologic type Surgery (rad) (rad) therapy diagnosis Site type
5.5 yr M PF
12yr, 1 1 mo F PF
5 Yr F PF
8yr ,7mo M Thalbrain- stem
10yr,2mo F PF
29 yr M PF
14 yr M PF
PNET, with Total
PNET, Undiff Subtotal
PNET, with Subtotal
glial Diff resection
glial Diff resection
neuronal resection Diff
PNET, Undiff Subtotal resection
PNET Subtotal resection
3600 (to C,)
8yr ,5mo PF Anaplastic
6 yr, 4 mo PF and PNET, Undiff
8.5 yr PF and PNET, Undiff
8 yr, 5 mo Thalamus; PNET,
LMS neuronal and glial
12yr,5 mo PF PNET with anaplastic glioma
1 1 yr PF PNET
5.5 yr PFand PNET LMS
PF: posterior fossa; LMS leptomeningeal spread; Thal: thalamus; Undiff undifferentiated; CS: craniospinal, PNET: primitive neuroec-
Center, Danville, Pennsylvania, and the Hospital of the University of Pennsylvania, Philadelphia, who were treated for PNET/MB between January 1970 and Au- gust 198 1 were examined. Over the time period, 44 pa- tients with PNET/MB were diagnosed and 24 were alive and in continuous remission for 5 years since initial therapy.
The 24 patients who survived 5 years without evi- dence of disease were a median of 9 years at the time of diagnosis (range, 5-29 years). They have been followed for a median of 8 years, 1 1 months (range, 5-1 5 years). All patients were seen yearly for a neurologic examina- tion and contrasted computerized tomography (CT) scan. However, magnetic resonance imaging (MRI) was not routinely performed in these patients.
Patients were treated in a standardized fashion. Gross total surgical resection was attempted in all patients. Routine preoperative ventriculoperitoneal shunting was not performed; permanent cerebrospinal fluid drainage was utilized postoperatively only if there was persistent hydrocephalus. All patients were treated with cranio- spinal radiotherapy supplemented with local radiother- apy to the primary site. Patients received a median dose of 3600 rad to the craniospinal axis and a median dose of 5200 rad to the tumor. Eight patients also received adjuvant chemotherapy (CCNU and vincristine).
Where possible, histologic specimens from the origi- nal, and, if applicable, recurrent tumors were examined by one of us (L.B.R.). Clinical and pathologic data then were analyzed to identify any factors which might be predictive of late recurrence. Parameters which were
todermal tumor; Diff differentiated; Rad radiation.
analyzed included sex, age at diagnosis, extent of resec- tion, extent of disease at diagnosis (T and M stage as suggested by Chang et aZ.19), tumor histologic type, the dose of cranial and local radiotherapy, and the use of chemotherapy.
Results Of the 24 long-term survivors, nine had recurrent
central nervous system (CNS) mass lesions at the site of their original tumor. One of these patients was found to have an asymptomatic posterior fossa mass lesion at the primary site on routine follow-up computed tomogra- phy (CT) 5.5 years after his original tumor was diag- nosed; this patient has refused further treatment. A sec- ond patient, who was asymptomatic, had a mass lesion seen on CT, performed as a surveillance study 10 years after initial diagnosis. Radionecrosis was found at reop- eration.
The remaining seven patients with recurrent mass le- sions all had histologically confirmed tumor recurrence, are described in Table 1 . All had symptoms of recurrent posterior fossa mass at the time of detection of their recurrent lesions. The patients with recurrent tumors were a median 8 years 7 months of age at the time of original diagnosis. Four were male and three female.
Recurrence occurred at a median of 8 years 5 months from diagnosis. The actuarial disease-free survival rate for our entire population 5 years after diagnosis was 54%, but fell to 41% at 10 years and 30% at 12 years (Fig. 1). For patients surviving 5 years, the predicted rate of disease-free survival at 10 years was 75% and at 12 years
828 CANCER August 15 1988 Vol. 62
0 40 80 120 160 TIME (months)
FIG. 1 . Actuarial survival from diagnosis for 44 patients with PNETIMB.
was 5 1 %. Three of seven patients developed recurrence at a period of time of greater than their original age at diagnosis plus 9 months. This occurred 1.3 years, 2.3 years and 2.2 years after this period of time, respectively.
There were no significant differences between those 5-year survivors who relapsed and those who did not with respect to age at diagnosis, sex, dose of radiation, extent of surgery, treatment with chemotherapy, or pres- ence of differentiation on original tumor histologic study (Table 2).
At the time of recurrence, one patient had an ana- plastic glioma and two others had tumors with mixed undifferentiated and glial elements. The original tumor
TABLE 2. 5-Year Disease-Free Survivors: Clinical Comparison of Late Relapsers Versus Continuous Responders
Median age at diagnosis
Sex (male/female) Surgical resection
Local (median) Craniospinal
(median) Chemotherapy (yes/no)
Late relapsers (N = 7)
9.5 yr (5-29 yr) 413 215
5200 rad 4000 rad
Continuous responders (N = 20)
8 yr, 10 mo (5-14 Yr) loll0 7/13
5 140 rad 3600 rad
TABLE 3. Reported 5-Year and 10-Year Survival Rates for Patients With Primitive Neuroectodermal Tumor/Medulloblastoma
No. of % 5-yr % IO-yr Reference Yr vatients survival survival
Hershatter ef al. Farwell et al. Park ef al. Berry et aL6 Chin and
Maruyamag Harisiadis and
ChangI4 Mealy and Hall4 Broadbent et ~ 1 . ~ King and
Sagerman Bloom ef aL3 Aroni2 Lefkowitz et al.
1940- 1983 1935-1979 1950- 1980 1958- 1978
1963-1975 1953-1973 1940-1976
1960- I972 1950-1964 1946-1968
127 33% 21% 143 22% 13% 144 47% (k4.8) 42% (f5.1) 122 56% 43%
23 35% 35%
58 40% 31% 45 41% 22% 31 29% 29%
24 38% 0% 82 32% 26% 14 46% 35%
44 54% 41%
in two of these patients had dial differentiation. One other patient, whose original tumor was differentiated, had an undifferentiated tumor at the time of relapse. The remaining three patients had undifferentiated tumors at diagnosis and relapse (Table 1).
Six of the seven patients with recurrent tumor have died; their median postrecurrence survival was 7 months. All tumors recurred at the primary site; in four patients this was associated with concurrent leptomen- ingeal dissemination.
There are a large number of series reporting long-term survivors of PNET/MB, and they have shown a variable decline in survival due to recurrent tumor between 5 and 10 years (Table 3). Although it was recognized as early as 1953 that craniospinal radiation had a major role in treating PNET/MB, standardization of doses and methods of delivery, as well as the use of megavoltage rather than orthovoltage irradiation, is relatively new. This creates difficulty in comparing different series and drawing conclusions from any one series.
King and Sagerman, in a series published in the American Journal of Roentgenology in 1975, reported 24 patients treated with radiation alone during the years 1960 to 1972. The 38% 5-year survival in this study is comparable to other series from this time, but the 10- year survival approaches 0%. However, only three chil- dren in this series were alive 6 years after diagnosis, so that this marked decline in survival takes on less signifi- cance. Other series report less dramatic but definite in- creasing mortality after 5 years. The largest reported series, 144 patients seen at the Hospital for Sick Chil- dren in Toronto, over a 30-year period, had a 5-year
No. 4 RECURRENT PNET
survival of 47% declining to 42% by 10 years. Hershat- ter et al., in a report of 127 patients treated with varying amounts and volumes of radiotherapy between 1940 and 1983 found an actuarial survival at 5 years of 33%, which fell to 21% by 10 years. Mealy and Hall4 re- ported late relapse, 3 years after treatment, in seven of 40 patients with PNET/MB. However, those patients who died greater than 5 years after diagnosis had re- ceived reduced dosages of radiotherapy and some had relapsed years before their death.
In contrast to these series reporting some decline in survival after 5 years, Broadbent et al. and Chin and Maruyama found no patients who had their initial re- lapse 5 years after diagnosis. So, in conclusion, the inci- dence of relapse greater than 5 years after diagnosis in the series reported to date is difficult to determine. It is unclear whether late relapse is due to what would now be considered less than optimal therapy. It is also un- clear whether many of the late deaths were in children who had initially had disease recurrence within 5 years of diagnosis, but died greater than 5 years after diag- nosis, since distinction between survival and disease-free survival was not made in these series. In our series, using in all patients what is presently accepted as necessary doses of radiotherapy, we found a decline in survival between 5 and 10 years after treatment and no plateau to the survival curve (Fig. 1).
Collins law also has been used to assess the probabil- ity of cure for patients with PNET/MB. Collins law states that disease-free survival of greater than age at diagnosis plus 9 months is equivalent to cure.2s22 Al- though this law was first applied to Wilms tumor, an embryonal kidney neoplasm, its proponents have stated it is appropriate to look at all embryonal tumors in this fashion.23 This implies that all primitive tumors have an intrinsic, unalterable growth rate. After definitive treatment, if any malignant cells remain, it will take the same amount of time to become clinically apparent as it did originally; assuming that the primitive neoplastic (or preneoplastic) cells were present from embryogenesis. The PNET/MB is the most common embryonal tumor of the central nervous system.
It is clear, in our series, that recurrent PNET/MB did not obey Collins law in three patients. In two patients relapse occurred 2 years outside the period of risk. Mealy and Hall suggested up to 10% of PNET/MB sur- vivors will develop recurrent PNET/MB or other brain neoplasms after the period of risk.4 Park et al. fro...