Predominance of Brain Tumors in an Extended Li-Fraumeni (SBLA) Kindred, Including a Case of Sturge-Weber Syndrome

Henry T. Lynch, M.D.1 Rodney D. McComb, M.D.2 Neal K. Osborn, B.S. Paul A. Wolpert, B.S.1 Jane F. Lynch, B.S.N.1 Zbigniew K. Wszolek, M.D.3 David Sidransky, M.D.4 Robert E. Steg, M.D.5

1 Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska.

2 Department of Pathology and Microbiology, Uni- versity of Nebraska Medical Center, Omaha, Ne- braska.

3 Department of Neurology, Mayo Clinic Jackson- ville, Jacksonville, Florida.

4 Otolaryngology/Head and Neck Cancer Research, Johns Hopkins University, Baltimore, Maryland.

5 Department of Neurology, Creighton University School of Medicine, Omaha, Nebraska.

Supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Ne- braska State Department of Health and Human Services.

The authors gratefully acknowledge Deborah Perry, M.D. (Children’s Hospital, Omaha, Ne- braska), who contributed the pathology slides for our review. They also thank Trudy Shaw, M.A., for her excellent technical assistance in the produc- tion of this article.

The contents of this article are solely the respon- sibility of the authors and do not necessarily rep- resent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services.

Address for reprints: Henry T. Lynch, M.D., Depart- ment of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178.

Received June 3, 1999; revision received Septem- ber 8, 1999; accepted September 8, 1999.

BACKGROUND. Li-Fraumeni syndrome (LFS) is characterized by a plethora of can- cers, most prominent of which is carcinoma of the breast followed by sarcomas, brain tumors, leukemia, lymphoma, lung carcinoma, and adrenocortical carci- noma (therefore, also referred to by the acronym SBLA syndrome).

METHODS. The family reported herein was first described 2 decades ago. Now extensive follow-up has shown the predictable occurrence of these tumor types, in addition to an excess of brain tumors and the finding of Sturge-Weber syndrome (SWS) in an LFS-affected family member.

RESULTS. A possible new feature of the disorder, suggestive of SWS, was identified in a patient in the direct genetic lineage. This patient had a rhabdomyosarcoma of the eyelid at age 29 months and at age 14 years was diagnosed with lymphoblastic lymphoma/acute lymphoblastic leukemia. A remarkable excess of brain tumors was identified in this family through this current update. The p53 germ-line mutation was not identified in any affected member of this family.

CONCLUSIONS. To the authors’ knowledge, this is the first example of SWS in the context of LFS. Brain tumors appear to be an important component of the tumor spectrum of LFS, as evidenced in this family. Cancer 2000;88:433-39. @ 2000 American Cancer Society.

KEYWORDS: Li-Fraumeni syndrome, Sturge-Weber syndrome, cancer genetics, brain tumors, p53 germline mutation.

T he first report of a family with a cancer phenotype now known to be consistent with the Li-Fraumeni syndrome (LFS) was in 1967.1-3 Information on this family was updated in 1990.4 Li and Fraumeni5,6 recognized this same familial phenotypic cancer pattern through clinical observations in concert with epidemiologic investi- gations of children who manifested rhabdomyosarcoma and other forms of cancer, particularly brain tumors, leukemia, and adrenocor- tical carcinoma, as well as multiple primary malignant neoplasms. They defined these tumor associations as a hereditary cancer syn- drome that now appropriately is designated LFS. Numerous studies of these familial tumor aggregations have provided confirmation that this cancer phenotypic pattern is characteristic of the syndrome.7 The molecular genetic basis for this complex hereditary tumor spectrum is due to a p53 germline mutation that was described first by Malkin et al. in 19909,10 and is present in ~50% of classical LFS families. This report is an update of a previously described family11 covering ap- proximately 2 decades.

FIGURE 1. Pedigree of a Li-Fraumeni syndrome family. Bold lines indicate tumors that have been diagnosed since the initial report11 on this family.

Pro65

8.83

d.65

Co66

d.66

Sar50

d.50

Br37 d.38

Sor43

Br41

B152

d.43

d.52

Lyx48

Lu56

d.58

#11

a.24

d.75

Lyx50 Lu55

816

Sar46 d.48

Ad23 d.24

Lým55 d.55

d. 12

Lu59

Ad3

73 77

Lu47 d.47

Leut 4

d.15

Leu35

Sar8

Br23

d.55

d.6

d.60

d.3

d.36

d.Inf

Leu1357

Br29 Pon43

Csu

Leu12

Bt10

d. 13

d.9

d. 13

d.25

d.11

d.44

45-56

ym3143 d.32

4842-51

8120

Sar10

813

814

Lu32

d.20

Co48 d.50

818 d.8

27-5837-42

d.3

33-51

33 37

d.11

d.3

d.5

Lym2436-46

d.32

18-36

19-29

8110

d.12

8-29

Sor2

Nb2

16-23

1-15

Lym 14

d.2

17 21

LEGEND

Cancer Sites

Male

Female

Individual number Unaffected

Adrenal Cortical

Current age

Breast

Brain Tumor

Lu53

Br45 47

Current age

Lou

Leukemia

Lung

d.54

d.86

age at death

Lyx

Larynx

Multiple Primary Cancers by Pathology

Pan

Pancreas

Pro

Prostate

Cancer by Death Certificate or Medical Records

Sar

Sarcoma

Number of Unaffected Progeny (Both Sexes)

Proband

Twins

Pedigree drawn by Tami Richardson-Nelson

MATERIALS AND METHODS

This study was approved by Creighton University’s Institutional Review Board. This LFS family was re- ported originally in 1978.11 It has been followed peri- odically since that time, thereby facilitating its current update. Key relatives were recontacted and sent a questionnaire that covered the family genealogic, medical, and cancer history background. Permission forms, when signed by living members of the family with cancer or by their legal next of kin, enabled us to secure primary medical and pathology documents and, whenever possible, slides and tissue blocks. In- terviews with key relatives were arranged whenever possible to cross check data for corroboration. An excess of brain tumors was identified in this kindred.

After DNA isolation, a 1.8-kb fragment of the p53 gene encompassing exons 5-9 was amplified from a lymphoblastic cell line of individual V-6 with the poly- merase chain reaction (PCR) and sequenced as de- scribed.12,13 The sequencing reactions were then elec- trophoresed on 8 M urea/6% polyacrylamide gels, fixed, and exposed to film.

Blood or lymphoblastoid cell lines, unfortunately, are unavailable on a sufficient number of relatives to

enable a genome-wide search for linked loci. It also is regrettable that the proband of this extended kindred (Fig. 1, individual III-3), died in 1975, before any knowledge of the p53 mutation in the LFS was avail- able. Neither the blood nor tissue from the proband is available to us; therefore, DNA analysis was not pos- sible.

RESULTS

Pedigree

Figure 1 shows the updated pedigree of the original kindred. Table 1 includes tumors that have been di- agnosed since the original publication. Table 2 is the complete brain tumor registry for the kindred. The pedigree and tumor tables have been cross referenced so that the LFS phenotype can be tracked through the family. The bold lines on the pedigree indicate tumors that have been identified since the initial report on this family with their specific bases for cancer confir- mation. Since the original publication, some changes have been made concerning individual diagnoses and ages at diagnosis. Two putative obligate mutation car- riers, namely, individuals III-15 (age 67 years) and

I Cancer by Pathology,

Colon

age at diagnosis

Csu

Cancer Site Unknown

Cancer by Family History,

Lym

Lymphoma

Neuroblastoma

TABLE 1 New Tumor Registry Since Original Publication
Pedigree no.	Gender	Age (yrs)ª	Basis of diagnosis	Diagnosis
III-8	M	55	PN	Non-Hodgkin lymphoma
III-10	M	59	PN	Small cell lung carcinoma
III-14	F	14	FR	Leukemia
III-23	M	66	FR	Tumor site unknown
IV-2	M	31	PN	lymphoma
IV-12	M	48	PN	Colon adenocarcinoma
IV-13	M	8	FR	Brain tumor
IV-21	M	32	PN	Nonsmall cell lung carcinoma
V-4	F	10	PA	Malignant neuroepithelial neoplasm
V-6b	M	2	PA	Embryonal rhabdomyosarcoma Lymphoblastic lymphoma/acute
V-6	M	14	PA	lymphoblastic leukemia
V-6	M	16	MR	Sturge-Weber syndrome
V-7	M	2	PA	Neuroblastoma (adrenal)

M: male; F: Female; PN: pathologic diagnosis, slides not available for review; FR: family report, no medical verification of disease; PA: pathologic diagnosis, slides available for review; MR: magnetic resonance imaging data.

a Age at diagnosis. For age at death, if applicable, see pedigree (Fig. 1). b Current report.

TABLE 2 Brain Cancer Tumor Registry
Pedigree no.	Gender	Age (yrs)ª	Basis of diagnosis	Diagnosis
II-6	M	52	PN	Glioblastoma multiforme
III-5	M	6	PN	Glioma
III-26	F	10	PN	Glioblastoma multiforme
IV-5	M	20	PA	Glioblastoma multiforme
IV-7	F	3	PN	Glioblastoma multiforme
IV-10	M	4	PN	Glioblastoma multiforme
IV-13	M	8	FR	Brain tumor
V-4	F	10	PA	Malignant neuroepithelial neoplasm

M: male; F: female; PN: pathologic diagnosis, slides not available for review; PA: pathologic diagnosis, slides available for review; FR: family report, no medical verification of disease. ª Age at diagnosis. For age at death, if applicable, see pedigree (Fig. 1).

III-22 (age 60 years), were living and well without any history of cancer at the time of this update.

Pathologic Findings

Six brain tumors originated in the cerebrum, one arose in the cerebellum, and one is undetermined (for pathology data, see Tables 1 and 2). The glioblastoma multiforme in individual IV-5, which originated in the basal ganglia and thalamus, showed extensive inva- sion of adjacent cerebrum and brainstem and promi- nent subpial and perivascular tumor cell aggregation. The heterogeneous cellular constituency included small, undifferentiated cells; elongated cells; gemisto-

FIGURE 2. Photomicrograph of the brain tumor in patient V-4 showing uniform small cells with large nuclei, prominent nucleoli, and frequent mitoses (hematoxylin and eosin [H&E]; original magnification, ×250).

cytic cells; and multinucleated tumor giant cells. Nu- cleoli varied from prominent to inconspicuous. There were widespread leptomeningeal metastases involving the entire length of the spinal cord. In one of the metastatic deposits in the thoracic leptomeninges, the tumor exhibited an astroblastoma-like pattern with perivascular pseudorosettes.

The neoplasm in individual V-4 was composed of small cells with large nuclei, prominent nucleoli, and variable cytoplasm (Fig. 2). Perivascular tumor cells had plump, eosinophilic cytoplasm, creating a pseu- dopapillary or pseudorosette-like appearance. A few unstained slides were available for immunohisto- chemistry, which showed diffuse expression of glial fibrillary acidic protein and focal expression of cyto- keratin, notably in the perivascular cells (Fig. 3). Epi- thelial membrane antigen was not detected. Rare cells exhibited synaptophysin immunoreactivity (polyclonal antiserum; Dako, Carpenteria, CA), but electron microscopy did not reveal neurosecretory granules or synapses. Therefore, the tumor was con- sidered predominantly glial with questionable focal neuroblastic differentiation.

Case Report

The patient who was followed in this case report (Fig. 1, individual V-6) was diagnosed with a rhabdomyo- sarcoma of the eyelid at age 29 months and was treated with surgical resection and chemotherapy. At age 14 years, he developed weight loss, fever, anemia, and a mildly elevated LDH. He was diagnosed with large cell lymphoma of B-cell phenotype and received combination chemotherapy. A bone marrow biopsy revealed lymphoblastic lymphoma, precursor B-cell type, that expressed HLA-DR, CD10 (CALLA), CD19,

FIGURE 3. Photomicrograph of the brain tumor in patient V-4 showing dark immunohistochemical staining for glial fibrillary acidic protein with perivascular accentuation (original magnification, ×250)

CD20, and CD24 by flow cytometry. After a chemo- therapy-induced remission, this neoplasm recurred at age 16 years as an acute lymphoblastic leukemia, pre- cursor B-cell type, with the same antigenic profile. He was administered chemotherapy, including intrathe- cal methotrexate, and promptly went into remission. The following year, he received an allogenic bone marrow transplantation consisting of plasma cell-de- leted donor bone marrow stem cells from his sister. Approximately 3.5 weeks posttransplantation, he de- veloped disorientation, aphasia, a dense right hemi- paresis, and focal seizures. Magnetic resonance (MR) imaging and MR angiography of the brain revealed leptomeningeal enhancement diffusely in the left frontal and parietal regions and enlargement of the left medullary, anterior caudate, and thalamostriate veins consistent with Sturge-Weber syndrome (SWS) (Fig. 4). An electroencephalograph (EEG) performed during a focal motor seizure demonstrated the pres- ence of focal epileptiform activity over the left cerebral hemisphere (Fig. 5). Cerebrospinal fluid studies were negative for infection and malignancy. He was treated with anticonvulsant therapy, and his aphasia and right hemiparesis gradually improved over a period of 7-10 days.

DNA Findings

The DNA of individual V-6 was analyzed as described above. The findings did not disclose the presence of the p53 germline mutation.

DISCUSSION

This family’s pedigree represents one of the most re- markable occurrences of brain tumor excess in LFS. A full explanation for these findings remains elusive.

FIGURE 4. T1-weighted axial magnetic resonance image of the brain after gadolinium administration demonstrates serpiginous enhancement within the sulci of the left frontal and parietal regions consistent with a leptomeningeal angioma.

FIGURE 5. Electroencephalogram during a focal motor seizure demonstrates repetitive spike, polyspike wave discharges over the left cerebral hemisphere associated with repetitive jerking of the right upper extremity and posturing of the right hand.

FP1-F3

F3-C3

C3-P3

P3-01

FP2-F4

F4-C4

C4-P4

P4-O2

1 sec 50 μV

The Cancer Phenotype in LFS

There is extant phenotypic heterogeneity in the tumor spectrum of LFS/SBLA. Kleihues et al.14 analyzed 475 tumors in 91 families with p53 germ line mutations that had been reported since 1990. Breast carcinomas

were the most frequently encountered malignant neo- plastic lesions (24.0%), followed by sarcomas (12.6%), brain tumors (12.0%), soft tissue sarcomas (11.6%), hematologic carcinomas (specifically, acute lympho- blastic leukemia and Hodgkin lymphoma; 4.2%), and adrenocortical carcinoma (3.6%).

Organ specific differences in the mean age of on- set of cancer among carriers of p53 germline muta- tions were observed.14 The earliest age of onset was for adrenocortical carcinoma (age 5 years), whereas sar- comas occurred at a mean age of 16 years, brain tumors at age 25 years, breast cancers at age 37 years, and lung carcinoma at age ~50 years. These investi- gators concluded that organ or target cell specificity of p53 germline mutations occur frequently and that the occasional familial clustering of certain of these tumor types appears to reflect the genetic background of the respective kindred. There also may exist an additional influence of environmental factors.

Brain Tumors

Eight brain tumors have been identified in this kin- dred. Seven have had histopathologic confirmation. Six of the eight patients were age ≤ 10 years, and only one patient was age > 20 years. Only one neoplasm (in individual V-4) was evaluated by immunohistochem- istry and electron microscopy, and this specimen con- sisted of only a small biopsy.

It appears that all brain tumors in this kindred are malignant neuroepithelial neoplasms with glial differ- entiation, i.e., malignant gliomas. However, several had a poorly differentiated or undifferentiated small cell component, and some had unusual features, such as perivascular pseudorosettes or large nucleoli. The possibility of ependymal or neuroblastic differentia- tion was suggested in some cases but was not con- firmed.

Brain tumors account for <2% of all forms of cancer in humans. However, the death rate from brain tumors is extremely high, thereby commanding inten- sive research into the genetic and environmental basis for their etiology. Genetic risk factors predisposing to brain tumors are reflected in the family in this report and other LFS families.

Dockhorn-Dworniczak et al.15 described an LFS family that showed an excess of adult cancers in one generation, whereas the succeeding generation showed an unusual clustering of brain tumors in early childhood. Brain tumors in association with other tu- mor types in LFS may show considerable variation. Specifically, Varley et al.16 described an extended LFS- like family characterized by an excess of gastric and breast carcinomas in association with glioma, sar- coma, and leukemia. Yuasa et al.17 described an infant

age 8 months with primary carcinoma of the choroid plexus who subsequently developed rhabdomyosar- coma of the anterior chest wall at the age of 1 year and 2 months. This child’s mother had liposarcoma of the left thigh at age 17 years, and one of the patient’s siblings had a rhabdomyosarcoma of the epipharynx at age 1 year. Those authors note that this is the fourth report of choroid plexus carcinoma occurring in LFS.

Louis and Von-Deimling18 discussed an assort- ment of central nervous system neoplastic disorders in hereditary conditions, such as neurofibromatosis types 1 and 2, tuberous sclerosis, von Hippel-Lindau disease, retinoblastoma, glioma in LFS, Gorlin syn- drome (multiple nevoid basal cell carcinoma syn- drome), Cowden disease, and the multiple endocrine neoplasia syndromes. The culprit genes have been localized or identified in many of these hereditary disorders. Bondy et al.19 found that hereditary nonpol- yposis colorectal carcinoma and familial adenoma- tous polyposis harbored an excess of brain tumors.

p53 in LFS and Brain Tumors

Mutation of the p53 gene is one of the most common molecular aberrations and has been identified in a large variety of human tumors, including those of the central nervous system. Li et al.20 studied the fre- quency of germline p53 mutations with respect to the incidence of brain tumors. They detected germline p53 mutations in 1 of 80 unselected cases and in 3 of 15 selected (family history positive) cases (20%). They concluded that germline p53 mutations may account for only a tiny fraction of the gliomas that occur in the general population, whereas the presence of a family history of cancer in a glioma-affected individual should prompt a search for a germline p53 mutation.

Kyritsis et al.21 found an excess of germline p53 mutations in patients with multifocal glioma, glioma in association with a second primary tumor, and gli- oma found as an integral lesion in families with di- verse cancers. Thus, relatives at high risk for glioma often can be identified and can receive genetic coun- seling. Thus, it may be possible to achieve early de- tection as well as avoidance of known environmental carcinogens.

Most studies have shown that the area between exon 5 and exon 9 of chromosome 17p is the region that harbors the LFS mutation. However, Frebourg et al.22 noted that the occurrence of p53 germline muta- tions in LFS has not been identified in all families manifesting the LFS phenotype and concluded that ~50% of patients with LFS do not harbor a germline mutation in the coding region of the p53 gene.

SWS

Our extended LFS-like family is remarkable for the presence of a genetically at-risk patient who mani- fested findings consonant with SWS and who also had well-documented multiple primary tumors, namely, a rhabdomyosarcoma of the eyelid in infancy (at age 29 months) and lymphoblastic lymphoma of precursor B-cell phenotype evolving to acute lymphoblastic leu- kemia. As far as we can determine (using a MEDLINE search of literature from 1981 to 1998), this is the first example of a patient with SWS occurring in an LFS- like family. It is possible that the SWS occurred by chance. It also is possible that the SWS represents a forme fruste of the LFS. However, we have not iden- tified any other example of SWS in an LFS kindred. It is possible that a modifier gene may have contributed to the inordinate excess of brain tumors as well as to the SWS in this kindred.

SWS is classified as a phakomatosis (also referred to as neuroectodermal dysplasias or neurocutaneous syndromes). The diagnosis of SWS usually is estab- lished on clinical grounds through the association of facial nevus and neurologic signs, including of sei- zures, hemiparesis, and hemianopia. Facial nevus flammeus often is present at birth and usually is uni- lateral, although bilateral findings may occur. Many authorities consider facial nevus flammeus to be es- sential for the diagnosis of SWS. However, Roach23 and Pascual-Castroviejo et al.24 did not consider this stigmata to be essential for the diagnosis of SWS.

Griffiths25 provided an extensive review of SWS and noted that, although many hundreds of cases of this disorder have been described, there are only a few instances of its familial occurrence. This includes a case in identical twins, a report of father and son who both were affected, and occasional findings of chro- mosomal trisomy. It was concluded that SWS usually is a sporadic disorder with no firm genetic basis for its etiology. It is noteworthy that, in Griffiths’s review,25 there was no evidence of an increased risk for malig- nancy in SWS, which is in contrast to findings in most of the phakomatoses.

In SWS, the age when signs and symptoms begin and the overall prognosis are highly variable. Seizures most often are focal and usually present in infancy. In data obtained from 171 individuals with SWS, seizures occurred in 80% of patients.26 Whereas the median age of onset of seizures was 6 months, it ranged widely from infancy to 23 years. The onset of seizures prior to the age of 2 years tends to increase the likelihood of future mental retardation and refractory epilepsy. In SWS, the EEG may show focal epileptiform activity

over the involved hemisphere,27 like that present in our patient.

Seizures are one of the most common neurologic complications in patients undergoing transplantation procedures.28,29 It is possible that toxic-metabolic fac- tors associated with intensive chemotherapy in con- cert with an allogenic bone marrow transplantation, including the administration of cyclosporine, made this patient with an underlying leptomeningeal angi- oma more susceptible to seizures in the early post- transplantation period. Focal neurologic abnormali- ties are common in which the anatomy of the leptomeningeal disease determines the nature of these findings. For example, hemiparesis may be found when there is involvement in the region of the central sulcus. There also may be developmental delay and poor intellectual function.25 SWS has been found in association with other phakomatoses, albeit rarely, in neurofibromatosis, in association with adenoma sebaceum (tuberous sclerosis), and in von Hippel- Lindau disease.25 Magnetic resonance imaging of the brain and orbits is the preferred diagnostic test for SWS.25 We are not aware of any reports of SWS in association with LFS.

There is no evidence of any other phakomatosis in this family that could explain their brain tumor excess. These findings may be due to the pleiotropic effect of an underlying genetic susceptibility gene(s), or they may be due to a modifier gene. Further research on this and other LFS-like families may help to explain these phenotypic features.

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