RAMB Maio/Junho 2015

ediatric

cancer

and

-F

raumeni

-F

raumeni

syndromes

review

for

the

pediatrician

ssoc

ras

2015; 61(3):282-289

283

ntroduction

Cancer is one of the leading causes of death in children

between the ages of 0 and 14 years, second only to trau-

ma.

As compared with adult tumors, pediatric cancers

generally exhibit lower latency periods, rapid growth

and more aggressive behavior. However, they are more

responsive to treatment, and the prognosis is usually

good.

2-5

In Brazil, the National Cancer Institute estimates

that approximately 11,300 new cases of cancer have been

diagnosed in patients under the age of 19 years in the year

2012, which accounts for approximately 3% of all ma-

lignancies diagnosed in the country. The most common

neoplasms in childhood (in Brazil and worldwide) are

leukemias, lymphomas, and central nervous system tu-

mors.

A diagnosis of pediatric cancer must prompt the hy-

pothesis of a hereditary cancer predisposition syndrome

in the family, particularly if there are concurrent congen-

ital abnormalities or positive family history of cancer. Ge-

netic conditions that may be associated with a higher risk

of cancer in childhood include: genodermatoses (i.e. neu-

rofibromatosis type 1 and tuberous sclerosis), overgrowth

syndromes (Beckwith-Wiedemann and Proteus syndromes)

and adult cancer syndromes which include increased risk

to cancer in infancy, childhood and adolescence, such as

Li-Fraumeni syndrome (LFS) and its variant – Li-Frau-

meni-like syndrome (LFL).

Approximately 5-10% of all tumors are associated

with inherited high-penetrance mutations in cancer pre-

disposition genes. However, an even higher proportion

of pediatric cancers may be associated with a familial his-

tory suggestive of hereditary cancer. Indeed, in a recent

study, conducted by our research group in Southern Bra-

zil, criteria for LFS/LFL were observed in 25% of a con-

secutive series of pediatric patients with tumors of the

LFS/LFL spectrum.

Several genes associated with cancer predisposition

syndromes have been identified in recent years, and spe-

cific diagnostic tests have become available. In this new

context, pediatricians can expect to be asked more ques-

tions on the risks of these genetic syndromes, as well as

on management and reduction of cancer risk in affected

children.

Therefore, the present article seeks to provide

a comprehensive and up-to-date review on Li-Fraumeni/

Li-Fraumeni-like syndromes.

ethods

The NCBI (PubMed) and SciELO databases were consult-

ed using the keywords Li-Fraumeni syndrome, Li-Frau-

meni-like syndrome and pediatric cancer and all manu-

scripts published between 1990 and 2014 using these

keywords were retrieved and reviewed.

eview

Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes

Li-Fraumeni syndrome (LFS; OMIM #151623) is a clini-

cally heterogeneous hereditary cancer predisposition syn-

drome characterized by an autosomal dominant inheri-

tance pattern, diagnosis of various tumor types at a young

age, multiple primary tumors, and a characteristic fami-

ly clustering pattern of a core spectrum of cancers (core

tumors including: bone and soft-tissue sarcomas, central

nervous system tumors, leukemia, adrenocortical carci-

noma, and breast cancer).

9,10

LFS is distinct from other

hereditary cancer syndromes in that it is associated not

with one (or a few) specific type(s) of cancer, but with a

broad spectrum of tumors.

Other cancer types have been detected in LFS fami-

lies and included in some of the diagnostic criteria in-

cluding bronchioloalveolar carcinoma, prostate cancer,

pancreatic cancer, germ cell tumors, and melanoma.

11,12

The diagnosis of cancer follows a bimodal distribution,

with many diagnoses before the age of 10 and a second

peak between the ages of 30 and 50 years.

Additional tumor types (ovarian, endometrial, esoph-

ageal, gastric, colorectal and thyroid cancer, choroid plex-

us carcinoma, lymphomas and Wilms’ tumor) have been

associated to a lesser extend to LFS and also to Li-Frau-

meni-like syndrome (LFL), classified according to the

Birch, Eeles 1 and Eeles 2, Chompret or modified Chom-

pret criteria. In LFL, average age at cancer diagnosis is

older than seen in LFS. Currently used criteria to suggest

these diagnoses are summarized in Table 1.

TP53

is the only gene that has been associated with

LFS/LFL.

The mean age at diagnosis of cancer in pa-

tients with LFS and germline

TP53

mutations is 25 years,

and the cumulative risk of cancer by the age of 30 is 50%,

exceeding 90% by age 60.

14-16

The estimated penetrance

of cancer in men with mutations in this gene is about

73%. In women, penetrance is complete (100%), possibly

due to the high frequency of breast cancer.

In addition to the broad spectrum of LFS-related tu-

mors, affected individuals are also at risk of developing

multiple synchronous or metachronous primary tumors.

In a study of 200 patients who had a single primary tu-

mor at the time of enrollment and were recruited from 24

LFS families, 30 (15%) developed a second primary tumor,

8 (4%) developed a third primary tumor, and 4 (2%) devel-

oped a fourth primary tumor.

Other studies have shown

that the odds of developing multiple primary tumors are