salivary gland carcinomas in children and adolescents: the italian trep project experience

Pediatr Blood Cancer 2014;61:1961–1968

Salivary Gland Carcinomas in Children and Adolescents:The Italian TREP Project Experience

Stefano Chiaravalli, MD,1 Marco Guzzo, MD,2 Gianni Bisogno, MD,3 Maria Debora De Pasquale, MD,4

Roberta Migliorati, MD,5 Francesco De Leonardis, MD,6 Paola Collini, MD,7 Michela Casanova, MD,1

Giovanni Cecchetto, MD,8 and Andrea Ferrari, MD1*

INTRODUCTION

Salivary gland carcinomas are extremely rare in pediatric age.

Epidemiological research based on the North American population-

based Surveillance, Epidemiology and End Results (SEER)

database identified 263 children and adolescents (aged 0–19 years)

registered from 1973 to 2006, while more than 12,000 adult cases

were collected during the same period [1]. Epidemiological studies

have identified an annual incidence between 0.8 [1] and 1.4 [2] per

million population under 20 years old. Various retrospective reports

have been published on childhood salivary gland tumors, but they

all included only a few cases of malignant epithelial tumor [3–28].

Like other very rare pediatric neoplasms, salivary gland carcinomas

can be considered “orphan” diseases, meaning that: (a) there is a

paucity of clinical and biological details about them and their

clinical behavior, and many pediatric oncologists and surgeons may

be unaware of the treatment options available; (b) no specific

clinical or scientific organizations have been established to support

their clinical management and related research; (c) it is very

difficult to conduct clinical trials on them, and this makes it hard to

develop evidence-based treatment guidelines, so their treatment is

usually individualized; and (d) dedicated financial resources are

limited.

In 2000, with the aim to improving the clinical management of

such tumors and stimulating research, a national-scale cooperative

initiative called the TREP project (Tumori Rari in Eta Pediatrica

[Rare Tumors in Pediatric Age]) was launched in Italy, dedicated to

“pediatric solid malignancies with an annual incidence<2/million,

that are not considered in other clinical trials” [29]. The TREP

project established a network of pediatric oncologists and surgeons,

in cooperation with other experts dealing with adult patients, to

develop diagnostic and therapeutic recommendations and collect

clinical data.

This article reports the clinical features of a series of children

and adolescents with salivary gland carcinomas prospectively

registered in the TREP database.

MATERIALS AND METHODS

Patients under 18 diagnosed with salivary gland carcinoma were

registered centrally as of January 1, 2000 by the TREP Data Center

(Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto,

Padova, Italy), using specific forms on clinical findings, histopa-

thology, diagnostic work-up, therapy, and follow-up. All patients, or

their guardians, gave their informed consent to their involvement in

the TREP study.

Clinical details were reviewed for the present analysis. In all

cases, the histological diagnosis was established directly by one of

Background. Salivary gland carcinomas are extremely rare inpediatric age. We report the clinical features of a series of children/adolescents with salivary gland carcinomas prospectively registeredin the Italian TREP (Rare Tumors in Pediatric Age) project.Procedures. Diagnostic/therapeutic guidelines were developed andshared among Italian pediatric oncology/surgical centers. Results.Seventeen patients were registered between 2000 and 2012,representing 19% of the cases expected to be seen based onepidemiological data. Tumors arose mainly in the parotid gland(14 cases). Inmost cases theywere low-grade tumors (14 cases), oftenwith a favorable clinical presentation, and low-stage disease. Allpatients underwent surgical resection, achieving histologically freemargins in 9/17 cases. Thirteen of the 14 patients with parotid glandtumors had parotidectomy (10 total, 3 superficial), while one had atumorectomy. Postoperative facial nerve lesionswere reported in two

cases. Adjuvant radiotherapy was given to 6 patients. The overallprognosis was good: only one patient with a huge high-grade tumorexperienced disease progression and died of the disease. The other16 patients were alive in first continuous remission 1–8 years afterdiagnosis. In 4/17 cases, the salivary gland carcinoma was a secondtumor occurring 6–9 years after another primary cancer. Conclu-sions. This is the first reported prospective national cooperative seriesof pediatric salivary gland carcinoma patients. Compliance with theTREP recommendations was high. These tumors are rarely managedby pediatric oncologists/surgeons. A broader international coopera-tion and better networking with otolaryngologists and head-necksurgeons expert on adult salivary gland carcinomas would beadvisable. Pediatr Blood Cancer 2014;61:1961–1968.# 2014 Wiley Periodicals, Inc.

Key words: adolescents; carcinoma; children; rare pediatric tumors; salivary glands; TREP project

1Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei

Tumori, Milano, Italy; 2Otorhinolaryngology Unit, Fondazione IRCCS

Istituto Nazionale dei Tumori, Milano, Italy; 3Hematology-Oncology

Division, Department of Pediatrics, Padova University Hospital,

Padova, Italy; 4Hematology/Oncology, Ospedale Pediatrico Bambino

Gesu IRCCS, Roma, Italy; 5Division of Pediatric Oncology, Pausilipon

Children’s Hospital, Napoli, Italy; 6Pediatric Hematology-Oncology

Division, University of Bari, Bari, Italy; 7Soft Tissue and Bone

Pathology, Histopathology, and Pediatric Pathology Unit, Fondazione

IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 8Pediatric Surgery,

Department of Pediatrics, Padova University Hospital, Padova, Italy

Conflict of interest: Nothing to declare.

�Correspondence to: Andrea Ferrari, Pediatric Oncology Unit,

Fondazione IRCCS Istituto Nazionale Tumori Via G. Venezian, 1-20133

Milano MI, Italy. E-mail: [email protected]

Received 4 April 2014; Accepted 16 May 2014

�C 2014 Wiley Periodicals, Inc.DOI 10.1002/pbc.25139Published online 17 August 2014 in Wiley Online Library(wileyonlinelibrary.com).

the pathologists on the TREP panel and/or centrally reviewed by the

panel. Histological diagnoses (histotype and grade) were handled

according to the 2005 World Health Organization (WHO)

Classification of Head and Neck Tumors [30], and the 2008 Armed

Forces Institute of Pathology (AFIP) Atlas of Tumor Pathology—

Tumors of the Salivary Glands [31]. Disease stage was defined

according to the tumor-node-metastases (TNM) staging system of

the Union for International Cancer Control (UICC) (7th ed.) [32].

The number of patients enrolled in the TREP database was

compared with the number of cases of salivary gland carcinoma

expected to be diagnosed in individuals under 18 years old in Italy

according to the AIRTum (Associazione Italiana Registro Tumori),

an Italian network of population-based cancer registries that

includes 22 general registries and three specialist registries, and

covers 33% of all Italian children [33].

Diagnostic and Therapeutic Guidelines

Magnetic resonance imaging (MRI) was recommended for the

preoperative assessment of the disease’s local-regional extent (and

the relationship between the tumormass and the facial nerve) and to

differentiate vascular lesions. Fine-needle aspiration biopsy

(FNAB) was considered helpful before treatment to confirm the

nature of the disease, for example, differential diagnosis with

vascular lesions or other malignancies (lymphomas, mesenchymal

tumors). However, it should be considered that cytology sometimes

fails to discriminate between benign or malignant salivary gland

neoplasms (since the differential diagnosis is mainly based on the

histological pattern), and it does not influence the surgical

approach. Incisional biopsy should be avoided—due to the risk

of tumor spillage and, in deep lesions, for the risk of facial nerve

injury—and so should tumorectomy.

Surgery was the mainstay of treatment. Parotidectomy (superfi-

cial or total) was recommended for both benign and malignant

parotid tumors, resecting the neoplasms with clear margins. When

tumors arose in the superficial glandular lobe, the safest approach

was considered the formal identification and dissection of the facial

nerve followed by resection of the supra-facial portion of the gland

(superficial parotidectomy). Given the high risk of postoperative

facial nerve injury, referral to a prime oncology center with expert

physicians professionally dedicated to the management of this

cancer was recommended. Intraoperative nerve reconstruction

might be considered. Simultaneous lymph node dissection was

only recommended in cases of clinical or radiological detectable

nodal involvement. Prophylactic lymphadenectomy should be

avoided because nodal involvement is rare in children. In case of

high-grade tumors, chest computed tomography (CT) scan was

suggested to exclude lung metastases.

Postoperative radiotherapy (total dose 56–60Gy) might be

indicated in selected cases (i.e., incomplete resections, locally

advanced disease, aggressive histological features such as a high

grade of malignancy and perineural invasion, multiple levels of

cervical lymph node involvement). Given the particular risk of post-

irradiation complications in children (facial growth retardation,

dental anomalies and second malignancies), the indication for

radiotherapy should be discussed case by case with the national

coordinator and other expert physicians. Chemotherapy has a

limited role in salivary gland carcinoma, for managing local

recurrences no longer amenable to further surgery or radiotherapy,

and with a palliative intent in cases with distant metastases: TREP

guidelines recommended that its use should be discussed with the

national coordinator.

Clinical and radiological follow-up was required, that is, local

and regional ultrasound every 4 months for the first 2 years, then

every 6 months up to 5 years after the tumor’s diagnosis, using MRI

in cases of suspected ultrasound. Annual chest-X ray was suggested

in cases with high-grade tumors.

RESULTS

From January 2000 to December 2012, there were 720 cases of

“rare pediatric tumors” registered in the TREP database by 39

different pediatric oncology and pediatric surgery centers; among

them, 17 patients (8 males and 9 females) aged 6–17 years (median

14 years) with a diagnosis of salivary gland carcinoma were

registered by nine centers. Fourteen patients had a parotid gland

tumor, one had tumor in the submandibular gland, and two in a

minor salivary gland of the palate. In four patients, the salivary

gland carcinoma was a second malignancy, occurring 6–9 years

after they had been diagnosed with acute lymphoblastic leukemia,

osteosarcoma, Ewing sarcoma and Hodgkin disease, respectively.

The patient with a previous diagnosis of Hodgkin disease had

received radiotherapy to the neck. Nor radiotherapy neither stem

cell transplantation were given to the other patients. Genetic

exploration was done in one case, and the result was negative.

Genetic tests were proposed to the patient with high-grade

mucoepidermoid carcinoma (MEC) arising 7 years after osteosar-

coma, but the clinical course of the disease was rapidly dismal and

the parents refused any further investigation.

Table I provides details of the 17 patients’ clinical characteristics,

treatment and outcome. A painless swelling was the initial sign in

15/17 cases, with an interval between its onset and the final diagnosis

ranging from one to 22 months (median 4 months). MRI was

performed in all but one case. FNAB was performed in four cases:

the cytological diagnosis defined the salivary gland origin of the

disease, but it did not discriminate between adenoma or carcinoma.

Tumor size ranged from 0.5 to 6 cm (median 2 cm): 12 patients had a

T1 tumor (2 cm or less in greatest dimension, with no extrapar-

enchymal extension), one case was T2 (tumor more than 2 cm but

less than 4 cm in size), three were T3 (tumors more than 4 cm in size

and/or with extraparenchymal extension), and one was T4 (also

involving skin and bone). Lymph node involvement was identified in

four cases, with peri-parotid nodes in three cases (classified as N1),

and submandibular and laterocervical nodes in one (classified as

N3). None of the patients had distant metastases at diagnosis.

Histology returned a diagnosis of MEC in 13 cases, acinic cell

carcinoma in three cases, and basal cell adenocarcinoma in one. As

for grade of malignancy, 14 cases were low-grade (10 G1 MEC,

3 acinic cell carcinoma, and 1 basal cell carcinoma), two were

intermediate-grade (G2 MEC), and one was high-grade (G3 MEC).

Histological evaluation reported the data on peri-neural invasion

and vascular emboli in nine cases: no any case had them.

All patients underwent surgery, achieving histologically free

margins in 9/17 cases. Ten of the 14 patients with parotid gland

tumor underwent total parotidectomy, three had a superficial

parotidectomy and one had a tumorectomy (with tumor rupture).

Postoperative facial nerve injuries were reported in two cases: in

both cases there was a facial nerve involvement and the surgical

approach implied nerve amputation to achieve oncological

adequate resection. In one case, an immediate reconstruction of

Pediatr Blood Cancer DOI 10.1002/pbc

1962 Chiaravalli et al.

TABLEI.

ClinicalCharacteristics,Treatm

entandOutcomeofthe17Cases

No.

Age,

gender

Symptom,

delay

Tumorsite

Tumor

size

TNM

Histotype

Surgery

Other

therapies

Facial

nerve

injury

Relapse

Outcome

Comments

Parotidglandtumors

115years,

male

Swelling,

9months

Leftparotid

gland

1.5cm

T1N1M0

Mucoepidermoid

carcinomaG2

Totalparotidectomy,

lymphadenectomy,

involved

surgical

margins

Radiotherapy60

GyonTandN

Yes

No

Alivein

firstCR

8years

after

diagnosis

312years,

female

Swelling,

1month

Leftparotid

gland

2cm

T1N0M0

Mucoepidermoid

carcinomaG1

Totalparotidectomy,

histologically

free

margins

No

No

No

Alivein

firstCR

8years

after

diagnosis

Previousdiagnosis

ofLLA

(6

years

before)

46years,

female

Swelling,

9months

Leftparotid

gland

4cm

T3N0M0

Basal

cell

carcinoma

(low-grade)

Totalparotidectomy,

involved

surgical

margins

Radiotherapy60

GyonT

Yes

No

Alivein

firstCR

7years

after

diagnosis

515years,

male

Swelling,

2months

Leftparotid

gland

2cm

T1N0M0

Acinic

cell

carcinoma

(low-grade)

Totalparotidectomy,

histologically

free

margins

No

No

No

Alivein

firstCR

6years

after

diagnosis

611years,

female

Swelling,

5months

Leftparotid

gland

1cm

T1N0M0

Mucoepidermoid

carcinomaG1

Totalparotidectomy,

histologically

free

margins

No

No

No

Alivein

firstCR

6years

after

diagnosis

78years,

female

Swelling,

4months

Leftparotid

gland

2cm

T1N1M0

Mucoepidermoid

carcinomaG1

Superficial

parotidectomy,

lymphadenectomy,

involved

surgical

margins

Radiotherapy54

GyonTandN

No

No

Alivein

firstCR

4years

after

diagnosis

813years,

male

Swelling,

12months

Rightparotid

gland

1.8cm

T1N0M0

Acinic

cell

carcinoma

(low-grade)

Tumorectomy,

tumor

involved

surgical

margins,tumor

rupture

and

contamination

Radiotherapy54

GyonT

No

No

Alivein

firstCR

4years

after

diagnosis

914years,

male

Swelling,

1month

Leftparotid

gland

1.3cm

T1N0M0

Mucoepidermoid

carcinomaG2

Totalparotidectomy,

histologically

free

margins

No

No

No

Alivein

firstCR

3years

after

diagnosis

10

15years,

female

Swelling,

22months

Rightparotid

gland

3cm

T2N0M0

Mucoepidermoid

carcinomaG1

Totalparotidectomy,

histologically

free

margins

No

Not

known

No

Alivein

firstCR

3years

after

diagnosis

12

11years,

female

Swelling,

3months

Leftparotid

gland

1cm

T3N0M0

Mucoepidermoid

carcinomaG1

Totalparotidectomy,

involved

surgical

margins

Radiotherapy54

GyonT

No

No

Alivein

firstCR

2years

after

diagnosis

Previousdiagnosis

ofEwing

sarcoma(9

years

before)

13

17years,

female

Swelling,

2months

Leftparotid

gland

1.7cm

T1N0M0

Acinic

cell

carcinoma

(low-grade)

Superficial

parotidectomy,

histologically

free

margins

No

No

No

Alivein

firstCR

2years

after

diagnosis


Salivary Gland Carcinoma in Children 1963

TABLEI.

(Continued

)

No.

Age,

gender

Symptom,

delay

Tumorsite

Tumor

size

TNM

Histotype

Surgery

Other

therapies

Facial

nerve

injury

Relapse

Outcome

Comments

14

12years,

female

Swelling,

3months

Leftparotid

gland

6cm

T3N1M0

Mucoepidermoid

carcinomaG1

Totalparotidectomy,

lymphadenectomy,

involved

surgical

margins

Radiotherapy

54GyonTand

N

No

No

Alivein

firstCR

2years

after

diagnosis

15

14years,

male

Unknown

Rightparotid

gland

2cm

T1N0M0

Mucoepidermoid

carcinomaG1

Totalparotidectomy,

lymphadenectomy,

involved

surgical

margins

No

Unknown

No

Lost

tofollow-up

16

17years,

male

Tumorfound

atfollow-up

forprevious

HD

Leftparotid

gland

1cm

T1N0M0

Mucoepidermoid

carcinomaG1

Superficial

parotidectomy,

histologically

free

margins

No

No

No

Alivein

firstCR

1yearafter

diagnosis

Previousdiagnosis

ofHD

(8years

before);

salivarygland

tumorarose

in

previous

radiationfield

Submandibularglandtumors

15

17years,

male

Swelling,14

months

Leftsubmandibular

gland

4cm

T4N3M0

Highgrade

mucoepidermoid

carcinoma

Macroscopically

incomplete

tumorectomy,

lymphadenectomy,

Chem

otherapy

(CDDP-5FU)no

response

—Tumor

progression

at1month

Diedofdisease

4monthsafter

diagnosis

Previousdiagnosis

of

osteosarcoma

(7yearsbefore)

Minorsalivaryglandtumors

16

8years,

male

Incidental

finding

Minorsalivary

glandofpalate

0.5cm

T1N0M0

Mucoepidermoid

carcinomaG1

Wideresection,

histologically

free

margins

No

—No

Alivein

firstCR

8years

after

diagnosis

17

10years,

female

Swelling,6

months

Minorsalivary

glandofpalate

1cm

T1N0M0

Mucoepidermoid

carcinomaG1

Tumorectomy,

then

widere-excision

withhistologically

free

margins

No

No

No

Alivein

firstCR

6monthsafter

diagnosis

T,primarytumor;N,involved

nodes;CR,complete

remission;LLA,acute

lymphoblastic

leukem

ia;HD,Hodgkin

disease.



the facial nerve was performed, by directly anastomosing the trunk

of the facial nerve to its distal branches by interpositional nerve

grafting, and this leaded to a partial recovery of the injury. Lymph

node dissection was performed in four cases with enlarged nodes: in

all cases, histological evaluation confirmed the lymph nodal

involvement.

Adjuvant irradiation (54–60Gy) was given to six patients due to

incomplete resections associated with N1 tumor and/or T3 tumor

(one patient had radiotherapy for tumor rupture and local

contamination): three patients received radiotherapy on primary

tumor, three on primary tumor plus involved nodes. Two patients

submitted to initial incomplete resection did not receive irradiation:

in one case radiotherapy was refused by parents and the patient was

lost at follow-up, in the other case radiotherapy was not delivered

for rapid tumor progression and dismal course. The latter, a patient

with a huge high-grade T4N3 tumor, received cisplatin and

5-fluorouracil chemotherapy after initial macroscopically-incom-

plete tumorectomy and lymphadenectomy: the tumor did not

respond to chemotherapy, lung metastases occurred, and the patient

died of progressive disease 4 months after it had been diagnosed.

This was the only patient who experienced tumor progression and

died. The other 16 patients were alive in first continuous remission

from 6 months to 8 years (median 4 years) after diagnosis.

Comparison Between Observed and Expected Cases

Based on the AIRTum data, the estimated annual incidence of

salivary gland carcinomas (calculated for the years 2000–2006) was

0.00 per million population among 0- to 9-year-olds, 1.10 for 10- to

14-year-olds, and 2.15 for 15- to 17-year-olds. The number of cases

of salivary gland carcinomas expected each year in Italy is 6.8 in the

whole population of individuals aged 0–17 years. The number of

cases registered in the TREP database was 1.3/year, with a ratio of

observed to expected cases of 0.19.

DISCUSSION

This study reports a prospective nationwide cooperative series of

pediatric salivary gland carcinomas collected over a relatively short

period of time. Table II lists the studies published on pediatric

salivary gland carcinoma in the last 30 years. Quite a large number

of these series were published very recently, suggesting that an

increasing attention is being paid to rare pediatric tumors. Apart

from a few epidemiological studies [1,2,34–37], the list mainly

comprises retrospective single-institution series, most of which

concerned only a handful of cases observed over a lengthy period of

time [3–28]. The only cooperative series were published by the

French pediatric oncology group, with a retrospective collection of

the cases seen at French pediatric oncology centers in the last three

decades [15,24]. It is noteworthy that most of the studies were

conducted by otolaryngologists and head–neck surgeons, not by

pediatric oncologists.

The TREP project is based on a network of pediatric oncology

and pediatric surgery centers: within a cooperative framework, the

project has the dual aim of stimulating research on very rare tumors

in children and adolescents, and developing practical clinical

guidelines, as well as offering an advisory service for physicians

encountering rare and difficult cases [29]. One of the tumor types on

which the TREP group has focused is salivary gland carcinoma. In

the same was as for other types of tumor, this study demonstrated

that national multicenter and prospective studies are feasible even

on very rare childhood tumors. Two issues emerged, however. First,

children and adolescents with salivary gland carcinoma were rarely

seen by pediatric oncologists and pediatric surgeons: only 19%

of the expected cases were treated at TREP centers. This may

represent a potential selection bias in our series. These patients were

presumably managed by otolaryngologists and head-neck surgeons

with expertise on adult salivary gland tumors. It is worth noting that

half of the cases in the current series were collected at the Istituto

Nazionale Tumori of Milan, where the pediatric oncology unit is

part of a cancer hospital, and this facilitates close cooperation with

adult head-neck surgeons. Elsewhere in Italy, pediatric oncology

and pediatric surgery units are usually part of a children’s hospital,

and this implicitly makes it necessary to establish a collaboration

with medical services for adults at other institutions. Secondly, this

experience shows that, although national-scale multicenter and

prospective studies are feasible, the number of cases of pediatric

salivary gland carcinoma that might be enrolled within a reasonable

period of time in a given country will always be limited, reducing

the chances of conducting clinical trials with a view to answering

scientific questions. Larger, international prospective cooperative

efforts are needed. With this in mind, the Italian TREP group

recently joined forces with groups focusing on rare pediatric tumors

in other European countries and together they launched the

European Cooperative Study group for Pediatric Rare Tumors

(ExPeRT) [38].

The development of diagnostic and therapeutic guidelines and

their circulation among pediatric oncology and pediatric surgery

units enabled a standardized approach to patients seen at the

centers involved in the TREP project. Compliance with the TREP

recommendations was high. To give some examples: preoperative

MRI was performed in all but one patient with parotid gland

tumor, (one had CT scan); parotidectomy (total or superficial) was

done in all but one case (operated elsewhere before the patient was

admitted to the TREP center that managed him afterwards); any

indications for radiotherapy were always discussed with the TREP

coordinators.

Despite the limited number of cases involved, our series

confirmed the typical traits of salivary gland carcinoma in pediatric

age [39–41]: (a) tumors usually occur in the second decade; (b) they

arise mainly in the parotid gland; (c) they are low-grade tumors in

most cases; (d) the clinical presentation is often favorable, with low-

stage disease; (e) the overall prognosis is generally good. What

remains to be seen is whether the generally good survival is related

to the favorable clinical features seen in most cases, or whether

there are age-related differences in the tumor’s biology and

aggressiveness. In our series, only one patient had a very aggressive

T4N3 high-grade tumor, and died of his disease.

Although the distribution of tumor types and sites appears to

differ between children and adults, given the rarity of these tumors,

it is generally agreed that pediatric cases should be treated

according to the schemes adopted for adult cases, which are much

more common [42]. Nevertheless, the indication for radiotherapy

need to be put with more caution, given the carried high risk of

severe late sequelae, particularly when delivered to young children

and in the light of a potential long term life (i.e., muscoloskeletal

growth retardation, functional damages, secondary cancer). There

is no a general agreement on radiotherapy indication, doses and

volume in children. In our series, post-operative radiotherapy was

delivered to six patients only, at a dose of 54–60Gy, in case of



TABLE II. Published Series on Pediatric Salivary Gland Carcinoma (in the Last Thirty Years)

Reference Series Major findings and conclusions

Baker et al. [3] Retrospective single-institution series 16 cases,

period: 1956–1981

Salivary gland tumors are to be treated according to

the same principles as for adult patients

Seifert et al. [34] Epidemiological study: 80 pediatric cases out of

3,017 cases, 1965–1984

Different incidence of tumor types in children/

adolescents as compared with adults

Shikhani et al. [4] 3 cases, 1955–1985 Review of the English literature (472 cases reported):

preponderance of female gender, parotid gland,

MEC

Lack et al. [5] Histopathological review 15 cases, 1928–1986 One tumor-related death

Fonseca et al. [6] 7 cases, 1959–1989 Parotid gland was the most frequent site

Callender et al. [7] Retrospective single-institution series 21 cases,

1944–1987

5-Year OS 90% postoperative RT recommended for

high-grade tumors or adverse prognostic factors,

i.e., soft tissue extension and perineural invasion

Rogers et al. [8] Retrospective single-institution series 8 cases,

1973–1992

6/6 Patients with localized disease were alive, 2/2 with

metastases died of the tumor

Kessler et al. [9] Retrospective single-institution series 8 cases,

1982–1991

2-Year OS 100%; neck dissection recommended only

in cases with clinically detectable neck metastases

Orvidas et al. [10] Retrospective single-institution series 19 cases,

1970–1997

One patient with adenoid cystic carcinoma died of the

tumor

Yu et al. [11] Retrospective single-institution series 46 cases,

1974–1999

Delay in diagnosis

De Cassia Braga

Ribeiro et al. [12]

Retrospective single-institution series 27 cases,

1953–1997

5-Year OS 81.6%; grade of differentiation was the only

significant prognostic factor for patients with MEC

Ethunandan et al. [13] 3 cases, 1974–1999 3 cases among 529 neoplastic lesions seen at the

maxillofacial unit at a district general hospital

Shapiro et al. [35] Epidemiological study (SEER) 95 cases,

1988–2001

7-year OS 94.2%

Guzzo et al. [14] Retrospective single-institution series 15 cases,

1975–2004

14/15 were alive; differences with adults regarding

histotypes and sites; similar outcome;

Vedrine et al. [15] Retrospective French cooperative studies 18 cases

of MEC, 1980–2000

5-Year OS 93.7%; 11 patients had previously had

another malignancy; survival rate did not differ in

patients with MEC as a secondary tumor

Rahbar et al. [16] Retrospective single-institution series 7 cases,

1994–2004

7/7 alive with no evidence of disease; superficial or

total parotidectomy with preservation of facial nerve

is the treatment of choice; RT to be used in selected

cases for the risk of sequelae

Ellies et al. [17] Retrospective single-institution series 12 cases,

1966–2000

10-year OS 75%

Laikui et al. [18] Retrospective multicenter series 19 cases,

1992–2004

Most were low-grade MEC 2/19 died of the disease

Aro et al. [19] Retrospective single-institution series 52 cases of

MEC of major salivary gland, 1976–2005

Loco-regional or distant failure in 45% and 67% of

high-grade and intermediate-grade MEC,

respectively; 0% in low-grade; aggressive approach

to be considered for intermediate-grade tumors

Muenscher et al. [36] Epidemiological study 128 cases, 1975–2000 Different tumor distribution compared with adults

Kupferman et al. [20] Retrospective single-institution series 61 cases,

1953–2006

OS 93% and 84% at 5 and 10 years, respectively;

lymphatic metastases in 37% of cases; permanent

facial paresis in 12%; RT given to 45%; RT is

beneficial for locoregional control

Ryan et al. [21] Retrospective single-institution series 49 cases

with MEC, 1953–2007

OS 98% and 94% at 5 and 10 years, respectively 22%

of patients treated with RT



incomplete resection associated with N1 tumor and/or T3 tumor, or

in case of tumor rupture and local contamination. Others suggested

to give radiotherapy only in case of intermediate or high-grade

histology, or in case of perineural invasion [24]. The small numbers

of our series, as well as for previously published studies, hinder the

possibility to define any conclusion. Careful planning is always

mandatory, however, as is the use of any techniques (i.e., three-

dimensional conformal radiotherapy) that might improve the

therapeutic index and reduce the radiation-related late effects.

The possibility of reducing doses or limiting volume [15] may be

considered.

An interesting finding in our series concerns the relatively high

proportion of salivary gland carcinomas occurring as second

tumors. Four of our 17 cases had a history of primary cancers

occurring 6–9 years earlier (involving acute lymphoblastic

leukemia, osteosarcoma, Ewing sarcoma and Hodgkin disease).

We know that mucoepidermoid carcinoma of the salivary glands

can arise as a second malignancy [43–46], but few cases have been

reported in pediatric age – most of them by the French group (with

11 cases, subsequently updated to 13) [15,24]. A recent SEER and

Childhood Cancer Survivor Study collected 23 cases from among

14,135 childhood cancer survivors, with a mean age of 8.3 years

when the first primary cancer was diagnosed, and a mean age of

24.8 years when the second salivary gland cancer came to

light [47]. Compared with the general population, childhood

cancer survivors had a 39-fold higher incidence of second salivary

gland cancers; this higher risk was associated with previous

radiotherapy and with the dose of radiation [46]. In our cohort, on

the other hand, only one of the four patients had previously

received radiotherapy to the neck, and the French group also

reported that some of their patients had received no radiotherapy

for their first cancer [15,24]. In such cases, the onset of salivary

gland carcinoma may relate to the role of chemotherapy and its

mutagenic potential, or to a genetic predisposition. It is noteworthy

that the French study also reported that salivary gland carcinoma

occurring, as a second cancer did not carry a worse prognosis than

when it was a first cancer [15,24].

In conclusion, our results add to the literature on the topic of

pediatric salivary gland carcinoma. The clinical guidelines

developed as part of the TREP project proved helpful and enabled

a standardized approach to patient management. Due to the rarity of

these diseases, we recommend that children and adolescents be

referred to specialized centers if possible. We are also convinced

that a fundamental goal of pediatric oncologists dealing with these

tumors should be to develop broad international cooperative

schemes and especially to ensure an active networking with

otolaryngologists and head-neck surgeons with an in-depth

experience of salivary gland tumors in adults.

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TABLE II. (Continued)

Reference Series Major findings and conclusions

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salivary gland carcinomas in children and adolescents: the italian trep project experience

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