Accepted Manuscript

Title: Pediatric sialoblastoma: evaluation and management

Author: Alexandria L. Irace, Eelam A. Adil, Natasha M. Archer, Victoria M.

Silvera, Antonio Perez-Atayde, Reza Rahbar

PII: S0165-5876(16)30081-7
DOI: http://dx.doi.org/doi: 10.1016/j.ijporl.2016.04.037
Reference: PEDOT 8073

To appear in: International Journal of Pediatric Otorhinolaryngology

Received date: 9-3-2016

Revised date: 27-4-2016
Accepted date: 28-4-2016

Please cite this article as: Alexandria L. Irace, Eelam A. Adil, Natasha M. Archer, Victoria M.
Silvera, Antonio Perez-Atayde, Reza Rahbar, Pediatric sialoblastoma: evaluation and
management, International Journal of Pediatric Otorhinolaryngology (2016),
http://dx.doi.org/doi: 10.1016/j.ijporl.2016.04.037.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
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 1

Pediatric Sialoblastoma: Evaluation and Management

Alexandria L. Irace BAa, Eelam A. Adil MD, MBAa,b, Natasha M. Archer MDc, Victoria M.

Silvera MDd, Antonio Perez-Atayde MDe, Reza Rahbar DMD, MDa,b

a
Boston Childrens Hospital, Department of Otolaryngology and Communication Enhancement,

300 Longwood Avenue, Boston, MA 02115, USA

b
Harvard School of Medicine, Otolaryngology, 25 Shattuck Street, Boston, MA 02115, USA
c
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Pediatric

Hematology/Oncology, 450 Brookline Avenue, Boston, MA 02215, USA

d
Boston Childrens Hospital, Department of Radiology, 300 Longwood Avenue, Boston, MA

02115, USA
e
Boston Childrens Hospital, Department of Pathology, 300 Longwood Avenue, Boston, MA

02115, USA

Financial Disclosures: None

Conflict of Interest: None

Correspondence:

Alexandria L. Irace, BA, Department of Otolaryngology and Communication Enhancement,

Boston Childrens Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Email

alexandria.irace@childrens.harvard.edu

Page 1 of 21
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Abstract

Objectives: Sialoblastoma is a rare congenital salivary gland tumor of epithelial origin. The

objectives of this study are to review the literature regarding clinical presentation of

sialoblastoma, evaluate the effectiveness of various treatment methods, and present guidelines

for evaluation and management in the pediatric population.

Data Sources: Case presentation and literature review

Review Methods: A comprehensive search was conducted to identify cases of pediatric

sialoblastoma in the English-language literature. The presentation, evaluation, and management

of reported cases were analyzed. We also report an invasive and recurrent case in a pediatric

patient to highlight the aggressive nature of these lesions.

Results: Sixty-two cases of pediatric sialoblastoma were reviewed. The age at initial

presentation ranged from before birth to 15 years. The parotid gland was the most common

location (n=47). Surgical excision was the primary treatment in all patients. Nine patients

developed metastatic disease of the lung, lymph nodes, or bone. Almost a third of patients had

recurrence and over two thirds of patients were tumor-free for at least 1 year following their last

treatment intervention.

Conclusion: Prompt and complete surgical excision should be recommended to prevent local

and systemic recurrence of pediatric sialoblastoma. Chemotherapy has also shown promise in

several cases, and clinical genomics may shed light on more therapy options. Patients should be

closely followed for at least 12 months following diagnosis, or longer depending on the

histopathological staging of the tumor.

Keywords: pediatric sialoblastoma, salivary gland tumor, parotid neoplasm, salivary embryoma,

congenital basal cell adenoma, congenital hybrid basal cell adenoma-adenoid cystic carcinoma

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1. Introduction

Sialoblastoma is a rare tumor that arises from the primitive duct epithelium of salivary

glands during the perinatal period. Lesions are typically detected by antenatal sonography or by

caregivers within the first few weeks of life. It is estimated that 2 to 5% of all salivary gland

tumors occur in children, with an annual incidence of 0.8 per million, making sialoblastoma

exceptionally uncommon [1,2]. This neoplasm has been reported to be three times as likely to

occur in the parotid gland than the submandibular gland [3]. Sialoblastoma is known to be

locally infiltrative and may metastasize to the lymph nodes or lungs if left untreated [4-6].

Due to the rarity of sialoblastoma, there is little consensus on its management. In this

article, we present a patient with a rapidly growing malignant and recurrent sialoblastoma of the

parotid gland. The patient underwent multiple surgical resections and cycles of chemotherapy.

We also review the literature to summarize patient presentation, management, and outcomes.

Our goal is to propose guidelines for evaluation and management of this rare tumor based on our

experience and the prior literature.

2. Methods

A case of a pediatric patient who presented with a large sialoblastoma of the parotid

gland is described. A literature search was performed using the online search databases PubMed,

EMBASE, CINAHL with Full Text, and Cochrane Library on August 1, 2015. Medical subject

headings (MeSH) terms included sialoblastoma, salivary embryoma, congenital basal cell

adenoma, congenital hybrid basal cell adenoma, and congenital hybrid basal cell adenoma-

adenoid cystic carcinoma. The term low-grade basaloid adenocarcinoma, a previously used

name for sialoblastoma, was excluded due to overlapping nomenclature with other salivary gland

tumors, as defined by the World Health Organization [3]. Search results were restricted to those

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written in the English language describing pediatric patients (under the age of 21 years of age)

and were not limited by year of publication. Separate articles describing the same patient were

considered one result.

3. Results

3.1 Case Presentation

A 5-month old male was referred to our institution with a left-sided firm facial mass. The

patient was noted at birth to have a 1 cm x 1 cm mass overlying the mandible. This was initially

stable and then rapidly grew to 3 cm x 3 cm by 2 months of age. Ultrasound of the mass at this

point showed a mildly heterogeneous, well-defined predominantly hypoechoic mass within the

left parotid gland with scattered internal hyperechoic foci (Fig. 1) and mild increased vascularity.

The mass was initially believed to be an infantile hemangioendothelioma and was monitored by

a local otolaryngologist in the patients home country. Its continued rapid growth prompted

referral to our institution for further management.

The mass on presentation was friable and warm to the touch. The patient had dysphagia

and left-sided facial nerve paralysis. Magnetic resonance imaging (MRI) revealed a large mass

extending intracranially via a widened left foramen ovale into the cavernous sinus. There was

also extension into the left external auditory canal/left middle ear cavity, lower eyelid and

possibly the superolateral orbit. The mass measured 12.1 cm anterior-posterior by 13.5 cm

craniocaudal by 9.5 cm transverse in maximal dimension. Tumor was isointense to muscle on

T1-weighted images (T1WIs) (Fig. 2A). T2-weighted images (T2WIs) showed areas of

intermediate signal intensity, suggesting components of tumor with a high cytoplasm to nucleus

ratio (Fig. 2B) that also corresponded to regions of reduced diffusivity on the ADC map (Fig.

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2C), and areas of increased signal consistent with high water content or necrosis. Post-contrast

T1WIs showed intense, heterogeneous tumor enhancement (Fig. 3). Contrast-enhanced

computed tomography (CT) showed heterogeneous tumor enhancement and bony destruction of

the left temporal, sphenoid, pterygoid, maxillary, mandibular, and zygomatic bones, and bony

remodeling/thinning of the squamosal portion of the temporal bone (Fig. 4). No areas of bone

destruction or flow voids were appreciated on MRI or CT. Chest CT revealed no metastatic

disease. Biopsy of the mass was guided by interventional radiology, and pathological

examination revealed a malignant tumor consistent with sialoblastoma.

The patient received 5 cycles of neoadjuvant chemotherapy as per the intermediate-risk

neuroblastoma regimen (carboplatin, cyclophosphamide/etoposide, and doxorubicin) in an effort

to shrink the tumor to a more easily resectable size. The mass shrank to approximately 3 cm x 4

cm following chemotherapy. He underwent aggressive surgical debulking of the extracranial

component of the tumor and total parotidectomy. Pathological examination of the resected

specimen confirmed the diagnosis of sialoblastoma with multifocal tumor necrosis and

infiltration but no evidence of lymphovascular invasion (Fig. 5).

Approximately one month following surgery, disease progression shown by MRI

prompted a 6-month course of adjuvant chemotherapy. Despite cyclophosphamide and

etoposide, tumor growth continued. After one cycle of doxorubicin and low-dose

cyclophosphamide, he exhibited a partial but transient response. The regimen was changed to 5-

fluoruracil, cisplatin, and vincristine, as delivered for hepatoblastoma. This treatment was

pursued due to the reported association of hepatoblastoma and sialoblastoma and the belief that

the liver and parotid gland are of similar embryonic origin [7-9]. The patient received 6 cycles of

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chemotherapy, without the last 2 doses of vincristine to prevent toxicity. Subsequently, a biopsy

revealed no active tumor and chemotherapy was stopped.

Six weeks later, 3 firm, subcentimeter mobile nodules were noted along the left mandible.

MRI showed evidence of sialoblastoma recurrence with extension toward the skull base. The

patient underwent resection of these isolated lesions and neck lymph node biopsy. Small foci of

residual left facial disease progressed rapidly. He began receiving irinotecan and temozolomide,

a second-line therapy for hepatoblastoma. After two cycles, disease progressed at the primary

site. He began daily oral pazopanib (100 mg), a multi-targeted tyrosine kinase receptor inhibitor,

because genetic testing was consistent with a missense mutation in the fibroblast growth factor

receptor 2 (FGFR2) tyrosine kinase gene in the transmembrane domain C382R. This was

suspected to be an activating mutation that could explain the patients persistent disease

progression. FGFR2 p.C382R mutations have been noted in endometrial and gastrointestinal

cancers [10], but have not been reported in sialoblastoma. No known specific FGFR2 inhibitors

had been identified, thus this patient was started on pazopanib, given promising results seen in

both children with solid tumors and adults with head and neck tumors [11,12]. Pazopanib dosage

was increased to 200 mg because of tumor growth. Tumor size then remained stable, but the

patient developed facial swelling. After changing treatment to docetaxel and cisplatin

chemotherapy, tumor growth continued.

The patient restarted the 5-fluororuacil, cisplatin, and vincristine regimen, to which he

previously exhibited a good response. Due to hearing loss and a strong response to vincristine,

cisplatin was removed from the regimen. After 5 cycles, MRI demonstrated regrowth of

sialoblastoma in the region of the left parotid gland and surrounding the mandible, retromolar

trigone and medial pterygoid. He received 3 large-fraction doses of local radiation therapy, but

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developed painful facial swelling. He received daily radiation and one dose of

carboplatin/paclitaxel as a radiosensitizer. The tumor shrank and became necrotic.

The family returned to their home country, but shortly thereafter the patients disease

progressed and they returned to our hospital. MRI showed marked increase in the tumor size

involving the left face and orbit, without pulmonary metastasis. There was intracranial

extraaxial tumor within the left middle cranial fossa. The parents opted for aggressive

chemotherapy with ifosfamide and etoposide, which was given on days 1 through 5 every 3

weeks with Neulasta given on day 7. After 3 cycles of this regimen, the tumor continued to grow.

Oral sorafenib and cyclophosphamide were attempted, in addition to intraarterial cisplatin

administration, but this resulted in increased pain and tumor growth. His last MRI was performed

at 35 months of age; the tumor extensively involved the left face, skull base, scalp and

intracranial space, left orbit, paranasal sinuses, oral cavity and left neck. No chemotherapy

options appeared to have any potential benefit. The patient was managed by palliative care and

passed two months later.

3.2 Literature Review

3.2.1 Demographics

The literature search yielded 62 unique reports of pediatric sialoblastoma written in the

English language [1,4-9,13-57]. Forty-four of these results were single case reports. Gender ratio

was almost evenly split, with slightly more males (n=33) than females (n=27) and 2 patients of

unidentified gender. Age at presentation ranged from the prenatal period to 15 years old [25], but

almost half of the cases presented at or before birth (n=30). The earliest clinical presentation of

sialoblastoma, detected on antenatal ultrasound, was in a male fetus at 26 weeks gestation [30].

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3.2.2 Location and Initial Treatment

The parotid gland was involved in almost three times as many cases as the submandibular

gland. There was only 1 report of sialoblastoma in the minor salivary glands [52], 1 in ectopic

salivary tissue [39], 1 in an eyelid [40], 2 identified as cheek masses [48,53], and 2 where the

location was not reported [7,14].

Sixty of 62 patients received treatment, while the other 2 were diagnosed posthumously

[5,8]. In every case, treatment involved partial or complete tumor excision. Thirty-seven cases

were initially treated through surgical excision of the tumor, without removing the affected

salivary gland. The remaining 23 cases involved both tumor excision and sialoadenectomy,

either to prevent recurrence or achieve tumor-free margins. Only 2 patients required sacrifice of

the facial nerve during surgery due to infiltration of the tumor into the nerve branches [18,51].

Facial nerve reconstruction was successful in both patients. Four patients underwent partial

tumor resection and required alternative treatment methods [1,15,34,40]. Chemotherapy was

administered to a total of 5 patients, with 1 receiving neoadjuvant therapy [9], 3 receiving

adjuvant therapy [13,34,40], and 1 receiving both [36]. Radiotherapy was administered to 4

patients [13,15,40].

3.2.3 Recurrence

After treatment of the primary tumor, 20 patients experienced recurrence.

All initial recurrences occurred within 3 to 17 months from the time of original diagnosis, with

16 cases recurring at or before 12 months. The highest number of recurrences was 6 in one

patient [4], but most patients experienced 1 or 2.

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3.2.4 Treatment for Recurrent Tumors

The most common treatment for tumor recurrence was surgical resection without gland

removal, which occurred in 11 of the 20 patients. Six patients underwent surgical resection with

gland removal [6,21,25,49,50,57], and 5 of these operations involved facial nerve sacrifice

[6,21,25,49,50]. The second most common treatment among these reports was chemotherapy,

which was administered to 9 patients. Interestingly, one study reports that just 2 courses of low-

dose chemotherapy were entirely curative for a large recurrent sialoblastoma [1]. Two other case

reports describe similar findings, with chemotherapy completely eradicating recurrent tumor in

these patients [18,46]. In our review, chemotherapy was frequently administered in conjunction

with surgical interventions or radiation treatments. Four patients received adjuvant chemotherapy

[4,48-50], and 2 of these patients also received neoadjuvant therapy [4,50]. A total of 6 patients

received radiation [4,5,15,20,49,51], 2 of whom underwent internal radiation, also known as

brachytherapy [20,51].

3.2.5 Metastases

Two patients presented with metastases prior to initial treatment of sialoblastoma. One

patient, 15 years of age, had evidence of metastatic disease in the lymph nodes and sphenoid,

temporal, and vertebral bones at presentation [25]. One other patient presented at 4 years of age

without any evidence of metastasis and was subsequently lost to follow up for 6 months, after

which she presented with multiple pulmonary metastases [36]. Seven patients had pulmonary or

lymph node metastates after initial treatment [4,5,15,18,20,46,50]. All metastases were seen in

patients with parotid sialoblastoma.

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3.2.6 Long-term Outcomes

Overall, 36 of 51 patients with a reported outcome were tumor-free for at least 1 year

following their last sialoblastoma-related intervention. However, because the duration of patient

follow-up was limited by the date of publication of each reviewed case report, the number of

patients meeting this criterion might actually be much higher. The longest reported follow-up

period was 43 years, during which time the patient remained in good health without any

recurrence of tumor [5]. Long-term complications of surgery are not common in the literature.

Residual facial palsy and paralysis occurred in 2 patients [15,50], and one patient suffered from

an intraoperative injury resulting in conductive hearing loss [57]. Only 2 sialoblastoma-related

mortalities have been reported [8,37].

4. Discussion

4.1 Background

In 1966, Vawter and Tefft were the first to describe sialoblastoma, naming it an

embryoma because of its predominance in neonates and young children [13]. Since their initial

report, clinicians and pathologists have used a variety of terms to describe this neoplasm:

congenital basal cell adenoma, congenital hybrid basal cell adenoma, low-grade basaloid

adenocarcinoma, and congenital hybrid basal cell adenoma-adenoid cystic carcinoma

[3,16,19,27,35]. In 1988, the term sialoblastoma was introduced to convey both the location

and dysontegenetic growth of the lesion [20].

Using a histopathological classification system, perinatal salivary gland tumors can fall

into one of four categories: 1) benign tumors that are analogous to their adult counterparts, 2)

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hamartomatous tumors with acinar differentiation, 3) tumors that resemble the embryonic

epithelial precursor to the major salivary glands (which includes sialoblastoma), and 4) tumors

that demonstrate malignancy from the onset [58]. There are histological markers for malignancy

in these neoplasms, including anaplasia, neurovascular invasion, and necrosis [19]. Though

sialoblastoma was previously thought to be benign, in 2005 the World Health Organization

reclassified it as a malignant epithelial salivary gland neoplasm [3]. This marked an important

turning point in clinicians understanding of this disease and provided insight on how aggressive

cases should be managed.

4.2 Imaging

Few reports describe the imaging appearance of sialoblastomas. Typically, these tumors

are lobulated, and can be non-infiltrating or locally invasive into adjacent muscle and bone. On

ultrasound, sialoblastomas are described as circumscribed and hypoechoic or mixed hypoechoic

(Fig. 1) [54,57]. On CT, sialoblastomas are intermediate in attenuation, and similar in attenuation

to muscle [34,57]. On MRI, sialoblastomas are reported as hypointense to brain parenchyma, low

or intermediate in signal on T1WIs and high intermediate or mildly hyperintense on T2WIs

suggesting a high nucleus/cytoplasmic ratio [26,34]. Focal areas of necrosis or hemorrhage may

be present [34]. Tumor may enhance poorly, heterogeneously or intensely [9,34,57]. Diffusion-

weighted imaging shows reduced diffusivity in non-necrotic areas of tumor in keeping with a

high nucleus-to-cytoplasm ratio (Fig. 2C) [34,52,59]. Small satellite lesions adjacent to the

dominant tumor have been noted [26]. The major differential considerations based on imaging

are hemangioblastoma and teratoma. Parotid hemangioblastomas are circumscribed lesions

characterized by homogeneous, intense enhancement on CT and MRI and display prominent

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intralesional flow voids. Teratomas are typically multiloculated solid and cystic tumors with

calcifications [60].

4.3 Pathology

Sialoblastoma is an infantile salivary gland tumor with a basaloid morphology that

recapitulates fetal salivary gland tissue. The tumor is composed of solid hypercellular nests,

islands or cords of basaloid epithelium with central ductules and separated by a

fibromyxomatous stroma. Nuclear palisading might be present at the periphery of the tumor

nests. The tumor has an infiltrative growth with invasion into adjacent soft tissue and sometimes

nerves (Fig. 5). Mitoses are usually frequent and focal necrosis might be observed. Tumor cells

are immunoreactive for low molecular weight cytokeratins, p63 and S100 protein. The nest

peripheral cells are immunoreactive to smooth muscle actin. Sialoblastoma behaves in a

malignant fashion with multiple recurrences and occasional regional metastases.

4.4 Treatment and Management

As we continue to learn more about the nature of sialoblastoma, we have developed a

preliminary understanding of appropriate treatment methods, particularly for malignant and

recurrent tumors. Though early surgical resection with clear margins is first line management,

there is no consensus about the most treatment course for aggressive tumors. This is due to the

rarity and variability of clinical presentations [50]. In the past, several authors have

recommended early surgical resection with negative margins as the preferred treatment

[7,19,24,61-63] and claim that radiation or chemotherapy should be considered only if the tumor

returns postoperatively or cannot be fully removed by surgical means [41]. However, others

argue that extensive surgery can be mutilating and leave significant cosmetic and nervous system

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sequelae that may be prevented by administering neoadjuvant chemotherapy or radiation

treatments [7,50]. Furthermore, several authors highlight the finding that sialoblastomas tend to

respond well to chemotherapy [1,4,6,34,36,46,50].

Despite the growing amount of literature on this topic, sialoblastoma remains an

unfamiliar and unpredictable clinical challenge for most pediatric medical practitioners. In this

report, we present a child with a particularly aggressive case that continued to progress after 2

resections, 10 different chemotherapy regimens, and 3 doses of radiation treatment. The only

regimen that was repeated 2 separate times consisted of 5-fluorouracil, cisplatin, and vincristine,

which eliminated the tumor upon initial administration but did not have a significant effect the

second time. In addition, recurrences of the tumor appeared to develop in different locations on

the head and neck, which made it difficult to localize new growth.

5. Conclusion

At present the best option for children with sialoblastoma seems to be surgical resection.

It is unclear, based on our literature search, how many patients with sialoblastoma have an initial

resection and no further sequelae. It is evident that the role of clinical genomics in more

aggressive sialoblastomas will be instrumental in helping pediatric oncologists more effectively

treat children with non-surgical options.

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Figure Legends

Figure 1. Ultrasound image shows a circumscribed, hypoechoic mass with scattered hyperechoic

foci (arrow).

Figure 2. A. Axial T1WI shows a large circumscribed mass with areas of dispersed fat (arrow).

B. Coronal T2WI shows tumor characterized by intermediate signal intensity with small foci of

dark signal (short arrow) consistent with hemorrhage and/or calcification. Tumor extends into

the left external auditory canal (long arrow). C. Axial ADC map shows areas of reduced

diffusivity (long arrow) indicating tumor with a high nucleus-to-cytoplasm ratio and areas of

increased diffusivity (short arrow) consistent with tumor components with high water content or

necrosis.

Figure 3. Axial T1W post-contrast image shows intense heterogeneous enhancement of tumor.

Tumor extends intracranially into the left cavernous sinus (arrow).

Figure 4. CT coronal reformatted post contrast image shows bony destruction of the left

mandible (white arrows), bony remodeling of the left squamosal bone (black arrowheads), and

tumor within the left cavernous sinus (black arrow).

Figure 5. Sialoblastoma histopathology. A. Hypercellular islands, nests and cords of tumor

separated by a fibromyxoid stroma. B. Tumor cells are immunoreactive to cytokeratin 19.

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