Salivary Gland Cancer

Updated by Vinita Takiar

BACKGROUND

What is the incidence of salivary cancers in the U.S.?

~2,500 cases/yr of salivary cancers (∼3% of all H&N cancers)

What is the sex predilection and median age at presentation for benign vs. malignant tumors?

Benign: female > male, 40 yo

Malignant: female = male, 55 yo

What is the most common type of benign tumor of the salivary gland, and where is it most commonly found?

Pleomorphic adenoma (65%). It is most commonly found in the parotid glands.

In addition to pleomorphic adenoma, what are some other benign salivary gland tumors?

Warthin tumor (papillary cystadenoma lymphomatosum), Godwin tumor (benign lymphoepithelial lesion, associated with Sjögren), and monomorphic adenoma (oncocytoma, basal cell)

What is the most common malignant salivary gland tumor, and where is it most commonly found?

Mucoepidermoid carcinoma. It most commonly arises in the parotid (most are low grade, but if the tumor is high grade, it needs to be managed with surgery + LND + adj RT).

How are tumors of the salivary gland separated into low vs. intermediate vs. high grade by histology?

Tumors should be assigned a grade by the pathologist. Some tumors are assumed a grade unless specified, though it should always be verified. Acinic cell carcinoma is typically a low-grade tumor. Carcinoma ex-pleomorphic adenoma (CexPA), and salivary ductal carcinomas are almost always high grade. Mucoepidermoid carcinoma must be graded. Adenoid cystic carcinoma (ACC) is often low grade, but rather than grading, pathologists will describe ACC as either tubular, cribriform (low), or solid (high). ACC is often grouped with high-grade tumors as its propensity for poorly defined borders and neurotropism almost always requires multimodal therapy. The nomenclature for salivary gland tumors is also evolving. Thus, mixed malignant tumors are rarely seen as the majority are CexPA, and most adenocarcinomas seen are aggressive salivary duct carcinoma or low-grade polymorphous adenocarcinoma (most commonly seen in the hard palate).

What is the relationship between the gland size and malignant nature of the salivary tumor?

Typically, the smaller the gland, the more malignant the tumor.

What is the approximate incidence ratio of benign to malignant tumors in the various salivary glands?

Approximate incidence ratios of benign to malignant tumors:

1. Parotid, ∼75:25

2. Submandibular gland, ∼50:50

3. Sublingual gland, ∼10:90

4. Minor salivary, ∼20:80

What is the most common malignant histology arising in the submandibular gland?

Adenoid cystic carcinoma is the most common malignant histology of the submandibular gland.

What is the most common malignant histology arising in the minor salivary glands?

Adenoid cystic carcinoma is the most common malignant histology of the minor salivary glands.

Where are the minor salivary glands found in the H&N?

Minor salivary glands are found in the mucosal lining of the aerodigestive tract. Most are in the oral cavity (OC) (85%–90%), with the palate (especially the hard palate) being the #1 site. They can be found in all sites of the OC, nasal cavity, paranasal sinus, oropharynx, and larynx.

What are the risk factors for developing salivary gland tumors?

Ionizing RT, personal Hx of tumor, and family Hx

What is the lymphatic drainage predilection of the parotid, submandibular/sublingual, and minor salivary glands?

Lymphatic drainage predilection:

Parotid: preauricular, periparotid, and intraparotid, with deep intraparotid nodes draining sequentially along the jugular nodes (levels II–IV)

Submandibular/sublingual: levels I–II nodes, less often levels III and IV

Minor salivary: depends on site of involvement and histology

How does the propensity for cervical LN mets relate to the site of origin of the salivary tumor?

The propensity for LN spread is greatest for the minor salivary gland > submandibular/sublingual > parotid gland malignancies.

What is the natural Hx of ACC?

ACC is often low grade (cribriform or tubular), but is very locally infiltrative. Perineural invasion with skipped lesions and involvement of large nerves is common, as is DM. Recurrence can be very late, though high-grade tumors (solid type) tend to have a more aggressive course. Nodal mets are uncommon (5%–8%).

What % of pts with adenoid cystic carcinoma ultimately go on to develop lung mets?

~40% of pts with adenoid cystic carcinoma ultimately develop lung mets.

WORKUP/STAGING

What is the most common presentation of parotid gland tumors?

A painless, solitary mass is the most common presentation of parotid gland tumors.

For what does a painful growth/mass in the salivary gland predict?

It predicts for malignancy or an inflammatory etiology/condition.

What are some other presenting Sx in pts with salivary gland tumors?

Pain, facial weakness from CN VII involvement, rapid growth of mass, skin involvement, neck nodes. Sensory changes of the face can occur from involvement of the trigeminal nerve branches (CN V), and dysarthria/dysphagia can occur from CN XII being affected.

What is the DDx for a parotid mass?

Primary tumor, mets, lymphoma, parotitis, sarcoid, cyst, Sjögren syndrome, stone, lipoma, hemangioma

What are the 2 most important factors that predict for nodal mets in salivary gland malignancies?

Grade and size are the 2 most important factors that predict for nodal mets: high grade (50%) vs. intermediate/low grade (<10%) and size (>4 cm: 20% vs. <4 cm: 4%).

What is the typical workup performed for salivary gland tumors?

Salivary gland tumor workup: H&P (CNs/nodes), CBC, CMP, CXR, CT/MRI H&N, and FNA Bx

How should Bx be obtained for pts who present with a salivary gland mass?

Some argue that a salivary gland mass should be removed regardless, so do not biopsy. However, FNA should be done (despite a false negative rate of 20%), as knowledge of the histology may impact the type of surgery.

What does the mnemonic SOOTH stand for in terms of tumor (T) staging of the H&N?

Salivary

Oral cavity

Oropharynx

Thyroid

Hypopharynx

(Mnemonic: SOOTH) SOOTH tumors are the H&N tumors with similar size-dependent T staging.

What is the T-staging breakdown for major salivary gland tumors?

T1: ≤2 cm

T2: >2 cm, ≤4 cm

T3: >4 cm (and/or extraglandular extension)

T4(a-b): local invasion of adjacent structures (see below)

What salivary gland tumors are considered T3?

T3 salivary gland tumors are tumors with extraglandular extension or tumors >4 cm.

What is the distinction between T4a vs. T4b major salivary gland tumors?

T4a: usually still resectable; skin, mandible, ear, facial nerve invasion

T4b: usually unresectable; skull base, pterygoid plate, carotid artery invasion

What is the nodal staging system used for major salivary gland tumors?

Nodal staging is the same as for other H&N sites (except for the nasopharynx):

Per the latest AJCC 7^th (2011) edition classification, what are the stage groupings for major salivary gland tumors?

N1: single, ipsi, ≤3 cm

N2a: single, ipsi, >3 cm, ≤6 cm

N2b: multiple, ipsi, ≤6 cm

N2c: bilat or contralat ≤6 cm

N3: >6 cm

Stage I: T1N0

Stage II: T2N0

Stage III: T3N0 or T1–3N1

Stage IVA: T4aN0–1 or T1–4aN2

Stage IVB: T4b any N or any TN3

Stage IVC: any T any NM1

On what is the staging system for the minor salivary gland tumors based?

Staging of the minor salivary gland tumors is based on the site of origin.

What are some important prognostic factors in salivary gland tumors?

Size, grade, histology, nodal status, and “named” nerve involvement are important prognostic factors.

What is the 5-yr OS for stages I–IV cancers of the salivary gland?

Stage I: 80%

Stage II: 60%

Stage III: 50%

Stage IV: 30%

What is the 5-yr OS of pts who present with facial nerve involvement?

The 5-yr OS is 65% with simple invasion and 10% if pts have nerve dysfunction (i.e., if symptomatic).

TREATMENT/PROGNOSIS

What is the general management paradigm for benign mixed/pleomorphic adenoma of the parotid?

Benign mixed/pleomorphic adenoma management paradigm: WLE, or superficial parotid lobectomy → observation (even if +margin or with extraglandular extension)

What is the management paradigm for low- to intermediate-grade tumors of the salivary gland?

Low- to intermediate-grade salivary gland tumor management paradigm: surgical resection with PORT for close (<2 mm) or +margin, unresectable Dz, pT3–4, PNI, capsule rupture, +nodes, or recurrent Dz

What is the management paradigm for high-grade tumors of the salivary gland?

High-grade salivary gland tumor management paradigm: surgical resection (facial nerve sparing if possible for parotid tumors), including LND if node+ → PORT

What is the role of concurrent chemoradiation (CRT)?

The level of evidence for CRT is weak. NCCN guidelines recommend consideration of definitive CRT for T4b disease or PORT + chemo for pathologic adverse features including intermediate or high grade, inadequate margins, PNI, +LN, and LVI.

What is the management paradigm for ACC with pulmonary mets?

ACC (cribriform or tubular) with pulmonary mets (typically asymptomatic with low tumor burden) management paradigm: same local therapy as in patients without mets because pulmonary mets have a long natural Hx

What is the difference between superficial, total, and radical parotidectomy?

Superficial: en bloc resection of gland superficial to CN VII

Total: en bloc resection of entire gland with nerve sparing

Radical: en bloc resection of entire gland + CN VII + skin + fascia +/– muscle

What are the indications for LND with salivary gland tumors?

A clinically+ neck. LND is often done for high-grade and large tumors, but in the clinically negative neck, if the patient is to get PORT, the role of LND is questionable.

What are the indications for PORT in the management of salivary gland cancers?

Adj RT is indicated for the following: high grade (regardless of margin), close/+ margin, pT3-T4 Dz, PNI, capsule rupture, tumor spillage, ECE, N2-N3 Dz, unresectable tumor/gross residual Dz, and recurrent tumor

For which cN0 salivary gland tumors, by histology, does elective nodal RT significantly reduce the incidence of nodal relapse?

Elective nodal RT is more likely to reduce the incidence of nodal relapse in pts with squamous, undifferentiated, or adenocarcinoma histologies. (Chen AM et al., IJROBP 2007)

When should bilat neck coverage with RT be considered for salivary gland neoplasms?

Treatment of the ipsi neck should be adequate for major salivary gland cancers. Bilat nodal treatment is indicated for high-grade minor salivary gland cancers affecting midline structures.

What are some ways to deliver RT/set up the RT fields in the Tx of parotid gland tumors?

RT delivery and set up of RT fields:

1. AP/PA wedge pairs (120-degree hinge angle) but difficult setup, exit through OC

2. Sup/Inf wedge pair (with 90-degree couch kick), avoids exit through OC but exits through brain

3. Single direct field with mixed energy beam (80% 15 MeV electron: 20% 6 MV photon) with bolus, electron portal 1 cm larger than the photon field b/c of IDL constriction with depth, higher dose to bone, keep contralat parotid at <30 Gy

4. IMRT

What are the PORT doses used in the management of salivary gland tumors?

60 Gy for –margin, 66 Gy for close/+margin, 70 Gy for gross residual, and 50–56 Gy to a low-risk neck

What RT techniques are used in the management of the ipsi neck?

RT techniques for the ipsi neck:

1. Single lat appositional electron field

2. Mixed electron-photon beam technique

3. Half beam block technique

4. IMRT

What key retrospective data demonstrated the importance of adding PORT for stages III–IV and high-grade salivary gland tumors?

MSKCC data (Armstrong JG et al., Arch Otolaryngol Head Neck Surg 1990; Harrison L et al., J Surg Oncol 1990) showed improved LC and survival.

What is the largest retrospective study demonstrating a benefit of adj RT for malignant salivary gland neoplasms?

Dutch NWHHT study (Terhaard CHJ et al., IJROBP 2005): 498 pts. Adj RT significantly improved LC in pts with T3-T4 Dz, a close margin, incomplete resection, bony invasion, and PNI.

What is the best RT modality for managing unresectable salivary gland tumors?

Neutrons (superior LC, with photons showing LC of 25% for inoperable cases). If no access to neutrons, many advocate concurrent CRT

When is surgical resection alone adequate in the management of recurrent salivary gland tumors?

If tumors are of low/intermediate grade, <3 cm, and there are no other risk features, then surgery alone may suffice.

TOXICITY

What is Frey syndrome, and from what does it result?

Auriculotemporal nerve syndrome (gustatory sweating or redness and sweating on the cheek area when the pt eats, sees, or thinks about or talks about certain kinds of food). It is a postop complication of parotidectomy.

What are some possible Tx sequelae from RT for parotid cancers?

The main concerning sequelae are related to the ear. Acute effects include otitis externa or media with mild hearing loss. Late effects include dry cerumen, otitis media, and hearing loss. ORN of the temporal bone (parotid cancer) is uncommon as is mandibular ORN. Since treatment is mostly unilateral, xerostomia is mild.

Above which RT doses can salivary gland function be compromised, resulting in xerostomia?

The parotid is the most sensitive gland due to a large component of serous glands which are highly radiosensitive. There is no dose threshold. Minimum doses to effect parotid function start at ∼14 Gy. Based on older data, mean doses of 26–30 Gy are still used as planning goals with IMRT, although doses as high as 40 Gy can still allow some recovery. The doses that result in damage to other salivary glands have not been well studied.

What is the general follow-up for pts with salivary gland neoplasms?

Per 2013 NCCN guidelines, H&P (q1–3mos for yr 1, q2–4mos for yr 2, q4–6mos for yrs 3–5, and q6–12mos thereafter), chest imaging if clinically indicated, and TSH q6–12mos if neck RT

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