Radiation Oncology: A Question-Based Review

Salivary Gland Cancer

Boris Hristov and Vincent J. Lee

image 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 gender predilection and median age at presentation for benign vs. malignant tumors?

1.     Benign: female > male, 40 yo

2.     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?

1.     Low grade: acinic cell carcinoma

2.     Intermediate grade: mucoepidermoid carcinoma, adenocarcinoma

3.     High grade: adenoid cystic carcinoma, squamous cell carcinoma, carcinoma expleomorphic adenoma (malignant mixed tumor), lymphoepithelioma (mostly Asians), ductal carcinoma

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 ratio of benign to malignant tumors:

1.     Parotid, ~75:25

2.     Submandibular gland, ~50:50

3.     Sublingual gland, ~10:90

4.     Minor salivary, ~10:90

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, wood dust inhalation, 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:

1.     Parotid: preauricular, periparotid, and intraparotid, with deep intraparotid nodes draining to levels II–III

2.     Submandibular/sublingual: level I–II nodes

3.     Minor salivary: depends on site of involvement, but LNs commonly involved b/c of rich lymphatic network

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 adenoid cystic carcinoma?

Perineural invasion with skipped lesions and late recurrence with DMs (up to 10–15 yrs with pulmonary mets, earlier for bone or viscera) are common. However, the rates are low for cervical nodal mets (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.

image Workup/Staging

What is the most common presentation of parotid gland tumors?

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 node, and dysphagia/otalgia from CN IX–XII palsies

What is the DDx for a parotid mass?

Primary tumor, mets, lymphoma, parotitis, sarcoid, cyst, Sjögren, stone, lipoma, hemangioma, and a prominent C1 transverse process

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 Bx

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

Excisional Bx is preferred, though FNA may be adequate (however, the FN rate is 20%).

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

1.     Salivary

2.     Oral cavity

3.     Oropharynx

4.     Thyroid

5.     Hyopharynx

(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?

1.     T1: ≤2 cm

2.     T2: 2–4 cm

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

4.     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?

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

2.     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):

1.     N1: single, ipsi, <3 cm

2.     N2a: single, ipsi, 3–6 cm

3.     N2b: multiple, ipsi, ≤6 cm

4.     N2c: bilat or contralat ≤6 cm

5.     N3: >6 cm

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

1.     Stage I: T1N0

2.     Stage II: T2N0

3.     Stage III: T3N0 or T1-3N1

4.     Stage IVA: T4aN0-1 or T1-4aN2

5.     Stage IVB: T4b any N or any TN3

6.     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 stage I–IV cancers of the salivary gland?

1.     Stage I: 80%

2.     Stage II: 60%

3.     Stage III: 50%

4.     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).

image 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: superficial parotidectomy with PORT for close (<2 mm) or +margin, unresectable Dz, pT3, 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: total parotidectomy (facial nerve sparing, if possible) with ipsi LND → PORT or CRT (RT volumes to encompass perineural pathways to the base of skull if “named” nerve involvement)

What is the management paradigm for adenoid cystic carcinoma with pulmonary mets?

Adenoid cystic carcinoma with pulmonary met management paradigm: same local therapy as in high-grade tumors since pulmonary mets have a long natural Hx (Garden AS et al., IJROBP 1995)

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

1.     Superficial: en bloc resection of gland superficial to CN VII

2.     Total: en bloc resection of entire gland with nerve sparing

3.     Radical: en bloc resection of entire gland + CN VII + skin + fascia +/− muscle

What are the indications for LND with salivary gland tumors?

High grade, large tumors, and a clinically + neck are all indications for elective LND.

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 what 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?

Whenever there is multilevel nodal involvement and >50% of removed nodes are involved; otherwise, the ipsi neck is adequate.

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

RT delivery and setup 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 4:1 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 50–54 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

What are the indications for chemo and the agents used for salivary cancer?

The indications for chemo (+/−RT) include unresectable, recurrent, or metastatic Dz, and the active regimens are cisplatin/5-FU or Adr/Cytoxan

What key retrospective data demonstrated the importance of adding PORT for stage 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, EBRT + implant is a good choice.

What is the key prospective randomized trial that demonstrated superior LC outcomes with the use of neutrons over photons/electrons in the Tx of unresectable salivary gland tumors?

RTOG-MRC trial (Laramore G et al., IJROBP 1993): 10-yr LRC was 17% vs. 56% (neutrons), SS. 10-yr OS was 15% vs. 25%, NSS.

How is neutron RT prescribed in the Tx of unresectable salivary gland tumors?

1.2 neutron Gy, 4 times/wk → 19.2 nGy for gross Dz (13.2 nGy for uninvolved nodes)

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.

image 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?

Xerostomia and otitis media with partial hearing loss

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

Usually, doses > 26–30 Gy result in salivary gland dysfunction/xerostomia.

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

Per the NCCN, 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