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Salivary Gland Cancer
131
References
Saku T, Hayashi Y, Takahara O et al. Salivary gland tumors among atomic bomb survivors,
1950-1987. Cancer. 1997;79(8):1465. Tumours of the Salivary Glands. In: Pathology and Genetics of Head and Neck Tumours,
Barnes L, Eveson JW, Reichart P, Sidransky D. (Eds), World Health Organization, Lyon
2005. p.209.
3. Anatomy
The salivary gland is located in the retromandibular– preauricular region. Major gland lies below the zygomatic arch, in front of and below the external acoustic meatus, and in front of the mastoid process. The inferior border of the gland rests between the angle of the mandible and the anterior border of the sternocleidomastoid muscle (figure-2).
Figure 2. Salivary glands anatomy.
4. Clinical Features
• Malignant salivary neoplasms present as a painless mass in approximately 75% of
patients. Rarely, patients are initially seen with pain or facial nerve palsy.
• A palpable mass arising in a salivary gland, associated with pain, and/or nerve
paralysis is more likely to be malignant than benign.
• Neurologic signs or symptoms indicative of facial nerve involvement are almost
always suggestive of a malignant rather than a benign tumor.
• It is believed that episodic pain suggests continued obstruction, whereas constant
pain is more suggestive of malignancy.
• Trismus, cervical adenopathy, fixation, numbness, loose dentition, or bleeding also
suggest the presence of malignancy.
Gustavo Arruda Viani
132
Histology
Description
Mucoepidermoid carcinoma
Most common salivary malignancy accounting for 29% to 43% of tumors Mucoepidermoid cancer is histologically classified into low and high grade. A
higher grade correlates with a poorer outcome
Adenoid cystic carcinoma
Adenoid cystic carcinoma is the most common malignancy of the submandibular
gland
Adenoid cystic carcinoma is characterized by slow growth, neurotropism, local
recurrence, and distant metastasis.
Acinic cell carcinoma
This tumor has a low-grade behavior and has the best survival rate of any salivary
malignancy
Parotid gland was the most common site of origin
Additional rare types
Low grade Polymorphous low-grade adenocarcinoma Epithelial-myoepithelial carcinoma Basal cell adenocarcinoma Papillary cystadenocarcinoma Myoepithelial carcinoma High grade Squamous cell carcinoma Small cell carcinoma Sebaceous carcinoma Mucinous adenocarcinoma Oncocytic carcinoma Adenocarcinoma Salivary duct carcinoma
• Lymphatic drainage varies according to the salivary gland compromised: for parotid
malignancies, the first site of lymphatic drainage is intraparotid lymph nodes, followed by level IB. For submandibular gland tumors the first site is adjacent perivascular nodes and then to the cervical region. The sublingual gland drains to the submental and submandibular nodes.
• The most commom site of metastases is the the lung, followed by bone and liver.
• Among the several histological subtypes, the adenoid cystic carcinoma has a high
risk of distant metastases that can occur as late as 10 to 20 years after diagnosis.
Reference
Fu KK, Leibel SA, Levine ML, et al. Carcinoma of the major and minor salivary glands.
Cancer 1977;40:2882-2890.
5. Pathology
Malignant salivary gland tumor is a heterogeneous group of tumors with varied degree of aggressiveness and composition (table-2).
Table 2. The most common salivary tumors for clinical practice
Salivary Gland Cancer
133
Exam
Description
CT
CT scan and/or MRI of the head and neck area are usually recommended for patients
with tumor of the major salivary glands, except in small, discrete, and freely mobile tumors involving the superficial lobe of the parotid gland (figure – 3)
MRI
MRI is preferred over CT scan for deep-lobe tumors and tumors of submandibular and
sublingual gland.
A carefully performed MRI can demonstrate soft tissue extension and document nerve
involvement without the risks of ionizing radiation, and is particularly valuable in evaluating tumor of the deep parotid lobe.
PET/CT
FDG-PET or PET/CT can be considered for patients with high-grade malignancies. Comparing PET/CT with CT alone in the evaluation of salivary gland malignancies,
the extent of the tumor, regional spread to the nodes, and distant disease were all signifi cantly more accurate for the PET/CT.
Imaging studies of the head and neck areas are important for detecting regional lymph
adenopathy.
Reference
Tumours of the Salivary Glands. In: Pathology and Genetics of Head and Neck Tumours,
Barnes L, Eveson JW, Reichart P, Sidransky D. (Eds), World Health Organization, Lyon
2005. p.209.
6. Diagnostic and Evaluation
• Diagnosis and evaluation of major salivary tumors start with a complete history and
physical examination.
• The majority (> 80%) of parotid tumors are benign (pleomorphic adenoma) and 20%
are malignant.
• Approximately 50% of submandibular tumors are benign while the other 50% are
malignant; most tumors of the sublingual glands are malignant.
• Though difficult to prove, generalizations about the pattern of malignancy within the
parotid gland ring true. The malignant gradient increases from anterior to posterior and from superficial to deep. The posterior mass is more likely to be malignant, as is the deep mass. The mass that causes facial nerve paralysis is likely malignant in nature.
• Masses of the submandibular gland and sublingual glands were more likely to be
malignant compared to parotid gland. Malignancy is also more common with increasing age .
• Histological diagnosis is necessary to treatment decisions. Histological diagnosis
may be by FNA. Table-3 summarizes imaging studies for evaluation.
Table 3. Initial evaluation for salivary gland with imaging studies
Gustavo Arruda Viani
134
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor ≤ 2 cm in greatest dimension without extraparenchymal extension (clinical or macroscopic
evidence of invasion of soft tissues; microscopic evidence alone does not constitute extraparenchymal extension for classification purposes)
T2
Tumor > 2 cm but not more than ≤ 4 cm in greatest dimension without extraparenchymal extension
T3
Tumor > 4 cm and/or tumor having extraparenchymal extension
T4a
Moderately advanced disease (tumor invades skin, mandible, ear canal, and/or facial nerve)
T4b
Very advanced disease (tumor invades skull base and/or pterygoid plates and/or encases carotid artery)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension
N2
Metastasis in a single or multiple ipsilateral lymph node or bilateral or contralateral lymph nodes N2a - metastasis in single ipsilateral lymph node > 3 cm but ≤ 6 cm in greatest dimension N2b - metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension N2c - metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension
N3
Metastasis in a lymph node, > 6 cm in greatest dimension
Distant metastasis (M)
M0 - no distant metastasis (no pathologic M0; use clinical M to complete stage group) M1 - distant metastasis
Figure 3. Normal anatomy on CT from major salivary gland.
References
Koyuncu M, Seşen T, Akan H, Ismailoglu AA, Tanyeri Y, Tekat A, Unal R, Incesu L.
Comparison of computed tomography and magnetic resonance imaging in the diagnosis
of parotid tumors. Otolaryngol Head Neck Surg. 2003;129(6):726. Kotecha S, Bhatia P, Rout PG. Diagnostic ultrasound in the head and neck region. Dent
Update. 2008;35(8):529.
7. Staging
The tumor node metastases (TNM) system of the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) have been used to stage hypopharyngeal cancers (table-4).
Table 4. TNM staging for laryngeal cancer
Salivary Gland Cancer
135
Reference
The American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for
this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer SBM, LLC.
8. Routes of Spread
• Salivary gland tumors can invade locally throughout the gland, compromising facial
nerve function if trunks of the nerve are invaded.
• Parotid tumours can spread via the intraparotid nodes to the subparotid nodes in the
retrostyloid space and thence to the retropharyngeal nodes, or directly to level II nodes.
• The risk of lymph node metastasis is related with T3 and T4 disease, involvement of
a pharyngeal site, and high-grade tumors.
• Adenoid cystic carcinomas particularly can invade nerve fibres spreading up the
facial nerve towards the stylomastoid foramen.
• Extraparotid extension can occur laterally into skin or medially into the
pterygopalatine fossa and lateral parapharyngeal space, resulting in trismus or invasion of the carotid sheath.
Reference
The American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for
this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer SBM, LLC.
9. Prognostic Factors
• One of the most important prognostic factors affecting treatment outcome is the
histologic grade or cellular differentiation of the tumor.
• Lymphatic spread, perineural spread, as well as tendency to local recurrence can be
predicted by histological subtype.
• Margin status is a significant prognostic factor for patients undergoing surgical
resection. Tumor margins >5 mm is associated with improved local control.
• Facial palsy is an important independent prognostic factor associated with local
control (65% regional control for complete facial nerve paralysis versus 91% for no or partial paralysis).
• Advanced age is also a significant prognostic factors associated with local control.
• Survival is directly influenced for advanced age, tumor size, lymph node posivity,
tumor grade and extraglandular extention.
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136
Study
Description
Garden et al. (1997):
Retrospective analysis of 166 patients with parotid gland malignancies treated with
surgery + RT.
On multivariate analysis, facial nerve sacrifice and pathologic cervical nodal disease
were associated with LF.
The actuarial 5-, 10-, and 15-year LC rates were 92, 90, and 90%, respectively.
Armstrong et al. (1990):
Matched-pair analysis of 92 patients treated with surgery vs. surgery and post-op RT. The addition of post-op RT improved outcome for patients with stage III/IV disease and
for patients with pathological + LN.
Terhaard et al. (2005):
Retrospective analysis of 538 patients treated for major salivary gland tumors. Post-op RT improved 10-year LC compared with surgery alone for patients with T3-4
tumors (18→84%), close (55→95%) and incomplete resection
(44→82%), bone invasion (54→86%), and PNI (60→88%).
Armstrong et al. (1992):
Retrospective review of 474 previously untreated patients with major salivary gland
cancers in an attempt to define indications for elective treatment of the neck.
Overall, clinically occult, pathologically + LN occurred in only 12% of patients. On
multivariate analysis, only primary tumor size and grade were significant risk factors.
Reference
Frankenthaler RA, Luna MA, Lee SS, et a. Prognostic variables in parotid gland cancer, Arch
Otolaryngol Head Neck Surg 117:1251-1256, 1991.
10. Treatment
• Major salivary gland tumors include several malignant histologies. The clinical
behavior and management of these tumors depends on both histology and tumor grade.
• Surgical resection is the first option treatment for patients with resectable tumors. A
tumorectomy is generally considered inadequate for these tumors. The extent of surgical resection of salivary gland tumors depends upon the histology and anatomic location of the tumor inside the organ (superficial or deep).
• Elective neck dissection of levels Ib-III is indicated for patients with lymph node
clinically negative, but with high-risk of local failure. High risk patients for local failure included: high-grade tumors, advanced age, T3 /T4 tumors, and facial nerve paulcy.
• A modified radical neck dissection (levels I – IV) should be indicated for patients
with clinically or radiographically apparent nodal metastases.
• Adjuvant radiotherapy is recommended for patients with high risk for local failure, or
for low grade tumors with perineural, vascular, and lymphatic invasion, lymph node involvement, extracapsular spread or positive margins. Patients considered as high risk for local failure but treated with no eletive neck dissection must be irradiated to improve the local control (table- 5).
• Definitive radiotherapy is incicated for patients medically inoperable or who have
unresectable disease.
Table 5. Clinical evidence for adjuvant radiotherapy in patients
with major salivary cancer
Salivary Gland Cancer
137
Study
Description
Mendenhall et al. (2004):
Retrospective analysis of 101 patients treated with RT for adenoid cystic carcinoma of
the head and neck.
Ten year LC was 43% for patients treated with RT alone compared to 91% for patients
treated with surgery and post-op RT.
On multivariate analysis, T stage and clinical nerve invasion influencedCSS.
References
Garden AS, El-Naggar AK, Morrison WH, et al. Postoperative radiotherapy for malignant
tumors of the parotid gland. Int J Radiat Oncol Biol Phys 1997; 37:79-85. Armstrong JG, Harrison LB, Spiro RH, et al. Malignant tumors of major salivary gland
origin. A matched-pair analysis of the role of combined surgery and postoperative
radiotherapy. Arch Otolaryngol Head Neck Surg 1990; 116:290-293. Terhaard CH, Lubsen H, Rasch CR, et al. The role of radiotherapy in the treatment of
malignant salivary gland tumors. Int J Radiat Oncol Biol Phys 2005;61:103-111. Armstrong JG, Harrison LB, Thaler HT, et al. The indications for elective treatment of the
neck in cancer of the major salivary glands. Cancer 1992; 69: 615-619. Mendenhall WM, Morris CG, Amdur RJ, et al. Radiotherapy alone or combined with surgery
for adenoid cystic carcinoma of the head and neck. Head Neck 2004;26:154-162.
11. Radiotherapy Technique
CT scanning should be used for planning ipsilateral beam arrangements to conform better to the PTV and avoid critical structures and mucosa. CT slices are obtained from the skull base to the arch of the aorta with slices of 3 or 5 mm thick. Patients should be immobilised lying supine with the neck slightly extended to move the orbits superiorly and reduce the chance of beams exiting through the eye. A thermoplastic shell with at least five fixation points should ideally be used even if the neck is not included in the treatment volume, as systematic and random errors will be smaller and CTV-PTV margins can be tighter (figure 4).
Figure 4. Thermoplastic mask for immbilisation during radiotherapy treatment.
Gustavo Arruda Viani
138
The planning CT (and MRI if performed) should be carefully evaluated to detect macroscopic residual disease or lymphadenopathy. Radiotherapy is usually indicated adjuvantly for patients with high risk features. No GTV is defined unless there is macroscopic residual disease. The CTV60 is contoured as the sites of possible microscopic disease. Particular attention is given to the deep excision margin which is likely to be close or involved if the facial nerve has been preserved. As a minimum, the medial extent of the CTV60 should be to the lateral surface of the internal jugular vein, but if the deep lobe of the parotid is thought to contain tumour, the parapharyngeal space should be included. The lateral extent of the CTV60 will be close to the surface of the skin. The position of the contralateral parotid on the planning CT can be a useful for guiding to the superior and inferior limits of the CTV60 (figure-5). The irregularity of PTV is treated better with conformal radiotherapy than conventional radiotherapy, but to reduce dose to organs at risk, an ipsilateral anterior and posterior oblique wedged beam arrangement can be planned conventionally. Care should be taken to avoid organs at risk, especially exit dose to the contralateral eye (figure-5).
Figure 5. Beam angles and isodose lines distribution in patients submmited to conformal radiotherapy due to major gland tumor.
Figure 6. Isodose lines from IMRT planning for major salivary tumor (a) CTV 60, (b) Isodose of 30 Gy white arrow, (c) coronal and (d) sagital view.
Salivary Gland Cancer
139
IMRT planning studies have showed a reduced dose to the cochlea. An equispaced seven to nine-beam coplanar technique has been described, but this risks increasing dose to the contralateral parotid. An ipsilateral four-beam IMRT planning solution has also been used but may not be better than a 3D-conformal beam arrangement (figure-6).
For adjuvant treatment in patients with negative margins a dose between 60–64 Gy at
1.8–2 Gy/fraction is generally recommended. For patients with positive margins dose 66 Gy at 1.8–2 Gy/fraction are used. For the cases treated by radiotherapy alone a dose of 70 at 1.8– 2 Gy/fraction is suggested. For the elective treatment of the neck doses of 50–54 Gy at 1.8–2 Gy/fx are used.
References
Eisbruch A, Ten Haken R, Kim H, et al. Dose, volume, and function relationships in parotid
salivary glands following conformal and intensity-modulated irradiation of head and neck
cancer. Int J Radiat Oncol Biol Phys 1999;45:577-587. Chao K, Deasy J, Markman J, et al. A prospective study of salivary function sparing in
patients with head-and-neck cancers receiving intensity-modulated or three-dimensional
radiation therapy: initial results. Int J Radiat Oncol Biol Phys 2001;49:907-916.
Conclusion
• Salivary malignancies are rare and make up 6% of all head and neck cancers.
• Several studies have shown tumor size, pathologic N stage, tumor grade (high versus
not high), use of adjuvant radiotherapy, bone invasion, and close or positive margins are significant prognostic factors for local control.
• Surgery has a pivotal role for the diagnosis and treatment of major salivary tumors.
Radiotherapy has also an important role in preventing locoregional recurrences in high-risk patients.