Salivary Gland Tumours

Presenter: Dr Mpho Sandamela Commentary : Dr Vukasinovic Moderator: Prof Mieny 14 February 2012

Epidemiology
Salivary gland neoplasm are rare
3-5% of all H+N tumours in US 0.5% of all cancers in the US( NCDR) Mean age at time dx = 60yrs Majority of tumours arise in the parotid gland 80% benign and 20% malignant Submandibular gland = 10% malignancy Minor salivary gland tumours 80% malignant and 20 % benign

Etiology
Environmental(alcohol and smoking) Viral(EBV,HIV,HPV16 and 18) Genetic Radiation Nuclear plant exposure Ultraviolet light Dietary High intake of polyunsaturated fats Silica dust Hormonal Early menarche Multiparity

Etiology
Oncogenes mutations and the overexpression of growth factors or growth factor-binding receptors are important in the genesis of salivary gland tumours
Epidermal growth factor receptor(EGFR or ErbB) Vascular endothelial growth factor(VEGF) c-Kit p53

Presentation
Asymptomatic swelling
Episodic swelling - duct obstruction

Pain more common in malignancy but it is not diagnostic Duration hx tends to be shorter in malignancy but also can be misleading as malignancy can present with long hx of asx swelling

Presentation
Malignancy maybe fixed to underlying structures or skin Facial nerve palsy Dysarthria lingual and hypoglossal n. involvement Ill fitting dentures Trismus

Presentation
Nodal involvement in association with salivary gland tumour is almost always malignant Direct extension into adjacent LN v/s actual lymphatic metastasis Less than 20%(parotid) mets to cervical LN The 10-year survival decreases from 63% 33% when patient has positive neck LN

Classification of Parotid Tumours

Benign Pleomorphic adenoma Warthins tumour Oncocytoma Granulomatous disease Monomorphic adenoma
Sebaceous adenoma Basal cell adenoma Myoepithelioma

HIV associated lympho-epithelial cysts

Classification of Parotid Tumours

Malignant Mucoepidermoid tumour(Low & high grade) Acinic cell tumour Adenoid cystic carcinoma Carcinoma ex-pleomorphic adenoma Adenocarcinoma(Low & high grade) Squamous cell carcinoma

AJCC STAGING OF SALIVARY GLAND TUMOURS

Primary Tumour (T) Tx primary cannot be assessed T0 no evidence of primary T1 tumour 2cm T2 tumour 2-4cm T3 tumour 4-6cm T4 tumour > 6cm Any T category can be sub-divided into : A no local extension B local extension including clinical involvement of skin or invasion of soft tissue, bone or nerves. Lymph Nodes (N) Nx nodal status cannot be assessed N0 no evidence of lymph node involvement N1 single ipsilateral lymph node < 3cm N2A single ipsilateral node 3-6cm N2B multiple ipsilateral nodes < 6cm N2C bilateral / contralateral nodes < 6cm N3 node > 6cm Distant Metastasis (M) Mx unable to asses presence of distant metastases M0 no evidence of distant metastases M1 distant metastases including lymph nodes outside the defined regional nodes

Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 or T1-3 N1 M0 Stage IV T4 N0 -1 M0 or any T any N/M1

Differential Diagnosis
Unilateral parotidomegaly
hypertrophy of the masseter muscle dental or brachial cysts neuroma of the facial nerve temporal artery aneurysm sebaceous cysts lymphadenopathy

Differential Diagnosis
Bilateral parotidomegaly
Drugs(OCP or thiouracil) endocrine disease (Diabetes, Cushings, Myxoedema) bulimia alcoholism cirrhosis

Diagnosis and Workup Imaging

US- ideal for initial assessment, shown to assist the diagnosis accuracy of FNA but poor for deep lobe evaluation Sialography is the gold standard for evaluating the duct system MRI-Sialography is an alternative for evaluating the ducts

Imaging
Benefit of pre-op imaging is proportional to the stage of disease Early cancer may not need imaging while Advanced cancer, both CT and MRI may be needed and compliment each other

Imaging
Indications for anatomical imaging
Clinical uncertainty of tumour extent Evaluation of deep lobe/extraglandular involvement Identification of potential cervical LN mets

Indications for functional imaging

Distant mets Previously treated necks

Imaging
o CT-Scan
o Modality of choice for suspected inflammatory disorders o can r/o salivary duct stone o demonstrate cortical bone involvement o define areas of necrosis in highly vascular tumours o Less expansive and widely available

Imaging
o MRI
o Modality of choice for palpable lesion/suspected cancer o Greater soft tissue detail/extraglandular pathology o Perineural spread and parotid portion of facial n. o Demonstrate medullary bone involvement o Intracranial extension of disease

Imaging
PET Scan
Very sensitive for metastatic LN < 8mm Helpful for previously treated H + N cancers

PET/CT Scan
Has increased value in salivary gland tumour staging Pittsburgh study(55pts) showed
sensitivity of 74.4% Specificity of 100%

Angiography or MRI-Angio
Can be used to assess carotid artery involvement

Biopsy
Fine-needle aspiration biopsy(FNAB) Is used as a screening test to differentiate inflammatory cells from atypical cells It is 85-95% sensitive, with a (+) predictive value of 84% and (-) predictive value of 77% Helps differentiate tumours of salivary gland origin from systemic or mets eg Lymphoma

FNAB
There is minimal risk of seeding Ultrasound guided FNAB has been found to be highly specific for malignancy with good sensitivity

FNAB
FNAB- Short falls It cannot differentiate pleomorphic adenoma from adenoid cystic carcinoma Pathologist dependent more accurate results from experienced pathologist Reporting benign ,malignant, indeterminate, or inadequate

Biopsy
Excisional Biopsy still an acceptable method for obtaining diagnosis
Superficial parotidectomy submandibular gland resection

Tru-cut biopsy not recommended

High risk of seeding Collateral damage

Treatment
Surgical primary therapeutic modality for benign and malignant tumours
Small tumours / located in superficial lobe
= Superficial parotidectomy

Deep-lobe tumours and those affecting both lobes

= Total parotidectomy

Surgical Treatment
Advanced high-grade parotid tumours = wide surgical margin excision with total conservative parotidectomy and modified radical neck dissection Preserve the facial nerve if not infiltrated Reconstructive surgery has made wider resections possible but survival results remain poor

Surgical Treatment
Submandibular gland
Benign inflammatory conditions = subcapsular enucleation of the gland Malignant/unclear tumours = more comprehensive procedure

Nerves at risk = marginal mandibular branch, lingual and hypoglossal nerve

Management of the Neck

Node positive neck Patients with ipsilateral + LN : ipsilateral radical neck dissection + contralateral neck nodes present as well, then a contralateral modified radical neck dissection is performed
(The contralateral internal jugular vein is then preserved to prevent venous congestion of the head)

Management of the Neck

Node negative neck Management is still controversial Some authors recommend resection of the nodes for high risk tumours (Undifferentiated mucoepidermoid carcinoma, SCC, adenocarcinoma and salivary duct carcinoma) T3 and T4 tumours Preop facial n. paralysis patient age over 54 years extraparotid extension of tumour and perilymphatic invasion

Radiotherapy
Postoperative adjuvant radiotx = great value in controlling loco-regional disease and improving survival Indications
high grade malignancy/unfavorable histology advanced clinical stage with facial n. involvement + margins of resection Recurrent disease + neck nodes following dissection Tumour spillage during surgery

radiotherapy
Most intensity-modulated radiation therapy (IMRT) has been delivered via linear accelerator, 3D conformal radiotherapy = better plans for targeted treatment area
High dose can be used, more effective Less collateral damage Reduced incidence and severity of xerostomia

Radiotherapy
Palliative radiotx = unresectable tumours
P-rad produced local control in 33% of cases High dose irradiation (fast neutron radiation) has improved local control to 60% v/s 25% for photon, but neuron radiation is being discontinued due to late normal cells toxicity

RadioTX
Benign tumours
used for treatment of recurrent benign mixed tumours especially when the recurrence is multifocal, or when further surgery poses a risk to the facial nerve there is however a risk of converting a benign lesion to an open wound

Chemotherapy
Role is limited to treatment of metastatic disease and palliation of loco-regional disease not amenable to salvage surgery or radiation therapy Cisplatin : most studied single agent
A study of 25 pts = 18 % showed response to locoregional disease and 7% response rate in metastatic disease with mean survival 14 months

Chemotherapy
Combination of chemo agents showed higher response rate but was not superior to singleagent with regards to survival Studies are underway comparing radiation plus concurrent cisplatin v/s radiation therapy alone in high-risk patients after surgical resection Chemo plus molecular targeted therapy currently being investigated

Hormonal receptors
Estrogen-receptor positivity is not frequent in salivary glands but a response to tamoxifen has been reported Androgen receptors have been described and response to anti-androgen therapy by AR (+) adenoca have also been reported

Molecular Targeted Therapy

A major breakthrough in determination of the molecular abnormalities underlying the different subtypes of salivary gland cancers Might lead to more active and specific targeted therapies
- Epidermal growth factor receptor(EGFR or ErbB) - Vascular endothelial growth factor(VEGF) - c-Kit

Molecular Targeted Therapy

Kit-pathway :
C-Kit proto-oncogene Common in 80% of adenoid cystic carcinoma Genetic mutations seen in GIST and germ cell tumours are not the same

Kit-pathway
Imatinib: (tyrosine kinase inhibitor)
15 pt= no objective response 9 pt = stable disease 6 pt = progressive disease

Study (-) probably due to lack of kit genetic alteration/mutations as seen in GIST Had significant toxicity However, combination with chemo agents shows promise

EGFR/ErbB2(HER2) pathway
Signal transduction pathways that regulate :
Cell cycle Inhibition of apoptosis Angiogenesis Tumour cell motility Invasion and metastasis behavior

HER2 rare in ACC, common in salivary duct cancers EGFR inhibitors have shown efficacy in non-small cell lung cancer and colo-rectal cancer In certain tumors = predictors of poor clinical outcome

EGFR/ErbB2 pathway
Transtuzumab : a recombinant monoclonal antibody direct against ErbB2
It enhanced response rate to cytotoxic agents in ErbB2-positive breast ca and in incurable salivary gland cancer Response rate average 45%

Gefitinib : orally active ErbB1- inhibitor ,was associated with a 53% stable disease rate in ACC, which was maintained for > 16weeks

EGFR/ErbB2 pathway
Cetuximab : a human-immune chimeric monoclonal antibody to ErbB1 also had about 50% response rate Lapatinib : reversibly inhibits ErbB1 + 2, is well tolerated, with tumor stabilization in 64% of pt New study: evaluating anti-tumour activity of a dual EGRF + HER2 inhibitor in recurrent and/or metastatic adenoid cystic cancer and other salivary gland cancers is underway

VEGF and p53

VEGF : angio-genetic and vascular permeability factor responsible for tumour associated microvascular angiogenesis + hyperpermeability p53 gene : a tumour suppressor gene
Arrests cell proliferation and induces apoptosis Mutations leads to tumour growth

Mutated p53 is potent stimulant of VEGF

VEGF
Surgical specimen from 45 pt with salivary gland cancer had VEGF and p53 expression Is used as a prognostic indicator along with age, LN mets, vascular invasion There is growing need of clinical studies with anti-angiogenic agents

References
1. 2. 3. 4. 4. 5. Ries LAG, Eisner MP, Kosary CL, et al. Edwards Bk, editor. SEER cancer statistics review. Bethesda (MD): National Cancer Institute; 19752002. DeVita jr VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology.Philadelphia: Lippincort Williams & Wilkins;2005., p. 662-732 Brandwein MS, Ferlito A, Bradley PJ, Hille JJ, Rinaldo A. Diagnosis and classification of salivary neoplasms: pathologic challenges and relevance to clinical outcome. Acta Otolaryngol 2002;122(7): 758-64 Silverman S. Demographics and occurrence of oral and pharyngeal cancers. The outcomes, the trends, the challenge. J Am Dent Assoc 2001;132(Suppl):7S11S. Frable MS, Frable WJ.Fine needle aspiration biopsy of salivary glands. Laryngoscope 1991;101:245-9 Bartels S, Talbot J, Ditomasso J,et al. The relative value of fine needle aspiration and imaging in the preoperative evaluation of parotid masses. Head Neck 2000;22(8):781-6

references
Lee YY et al. Imaging of salivary gland tumours. Euro J Radial(2008):66;419-436 Jeannon JP. Management of advanced parotid cancer. Eur J Surg Oncol(2009):35;908-915 Milano A et al. Recent advances in the treatment of salivary gland cancers. Oral oncology(2007):43;729-734 Agulnik M et al. An update on the systemic therapy of malignant salivary gland cancers: role of chemotherapy and molecular targeted agents. Curr.Med.Chem. Anti-Cancer Agents;2004,4,533551 Adams EJ et al. A comparison between cobalt and linear accelerator-based treatment plans for conformal and intensitymodulated radiotherapy. Br J Radiol.2008 Apr;81(964):304-10