Oncology

Salivary Gland Cancers

Salivary Cancer

What every physician needs to know:

Salivary cancers are diverse in presentation, pathology, natural history and probably causation. Most often, patients are evaluated and managed by an otolaryngologist (ENT) physician or HN cancer surgeon, but in recent years there has been increasing multidisciplinary care.

Salivary gland neoplasms, particularly in the major glands, parotid, submandibular and sublingual, are frequently benign, greater than 50%, e.g. parotid pleomorphic adenomas. Warthins tumors are second in frequency with mucoepidermoid the most common carcinoma.

Of note, tumors of minor salivary glands distributed throughout the upper aerodigestive tract will more often be malignant in origin - adenoid cystic carcinoma (ACC) is the most common. Overall survival relates to tumor stage and histology.

Are you sure your patient has salivary gland cancer? What should you expect to find?

Most patients present with a mass in the head and neck area, which may be appreciated as a fullness, asymptomatic, and slowly progressive over a period of months. One classic sign of malignant transformation is the long-standing slow-growing lesion that undergoes a rapid growth phase over a period of weeks to months. The initial pattern of tumor spread tends to be local invasion, with eventual tumor fixation to adjacent normal tissues and skin infiltration.

Parotid cancers may infiltrate the 7th cranial nerve, and ACC has a tendency to develop "skip" nerve lesions which may culminate in cranial nerve or skull base involvement. These ominous clinical findings, however, are typically seen in the advanced stages of disease. Tongue tumors, or those obstructing trachea or a bronchus may lead to early symptoms. Distant metastases at presentation are unusual.

Beware of other conditions that can mimic salivary gland cancer:

The usual clinical presentation of a salivary gland tumor is a progressive head and neck region mass, with quite variable pace from one patient to another, and clinical signs associated with tumor location and size.

  • Major salivary gland tumors, of the parotid and submandibular glands are often benign adenomas.

  • This is in contrast to minor salivary gland neoplasms which may arise virtually anywhere in the upper aero-digestive tract - ACC the most common.

A history of a cutaneous malignancy, such as melanoma or squamous cell carcinoma, should be sought, as the peri-glandular and intra-grandular nodes are common sites of metastases. Treatment options will vary should the parotid mass be a metastasis.

Appreciation of an enlarging mass typically prompts:

  • ENT consultation.

  • Physical examination.

  • CT imaging.

  • Consideration of fine needle aspiration (FNA) or biopsy. The latter is more reliable for salivary gland tumors to differentiate benign from malignant, and for pathologic classification.

Metabolic derangements are not associated and distant metastases uncommon at the initial diagnosis.

Clinical findings depend on tumor site, stage and histology. For instance:

  • Infiltrating parotid tumors may result in a peripheral 7th cranial nerve deficit. Patients who present with a Bell's palsy, should be cautiously examined to rule out a parotid malignancy.

  • Ductal and mucoepidermoid carcinomas often disseminate to regional cervical lymph nodes, while ACC is much less likely to involve regional nodes despite high risk of bone and lung metastases.

A complete head and neck examination, including flexible fiberoptic examination of the nasopharynx, oropharynx and larynx, should be performed. With nasopharygeal primary tumors or infiltrating skull base disease, MRI is a favored imaging technique over CT.

A systematic clinical examination, a routine laboratory panel, urinanalysis, imaging (including chest x-ray), and biopsy will rule out metastatic cancer masquerading as a primary salivary malignancy. Be alert to the potential for a breast ductal cancer to metastasize to the parotid region. Medial supraclavicular adenopathy may herald a lung primary cancer, and a chest CT scan may be appropriate in these cases. Clinical symptomatology or signs of other sites of disease involvement should prompt further investigation.

Which individuals are most at risk for developing salivary gland cancer:

Salivary gland tumors make up about 5% of all head and neck neoplasms, and causation is largely unknown. There has been an association of these tumors with radiation exposure in Japan, after therapeutic head and neck radiotherapy, and in children treated with whole brain radiotherapy for acute lymphocytic leukemia.

There is no clear association with viruses or hormonal exposures. Workers in rubber manufacturing, metal industries, woodworking and hair-dressing may have added risk.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

After establishment of the clinical and laboratory data base, outlined above, there should be multidisciplinary discussion of the findings with particular attention to site, stage, and pathology. Only then can treatment planning be optimal. Ultrasound can be combined with FNA and also to detect the presence of adenopathy.

With respect to imaging, we favor CT for evaluation of the soft tissues of the head and neck, parotid glands, oropharynx, oral cavity and the neck. However, MR may be more telling for malignancies of the nasopharynx and skull base - and at times the techniques may be complimentary. If there is concern for perineural spread, MRI can define the extent of facial nerve invasion, which may track into the temporal bone.

The value of chest CT or PET CT will depend on the perceived risk of metastatic involvement. For patients with well differentiated salivary malignancies (e.g. mucoepidermoid or myoepithelial carcinomas), systemic imaging will have a low yield. In contrast, poorly differentiated mucoepidermoid and ductal carcinomas or high-grade adenoid cystic carcinoma are much more likely to disseminate widely. Thus, baseline chest CT may be indicated in these settings.

The value of PET CT is under investigation. While this is generally a useful study to evaluate the chest, abdomen, and bones, often ACC is not highly FDG-avid. Furthermore, lung expansion providing more parenchymal detail may be better with contrast-enhanced CT.

Staging

Table I. TNM staging for salivary gland cancers.

Table I.

What therapies should you initiate immediately i.e., emergently?

Emergency therapy is uncommon in management of patients with salivary cancers, as severe hyponatremia or hypercalcemia and other metabolic derangements are rare. However, an occasional patient may present with an obstructing airway tumor involving the larynx, trachea or bronchus, which may require the placement of a surgical airway. In this setting, a decision regarding possible surgical resection or radiotherapy (+/-chemotherapy) will depend upon the pathologic diagnosis and extent of disease. Multidisciplinary evaluation is crucial in such cases.

What should the initial definitive therapy for the cancer be?

Following the diagnosis and staging evaluation as outlined above, medically sound patients can be separated into 3 groups:

  • Disease localized and resectable.

  • Patients with disease presentation in a site such as the nasopharynx, reducing prospects for a complete surgical resection.

  • Advanced disease not amenable to effective local therapy or with distant metastases.

Localized, resectable disease

Surgery

Surgery is the core of management for benign and malignant salivary cancers.

Surgical resection should be delivered by an experienced head and neck surgeon, as the pre-operative and intra-operative decision-making has profound implications for function, outcomes and the need for adjuvant therapies. For example, intra-operative management of the facial nerve and lymph nodes necessitates appropriate pre-operative counseling and evaluation. Further, the availability of a reconstructive surgeon should be anticipated. The role of frozen sections for salivary gland cancers is also an area of controversy.

Radiation therapy

Indications for post-operative radiation therapy include:

  • High-grade malignancies, particularly if resection margins are narrow or involved.

  • Perineural spread.

  • Nodal metastasis.

  • All adenoid cystic carcinomas.

When post-operative radiation therapy is indicated and depending on the margin status, the radiation dose is 60-64 Gy with intensity modulated radiation therapy (IMRT) to the post-operative tumor bed. The draining lymphatics in the neck are treated to a microscopic dose of 50-60 Gy depending on the nature of disease. It is important to identify and treat the nerve of involvement to the base of the skull.

Chemotherapy

As a generalization, routine adjuvant chemotherapy after definitive surgical resection followed (or not) by radiotherapy is not recommended.

Unresectable disease

For patients with disease considered unresectable, radiotherapy is the secondary treatment of choice. Radiation therapy is typically delivered to a dose of 66-70 IMRT over a course of 6 to 7 weeks. There has been an early experience with use of concomitant chemotherapy as a sensitizing mechanism to increase efficacy, but this should most often be recommended on a clinical trial. Commonly used regimens include:

  • Weekly cisplatin (30mg/m2/wk).

  • Weekly paclitaxel (40mg/m2/wk) and carboplatin (AUC 1.5).

Advanced disease

For patients with advanced disease, therapeutic goals are palliative. Local tumor control in the primary region is usually necessary for overall symptom control and to avoid progressive cranial neuropathies. Palliative surgery or radiotherapy, or both, should be discussed. It may be best initially to address local treatment for the primary tumor and draining cervical nodes, while observing the pace of systemic disease - much variability can occur.

As previously indicated, systemic therapy is most strongly indicated in patients with symptomatic or clearly and rapidly progressive disease. This is especially true for patients with ACC, for whom chemotherapy has only modest activity.

Adenocystic carcinoma

Commonly used regimens, which yield partial tumor responses in 20-30% of patients, include:

  • Cisplatin 75mg/m2 IV day 1 plus vinorelbine 25mg/m2 IV days 1 and 8 every 21 days.

  • Cisplatin 75-100mg/m2 IV followed by fluorouracil 1000mg/m2/day IV continuous infusion days 1-4 every 21 days.

  • Cyclophosphamide 500mg/m2 IV day 1, doxoburibin (Adriamycin) 50mg/m2 IV day 1, cisplatin 50mg/m2 IV day 1 every 21 days (CAP).

Oral tyrosine kinase inhibitors, such as gefitinib, erlotinib, and lapatinib are under study.

High-grade ductal carcinomas

Commonly used regimens include:

  • Cyclophosphamide 500mg/m2 IV day 1, doxorubicin (Adriamycin) 50mg/m2 IV day 1, cisplatin 50mg/m2 IV day 1 every 21 days (CAP).

  • Platinum-taxane combinations (e.g. cisplatin 75mg/m2 IV and docetaxel 75mg/m2 IC day 1 every 21 days OR carboplatin AUC 5 and docetaxel 75mg/m2 day 1 every 21 days).

If human epidermal growth factor receptor 2 (HER2) is highly expressed or amplified, entry to a study with chemotherapy and trastuzumab may be desirable.

Poorly differentiated and high-grade mucoepidermoid cancers

These tumors may be very responsive to regimens which are active in squamous cancers of the head and neck, including:

  • Cisplatin 75-100mg/m2 IV day 1 followed by fluorouracil 1,000mg/m2/day IV continuous infusion days 1-4 every 21 days.

  • Carboplatin AUC 5 day 1 followed by fluorouracil 1,000mg/m2/day IV continuous infusion days 1-4 every 21 days.

  • Platinum-taxane combinations (e.g. cisplatin 75mg/m2 IV plus docetaxel 75mg/m2 IV day 1 every 21 days OR carboplatin AUC 5 and docetaxel 75mg/m2 day 1 every 21 days).

  • Methotrexate 40mg/m2 IV weekly.

The value of multidrug regimens and the addition of molecular targeted therapies such as cetuximab are to be determined.

What should you tell the patient and the family about prognosis?

Salivary cancers are diverse in origin, stage, pathology and expected natural behavior - so unlike "one size fits all" it is important to speak with the patient and family in a warm but direct manner, indicating the type of cancer, the extent of disease and how best to approach therapy. For many patients, surgical resection can be expected to be curative. Nevertheless, all patients will require systematic follow-up.

We typically will propose that patients with favorable prognosis are followed every 3 months for 2 years then less frequently. The precise schedule will vary dependent upon the site and surgical pathologic findings.

One may discuss with patients the implications of adverse histological features to provide an overall sense of whether they have a "high-risk" or a "low-risk" tumor, which can prepare the patient for issues surrounding adjuvant therapies and surveillance.

For patients with recurrent disease not amenable to curative salvage therapy or widespread metastases, the need for immediate systemic therapy may vary widely. Given the clinical heterogeneity of these diseases, life span predictions should be made with caution.

What if scenarios.

One potential pitfall is that some widely metastatic salivary tumors, such as ACC or myoepithelial cancer, may have an indolent clinical course. Treating such patients with conventional chemotherapy may risk substantial toxicity with only a modest prospect of clinical benefit. This is particularly the case with ACC metastatic to lung, which is at times a very slow-growing malignancy. This allows for an observation period over 2-3 months, sometimes longer, before a decision to commence systemic therapy, whether platinum-based chemotherapy or an experimental molecular targeted program.

On the contrary, if there is rapid progression of disease with lung and bone involvement, and clearly objective changes over a brief period, then palliative therapy should be considered.

For symptomatic or potentially compromising osseous sites, such as spinal metastases, consideration should be given to palliative radiotherapy.

Follow-up surveillance and therapy/management of recurrences.

Systematic follow-up is indicated, but with scheduling that must be individualized according to the patient's general medical condition, tumor type, staging and initial therapy.

As a generalization, follow-up will be:

  • History and physical every 3 months over 2 years for salivary cancer patients with disease in remission after primary therapy.

  • Head and neck CT imaging will be obtained at 6 month intervals in the asymptomatic patient.

  • Bone and lung are the most common sites of distant disease recurrence, and imaging is considered dependent upon the initial tumor histology and staging data, and clinical findings.

For patients with locally recurrent disease, consideration of salvage surgery (or possibly re-irradiation) will be dependent upon:

  • site

  • histology

  • extent of prior therapy

  • interval since initial presentation

  • absence of threatening metastatic disease

  • patient's general medical condition.

Chemotherapy may be an option as outlined above.

Pathophysiology

While chemotherapy with platinum-based regimens represents the most common therapeutic approach to advanced disease, biological targets have been increasingly identified. This has led to ongoing trials with individualized therapy. Estrogen receptors (alpha/beta) have been described in greater than 50% of ductal carcinomas.

The epidermal growth factor receptor (EGFR) is routinely expressed but activating mutations are not seen. HER 2 expression and androgen receptors are identified in 50 to 95% of cases. In ACC, C-KIT expression is increased in up to 90% of cases, but driving mutations are not seen.

To date, trials with hormonal therapy, trastuzumab, cetuximab, and oral tyrosine kinase inhibitors have demonstrated only modest activity and entry to ongoing clinical trials is recommended.

What other clinical manifestations may help me to diagnose salivary gland cancer?

The most important clinical consideration to a prompt and early diagnosis is a thorough history and physical examination, with attention to complaints referable to the head and neck region. Asking patients directly about any appreciable facial lesion, nodules, mass or discomfort may give direction to the physical examination.

It is important to be systematic in examining the scalp, face, neck, and oral cavity. One should also check for cranial nerve function and palpate the submentum, parotid areas and neck. Oral and oropharynx examination should include not only inspection with adequate lighting but also palpation of the tongue and floor of mouth.

Any evidence of hoarseness or stridor should be further investigated, possibly with help from an ENT physician. Any patient with "Bells Palsy" warrants a thorough evaluation of the parotid region and possibly an imaging study. Long standing parotid masses also warrant evaluation by an otolaryngologist.

What's the evidence?

Risk Factors/Etiology

Belsky, JL, Tachikawa, K, Cihak, RW. "Salivary gland tumors in atomic bomb survivors, Hiroshima-Nagasaki, 1957-1970". JAMA. vol. 219. 1972. pp. 864-8.

Saku, T, Hayashi, Y, Takahara, O. "Salivary gland tumors among atomic bomb survivors, 1950-1987". Cancer. vol. 79. 1997. pp. 1465-75.

Modan, B, Chetrit, A, Alfandary, E. "Increased risk of salivary gland tumors after low-dose irradiation". Laryngoscope. vol. 108. 1998. pp. 1095-7.

Edge, SB, Byrd, DR, Compton, CC. AJCC Cancer Staging Manual (ed 7). Springer SBM, LLC. 2009.

Management

Locati, LD, Guzzo, M, Olmi, P. "Management of Salivary Cancer". Head and Neck Cancer: Multimodality Management. Springer Science-Business Media, LLC. 2011. pp. 521-33.

Garden, AS, El-Naggar, AK, Morrrison, WH. "Postoperative radiotherapy for malignant tumors of the parotid gland". Int J Radiat Oncol Biol Phys. vol. 37. 1997. pp. 79-85.

Samant, S, van den Berkel Kies, M. "Concurrent Chemoradiation for Adenoid Cystic Carcinoma of the Head and Neck". Head Neck. vol. 34. 2012. pp. 1263-8.

Haddad, RI, Posner, MRPM, Norris, CM. "Chemoradiotherapy for adenoid cystic carcinoma: preliminary results of an organ sparing approach". Am J Clin Oncol. vol. 29. 2006. pp. 153-7.

Laurie, SA, Ho, AL, Fury, MG. "Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review". Lancet Oncol. vol. 12. 2011. pp. 815-824.

Glisson, BS, Blumenschein, G, Francisco, M. "Phase II trial of gefitinib in patients with incurable salivary gland cancer". ASCO Annual Meeting Proceedings. vol. 23. 2005. pp. 508s.

Agulnik, M, Cohen, EW, Cohen, RB. "Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erb B2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of salivary glands". J Clin Oncol.. vol. 25. 2007. pp. 3978-84.

Prognosis

McHugh, CH, Roberts, DB, El-Naggar, AKH. "Prognostic factors in mucoepidermoid carcinoma of the salivary glands". Cancer. vol. 118. 2011. pp. 3928-36.

Bhayani, MK, Yener, M, El-Naggar, A. "Prognosis and risk factors for early-stage adenoid cystic carcinoma of the major salivary glands". Cancer. vol. 118. 2011. pp. 2872-8.

Williams, MD, Roberts, D, Blumenschein, GR. "Differential expression of hormonal and growth factor receptors in salivary duct carcinomas: biologic significance and potential role in therapeutic stratification of patients". Am J Surg Pathol. vol. 31. 2007. pp. 1645-52.

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