Management of salivary gland tumors

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Tumors of the salivary glands are relatively rare, representing 2.5–3.0 per 100,000 of all tumors per year and 2–6.5% of all head and neck tumors.
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Management of salivary gland tumors Expert Rev. Anticancer Ther. 12(9), 1161–1168 (2012)

Guy Andry1*, Marc Hamoir2, Laura D Locati3, Lisa Licitra3 and Johannes A Langendijk4 Department of Surgery, Jules Bordet Institute, ULB, 1 Rue Héger-Bordet, 1000 Brussels, Belgium 2 Head and Neck Surgery Department, Catholic University of Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium 3 Head and Neck Cancer Unit, Medical Oncology Department, IRCCS Istituto Nazionale dei Tumori, 1 Via Venezian, 20133 Milano, Italy 4 Dept of Radiation Oncology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands *Author for correspondence: Tel.: +32 254 131 61 Fax: +32 254 131 41 [email protected] 1

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Surgery after proper imaging (MRI or CT scan) is the main stay of treatment for salivary gland tumors. Although excision margins should be ≥5 mm for malignant tumors in cases of parotid gland carcinoma, the facial nerve should be preserved whenever it is not infiltrated. Adjuvant external radiation is indicated for malignant tumors with high-risk features such as close (or invaded) margins, perineural speed, lymphatic and/or vascular invasion, lymph-node involvement and high-grade histology. A Phase II trial testing adjuvant concomitant cisplatin plus radiation therapy versus adjuvant radiation therapy alone after surgery is currently under investigation for high-risk salivary gland cancer. For inoperable cancers, photons combined with proton boost seem to be a valuable option. Even if protons or carbon ions are promising, access to the latter is limited for usual treatment. For recurrent and/or metastatic cancer, polychemotherapy (cisplatin based) gives a 25% response rate in adenoid cystic carcinoma and should be used when the disease is overtly in progression. Targeted therapies with anti-EGF receptor molecules, antiangiogenic agents and tyrosine kinase inhibitors are ongoing, but more trials are needed to establish their efficacy, as is the use of bortezomib followed by doxorubicin. The products of fusion oncogenes, which have a pathogenic role in some adenoid cystic carcinoma and mucoepidermoid carcinomas, are of interest as potential therapeutic targets. Keywords: adenocarcinoma • adenoid cystic • chemotherapy • mucoepidermoid • pleomorphic adenoma  • radiation therapy • salivary gland tumors • surgery • targeted molecular therapy

Tumors of the salivary glands are relatively rare, representing 2.5–3.0 per 100,000 of all tumors per year and 2–6.5% of all head and neck tumors. They comprise a group of more than 35 morphologically different neoplasms with various natural courses requiring specific treatment approaches depending on the pathology [1,2] . In this regard, review by an experienced pathologist is a necessary step in each individual case to accurately define the histological subtype. A misdiagnosed malignant adenocarcinoma incorrectly diagnosed as benign mixed tumor may occur, leading to recurrence, which can become a a life-threatening situation. Salivary neoplasms are typically divided into two groups: those arising in the major salivary glands (parotid, submandibular and sublingual gland) and those arising in the minor salivary glands lining the oral cavity, the pharynx, the larynx, the nasal cavity and the paranasal sinuses. Primary cancers arising in major salivary glands are staged according to the TNM classification, whereas minor salivary carcinoma are staged according to their anatomic site of 10.1586/ERA.12.92

origin (as described above: lip, buccal mucosa, and so on) [3] . Recently, Boukheris et al. reported on the incidence of carcinoma of the major salivary glands derived from a population-based study in the USA according to the WHO classification: all ages considered, squamous cell (IR: 3.44) and mucoepidermoid carcinomas (IR: 3.23) predominated among males, whereas up to the age of 50 years, mucoepidermoid (IR: 2.67), acinic cell (IR: 1.57) and adenoid cystic (IR: 1.40) carcinomas were most common among females; thereafter, acinic cell and adenoid cystic carcinomas (ACCs) were equal among both genders, mucoepidermoid carcinoma being in excess among males (IR: 1.57) [4] . In children, neoplasms of salivary origin are even rarer than in adults. Although most of the salivary tumors in childhood are tumorlike lesions, young patients with progressively enlarging lumps in the area of a salivary gland should be investigated in order to establish a final diagnosis, that is, to exclude malignancy. The difficulty in achieving a proper diagnosis by clinical and radiological parameters implies

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that surgical removal should be performed with adequate margins. This was emphasized by a recent retrospective series reported by Muenscher et al., who stated that mucosal cysts, adenomas and sialadenitis represented 71% of the operated children younger than 14 years. In the remaining patients, 22.5% were carcinomas (in particular, epithelial–myoepithelial, salivary duct and mucoepidermoid carcinomas), while metastases and lymphomas represented 4 and 1.5% of the total series, respectively [5] . Parotid tumors

The acinar, ductal and myoepithelial cells that comprise the parotid tissue can give rise to a wide variety of benign and malignant neoplasms [2] . Except in a minority of patients with suspicious symptoms of malignancy such as facial palsy (partial vs complete), pain or invasion of adjacent structures (skin, muscle and/or bone), benign and malignant parotid neoplasms present initially in a similar way, that is, a painless swelling in the gland frequently located beyond the angle of the mandible. Fine needle aspiration biopsy with or without the guidance of ultrasonography will provide a cytologic diagnosis with a reasonable accuracy (81–98%) depending on the experience of the pathologist, but the falsenegative rate may be as high as 10% [2] . This emphasizes the prominent role of a well-trained pathologist, who is the corner­ stone of the accurate diagnosis [2,5,6] . This may help to inform the patient before the operation of the possibility of sacrificing one or more branches of the facial nerve when they cannot be dissected microscopically free from the tumor [6] . Nevertheless, for tumors exceeding 3 cm, a preoperative MRI (or CT scan) will be helpful in determining the extension of the disease and its topography. Unsuspected polylobulated or multicentric tumors may be revealed, ‘deep lobe’ tumors will become evident (seldom detected clinically) and the relationship with the facial nerve can be more accurately determined [7] . Surgery is the mainstay for the treatment of malignant tumors. The technique of surgical excision of parotid tumors has been a matter of debate; whereas some surgeons have advocated extensive radical parotidectomy, superficial parotidectomy with safe margins around the tumor remains the standard procedure for most tumors located laterally to the facial nerve [8,9,101] . Facial nerve preservation is advocated whenever it is not infiltrated by the tumor [101] . Intraoperative decision is left to the findings of the surgeon who should be an experienced head and neck surgeon. Unfortunately, no evidence-based (level 1 or 2) reported analysis addressing surgical techniques has been published so far. Accordingly, we have to rely on ‘experience-based’ retrospective studies due to the rarity of the disease, the great variety of histological origins and the aggressiveness of the tumor even in each morphologic subclass (grading, histopathologic characteristics, immunocytochemistry and so on) consequently leading to variable natural courses. The latter factors rely on the expertise of the pathologist. It is needless to say that the number of treated patients would influence the expertise of both the surgeon and the pathologist. 1162

The question of margins around the tumor is also a matter of definition: typically, a sufficient layer of salivary tissue around the tumor should be removed, but in most cases, at least part of the operation will involve controlled dissection on the capsule of the tumor where it abuts the plane of the facial nerve. Therefore, the terminology of ‘subtotal’ parotidectomy has been proposed to describe a less than complete parotidectomy. However, this term is ambiguous because it implies different kinds of surgery depending on the team who performs it. When the neoplasm is located in the deep lobe of the parotid gland, extending to the prestylian parapharyngeal space, because the superficial lobe, at least partly, needs to be removed to have access to the deep lobe, a total parotidectomy is most often realized. However, in some circumstances, it is possible to preserve part of the superficial lobe when safe margins can be achieved under continuous visual control of the nerve, justifying the use of loops and monitoring of the nerve [10] . When some branches or the main trunk of the facial nerve must be sacrificed for oncological reasons, immediate repair should be attempted either by inter­positional sural (or great auricular) nerve graft, by hypoglossal facial nerve transfer or by free muscle flap with or without cross-face sural nerve graft. These techniques and others, such as regional muscle transpositions or static facial support, are described in detail in a recent review by Anderson and are beyond the scope of this paper  [11] . The need for postoperative ­radiotherapy should not preclude the use of facial nerve ­reconstruction [11] . Neck lymph node dissection should be accomplished according to the rules established for high-grade and high-stage tumors in clinical N0 neck and for all clinical positive and/or suspicious lymph node involvement as detected by imaging [12,101] . Whereas there is still controversy about the role of elective neck dissection in cN0 neck, it is easy for an experienced surgeon to realize during the surgical procedure a level IIa superselective neck dissection and to ask for frozen section on the resected lymph nodes: it will give useful information peroperatively without increased morbidity. If there is lymph node involvement, levels IIb, III and IV can be selectively dissected during the same anesthesia to avoid further operation. Postoperative radiotherapy will be proposed in case of multiple lymph nodes involvement or extracapsular spread [101] . The impact of lymph node metastases on survival has been reported in a large series of patients with major salivary gland tumors, from the SEER cancer database by Bhattacharyya and Fried [13] : mean survival time was 100 months for patients without nodal involvement versus 59 months for those with any pathologically positive node. The role of PET scanning remains a matter of investigation [14] , as it is for other submaxillary gland cancers. Submandibular gland & sublingual tumors

Tumors originating in the submandibular and sublingual glands are more likely to be malignant (~50 and 80%, respectively) as compared with those originating in the parotid glands. Therefore, fine needle aspiration biopsy, preferably under ultrasonographic guidance, should be advocated in order to give more information to the patient before surgical removal. Ultrasound is not needed Expert Rev. Anticancer Ther. 12(9), (2012)

Management of salivary gland tumors

in most cases but may be helpful in selected cases. MRI (or CT scan depending on institutional availability) are useful when size or adherence to adjacent structures raise questions of sacrificing more than the gland (e.g., lingual or hypoglossal nerve, muscles, marginal resection of the mandible and so on). The involvement of lymph node(s) should also be addressed by this imaging procedure, implying a radical modified or selective neck dissection depending on the clinical nodal stage, with the consent of the informed patient [101] . Minor salivary gland

Early diagnosis of minor salivary gland carcinomas is often difficult, as these neoplasms generally arise slowly from a painless lump in the submucosa of the palate, the oral cavity, the base of the tongue, the pharyngolarynx or the nasal cavity. Symptoms will even develop later in tumors originating in the paranasal sinuses, mimicking nasal obstruction with or without epistaxis. All studies reported on malignant tumors in the minor salivary glands are of a retrospective nature, and the wide variety of histologies involved renders the comparison between treatment approaches and results very difficult to interpret [15] . As for major salivary gland cancers based on numerous retro­ spective studies, generally recognized prognostic factors are tumor size, grade, surgical margins and lymph node status, which are used for a tentative of rational design for treatment strategies. A matter of debate has been when the tumor is close to the surgical margin, should it be considered as ‘border-line’? In this situation, should the surgeon excise an additional piece of tissue from the surgical bed [15] ? Fortunately, these issues were resolved in the National Comprehesive Cancer Network guidelines [101] : a clear margin is ≥5 mm from the invasive tumor front, a close margin is ≤5 mm from the tumor front. Complete surgical removal of all the tumor site (primary and lymph nodes, when involved) should be attempted when the disease is resectable. Therefore, initial clinical evaluation should include MRI (or CT scan) of the head and neck area. Adverse factors like close positive margins, intermediate or high-grade tumors, (peri)neural invasion, lymphatic (and/or vascular) invasion and/or lymph node metastases are decisional features for adjuvant (chemo) radiation (see below). Adjuvant treatment

Postoperative radiotherapy is generally advocated in case of adverse prognostic factors based on pathology, such as high-grade, close or positive surgical margins, lymph node metastases, perineural growth and vascular invasion. There are no randomized controlled trials in which the added value of postoperative radiotherapy has been investigated versus surgery alone, but the results of numerous retrospective analyses showed a marked improvement in local control with surgery followed by postoperative radiotherapy as compared with surgery alone, despite the fact that patients treated with postoperative radiotherapy generally had more adverse factors as compared with those treated with surgery alone [16,17] . In a nationwide study performed in The Netherlands, Terhaard et al. found a relative risk of 9.7 when postoperative radiotherapy www.expert-reviews.com

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was omitted, after correction for the imbalance between the two groups. In addition to improvement of local control, regional control also appears to improve in salivary gland tumors, in particular, in patients with pathological nodes [17] . Local and regional control rates after surgery and post­operative radiotherapy are generally above 80%. However, in cases with multiple adverse prognostic factors, local control rates may drop below 70%. Moreover, approximately a third of patients will develop distant metastases [17] . Given these results, it is not surprising that some authors investigated the additional value of postoperative chemoradiation instead of postoperative radiotherapy alone [18–20] . The results of two retrospective series indicate that chemoradiation may result in better outcome in terms of local control. Although more data are needed to draw definitive conclusions on the added value of chemotherapy, post­operative chemo­radiation may be considered in selective cases with multiple adverse prognostic factors. Inoperable salivary gland tumors

Inoperable, unresectable or recurrent salivary gland tumors are a major challenge for radiation oncologists. ACC is the predominant histologic subtype in this category due to perineural tumor growth, which can sometimes be very extensive, involving major parts of the base of the skull. The results of conventional radiotherapy using photons are generally poor, with local control rates varying from 4 to 50% in the more recent series [17,21,22] . Terhaard et al. found a dose–effect relationship for the inoperable cases with significantly better local control when the total dose administered was at least 66 Gy [17] . However, in many cases, this total dose cannot be administered without exceeding the tolerance dose of critical structures and thus not without un­acceptable risks of severe late radiation-induced toxicity (e.g., severe visual impairment). In the past, radiotherapy with fast neutrons provided promising results. In a prospective randomized study, local control at 2 years significantly improved from 17% with photons up to 67% with neutrons, which also translated into a trend toward improved survival. These favorable results have been confirmed in a number of later reviews [23] . The main disadvantage of fast neutrons, however, is that the quality of the dose distributions that can be achieved is less favorable than that of the currently used photon techniques which indeed resulted in higher rates of grade 3 or higher late radiation-induced toxicity from 4% with photons up to 19% with neutrons [23] . In this regard, radiation with particles other than fast neutrons, such as protons and carbon ions, is more promising. Owing to their unique beam properties, protons and, to a larger extent, carbon ions, allow for a high tumor dose with much lower doses to the normal tissues. Recently, Pommier et al. obtained an excellent local control rate of 93% using photons combined with a proton boost [24] . In this regard, carbon ions may be even more promising as they combine optimal dose distributions with a higher relative biological effectiveness similar to neutrons. Limited data on the effectiveness of carbon ions indeed show promising results with a local control rate of 78% compared with 25% as observed after photon radiotherapy alone [25] . 1163

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Although these results appear promising, the limited access toward these treatment modalities precludes a widespread use of this type of radiation. Duration of follow-up

After treatment, salivary gland tumor may fail locally or in the regional lymph node after a long period of time [1,2] , in particular, in cases of ACC mucoepidermoid carcinoma and adenocarcinoma ex pleomorphic adenoma. Therefore, these patients should be subjected to lifetime follow-up. Chemotherapy & targeted therapies

Chemotherapy has a defined role as palliative treatment in recurrent and/or metastatic disease, although no chemotherapy regimen has been proven to improve overall survival or disease-free survival in these tumors. In the past 30 years, no significant improvements have been obtained despite the use of new compounds such as taxanes and gemcitabine. Phase III trials have never been conducted, while Phase II studies are common, often including few patients with heterogeneous histotypes, although ACC is commonly the most represented histology. Monochemotherapy regimens in ACC patients gained a response rate (RR) of 13% with a response duration ranging from 5 to 20 months. The most studied polychemotherapy regimen is cisplatin, doxorubicin and cyclophosphamide (CAP regimen) that is associated with a RR of 25%; response duration may vary greatly from 6 to 77 months [26] . Although poly-chemotherapy seems to be associated with improved RR over monochemotherapy, toxicity is enhanced, putting into question whether to resort to mono- or polychemotherapy in this palliative setting. CAP or, alternatively, a cisplatin regimen may represent the reference schedules in fit patients. However, in cases of slow disease progression and asymptomatic patients (as often happens in ACC), chemotherapy could be delayed up to an evident progression or to the emergence of symptoms. For the remaining histotypes, there is even less evidence. Natural history may vary according to the histotypes; it can be frequently indolent but, broadly speaking, not as much as for ACC. On the basis of the evidence that there is no response reported in second-line treatment, a recommendation in this ­context is difficult to make. Chemotherapy in a different context other than palliation is investigational. Two retrospective studies seem to suggest a favorable trend for chemotherapy in combination with radiotherapy after surgical resection in high-risk patients [18,20] . A prospective randomized trial of the Radiation Therapy Oncology Group comparing concomitant cisplatin and radiotherapy versus radiotherapy alone in high-risk patients will address this question [102] . Owing to the poor results with chemotherapy, there is an urgent need to explore new types of treatment. Great expectations have been put into tailored therapies: specifically, the EGF receptors family (EGFR and HER2), KIT and androgen receptors are the most investigated molecular targets in salivary glands cancer. Their expression seems to be linked more to the histogenetic origin of the tumor cells rather than its pathogenetic role in salivary gland cancer development: tyrosine kinase (TK) receptors, 1164

with the exception of HER2, are more frequently associated with tumors of intercalated duct origin, while androgen receptor expressions seems to be restricted to histotypes derived from the excretory duct (Table 1) . This characteristic probably partly justifies the lack of success of targeted therapies in these cancers. No objective response has been observed in virtually any of the trials with targeted therapies, the best response described is a prolonged stable disease (Table 2) . However, in the case of ACC, typically characterized by durable tumor stabilization periods, it is questionable whether ‘stable disease’ or ‘disease control’ rates can be attributed to the drug activity rather than to the natural history of the disease itself. Only one partial response was recorded in a Phase II trial with trastuzumab, a monoclonal antibody antiHER2 in a patient with HER2 overexpressing mucoepidermoid carcinoma (MEC) [27] . Objective responses to androgen deprivation therapy (ADT) have been reported. The activity of ADT seems to be limited to androgen receptors expressing cancers and almost exclusively to male patients [28] . In this context, a prospective international trial is underway to clarify the role of ADT over chemotherapy in metastatic, AR-expressing, salivary gland cancer patients. Antiangiogenic agents are under evaluation in advanced salivary gland cancers. A partial remission was described in the case of an ACC patient enrolled in a Phase I study after three courses with axitinib, a potent inhibitor of VEGF receptors 1–3, at a dose of 15 mg [29] . This evidence suggested an activity of anti­ angiogenic compounds, supporting the need for further investigation. Two trials are currently ongoing with sorafenib, a TK inhibitor of BRAF, VEGF receptors 1–3, PDGF receptor-β, RET and KIT. One study is restricted to ACC patients only, while the other trial is open to all salivary gland cancer histotypes that will be separately analyzed. In c-kit-overexpressing ACC dasatinib, an oral multi-BCR/ABL and Src family TK inhibitor and vorinostat, an inhibitor of histone deacetylases, are prospectively studied [103] . Bortezomib, a proteosome inhibitor, has been investigated in 24 patients with progressive ACC [30] . On day 1 and 8, doxorubicin 20 mg/m2 was added intravenously to bortezomib in case of disease progression. No objective response was recorded with bortezomib alone, while one partial response was found in ten evaluable patients who received the combined therapy (bortezomib plus doxorubicin), suggesting a synergistic activity of this combination. Furthermore, compounds targeting FGF receptors 1 and 2 and anaplastic lymphoma kinase are objects of ongoing trials in ACC patients [103] . The products of fusion oncogenes, which have a recognized pathogenetic role in the development of MEC and ACC, are of interest as potential therapeutic targets. The MECT1–MAML2 fusion protein is derived from the translocation involving the MECT1 and MAML2 genes, t(11;19)(q12;p13), and it has been identified in most of the MECs [31–36] . The MECT1–MAML2 transcript has a diagnostic value (more common in low-grade MEC) [37–42] and a prognostic role (fusion-positive MEC cases have a better outcome compared with fusion-negative tumors) [34,43] . Expert Rev. Anticancer Ther. 12(9), (2012)

Management of salivary gland tumors

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Table 1. Molecular tumor markers investigated in salivary gland carcinomas. Histology

EGFR EGFR HER2 HER2 c-kit KIT Androgen TRK-A BRAF expression amplifica- expression amplifica- expression activating receptor expression mutation tion tion mutations expression

Adenoid cystic cancer

Yes

Muco­ epidermoid cancer

Yes

None [39,48]

Adeno­ carcinoma

Yes

Rare Contro­ versial data†

None [39,40]

Yes

Yes

Yes [49]

Rare

Not Yes investigated

Not None [47] investigated

Not Yes investigated

Yes [37]

Rare

Not Yes investigated

Yes

None [47]

None [50]

Yes [39,47,50]

Rare

Not Yes investigated

Yes [42]

Not investigated

[37–39]

Salivary Yes duct cancer

Rare Contro­ versial data‡

Yes [42]

None [47]

[41]

Yes

† No EGFR gene amplification has been found in two papers [38,39], while EGFR gene amplification was 67% in a series of 24 ACC cases in another report [37]. EGFR gene amplification has been investigated in 24 patients within a Phase II study with cetuximab. Three cases (two ACC and one non-ACC) showed trisomy or low polisomy of chromosome 7 [51]. ‡ The presence of multiple KIT mutations in ACC has been demonstrated in one paper only [38], while in two other reports, no activating mutations were found. EGFR: EGF receptor.

ACC is characterized by a reciprocal t(6;9)(q22-23;p23-24) grading, perineural spread, lymphatic and/or vascular invatranslocation resulting in the MYB–NFIB fusion oncogene [44] . sion, lymph node involvement. Concomitant cisplatin plus RT The transcript of the fusion oncogene is present in one third of versus RT alone are currently addressed in Phase B trial for salivary ACC, suggesting that its pathogenetic role is limited to a high-risk salivary cancer after surgery. Inoperable cancers may subset of ACC only. Increasing age (>50 years) is the only clinical be irradiated with photons combined with proton boost when feature to which MYB–NFIB was significantly related in a series of technique available. Polychemotherapy (cisplastin based) gives 58 ACCs [45] . Some therapeutic strategies directly targeting MYB 25% response rate for recurrent non-operable adenoid cystic such as DNA vaccines and antisense MYB oligodeoxy­nucleotide, carcinoma. Targeted therapies with anti-EGF receptor, thyrosine or directed against MYB–NFIB transcriptional targets, are under kinase inhibitors are under investigation, as are bortezomib plus investigation [46] , supporting a potential therapeutic role of these doxorubicin. compounds. Chemotherapy has a role as palliative treatment in recur- Five-year view rent and/or metastatic disease. In ACC patients, chemotherapy Treatment results are difficult to analyze due to the variety can be delayed until the appearance of symptoms or at disease of histologies involved in the spectrum of salivary gland neoprogression. A cisplatin-based polychemotherapy in fit patients plasms. Surgery remains the mainstay of initial treatment and may obtain a higher RR over monochemotherapy (25 vs 13%). should provide specimens with clear margins to the patholoTailored therapies have gained disappointing results so far. gist who needs to be dedicated to these proteiform diseases in However, new agents are currently under investigation. The product of fusion onco- Table 2. Target therapies and clinical trials. genes, involved in the genesis of ACC and Target Drug Hystotypes, Response Stable disease Ref. mucoepidermoid carcinomas, are also dispatients (n) rate (%) (%) (>6 cussed, with the potential role of targeted months) (%) therapies in this line. HER2

Trastuzumab

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8

Not reported

[27]

0

67 (0)

[52]

0

80 (50)

[51]

0

59 (47)

[53]

Non-ACC (12)

Expert commentary

Surgical resection of salivary gland cancer with >5 mm margins is the key to initial treatment. The preservation of the facial nerve when not infiltrated is re­commended. Selective neck node dissection is advocated for high-grade tumors and should be tailored to preoperative imaging (CT/MRI or ultrasound). Adjuvant external radiation therapy (RT) is indicated for high-risk tumors: close or invaded margins, histological type and

ACC (2)

EGFR

Gefitinib

ACC 19) Non-ACC (9)

EGFR

Cetuximab

ACC (23)

HER2/ EGFR

Lapatinib

c-kit

Imatinib

ACC (16)

0

60 (13)

[54]

c-kit

Imatinib

ACC (10)

0

20 (20)

[55]

Non-ACC (7) ACC (19) Non-ACC (17)

ACC: Adenoid cystic carcinoma; EGFR: EGF receptor.

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order to establish accurate diagnosis. Radiotherapy with new ions (­c arbon and protons) or association of chemoradiation would be of importance for high-risk operated tumors and for inoperable tumors. No randomized Phase III studies could be achieved so far due to the low number of patients’ accrual in each subclass. Since no standard treatment for recurrent and/or metastatic disease has been defined so far, all efforts should be made to gather enough material from multi-institutional collaborations. This would provide frozen material to molecular investigations, hopefully leading to a better understanding of molecular pathways and consequently to targeted therapies individually selected based on the cellular type and subtype. The new communication networks offered by computerized engineering are certainly tools to allow pathologists and biologists to share their experiences and views on an increasing number of cases and therefore are facilitating pathways that may be

targeted by upcoming molecules. In the same way, cooperative groups of clinicians should organize tissue banking and define what primary and secondary end points are of importance in prospective randomized trials stratified by histologic type and relevant prognostic factors in these diseases. ‍Acknowledgement

The authors gratefully acknowledge the help of Carine Vanderstraeten in the preparation of this manuscript. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Complete surgical resection, with adequate free margins, is the mainstay for treatment of neoplasms of salivary gland tumors. Although in parotid gland surgery, facial nerve preservation remains challenging because most tumors have close contact with some branches of the nerve, experienced surgeons should preserve the (branches of the) nerve not infiltrated by the tumor. When the tumor is located in the deep lobe of the parotid gland extending to the parapharyngeal space), a total parotidectomy is frequently indicated requiring skeletonization and elevation of the facial nerve when it is not infiltrated. • MRI (or when not available, computed tomography) gives sensitive imaging definition in predicting malignancy and delineation of the tumors, as well as relationships between the tumor and adjacent structures (nerve, bone and cartilage). Lymph node involvement should also be assessed. Fluodeoxyglucose PET–computed tomography is under investigation and could be helpful for detecting distant metastases. • Fine needle aspiration biopsy has been reported to provide a cytologic diagnosis with accuracy depending on the experience of the pathologist (81–98%), giving more information to both the patient and the surgeon in planning surgery. • Although pleomorphic adenoma of the parotid gland is considered as a benign disease, as it can recur more than 20 years after surgical treatment, malignant transformation (carcinoma ex pleomorphic adenoma) may occur, and distant metastases have been reported many years after the initial treatment. • Postoperative radiotherapy has demonstrated improvement of locoregional control in cases of adverse prognostic factors based on pathology (T size, lymph node involvement, close/positive margins, vascular/perineural invasion and high grade), according to multivariate analysis in retrospective cohorts of patients. • Postoperative chemoradiation is under current investigation in selective cases with multiple adverse prognostic factors • Inoperable tumors are better treated by protons or carbon ions allowing high local control (78%) with optimal-dose distribution; data are promising but access to these modalities is limited; therefore, photons combined with proton boost are suggested for current use. with immunocytochemistry when appropriated, a warranted aid for the clinicians.

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Razfar A, Heron DE, Branstetter BF 4th, Seethala RR, Ferris RL. Positron emission tomography-computed tomography adds to the management of salivary gland malignancies. Laryngoscope 120(4), 734–738 (2010). Carrillo JF, Maldonado F, Carrillo LC et al. Prognostic factors in patients with minor salivary gland carcinoma of the oral cavity and oropharynx. Head Neck 33(10), 1406–1412 (2011). Pohar S, Gay H, Rosenbaum P et al. Malignant parotid tumors: presentation, clinical/pathologic prognostic factors, and treatment outcomes. Int. J. Radiat. Oncol. Biol. Phys. 61(1), 112–118 (2005). Terhaard CH, Lubsen H, Rasch CR et al.; Dutch Head and Neck Oncology Cooperative Group. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int. J. Radiat. Oncol. Biol. Phys. 61(1), 103–111 (2005). Tanvetyanon T, Qin D, Padhya T et al. Outcomes of postoperative concurrent chemoradiotherapy for locally advanced

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major salivary gland carcinoma. Arch. Otolaryngol. Head Neck Surg. 135(7), 687–692 (2009). 19

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Tanvetyanon T, Padhya T, McCaffrey J et al. Prognostic factors for survival after salvage reirradiation of head and neck cancer. J. Clin. Oncol. 27(12), 1983–1991 (2009). Schoenfeld JD, Sher DJ, Norris CM Jr et al. Salivary gland tumors treated with adjuvant intensity-modulated radiotherapy with or without concurrent chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 82(1), 308–314 (2012).

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Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Villaret DB. Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103(12), 2544–2550 (2005).

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Chen AM, Bucci MK, Quivey JM, Garcia J, Eisele DW, Fu KK. Long-term outcome of patients treated by radiation therapy alone for salivary gland carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 66(4), 1044–1050 (2006).

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Huber PE, Debus J, Latz D et al. Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam? Radiother. Oncol. 59(2), 161–167 (2001).

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Pommier P, Liebsch NJ, Deschler DG et al. Proton beam radiation therapy for skull base adenoid cystic carcinoma. Arch. Otolaryngol. Head Neck Surg. 132(11), 1242–1249 (2006).

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Schulz-Ertner D, Nikoghosyan A, Didinger B et al. Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation therapy techniques. Cancer 104(2), 338–344 (2005). Laurie SA, Ho AL, Fury MG, Sherman E, Pfister DG. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol. 12(8), 815–824 (2011).

•• An outstanding and updated review involving patients with metastatic adenoid cystic carcinoma: evidence about the use of chemotherapy and targeted therapy are summarized. 27

Haddad R, Colevas AD, Krane JF et al. Herceptin in patients with advanced or metastatic salivary gland carcinomas. A Phase II study. Oral Oncol. 39(7), 724–727 (2003).

•• Only trial published on herceptin in salivary gland carcinoma.

Review

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Jaspers HC, Verbist BM, Schoffelen R et al. Androgen receptor-positive salivary duct carcinoma: a disease entity with promising new treatment options. J. Clin. Oncol. 29(16), e473–e476 (2011).

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Rugo HS, Herbst RS, Liu G et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J. Clin. Oncol. 23(24), 5474–5483 (2005).

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ArgirisA, GhebremichaelM, BurtnessB, AxelrodRS, DecontiRC, ForastiereAA. A Phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303).Cancer117(15), 3374–3382(2011).

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Anzick SL, Chen WD, Park Y et al. Unfavorable prognosis of CRTC1-MAML2 positive mucoepidermoid tumors with CDKN2A deletions. Genes. Chromosomes Cancer 49(1), 59–69 (2010).

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Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, El-Naggar AK. CRTC1/ MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin’s tumors: implications for histogenesis and biologic behavior. Genes. Chromosomes Cancer 46(7), 708–715 (2007).

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Martins C, Cavaco B, Tonon G, Kaye FJ, Soares J, Fonseca I. A study of MECT1MAML2 in mucoepidermoid carcinoma and Warthin’s tumor of salivary glands. J. Mol. Diagn. 6(3), 205–210 (2004).

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Behboudi A, Enlund F, Winnes M et al. Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes. Chromosomes Cancer 45(5), 470–481 (2006).

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Okabe M, Miyabe S, Nagatsuka H et al. MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma. Clin. Cancer Res. 12(13), 3902–3907 (2006).

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Fehr A, Röser K, Belge G, Löning T, Bullerdiek J. A closer look at Warthin tumors and the t(11;19). Cancer Genet. Cytogenet. 180(2), 135–139 (2008).

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Locati LD, Perrone F, Losa M et al. Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs). Oral Oncol. 45(11), 986–990 (2009).

•• An immunohistochemical study of a large series of salivary gland cancers,

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Review

Andry, Hamoir, Locati, Licitra & Langendijk

including a wide range of histotypes, in which the correlation between the immunophenotyping profile, the histology and the therapeutic implications is underlined. 38

39

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Sequeiros-Santiago G, García-Carracedo D, Fresno MF, Suarez C, Rodrigo JP, Gonzalez MV. Oncogene amplification pattern in adenoid cystic carcinoma of the salivary glands. Oncol. Rep. 21(5), 1215–1222 (2009). Vidal L, Tsao MS, Pond GR et al. Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib. Head Neck 31(8), 1006–1012 (2009). Seethala RR, Cieply K, Barnes EL, Dacic S. Progressive genetic alterations of adenoid cystic carcinoma with high-grade transformation. Arch. Pathol. Lab. Med. 135(1), 123–130 (2011).

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Vila L, Liu H, Al-Quran SZ, Coco DP, Dong HJ, Liu C. Identification of c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland. Mod. Pathol. 22(10), 1296–1302 (2009).

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Negri T, Tamborini E, Dagrada GP et al. TRK-A, HER-2/neu, and KIT expression/ activation profiles in salivary gland carcinoma. Transl. Oncol. 1(3), 121–128 (2008).

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Seethala RR, Dacic s, Cieply K et al. A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am. J. Surg. Pathol. 34(8), 1106–1121 (2010).



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Interesting paper on the prognostic role of MECT1/MAML2 translocation in mucoepidermoid and nonmucoepidermoid carcinoma histotypes. Persson M, Andrén Y, Mark J, Horlings HM, Persson F, Stenman G. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and

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in a large series of salivary duct cancers (a very rare histotype) and their correlation with treatment.

head and neck. Proc. Natl Acad. Sci. USA 106(44), 18740–18744 (2009). 45

Mitani Y, Li J, Rao PH et al. Comprehensive analysis of the MYB–NFIB gene fusion in salivary adenoid cystic carcinoma: incidence, variability, and clinicopathologic significance. Clin. Cancer Res. 16(19), 4722–4731 (2010).

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Locati LD, Bossi P, Perrone F et al. Cetuximab in recurrent and/or metastatic salivary gland carcinomas: a Phase II study. Oral Oncol. 45(7), 574–578 (2009).

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Glisson BS, Blumenschein G, Francisco M et al. Phase II trial of gefitinib in patients with incurable salivary gland cancer. J. Clin. Oncol. 23(16 Suppl.), Abstract 5532 (2005).

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Agulnik M, Cohen EW, Cohen RB et al. Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J. Clin. Oncol. 25(25), 3978–3984 (2007).

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Hotte SJ, Winquist EW, Lamont E et al. Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital Phase II consortium study. J. Clin. Oncol. 23(3), 585–590 (2005).

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Pfeffer MR, Talmi Y, Catane R, Symon Z, Yosepovitch A, Levitt M. A Phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol. 43(1), 33–36 (2007).

•• Excellent paper which points out the role of the MYB–NFIB gene fusion product in a subset of adenoid cystic carcinoma cases and its potential therapeutic value. 46

Stenman G, Andersson MK, Andrén Y. New tricks from an old oncogene: gene fusion and copy number alterations of MYB in human cancer. Cell Cycle 9(15), 2986–2995 (2010).



Remarkable review on MYB-fusion products in solid tumors including salivary gland cancer, mechanisms of gene activation and therapeutic prospects.

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Dahse R, Kromeyer-Hauschild K, Berndt A, Kosmehl H. No incidence of BRAF mutations in salivary gland carcinomas – implications for anti-EGFR therapies. J. Biomed. Biotechnol. 2009, 13–15 (2009).

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Lujan B, Hakim S, Moyano S et al. Activation of the EGFR/ERK pathway in high-grade mucoepidermoid carcinomas of the salivary glands. Br. J. Cancer 103(4), 510–516 (2010).

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Press MF, Pike MC, Hung G et al. Amplification and overexpression of HER-2/neu in carcinomas of the salivary gland: correlation with poor prognosis. Cancer Res. 54(21), 5675–5682 (1994).

Websites 101

Williams MD, Roberts DB, Kies MS, Mao L, Weber RS, El-Naggar AK. Genetic and expression analysis of HER-2 and EGFR genes in salivary duct carcinoma: empirical and therapeutic significance. Clin. Cancer Res. 16(8), 2266–2274 (2010).

Head and neck cancers – Principles of Surgery. National Comprehensive Cancer Network GuidelinesTM Version 2.2011 1–6 (2011). www.nccn.org/professionals/physician_gls/ pdf/head-and-neck.pdf

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RTOG 1008 Protocol Information. www.rtog.org/ClinicalTrials/ ProtocolTable/StudyDetails. aspx?study=1008

•• Focused on the immunohistochemical and molecular profile of EGF family receptors

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ClinicalTrials.gov. www.clinicaltrials.gov

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Expert Rev. Anticancer Ther. 12(9), (2012)